WO2002022139A1

WO2002022139A1 - Intraarticular agent for the treatment of osteoarthritis

Info

Publication number: WO2002022139A1
Application number: PCT/IB2000/001300
Authority: WO
Inventors: Robert Theiler
Original assignee: Individual
Current assignee: Individual
Priority date: 2000-09-14
Filing date: 2000-09-14
Publication date: 2002-03-21
Anticipated expiration: 2003-03-14
Also published as: AU2000268609A1

Abstract

Gelling agents and agents that are solidifying due to cross-linking as agents for the treatment of osteoarthritis are described.

Description

Intraarticular agent for the treatment of osteoarthritis

Technical Field

The present invention concerns an agent for the intraarticular treatment of osteoarthritis, in particular an agent comprising a gel forming agent or a solidifying agent such as e.g. a gel forming agent with cross-linking ability.

Background Art

Osteoarthritis, i.e. painful joints, is due to a production deficiency of hyaluronic acid (HA) . HA is a high molecular weight, straight-chain heteropolysaccha- ride consisting of alternating residues of D-glucuronic acid and N-acetyl-D-glucosamine that is present in the synovial fluid of joints where it has a function as a lu- bricant and as a shock absorber.

With water, HA forms a highly viscous solution.

Hitherto, specific fractions of hyaluronic acid, or rather salts of HA, have been used for treating osteoarthritis, i.e. damaged bone joints. Such fractions differ e.g. in the viscosity of the respective solutions.

Such application, as well as the isolation of useful fractions of hyaluronic acid for such purposes, is e.g. described in US 5,925,626, US 5,631,241, US 5,442,053 and 5,166,331.

It is also already known to crosslink hyaluronic acid such that it is suitable for visco-supplemen- tation of joints (see EP 0 939 086) .

Although such treatment with hyaluronic acid has proved to be suitable to reduce the pain in joints, it is quite expensive and the treatment has to be repeated regularly. Therefore, there is still a need for an alternative, cheaper and preferably longer lasting alternative .

Disclosure of the Invention

It is therefore an object of the present invention to provide an improved agent for the intraarticular treatment of osteoarthritis. It is a further object of the present invention to provide such an agent that is a viscosupplementa- tion agent.

It has now surprisingly been found that specific gelling agents or solidifying agents (also referred to as prepolymer, or reactive polymer resin) can be used instead of hyaluronic acid, in particular celluloses including cellulose derivatives and "mixed" celluloses such as hydroxypropyl methyl cellulose.

While hyaluronic acid is soluble in water leading to more or less viscous solutions dependent on the fraction and concentration used, it can only be transferred into a gel by cross-linking (see EP 0 939 086) . Such cross-linking, and in particular the use of cross-linking agents, can be avoided by using readily gelling agents such as celluloses.

In view of their greater ability to migrate to inflamed tissue, gelling agents with slightly acidic groups such as OH-groups are preferred. Thus, a preferred cellulose is e.g. hydroxypropyl methylcellulose . Another gelling agent with very good gelling properties, that for said good gelling properties can be used in very small amounts, are vinyl polymers such as e.g. polyacrylates .

Polyacrylates have the great advantage that they lead to very viscous gels in small amounts, their disadvantage, however, is that they need a neutralizing agent in order to achieve the desired gelling. Preferred neutralizing agents are of course such that are physiologically acceptable and much preferred, such neutralizing agents are effective substances, e.g. anti-inflammatory agents such as steroids, non-steroidal anti-inflam- matory agents, cytokine-binding antibodies, anti-infec- tuous agents such as antibiotics.

Such effective substances can of course also be incorporated in a cellulose preparation.

Since also gels, similar to viscous solu- tions, due to their features lead to reduced protection with time, the effect can be enhanced if such gelling agents are furthermore cross-linked to "stabilize" the structure. Such viscosupplementation leads to a shock absorbing mass, a buffer, provided that said cross-linked polymer has sufficient elasticity. Methods to enhance elasticity of a formed polymer and to achieve cross- linking are known in the field of polymer chemistry and agents that are physiologically acceptable are also known . Besides of elastic cross-linked products also inelastic products may be used if the bones are already damaged to an extent where a "bone restitution" seems appropriate .

The term solidifying agent encompasses all physiologically acceptable cross-linkable resins or pre- polymers, respectively. Such reactive polymer resins e.g.' are gelling agents comprising reactive groups such as suitably substituted celluloses.

Celluloses, as well as polyacrylates, have the advantage that - due to the inability of the bodies of several mammals including man to degrade (digest) them - they have good long lasting properties. Also with regard to the cross-linked polymers, not only the prepolymer but also the cross-linking agent, or the groups produced upon cross-linking should be undegradable to improve the long time effect. Modes for Carrying Out the Invention Although a broad variety of celluloses is usable, due to the presence of OH groups, hydroxy substi- tuted celluloses, such as hydroxypropyl methylcellulose, are preferred.

Hydroxy substituted celluloses, as well as other "acidic" substituted compounds, more readily migrate to an inflamed place than "not acidic" substituted compounds, however very acidic groups or too many acidic groups might lead to undesired solubility.

Dependent on the viscosity desired, different concentrations can be applied whereby the injectability must be conserved. This may be achieved by suitably low concentration or - in the case of gelling agents needing neutralization - by mixing with the neutralization agent just prior to injection so that gelling does not yet occur within the syringe. The same procedure is also suitable for solidifying agents, whereby the solidifying agent, prior to application, is present in one component and the cross-linking agent in a second component, and whereby both components are mixed just prior to application. Possibly, one of the components can furthermore comprise a catalyst or other reaction/reactivity improv- ing agent .

In the case of a solidifying agent, a similar method can be applied, whereby one of the components comprises a resin component and the second component a cross-linking agent. Furthermore, one of the components may comprise a catalyst and/or other reaction/reactivity improving agent .

Besides of the gelling or solidifying agent, the gelling or solidifying agent comprising solution may be supplemented with physiologically acceptable or even necessary substances, such as isotonicity providing agents, but also with other effective substances to e.g. reduce the inflammation and/or pain. Wherever a gelling or solidifying compound or other possible ingredients are mentioned, it is also within the scope of the present invention that mixtures of such compounds, e.g. mixtures of gelling agents, mix- tures of solidifying agents etc. can be used provided that they are compatible with each other. Such possible mixtures are e.g. mixtures of different cellulose derivatives .

The gelling or solidifying agent comprising injectable medical agent is preferably stored in sterile syringes of e.g. 2 ml, 3 ml and 4 ml volume, whereby for the production of a cross-linked product, in particular in the case of damaged bones, larger amounts and therefore larger syringes, or infusion bags with volumes up to 200 ml may be suitable.

An example for a suitable cellulose solution comprises

i) hydroxypropyl methylcellulose 23.0 g (e.g. Methocel E 4 M Premium) ii) balanced salt solution ad. 1 liter

the balanced salt solution e.g. comprises

sodium chloride 4.90 g potassium chloride 0.75 g calcium chloride 0.48 g magnesium chloride 0.50 g sodium acetate 3.90 g sodium citrate 1.70 g hydrochloric acid ad pH 7.45 water ad 1 liter

The hydroxypropyl methyl cellulose is e.g. added to about 1/3 of the needed balanced salt solution that previously was heated to about 60 °C. As soon as the product is homogeneous, the remaining balanced salt solu- tion (cool) is added. The obtained gel is then dosed into syringes or vials or other sterilizable containers and sterilized according to known methods.

A respectively prepared product can be di- rectly injected into a joint to be treated with the same methods known for the treatment with hyaluronic acid..

An analogous method can be applied to prepare other sterilized gelling or solidifying components and neutralizing or cross-linking components. While there are shown and described presently preferred embodiments of the invention, it is to be distinctly understood that the invention is not limited thereto but may be otherwise variously embodied and practiced within the scope of the following claims.

Claims

1. Use of at least one gelling or solidifying agent for the preparation of a medicament for the intraarticular treatment of osteoarthritis.

2. The use of claim 1 wherein the gelling agent is a cellulose derivative, in particular an OH substituted cellulose derivative.

3. The use of claim 2 wherein the gelling agent comprises and preferably is hydroxypropyl methyl cellulose .

4. The use of claim 1 wherein the gelling agent is a vinyl polymer, in particular a polyacrylic acid.

5. The use of anyone of claims 1 to 4 , wherein the solidifying agent is a reactive polymer resin, that solidifies if cross-linked.

6. A medical 2 -component-composition, in par- ticular as agent for the intraarticular treatment of osteoarthritis, wherein one component comprises a solidifying agent and a second component comprises a cross- linking agent.

7. The composition of claim 6, wherein one of the components comprises a catalyst that activates the cross-1inking .

8. A method for preparing a gelled or solidified agent comprising mixing a gelling agent with a neutralizing agent, or a solidifying agent with a cross- linking agent, whereby the mixing is performed directly prior to injection.

9. A medical composition comprising in one or more components a gelling or solidifying agent of one of claims 1 to 5 and at least one further effective sub- stance.

10. The composition of claim 6 wherein the further effective substance is selected from the group comprising anti-inflammatory agents such as steroids, non-steroidal anti-inflammatory agents, cytokine-binding antibodies, anti-infectuous agents such as antibiotics, and mixtures thereof .

11. Use of a composition of claim 9 or 10 for the preparation of a medicament for the intraarticular treatment of osteoarthritis.