MX2010001330A - Compositions and methods for treatment and prevention of osteoarthritis. - Google Patents

Abstract

The present invention is in the fields of medicine, pharmaceuticals, neutraceuticals and rheumatology. In one aspect, the invention provides pharmaceutical compositions for the treatment and/or prevention of osteoarthritis in mammals, particularly humans, comprising sodium bicarbonate and calcium gluconate, and optionally comprising one or more additional components. The invention also provides methods of treating or preventing osteoarthritis by administering to a mammal, preferably via intraarticular injection, one or more compositions of the invention.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT AND PREVENTION OF OSTEO ARTHRITIS BACKGROUND OF THE INVENTION Field of the Invention The present invention is in the fields of medicine, pharmaceuticals, nutraceuticals and rheumatology. The invention relates to the use of compositions comprising sodium bicarbonate and calcium gluconate in methods for the treatment and / or prevention of asteoarthritis, and with the use of such compositions in the manufacture of products for their treatment and / or prevention.

State of the art Osteoarthritis Osteoarthritis (OA) is the most common joint disease in mammals and is characterized by a progressive deterioration of the components of articular cartilage, mainly proteoglycans. Articular cartilage in OA tends to lose mechanical strength, elasticity and smoothness and is continually abraded by movements of the joint. This leads to a reactive bone remodeling with the formation of osteophytes, microfractures, echumenisation of subchondral bone and pseudocysts, as well as exposure of the underlying bone joint.

The clinical manifestations of OA are joint pain, cramps in the morning or after resting, night pain, limited joint mobility / or joint deformity. B joint pain in OA can be caused not only by synovitis but also by a stretching of the joint capsule or its ligaments, periosteal irritation due to the formation of osteophytes, trabecular microfractures, hypertension or muscle spasms.

The disruption and disorganization of the aggregation of proteoglycans and glycosaminoglycans are accompanied by an increase in water in the matrix decreasing its rigidity, increases the vulnerability of the tissue to mechanical and chemical damage, giving as a response that the chondrocyte releases Interteucine 1 (IL-1) and nitric oxide, in response to the fragments of fibronectin that are formed increasing the release of proteases with the consequent degradation of collagen destabilizing the chondroid matrix and increasing the water content.

The joints that are most frequently affected by osteoarthrosis are in decreasing order: the distal interlalangias, first caipometacarpal, proximal interphalangeal, knees, first phalangeal metatarsal, and coxofemoral joints.

Osteoarthritis has a high prevalence and is one of the main causes of pain and disability in older adults. It lacks specific treatment and the available ones are of high socio-sanitary cost, in addition, they are focused only on controlling and reducing the pain and inflammation associated with the disease (ie, obtaining symptomatic relief), and do not fight the disease as such.

In the Mexican patent application number PA / A / 2006/002927 and PA / A / 2005/00605 entitled "Derivatives of bicyclic imino acids as inhibitors of matrix metalloproteinases"; describes imino acid derivative compounds which are suitable for producing medicaments for the prophylaxis and therapy of diseases whose evolution includes an increase in matrix metalloproteinase activity; such as degenerative joint diseases, connective tissue diseases, periodontal disease, diseases of the locomotor system, and inflammatory or carcinogenic diseases, as well as those diseases that result from injuries to the joints, meniscus, ball joint or ligaments, disturbances in the healing of wounds, alteration of bone metabolism, ulceration, stenosis, arthropathy, myalgia, anorexia or septic shock.

In the Mexican patent application number PA / A / 2004/00085 entitled "H use of heparinoid derivatives for the treatment and diagnosis of disorders that can be treated with heparinoids". heparinoid derivative compounds useful for the prevention and treatment of diseases that are associated with an activity of matrix metalloproteinases are disclosed.

The Mexican patent application number PA / a / 2003/004965 entitled "The use of low molecular weight heparin for the treatment of osteoarthrosis", describes the use of heparinoid derivatives, which contain a chelating agent that is covalently linked to the heparinoid and a paramagnetic metal cation of the transition metal series (Se, Ti, V, Cr, Mn, Fe, Co. Ni, Cu, Mo, u) or lanthanides. The derivatives are suitable for producing drugs for therapeutic and diagnostic purposes, for locating administered doses and for monitoring the success of the treatment of diseases such as osteoarthritis and thrombosis.

U.S. Patent Nos. 6,207,672 and 5,856,358, respectively, "Alkylaminohydroamic acid and N-substituted heterocyclic acids" and "Mono- and disulfo- and their use in the treatment of disorders of the bone matrix "claim the use of several compounds for the treatment of osteoarthrosis.

Currently, there is no specific treatment for OA, there are only some strategies that are often used to allow the mobility of the patient, or to control or diminish the primary symptoms of the disease, such as pain and inflammation: Some options used to improve the mobility are: (a) Physical medicine and rehabilitation; (b) Loss of weight when the load-bearing joints are affected and the patient is overweight; (c) Biomechanical management such as girdles, external prosthesis, etc.

Pharmacological treatment of OA symptoms In the pharmacological treatment of the symptoms of osteoarthrosis, a wide variety of resources are included to control and reduce the pain associated with the disease. Among such options are the following: (a) Analgesic administration such as paracetamol and screening; (b) Administration of non-steroidal anti-inflammatory drugs (NSAIDs), viscosupplementation, corticosteroids and / or narcotics; (c) Orthopedic surgery; Y (d) Experimental treatments (transplantation of cartilage and mesenchymal cells, administration of inhibitors of atocinas (IL-l, tumor necrosis factor alpha, etc.), administration of inhibitors of metalloproteinases, administration of inhibitors of nitric oxide synthetase, administration of growth factors, gene therapies, chondroprotective administration.

Therefore, there are several modalities for the treatment of OA which also includes non-pharmacological treatments (such as patient education, weight control, physical and occupational therapy) and the aforementioned pharmacological therapies. In both cases the management of osteoarthritis is predominantly palliative, focused on the relief of symptoms such as pain or inflammation. However, by not attacking the problem from the mechanisms that produce it, cartilage deterioration continues to advance despite pharmacological or physical interventions for the treatment of the disease and symptoms.

The most commonly used medications for the treatment of osteoarthritis are NSAIDs (Abramson SB, The role of NSAIDs in the treatment of osteoarthritis, Brandt D. Doherty M, Lohmlander LS (Eds), Oxford University Press, 2003: 251-258, and Schnitzer TJ American Cdlege of Rheumatdogy Update of ACR guidelines for osteoarthritis: role of the coxibs J? A /? Symptom Manage. 2002: S24-S30), which are common analgesics that reduce pain and inflammation. This type of medication includes aspirin, ibuprofen and naproxen.

This class of drugs acts by blocking the synthesis of prostaglandins by a non-selective inhibition of the enzyme Cyclooxygenase (Vane JR, Bakhle YS, Botting RM, Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxico !. 1998, 38: 97-120). Although NSAIDs are strongly prescribed to reduce joint pain and cramping, the inflammatory component of OA is usually minimal, therefore the benefit of the administration of such drugs in the treatment of OA is controversial. In addition, the inhibition of prostaglandin biosynthesis is directly related to severe adverse effects including gastrointestinal bleeding, hypertension, congestive heart failure, hyperkalemia, renal failure and inhibition of platelet aggregation (Zeisel SH, Regulation of Nutraceuticals, Science, 1999, 285: 1853-1855, Halsted CH Dietary supplements and functional foods: 2 sides of the coin Am Clin Nutr 2003. 77: 1001 S-1007S; Diplock AT, Aggett PJ. Ashwell M, Bornet F, Fem FB, Roberfroid MB. Scientific concepts óf functional foods in Europe; consensus document. Br J Nutr. 1999. 81: S1-S27). In April 2005, the Food and Drug Administration (FDA) requested NSAID manufacturers to include a warning label on the product, alerting consumers to an increased risk of cardiovascular events and intestinal bleeding. These drawbacks draw attention to an assessment of the risks and benefits of therapy compared to one of less toxicity, or at least a lower risk for OA.

Another type of medication, the specific inhibitors of cyclooxygenase II (COX2, or coxibs) have shown an analgesic and anti-inflammatory effect in patients with OA similar to that produced by NSAIDs, but with fewer gastrointestinal adverse events (Ramsey SD, Spencer AC, Topolski TD, Belza B, Patrick DL Use of altemative therapies by older adults with osteoarthritis, Arthntis Reum 2001, 45: 222-227). However, numerous reports of heart attacks and strokes have led the FDA to reassess the risks and benefits of COX-2 inhibitors. As a result of this evaluation, the drugs rofecoxib (marketed in the United States of America under the name of VIOXX®) and valdecoxib (marketed in the United States of America under the name of BEXTRA®) have been withdrawn from the US market, after receiving reports on heart attacks in patients who consumed them (Lane NE, Pain management in osteoarthritis: the role of COX-2 inhibitors, J rheumatol, 1997, 24: 20-24). Celecoxib (marketed in the United States of America under the name of Celebrex®), is still available but with labels with serious warnings and with the recommendation to be prescribed at the lowest dose and for the shortest possible time to avoid adverse events.

In another therapeutic option, pain and secondary inflammation in OA can be effectively relieved by an intra-articular injection of spheroids. Although the long-term impact and safety of them, especially on the anatomical structure of the knee is still unknown. While corticosteroids may be a useful way to treat the short-term symptoms of OA, they have the disadvantage that the palliative effect of corticosteroid injection seems to remain for only 1 to 3 weeks and that such injections could produce long-term term joint damage. Other implications of the use of corticosteroid injections include the appearance of synovitis, cutaneous atrophy (local) and steroid arthropathy.

The use of natural glucosamine and chondroitin sulfate ingested against the degeneration of articular cartilage and other locations has recently received much attention. Especially when a beneficial effect of glucosamine and chondroitin sulfate on OA of the knee was reported, although the general conclusion was that the results were promising but insufficient evidence to support the conclusion that such additives are useful in the treatment and prevention of OA (Pelletier JP, Martell-Peletero J. Raynauld, JP.Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow. Arthritis Research and Therapy. 2006, 8: 206).

A treatment of OA that has shown an effectiveness of 70 to 90% and produces excellent results is the transplantation of autologous cultures of chondrocytes. This consists of planting the patient's condral cellular material in a suitable medium and after that it grows it is implanted in the damaged tissue to cover its defects (Vladimir B. Autologous chondrocyte transplantation, American Academy of Orthopedic Surgeons Annual Meeting, 2000, pp. 1- 6.). Despite being a promising procedure, carrying it out is quite expensive and requires a lot of time for the implant to be ready.

Another treatment that is currently very popular involves intraarticular administration of commercially available artificial synovial fluid such as Hyalgan® (Sanofi-Aventis US; Bridgewater, NJ), Orthovisc® (DePuy Mitek, Inc. Raynham, MA), Artzal ® / Supartz® (Genzyme Corp Cambridge, MA). This substance only acts by modifying the rheology of the synovial fluid, producing an almost immediate sensation of freedom of movement and a marked reduction of pain in patients with OA. However, its effect is temporary because it remains in the joint chamber for only 72 h before it is absorbed and metabolized. In addition, the original problem is not corrected and the cartilage of joint damage is not restored. From This way, although this treatment produces temporary relief, the deterioration continues.

Therefore, it is clear that there is a need in the state of the art for more specific strategies for the treatment and / or prevention of OA. which not only produce a temporary relief to the symptoms associated with the disease but also, affect and reverse the underlying causes of the disease.

BRIEF SUMMARY OF THE INVENTION The present invention relates to the use of sodium bicarbonate and calcium gluconate for the treatment and / or prevention of OA, as well as a pharmaceutical composition containing said components which are used for the manufacture of products for the treatment of OA.

In one embodiment, the invention provides a pharmaceutical composition for the treatment of OA in mammals, composed of sodium bicarbonate and calcium gluconate. In such incarnation, sodium bicarbonate is present in concentrations of about 5% -10% (w / v) (more particularly about 6% -8% (w / v), about 6% -7% (p / v) or about 6.5% (w / v), and calcium gluconate is present at concentrations of about 0.5% -5% (w / v) (more particularly. around l% -2% (w / v) or approximately 1.5%. In the preferred embodiment, the composition of the invention is composed of approximately 6.5% (w / v) sodium carbonate and about 1.5% calcium gluconate. The composition of the invention may be in any acceptable form, but preferably in solid form or aqueous solution, and preferably in aqueous solution.

In further embodiments, the invention provides such compositions comprising one or more additional components useful to assist in the treatment and / or prevention of OA. Such compositions may comprise, for example, one or more additional components, at least one NSAID (including but not limited to aspirin, diclofenac, aceclofenac, ketorolac, ibuprofen, flurbiprofen, ketoprofen, and naproxen) and salts, esters and pharmacologically acceptable derivatives thereof. ), at least one immunosuppressant dependent on non-spheroidal immunophilin (including but not limited to calcineurin inhibitors such as cyclosporin, tacrolimus, ascomycin, pimecrolimus, as well as other agents such as peptides, peptide fragments or peptide-like fragments that inhibit the activity of the calcineurin phosphates, and rapamycin (sirolimus), fujimycin (tacrolimus), and everolimus which bind to the protein FK506). at least one COX-1 (including but not limited to aspirin, ibuprofen and naproxen), at least COX-2 inhibitor (including but not limited to celecoxib, rofecoxib, valdecoxib, lumiracoxib, meloxicam and nimesulide), at least one corticosteroid (including but not limited to betamethazone, budesonide, cortisone, dexamethasone, hydrocortisone, methyprednisolone, prednisone, prednisone and triamcindone). at least one glucosamine glucan (including but not limited to glucasamine or glucosamine sulfate), at least one proteoglycan (including but not limited to heparan sulfate or chondroitin sulfate). at least one hyaluronic acid and synovial fluid (including but not limited to Hyalgan®, Orthovisc®, ArtzalO / Supartz® and Synvisc®.) Some additional components useful for inclusion in the composition of the present invention will be familiar to any technician skilled in the art. matter.

In appropriate embodiments, the compositions of the present invention are formulated for oral or parenteral administration, and preferably for parenteral administration such as in injectable form. In such particular embodiment, the compositions are formulated to be administered to an animal, such as a mammal, via intra-articular injection.

In another embodiment, the invention provides a method for the treatment or prevention of OA in mammals (such as humans), comprising administration to said mammal in amounts necessary for the treatment or prevention of OA of ??? a pharmaceutical composition containing sodium bicarbonate and calcium glucoate, such as in one or more of the compositions of the invention previously described. According to this method, the compositions are administered to the mammal orally or parenterally, preferably parenterally via injection. In these particular methods, the compositions are administered to the mammal by intra-articular injection. In further embodiments, the methods of the invention comprise the supplementary administration of, preferably intraarticularly, a hyperosmolar solution of sodium chloride (particularly where the concentration of sodium chloride in the hyperosmolar solution is approximately 1.77 g / 10 mL). to decrease the water content within the chondral matrix and restore the loss of chlorine produced by the exchange of HCO3VCK Other embodiments of the present invention will be apparent to any technician with ordinary skill in the art in light of the following description and claims of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a flow chart illustrating the method by which the participants were selected for the ondrium ® / methylprednisolone study.

FIG. 2 is a bar graph which illustrates the change in the WOMAC pain index in each treated group evaluated after four injections. The bars with different letters are significantly different (p < o.05.test LSD).

FIG. 3 is a bar graph which shows the change in the functional index of Luquesne in each treated group evaluated after four injections. The bars with different letters are significantly different (p <0.05, LSD test).

DETAILED DESCRIPTION OF THE INVENTION Unless defined, all technical terms used herein have the same meaning as commonly understood by a technician with ordinary skills in the subject matter of the invention. Notwithstanding any method and material similar or equivalent to that described herein may be used in the practice or evaluation of the present invention, preferred methods and materials are described below.

DEFINITIONS Approximately, close to: Used here when referring to a numerical value this term means a value of ± 10% of the indicated value (for example, approximately 50 ° C covers a temperature range of 45 ° C to 55 ° G, inclusive, similarly, approximately 100 mM covers a concentration range of 90 mM to 110 mM).

United: Used herein the term "attached" refers to a linkage which may be of a covalent type, for example by chemical coupling, or non-covalent. for example, ionic interaction, hydrophobic interaction. hydrogen bridge, etc.

The covalent bonds can be, for example, ester, ether, phosphoester, thioester. thioether, urethane. amide, amine, peptide. Measure, hydrazone, hydrazide, carbon-sulfur, carbon-phosphorus and the like. The attached term is so broad that it includes terms such as coupled, conjugated, linked.

Disease, disorder, condition. Used here, the term disease or disorder refers to any human or animal condition including tumors, cancer, allergies, addiction, autoimmunity, infection, poisoning or weakening of the optimal mental and bodily condition. 0 term condition as used herein includes disease or disorder but also refers to a physiological state. For example, fertility is a physiological state but not a disease or disorder; therefore, compositions useful for the prevention of pregnancy by decreasing fertility should therefore be described as adjuncts as a treatment of a condition (fertility), but not as a treatment of a disorder or disease.

Other conditions included by the use of this term should be understood by any technician with minimum knowledge of the subject.

Effective amount: As used herein, the term "effective amount" refers to the amount of a certain compound, conjugate or composition that is necessary or sufficient to effect a desired biological effect. An effective amount of a certain compound, conjugate or composition in accordance with the methods of the present invention would be the amount that reaches the chosen result, and such amount can be determined routinely by an experienced technician in the area, using assays that are part of the knowledge of the technique or are described in this invention, without the need for undue experimentation. For example, an amount effective to treat or prevent OA could be the amount necessary to prevent the development and / or progression of the symptoms and / or the underlying physiological causes of OA, such as preventing or reducing the increase in water in the cartilaginous matrix which would decrease the rigidity of the matrix, reducing or preventing joint pain or stiffness, reducing or preventing the disruption of proteoglycans and / or glycosaminoglycans in one or more joints, etc. The term is also synonymous with "sufficient quantity". The effective amount for any particular application may vary depending on factors such as the disease, disorder or condition to be treated, the particular composition to be administered, the route of administration, the size of the subject, and / or the severity of the disease or condition.

A technician with average skill in the art can empirically determine the effective amount of a particular compound, conjugate or composition of the present invention, in accordance with the assistance provided herein, without the need for undue experimentation.

One, a: When the terms "one" or "one" are used in this invention they mean "at least one" or "one more" unless it has been Indicate otherwise, as such the terms "One or One", "One or more" and "At least one" can be used here interchangeably.

Peptide, polypeptide, protein: As used herein, the term "polypeptide" comprises a "single polypeptide" as well as several "polypeptides", and refers to a molecule composed of monomers (amino acids) linked by amide bond (also known as pepitica) ). The term "polypeptide" refers to any chain or chains of two or more amino acids, and does not refer to a specific length of the product. Thus, peptides, dipeptides, tripeptides, oligopeptides, protein, amino acids or any other term used to refer to a chain or chains of two or more amino acids, are included within the definition of polypeptide, and the term polypeptide can be used in place of or exchange for any of these terms.

The term polypeptide is also proposed to refer to the product of post-expression modifications of the polypeptide, including without limitation, glycosylations, acetylations, phosphorylations, amidation, block derivatization or protection of known groups, proteditic cleavage. or modifications by amino acids that are not found naturally.

A polypeptide can be derived from a biological source naturally or produced by recombinant technology, but is not necessarily translated from a certain amino acid sequence. This can be generated by any form including chemical synthesis. In accordance with this definition, the polypeptides used in the present invention may be of a size of 3 or more. 5 or more, 10 or more, 20 or more, 25 or more, 50 or more, 75 or more, 200 or more, 500 or more, 1000 or more, or 2000 or more amino acids. The polypeptides may have a defined three-dimensional structure, however they may not necessarily have such a structure. Polypeptides with a defined three-dimensional structure are referred to as "folded" (folded structure), and polypeptides that do not possess a defined three-dimensional structure, but that can take a large number of different conformations, and are referred to as "deployed" (expanded structure).

As used herein, the term "glycoprotein" refers to a protein bound to at least one carbohydrate residue by N-glycosidic or O-glycosidic bond, to the asparagine or serine residues.

By an isolated polypeptide or fragment, variant, or derivative thereof is meant a polypeptide that is not in its natural form. A particular level of purification is not required. For example, an isolated polypeptide can be removed from its natural or native environment. The peptides and recombinantly produced prpteins and proteins expressed in host cells are considered as isolates for purposes of the invention, as well as native or recombinant polypeptides that have been separated, fractionated or partially or substantially purified by an appropriate technique.

Fragaments were also included as polypeptides. derivatized, analogues or variants of the previous polypeptides or any combination thereof. Polypeptide fragments, as a term or phrase used herein, include proteolytic fragments, as well as cancellation fragments, in addition to the specific fragments discussed elsewhere in this document. Variants of useful polypeptides in accordance with the present invention include fragments as discussed above, and also polypeptides with altered amino acid sequences due to amino acid substitutions, deletions or insertions. These variants can occur naturally or artificially that can be produced using known techniques of mutagenesis.

The polypeptide variants can comprise conserved and non-conserved amino acid substitutions, deletions or additions. Aminopeptide variants can also be referred to as analogous peptides.

Derivatives of polypeptides useful in accordance with the present invention are polypeptides that have been altered such that they exhibit additional features not found in the native polypeptides. Examples of these include fusion of proteins, polypeptides having one or more residues chemically derivatized by the reaction of a side functional group, and peptides containing one or more derivatives of the naturally occurring amino acids, or of the standard amino acids ( for example, -hydroxyproline can be substituted by proline, 5-hydroxylysine can be substituted by lysine, 3-methylhistidine can be substituted by histidine, homoserin can be substituted by serine, ornithine can be substituted by lysine, etc.) Treatment: As it has been handled here, the term treatment, treat, treat, refers to prophylaxis and / or therapy, particularly when the aim is to prevent or diminish a physiological change or undesirable disorder, such as the development and / or progression of the OA.

The desired or beneficial clinical result includes, but is not limited to, relief of symptoms, decrease in disease progression, stabilization of the disease state, delaying the progression of the disease, and rendering it totally or partially undetectable.

The treatment can also prolong survival and / or increase the quality of life compared to the expectations of survival and / or quality of life that would be had if the treatment was not received.

By subject, or individual, or animal or mammal, is meant any mammalian subject, for which the diagnosis, prediction or therapy is desired. Subject or mammal includes humans and other primates, domestic animals, farm animals, zoo animals, sports animals, or pets such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, donkeys, sheep, cows and similar animals .

SYNOPSIS The present invention is related to the use of sodium bicarbonate and calcium gluconate for the treatment and / or prevention of articular diseases such as OA, as well as with a pharmaceutical composition containing said components and methods for the manufacture of the same In an additional incorporation, the composition provides methods for the use of the composition in the manufacture of products for the treatment and / or prevention of joint diseases such as OA. According to certain embodiments, the present invention provides a carefully planned combination for the treatment and / or prevention of OA, for example by the administration of a solution that activates the buffering capacity of the proteins that form the cartilage. (for example, a solution of sodium bicarbonate) which promotes the organisation of ionized calcium, together with a solution that allows the union of chondral and bone proteins "among themselves (for example, a solution of calcium gluconate). In other embodiments * the composition of the present invention may additionally encompass one or more components or compounds that are useful for the treatment or prevention of articular diseases such as OA, and / or the symptoms associated with said articular diseases: such conditions are described then.

The composition and methods of the present invention not only alleviate and / or remedy the symptoms of joint diseases such as OA (for example pain and inflammation), but also here are different factors that trigger articular diseases such as OA, relieving , treating and / or rooting the causes and the fundamental symptoms of the disease.

A simple and low-cost treatment was developed for the treatment of osteoarthritis, based on the restoration of the joint surface of the synovial joints after the loss or degeneration of the cartilage when administering intra-articularly a solution comprising sodium bicarbonate and gluconate. of calcium, particularly the administration of aqueous solutions where the concentration of sodium bicarbonate is in the range of 0.1 to 99.9% (w / v) (particularly between 6.5% (w / v) or between 6.75% (w / v)), and that of calcium gluconate between 0.1 to 99.9% (w / v), (particularly between 0.75% (w / v) to q .5% (w / v)). In certain additions the sodium bicarbonate is present in a concentration between 5% -10% (w / v) (more particularly, between 6% -8% (w / v), between 6% -7% (w / v) between 6.5% (p / v), between 6.75% (p / v)) (more particularly between 0.75% -2% (p / v), close 0.75% (p / v) close to 1% (p / v) or about 1.5% (w / v) In certain preferred embodiments, the composition of the invention comprises about 6.5% (w / v) or about 6.75% (w / v) sodium bicarbonate and about 0.75% (w / w) v) or about 1.5% (w / v 9 calcium gluconate) In such incorporation, the compositions comprise about 6.75% (w / v) sodium bicarbonate and about 6.75% (w / v) sodium bicarbonate and about 1.5 % (w / v) calcium gluconate.

While not wishing to be limited to any particular theory, it is believed that one of the components of the composition of the present invention, sodium bicarbonate, functions in this composition and method, activating the buffering capacity of the proteins in the joint, allowing in this way, the union of ionized calcium (organismic calcium) to the chondral and bone proteins in the joint, which reinforces the joint and the bone matrix. This It is believed that sodium bicarbonate stimulates the buffer capacity of chondral and bone proteins to produce the organisation of ionized calcium to these proteins.

Similarly, it is believed that the other component of the composition of the present invention, calcium gluconate, functions in the present composition and methods, stimulating the binding of chondral and bone proteins to each other. This would favor the formation of an interface to the subchondral bone, which would limit the disruption of the proteins, increasing the structure and rigidity of the aforementioned matrices.

Using the composition and methods of the present invention as described herein, the pain associated with the disease is decreased and joint mobility is improved.

Hydric accumulation in the matrix and hypochloremia in the extracellular fluid resulting from the administration of sodium bicarbonate is regulated by the administration of a hyperpsmolar sodium chloride solution (preferably at concentrations of 1.77g / 10ml) at 2.0 g / 10ml, more preferably at a concentration of about 1.75 g / IOml to about 1.85 g / 10 ml and even more preferably at a concentration of about 1.77 g / 10 ml).

The composition and methods of the present invention can be used not only for the treatment and / or prevention of OA, but also also for the treatment and / or prevention of any other inflammatory disease that causes joint damage. Additionally. the use of the composition and methods of the present invention is not restricted to humans; it can also be used in any animal, alone or in combination with any other drug or pharmaceutically active compound designed for the treatment of the symptoms of joint disease, or any other substance that can be administered intra-articularly. Such additional uses and compositions are also described below.

Compositions Therefore, in one embodiment, the invention provides a pharmaceutical composition for the treatment of joint disease, including, but not limited to, OA in mammals. The pharmaceutical compositions according to the aspects of the invention comprise sodium bicarbonate and calcium gluconate. In another embodiment, the invention provides a pharmaceutical composition for the treatment of joint diseases, including but not limited to OA. in mammals. A typical (excellent) composition according to the aspects of the invention comprises sodium bicarbonate and calcium gluconate. In such additions sodium bicarbonate is present at concentrations ranging from 0.1% to 99.9% (w / v). adequately about 1% to 50% (w / v) to about 2.5% to 25% (w / v), more adequately 5% to 10% wax (w / v), still more appropriately about 6% to 8% % (w / v), approximately 6% to 7% (w / v), or approximately 6.5%.

Similarly, in certain embodiments, calcium gluconate is present at concentrations of 0.1% to 99.9% (w / v). adequately from 0.25% to about 50% (p / v), about 0.5% to 25% (p / v), about 0.5% to 10% (p / v), or about between 0.5% and 5% ( p / v), more adequately between about 1% (p / v) to 2% (p / v), and still more adequately about 1.5% (p / v).

In a particularly preferred embodiment the composition of the invention comprises about 6.5% (w / v) sodium bicarbonate and about 1.5% calcium gluconate.

In a further embodiment, the composition of the invention may include one or more of the following components, particularly when these additional components are useful to aid in the treatment and / or prevention of OA. Such composition of the invention may include, for example, at least one NSAID (including but not limited to aspirin, ibuprofen, aceclofenac, deiclofenac, naproxen, etodolac, fluribiprofen, fenoprofen, ketoprofen, suprofen, fendbufen, fluprofen, sodium tolemtin, axaporzine, zomepirac, sulindaco, indomethacin, piroxicam, nabumetone, meclofenamate sodium. diflunisal, flufenisal, piroxicam. ketorolac, sudoxicam and isoxicam, and their salts, esters and pharmacologically acceptable derivatives).

In a further embodiment, the compositions of the invention may include at least one non-steroidal immunosuppressant-dependent immunofluid (NsIDI), any non-steroidal agent that suppresses the secretion or production of proinflammatory atocins, that bind immunofillin, or that cause a decrease in the regulation of the proinflammatory reaction. Some NsIDI's, useful for inclusion in the present invention include, but are not limited to inhibitors of calcineurin, cyclosporin, tacrolimus, ascomycin, pimecrolimus, as well as other agents (peptides, peptide fragments, chemically modified peptides, or peptide analogs) which inhibit the phosphatase activity of calcineurin. Also included are rapamycin (sirolimus) and everolimus, which bind to the binding protein FK506. and they block the antigen-induced proliferation of white blood cells and the secretion of atocines.

In a further embodiment, the invention combination can comprise at least one COX-1 inhibitor (including but not limited to aspirin, ibuprofen, naproxen) In another embodiment, the compositions of the invention may comprise at least one COX-2 inhibitor (including but not limited to celecoxib, rofecoxib. valdecoxib. lumiracoxlb. meloxicam, nimesulide and the like, tramadol, etoricoxib).

In further embodiments, the compositions of the invention may comprise at least one corticosteroid (including but not limited to betamethazone, budesonide, cortisone, dexamethasone, hydrocortisone, methylpredinisolone, prednisolone, prednisone, and triamcinolone).

In further embodiments, the composition of the invention may comprise at least one glycosaminoglycan (including but not limited to glucosamine or glucosamine sulfate).

In further embodiments, the composition of the invention may comprise at least one proteoglycan (including but not limited to heparan sulfate or chondroitin sulfate).

In a further embodiment, the composition of the invention may comprise at least one hyaluronic acid.

In further embodiments, the composition of the invention may comprise synovial fluid! artificial. In synovial fluid suitable for use in connection with the present invention includes but is not limited to Hyalgan® (Sanofi-Aventis US, Bridgewater, NJ), Orthovisc® (DePuy Mitek, Inc., Raynham, MA), Artzal® / Supartz® (Seikagaku Corpn., Tokyo, Japan) and Synvisc® (Genzyme Corpn, Cambridge, MA).

In other embodiments, the compositions of the invention comprise combinations of one or more of the components described above. Additional components suitable for inclusion in the composition of the present invention will be familiar to a person skilled in the art.

The concentrations, absolute amounts and relative amounts (relative to the concentration or absolute amounts of sodium bicarbonate and calcium gluconate) of one or more additional agent compounds that are optionally included in the compositions of the invention will be familiar to a person skilled in the art. . For example, additional components or agents (one or more corticosteroids, one or more NSAIDs, one or more COX-1 inhibitors, one or more COX-2 inhibitors, etc.) may be present in any amount for example near 0.01% to 99% (eg close to 0.01%, close to 0.1%, close to 10%, close to 20%, close to 30%, close to 40%, close to 50%, close to 60%, close to 70 %, close to 80%, or close to 90%), in relation to weight / volume (w / v) or weight / weight (w / w), of the concentration or absolute amounts of sodium bicarbonate or calcium gluconate, which they are present in the compositions.

The compositions of the invention may be in any form of administration, but preferably in solid or aqueous form, and more preferably in an aqueous solution such as in a saline solution. buffer, comprising one or more of the physiologically acceptable buffers and / or carriers, such as an amount of a pharmacologically acceptable buffer, to maintain the pH of the composition within the range of 4.5 to 7.4, a sufficient amount of an isotonic agent for obtain an osmolarity of between 220 masmol / kg at 350 msmol / kg and water QS.

The composition of the present in the form of a solution can optionally be preserved, manufactured aseptically and / or sterilized, for example, by filtration through filters.

In order to reduce the possibility of adverse events by the presence of additives, the liquid form of the invention can be prepared free or substantially free of preservatives. As the phrase "free or substantially free of preservatives" is used herein, it means that the formulation contains less than 0.0001% (weight / volume) of preservatives, more suitably less than 0.00001% (weight / volume) of preservatives, still more adequately, free of charge. Conservatives The formulations to be used for live administration must be sterile. This can be carried out by filtration in sterile membranes. The use of these membranes can eliminate the need for preservatives in the liquid formulations of the present invention. However, certain liquid compositions of the invention they may comprise one or more preservatives and / or one or more stabilizers.

Preservatives that may be suitable for use in the present invention include, but are not limited to, acetic acid and its alkali salts such as ethylenediaminetetracetic acid (EDTA). benzyl alcohol, methylparaben, propBparaben, butylparaben, chlorobutanol, phenyl ethyl alcohol, metuparaben, propylparaben. Butylparaben, chlorobutanol, thimerosal, propylene glycol, sorbic acid, benzoic acid derivatives. The preservatives could be used at concentrations between 0.001% to 0.5% (w / v) in the final composition. B EDTA at concentrations between 0.005% to 0.1% (w / v) is the preferred preservative in the combination of the present invention.

In another embodiment, the preservative-free liquid formulations and compositions of the present invention can also be provided in single-dose containers.

Such containers are acceptable for transporting the therapeutic dose of the composition of the invention, particularly topically, orally, intradermally, or via injection. In this embodiment of the invention, the composition can be contained effectively in a package comprising a container with a capacity of 1 mL or more. In another phase of the invention, particularly in that in which the composition of the invention is administered in a form of suitable dosage for parenteral administration, e.g. Via intra-articular injection, the composition can be contained in a package formed by a syringe containing one or more of the compositions of the invention, particularly when the syringe containing the composition is contained within a sterile package, in such cases, the sterile package is open, and the composition of the invention is administered to the affected joint of the patient by intra-articular injection.

The composition of the present invention can be administered to the patient by any suitable mode of administration, including, orally, topically, transdermally. sublingual, parenteral or similar. In certain incarnations, the compositions are administered directly to the joint in which the OA or other joint disease has manifested. Said administration can be carried out topically or transdermally using the strategies and mechanisms described herein or others that are evident to a person skilled in the art. The administration can also be carried out by intra-articular injection of one or more compositions of the invention in the affected joint or in the vicinity of the joint space. Intraarticular injection methods or pharmaceutical compositions are known to a mid-level technician and are also described below.

Thus, in certain embodiments, the compositions of the invention can be formulated for oral administration, including solid or liquid forms. In alternative embodiments, the compositions of the invention can be formulated for direct administration to the mucosa, including the buccal mucosa (oral administration) or the oral mucosa below the tongue (sublingual administration). Solid forms for oral administration include tablets, pills, powders, particles and granules. In such forms of administration, the compositions of the invention are admixed with at least one pharmaceutically acceptable excipient to carrier such as (a) fillers such as starch, lactose, sucrose, glucose, mannitol, dicalcium phosphate or micrcrystalline cellulose; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone and acacia; (c) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, silicates, carboxymethylcellulose, pregelatinized starch; lubricants such as calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and / or (e) glidants such as talcum, silicon dioxide and starch. In the case of capsules, tablets or pills, the administration form may comprise buffering agents.

Solid compositons of a similar type can be used as fillers in soft and hard gelatin capsules using excipients such as lactose or polyethylene glycols of high molecular weight, oils and the like. Solid compositions such as tablets, capsules and granules can be prepared with enteric layers or other layers that are well known in pharmaceutical formulation.

The solid forms can optionally contain opacifiers, dyes and / or flavors, which can be formulated in such a way that they release the active ingredient only, or preferentially, in certain parts of the intestinal tract, optionally in a delayed manner (USPTO 5,271,946). ? Active compound can also be present in microcapsules, if appropriate, with one or more of the excipients mentioned above.

In other embodiments, the compositions of the invention are formulated for parenteral administration. For example, liquid forms of the composition of the present invention that are suitable for parenteral (including injections) or oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and el'txirs. In addition to the active ingredients, liquid forms may contain, diluents or solvents commonly used. Water is the solvent of choice for the formulations of the invention, however, they are also suitable for use water combinations with other physiologically acceptable solvents. Other solvents, solubilizing agents or emulsifiers suitable for use in place of, or in addition to, water include but are not limited to saturated aliphatic alcohols, or polyvalent alcohols which contain from 2-6 carbon atoms (including but not limited to to ethanol, 1,2-propylene glycol, sorbitol and glycerin), polyglycolates such as polyethylene, and surfactants / emulsifiers such as fatty acid esters or sorbitan, and mixtures thereof. Oils, in particular, cottonseed oil, peanut, or corn, may also be used in the compositions. Additional solvent combinations in the aqueous solution should preferably not exceed approximately 15% (w / v) of the total composition. In addition to the inert diluents, the oral compositions may include adjuvants such as wetting agents, emulsifiers and suspending agents (eg microcrystalline cellulose, carboxymethylcellulose, hypromellose, carbopol and the like) surfactants, humectants, sweeteners, flavorings, and perfuming agents, including some of the described below. Liquid forms that provide the active ingredients in suspension may comprise, in addition to the active agent, one or more suspending agents such as microcrystalline cellulose, aluminum magnesium silicate, bentonite. agar-agar hypromellose, sodium carboxymethylcellulose, carbopol / saithe, pectin. acacia, tragacanth or mixtures of them.

Formulations suitable for parenteral administration (e.g., via injection, particularly intra-articular injection) include aqueous solutions of active compounds their water-soluble form, for example water-soluble salts and alkaline solutions. Alkaline salts include ammonium salts prepared, for example, with Tris, choline hydroxide, bis-Tris propane, N-methylglucamine, or arginine.

Additionally, suspensions of the active compound in the form of oily injections can also be administered. Suitable lipophilic solvents or vehicles include sesame oil, synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400.

Injectable aqueous suspensions may contain substances that increase their viscosity, for example, carboxymethylcellulose, sorbitol, and / or dextran. Optionally, the suspensions may also contain stabilizers.

Certain compositions of the invention may also contain agents that increase the solubility of the active agents of the invention. Some agents that increase solubility and that are suitable for use in the composition include, but are not limited to, polyvinylpyrrolidone (preferably grade 25, 30, 60 or 90), polaxamer, pdisorbate 80, sorbitan monooleate 80 and polyethylene glycols (molecular weight 200 to 600).

Certain compositions of the invention may contain one or more agents used to produce a sotonic solution, particularly in those compositions in which water is used as a solvent. Such agents are particularly useful in compositions formulated for parenteral administration, particularly by intra-articular injection, since they adjust the osmotic pressure of the solution to the same osmotic pressure of the injection site. Some agents that are suitable for this use in the composition include, but are not limited to, sodium chloride, sorbitol, propylene glycol, dextrose, sucrose, and glycerin, and other sotonic agents that are known in the art (Reich et al .. "Chapter 18: Tonicity, Osmoticity, Osmolality and Osmolarity," n: Remington: The Science and Practice of Pharmacy, 20th Edition, Uppincott Williams and Wilkins, Ph.P., PA (2000)).

It is desirable that the composition of the invention that is administered in liquid form (including oral, topical or parenteral) have a pH between 4.5 to 7.8, preferably 5.5 to 7.4, for physiological reasons.

Accordingly, in further embodiments, the compositions of the invention may comprise one or more pH buffering agents or combinations thereof, which are used to adjust and / or maintain the composition at a desired pH. The damping agents which are suitable for use in the composition include, but are not limited to, citric acid, sodium citrate, sodium phosphate. { dibasic, heptahydrate form). and boric acid or equivalent, or combinations thereof.

The appropriate amounts of the buffering agents, or combinations thereof, which are used in the compositions of the invention can be determined by a person skilled in the art without the need for experimentation, particularly in view of the guidance contained herein and standard formulations such as the Pharmacopoeia of the United States (Remington, The Science and Practice of Pharmacology) and the like, whose disclosures are here entirely incorporated by reference.

Method of use In further embodiments of the invention, the compositions of the present invention can be used therapeutically in regimens for the treatment of mammals affected by certain diseases, particularly joint diseases such as OA and others described elsewhere in the text. Therefore, in further embodiments, the invention provides methods for the treatment or prevention of diseases of the joints or disorders such as OA in mammals (such as humans), the administration comprising to such mammal in amounts suitable for treatment or prevention of a composition of sodium bicarbonate and calcium gluconate, and optionally one or more additional components useful in the treatment of or prevention of diseases of the joints and / or symptoms associated with them.

In related embodiments, the invention provides methods for reducing or preventing the progression of joint inflammation or progression of damage to a more advanced degenerative joint disease, such as OA, in a patient, comprising administering a therapeutically effective amount of a more of the compositions of the present invention. Suitable compositions for carrying out these methods include the compositions of the invention that have already been described.

According to certain methods of the invention, one or more compositions of the present invention are administered to a patient, who suffers or is predisposed to OA or a similar disease, by any form of administration available, including oral, buccal, topical, transdermal, sublingual, parenteral or similar. In certain incarnations, the compositions are administered directly to the joint in which the OA or other disease or disorder has manifested.

Administration can be carried out via a topical or trans-modal route using strategies and mechanisms described in other parts of the document. Accordingly, the composition can be administered orally or parenterally, and preferably parenterally via injection.

In such particular methods, the compositions are administered to the mammal via intra-articular injection in the affected joint or in the space surrounding it. Methods of intra-articular injection of pharmaceutical compositions are known to a person skilled in the art and described below.

Suitable doses (e.g., amounts, volumes, etc.) of the compositions of the invention will be apparent from the examples shown below. In certain embodiments, an injection volume of between about 2 ml to about 10 ml (about 2 ml, about 2.5 ml about 3 ml about 3.5 ml about 4 ml about 4.5 ml about 5 mi, approximately 5.5 mi, approximately 6 mi, approximately 6.5 mi, approximately 7 mi, approximately 7.5 mi, approximately 8 mi, approximately 8.5 mi, approximately 9 mi, close to 9.6 mi or close to 10 mi) of one or more of the compositions of the present invention is introduced into the mammal. Other useful doses will be apparent to a technician trained in the subject based on the disclosure of this document and the available knowledge.

In further embodiments, the methods of the invention will comprise administration to a mammal, preferably via intra-articular injection, a hyperosmolar solution of sodium chloride, preferably when the solution is prepared according to the methods described above for the formulation of the compositions of the invention. invention. Therefore, in conjunction with the administration of one or more of the compositions of the invention, the patient is also administered a hyperosmolar solution of sodium chloride at the same site of the administration of one or more compositions of the invention. By "in conjunction with the administration of one or more compositions of the invention" it is understood that the hyperosmolar solution of sodium chloride is administered contemporaneously (Le just before, at the same time, or just after) of one or more compositions of the invention, or sometimes after the end of the multi-monthly treatment regimen. In suitable inoculations, the concentration of sodium chloride in the hyperosmolar solution is about 1.7 g / 10 mL or about 2 g / 10 mL, more suitably about 1.7 g / 10 mL at 2 g / 10 mL or about 1. 75 g / 10 mL or 1.85 g / 10 mL and even more adequately 1.77 g / 10 mL While not wishing to be limited to any particular theory, it is thought that administration of the hyperosmolar solution of sodium chloride acts to decrease the content of water within the condral matrix, reversing the loss of chlorine produced by the HCOaVCh exchange According to the methods of the invention, the compositions of the invention (and optionally the hyperosmolar solution of sodium duroxide) can be administered to patients according to a wide variety of dosage programs. For example, the compositions may be administered once a day for a certain time (ie 4 to 8 weeks or more), or according to a weekly schedule (eg one day per week, two days per week, three days per week, 4 days a week, 5 days a week, six days a week, or 7 days a week, for a set amount of time (eg 4 to 8 weeks) A specific example of a weekly dose schedule is the administration of the composition of the invention on days 1, 8, 15 and 22 of the treatment period In alternative embodiments the compositions of the invention can be administered intermittently over a period of months For example, the compositions of the invention can be administered weekly for three consecutive weeks biannually (ie repeat the weekly dosing schedule every six months). or these can be administered once a month for a period of 2, 3, 4. 5. 6, 7, 8 or more months. The administration regimen may be continued for extended periods (e.g. in the order of years) to maintain the therapeutic benefit provided by the initial treatment. In other embodiments, maintenance of such therapy may be affected by following an acute dosing regimen designed to reduce the immediate symptoms of degenerative joint disease, disease or disorder, such as OA. In most embodiments, however, the compositions of the invention are administered to the patient according to the methods described herein, at least until the symptoms of the disease or joint disorder, such as OA, are alleviated or reduced. More commonly, the compositions of the invention and the methods of the invention are used for a period of time after the symptoms are reduced to a tolerable level or completely eliminated, resulting in an improvement of the physiological structure of the joint by a reduction or elimination of the underlying or fundamental physiological causes of the disease or joint disorder.

The amount of the compositions of the invention administered each time throughout the treatment period may be the same; alternatively, the amount administered at each time during the intervention period may vary (e.g., the amount administered to a given time may be more or less than the amount previously administered). For example, a given dose during therapy maintenance may be less than those administered during the acute phase of treatment. An appropriate dosage scheme depending on the circumstances will be apparent to a technician trained in the subject.

It will be readily understood by someone with ordinary skill in the relevant art that other suitable modifications and adaptations for the methods and applications described herein are obvious and can be made without deviating from the scope of the invention or any incorporation thereof. Having described the present invention in detail, it can be understood more clearly by reference to the following examples, which are included only for purposes of the invention and are not intended to limit the invention.

EXAMPLES EXAMPLE 1: EFFECT OF THE INTRAARTICULAR ADMINISTRATION OF THE ANTI-OA FORUMLATION ON THE WOMAC AND LEQUESNE INDICES.

In the present experiment, we included 18 patients with an average age of 57. 6 years with diagnosis of gonartrosls grade II to V according to Kellgren and Lawrence criteria. The patients underwent a test with intra-articular application (10 mL) of a Liquid composition of calcium gluconate and sodium bicarbonate where sodium bicarbonate is at a concentration of 6.75% (w / v) and where calcium gluconate is at a concentration of 1.5% (w / v). every month for 6 months, an intra-articular injection of sodium chloride was performed at the end of the treatment. The evaluation of the result was carried out through the Womac and Lequesne indexes before and after the intra-articular application of the formula developed in the invention, obtaining a noticeable improvement in pain and physical activity rates of 90% of patients (Table 1 ).

Table 1. Womac and Lequesne index before and after submitting patients to intra-articular injection of the formula developed.

EXAMPLE 2. Evaluation of the efficacy of Kondrium ®, compared mefflprednisolone in the treatment of knee osteoarthrosts.

Kondrium® is the name of a pharmaceutical composition described in the North American patent application No. 60 / 953,724 entitled "Composition and method for the prevention and treatment of osteoarthritis". This composition activates the buffer (buffer) capacity of the proteins that form the cartilage, which promotes the organization of ionized calcium, and also allows the binding between chondral and bone proteins to each other. This study was designed to evaluate and compare the efficacy of kondrium® and methylprednisolone as a positive control in the treatment of osteoarthrosis. Methylprednisolone was chosen as a control because it is currently the only medically accepted drug for the treatment of osteoarthrosis.

Methods Study design A clinical study was carried out, with active control, double blind, in three parallel groups with aletarory allocation. The study lasted 16 weeks. The study was approved by an ethics committee and conducted in accordance with the ICH (International Conference of Harmnonization) guidelines, good practices in clinical research (GCP) and the Helsinki declaration. All patients contributed their informed knowledge in writing before the start of the study.

The identity of the drug remained blinded to patients, the staf of researchers, the staff that carried out some measurements and analysis of the data, from the random assignment to the closing of the databases. The treatments were identical in packaging, labeling, administration scheme and appearance.

Patients The study included 17 patients with knee diagnosis (according to the criteria of the American College of Rheumatology). The patients were recruited by advertisements and were studied at the San José hospital in Querétaro, Mexico. The inclusion criteria were the following: Men and women over 40 years of age with at least one year of symptomatic evidence of knee osteoarthrosis with desire to participate in the study. Radiographic evidence of knee OA grade II to IV according to the criteria of Kellgren and Lawrence. patients who had not received intra-articular injection of corticosteroids within 3 months prior to the intervention. Patients were excluded if they had: history of adverse reaction to the study drugs, pregnancy, uncontrolled hypertension, active infection, arthroscopic surgery within three months prior to the study inoculation, X-ray diagnosis of knee OA grade I (according to the Kellgren and Lawrence criteria).

B sample size was calculated according to the following considerations: a) A clinically significant minimum change of 3.1 points in the overall WOMAC and Lequesne score between the group contrd and the treatment groups, b) alpha value of 5% (0.05) and a beta power of 80%, c) abandonment rate of 20%. With these considerations, 11 subjects were required according to the study design.

During the study, concomitant treatment with analgesics (different from rescue medication) and systemic corticosteroid was not allowed. During the study Patients were allowed to use rescue medication (acetaminophen 3g / d), although the use of rescue medication was prohibited before the baseline visit.

Study procedure The patients were evaluated personally during 6 monthly visits. After providing their written informed consent (Visit # 1), the patients were scrutinized and selected according to predetermined criteria. Visit 2 was the baseline evaluation. During this visit, the selected patients were assigned an identification number and were randomly assigned to receive an intraartitucular injection of ondrium®, kondrium-F® or methylprednisolone (80 mg) monthly during the following 3 months with a month of spacing between each injection (Visit 3, 4 and 5). Visits # 3, # 4 and # 5 served as intermediate evaluations and visit # 6 was the final evaluation corresponding to the end of the intervention period.

Ondrium® is an aqueous formulation containing 6.75% (Weight / volume w / v) of sodium bicarbonate and 0.75% (w / v) calcium gluconate. Kondrium-F® is an aqueous formulation containing 6.75% (w / v.) Of sodium bicarbonate and 1.5% (w / v) calcium gluconate.

The adherence to treatment was evaluated for the unused vials and the number of injections received for each treatment.

Efficacy evaluation The main objective of the study was to demonstrate the superiority of kondrium® or kondrium®-F compared to methylprednisolone in the treatment of patients with knee OA. The primary efficacy variable was the change from the baseline to the final evaluation in the WOMAC pain index (Western Ontario and McMastern University OA Index), and the Lequesne functionality index.

Safety Evaluation and Tolerance During the first visit, subjects were informed of all possible side effects, benefits and potential risks of the study. Adverse reactions were monitored by the health journals, nursing assessment and personal interview at visits # 2, 3, 5 and 6. Subjects were also asked to record any adverse symptoms and inform the appropriate physician immediately. . All adverse events reported by patients or discovered by the investigator during the study were recorded and evaluated in terms of severity, severity and potential relationship with the study medication. The safety evaluation consisted of routine laboratory tests (hematology, biochemistry and urinalysis), evaluation of vital signs, and electrocardiogram, which were carried out during the scrutiny, the baseline period and at the end of the study.

Statistic analysis The data analysis was carried out using the SPSS program for Windows version 10.0. Baseline demographic variables and attachment were analyzed by means of the test? 2. An analysis of variance (ANOVA) was used to determine if the three groups were different in the mean value of the change from the baseline in the WOMAC and Lequesne indices. The effect of the treatment is shown as the effect of the treatment controlled by the basal values. The comparison of pairs between treatments was performed using the LSD test. All statistical tests were performed at a significance level of 0.05.

RESULTS During the months of December 2007 and February 2008, a total of 161 patients were screened to participate in the study. 44 of them did not meet the inclusion criteria and were excluded from the study. The remaining 117 subjects were randomly assigned to receive one of the three study treatments (Figure 1), and all of them received the assigned treatment. 11 patients (10.2%) abandoned the study. 4 of the ondrium® group (3 due to personal reasons and 1 due to unsatisfactory therapeutic effect), 4 of the Kondrium®-F group (3 due to personal reasons and 1 due to unsatisfactory therapeutic effect), and 4 of the meth prednisolone group (3 for personal reasons and one for unsatisfactory therapeutic effect).

The baseline demographic characteristics of the 117 patients enrolled in the study were not different between the groups, so it was considered that they had no influence on the outcome of the study (Table 2). The majority of patients were women (80.2%), the average age was 54.7 ± 9.06 years and the average duration of the disease was approximately 7 years. A large proportion of the study subjects were obese, as indicated by the average body mass index greater than 30. The radiographic analysis showed no significant difference between the treatment groups in the distribution of the severity of the narrowing of the intra-articular space and the formation Marginal osteophytes within the compartment of the knee. In most patients (80%), the intensity of pain was moderate to severe. At the end of the study, patients in all three treatment groups showed an improvement in the score of the three ddor measurements, stiffness and functionality, as well as the overall score of WOMAC and Lequesne, with respect to the baseline (Table 3 and 4); The improvement in the total WOMAC score was the greatest and significantly different in the two groups of Kondrium with respect to the group that received metuprednisolone. The average change in the total WOMAC score was -11.28, -10.40 and -7.34 in the groups that received Kondrium ®, Kondrium ® - F and metüprednisolone respectively. No differences were observed between the Kondrium® and Kondrium®-F groups (Table 3, Figure 2). FJ average change in the Lequesne functionality index was also different between the Kondrium® and Kondrium®-F groups and the metüprednisolone group. The average change in the Lequesne functionality index was -9.33 for the group that received treatment with Kondrium®, -8.46 for the group that received Kondrium®-F, and -5.2 for the group that received metüprednisolone (Table 4, Figure 3 ).

There were no differences between the treatment groups in the percentage of patients who experienced adverse events during the study, gonalgia was the most commonly reported adverse event in the three groups. However, the gonalgia disappeared within the first 5 days.

The purpose of this study was to evaluate the efficacy and safety of the use of intraarticular injections of Kondrium® for the treatment of OA of knee. We have shown that four-month treatment with ondrium® or Kondrium®-F is significantly more effective than metflprednisolone with respect to changes in the overall WOMAC score and the Lequesne functionality index. This superiority of Kondrium® indicates the effectiveness of these compositions taken as examples in the present invention, which in this study were more effective than methylprednisolone.

This study also showed that both Kondrium® and Kondrium®-F were safe and free of adverse events. B positive effect and the absence of adverse events with the administration of sodium bicarbonate / calcium gluconate make this procedure an attractive alternative for patients with osteoarthroses of the knee.

Table 2. Baseline demographic characteristics of patients with osteoarthrosis of the knee by study group.

Group of patients KONDRIUM KONDRIUM / Methylprednisolone N = 34 N = 36 N = 35 Men (%) 8.3 20.5 30.6 Women (%) 91.7 79.5 69.4 Age (years) 55.49 ± 9.76 54.46 ± 8.83 54.47 ± 8.81 I C (kg / m2) 31.06 ± 4.92 31.63 ± 4.77 30.46 ± 4.86 BMI > 30 (%) 47.2 64.1 50 Table 3. Measurements of the WOMAC subscales after 4 months of 5 treatment. * Indicates significant difference with respect to the group of methylprednisolone (p <0.05, LSD test) Group of patients KONDRIUM KONDRIUM / Methylprednisolone Pain Basal, Media 6.15 (5.30 to 7.0) 6.08 (5.25 to 6.91) 4.72 (3.52 to 6.92) (95% Cl) Final, Average 2.00 (1.39 to 2.20 (1.32 to 3.08) 2.57 (1.70 to 3.44) (95% Cl) 2.61) Change, Mean -3.82 (-4.61 to -3.59 (-4.33 to -2.76 (-3.52 to - (95% Cl) 3.03) 2.86) 2.00) Rigidity Basal, Average 5.97 (5.24 to 5.98 (5.15 to 6.82) 4.79 (3.94 to 5.64) (95% Cl) 6.69) Final, Average 2.11 (1.51 to 2.17 (1.46 to 2.89) 2.77 (i: 84 to 3.70) (95% Cl) 2.72) Change, Mean -3.65 (-4.36 a - -3.60 (-4.26 a - -2.42 (-3.10 a - (95% Cl) 2.94) * 2.94) * 1.74) Physical activity Basal, Average 17.80 (15.89 to 17.85 (15.76 to 14.47 (11.85 a (95% Cl) 19.71) 19.93) 17.09) Final, Average 5.97 (4.23 to 6.89 (4.62 to 9.15) 8.19 (5.48 to 10.91) (95% Cl) 7.72) Change, Mean -11.28 (13.43 a - -10.40 (12.40 a - -7.34 (-9.41 a - (95% CI) 9.13) * 8.39) * 5.27) 'Significantly different to the control group of methylprednisolone in the univariate analysis controlled by the baseline value and the comparison of pairs of means (LSD) Table 4. Measurements of the subscales of the Lequesne functionality index after 4 months of treatment. * Significant difference with respect to the methylprednisolone group (p <0.05, LSD test) Group of Patients KONDRIUM KONDRIUMA Methylprednisolone Pain Basal Average (95% Cl) 5.58 (5.06 to 6.10) 5.40 (4.93 to 5.87) 4.34 (3.67 to 5.019) Final Medium (95% Cl) 2.62 (2.04 to 3.19) 2.40 (1.68 to 3.12) 2.86 (2.08 to 3.64) Change, Mean (95% Cl) -2.65 (-3.39 a - -2.80 (-3.48 a - -1.96 (-2.68 a - 1.92) 2.13) 1.25) Maximum Distance from March Basal average (95% Cl) 4.62 (3.74 to 5.50) 4.03 (338 to 4.68) 3.24 (2.42 to 4.06) Final, Medium (95% Cl) 1.73 (0.95 to 2.51) 2.07 (133 to 2.80) 2.90 (2.07 to 3.72) Change, Mean (95% Cl) -2.49 (-3.26 a - -1.91 (-2.62 a - -0.75 (-1.48 a - 1.72) * 1.21) * 0.02) Daily activities Basal Average (95% Cl) 8.58 (7.16 to 10.00) 7.53 (6.70 to 8.36) 6.93 (5.85 to 8.01) Final, Medium (95% CI) 4.08 (337 to 4.78) 3.90 (3.18 to 4.62) 4.62 (352 to 5.72) Cambra, Media (95% CI) -3.87 (-4.73 a - -3.71 (-4.50 a - -2.80 (-3.61 a - 3J0U 2.92? * - 'Significantly different from the control group of methylprednisolone in the univariate analysis controlled by the baseline value and the comparison of pairs of means (LSD) Having now completely described the invention in some details by means of illustration and examples for purposes of clarity and understanding, it will be obvious to a technician with ordinary skills in the area such that it can be developed by modification or change of the invention within a wide range of conditions, formulations and other parameters without affecting the approach of the invention, or any specific embodiment thereof, and such modifications or changes will fall within the scope of the following claims.

All publications, patents and patent applications mentioned in the specifications are indicative of the level of skills of technicians trained in the materia to which the invention belongs, and are incorporated here.

Claims (53)

1 . A pharmaceutical composition for the treatment of OA in mammals, comprising the administration of sodium bicarbonate and calcium gluconate.

2. A pharmaceutical composition according to claim (1) wherein the concentration of sodium bicarbonate is in the range of 0.1% to 99.95 (w / v) and the concentration of calcium gluconate between 0.1% to 99.9% (w / v) ).

3. The pharmaceutical composition of claim 1, wherein the sodium bicarbonate is at concentrations of 5% -10% (w / v) and where the concentration of calcium gluconate is between 0.5% -5% (w / v).

4. The pharmaceutical composition of claim 3, wherein the sodium bicarbonate is at concentrations of 6% -8% (W / v).

5. The pharmaceutical composition of claim 3, wherein the sodium bicarbonate is present at concentrations of 6% -7% (w / v).

6. The pharmaceutical composition of claim 3. wherein the sodium bicarbonate is present at a concentration of 6.5% (w / v).

7. The pharmaceutical composition of claim 3, wherein the calcium gluconate is present at concentrations of between 0.5% -. 2.5% (p / v).

8. The pharmaceutical composition of claim 3, wherein the calcium gluconate is present at a concentration of l% -2% (w / v).

9. The pharmaceutical composition of claim 3, wherein the calcium gluconate is present at a concentration of 1.5% (w / v).

10. The pharmaceutical composition of claim 1, wherein the sodium bicarbonate is present at a concentration of about 6.5% (w / v) and where the calcium gluconate is present at a concentration of about 1.5% (w / v).

1. The pharmaceutical composition of claim 1, wherein the composition is an aqueous solution.

12. The pharmaceutical composition of claim 1, wherein the composition is a solid form.

13. The pharmaceutical composition of any of claims 1-12, wherein said composition may comprise one or more additional components selected from the group of at least one NSAID, at least one NsIDI, at least one inhibitor of COX-1, at least one inhibitor of COX-2, at least one corticosteroid, at least one glycosaminoglycan, at least one proteoglycan, at least one hyaluronic acid, and synovial fluid.

14. The pharmaceutical composition of claim 13, wherein the at least one NSAID is selected from the group consisting of aspirin, diclofenac, aceclofenac, ketorolac, ibuprofen, flurbiprofen, ketoprofen, and naproxen, and pharmaceutically acceptable derivatives, salts or esters thereof.

15. The pharmaceutical composition of claim 13, wherein at least one NsIDI is selected from the group of inhibitors of calcineurin, rapamycin (sirolimus), fujimycin (tacrolimus) and everolimus.

16. The pharmaceutical composition of claim 13, wherein at least one COX-1 inhibitor is selected from the group of aspirin, ibuprofen, naproxen.

17. The pharmaceutical composition of claim 13, wherein at least one COX-2 inhibitor is selected from the group consisting of celecoxib, rofecoxib, valdecoxib, lumiracoxib, meloxicam, tramadol and nimesulide.

18. The pharmaceutical composition of claim 13, wherein at least one corticosteroid is selected from the group consisting of betamethazone, budesonide, cortisone, dexamethazone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.

19. The pharmaceutical composition of claim 13, wherein at least one glycosaminoglycan is glucosamine or glucosamine sulfate.

20. The pharmaceutical composition of claim 13, wherein the proteoglycan is heparan sulfate or chondroitin sulfate.

21. The pharmaceutical composition of claim 1, wherein the composition is formulated for oral or parenteral administration.

22. The pharmaceutical composition of claim 13, wherein the composition is formulated for oral or parenteral administration.

23. The pharmaceutical composition of claim 21 or 22, wherein the composition is formulated for parenteral administration.

24. The pharmaceutical composition of claim 23, wherein said formulation for parenteral administration is an injectable formulation.

25. The pharmaceutical composition of claim 23, wherein said injectable formulation is suitable for intra-articular injection.

26. A method for the treatment or prevention of OA in mammals, which comprises administering to said mammals a adequate amount of a preventive solution or for the treatment of OA composed of sodium bicarbonate and calcium gluconate.

27. The method of claim 26, wherein said sodium bicarbonate is present at concentrations ranging from about 0.1% up to 99.9% (w / v) and where said calcium gluconate is present in a concentration of 0.1% up to 99.9 % (p / v).

28. The method of claim 26, wherein sodium bicarbonate is present at concentrations ranging from about 5% -10% (w / v), and where calcium gluconate is present at concentrations of 0.5% -5% (p. / v).

29. The method of claim 26, wherein sodium bicarbonate is present at concentrations ranging from about 6% -8% (w / v).

30. The method of claim 26, wherein the sodium bicarbonate is present in concentrations ranging from about 6% -7% (w / v).

31. The method of claim 26, wherein the sodium bicarbonate is present at a concentration of about 6.5% (w / v).

32. The method of claim 26, wherein the calcium gluconate is present, at concentrations ranging from about 0.5% -2.5% (w / v).

33. The method of claim 26, wherein calcium gluconate is present at concentrations ranging from about l% -2% (P / v).

34. The method of claim 26, wherein the calcium gluconate is present at a concentration of about 1.5% (w / v).

35. The method of claim 26, wherein the sodium bicarbonate is present at a concentration of about 6.5% (w / v) and where the calcium gluconate is at a concentration of about 1.5% (w / v).

36. The method of claim 26, wherein the composition is an aqueous solution.

37. The method of claim 26, wherein said composition is a solid form.

38. The method of any of claims 26-37, wherein said composition may comprise one or more of the additional components selected from the group consisting of at least one NSAID, at least one NsIDI, at least one COX-1 inhibitor, at least a COX-2 inhibitor, Kal minus a corticosteroid, at least one glycosaminoglycan, at least one proteoglycan, at least one hyaluronic acid, and synovial fluid.

39. The method of claim 38, wherein the at least one NSAID is selected from the group consisting of aspirin, diclofenac, aceclofenac, ketorolac, ibuprofen, flurbiprofen, ketoprofen, and naproxen, and pharmaceutically acceptable derivatives, salts or esters thereof.

40. The method of claim 39, wherein at least one NsIDI is selected from the group of inhibitors of calcineurin, rapamycin (sirolimus), fujimycin (tacrolimus) and everolimus.

41. The method of claim 39, wherein at least one COX-1 inhibitor is selected from the group of aspirin, ibuprofen, naproxen.

42. The method of claim 39, wherein at least one COX-2 inhibitor is selected from the group consisting of celecoxib, rofecoxib, valdecoxib, lumiracoxib, meloxicam, tramadol, etoricoxib and nimesulide.

43. The method of claim 39, wherein at least one corticosteroid is selected from the group consisting of betamethazone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.

44. The method of claim 39, wherein at least one glycosaminoglycan is glucosamine or glucosamine sulfate.

45. The method of claim 39, wherein the proteoglycan is heparan sulfate or chondroitin sulfate.

46. The method of claim 26, wherein the composition is formulated for oral or parenteral administration.

47. The method of claim 39, wherein said composition is administered to the mammal orally or parenterally.

48. The method of claim 46 or 47, wherein said composition is administered parenterally.

49. The method of claim 48 wherein said parenteral administration is carried out by injection.

50. The method of claim 49, wherein said injection comprises intra-articular injection.

51. The method of claim 26, wherein said mammal is a human.

52. The method of claim 26, comprising the intra-articular administration to said mammal of a sodium chloride solution.

53. The method of claim 52, wherein the concentration of sodium chloride in said hyperosmolar solution of sodium chloride is 1.77 g / lO mL COMPOSITIONS AND METHODS FOR THE TREATMENT AND PREVENTION OF OSTEO ARTHRITIS SUMMARY OF THE INVENTION The present invention is in the field of medicine, pharmaceuticals, nutraceuticals and rheumatology. The invention provides a pharmaceutical composition for the treatment and / or prevention of osteoarthritis in mammals, particularly in humans, comprising the administration of sodium bicarbonate and calcium gluconate, and optionally comprising one or more additional components. The invention also provides a method for the treatment and / or prevention of osteoarthritis in mammals by administration, preferably via intra-articular injection, of one or more compositions of the invention.