NZ534552A - Treatment of connective tissue diseases using a mussel extract and a COX-2 selective NSAID - Google Patents

Abstract

Disclosed is a method of treatment or prevention of a connective tissue disease or the symptoms thereof in a non-human animal, wherein the non-human animal is administered a composition including a therapeutically effective amount of at least one COX-2 selective NSAID compound and mussel extract and wherein the composition, upon administration to a non-human animal exhibits an enhanced effect compared with each component administered independently. Also disclosed is the use of a therapeutically effective amount of at least one COX-2 selective NSAID compound and mussel extract in the manufacture of a medicament for the treatment or prevention of a connective tissue disease or the symptoms thereof.

Description

New Zealand Paient Spedficaiion for Paient Number 534552 PATENTS FORM NO. 5 Fee No. 4: $250.00 James & Wells ref: 29802 / 29 inteii^t^rpropB^ Office of N.z. 2 9 AUG 2005 received PATENTS ACT 1953 COMPLETE SPECIFICATION After Provisional No: 534552 Dated: 5 August 2004 IMPROVED JOINT THERAPY We, Bomac Research Limited, of 102 Wiri Station Road, Manukau City, Auckland, New Zealand, a New Zealand company do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement: IMPROVED JOINT THERAPY TECHNICAL FIELD The present invention relates to improved joint therapy. In particular, the present 5 invention provides an alternative therapy for the treatment or prevention of connective tissue diseases and the symptoms thereof for animals such as dogs, cats and horses using at least one non-steroidal anti-inflammatory drug (NSAID) with a high selectivity to cyclooxygenase-2 (COX-2) inhibition in combination with an extract of mussel, preferably Perna or Mytilus genus.

BACKGROUND ART The connective tissues of human and non-human animals are constantly subject to stresses and strains from mechanical forces that can result in afflictions such as arthritis (rheumatoid and osteoarthritis), joint inflammation and joint stiffness. This 15 is the same for both human and non-human animals and tends to be more prevalent in older age. The causes behind rheumatoid and osteoarthritis are different. Rheumatoid arthritis is characterised as an autoimmune disease affecting both the joints and systemic immune functions. Osteoarthritis results from deterioration of cartilage which may result in local inflammation of the joint(s). 20 The majority of non-human animals, and particularly companion animals, tend to be afflicted predominantly by osteoarthritis.

In osteoarthritis, increased stress in the joints results in loss of integrity of the cartilage matrix. Resulting damage causes acceleration in deterioration of cartilage and synovial fluid. The body has a natural capability to restore and 25 synthesise normal collagen structures but with aging, there is a decreased ability to 2 restore collagen. In the case of osteoarthritis, symptoms of the condition include pain in the joint, redness, heat, joint effusion, joint oedema and loss of joint function.

The treatment of connective tissue afflictions in both humans and non-humans can 5 be problematic.

It is usually not an option for the sufferer to stop normal movements associated with day to day activities. Consequently, treatment is often directed at treatment of the symptoms of the afflictions and not the overall cause.

Typical drug treatments include use of steroids such as corticosteroids and other 10 anti-inflammatory materials such as high doses of aspirin for humans. In veterinary drug treatments, hyaluronic acid and polysulfonated glycosaminoglycan are used, particularly for equines to reduce connective tissue pain and swelling. Unfortunately, almost all of these remedies lose their effectiveness over time and also have side effects such as stomach ulceration, platelet deactivation and/or 15 decreased blood supply to the kidney.

More recently, non-steroidal anti-inflammatory drugs (NSAID's) have been developed that specifically inhibit cyclooxygenase-2 (COX-2) activity without inhibiting cyclooxygenase-1 (COX-1) activity. Such NSAID's result in fewer gastrointestinal complication side effects common with non-selective NSAID's.

NSAID activity including the characteristics of COX-1 and COX-2 enzymes are extensively described in the prior art, for example the article 'Practical COX-1 and COX-2 Pharmacology: What's it all About? by C. Jones.

By way of example, one COX-2 selective drug remedy widely used for treatment of joint problems is carprofen, sold by Pfizer under the trade name Rimadyl® with 25 related patents US 4,264,500 and US 6,013,808. 3 Carprofen has the formula: It is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class that 5 includes ibuprofen, maproxen and ketoprofen. Carprofen is the non-proprietary designation for a substituted carbozole, 6-chloro-alpha-methyl-9H-carbozole-2-acetic acid. The empirical formula is C15H12CIN02 and the molecular weight is 273.72. Carprofen is a white, crystalline compound. It is freely soluble in ethanol but practically insoluble in water at 25°C.

Carprofen has been widely used in veterinary treatments as it is a selective COX-2 inhibitor and has only limited side effects in treatment of animals, particularly canine species. These side effects can however be serious, with hepatotoxicity (acute hepatic necrosis) or liver damage a known adverse effect of carprofen when taken by dogs.

Unfortunately, prolonged usage of carprofen is often out of reach of many due to its cost approximately $US1.00 per tablet which is taken twice daily and fears (whether reasoned or unreasoned) of side effects or dependency of treatment. Ultimately, carprofen merely treats the symptoms rather than treating the underlying cause, in the case of osteoarthritis, to rebuild degenerated cartilage.

Alternative natural product therapies have also been considered for treatment of osteoarthritis, joint problems and inflammation generally.

Natural products derived from plants and foods have frequently been the source of effective drugs and recently there has been an increased interest in the analysis of 4 these natural products, especially if a clinical benefit can be established.

Compounds identified in food that can assist in joint remedies include orally administered chondroprotective agents, glucosamine and chondroitin sulphate, which in the body are normal constituents of cartilage. There are reports that 5 these substances have beneficial effects in humans however, there are few reports in relation to veterinary applications.

Certain marine organisms contain compounds that, when administered to humans and non-human animals have been shown to aid in the alleviation of inflammation. One of these organisms are mussels and more specifically, Perna canaliculus 10 (Green lipped or green shell mussel). The anti-inflammatory activity of Perna canaliculus was first identified in a clinical study on leukaemia.

Initial assessment of the anti-inflammatory activity of Perna canaliculus was first attempted using a polyarthritis model in rats (Cullen et al 1975). A subsequent study (Miller and Ormrod 1980) showed that mussel preparations when 15 administered intraperioneally gave a significant reduction to the swelling of a carrageenan-inducted rat paw edema.

Rainsford and Whitehouse, 1980, showed that freeze-dried powder preparation of the whole mussel given orally to rats showed modest anti-inflammatory effect. Another study (Korthauer and Delatorre 1992) found that the oral administration of 20 a glycosaminoglycan extracted from Perna canaliculus to dogs with arthritis alleviated signs of lameness or faulty posture.

In WO 96/05164, it is established that lipid fractions of Perna canaliculus are a rich source of compounds which in semipurified extracts, have shown a measure of anti-inflammatory activity when tested.

WO 96/05164 describes that a lipid extract of Perna canaliculus or Mytilus edulis has an active component that has been shown to have anti-inflammatory effects.

WO 00/56164 describes a pet food that incorporates a supplemental amount of mussel extract for the purposes of alleviating joint inflammation.

Combination therapies have also been considered, for example, the applicant's related application, WO 01/05411 describes a particular combination of natural 5 anti-inflammatory components including Perna canaliculus, shark cartilage and use of enhancing agents including a bark extract rich in antioxidant compounds.

A problem noted from use of mussel supplementation is that the therapy takes time to show results - 8 weeks in the case of the Korthauer and Delatorre reference described above and 1 to 2 months before stabilisation in the case of the 10 applicants related application WO 01/05411. In the interim time period between stabilisation and initial therapy the sufferer still exhibits, to a lessening extent over time, symptoms of pain, swelling and limitation of movement.

Thus it is an object of the present invention to provide an alternative therapy that addresses the foregoing problems or at least to provide the public with a useful 15 choice.

All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and 20 pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art, in New Zealand or in any other country.

It is acknowledged that the term 'comprise' may, under varying jurisdictions, be 25 attributed with either an exclusive or an inclusive meaning. For the purpose of this specification, and unless otherwise noted, the term 'comprise' shall have an 6 inclusive meaning - i.e. that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements. This rationale will also be used when the term 'comprised' or 'comprising' is used in relation to one or more steps in a method or process.

Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only.

DISCLOSURE OF INVENTION For the purposes of this specification the term 'mussel' refers to any of several 10 marine bivalve molluscs, especially edible members of the family Perna and Mytilus.

The term 'extract' as used herein refers to a preparation of one or more components derived (i.e. separated away) or processed from a mussel as found in nature.

More preferably, the term 'extract' refers to either a powdered form of the mussel meat (not including the shell) or a concentrated preparation of the lipid portion of the mussel meat. However, it should be appreciated that the term 'extract' also encompasses other powdered or liquid forms of the mussel meat or a specific portion or portions thereof.

The term 'symptom' refers to any subjective evidence of disease or patient's condition According to one aspect of the present invention there is provided a method of treatment or prevention of a connective tissue disease or the symptoms thereof in an animal, wherein the animal is administered a composition containing a 25 therapeutically effective amount of at least one COX-2 selective NSAID compound 7 and mussel extract.

Preferably the connective tissue disease treated or prevented is selected from: osteoarthritis, joint inflammation, cartilage degradation, hip dysplasia, or combinations thereof.

Preferably, the composition may be used for treatment of both the underlying cause and symptoms associated with connective tissue afflictions. Most preferably, the symptoms may include pain and reduced mobility of the joint and the underlying cause is primarily due to degradation of cartilage from the joint. However, this should not be seen as limiting as it should be appreciated by those 10 skilled in the art that, due to the potent anti-inflammatory nature of the composition, other inflammation related disorders may also be able to be treated using the composition of the present invention such as rheumatoid arthritis inflammation. These include strained ligaments or muscles, or for postoperative use to control pain associated with soft tissue and orthopaedic surgeries. In one preferred 15 embodiment, the composition of the present invention is used for treatment of hip dysplasia.

The inventor's have unexpectedly found that the combination of a COX-2 selective NSAID compound and mussel extract results in an improved therapy for animals suffering from connective tissue diseases and related symptoms including joint 20 inflammation, osteoarthritis and cartilage degradation. It is understood by the applicant that a synergy exists between the two components whereby the strong anti-inflammatory effects of a COX-2 selective NSAID compound complement the anti-inflammatory and cartilage recuperative effects associated with mussel extract thus resulting in a more potent therapy for sufferers. The mechanism envisaged 25 by the applicants is one where, the fast acting anti-inflammatory effects of a COX-2 selective NSAID compound allow the mussel extract cartilage regenerative effects to take place sooner than if the mussel extract were administered alone. 8 A further unexpected effect noted as well includes the surprising ease with which the COX-2 selective NSAID compound actively combines with the mussel extract and the resulting positive stability of the combination.

A yet further unexpected effect of the combination is the prevention of side effects 5 during treatment. Known side effects of NSAID's include stomach ulceration and/or liver dysfunction. It is understood that mussel extract may protect the gastrointestinal tract and thus prevent ulceration and alleviate detrimental effects on the liver.

Preferably, the NSAID compound may be a COX-2 selective NSAID compound. 10 More preferably, the COX-2 selective NSAID compound may be selected from: carprofen, maproxen, ibuprofen, ketoprofen, piroxicam, diclofenac, etodolac, flunixin, deracoxib, meloxicam, celecoxib, rofecoxib, and combinations thereof.

Most preferably, the COX-2 selective NSAID compound may be carprofen.

Preferably, the mussel may be of Perna or Mytilus genus. Most preferably, the 15 mussel may be Perna canaliculus.

In preferred embodiments, the composition may be in a form suitable for oral administration, although this should not be seen as limiting as it should be appreciated by those skilled in the art that other formulations may be possible including: capsules, injectable formulations, suspensions, drinks or tonics, 20 powders, food ingredients, a sublingual wafer, implants, transdermal patches, suppositories, topical creams/gels and the like e.g. like Deep Heat™. Most preferably, the composition may be formulated for oral administration in the form of a tablet or capsule.

Most preferably, the composition may further include: carriers, diluents, fillers, 25 flavourings, colourings, excipients, modifiers, humectants, stabilisers, emulsifiers, and other known formulation components. 9 In preferred embodiments, the animal to be treated may be a companion animal. More preferably, the animal may be from the species canine, feline or equine.

Most preferably, the animal may be a domestic pet dog. However, this should not be seen as limiting as it should be appreciated by those skilled in the art that based 5 on previous results found for COX-2 selective NSAID compounds when used alone and mussel extracts when used alone, the combination therapy of the present invention may be used in other animals, including humans. For example, carprofen has been used to treat cats, rabbits, chinchillas, rats and birds.

Preferably, a therapeutically effective dose rate of COX-2 selective NSAID 10 compound in the composition of the present invention may be approximately 0.5 to 5.0 mg NSAID per kilogram of animal weight per day. More preferably, it is envisaged that the dose may be between 2.0 and 4.0 mg NSAID per kilogram of animal weight per day.

Preferably, a therapeutically effective dose rate of mussel extract in the 15 composition of the present invention may be approximately 5 to 100 mg mussel extract per kilogram of animal weight per day. More preferably, it is envisaged that the dose may be between 10 and 25 mg mussel extract per kilogram of animal weight per day.

It should be appreciated by those skilled in the art that a dosage of mussel extract 20 greater than 100 mg mussel extract per kilogram of animal weight per day may also be taken without harm. Mussel extracts are generally non-toxic and have naturally occurring sources. Higher doses are unlikely to produce any toxic reactions to the animal and may in fact be advantageous for some animals that require additional supplementation.

It should further be appreciated by those skilled in the art that dose rates of both COX-2 selective NSAID compound and mussel extract may also vary depending on the metabolism level, age, gender, species or genetics of the animal and other biochemical factors, such as seasonal dietary requirements.

According to a further aspect of the present invention there is provided the use of a therapeutically effective amount of at least one COX-2 selective NSAID compound 5 and mussel extract in the manufacture of a medicament for the treatment or prevention of a connective tissue disease or the symptoms thereof.

According to a further aspect of the present invention there is provided a method of treatment or prevention of a connective tissue disease or the symptoms thereof by the steps of: a. oral administration of a composition including at least one COX-2 selective NSAID compound and mussel extract for a time period of between 1 and 8 weeks; and subsequently, b. oral administration of a composition or medicament including mussel extract and no COX-2 selective NSAID compound.

According to a further aspect of the present invention there is provided the use of at least one COX-2 selective NSAID compound and mussel extract for the treatment or prevention of a connective tissue disease or the symptoms thereof in an animal.

It is envisaged that the composition of the present invention may be used as a 'first 20 line of treatment' for connective tissue afflictions including joint inflammation, osteoarthritis and/or cartilage degradation. This is due to the synergistic effects of the combination stabilising the affliction quickly and addressing both the symptoms of the affliction (inflammation) and the underlying cause (cartilage degradation).

Following treatment by the composition of the present invention, over an initial 25 period, it is envisaged by the applicant that a sufferer would shift to a stabilising 11 treatment such as that described in the applicant's publication WO 01/05411 after treatment with the composition of the present invention.

It should be appreciated by those skilled in the art that advantages gained from preferred embodiments of the composition of the present invention may include but 5 are not limited to: • COX-2 selective NSAID compounds need only be used for a short duration. Some NSAID studies have shown that NSAID drugs may exhibit reduced effectiveness over time hence the short duration of use in the present invention is desirable to avoid this reduced effectiveness.

• A reduced cost of treatment as the COX-2 selective NSAID compound is removed following the initial therapy with the composition of the present invention.

• Potential side effects are minimised as the composition of the present invention lowers the dependency and duration of treatment with COX-2 selective NSAID compounds compared with use of NSAID compounds alone.

• By use of mussel extract, the present invention takes advantage of a 'natural' alternative, which are increasingly becoming preferred by human patients or human pet animal owners in many medical treatments.

• The lay time associated with prior art mussel extracts used for treating joint inflammation is effectively erased or at least significantly reduced.

BEST MODES FOR CARRYING OUT THE INVENTION The invention will now be described with reference to examples of preferred 12 formulations known to the inventors.

For the purposes of the examples below, reference will be made to use of green lipped mussel as the mussel component in the composition. This should not be seen as limiting as it should be appreciated by those skilled in the art that other 5 types of mussel may also be used in accordance with the present invention. Basis for this may be found in the prior art for example the fact that Mytilus edulis has proven anti-inflammatory effects (WO 96/05164).

Further, for the purposes of the examples below, reference will be made to use of carprofen as the COX-2 selective NSAID compound in the composition. This 10 should not be seen as limiting as it should be appreciated by those skilled in the art that other types of COX-2 selective NSAID compounds may also be used in accordance with the present invention.

Preferred Dosages It has been found by the applicant that the preferred dosage ranges are largely 15 dependent on the body weight of the animal and are envisaged as being as shown in Table 1 below.

Table 1 - Preferred Dosage Ran ges Per Day Body Weight of the animal to be treated rkgl Carprofen [mg] Green Lipped Mussel [mg] 6 to 12 140 13 to 25 50 280 26 to 50 100 560 It should be appreciated that quantities outside of these ranges may also be appropriate depending on other characteristics of the animal including species, 20 breed, age, sex, genetics and physiology of the animal. Dosages may also be 13 taken across different time periods of the day e.g. the dose split in two and half administered in the morning and half in the evening.

The ranges given should also not be seen as limiting as it should be appreciated by those skilled in the art that the composition may also to be used for animals of 5 weights less than 6kg or greater than 50 kg and the amounts of carprofen (or COX-2 selective NSAID compound generally) and green lipped mussel varied accordingly following similar ratios.

Dosage It is the inventor's experience that the preferred dosage largely follows that of carprofen when taken alone.

This is an initial dose of 2 to 4 mg/kg of animal body weight taken once daily or in two equally divided doses per day.

It should be appreciated by those skilled in the art that the on-going dosage level 15 may be largely dependent on the clinical response to treatment by the animal under treatment although it is envisaged that, for the present invention, treatments will continue with a daily dosage taken for a period of one to two months.

Following treatment with the composition of the present invention, it is envisaged that the animal will be further treated with the composition as disclosed in the 20 applicant's related publication, WO 01/05411 for future treatment.

It should be appreciated by those skilled in the art that the above described invention provides an animal treatment for joint disorders that is effective at treating both the symptoms of the disorder as well as the underlying cause of the disorder i.e. cartilage degradation and associated inflammation. It is also 25 envisaged that the combination formulation also acts quickly to treat the disorder 14 and is more cost effective long term with fewer potential side effects.

Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims. 3 0 JAM 2008 2. 3. 4. 7.

A method of treatment or prevention of a connective tissue disease or the symptoms thereof in a non-human animal, wherein the non-human animal ^administered a composition including a therapeutically effective amount of a\least one COX-2 selective NSAID compound and mussel extract and whereirMhe composition, upon administration to a non-human animal exhibits amenhanced effect compared with each component administered independently The method of damn 1 wherein the connective tissue disease treated or \ x prevented is selected\om: osteoarthritis^oint inflammation, cartilage degradation, hip dysplasi^or combinations^hereof.

The method of claim 1 whereii\jhe connective tissue disease symptoms are alleviated.

The method of claim 1 or claim 3 wherWi the connectiv^issue disease symptoms treated or prevented include: p^in, reduced mobmfy of the joint, reduced mobility, cartilage degradation from rfye joint, and combinations thereof.

The method as claimed in any one of claims 1 to 4 wherein the composition is orally administered to protect the gastrointestinal tract from1' side effects of NSAID treatment.

The method of claim 5 wherein the side effects include ulceratiofts^nd alleviation of detrimental effects on the liver.

The method as claimed in any one of the above claims wherein the COX^ selective NSAID compound or compounds are selected from: carprofen, maproxen, ibuprofen, ketoprofen, piroxicam, diclofenac, etodolac, flunixin, 16 m 3 fill ft? C 4*|j| Sir

Claims (16)

WHAT WE CLAIM IS:

1. A method of treatment or prevention of a connective tissue disease or the symptoms thereof in a non-human animal, wherein the non-human animal is administered a composition including a therapeutically effective amount of at least one COX-2 selective NSAID compound and mussel extract and wherein the composition, upon administration to a non-human animal exhibits an enhanced effect compared with each component administered independently.

2. The method of claim 1 wherein the connective tissue disease treated or prevented is selected from: osteoarthritis, joint inflammation, cartilage degradation, hip dysplasia, or combinations thereof.

3. The method of claim 1 wherein the connective tissue disease symptoms are alleviated.

4. The method of claim 1 or ciaim 3 wherein the connective tissue disease symptoms treated or prevented include: pain, reduced mobility of the joint, reduced mobility, cartilage degradation from the joint, and combinations thereof.

5. The method as claimed in any one of claims 1 to 4 wherein the composition is orally administered to protect the gastrointestinal tract from side effects of NSAID treatment.

6. The method of claim 5 wherein the side effects include ulceration and alleviation of detrimental effects on the liver.

7. The method as claimed in any one of the above claims wherein the COX-2 selective NSAID compound or compounds are selected from: carprofen, maproxen, ibuprofen, ketoprofen, piroxicam, diclofenac, etodolac, flunixin, 16 '"'^'yctear pr& Office of N.Z. 'Pfeay 30 \ RECE J4ft! 2008 [VED deracoxib, meloxicam, celecoxib, rofecoxib, and combinations thereof. 8\ The method as claimed in any one of the above claims wherein the mussel extract is frohn Perna or Mytilus species. 9. ~n^e method as claimed in any one of the above claims wherein the composition is formulated for oral administration. 10. The method as claimed Ni any one of the above claims wherein the non-human animal to be treated\s from species including: canine, feline or equine. 11. The method as claimed in any one\>f the above claims wherein the therapeutically effectiv^amount of COX-2 selective NSAID compound is 0.5 to 5.0 mg NSAID per tomogram of animal weight per day. \ "x- \ \ 12. The method as claimed in anyspne of the abo\/e claims wherein the \ ^ therapeutically effective amount of mussel extracts 5 to 100 mg mussel \ ^ extract per kilogram of animal weigmper day. \ 13. Use of a therapeutically effective amountsof at least one E^OX-2 selective NSAID compound and mussel extract in the\manufacture of\a medicament for the treatment or prevention of a connective\issue disease the symptoms thereof. 14. The use of claim 13 wherein the connective tissue disease treated or prevented is selected from: osteoarthritis, joint inflammation, cartilage degradation, hip dysplasia, and combinations thereof. 15. The use of claim 13 wherein the symptoms are alleviated. 16. The use of claim 13 or claim 15 wherein the connective tissue diseas symptoms treated or prevented includes: pain, reduced mobility of the 17 deracoxib, meloxicam, celecoxib, rofecoxib, and combinations thereof.

8. The method as claimed in any one of the above claims wherein the mussel extract is from Perna or Mytilus species.

9. The method as claimed in any one of the above claims wherein the composition is formulated for oral administration.

10. The method as claimed in any one of the above claims wherein the non-human animal to be treated is from species including: canine, feline or equine.

11. The method as claimed in any one of the above claims wherein the therapeutically effective amount of COX-2 selective NSAID compound is 0.5 to 5.0 mg NSAID per kilogram of animal weight per day.

12. The method as claimed in any one of the above claims wherein the therapeutically effective amount of mussel extract is 5 to 100 mg mussel extract per kilogram of animal weight per day.

13. Use of a therapeutically effective amount of at least one COX-2 selective NSAID compound and mussel extract in the manufacture of a medicament for the treatment or prevention of a connective tissue disease or the symptoms thereof.

14. The use of claim 13 wherein the connective tissue disease treated or prevented is selected from: osteoarthritis, joint inflammation, cartilage degradation, hip dysplasia, and combinations thereof.

15. The use of claim 13 wherein the symptoms are alleviated.

16. The use of claim 13 or claim 15 wherein the connective tissue disease symptoms treated or prevented includes: pain, reduced mobility of the ■& ® . GtW SB 3 ® o,2 iO so •■o CET CO 17