WO1998044929A1

WO1998044929A1 - Composition comprising a hydrolysed collagen protein and glucosamine for the treatment of arthroses

Info

Publication number: WO1998044929A1
Application number: PCT/US1998/006869
Authority: WO
Inventors: Andrew E. Myers
Original assignee: Richardson Labs, Inc.
Priority date: 1997-04-10
Filing date: 1998-04-09
Publication date: 1998-10-15
Also published as: JP2001524080A; EP0991413A1; AU6954598A

Abstract

A therapeutic composition that is capable of functioning as an analgesic while also furnishing a pharmacological support for connective tissue repair and regeneration is disclosed. The present composition contains, as essential ingredients, hydrolyzed collagen protein and glucosamine (and/or a therapeutically acceptable salt thereof).

Description

COMPOSITION COMPRISING A HYD R OLYSED COLLAGEN PROTEIN AND GLUCOSAMINE FOR THE TREATMENT OF ARTHROSES

BACKGROUND OF TEE INVENTION 5

1. Field of the Invention

The present invention relates to a composition for treatment of degenerative joint diseases, and to a method of treating arthroses.

2. Background Information

10 Degenerative joint diseases or arthroses are conditions where degenerative changes in cartilage lead to a breakdown in the integrity of the structural matrix of cartilage or tendonous tissues. Conventionally referred to as arthritis, the complaints associated with the degenerative changes occur most frequently in individuals over 50. Arthritis affects over 40 million 15 Americans (1 in 7). 80% of Americans over 50 have arthritis. Over 45, women experience arthritis 10 times more than men. In short, Arthritis is the primary cause of disability in Americans

Arthritis affects primarily the weight bearing joints (hips, knees, etc.) and the joints of the fingers. Symptoms include early morning stiffness, 20 stiffness following periods of rest, pain that worsens on joint use and loss of joint function.

Cartilage provides the cushion and frictionless mobility of. joints. Comprised of two key components, collagen and glycosaminoglycans, cartilage is constantly under a process of natural repair and regeneration. 25 Because of overuse, injury or other causes, many individuals overwhelm their body's ability to keep up with the natural process of repair. The result is cartilage that becomes increasing dry and inflexible leading to pain and eventual joint restriction.

The pathogenesis of arthroses is by no means an inevitable

30 phenomenon of aging, as a healthy joint is capable of functioning for a lifetime. In medical science, a differentiation is made between primary and secondary arthroses, the latter developing- from known precedent diseases, whereas in cases of primary arthroses no basic disease is determinable.

Rather, these diseases manifest in an imbalance between mechanical stress and mechanical resistance of the joint cartilage.

The conservative treatment measures in the cases of coxarthroses and gonarthroses, respectively, and operative measures such as artificial joint prosthesis is sufficiently known.

Steroids, such as corticosteroids, and other anti-inflammatory materials, such as non-steroidal anti-inflammatory drugs ("NSAIDs") and high doses of aspirin, are widely used for the treatment of these ailments, Pharmocol. Res. Commun. 10:557-569 (1978) by Vidal et al. While these materials often relieve the pain and swelling associated with maladies arising from connective tissue problems, they offer no support for repair processes.

Furthermore, NSAIDs may also inhibit the body's own natural healing processes, leading to further deterioration of the connective tissue. These prior efforts may be characterized as providing only temporary palliative or symptomatic relief in as much as they furnish no pharmacological support system for the repair and regeneration of connective tissue.

It would be a significant advance in the art to develop a therapeutic composition that is capable of functioning as an analgesic while also furnishing pharmacological support for connective tissue repair and regeneration. Relatedly, it would be a significant advance in the art to develop a method of treatment for arthroses in a patient in need of such treatment that is capable of satisfying the above mentioned objectives.

SUMMARY AND OBJECTS OF THE INVENTION

An object of the present invention is to provide agents for the treatment of arthroses that are suitable for alleviating and curing effects on arthroses.

Another object of the present invention is to provide a patient- compatible therapeutic composition for the treatment of arthroses. Another object of the present invention is to provide a therapeutic composition for the protection and repair of connective tissue, including cartilage, tendons, and joint tissues.

A particular object of the present invention is to provide a novel therapeutic composition comprising nutritional elements in a synergistic combination that is effective in promoting the repair and regeneration of joint and connective tissues.

A further object of the present invention is to provide a method for treating arthritis by administering to a patient in need of such treatment an effective amount of the present novel therapeutic composition.

Applicant has discovered the surprising result that the combination of nutritional elements represented by hydrolyzed collagen protein (HCP) and glucosamine (or a therapeutically acceptable salt) offer therapeutic support for arthritis sufferers and a method for mamtaining joint tissue health. The present therapeutic composition of HCP and glucosamine has a positive effect on connective tissue maintenance and is capable of offering additional nutritional support for osteoporotic individuals. The present invention further contemplates a method of treating arthroses and a method of maintaining joint tissue health. The present invention offers the surprising benefit of providing a therapeutic composition which supplies co-factors for the repair and regeneration of connecting tissue, such as cartilage, while concurrently functioning as an analgesic, and a method of treatment using such a composition.

DETAILED DESCRIPTION OF THE INVENTION

The present composition includes two essential ingredients: hydrolyzed collagen protein in combination with glucosamine and/or pharmacologically acceptable salts thereof, which, in combination, act synergistically to stimulate both collagen and proteoglycan synthesis.

Hydrolyzed collagen protein, particularly enzymatically hydrolyzed collagen having a molecular weight of up to 80 kilodaltons, capable of being synergistically combined with at least one of glucosamine and pharmacologically acceptable inorganic glucosamine salts herein is available, and is generally described in U.S. Patent No. 4,804,745, the complete disclosure of which is incorporated herein by reference. In general, the hydrolyzed collagen protein can have a molecular weight in the range of about 1 to about 300 kilodaltons. Lower molecular weight fractions of hydrolysed collagen protein in the range of about 1 to 10 kilodaltons can, if desired, be used alone or in combination with one or more higher molecular weight fractions of hydrolyzed collagen protein. Higher molecular weight fractions include hydrolyzed collagen protein and fractions thereof in the range of about 100 to 300 kilodaltons. It has been determined that particularly efficient assimilation characteristics and a particularly good efficiency against arthroses, are observable when hydrolyzed collagens having an average molecular weight of from 10,000 to 80,000 (10 to 80 kilodaltons) are employed. Higher molecular weight preparations are generally less readily soluble in cold water. Lower molecular weight products are also more difficult to prepare in acceptable forms for application. Proteins not recovered from a collagen base have proven to be ineffective or substantially less effective. Prior studies have been directed to the use of hydrolyzed collagen protein singly, and an illustrative such study is Adam, M., Osteoarthrosis therapy with gelatin preparations: Results of a clinical study, Therapiewoche,

1991, 38:2456-2461, the complete disclosure of which is hereby incorporated by reference, and none involve hydrolyzed collagen protein in effective synergistic combination with the second essential ingredient in the present invention.

The glucosamine and pharmaceutically acceptable salts thereof are available, and, in general, are described in U.S. Patent No. 5,587,363 and U.S. Patent No. 5,364,845, the complete disclosures of which are incorporated herein by reference. Suitable salts include, among others, glucosamine sulfate and glucosamine hydrochloride. Glucosamine may, if desired, include or be comprised of crude forms thereof. Glucosamine and its pharmaceutically acceptable salts combine well with the hydrolyzed collagen protein base of the composition, providing the primary substrates for both collagen and proteoglycan synthesis. Glucosamine is the preferred substrate for proteoglycan synthesis, including chondroitin sulfates and hyaluronic acid. The glucosamine is, preferably, in a salt form so as to facilitate its delivery and uptake by the patient. The preferred salt forms are glucosamine sulfate and glucosamine hydrochloride. As used herein, patient includes veterinary patients, such as veterinary mammalian patients, and also human patients unless otherwise stated. Glucosamine has been shown to be rapidly and almost completely absorbed into humans and animals after oral administration. A significant portion of the ingested glu∞samine localizes to cartilage and joint tissues, where it remains for long time periods. This indicates that oral adrninistration of glucosamine reaches connective tissues, where glucosamine is incorporated into newly-synthesized connective tissue.

In vitro, glucosamine can lead to increased synthesis of collagen and glycosaminoglycans from fibroblasts which is the first step in repair of connective tissues. Glucosamine and its pharmaceutically acceptable salts have also exhibited reproducible improvement in symptoms and cartilage integrity in humans with osteoarthritis in a series of studies, such Tapadinhas

MJ, et al., Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal, Pharmatherapeutica 3:157-

168 (1982); DOAmbrosio et al., Glucosamine sulphate: a controlled clinical investigation in arthrosis, Pharmatherapeutica 2:504-508 (1981); Pujalte JM, et al., Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis, Curr. Med. Res. Opin. 7:110-114 (1980);

Vaz AL., Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients. Curr. Med. Res. Opin. 8:145-149 (1982); Rovati LC, Clinical research in osteoarthritis: design and results of short-term and long-term trials with disease-modifying drugs, Int. J. Tissue React. (SWITZERLAND)

14:243-251 (1992); and Vajaradul Y., Double-blind clinical evaluation of intra-articular glucosamine in outpatients with gonarthrosis, Clin. Ther. 3:336-343 (1981), the complete disclosures of which are incorporated herein by reference. These studies are devoid of any suggestion of the present invention. Clinical investigations have documented the surprising result that the combination of the nutritional elements represented by hydrolyzed collagen protein ("hydrolyzed collagen" as sometimes may be elsewhere referred to herein) and glucosamine and/or its pharmaceutically acceptable salts offer therapeutic support for patients suffering from arthritis, and a method for treating such disease from both the analgesic and nutritional standpoints.

The present therapeutic composition manifests a number of unique and unexpected advantages. Clinical research in arthroses indicates that the synergistic effects of the therapeutic composition exceed the benefits obtainable from adrrjinistration of the ingredients singly. This unexpected result obtains from effects seen at the level of connective tissue. There is a marked increase in chondrocyte activity and fibroblast proliferation, indicating that connective tissue synthesis has been stimulated. This increase in synthesis is exceptional in that the enzymatic mechanisms related to collagen and glycosaminglycan synthesis are enhanced well beyond normal activity levels. It is postulated that a reduction in chondrocyte inhibitory factors, such as cytokines, interferons and prostoglandins may be responsible for this unexpectedly enhanced activity, or that the components themselves may have a catalytic or co-catalytic effect. Additional findings relate to a localized reduction in inflammatory products from activated mononuclear cells known to decrease fibroblast proliferation.

The present therapeutic composition in principle has the effect of maintaining and re-establishing overall composition of cartilage glycosaminoglycans, in spite of tissue age. In experimental models, the data suggest that the proportion of chondroitin sulfate, which generally falls with increasing age, is maintained versus that of keratin sulfate and hyaluronate. Therefore, in vivio, the consistent supplementation with the present therapeutic composition may forestall at least some age-related changes in cartilage composition heretofore considered to affect the ability of proteoglycan elements to aggregate with one another or to interact with collagen.

Glucosamine sulfate and its pharmaceutically acceptable salts taken supplementary can be used by the patient to produce primarily glycosamineglycans ("GAGs"), and secondarily collagen. By providing glucosamine sulfate and/or its pharmaceutically acceptable salts in compositional combination with hydrolyzed collagen protein, the present therapeutic composition advantageously enables a relative enhancement in GAG synthesis with a concomitant reduction in consumption of glucosamine and its salts in collagen synthesis.

The present invention offers further advantages over conventional compositions and methods of treatment. Among these, administration of the present therapeutic composition advantageously does not require ever increasing dosages of the essential ingredients during the treatment period. This advantage results because the present therapeutic composition provides an effective balanced combination of analgesia and pharmacological support for the treatment of the underlying disease. Maintenance dosing at a reduced dosage level can, where appropriate, be administered thereafter.

The present therapeutic composition can be administered to the patient in a number of efficacious forms. In the so-called "scoop" form, the present composition can be supplied in a powder form which is at least substantially homogeneous compositionally and has a substantially homogeneous particle size distribution. The substantially homogeneous particle size distribution means that as a result of mixing, blending or otherwise effectively combining the at least two essential ingredients, the hydrolyzed collagen protein plus the glucosamine and/or its acceptable salts each have the desired pre-selected particle sizes. As a variation of this embodiment, the two ingredients can be combined and the combined form can be rendered pulverulent such that the particles themselves are substantially homogeneous from the compositional standpoint. In principle, fluidized bed techniques can be adapted for the preparation of the foregoing powder formulations. The scoop form of the composition can be measured out dry, such as with a measuring scoop, for administration to the patient. For instance, for veterinary mammalian patients, such as pets (dogs and cats) or race or farm animals (horses, cows etc.), the dosage is scooped in dry form and can be added to the veterinary patient's diet, such as in the animal feed. For human patient administration, the scoop method can also be similarly used.

The present invention can also be administered to the patient, human or veterinary mammalian patient, in capsule or tablet form. Tablets can, if desired, be coated or uncoated. Suitable tableting procedures include those generally described in Perry's Chemical Engineer's Handbook, page 8-62 to 8- 64 (4^th Edition 1963), Ullmann's Encyclopedia of Industrial Chemistry, volume A19, pages 245-256 (Springer Verlag 1991), Ullmann's Encyclopedia of Industrial Chemistry, volume B2,pages 7-31 to 7-37 (Springer Verlag

1988), and Lieberman (editor), Pharmaceutical Dosage Forms: Tablets, volumes 1 and 2 (Marcel Dekker 1980), the complete disclosures of which are hereby incorporated by reference. The present therapeutic composition can also be administered in capsule or gel-cap form. The size of each dosage and the interval of dosing to the patient effectively determines the size and shape of the tablet or capsule. By present preference, each capsule and each tablet contains both of the present essential ingredients in pre-determined amounts to simplify the patient's treatment regimen.

As apparent from the foregoing, the present therapeutic composition can be administered orally. Oral administration is preferred because of convenience to the patient as well as the dosing schedule. The composition can be administered in powder form, but is, for at least some patients, more readily administered in solution. The solution media can be water or any consumable liquid or beverage. By present preference the beverage and consumable liquids are non-carbonated, and can, if desired, also be non-alcoholic. The therapeutic composition can be provided for administration in the form of a so- called instantized (powdered) formulation for ready swallowing or ready dissolution in the selected liquid for subsequent administration to the patient, or can be provided in pre-mixed solution for immediate use or as a pre-mixed dilutable concentrate. The pre-mixed form can be packaged in suitable containers such as, cans, bottles or the like for storage prior to use. A predetermined amount of a powdered solid pre-mix formulation can also be packaged in one or more sachets. The composition can also be administered in the form of a paste, compact, emulsion, elixir, granules, syrup, lozenges, gum, or candied formulation. The two essential ingredients are relatively neutral in taste, and thus they can, if desired, be combined with flavoring materials, sweeteners, and/or aroma ingredients. The composition can also include other additives known in the nutritional and pharmaceutical arts such as, for instance, multi-vitamins, minerals, or nutritional elements, among others. In the present invention, the composition includes relative amounts of the two essential ingredients. The present compositions are formulated to provide an effective amount of hydrolyzed collagen protein, such as in adrninistration, e.g. dosing, to the patient. The hydrolyzed collagen is, in general, dosed so that the patient, human or veterinary mammalian patient, can receive a hydrolyzed collagen dosage in the range of 0.5 to 12 grams. An efficient therapy can involve daily doses of from 5 to 12 grams hydrolyzed collagen protein.

The present compositions are formulated to provide an effective amount of the glucosamine and/or its pharmaceutically acceptable salts, such as in the administration, e.g. dosing, to the patient. In general, the dosage is in a range of about 0.25 to 3.0 grams, depending on the patient, human or veterinary, receiving treatment. By present preference, in an effective daily dose of the present therapeutic composition, the patent can receive about 0.75 gram to about 2.0 grams of the glucosamine and/or its pharmaceutically acceptable salts.

In a presently preferred formulation, the present therapeutic composition is administered to a patient, such as a human patient, in which the daily dosage is about 7 to about 8 grams of hydrolyzed collagen protein in combination with about 1.5 to about 2.0 grams of the glucosamine and/or its pharmaceutically acceptable salts, e.g. in a weight ratio of about 3.5 to about 5.3. The relative amounts of effective ingredients within a dose or dosing schedule can be adjusted as appropriate for efficacious administration to veterinary patients.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising, as the essential ingredients, hydrolyzed collagen protein having a molecular weight of 1-300 kilodaltons; and at least one of glucosamine or pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, wherein the molecular weight of the hydrolyzed collagen protein is from 10 to 80 kilodaltons.

3. The composition according to claim 1, wherein the pharmaceutically acceptable salts of glucosamine are selected from the group consisting of glucosamine sulphate and glucosamine hydrochloride .

4. The composition of claim 1 wherein the composition is a powdered composition.

5. The composition according to claim 1, wherein said composition is tableted.

6. The composition according to claim 1, wherein the composition is gel-capped.

7. A method for treating arthroses comprising administering to a patient having need of said treatment an effective daily dosage of a composition according to claim 1.

8. The method according to claim 7, wherein said daily dosage comprises the combination of 7-8 grams of hydrolyzed collagen protein in combination with 1.5 to 2.0 grams of the glucosamine and/or its pharmaceutically acceptable salts.

9. A method according to claim 7, wherein the composition is administered to the patient in the form of a paste, syrup solution, granite, tablet or instantized powder.

10. A method according to claim 7, wherein the composition contains at least one member selected from the group consisting of flavoring agent, sweetener and aroma ingredien .

11. A method according to claim 7, wherein the composition is dosed so that the patient receives 0.5 to 12 grams of hydrolyzed collagen protein in combination with 0.25 to 3 grams of at least one of glucosamine and its pharmaceutically acceptable salts .