EP1317263A1

EP1317263A1 - Use of rhein for preparing a medicine for preventing articular cartilage damage

Info

Publication number: EP1317263A1
Application number: EP01969904A
Authority: EP
Inventors: Suzy Charbit; François SCHUTZE; Alain Taccoen; Jean-Pierre Pelletier; Diego Provvedini
Original assignee: Negma Lerads SA
Current assignee: Negma Lerads SA
Priority date: 2000-09-15
Filing date: 2001-09-14
Publication date: 2003-06-11
Also published as: WO2002022119A1; US6610750B1; MXPA03002242A; CA2422093A1; IL154917A0; AU2001290033A1

Abstract

The invention concerns the use of rhein and rhein derivatives in therapy. Rhein and rhein derivatives are used in human and veterinary therapy for preventing and/or limiting articular cartilage damage, if required in combination with an analgesic, an antipyretic, a non-steroidal anti-inflammatory agent or a COX-2 inhibitor. The invention is applicable in rheumatology therapy.

Description

USE OF A RHEINE FOR THE PREPARATION OF A MEDICAMENT FOR THE PREVENTION OF DEGRADATION OF JOINT CARTILAGE.

The present invention relates to the treatment of rheumatic affections, and more particularly the prevention of the degradation of articular cartilage, with a view to the treatment of osteoarthritis, by administration of an effective dose of rhein or rhein derivative, in particular diacerhein. , as well as the use of rhein or a rhein derivative for the manufacture of a medicament for the prevention of the degradation of articular cartilage and the treatment of osteoarthritis.

Hitherto, rheins have been used in human and veterinary medicine as active principles of medicaments, in particular as anti-inflammatories for the long-term treatment of arthritis. In human medicine, rhein derivatives, in particular diacerein, have been administered to patients suffering from osteoarthritis manifested by movement difficulties, deformities and pain. These effects could be mitigated and the patients were able to regain their mobility. The use of anti-inflammatory drugs, as well as other analgesics and antipyretics, has achieved the goal of limiting pain and functional symptoms of osteoarthritis, and this type of treatment is aimed in particular at reducing pain, inflammation of the joints and functional disorders. However, the causes, origins, triggering and progression of these diseases are not taken into account by these treatments.

We know that the origin and the progression of osteoarthritis imply a progressive degradation of the cartilages. The aim of the inventors has been to find a way to stop, prevent or limit the degradation of the cartilage, and consequently to have a favorable influence on the course of the disease. This object has been achieved in accordance with the present invention by the development of a process for the manufacture of a medicament for the prevention of loss of joint space, and therefore of. degradation of articular cartilage for the treatment of osteoarthritis, including the administration of rhein or rhein derivatives, in particular diacerhein. With this administration, it is possible not only to treat the symptoms of osteoarthritis, but also to interrupt, prevent or limit the loss of joint space and the destruction of cartilage, thereby favorably influencing the development of disease.

Osteoarthritis is a disease manifested by degeneration of the joint characterized by fragmentation and erosion of the articular cartilage, which becomes soft, eroded and thinner with an alteration of the subchondral bone, an enlarged bone, accompanied by outgrowths of marginal osteophytes and changes resulting in the appearance of pain and stiffness, and ultimately functional loss. Osteoarthritis mainly affects the joints supporting the weight of the body. When clinically established, osteoarthritis is an important cause of morbidity and disability, particularly in the elderly, due to joint pain, morning stiffness and limited mobility, often involving the neck, lower back, knees, hips and finger joints. Osteoarthritis can also develop in joints that have suffered injuries or trauma or that have been subjected to prolonged heavy loads.

Osteoarthritis is the most common form of arthritis affecting around 10% of the population, and almost 50% of people over the age of 60. The prevalence of osteoarthritis in women under 45, 45 to 60, and over 60 is 2%, 30% and 68%, respectively. In humans, for the same age groups, it is 3%, 24.5% and 58% respectively. These values can only increase in the future due to the aging of the population and the increase in the lifespan. In developed countries, osteoarthritis is the main cause of hip and knee prostheses, and is surpassed, as a debilitating disease, only by heart conditions. Osteoarthritis is therefore a major public health problem.

Although the causes of osteoarthritis are not clearly identified, it is assumed that the onset and progression of the disease involve mechanical factors and biological mediators which result in progressive degradation of the cartilage matrix accompanied by osteophytosis , sclerosis of the subchondral bone and alteration of synovial tissue to varying degrees. Osteoarthritis affects all components of the joint, including the bone, muscles, tendons, fibrous capsule, synovial membrane, and joint cartilage. It is assumed that the degradation of the cartilage results from an imbalance between catabolic and anabolic processes controlled by the chondrocytes. Chondrocytes, like synoviocytes, maintain cartilage homeostasis and are activated to increase the degradation of the cartilage matrix by inflammatory cytokines such as Interleukin-1 (IL-1) and "tumor necrosis factor α" ( TNFα, tumor necrosis factor α) which come from mononuclear cells and macrophages, as well as other types of cells and induce the expression of many genes to promote the synthesis of various proteins which contribute to inflammation. Also, chondrocytes for osteoarthritis patients _.. exhibit a greater number of IL-1 receptors than healthy individuals of cells.

The main goal of osteoarthritis treatment has always been to limit the pain and functional symptoms of illness through medical treatment, physiotherapy and patient education.

Osteoarthritis has been treated with anti-inflammatory drugs such as corticosteroids, for example hydrocortisone and betamethasone, which work by inhibiting prostaglandin synthesis. The usual pharmacological treatment of osteoarthritis is based mainly on the use of conventional non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac, new NSAIDs such as inhibitors of cyclo-oxygenase-2, pain relievers such as acetaminophen, and other substances belonging to distinct classes of drugs, such as diacerein.

The most recent nonsteroidal anti-inflammatory drugs (NSAIDs) available today have the effect of inhibiting both the action of cyclooxygenase-1 (COX-1, a constitutive enzyme) and that of cyclooxygenase -2 (COX-2, induced in the establishment of inflammation), and therefore to inhibit the synthesis of prostaglandins and thromboxane. Inhibition of COX-2 is thought to be the basis, at least in part, of the antipyretic, analgesic and anti-inflammatory action of NSAIDs, but simultaneous inhibition of COX-1 produces undesirable side effects, in particular especially the effects leading to gastric ulcers, which result from less prostaglandin formation. NSAIDs include aspirin which acetylates cyclooxygenase irreversibly, and several other classes of organic acids, including derivatives of propionic acid such as ibuprofen and naproxen, derivatives of acetic acid such as 1 indomethacin and other similar products, enolic acids such as piroxicam, all of which compete with arachidonic acid at the active site of cyclooxygenase. Acetaminophen has very weak anti-inflammatory activity but is effective as an antipyretic and analgesic drug, and avoids certain effects side effects of NSAIDs such as damage to the gastrointestinal tract and blockage of platelet aggregation.

Nonsteroidal anti-inflammatory drugs (NSAIDs), and other analgesic and antipyretic drugs fall into the following categories, according to a classification based on chemical structure.

The salicylic acid derivatives (aspirin, sodium saïicylate, ^magnesium and choline trisalicylate, salsalate, diflunisal, aspirin, sulfasalazine, olsala- zine) derivatives, para-aminophenol (acetaminophen), indole derivatives and indene acetic acid (indomethacin, sulindac, etodolac), hetero-arylacetic acids (tolme- tine, diclofenac, ketorolac), arylpropionic acids (ibuprofen, naproxen, flurbiprofen, ketoprofen, fenofanene, oxaprozin) or fenamates (mefenamic acid, meclofenamic acid), enolic acids such as oxicams (piroxicam, tenoxicam) and pyrazolidinethiones (phenylbutazone, oxyphenthatrazone), and alkanones (nabumetone).

In addition to sharing several therapeutic activities, nonsteroidal anti-inflammatory drugs (NSAIDs) also share some of the unwanted side effects listed below. The most common effect is a tendency to induce gastric or intestinal ulceration and bleeding which may be accompanied by anemia from blood loss. Patients who use NSAIDs chronically have a three times higher relative risk of a severe gastrointestinal incident compared to those who do not. The tendency to cause such ulceration and bleeding varies greatly from one NSAID to another. The gastric damage caused by these agents can result from two distinct mechanisms. Although local irritation resulting from oral medication promotes acid return to the gastric mucosa and induces tissue breakdown, parenteral administration also causes damage and bleeding, correlated with the inhibition of the biosynthesis of prostaglandins, in particular PGI ₂ and PGE ₂ which act as cytoprotective agents in the gastric mucosa. These eicosanoids inhibit the secretion of acid by the stomach, improve the mucosal blood flow and promote the secretion of a cytoprotective mucus in the intestine; inhibiting their synthesis therefore makes the stomach more sensitive to undesirable actions. All NSAIDs, except p-aminophenol derivatives, tend to cause gastrointestinal side effects ranging from moderate dyspepsia and heartburn to ulceration of the stomach or duodenum, sometimes with a fatal effect.

As indicated above, the side effects shared by nonsteroidal anti-inflammatory drugs (NSAIDs), recalled in particular by Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition, cGra Hill), are gastric ulceration and intolerance -intestinal (lesser side effects are observed with salicylates and p-aminophenols), blocking of platelet aggregation (inhibition of thromboxane synthesis), inhibition of uterine motility (prolongation of gestation), inhibition of prostaglandin-dependent renal functions (which is particularly important in patients with reduced renal blood flow; retention of Na ⁺ , K ⁺ and water (edema) may reduce the effectiveness of antihypertensive regimes ), and hypersensitivity reactions (resulting more from aspirin than from other non-acetylated salicylates).

The latest research in the treatment of osteoarthritis has focused on the development of safer non-steroidal anti-inflammatory drugs (NSAIDs), based on a better understanding of their mechanism of action and the pathogenesis of inflammation. The discovery of at least two isoforms of the enzyme cyclooxygenase (COX) has opened up new perspectives towards the development of potentially more specific and safer drugs.

Also, a new class of drugs, cyclooxygenase-2 inhibitors (COX-2) has been developed for the symptomatic treatment of osteoarthritis and other inflammatory diseases. COX-2 inhibitors, such as celecoxib and rofecoxib, have shown efficacy comparable to that of NSAIDs with fewer side effects on the upper gastrointestinal tract.

Recent work has been carried out on the use of diacerein in the treatment of osteoarthritis. This compound is known for its moderate anti-inflammatory, antipyretic and analgesic activity, even in osteoarthritis, as well as its good safety in use. Preparation methods have been developed for obtaining, in good yield, diacerein of purity compatible with use in the pharmaceutical field, having a low content of aloemodine and other undesirable impurities. It has been observed that a diacerein prepared under such conditions, in pharmaceutical form, can exert an activity allowing its application in the treatment of inflammatory conditions which can affect the joints.

The mechanism of action of diacerhein differs from that of non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids. Diacerein, and more particularly its active metabolite, rhein, is an IL-1 inhibitor. In fact, in vitro and animal model studies of osteoarthritis have shown that diacerhein and rhein inhibit IL-1 and other cytokines (IL-6 and TNF). These effects explain, at least in part, the favorable action of diacerein in the treatment of osteoarthritis symptoms.

In addition, neither diacerein nor rhein inhibits the biosynthesis of prostaglandins; indeed, no inhibitory effect has been observed on the production of phospholipase, cyclo-oxygenase or lipo-oxygenase. This characteristic seems to explain the excellent gastric tolerance of orally administered diacerhein.

All of the above-mentioned nonsteroidal anti-inflammatory drugs (NSAIDs) used today for the treatment of osteoarthritis symptoms actually treat the disease only superficially, i.e. pain and functional disorders.

The object of the present invention is to allow a new treatment which acts not only on the symptoms of osteoarthritis and brings short-term relief to the patient, but also on the underlying pathologies and thus makes it possible to bring to the patient long-term relief. In the field of rheumatology, and in particular in that of osteoarthritis, it is desirable to be able to have a medicament which can have a "structural modification" effect, that is to say an effect capable of avoid degradation of cartilage. Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics that have been tested in animal models for a possible effect of this type have not shown any significant results on the breakdown of cartilage. Nor has a corresponding effect been observed in clinical trials in humans. Thus, no known drug has a "structural modification" effect capable of preventing the breakdown of cartilage.

Following the favorable results obtained with diacerein with regard to therapeutic efficacy without gastric side effect, the applicant's research has focused on the possibility of a "structural modification" effect of diacerein in patients suffering from osteoarthritis, and more particularly on the effects of diacerein on the breakdown of cartilage.

The work undertaken has shown, surprisingly, that diacerein has a significant effect on the loss of joint space, and therefore on the degradation of cartilage, and that it could then be useful to administer Diacerein to patients suffering from this progressive disease of the joints, to avoid the degradation of the cartilage.

The present invention therefore relates to the use of diacerein, and more generally rhein and rhein derivatives, in human and veterinary therapy for the treatment of the degradation of articular cartilage, for the treatment of osteoarthritis by preventing and / or limiting the degradation of articular cartilage.

Another subject of the invention is the use of rhein and rhein derivatives, in particular diacerein, for the manufacture of a medicament for preventing and / or limiting the degradation of articular cartilage, and thus treating arthritis.

Rhein and its derivatives which can be used in the invention, in particular diacerein, can be represented by the following general formula (I):

in which R represents a hydrogen atom, or an alkyl group, for example a methyl, ethyl or propyl group, or an alkali or alkaline earth metal atom, for example a sodium, potassium or calcium atom, Ri and R ₂ , identical or different, represent a hydroxy group or an acyloxy group of formula R'-COO- in which R 'is an alkyl group of 1 to 4 carbon atoms, for example a methyl, ethyl or isopropyl group.

In the general formula (I) above, R preferably represents a hydrogen atom, and i and R ₂ preferably represent a hydroxy or acetoxy group. The general formula

(I) above in which R is a hydrogen atom and Ri and R ₂ are an acetoxy group -COOCH ₃ is that of diacerein.

The effects of rhein derivatives, and more particularly of-, diacerein, on joint line loss and degradation of articular cartilage, and their usefulness for the effective treatment of osteoarthritis have been verified by precise radiographic techniques in as part of a 3-year, double-blind, placebo-controlled study of 507 patients with osteoarthritis of the hip. The unexpected results of the study have shown that diacerhein has a favorable "structural modification" effect useful for the treatment of osteoarthritis, demonstrated by radiography, which is the recognized and validated measure in the medical field. of the disease, revealing a decrease in the loss of joint space and less degradation of the cartilage.

The results of the study confirm a statistically significant "structural modification" effect resulting from the administration of diacerein to patients suffering from osteoarthritis.

There was nothing to predict such results and that diacerein could have an activity of prevention, limitation and interruption of the degradation of cartilage, and consequently a capacity to treat the evolution of the disease and not only its symptoms.

The results also show that diacerein, in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) and / or analgesics, may constitute a drug of primary importance for the treatment of osteoarthritis.

In addition, it is known that an NSAID and / or a COX-2 inhibitor has a rapid anti-inflammatory effect but is generally ineffective, or even harmful, for the treatment of the progression of osteoarthritis. On the contrary, surprisingly, the association of rhein or diacerein with an NSAID or a COX-2 inhibitor is potentially more effective and provides better clinical effects than each of the treatments applied separately. The potential synergistic effects of this combination may seem surprising since diacerein does not manifest its effects until three or four weeks after its administration, while NSAIDs act quickly but have no effect on the breakdown of articular cartilage.

Diacerein and rhein can be prepared by methods known in the art, and for example from aloe or senna leaf extracts, such as sennosides, or by acetylation of barbaloin followed by oxidation by chromium oxide. One can also use the synthetic methods described in patents EP 801639 and EP 909268. These methods consist, for example, in carrying out a Diels-Alder reaction on a naphthoquinone such as juglone by means of an acyclic diene to obtain a tetrahydroanthraquinone which can be easily transformed into rhein and diacerein after oxidative deprotection.

The diacerein obtained by these processes can be purified if necessary to achieve a product that perfectly meets pharmaceutical standards and offers all the desired guarantees. For example, one can use the purification process described in patent EP 754173, according to which a soluble salt of diacerein is prepared by the action of triethylamine and potassium acetate, then hydrolysis is carried out in a weakly acid medium.

Diacerein and rhein have low solubility in water and in alcohols, and are therefore preferably administered orally. The usual oral administration forms in the pharmaceutical field may be suitable, and for example, the medicament may be administered in the form of tablets, capsules or soft gelatin capsules.

A particularly preferred form of administration is that described in patent EP 862423 describing capsules. or capsules in which the diacerein is mixed with a liquid oil and a nonionic surfactant, allowing good bioavailability to be obtained. Another form which can be used in the invention, described in US Pat. No. 6,124,358, is prepared by the micronization of rhein or diacerein with a lauryl sulfate, for example sodium lauryl sulfate.

The dosage is determined by the practitioner depending on the condition of the patient, but it is generally between 25 mg and 500 mg per day, preferably between 50 mg and 100 mg per day. It is relatively independent of the patient's weight in adults. Unit doses, for oral administration, are generally between 25 mg and 50 mg.

Studies to demonstrate the "structural change" effect of rhein and diacerein on joint cartilage have confirmed that they effectively limit and prevent cartilage breakdown in patients with osteoarthritis.

In the three-year, double-blind, placebo-controlled study, 507 patients with moderate or severe osteoarthritis of the hip received either diacerein (50 mg twice daily) or an identical placebo. The first assessment criterion, by radiological observation, was the reduction of the joint space by at least 0.5 mm during the study, reflecting the progression of the loss of articular cartilage. The evolution of the decrease in joint space, expressed in mm per year, was also measured in patients who followed the treatment to its end.

A total of 482 patients were followed, at least two x-rays having been taken on each of them. These patients were divided into two groups of 281 having substantially the same basic characteristics. Placebo was administered to patients in one of the groups while those in the other group received diacerein. In the placebo group, 62.7% of patients showed radiographic progression of the disease over the period studied, while this percentage was reduced to 53.9% in the group who received diacerein. The treatment was followed for the entire three years by 269 patients, of which 55.1% in the placebo group and 41.2% in the diacerein group showed progression in their condition verified by radiology. In these 269 patients, the annual rate of joint line reduction was significantly lower in those receiving diacerein than in those receiving placebo (0.18 mm / year and 0.23 mm / year respectively).

It is thus found that treatment with diacerein causes a significant "structural modification" effect over a period of three years, compared with the placebo effect.

Since diacerhein and rhein have an inhibitory effect on IL-1 and other cytokines of the immune system, their use can be considered in the treatment of inflammatory and autoimmune diseases, including chronic heart failure, arthritic psoriasis, egener granulomatosis, endometriosis, bone metastases and osteoporosis.

Claims

1. Use of rhein and rhein derivatives in human or veterinary therapy to prevent and / or limit the degradation of articular cartilage.

2. Use according to claim 1, characterized in that the rhein and the rhein derivative are represented by the general formula (I):

in which R represents a hydrogen atom, or an alkyl group, or an alkali or alkaline earth metal atom, R _x and R ₂ , which are identical or different, represent a hydroxy group or an acyloxy group of formula R'-COO - in which R 'is an alkyl group of 1 to 4 carbon atoms.

3. Use according to claim 2, characterized in that the derivative is rhein or diacerein.

4. Use according to any one of the preceding claims, characterized in that the rhein derivative is administered in an amount of 25 to 500 mg per day.

5. Use according to any one of the preceding claims, characterized in that the rhein derivative is in the form which can be administered orally.

6. Use of rhein and rhein derivatives for the manufacture of a medicament for the prevention and / or limitation of the degradation of articular cartilage.

7. Use according to claim 6, characterized in that the rhein and the rhein derivative are represented by the general formula (I):

8. Use according to claim 7, characterized in that the derivative is rhein or diacerein.

9. Use according to any one of claims 6 to 8, characterized in that the rhein derivative is administered in an amount of 25 to 500 mg per day.

10. Use according to any one of claims 6 to 9, characterized in that the rhein derivative is in form which can be administered orally.

11. Use according to claim 10, characterized in that the unit dose is between 25 mg and 50 mg.

12. Use according to any one of claims 6 to 11, characterized in that the rhein derivative is associated with an analgesic, an antipyretic, a non-steroidal anti-inflammatory or a COX-2 inhibitor.