WO2015039989A1

WO2015039989A1 - Composition comprising at least one viscoelastic polymer

Info

Publication number: WO2015039989A1
Application number: PCT/EP2014/069613
Authority: WO
Inventors: André WOLFSTEIN; Nicole BIELEFELDT; Gillian RODDEN; Neil Hunter
Original assignee: Carl Zeiss Meditec AG; Hyaltech Ltd
Current assignee: Carl Zeiss Meditec AG; Hyaltech Ltd
Priority date: 2013-09-20
Filing date: 2014-09-15
Publication date: 2015-03-26
Anticipated expiration: 2016-03-20
Also published as: GB2518405A; GB201316726D0

Abstract

The invention relates to a composition comprising at least one viscoelastic polymer, wherein the at least one viscoelastic polymer is covalently cross-linked by means of at least one radical scavenger. The invention also relates to a method for producing a composition comprising at least one viscoelastic polymer.

Description

Composition comprising at least one viscoelastic polymer

Field of the Invention The invention relates to a composition comprising at least one viscoelastic polymer. The invention further relates to a method for producing a composition comprising at least one viscoelastic polymer.

Prior Art

The synovial fluid is a natural lubricant of a joint which reduces friction and takes care of transport of agents for nutrition of cartilage. One of the major component of the synovial fluid is hyaluronic acid in the form of sodium hyaluronate. The hyaluronic acid is synthesized by synovial tissue and secreted into the synovial cavity where it coats the ligaments and the surface of cartilage. Therefore the hyaluronic acid protects the cartilage for mechanical abrasion and irritation of pain receptors.

Document US 2010/0184720 A1 discloses injectable aqueous pharmaceutical com- positions in the form of a gel. The gel is made up of hyaluronic acid or one of the salts thereof as a viscoelastic polymer together with one or more polyols to achieve an elevated resistance to degradation.

As a disadvantage of known compositions like pharmaceutical compositions and medical devices it should be regarded that these are only relatively poorly suited for prophylaxis or treatment of inflammatory arthropathy and joint diseases. Detailed Description of the Invention

It is the object of the present invention to provide a composition having improved anti-inflammatory properties and comprising at least one viscoelastic polymer. A further task of the invention consists in providing a method for manufacturing such compositions comprising at least one viscoelastic polymer.

According to the invention, these objects are achieved by a composition having the features of claim 1 as well as by a method having the features of claim 9. Advantageous developments of the invention are specified in the respective dependent claims, wherein advantageous developments of the composition are to be regarded as advantageous developments of the method and vice versa.

In a composition according to a first aspect of the invention, comprising at least one viscoelastic polymer, it is provided that the at least one viscoelastic polymer is cova- lently cross-linked by means of at least one radical scavenger. The present invention is based on the finding that inflammatory processes, for example of a joint, can cause or worsen degenerative disease like arthritis or osteoarthritis. Proinflammatory cytokines are involved in the pathogenesis of such inflammatory processes. For example, rheumatoid arthritis is a chronic inflammatory disease characterized by synovitis involving synovial hyperplasia with neoangiogenesis and infiltration of lymphocytes and macrophages into the synovial tissue. These proinflammatory cytokines (e.g. TNF-a) stimulate the production of reactive oxygen by inflammatory cells which further activates the inflammatory cells. This indicates that reactive oxygen and maybe other radicals and reactive molecules play an important role in the generation of inflammation. Thus, arthritis and other degenerative diseases can be prevented and treated by means of the inventive composition, which comprises at least one viscoelastic polymer that is cross-linked by means of at least one radical scavenger.

The term viscoelastic polymer within the scope of the present invention is generally understood to also relate to pharmaceutically acceptable salt(s) of said viscoelastic polymers, besides relating to uncharged viscoelastic polymers. Further, the phrase "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds of the invention that are safe and effective for topical and/or systemic uses in mammals, in particular humans and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the present invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicy- late, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisi- nate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.

A radical scavenger is a chemical substance which is able to react with free radicals in order to prevent unwanted reaction products and to remove and/or de-activate said radicals. The radical scavenger is thus acting as a sink for free radicals to re- move them from the physiological space. This in turn has the biological effect that the composition of the invention removes reactive oxygen and other radicals and reactive molecules without acting directly on biological tissue. Covalent binding or linking of the radical scavenger to the viscoelastic polymer offers various advantages. First, high antioxidant activity and scavenging of free radicals is exhibited, thereby diminishing the concentrations of reactive oxygen species in a patient's joint. Further, the fixation of the radical scavenger to the viscoelastic polymer by means of covalent cross-linking will restrict the radical scavenging activity to the area where the free radicals are generated within the patient's joint. Still further, by covalent binding of the radical scavenger to the at least one viscoelastic polymer, it is reliably excluded that the radical scavenger diffuses into adjoining tissue. Also, radical scavenger compounds with low water solubility can be used because aggregation or precipitation are prevented by the attachment to the viscoelastic polymer.

In simplest configuration, the composition is composed of a solution of a single viscoelastic polymer, which is covalently cross-linked by means of one cross-linking agent with radical scavenging properties, i.e. a cross-linking radical scavenger. Further, the composition can additionally include plural different cross-linked or non- cross-linked viscoelastic polymers and/or further additives. Independently thereof, it can also be provided that two or more different radical scavengers are used to cross-link one or more viscoelastic polymers, for example to form a multiple cross- linked network. A cross-linking agent that can be used in connection with the present invention is firstly capable of reacting with the at least one viscoelastic polymer and linking the viscoelastic polymer together. Therefore, the cross-linking agent typically contains at least two reactive groups that can react with functional groups of the target molecule. Cross-linking agents useful in the present invention thus may include, but are not limited to chemical compounds comprising structural elements that are derived from an imidoester, an epoxide, e.g. ethylene glycol diglycidyl ether, a dialdehyde, e.g. glutaraldehyde, a N-hydroxysuccinimide ester, e.g., 2,3- dibromopropionyl-N-hydroxysuccinimide ester, sulfo-N-hydroxysuccinimide ester, and chlorambucil-N-hydroxysuccinimide ester, a carbodiimide, e.g. 1 -ethyl-3-(3- dimethylaminopropyl) carbodiimde hydrochloride, genipin, a maleimide, a haloace- tyl, a pyridyl disulfide, a hydrazide, a riboflavin, a bioflavonoid, a flavonoid, e.g. proanthocyanidin, catechin, epicatechin, epigallo catechin, epicatechin gallate, epi- gallocatechin gallate, quercetin, chalcones, apigenin, luteolin, a polymethoxylated flavone, quercitoi, kaempferol, myricetin, an anthocyanin, resveritrol, an isofla- vanoid, daidzein, genestiein, nobiletin, tangeretin, and tannic acid, a 6- maleimidohexanoic acid active ester, disuccinimidyl suberate, bis(sulfosuccinimidyl)suberate, an azide, a diazirine, sulfosuccinimidyl-4-(N- maleimidomethyl)cyclohexane-1 -carboxylate, and derivatives thereof. A cross- linking agent can also be an oligomer and/or a polymer containing multiple identical or different functional reactive groups, e.g., a polyepoxy compound, and a poly(hydroxy acid).

Secondly, a cross-linking agent to be used as radical scavenger in connection with the present invention has radical scavenging properties that are conserved after cross-linking the viscoelastic polymer. Basically, three types of reactions between radicals and the radical scavenger(s) are possible. First, a radical ion may be "neutralized" by loss of electrons (redox reaction). In this case, the scavenger is recyclable. Second, a radical is "neutralized" by formal uptake or release of H atoms (redox reaction). The scavenger in this case is recyclable, too. Third, the radical may react with the radical scavenger to form a covalent binding (radical addition reaction). In this case, the scavenger usually is not recyclable. However, in all cases, the result is a more stable, less aggressive product. In an advantageous development of the invention, it is provided that the scavenger comprises at least one aromatic group. Use of a scavenger with an aromatic group offers various advantages. Aromatic structural elements exhibit high antioxidant activity and scavenge free radicals, thereby effectively diminishing the concentrations 5 of reactive species in the patient's joint. Aromatic compounds are also able to form stable radicals because of the derealization of the impaired electron into the aromatic electron system. Generally, the cross-linking radical scavenger of the present invention may comprise one or more homocyclic, heterocyclic, polycyclic, atypical and/or substituted aromatic structural elements.

10 In a further advantageous development of the invention, it is provided that the at least one scavenger comprises at least one structural element derived from the group consisting of modified and/or unmodified phenols, polyphenols, hydroxycin- namic acids, phenylpropenes, cumarins, hydroxycumarines, isocoumarins, chro- mones, hydroxybenzoic acids, in particular salicylic acid and acetylsalicylic acid, i s tocopheroles, tocotrienols, propofol, phenolic acids, phenolic aldehydes, N-(2,3- dihydro-7-hydroxy-2,2,4,6-tetramethyl-1 H-inden-1 -yl)-4-(3-methoxyphenyl)-1 - piperazineacetamide, butylhydroxyanisole, butylhydroxytoluene, galvinoxyl, benzo- quinones, acetophenones, tyrosine derivatives, phenylacetic acids, naphthoquinones, xanthonoids, stilbenoids, in particular resveratrol, anthraquinones, fla-

20 vonols, dihydroflavonols, tannins, pseudo tannins, anthocyanins, anthocyanidins, flavanol monomers, in particular catechins, flavanol polymers, in particular proan- thocyanidins, flavanones, flavones, chalconoids, isoflavonoids, neoflavonoids, lig- nans, neolignans, biflavonoids, catechol melanins, flavolans, theaflavins, thea- rubigins, aminoflavones, and aminohydroxyflavones. In this way the radical-

25 scavenging properties, the viscoelastic properties and last but not least also the cross-linking properties of the viscoelastic polymer can be optimally adjusted to the respective purpose of the composition.

By modified and/or unmodified hydroxycinnamic acids are to be understood for instance 3-caffeoyl quinic acid, 3-p-caffeoyl quinic acid, 4-caffeoyl quinic acid, 5- 30 caffeoyl quinic acid, 3-feruloyl quinic acid, p-cumaroylglucose, feruloylglucose, caf- feic acid-4-O-glucoside, p-coumaric acid-O-glucoside, and feruloylic acid-O- glucoside. The term modified and/or unmodified cumarins or hydroxycumarines refers for instance to cumarin, umbelliferone, herniarin, esculetin, scopoletin, and fraxetin.

By modified and/or unmodified phenolic acids and hydroxybenzoic acids for instance phenolic acid, hydroxycinnamic acid, coumaric acid, ferulic acid, caffeic acid, sinapic 5 acid, gallic acid, salicylic acid, acetylsalicylic acid, 4-hydroxy benzoic acid, 2,3- dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid, 3- methoxy-4-hydroxybenzoic acid and ellagic acid are to be understood.

Tocopheroles comprise in particular alpha-Tocopherol, beta-Tocopherol, gamma- Tocopherol, and delta-Tocopherol. Tocopherols and tocotrienols are fat-soluble an- 10 tioxidants. By way of covelantly binding one or more of these compounds to the vi- soelastic polymer, the composition can also be used advantageously in an aqueous solution.

Suitable stilbenoids exhibiting particulary good scavenger properties comprise the aglycones piceatannole, pinosylvine, pterostilbene, and resveratrol. Resveratrol i s (3,5,4'-trihydroxy-trans-stilbene) for example comprises three functional OH-groups that can be readily used to cross-link the viscoelastic polymer. Additionally, resveratrol provides excellent radical-scavenging and anti-inflammatory properties to the viscoelastic polymer.

Tannins are polyphenolic compounds from plants and have molecular weights rang- 20 ing from 500 to over 3,000 (gallic acid esters) and up to 20,000 g/mol (proanthocya- nidins). There are three major classes of tannins. The base unit of the first class consists of gallic acid, the base unit of the second class consists of flavone, and the base unit of the third class consists of phloroglucinol. Pseudo tannins are low molecular weight compounds associated with other compounds. Tannins and pseudo 25 tannins exhibit good antioxidant properties.

Proanthocyanidins, in particular oligomeric proanthocyanidins not only provide excellent cross-linking and radical scavenging properties, but also inhibit hyaluroni- dases (EC 3.2.1 .35), a family of enzymes that degrade hyaluronic acid. Thus, use of proanthicyanidines also provides for an elevated resistance to degradation if hyalu- 30 ronic acid and/or a hyaluronic acid derivative is used as viscoelastic polymer. Proanthocyanidins are naturally occurring plant metabolites widely available in fruits, vegetables, nuts, seeds, flowers, and bark. Other plant sources of proanthocyanidins include wine, cranberries, and the leaves of bilberry, birch, and ginkgo. Proanthocyanidins are part of a specific group of flavonoids. Flavonoids are further categorized by sub-groups. Proanthocyanidins belong to the category known as con- densed tannins, one of the two main categories of plant tannins. Grape seed extract contains oligomeric proanthocyanidins made up of dimers or trimers of (+)-catechin and (-)-epicatechin. The naturally occuring procyanidin dimers are comprised of procyanidins B1 , B2, B3, B4, B5, B6, B7, and B8. There are several procyanidin trimers which include procyanidin C1 and 02. Several gallolyl procyanidins, which are most commonly the gallate esters of the dimeric procyanidins, and some free gallic acid exist. Esterification of (-)-epicatechin and procyanidin B2 by gallic acid further increases their free radical scavenging ability. Dimeric proanthocyanidins having the C4-C8 linkage have greater free radical scavenging activity than the C4-C6 linkage. Tetramers or greater of these flavonols are denoted as polymeric proanthocyanid- ins. Further, proanthocyanidins exhibit a high specificity for the hydroxyl free radical, trap lipid peroxides and free radicals, chelate to free iron molecules, inhibit iron- induced lipid peroxidation, inhibit xanthine oxidase, a major generator of free radicals, and inhibit hyaluronidase, elastase and collagenase, which can degrade synovial liquids as well as connective tissue structures. The term modified and/or unmodified flavanol monomers and flavanol polymers refers in particular to catechins like catechin, epicatechin, gallocatechin, epigallocate- chin, proanthocyanidins, and prodephinidine. Proanthocyanidins and prodephinidi- nes are colorless pre-stages of anthocyanidins. In a sour environment carbocations can be generated from proanthocyanidins and prodephinidines that exhibit espe- daily well radical scavenging properties. The carbocations are for instance formed in the presence of oxygen.

Anthocyanins and anthocyanidines are flavylium cation derivatives of anthocyanins. Anthocyanidins comprise e.g. aurantinidin, cyaniding, delphinidin, europinidin, luteo- linidin, pelargonidin, malvidin, peonidin, petunidin, and rosinidin. Anthocyanines and anthocyanindines generally provide at least two functional groups (i.e. OH-groups) that can be readily used to cross-link the viscoelastic polymer. Further, anthocyanines and anthocyanindines additionally exhibit excellent radical scavenging and anti-inflammatory properties. Flavanones and flavones are a class of flavonoids based on the backbone of 2- phenylchromen-4-one (2-phenyl-1 -benzopyran-4-one) and exhibit particularly good scavenger properties. Still further, flavones have the additional advantage of being colored compounds. Flavones that can be used in connection with the present in- 5 vention include for example apigenin, acacetin, luteolin, chrysin, chrysoeriol, dios- metin, tectochrysin, scutellarein, eupatorin, genkwanin, sinensetin, and wogonin. Synthetic flavones include for example 4'-amino-6-hydroxyflavone, diosmin and fla- voxate.

Suitable theaflavines for use in the present invention include e.g. theaflavin-3- 10 gallate, theaflavin-3'-gallate, and theaflavin-3-3'-digallate. Still further, thearubigins may be used which are polymeric polyphenols.

Further advantages arise if the at least one radical scavenger is one of 4'-amino-6- hydroxyflavone, 4',5,7-trihydroxyflavone, 3',4',5,7-tetrahydroxyflavone, and 5,7- dihydroxyflavone. Since each of the named compounds has at least two functional i s groups, the scavenger may be used in a particularly simple way as cross-linking agent. Moreover, all named compounds have excellent radical scavenging properties.

A particularly good manageability of the composition is achieved in a further embodiment of the invention by the fact that the composition contains a dye and/or a 20 radiopaque material. This allows for better and easier handling of the composition.

The dye and/or the radiopaque material may be covalently bonded to the viscoelastic polymer. It may also be provided that the radical scavenger is colored and acts as a dye.

In a further advantageous development of the invention, it is provided that the vis- 25 coelastic polymer comprises a polysaccharide, in particular cellulose, a cellulose ether with methyl and/or ethyl and/or propyl groups, in particular hydroxypropyl me- thylcellulose, hydroxyethyl methylcellulose and/or methylcellulose, a glycosami- noglycan, in particular hyaluronic acid, chondroitin sulphate, dermatan sulphate, heparin, heparan sulphate, keratan sulphate, alginic acid, polymannuronic acid, po- 30 lyguluronic acid, polyglucuronic acid, amylose, amylopectin, callose, chitosan, poly- galactomannan, dextran, xanthan and/or a mixture thereof. Hereby, in particular the viscoelastic properties of the composition and its biological degradation rates can be adapted to the respective purpose of employment and use in an optimal way. Therein, basically, it can also be provided that the composition includes two or more polysaccharides of the same type, which may only differ with regard to the kind and/or molecular proportion of cross-linking radical scavenger. The term "a polysac- 5 charide" is intended to comprise a polysaccharide containing at least one carboxyl group. The polysaccharide chosen may initially contain carboxyl groups or it may be derivatized to contain carboxyl groups. Examples of carboxyl-containing polysaccharides include, but are not limited to, carboxymethyl cellulose, carboxymethyl chitin, carboxymethyl chitosan, carboxymethyl starch, alginic acid, pectin, carboxymethyl

10 dextran, and glucosaminoglycans such as heparin, heparin sulfate, chondroitin sulfate and hyaluronic acid (HA). The most preferred carboxyl-containing polysaccharides are carboxymethyl cellulose, carboxymethyl chitin and HA. The most preferred carboxyl-containing polysaccharide is HA. The composition of the invention may include a carboxyl-containing polysaccharide, or alternatively, a pharmacologically i s acceptable salt of the polysaccharide can be used, e.g., hyaluronan. Suitable pharmacologically acceptable salts are alkali or alkaline earth metal salts. Therefore, in one embodiment, the composition contains cross-linked sodium hyaluronate. As already mentioned, the phrase "physiologically acceptable salts thereof" is intended to include those derivatives wherein one or more of the acidic protons of the carbox-

20 ylic acid groups of the viscoelastic polymer is/are substituted by a counterion. Suitable counterions may include groups I, II, III and IV metals, ammonium complexes, amino acid complexes, etc. For example, the physiologically acceptable salt can include sodium, lithium, magnesium, potassium, ammonium ion and various amino acids as counterions. Hyaluronic acid ("HA") provides the unique advantage that the

25 physiology of the mammal that requires treatment can more readily accept an endogenous substance rather than a different material, such as for example a polyethylene oxide.

In a further advantageous development of the invention, it is provided that the composition is formulated for use as an artificial synovial fluid. The composition thus 30 could also be denominated as a pseudo-synovial liquid. In this case, the composition preferably has a rheology equal or similar to that of natural synovial liquid.

In a further advantageous development of the invention, it is provided that the composition is formulated for preventing and/or treating osteoarthritis, in particular rheumatoid arthritis. Because of the radical scavenging properties and the elevated resistance to degradation of the cross-linked viscoelastic polymer, the composition is most suitable for prevention and/or treatment of such joint diseases. Rheumatoid arthritis is an inflammatory disease which is associated with reactive oxygen. By injection of the composition into the synovial cavity, free radicals within the synovial cavity may be buffered by means of the cross-linked scavenger, thus providing a strong and long-term anti-inflammatory effect by reducing the concentration of reactive oxygen and the like within the synovial cavity. Further, the viscoelastic polymer still provides for anti-shock pad and friction reduction. Because of the covalent cross-linking, the scavenger is kept in the area where the inflammation process would take place. Further, the diffusion of the scavenger into body fluids and abutting tissue, which might cause unwanted local or systemic pharmacological effects, is prevented.

In a further advantageous development of the invention, it is provided that the com- position is constituent of a medical device and/or a pharmaceutical composition. In this way, the composition can be adapted particularly easily to different applications. In the context of the present invention, a medical device is any instrument, apparatus, appliance, material or other article that is used alone or in combination for diagnosis, prevention, monitoring, treatment, compensation, or alleviation of a disease, an injury, or a handicap as well as for investigation, replacement, or modification of a patient's anatomy or of a physiological process. A pharmaceutical composition (medicinal product) achieves its principal action by pharmacological, metabolic or immunological means. A pharmaceutical composition may also be used as a means to assist a medical device in its function. It may be provided that the composition of the invention is the sole constituent or one of several constituents of the medical device and/or the pharmaceutical composition.

A second aspect of the invention relates to a method for producing a composition, comprising the steps of covalently cross-linking at least one viscoelastic polymer by means of at least one radical scavenger, and using said cross-linked viscoelastic polymer as an ingredient of the composition. By the covalent binding of the at least one radical scavenger to the at least one viscoelastic polymer, it is reliably excluded that the scavenger diffuses into adjoining tissue and adversely affects it during the use of the composition. Hereby the composition can be employed in a particularly effective and safe way and is capable of sustaining its effect over a long period of time, since its biological degradation rate in comparison with compositions with non- cross-linked viscoelastic polymers is considerably decreased. In addition, the treated tissue as well as abutting tissue is reliably protected against free radicals. In its simplest configuration, the composition according to the invention is produced with one kind of viscoelastic polymer, which is cross-linked by a single type of covalently bonded radical scavenger. Alternatively, it can be provided that plural different viscoelastic polymers and/or further additives are used to produce the composition. Independently thereof, it can also be provided that two or more different radical scavenging compounds are used to covalently cross-link one or more viscoelastic polymers, whereupon the cross-linked viscoelastic polymer - optionally with further additives - is used for producing the composition. The respective suitable reaction type for covalently cross-linking the radical scavenging compound(s) to the viscoelastic polymer depends on the functional groups present in each case. Further ad- vantages rendered can be gathered from the explanations given as to the first aspect of the invention, wherein advantageous embodiments of the first aspect of the invention are to be regarded as advantageous embodiments of the second aspect of the invention and vice versa.

In an advantageous development of the invention, it is provided that a radical scav- enger comprising at least one aromatic group is used. Use of a scavenger with an aromatic group offers various advantages. Aromatic structural elements exhibit high antioxidant activity and scavenge free radicals, thereby effectively diminishing the concentrations of reactive species in the patient's joint. Aromatic compounds are also able to form stable radicals because of the derealization of the impaired elec- tron into the aromatic electron system. Generally, the cross-linking radical scavenger of the present invention may comprise one or more homocyclic, heterocyclic, polycyclic, atypical and/or substituted aromatic structural elements.

In a further advantageous development of the invention, it is provided that a radical scavenger comprising at least two reactive groups that can react with functional groups of the viscoelastic polymer is used for cross-linking the viscoelastic polymer, wherein the reactive groups are independently selected from a group consisting of amino, hydroxyl, thiol, carboxyl, and epoxy. Hereby the covalent cross-linking reaction of the radical scavenger can be optimally adjusted to the reactive functional groups of the viscoelastic polymer present in each case. One generally could use a preferably yet available scavenger which has already functional groups which can be used directly and without further derivatization reactions to covalently cross-link the viscoelastic polymer.

5 In a further advantageous development of the invention, it is provided that in order to cross-link the viscoelastic polymer by means of the at least one radical scavenger, the viscoelastic polymer and/or the at least one radical scavenger is functionalized by adding and/or modifying a functional group and covalently cross-linked via the added functional group. In other words it is provided that the radical scavenger 10 and/or the viscoelastic polymer are first modified by introduction or conversion of one or more functional groups. Subsequently the cross-linking is effected by means of the newly introduced functional group(s). Hereby even reactants can be employed that otherwise are not or not easily capable of being covalently bonded.

In a further advantageous development of the invention, it is provided that the at i s least one radical scavenger is covalently bonded to the viscoelastic polymer via an ether group and/or via an ester group and/or via an amide group. For example, the so-called Williamson ether synthesis can be used for cross-linking the viscoelastic polymer by means of the scavenging compound. The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and an alcohol involving 20 the reaction of an alcoholate ion with a primary halide of the viscoelastic polymer. A covalent bonding via ester groups is recommendable for instance if the radical scavenger has hydroxyl groups and the viscoelastic polymer has carboxylic acid groups or vice versa. In analogy, a cross-linking via an amide group via reactions of a carboxylic acid with an amine can be achieved. It goes without saying that the radical 25 scavenging compound and the viscoelastic polymer need to comprise the corresponding functional groups.

In a further advantageous development of the invention, it is provided that the cross- linking is effected by a phase-transfer-process and/or by an interfacial reaction and/or by a Schotten-Baumann reaction. A phase-transfer-process may include the 30 use of a phase transfer catalyst (PTC) to facilitate the migration of a reactant from one phase into another phase where reaction occurs. Phase transfer catalysis is a special form of heterogeneous catalysis. Ionic reactants are often soluble in an aqueous phase but insoluble in an organic phase in the absence of the phase trans- fer catalyst. The catalyst functions like a detergent for solubilizing the salts into the organic phase. Phase transfer catalysis refers to the acceleration of the reaction upon the addition of the phase transfer catalyst. By using a phase-transfer-process, faster reactions with higher conversions or yields and fewer by-products are obtain- able. Further, radical scavengers and viscoelastic polymers may be used that are each not or little soluble in the solvent of the other reactant. Still further, phase- transfer-processes are not limited to systems with hydrophilic and hydrophobic reac- tants but may also be employed in liquid/solid and liquid/gas reactions. The cross- linking reaction may also take place at the interface between two phases of immis- cible solvents containing the radical scavenging compound in one solvent phase and the viscoelastic polymer in the other solvent phase. This is known as interfacial reaction in a two-phase system. Also, a hydroxyl group of the radical scavenger - e.g. a hydroxyflavone - may bind by esterification to carboxyl-groups of a viscoelastic polymer, e.g. to hyaluronic acid, via acid chlorides or acid anhydrates in the pres- ence of potassium carbonate or pyridine according to the Schotten-Baumann reaction. However, the method of the second inventive aspect generally is not limited to a specific synthetic pathway. For example, a radical scavenger comprising one or more phenolic groups can be bound to carboxyl-groups of a viscoelastic polymer by the mild Steglich esterification using dicyclohexylcarbodiimid (DCC) and 4- (dimethylamino)-pyridin (DMAP) as catalyst.

In a further advantageous development of the invention, it is provided that the composition is prepared for use as an artificial synovial fluid. The composition thus could also be denominated as a pseudo-synovial liquid. The rheology of the composition is preferably adjusted to a rheology equal or similar to that of natural synovial liquid. Further features of the invention appear from the claims as well as based on the following embodiments. The features and feature combinations mentioned above in the description as well as the features and feature combinations mentioned below in the embodiments are usable not only in the respectively specified combination, but also in other combinations without departing from the scope of the invention.

Preferred Embodiments of the Invention Rheumatoid arthritis is an inflammatory disease which is associated with reactive oxygen. A composition, comprising a viscoelastic polymer like hyaluronic acid that is covalently cross-linked with a scavenger or antioxidant may be injected into the synovial cavity for buffering of the free radicals in order to reduce the concentration of reactive oxygen, thus inhibiting inflammation processes. The covalent cross- linking prevents diffusion of the scavenger into body fluids and abutting tissue. Thus, dilution of the scavenger into adjacent tissue is avoided and the scavenger is reliably maintained at its site of use. Further, the viscoelastic polymer which is placed in the synovial cavity acts as anti-shock pad and reduces friction within the joint. Cross-linking of the viscoelastic polymer results in improved viscoelastic properties and more stability regarding degradation of the viscoelastic polymer by chemical and mechanical influences.

Radical scavengers are able to react with free radicals to form more stable radicals. For some scavenging compounds, e.g. flavones, this effect is enabled by derealization of the impaired electron into the aromatic delocalized π-electron system.

A radical scavenger to be used in connection with the present invention comprises at least two reactive groups for cross-linking of a viscoelastic polymer. The cross- linked viscoelastic polymer has improved elasticity and anti-inflammatory activity and can thus be used for preparing a composition that can be injected into a patient's synovial cavity to prevent and/or treat rheumatoid arthritis and/or other inflammatory diseases. Generally, the composition may be formulated as a pharmaceutical composition or used as a constituent of a medical device.

An example for a suitable viscoelastic polymer is hyaluronic acid (HA). Hyaluronic acid is a polysaccharide with repeating disaccharide units of [D-glucuronic acid-β- 1 ,3-N-acetyl glucosamine] linked by β-1 ,4-glycosidic bonds and has the general formula

I n For cross-linking purposes, the carboxyl-groups and/or the primary and secondary hydroxyl-groups of hyaluronic acid could be used to bind a bivalent or polyvalent scavenger covalently.

It is particularly advantageous to use a commercially available scavenger which al- 5 ready has corresponding functional groups to cross-link it selectively to the hyaluronic acid. If this is not the case, the scavenger can be chemically modified by introduction of adequate functional groups and/or by transformation of already existing functional groups.

Suitable scavengers that can be used to cross-link hyaluronic acid may comprise for

10 example flavone as a structural element. Flavones share a common structural element (2-phenyl-4H-chromen-4-one) with the general formula

Flavones have been described as scavengers (Cotelle et al., Scavenger and antioxidant properties of ten synthetic flavones, Free Radical Biology and Medicine, i s Volume 13, Issue 3, September 1992, Pages 21 1 -219.)

The commercially available 4'-amino-6-hydroxyflavone (2-(4-aminophenyl)-6- hydroxy-4H-chromen-4-one), having the formula

can be covalently bonded to carboxyl-groups of hyaluronic acid (HA). A HA-flavone- conjugate can be obtained e.g. by the reaction of CNBr-activated hyaluronic acid with vicinal diols and 4'-amino-6-hydroxyflavone, resulting in the following structure:

In a second reaction, the free hydroxyl group of 4'-amino-6-hydroxyflavone can be further used to cross-link said HA-flavone-conjugate, for example via an esterifica- tion reaction with free carboxylic groups of the HA:

If phenolic compounds are used, for example hydroxyflavones like

enin, 4',5,7-trihydroxyflavone),

(luteolin, 3',4',5,7-tetrahydroxyflavone), or

(chrysin, 5,7-dihydroxyflavone), their phenolic hydroxyl groups may also be used to cross-link HA via its carboxyl- groups by an esterification reaction, for example via corresponding acid chlorides or acid anhydrates in the presence of potassium carbonate or pyridine according to the so-called Schotten-Baumann reaction:

(with R_1-3= H, OH).

It is understood that various positional isomers can be formed by this reaction if the phenolic scavenging compound comprises a plurality of hydroxyl groups.

Other polyphenolic flavones can be used to cross-link HA by their phenolic hydroxyl- groups, too. Flavanones and flavones are a class of flavonoids based on the backbone of 2-phenylchromen-4-one (2-phenyl-1 -benzopyran-4-one) and exhibit particu- larly good scavenger properties. Still further, flavones have the additional advantage of being colored compounds. Flavones that can be used in connection with the present invention include for example apigenin, acacetin, luteolin, chrysin, chrysoeriol, diosmetin, tectochrysin, scutellarein, eupatorin, genkwanin, sinensetin, and 5 wogonin. Synthetic flavones include for example 4'-amino-6-hydroxyflavone, dios- min and flavoxate.

Generally, the covalent bonds of scavenging compounds with free hydroxyl groups may be either ester or ether bonds. An example of HA which is cross-linked by hy- droxyflavones via ether bonds has the following structure:

(with R _3= H, OH).

Hyaluronic acid and other viscoelastic polymers which are cross-linked according to the present invention generally possess improved physical properties and can be used to prevent or treat inflammations by removal of reactive oxygen radicals or i s other aggressive radical species.

Other suitable scavengers that may be used to cross-link viscoelastic polymers comprise for example resveratrol (/rans-3,5,4'-trihydroxystilbene), having the formula

Further scavengers may comprise at least one structural element derived from an- thocyanins and anthocyanidines, which are flavylium cation derivatives of antho- cyanins. Anthocyanidins comprise e.g. aurantinidin, cyaniding, delphinidin, eu- ropinidin, luteolinidin, pelargonidin, malvidin, peonidin, petunidin, and rosinidin.

Other suitable scavengers comprise compounds having at least one structural element derived from proanthocyanidins, in particular oligomeric proanthocyanidins. These structural elements not only provide excellent cross-linking and radical scavenging properties, but also inhibit hyaluronidases (EC 3.2.1 .35), a family of enzymes that degrade hyaluronic acid. Thus, use of proanthicyanidines also provides for an elevated resistance to degradation if hyaluronic acid and/or a hyaluronic acid derivative is/are used as viscoelastic polymer(s).

Of course, the viscoelastic polymers can generally be cross-linked with different cross-linking agents at the same time and/or in further cross-linking steps. This allows for a particularly precise adjustment of both the mechanical as well as the chemical properties of the viscoelastic polymer.

Normally ether linkages on HA tend to be more robust than ester linkages under physiological conditions. Therefore, it is possible to specifically control the biological degradability of the cross-linked HA on the one hand via the kind and the molar contents of the cross-linking agent and on the other hand via the kind of the covalent linkage, for instance via ester and/or ether bonds. For instance the cross-linking scavenger can be used in relation to the viscoelastic polymer in molar contents of between 1 :10 and 1 :100, i.e. for instance in a proportion of 1 :10, 1 :15, 1 :20, 1 :25, 1 :30, 1 :35, 1 :40, 1 :45, 1 :50, 1 :55, 1 :60, 1 :65, 1 :70, 1 :75, 1 :80, 1 :85, 1 :90, 1 :95 or 1 :100. The cross-linked viscoelastic polymers of the present invention can generally be provided with a comparatively high biological stability. Therefore, the benefit for a patient in need of such a treatment is superior and longer lasting pain relief compared to non-cross-linked polymers as well as to polymers that are cross-linked by non-scavenging compounds.

The coupling reactions do not necessarily have to take place in the same medium. The coupling reactions generally could also take place at the interface between two phases of immiscible solvents containing the scavenger compound and hyaluronic acid and/or other viscoelastic polymers in the particular solvent phase. This is known as an interfacial reaction in a two-phase system.

Claims

A composition comprising at least one viscoelastic polymer,

characterized in that

the at least one viscoelastic polymer is covalently cross-linked by means of at least one radical scavenger.

The composition according to claim 1 ,

characterized in that

the radical scavenger comprises at least one aromatic group.

The composition according to claim 2,

characterized in that

the at least one radical scavenger comprises at least one structural element derived from the group consisting of modified and/or unmodified phenols, polyphenols, hydroxycinnamic acids, phenylpropenes, cumarins, hydroxy- cumarines, isocoumarins, chromones, hydroxybenzoic acids, in particular salicylic acid and acetylsalicylic acid, tocopheroles, tocotrienols, propofol, phenolic acids, phenolic aldehydes, N-(2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl- 1 H-inden-1 -yl)-4-(3-methoxyphenyl)-1 -piperazineacetamide, butylhydroxyani- sole, butylhydroxytoluene, galvinoxyl, benzoquinones, acetophenones, tyrosine derivatives, phenylacetic acids, naphthoquinones, xanthonoids, stilbe- noids, in particular resveratrol, anthraquinones, flavonols, dihydroflavonols, tannins, pseudo tannins, anthocyanins, anthocyanidins, flavanol monomers, in particular catechins, flavanol polymers, in particular proanthocyanidins, fla- vanones, flavones, chalconoids, isoflavonoids, neoflavonoids, lignans, neolig- nans, biflavonoids, catechol melanins, flavolans, theaflavins, thearubigins, aminoflavones, and aminohydroxyflavones.

The composition according to claim 3,

characterized in that

the at least one radical scavenger is one of 4'-amino-6-hydroxyflavone, 4', 5,7- trihydroxyflavone, 3',4',5,7-tetrahydroxyflavone, and 5,7-dihydroxyflavone.

The composition according to any one of claims 1 to 4,

characterized in that

the viscoelastic polymer comprises a polysaccharide, in particular cellulose, a cellulose ether with methyl and/or ethyl and/or propyl groups, in particular hy- droxypropyl methylcellulose, hydroxyethyl methylcellulose and/or methylcellu- lose, a glycosaminoglycan, in particular hyaluronic acid, chondroitin sulphate, dermatan sulphate, heparin, heparan sulphate, keratan sulphate, alginic acid, polymannuronic acid, polyguluronic acid, polyglucuronic acid, amylose, amy- lopectin, callose, chitosan, polygalactomannan, dextran, xanthan and/or a mixture thereof.

The composition according to any one of claims 1 to 5 for use as an artificial synovial fluid.

The composition according to claim 6 for preventing and/or treating osteoarthritis, in particular rheumatoid arthritis.

The composition according to any one of claims 1 to 7,

characterized in that

the composition is constituent of a medical device and/or a pharmaceutical composition. 9. A method for producing a composition, comprising the steps of covalently cross-linking at least one viscoelastic polymer by means of at least one radical scavenger, and using said cross-linked viscoelastic polymer as an ingredient of the composition.

10. The method according to claim 9, wherein a radical scavenger comprising at least one aromatic group is used. 1 1 . The method according to claim 9 or 10, wherein a radical scavenger comprising at least two reactive groups that can react with functional groups of the viscoelastic polymer is used for cross-linking the viscoelastic polymer, wherein the reactive groups are independently selected from a group consisting of amino, hydroxyl, thiol, carboxyl, and epoxy.

The method according to any one of claims 9 to 1 1 , wherein in order to crosslink the viscoelastic polymer by means of the at least one radical scavenger, the viscoelastic polymer and/or the at least one radical scavenger is function- alized by adding and/or modifying a functional group and covalently cross- linked via the added functional group.

The method according to claim 12, wherein the at least one radical scavenger is covalently bonded to the viscoelastic polymer via an ether group and/or via an ester group and/or via an amide group.

The method according to any one of claims 9 to 13, wherein the cross-linking is effected by a phase-transfer-process and/or by an interfacial reaction and/or by a Schotten-Baumann reaction.

15. The method according to any one of claims 9 to 14, wherein the composition is prepared for use as an artificial synovial fluid.