WO2023144118A1 - Methods of therapy comprising simultaneous administration of methotrexate and folic acid - Google Patents

Abstract

METHODS OF THERAPY COMPRISING SIMULTANEOUS ADMINISTRATION OF METHOTREXATE AND FOLIC ACID 5 Methotrexate (MTX) is an antineoplastic agent used the treatment of a wide variety of diseases including cancers and inflammatory autoimmune diseases such as psoriasis, Crohn's disease, and rheumatoid arthritis. Administered orally or by subcutaneous injection in low doses, MTX inhibits a number of folate dependent metabolic steps that lead to a state of effective folate 0 deficiency. It is likely that some of the adverse effects of MTX are due said folate deficiency, and the main factor affecting adherence to MTX is the occurrence of adverse effects, rather than lack of response. Although MTX side effects could be decreased by supplementation in folic acid (FA), the current guideline on folate administration is not precisely established. Now the inventors show that co-administration of MTX with FA on the same day is effective 5 compared to FA application one day after MTX. MTX metabolism was not affected, as demonstrated by the MTX-PG concentrations. The biological tolerance between the protocols was comparable. Thus, co-administration of MTX and FA seems to be possible and may be more convenient to the patients and improve compliance at the end.

Description

METHODS OF THERAPY COMPRISING SIMULTANEOUS ADMINISTRATION

OF METHOTREXATE AND FOLIC ACID

FIELD OF THE INVENTION:

The present invention is in the field of medicine.

BACKGROUND OF THE INVENTION:

Methotrexate (MTX) is an antineoplastic agent used the treatment of a wide variety of diseases including cancers and inflammatory autoimmune diseases such as psoriasis, Crohn’s disease, and rheumatoid arthritis. MTX is an antifolate agent with a chemical structure similar to that of folic acid and folinic acid, but its exact mechanism of action is still unclear. Administered orally or by subcutaneous injection in low doses, MTX inhibits a number of folate dependent metabolic steps that lead to a state of effective folate deficiency. It is likely that some of the adverse effects of MTX are due said folate deficiency, and the main factor affecting adherence to MTX is the occurrence of adverse effects, rather than lack of response. Between 7% and 30% of patients suffering from rheumatoid arthritis discontinue MTX in the first year due to toxicity. Although MTX side effects could be decreased by supplementation in folic acid (FA), the current guideline on folate administration is not precisely established. According to pharmacokinetic, it is consider that it is better to administer the compounds sequentially due to the fact that FA would inhibit the therapeutic effects of MTX.

SUMMARY OF THE INVENTION:

The present invention is defined by the claims. In particular, the present invention relates to methods of therapy that comprises simultaneous administration of methotrexate and folic acid.

DETAILED DESCRIPTION OF THE INVENTION:

The first object of the present invention relates to a method of therapy in a patient in need thereof comprising administering to the patient a therapeutically effective combination of methotrexate and folic acid wherein folic acid and methotrexate are simultaneously administered to the patient.

As used herein, the term “patient” denotes a mammal, preferably a human suffering from a disease wherein therapy with methotrexate is recommended. In some embodiments, the patient suffers from a cancer.

In some embodiments, the patient suffers from an inflammatory autoimmune disease. In some embodiments, the patients suffers from an inflammatory autoimmune disease selected from the group consisting of arthritis, rheumatoid arthritis, acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, dermatitis including contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, and atopic dermatitis, x-linked hyper IgM syndrome, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, polymyositis/dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma, systemic scleroderma, sclerosis, systemic sclerosis, multiple sclerosis (MS), spino-optical MS, primary progressive MS (PPMS), relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, and ataxic sclerosis, inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, transmural colitis, autoimmune inflammatory bowel disease, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleritis, respiratory distress syndrome, adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, rheumatoid spondylitis, sudden hearing loss, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis, Rasmussen's encephalitis, limbic and/or brainstem encephalitis, uveitis, anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, autoimmune uveitis, glomerulonephritis (GN), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or membranous proliferative GN (MPGN), rapidly progressive GN, allergic conditions, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE) or systemic lupus erythematodes such as cutaneous SLE, subacute cutaneous lupus erythematosus, neonatal lupus syndrome (NLE), lupus erythematosus disseminatus, lupus (including nephritis, cerebritis, pediatric, non-renal, extra-renal, discoid, alopecia), juvenile onset (Type I) diabetes mellitus, including pediatric insulin-dependent diabetes mellitus (IDDM), adult onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis, lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitides, including vasculitis, large vessel vasculitis, polymyalgia rheumatica, giant cell (Takayasu's) arteritis, medium vessel vasculitis, Kawasaki's disease, polyarteritis nodosa, microscopic polyarteritis, CNS vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS), temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia pemiciosa), Addison's disease, pure red cell anemia or aplasia (PRC A), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen-antibody complex-mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Bechet's or Behcet's disease, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid such as pemphigoid bullous and skin pemphigoid, pemphigus, optionally pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus-membrane pemphigoid, pemphigus erythematosus, autoimmune polyendocrinopathies, Reiter's disease or syndrome, immune complex nephritis, antibody-mediated nephritis, neuromyelitis optica, polyneuropathies, chronic neuropathy, IgM polyneuropathies, IgM-mediated neuropathy, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis); subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Grave's disease, polyglandular syndromes such as autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis, allergic encephalomyelitis, experimental allergic encephalomyelitis (EAE), myasthenia gravis, thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, giant cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, lymphoid interstitial pneumonitis, bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, primary biliary cirrhosis, pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac disease, Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AGED), autoimmune hearing loss, opsoclonus myoclonus syndrome (OMS), polychondritis such as refractory or relapsed polychondritis, pulmonary alveolar proteinosis, amyloidosis, scleritis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis, optionally benign monoclonal gammopathy or monoclonal gammopathy of undetermined significance, MGUS, peripheral neuropathy, paraneoplastic syndrome, channelopathies such as epilepsy, migraine, arrhythmia, muscular disorders, deafness, blindness, periodic paralysis, and channelopathies of the CNS, autism, inflammatory myopathy, focal segmental glomerulosclerosis (FSGS), endocrine opthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases, diabetic nephropathy, Dressier's syndrome, alopecia greata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyl), and telangiectasia), male and female autoimmune infertility, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, bird-fancier's lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampler's syndrome, Caplan's syndrome, dengue, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, flariasis, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis, or Fuch's cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection, rubella virus infection, post-vaccination syndromes, congenital rubella infection, Epstein-Barr virus infection, mumps, Evan's syndrome, autoimmune gonadal failure, Sydenham's chorea, post-streptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, giant cell polymyalgia, endocrine ophthamopathy, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemiareperfusion injury, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway disease, silicosis, aphthae, aphthous stomatitis, arteriosclerotic disorders, aspermiogenese, autoimmune hemolysis, Boeck's disease, cryoglobulinemia, Dupuytren's contracture, endophthalmia phacoanaphylactica, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman- Rich's disease, sensoneural hearing loss, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, leucopenia, mononucleosis infectiosa, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis (e.g. chronic pancreatitis), polyradiculitis acuta, pyoderma gangrenosum, Quervain's thyreoiditis, acquired splenic atrophy, infertility due to antispermatozoan antobodies, non-malignant thymoma, vitiligo, SCID and Epstein-Barr virus-associated diseases, acquired immune deficiency syndrome (AIDS), parasitic diseases such as Lesihmania, toxic-shock syndrome, food poisoning, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine failure, peripheral neuropathy, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), alopecia totalis, dilated cardiomyopathy, epidermolisis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or nonpurulent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, an eosinophil-related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilia-myalgia syndrome, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, or granulomas containing eosinophils, anaphylaxis, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosing cholangitis, sclera, episclera, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia, autoimmune disorders associated with collagen disease, rheumatism, neurological disease, ischemic re-perfusion disorder, reduction in blood pressure response, vascular dysfunction, antgiectasis, tissue injury, cardiovascular ischemia, hyperalgesia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, reperfusion injury of myocardial or other tissues, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, acute serious inflammation, chronic intractable inflammation, pyelitis, pneumonocirrhosis, diabetic retinopathy, diabetic large-artery disorder, endarterial hyperplasia, peptic ulcer, valvulitis, and endometriosis.

In particular, the patient suffers from psoriasis, Crohn’s disease or rheumatoid arthritis. More particularly, the patient suffers from rheumatoid arthritis.

As used herein, the term “rheumatoid arthritis” has its general meaning in the art and refers to rheumatoid arthritis such as revised in the World Health Organisation Classification M05- M14.

As used herein, the term "treatment" or "treat" refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).

As used herein, the term “methotrexate” or “MTX” has its general meaning in the art and denotes the dihydrofolate reductase antagonist. The IUPAC name of MTX is disodium; (2S)-2- [[4- [(2, 4-diaminopteridin-6-yl)methyl-methylamino] benzoyl] amino] pentanedioate.

As used herein, the term “folic acid” or “FA” has its general meaning in the art and refers to the N-acyl-amino acid that is a form of the water-soluble vitamin B9. The term is also known as “folate”, “vitamin B9” and “folacin”. The IUPAC name of FA is (2S)-2-[[4-[(2-amino-4- oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid.

As used herein, the term “combination” is intended to refer to all forms of administration that provide a first drug together with second drug. Drugs administered in combination have biological activity in the subject to which the drugs are delivered.

According to the present invention, the drugs are administered simultaneously. As used herein, the term "simultaneously" is meant to refer to administration of one or more therapeutic agents at the same time. Simultaneously includes administration contemporaneously, that is during the same period of time. In some embodiments, the one or more therapeutic agents are administered simultaneously in the same hour, or simultaneously in the same day. Simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, sub-cutaneous routes, intramuscular routes, and local routes (e.g., synovial, etc.). The therapeutic agents can be administered by the same route or by different routes. For example, methotrexate is administered subcutaneously or orally while folic acid is administered orally. In some embodiments, the patient is first administered with one or more cycles wherein the folic acid and methotrexate are administered simultaneously. As used herein, the term “cycle” refers to a period of time during the treatment is administered to the patient. Typically, a cycle of therapy is followed by a rest period during which no treatment is given. Following the rest period, one or more further cycles of therapy may be administered, each followed by additional rest periods.

As used herein, the term "therapeutically effective combination" as used herein refers to an amount or dose of each drugs (i.e. FA and MTX) that is sufficient to treat RA. A therapeutically effective amount of drug may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of drug to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects. The efficient dosages and dosage regimens of drug depend on the disease or condition to be treated and may be determined by the persons skilled in the art. A physician having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of drug employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable dose of a composition of the present invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect according to a particular dosage regimen. Such an effective dose will generally depend upon the factors described above. For example, a therapeutically effective amount for therapeutic use may be measured by its ability to stabilize the progression of disease. A therapeutically effective amount of a therapeutic compound may decrease tumor size, or otherwise ameliorate symptoms in a subject. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected. An exemplary, non-limiting range for a therapeutically effective amount of drug is about 0.1-100 mg/kg, such as about 0.1-50 mg/kg, for example about 0.1-20 mg/kg, such as about 0.1-10 mg/kg, for instance about 0.5, about such as 0.3, about 1, about 3 mg/kg, about 5 mg/kg or about 8 mg/kg. An exemplary, non-limiting range for a therapeutically effective amount of an antibody of the present invention is 0.02-100 mg/kg, such as about 0.02-30 mg/kg, such as about 0.05-10 mg/kg or 0.1-3 mg/kg, for example about 0.5-2 mg/kg. Administration may e.g. be intravenous, intramuscular, intraperitoneal, or subcutaneous, and for instance administered proximal to the site of the target. Dosage regimens in the above methods of treatment and uses are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. In some embodiments, the efficacy of the treatment is monitored during the therapy, e.g. at predefined points in time. As non-limiting examples, treatment according to the present invention may be provided as a daily dosage of the agent of the present invention in an amount of about 0.1-100 mg/kg, such as 0.2, 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/kg, per day, on at least one of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least one of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 after initiation of treatment, or any combination thereof, using single or divided doses every 24, 12, 8, 6, 4, or 2 hours, or any combination thereof.

Typically, the drug of the present invention is administered to the subject in the form of a pharmaceutical composition which comprises a pharmaceutically acceptable carrier.

In some embodiments, the folic acid and methotrexate are embedded in the same pharmaceutical composition. Thus a further object of the present invention relates to a method of therapy in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective combination of methotrexate and folic acid.

Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat. For use in administration to a subject, the composition will be formulated for administration to the subject. For instance, sterile injectable forms of the compositions of this invention may be aqueous or an oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. The compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include, e.g., lactose. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including synovial tissue. Suitable topical formulations are readily prepared for each of these areas or organs. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Patches may also be used. The compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

FIGURES:

Figure 1. MTX ± FA effect on MTX efficacy

A-C: Clinical monitoring during rat AIA. A: Articular index (range from 0 to 4) from D8 to D17 in no MTX (control), MTX, MTX + FA and MTX + FA (Id) groups. B: Ankle circumference (representing the mean between the two ankles circumference) from D8 to D17 in no MTX (control), MTX, MTX + FA and MTX + FA (Id) groups. C: Body weight gain (g) from DO to D17 in in no MTX (control), MTX, MTX + FA and MTX + FA (Id) groups. MTX group included 13 AIA rats, MTX + FA and MTX + FA (Id) groups included each 14 AIA rats, and no MTX group included 18 AIA rats for each graph. Data are presented as mean ± standard error of the mean (SEM). D-E: MTX-PG dosage in erythrocytes at D17 in AIA rats. D: MTX-PG concentrations (nM) in MTX, MTX + FA and MTX + FA (Id) groups. Baseline at 0 indicates absence of MTX-PG in 2 animals which did not receive MTX (no MTX). Data are presented as mean ± standard deviation (SD). E: Linear regression between MTX-PG 1 concentration (nM) and articular index (Al) in MTX group (Spearman coefficient: -0.81; p<0.05), MTX + FA group (Spearman coefficient: -0.97; p<0.001) and MTX + FA (Id) group (Spearman coefficient: -0.66; p=0.1). All groups included each 7 AIA rats. MTX: methotrexate; FA: folic acid; AIA: adjuvant-induced arthritis; D: day. Figure 2. MTX ± FA effect on joint bone loss at D17 in AIA rats

A: Representative 3D p-CT overall reconstruction of ankle and navicular bone (37 slices) for no MTX, MTX, MTX + FA and MTX + FA (Id) groups. B: Representative cortical and trabecular reconstruction of navicular bone (37 slices) for no MTX, MTX, MTX + FA and MTX + FA (Id) groups. C-D: Cortical porosity (C; Ct. porosity) and bone volume/total volume (D; BV/TV) for MTX, MTX + FA and MTX + FA (Id) and no MTX groups. MTX group included 13 AIA rats, MTX + FA and MTX + FA (Id) groups included each 14 AIA rats, and no MTX group included 18 AIA rats for each graph. Data are presented as mean ± SD. MTX: methotrexate; FA: folic acid; AIA: adjuvant-induced arthritis; D: day.

Figure 3. MTX ± FA effect on hematology and hepatic parameters.

A-G: Complete blood count at D17 in AIA rats. White blood cells (A) concentration (G/L), lymphocytes (B) concentration (G/L), neutrophiles (C) concentration (G/L), redblood cells (D) concentration (T/L), mean corpuscular volume (E) concentration (fL), hemoglobin (F) concentration (g/dL), and platelets (G) concentration (G/L) in MTX, MTX + FA and MTX + FA (Id) groups. H-J: Transaminases and creatinine dosage in serum at D17 in AIA rats. ALAT (H) concentration (U/L), ASAT (I) concentration (U/L), and creatinine (J) concentration (mg/dL) in MTX, MTX + FA and MTX + FA (Id) groups. MTX group included 13 AIA rats, MTX + FA and MTX + FA (Id) groups included each 14 AIA rats for each graph. All data are presented as mean ± SD. MTX: methotrexate; FA: folic acid; AIA: adjuvant-induced arthritis; D: day.

EXAMPLE:

Methods:

Female Lewis rat were randomly divided in three groups and received an injection of Mycobacterium butyricum defining day (D) 0 to induce arthritis. We also used an historical AIA control group. Treatment began on D9, one day before the arthritis in this model. The first group received only MTX (MTX group, n=13), the second group received MTX and FA at the same day (MTX+FA group, n=14) and the third group received FA one day after MTX administration (MTX+FA(ld), n=14). MTX was administrated at a dose of 1 mg/kg intraperitoneally (IP) every three days (4) and FA was delivered at a dose of 0.17 mg/kg IP. Arthritic index (Al) and ankle circumference (AC) were monitored to assess the disease progression and severity. Microcomputed tomography was performed to assess bone loss in ankle. Moreover, complete blood count, transaminases and MTX-PG dosage were performed. Results:

Arthritis started at DIO in all groups. Al and AC were similar in all groups at the various time points. Arthritis severity was lower (p<0.001) in all groups (D17; Al (mean and standard deviation): 1.4 ± 1.6; AC: 35 ± 7 mm) compared to AIA rats which normally develop a higher level of arthritis from D12 to D17 (D17; Al: 3.3 ± 0.6; AC: 42 ± 4 mm). Even if a trend of decreased bone loss was observed on total ankle reconstruction in the three MTX groups compared to AIA rats, bone erosion and bone loss parameters were found at a similar level in all groups (Figures 1A, IB, 1C, ID, IE). Cortical porosity was around 0.40% ± 0.15 and bone volume / total volume was around 0.22% ± 0.13 (Figures 2A, 2B, 2C, 2D). MTX-PG 1 were found at a similar level in all groups, with a negative correlation between MTX-PG concentration and Al in MTX and MTX±FA groups (p<0.05 and p<0.01, respectively). Finally, white blood cells, red blood cells, platelets, hemoglobin, and mean corpuscular volume were found at a similar level in all groups (Figures 3A, 3B, 3C, 3D, 3E, 3F, 3G). Transaminases and creatinine were expressed at a similar level in all MTX groups (Figures 3H, 31, 3J).

Conclusion:

Co-administration of MTX with FA on the same day is effective compared to FA application one day after MTX. MTX metabolism was not affected, as demonstrated by the MTX-PG concentrations. The biological tolerance between the protocols was comparable. Thus, coadministration of MTX and FA seems to be possible and may be more convenient to the patients and improve compliance at the end.

REFERENCES:

Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

Claims

CLAIMS:

1. A method of therapy in a patient in need thereof comprising administering to the patient a therapeutically effective combination of methotrexate (MTX) and folic acid (FA) wherein folic acid and methotrexate are simultaneously administered to the patient.

2. The method of claim 1 wherein the patient suffers from a cancer.

3. The method of claim 1 wherein the patient suffers from an inflammatory autoimmune disease.

4. The method of claim 1 wherein the patient suffers from psoriasis, Crohn’s disease or rheumatoid arthritis.

5. The method of claim 1 wherein the patient suffers from rheumatoid arthritis.

6. The method of claim 1 wherein MTX and FA are be administered by the same route or by different routes.

7. The method of claim 1 wherein MTX is administered subcutaneously or orally while FA is administered orally.

8. The method of claim 1 wherein FA and MTX are administered to the patient through the same pharmaceutical composition.