HRP20050355A2 - Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines - Google Patents

Description

Previous knowledge

The invention relates to the treatment of immune disorders.

Immunoinflammatory disorders are characterized by inappropriate activation of the body's immune system for defense. Instead of targeting infectious agents, immune responses target and damage the body's own tissues or transplanted tissues. The tissue targeted by the immune system varies by disorder. For example, in multiple sclerosis, the immune response is directed at neuronal tissue, while in Crohn's disease, the digestive tract is targeted. Immunoinflammatory disorders affect millions of individuals and include conditions such as asthma, allergic intraocular inflammatory diseases, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatoses, inflammatory bowel disease, or gastrointestinal disorders (eg, Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritis/inflammation, psoriasis, rheumatoid arthritis and systemic lupus erythematosus.

Current treatment regimens for immunoinflammatory disorders typically rely on immunosuppressive agents. The effectiveness of these agents can vary and their use is often accompanied by undesirable side effects. Therefore, improved therapeutic agents and methods for the treatment of immunoinflammatory disorders are needed.

Summary of the invention

In one aspect, the invention provides a composition containing a selective serotonin reuptake inhibitor (SSRI) (or its analog or its metabolite) and a corticosteroid in amounts that are together sufficient for the treatment of immunoinflammatory disorders in a patient in need thereof. If desired, the composition includes one or more additional compounds (eg, glucocorticoid receptor modulator, NSAID, COX-2 inhibitor, DMARD, biologic, xanthine, anticholinergic compound, beta-receptor agonist, bronchodilator, nonsteroidal clacineurin inhibitor, vitamin D analog, psoralen , retinoid or 5-aminosalicylic acid). The preparation can be formulated, for example, for topical administration or for systemic administration.

In the next aspect, the invention presents a method of reducing the secretion or production of a proinflammatory cytokine in a patient, by giving the patient an SSRI or its analog or its metabolite and a corticosteroid, simultaneously or within 14 days of each other, in amounts sufficient to reduce the secretion or production of a proinflammatory cytokine in the patient .

In a related aspect, the invention presents a method of treating a patient who is diagnosed with an autoimmune disorder or is at risk of developing it, by giving the patient an SSRI or its analog or its metabolite and corticosteroids at intervals of up to 14 days in amounts sufficient to treat the patient.

In one of the following methods, the patient may also be given one or more additional compounds (eg, glucocorticoid receptor modulator, NSAID, COX-2 inhibitor, DMARD, biologic, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, nonsteroidal clacineurin inhibitor, vitamin analog D, psoralen, retinoid or 5-aminosalicylic acid).

If desired, SSRI and/or corticosteroid can be given in low and high dose. Preferably, the drugs are given up to 10 days apart, more preferably up to five days apart, and even more preferably within twenty-four hours or even simultaneously.

In a corresponding aspect, the invention presents a method of treating immunoinflammatory disorders in a patient who needs it, by simultaneously giving the patient an SSRI (or its analog or its metabolite) and a corticosteroid in amounts that are more effective for the treatment of immunoinflammatory disorders than corticosteroids given without an SSRI.

In the next aspect, the invention presents a method of treating immunoinflammatory disorders in a patient who needs it, by simultaneously giving the patient an SSRI (or its analog or its metabolite) and a corticosteroid in amounts that are together more effective for the treatment of immunoinflammatory disorders than an SSRI given without corticosteroids.

In the next aspect, the invention presents a method of treating immunoinflammatory disorders in a patient who needs it, by administering a corticosteroid to said patient, and by administering an SSRI (or its analog or its metabolite) to the patient, whereby: (i) the corticosteroid and the SSRI are administered simultaneously and ( ii) adequate amounts of corticosteroids and SSRIs given to a patient are more effective for the treatment of immunoinflammatory disorders than corticosteroids given in the absence of SSRIs or SSRIs given in the absence of corticosteroids.

The invention also provides a pharmaceutical composition in the form of a unit dose, and the composition contains a corticosteroid and an SSRI or an analog thereof or a metabolite thereof, wherein the amounts of corticosteroids and SSRIs, when given to said patient, are more effective than corticosteroids in the absence of SSRIs or given SSRIs in the absence of corticosteroids.

The invention also features a kit including (i) a composition comprising an SSRI or an analog thereof or a metabolite thereof and a corticosteroid, and (ii) instructions for administering the composition to a patient diagnosed with an autoimmune disorder.

In a related aspect, the invention provides a kit that includes: (i) an SSRI (or its analog or its metabolite) and (ii) a corticosteroid and (iii) instructions for administering the preparation to a patient diagnosed with an autoimmune disorder.

If desired, the corticosteroid can be replaced according to the methods, compositions and kits of the invention with a glucocorticoid receptor modulator or other steroid receptor modulator.

Therefore, in one aspect, the invention provides a composition containing an SSRI (or its analog or its metabolite) and a glucocorticoid receptor modulator in amounts sufficient for the treatment of an immunoinflammatory disorder in a patient in need thereof. If desired, the preparation may contain one or more additional substances. The compound can be formulated, for example, for topical administration or systemic administration.

In the next aspect, the invention presents a method of reducing the secretion or production of a proinflammatory cytokine in a patient, by giving the patient an SSRI (or its analog or its metabolite) and a glucocorticoid receptor modulator, simultaneously at a distance of up to 14 days from each other, and in amounts sufficient to reduce the secretion of a proinflammatory cytokine or its production in the patient.

In a related aspect, the invention presents a method of treating a patient who has been diagnosed with an immunoinflammatory disorder or is at risk for it, an SSRI (or its analog or its metabolite) and a glucocorticoid receptor modulator at the same time at a distance of up to 14 days from each other, and in amounts sufficient for the treatment of the patient. Preferably, the drugs are given up to 10 days apart, more preferably up to five days apart, and even more preferably within twenty-four hours of each other or even simultaneously.

In a corresponding aspect, the invention presents a method of treating immunoinflammatory disorders in a patient who needs it, by simultaneously administering to the patient an SSRI, its analog or its metabolite, and a glucocorticoid receptor modulator in amounts that together are more effective for the treatment of immunoinflammatory disorders than corticosteroids given without an SSRI.

In the next aspect, the invention presents a method of treating immunoinflammatory disorders in a patient who needs it, by simultaneously administering to the patient an SSRI or its analog or its metabolite, and a glucocorticoid receptor modulator in amounts that together are more effective for the treatment of immunoinflammatory disorders than an SSRI given without a glucocorticoid receptor modulator .

In the next aspect, the invention presents a method of treating immunoinflammatory disorders in a patient who needs it, by administering a glucocorticoid receptor modulator to said patient, and by administering an SSRI (or its analog or its metabolite) to the patient, wherein: (i) the glucocorticoid receptor modulator and the SSRI are given simultaneously, and (ii) appropriate amounts of the glucocorticoid receptor modulator and SSRI given to the patient are more effective for the treatment of immunoinflammatory disorders compared to a given glucocorticoid receptor modulator in the absence of an SSRI or a given SSRI in the absence of a glucocorticoid receptor modulator.

The invention also provides a pharmaceutical composition in dosage unit form, the composition comprising a glucocorticoid receptor modulator and an SSRI (or an analog thereof or a metabolite thereof), wherein the amounts of the glucocorticoid receptor modulator and the SSRI, when administered to said patient, are more effective than the glucocorticoid receptor modulator in absence of an SSRI or a given SSRI in the absence of a glucocorticoid receptor modulator.

The invention also provides a kit including (i) a composition comprising an SSRI (or an analog thereof or a metabolite thereof) and a glucocorticoid receptor modulator, and (ii) instructions for administering the composition to a patient diagnosed with an autoimmune disorder.

In a related aspect, the invention provides a package that includes: (i) an SSRI or its analog or its metabolite, and (ii) a glucocorticoid receptor modulator, and (iii) instructions for administering the preparation to a patient diagnosed with an autoimmune disorder.

If desired, the corticosteroid can be replaced according to the methods, compositions and kits of the invention, with a glucocorticoid receptor modulator or other steroid receptor modulator.

As described herein, an SSRI or an analog thereof or a metabolite thereof in the absence of corticosteroids also has anti-inflammatory activity. Therefore, the invention also provides a method of preventing the secretion of one or more proinflammatory cytokines in a patient in need thereof, by administering to the patient an SSRI in an amount sufficient to prevent the secretion of proinflammatory cytokines in the patient.

In a related aspect, the invention provides a method of treating a patient diagnosed with an immunoinflammatory disorder by administering to the patient an SSRI (or an analog thereof or a metabolite thereof) in an amount and for a duration sufficient to treat the patient.

The invention also features a package that includes (i) an SSRI (or an analog thereof or a metabolite thereof), and (ii) instructions for administering the SSRI to a patient diagnosed with an autoimmune disorder.

In the next aspect, the invention presents a pharmaceutical composition containing an SSRI (or its analog or its metabolite) and another compound selected from the group consisting of: xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, nonsteroidal calcineurin inhibitor, vitamin D analog, psoralen, retinoid and 4-aminosalicylic acid.

The invention provides a method of identifying combinations of compounds useful for preventing the secretion of proinflammatory cytokines in a patient in need of such treatment by: (a) contacting the cells in vitro with an SSRI (or its analog or its metabolite) and the candidate compound, and (b) determining whether the combination of an SSRI and a candidate compound reduces cytokine levels in blood cells stimulated to secrete cytokines, compared to cells exposed to the SSRI but not to the candidate compound or to cells exposed to the candidate compound but not interaction with an SSRI, wherein a reduction in cytokine levels identifies the combination as useful for the treatment of a patient in need of such treatment.

Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms including isomers such as the corresponding diastereomers and enantiomers, salts, esters, solvates and polymorphs, as well as racemic mixtures and pure isomers of the compounds described herein.

"SSRI" refers to any member of a class of compounds that (i) inhibits serotonin uptake by neurons in the central nervous system, (ii) has an inhibition constant (Ki) of 10 nM or less, and (iii) selectivity for serotonin about the nanonorpinephedrine ratio (i.e., ratio Ki(norpineferdine) to Ki(serotonone) is greater than 100). Typically, SSRIs are given in doses greater than 10 mg per day when used as antidepressants. Exemplary SSRIs for use in the invention are described herein.

"Corticosteroid" refers to a natural or synthetic steroid hormone that can be derived from cholesterol and is characterized by a hydrated cyclopentaneperhydro-phenanthrene ring system. Natural corticosteroids are generally obtained from the adrenal cortex. Synthetic corticosteroids can be halogenated. Examples of corticosteroids are shown here.

"Nonsteroidal immunophilin-dependent immunosuppressant" or "NsIDI" means a nonsteroidal agent that reduces proinflammatory cytokine production or secretion, binds immunophilin, or causes a reduction in the anti-inflammatory response. NsIDIs include calcineurin inhibitors such as cyclosporine, tacrolimus, ascomycin, pimecrolimus, as well as other agents (peptides, peptide fragments, chemically modified peptides or peptide mimetics) that inhibit calcineurin phosphonate activity. NsIDIs also include repamycin (sirolimus) and everolimus, which bind to the FK5065-binding protein, FKBP-12, block antigen-induced white blood cell proliferation and cytokine secretion.

"Low dose" means at least 5% less (eg, at least 10%, 20%, 50%, 80%, 90% or even 95%) than the lowest standard recommended dose of a particular compound formulated for a given route of administration for the treatment of any human disease or condition. For example, a low-dose corticosteroid formulated for inhalation will be different from a low-dose corticosteroid formulated for oral administration.

"High dose" means at least 5% (eg, at least 10%, 20%, 50%, 100%, 200% or even 300%) greater than the highest standard recommended dose of a particular compound for the treatment of a human disease or condition.

"Intermediate dose" refers to a dose between a low dose and a high dose.

"Dose equivalent to a dose of prednisolone" means a dose of corticosteroid that, in combination with a given dose of an SSRI or its analog or its metabolite, produces the same anti-inflammatory effect in a patient as a dose of prednisolone in combination with that dose.

"Treatment" means the administration or prescription of a pharmaceutical preparation for the treatment or prevention of an immunoinflammatory disease.

"Patient" means any animal (eg human). Other animals that can be treated using the methods, preparations and kits of the invention are: horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, fish and birds. In one embodiment of the invention, the patient is a subject for the treatment described herein who does not have clinical depression, anxiety or panic disorder, attention deficit disorder, borderline personality disorder, sleep disorder, headache, premenstrual syndrome, irregular heartbeat, schizophrenia, Tourette's syndrome, or phobias.

"Sufficient amount" means the amount of a compound in a combination of the invention necessary for the treatment or prevention of an immunoinflammatory disease in a clinically relevant manner. Sufficient amounts of an active compound used in the practice of this invention for the therapeutic treatment of conditions caused by or contributing to an immunoinflammatory disease vary depending on the route of administration, age, body weight, and general health of the patient. Ultimately, the prescriber will decide on the appropriate amount and dosage regimen. Additionally, an effective amount may be an amount of a compound in a combination of the invention that is safer and more effective for the treatment of a patient having an immunoinflammatory disease than each individual agent given alone, as determined and approved by a regulatory agency (such as the U.S. Food and Drug Administration).

"More effective" means that the treatment shows greater efficacy or is less toxic, safer and more convenient, or cheaper than another treatment with which it is compared. Efficacy can be measured by an expert using a standard method suitable for a given indication.

The term "immunoinflammatory disorder" encompasses a variety of conditions including autoimmune diseases, proliferative skin diseases, and inflammatory dermatoses. Immunoinflammatory disorders result in the destruction of healthy tissue by the inflammatory process, disturbed regulation of the immune system and unwanted cell proliferation. Examples of immunoinflammatory disorders are: acne vulgaris, acute respiratory distress syndrome, Addison's disease, allergic rhinitis, allergic intraocular inflammatory disorders, ANCA-associated vasculitis of small vessels, ankylosing spondylitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, Bechet's disease, Bell's palsy, bullous pemphigoid, cerebral ischemia, chronic obstructive pulmonary disease, Cogan syndrome, contact dermatitis, COPD, Crohn's disease, Cusging syndrome, dermatoioositis, diabetes mellitus, discoid lupus erythematosus, eosinophilic fascitis, erythema nodusum, exfoliative dermatitis, fibromyalgia , focal glomerulosclerosis, large cell arterioles, gout, arthritis caused by gout, transplant rejection disease, hand eczema, Henoch-Schonlein purpura, herpes gestationis, hirsuitism, idiopathic kerato-scleritis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, inflammatory bowel or gastrointestinal nor disorder, inflammatory dermatosis, ringworm, lupus nephritis, lymphomatous tracheobronchitis, macular edema, multiple sclerosis, myasthenia gravis, myositis, osteoarthritis, pancreatitis, pemphigoid gestatinosis, pemphigus vulgaris, polyarteritis nodosis, polymyalgia rheumatica, pruritus of scrotum, pruritis/inflammation, psoriasis, psoriatic arthritis, rheumatoid arthritis, relapsing polychondritis, rosacea due to sarcoidosis, rosacea due to scleroderma, rosacea due to Sweer syndrome, rosacea due to systemic lupus erythematosus, rosacea due to utricaria, rosacea due to pain associated with zoster, sarcoidosis, scleroderma, segmental glomerulosclerosis, septic shock syndrome, shoulder tendinitis or bursitis, Sjorgen's syndrome, Still's disease, shock-induced brain cell death, Sweet's disease, systemic lupus erythematosus, systemic sclerosis, Takayasu's arthritis, transient arteritis, toxic epidermal necrosis, type-1 diabetes, ulcerative colitis, uveitis, vasculitis tis and Wegener's granulomatosis.

"Nondermal inflammatory disorder" includes, for example, rheumatoid arthritis, inflammatory bowel disease, and chronic obstructive pulmonary disease.

"Dermal inflammatory disorder" or "inflammatory dermatosis" includes, for example, pphoria, acute febrile neurophilic dermatosis, eczema (eg, asthetic eczema, dyshidrotic eczema, vesicular palmoplantar eczema), balanitis circumscripta plasmacellularis, balanoposthitis, Bechet's disease, erythema anus, erythema multiforme, anus granuloma, lichen nitidus, lichen planus, lichen sclerosus and atropicus, chronic lichen simplex, lichen spinulosus, nummular dermatitis, pyroderma gangrene, sarcoidosis, subcorneal pustular dermatosis, utricaria and transient acantholytic dermatosis.

"Proliferative skin disease" means a benign or malignant disease characterized by accelerated cell division in the epidermis or dermis. Examples of proliferative skin disease are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinoma of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant keratosis, premalignant keratosis, acne and seborrheic dermatitis.

As one skilled in the art will recognize, a particular disease, disorder or condition may be characterized by proliferative skin disease and inflammatory dermatosis. An example of such a disease is psoriasis.

"Sustained release" or "controlled release" means that the therapeutically active component is released from the formulation at a controlled rate so that a therapeutically suitable blood level (but below the toxic level) of the component is maintained over an extended period of time ranging from, e.g., 12 to about 24 hours and thereby enable, for example, a dose cycle of 12 to 24 hours.

In the generic description of the compounds of the invention, the number of atoms of a particular type in a substituted group is generally given in rapson, eg an alkyl group containing from 1 to 7 carbon atoms or C1-7alkyl. Such a group statement indicates a specific group that can have any integer number of atoms in the given range. For example, an alkyl group of 1 to 7 carbon atoms includes C1, C2, C3, C4, C5, C6 and C7. C1-7heteroalkyl, for example, contains 1 to 7 oleic atoms and one or more heteroatoms. Other atom numbers of other atom types may be indicated in a similar manner.

"Acyl" means a chemical residue of the formula R-C(O)- wherein R is selected from C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C2-6heterocyclyl, C6-12aryl, C7-14alkaryl, C3-10alkheterocyclyl, or C1-7heteroalkyl .

"Alkoxy" refers to a chemical substituent of the formula -OR wherein R is selected from C1-7alkyl, C2-7alkenyl, C2-7alkynyl, C2-6heterocyclyl, C6-12aryl, C7-14alkaryl, C3-10alkheterocyclyl, or C1-7heteroalkyl.

"Aryloxy" means a chemical substituent of the formula -OR in which R is a C6-12 aryl group.

"C6-12aryl" refers to an aromatic group having a ring system containing carbon atoms with conjugated �-electrons (eg, phenyl). An aryl group has from 6 to 12 carbon atoms. Aryl groups may include a monocyclic, bicyclic or tricyclic ring wherein each ring is preferably five or six membered. The aryl group can be substituted or unsubstituted. Examples of substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted nitro, disubstituted amino, and quaternary amino.

"Amido" refers to a chemical substituent of the formula -NRR', in which the drier is part of an amide bond (e.g. -C(O)-NRR') and in which R and R' are each optionally C1-7alkyl, C2-7alkenyl, C2- 7alkynyl, C2-6heterocyclyl, C6-12aryl, C7-14alkaryl, C3-10alkheterocyclyl, and C1-7heteroalkyl, or -NRR' forms a C2-6 heterocyclic ring, which is as defined above, and contains at least one nitrogen atom as which include piperidino, morpholino and azabicyclo.

"Halide" or "halo" means bromine, chlorine, iodine or fluorine.

The term "pharmaceutically acceptable salt" represents salts that are within the scope of medical evaluation suitable for use in human tissue and lower animal tissue, without undesirable toxicity, irritation, allergic response and the like, and have a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Salts can be prepared in situ during final isolation and purification or in a separate step by reaction of a free base functional group with a suitable organic acid. Representatives of salts formed by acid addition are acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, isothionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate and the like. Representatives of alkali metal salts are sodium, lithium, potassium, calcium, magnesium as well as non-toxic ammonium, quaternary ammonium salts and amine cations including but not limited to ammonium, tetramethylamino, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

Compounds useful in the invention include those described include those described herein in any of their pharmaceutically acceptable forms including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates and polymorphs thereof as well as racemic mixtures of pure isomers of the compounds described herein. For example, "paroxetine" refers to the free base as well as any corresponding pharmaceutically acceptable salt (eg, paroxetine maleate, paroxetine hydrochloride hemihydrate, and paroxetine mesylate).

Other features and advantages of the invention will be apparent from the following detailed description and from the claims.

Detailed description

The invention provides methods, compositions and kits for administering an effective amount of an SSRI or a corresponding analog or metabolite, alone or in combination with a corticosteroid or other compound for the treatment of immunoinflammatory disorders.

In one embodiment of the invention, treatment of an immunoinflammatory disorder is performed by administering an SSRI (or a corresponding analog or metabolite) and a corticosteroid to a patient in need of such treatment.

The invention is described in more detail below.

Selective serotonin uptake inhibitors

The methods, compositions and kits of the invention employ an SSRI or a structural or functional analog thereof. Suitable SSRIs include cericlamin (eg, cericlamin hydrochloride), citalopram (eg, citalopram hydrobromide), clovoxamine, cyanodothiepine, dapoxetine, escitalopram (escitalopram oxalate), femoxetine (eg, femoxetine hydrochloride), fluoxetine (eg, fluoxetine hydrochloride); fluvoxamine (eg fluvoxamine maleate); ifoxetine; indalpine (eg indalpine hydrochloride); indeloxazin (eg indeloxazin hydrochloride); litoxetine; milnacipran (eg, milnacipran hydrochloride); paroxetine (eg, paroxetine hydrochloride bemihydrate; paroxetine maleate; paroxetine mesylate); sertraline (eg, sertraline hydrochloride); tametraline hydrochloride; viqualin and zimeldine (eg zimeldine hydrochloride).

Ceriklamin

Ceriklamina has the following structure:

[image]

Structural analogues of ceriklamin are those with the formula:

[image]

as well as pharmaceutically acceptable salts, wherein R1 is C1-C4 alkyl, and R is H or C1-C4 alkyl, R3 is H, C1-C4 alkyl, C2-C4 allenalkyl, phenylalkyl or cycloalkylalkyl with 3 to 6 carbons in the ring, alkanoyl, phenylalkanoyl or cycloalkylcarbonyl having 3 to 6 carbons in the ring or R2 and R2 form together with the nitrogen atom to which they are attached heterocyclic saturated with 5 to 7 attached rings, oxygen and sulfur or nitrogen, and this nitrogen heteroatom can carry C2-4alkyl .

Examples of analogues of the ceriklamisin structure are:

2-methyl-2-amino-3-(3,4-dichlorophenyl)-proanol,

2-pentyl-2-amino-3-(3,4-dichlorophenyl)-propanol,

2-methyl-2-methylamino-3-(3,4-dichlorophenyl)-propanol,

2-methyl-2-dimethylamino-3-(3,4-dichlorophenyl)-propanol,

and their pharmaceutically acceptable salts.

Citalopram

Citalopram has the following structure:

[image]

Structural analogues of citalopram have the formula:

[image]

as well as pharmaceutically acceptable salts, wherein each R1 and R2 is independently selected from the following group: bromine, Cl, fluoro, trifluoromethyl, cyano, and R-CO-, wherein R is C1-C4 alkyl.

Examples of structural analogues of citalopram (which are therefore structural analogues of SSRIs according to the invention) are: 1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bromophthalan, 1-(4'-chlorophenyl)-1-(3 -dimethylaminopropyl)-5-chlorophthalan, 1-(4'-bromophenyl)-1-(3-dimethylaminopropyl)-5-chlorophthalan, 1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)- 5-chlorophthalan, 1-(4'-chlorophenyl)-1-(3-dimethylaminopropyl)-5-trifluoromethyl-phthalan, 1-(4'-bromophenyl)-1-(3-dimethylaminopropyl)-5-trifluoromethyl-phthalan, 1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-trifluoromethyl-phthalan, 1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-fluorophthalan, 1-(4'- chlorophenyl)-1-(3-dimethyl-aminopropyl)-5-fluorophthalan, 1-(4'-chlorophenyl)-1-(3-dimethylaminopropyl)-5-phthalancarbonitrile, 1-(4'-fluoro-phenyl)-1 -(3-dimethylaminopropyl)-5- phthalancarbonitrile, 1-(4'-cyanophenyl)-1-(3-dimethylaminopropyl)-5- phthalancarbonitrile, 1-(4'-cyanophenyl)-1-(3-dimethylaminopropyl)-5 -chlorophthalan, 1-(4'-cyanophenyl)-1-(3-dimethylaminopropyl)-5-trifluoromethylphthalan, 1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl) propyl)-5-phthalenecarbonitrile, 1-(4'-chloroenyl)-1-(3-dimethylaminopropyl)-5-propionylphthalene, 1-(4-(chlorophenyl)-1-(3-dimethylaminopropyl)-5-propionylphthalene, and their pharmaceutically acceptable salts.

Clovoxamine

Clovoxamine has the following structure:

[image]

Structural analogues of clovoxamine are those with the formula:

[image]

as well as pharmaceutically acceptable salts, wherein Hal is chlorine, bromine or fluorine, and R is cyano, methoxy,

ethoxy, methoxymethyl, ethoxymethyl, methoxyethoxy or cyenomethyl.

Examples of structural analogues of clovoxamine are: O-(2-aminoethyl)oxime, 4'-chloro-5-(2-methoxy-ethoxy)valerophenone-O-(2-aminoethyl)oxime, 4'-chloro-6-methoxycaprofenone-O -(2-aminoethyl)-oxime, 4'-chloro-6-ethoxycaprofenone-O-(2-aminoethyl)oxime, 4'-bromo-5-(2-methoxyethoxy)valerophenone-O-(2-aminoethyl)oxime; 4'-bromo-5-methoxyvalerophenone-O-(2-aminoethyl)oxime; 4'-chloro-6-cyano-caprofenone-O-(2-aminoethyl)oxime, 4'-chloro-5-cyanovalerophenone-O-(2-aminoethyl)oxime, 4'-bromo-5-cyanovalero-phenone-O -(2aminoethyl)oxime, and their pharmaceutically acceptable salts.

Femoxetine

Femoxetine has the following structure:

[image]

Structural analogues of femoxetine are those with the formula:

[image]

in which R1 represents a C1-4alkyl or C2-4alkynyl group or a phenyl group that may be substituted with C1-4alkyl, C1-4alkylthio, C1-4alkosy, bromine, chlorine, fluorine, nitro, acylamino, methanesulfonyl, methylenedioxy or tetrahydronaphthyl, R2 represents C1-4 alkyl or C2-4 alkynyl group and R3 represents hydrogen, C1-4 alkyl, C1-4 lkoxy, trifluoroalkyl, hydroxy, bromine, chlorine, fluorine, methylthio or aralkyloxy.

Examples of structural analogs of femoxetine are shown in Examples 7-67 of U.S. Pat. Patent no. 3,912,743, and incorporated herein by reference.

Fluoxetine

Fluoxetine has the following structure:

[image]

Structural analogues of clovoxamine are those with the formula:

[image]

as well as pharmaceutically acceptable salts, wherein each R 1 is independently hydrogen or methyl, R is naphthyl or

[image]

where each R 2 and R 3 are independently bromine, chlorine, fluorine, trifluoromethyl, C 1-4 alkyl, C 1-3 alkoxy, or C 3-4 alkenyl, and each n and m are independently 0, 1 or 2. When R is naphthyl, it may be α-naphthyl or β-Naphthyl.

Examples of structural analogs of fluoxetine are: 3-(p-isopropoxyphenoxy)-3-phenylpropylamine-methanesulfonate, N,N-dimethyl 3-(3',4'-dimethoxyphenoxy)-3-phenylpropylamine-p-hydroxybenzoate, N,N-dimethyl -3-(β-naphthoxy)-3-phenylpropylamine-bromide, N,N-dimethyl 3-(β-naphthoxy)-3-phenyl-1-methylpropyl-amine-iodide, 3-(2'-methyl-4' ,5'-dichlorophenoxy)-3-phenylpropylamine-nitrates, 3-(p-t-butylphenoxy)-3-phenylpropylamine-glutarate, N-methyl 3-(2'-chloro-p-tolyloxy)-3-phenyl-1 -methylpropylamine lactate, 3-(2',4'-dichlorophenoxy)-3-phenyl-2methylpropylamine citrate, N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate, N-methyl-3-(p-tolyl-oxy)-3-phenylpropylamine-sulfate, N,N-dimethyl-3-(2',4'-difluorophenoxy)-3-phenylpropyl-amine-2,4dinitrobenzoate, 3- (o-ethylphenoxy)-3-phenylpropylamine dihydrogen-phosphate, N-methyl 3-(2'-chloro-4'-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate, N,N-dimethyl 3-(2'- alkyl-4'-fluorophenoxy)-3-phenyl-propylamine-succinate, N,N-dimethyl-3-(o-isopropoxyphenoxy)-3-phenyl-propylamine-phenylacetate, N,N- dimethyl-3-(o-bromophenoxy)-3-phenyl-propylamine-β-phenylpropionate, N-methyl-3-(p-iodophenoxy)-3-phenyl-propylamine-propiolate, and N-methyl-3-(3- n-propylphenoxy)-3-phenyl-propylamine-decanoate.

Fluvoxamine

Fluvoxamine has the following structure:

[image]

Structural analogues of clovoxamine are those with the formula:

[image]

as well as pharmaceutically acceptable salts, wherein R is cyano, cyanomethyl, methoxymethyl or ethoxymethyl.

Indalpine

Indalpin has the following structure:

[image]

Structural analogues of clovoxamine are those with the formula:

[image]

as well as pharmaceutically acceptable salts, wherein each R1 is independently a hydrogen atom, a C1-C4 alkyl group or an aralkyl group in which the alkyl has from 1 to 2 carbon atoms, R2 is hydrogen, C1-4alkyl, C1-4alkyl or C1-4alkylthio, chlorine, bromine, fluorine, trifluoromethyl, nitro, hydroxy or amino, and amino can be substituted by one or more C1-C4 alkyl groups, an acyl group or a C1-C4 alkylsulfonyl group, A represents -CO or -CH2-group and n is not 0, 1 or 2.

Examples of structural analogues of indalpine are: indolyl-3-(piperidinyl-4-methyl)-ketones, (methoxy-5-indolyl-3)(piperidinyl-4-methyl)-ketones, (chloro-5-indolyl-3)(piperidinyl -4-methyl)-ketones; (indolyl-3)-1-(piperidinyl-4)-3-propanones, indolyl-3-piperidinyl-4-ketones; (methyl-1-indolyl-3)(piperidinyl-4-methyl)-ketones, (benzyl-1-indolyl-3)(piperidinyl-4-methyl)-ketones; [(Methoxy-5-indolyl-3)-2ethyl]-piperidine, [(methyl-1-indolyl-3)-2-ethyl]-4-piperidine, [(indolyl-3)-2-ethyl]-4- piperidine; (indolyl-3-methyl)-4-piperidine, [(chloro-5-indolyl-3)-2-ethyl-4-piperidine, [(indolyl-b3)-3-propyl]-4piperidine, [(benzyl-1 -indolyl-3)-2-ethyl]-4-piperidine, and their pharmaceutically acceptable salts.

Indeloxazin

Indeoxazin has the following structure:

[image]

Structural analogues of clovoxamine are those with the formula:

[image]

as well as pharmaceutically acceptable salts, wherein R1 and R3 each represent a hydrogen atom, C1-C4 alkyl or phenyl, R2 is hydrogen, C1-4alkyl, C4-7cycloalkyl, phenyl or benyl; one of the drawn drugs indicates a single bond and the other indicates a double bond, or mixtures of their tauromers.

Examples of structural analogues of indeoxazine are: 2-(7-indenyloxymethyl)-4-isopropylmorpholine; 4-butyl-2-(7-indenyloxymethyl)morpholine; 2-(7-indenyloxymethyl)-4-methylmorpholine; 4-ethyl-2-(7-indenyloxy-methyl)morpholine, 2-(7-indenyloxymethyl)-morpholine; 2-(7-indenyloxymethyl)-4-propylmorpholine; 4-cyclohexyl-2-(7-indenyloxymethyl)morpholine; 4-benzyl-2-(7-indenyloxymethyl)-morpholine; 2-(7-indenyloxymethyl)-4-phenylmorpholine; 2-(4-indenyloxymethyl)morpholine; 2-(3-methyl-7-indenyloxymethyl)-morpholine; 4-isopropyl-2-(3-methyl-7-indenyloxymethyl)morpholine; 4-isopropyl-2-(3-methyl-4-indenyloxymethyl)morpholine; 4-isopropyl-2-(3-methyl-5-indenyloxymethyl)morpholine; 4-isopropyl-2-(1-methyl-3-phenyl-6-indenyloxymethyl)morpholine; 2-(5-indenyloxymethyl)-4-isopropylmorpholine, 2-(6-indenyloxymethyl)-4-isopropylmorpholine; and 4-isopropyl-2-(3-phenyl-6-indenyloxymethyl)morpholine and their pharmaceutically acceptable salts.

Milnacipram

Milnacipram has the following structure:

[image]

Structural analogues of milnacipram are those with the formula:

[image]

as well as pharmaceutically acceptable salts, wherein each R is independently hydrogen, bromine, chlorine, fluorine, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro or amino, each R 1 and R 2 independently represents hydrogen, C 1-4 alkyl, C 6-12 aryl, C7-14alkylaryl, which may be substituted, preferably in the para position with bromine, chlorine or fcupor or R1 and R2 together form a 5- or 6-membered heterocyclyl with adjacent nitrogen atoms, R3 and R4 represent hydrogen or a C1-4alkyl group or R3 and R4 forms with the adjacent nitrogen atom a heterocyclyl that has 5 or 6 members and may contain an additional heteroatom selected from nitrogen, sulfur and oxygen.

Examples of structural analogues of milnacipram are: 1-phenyl 1-aminocarbonyl-2-dimethylamino-methyl-cyclopropane, 1-phenyl-1-dimethylaminocarbonyl-2-dimethylaminomethyl-cyclopropane, 1-phenyl 1-ethyl-aminocarbonyl-2-dimethylaminomethyl-cyclopropane, 1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclo-propane, 1-phenyl-2-dimethylaminomethyl-N-(4'-chlorophenyl)cyclopropane-carboxamides, 1-phenyl-2-dimethyl-aminomethyl-N-(4 '-chlorobenzyl)cyclopropane-carboxamides, 1-phenyl-2-dimethylaminomethyl-N-(2-phenylethyl)cyclopropane-carboxamides, (3,4-dichloro-1-phenyl)-2-dimethylaminomethyl-N,N-dimethylcyclopropane-carboxamides , 1-phenyl1-pyrrolidinocarbonyl-2-morpholinomethyl-cyclopropane, 1-p-chlorophenyl-1-amino-carbonyl-2-aminomethyl-cyclopropane, 1-o-chlorophenyl-1-aminocarbonyl-2-dimethylaminomethyl-cyclopropane, 1-p -hydroxyphenyl-1-aminocarbonyl-2-dimethylaminomethyl-cyclopropane, 1-p-nitrophenyl-1-dimethylamino-carbonyl-2-dimethylaminomethyl-cyclopropane, 1-p-aminophenyl-1-dimethylaminocarbonyl-2-dimethylamino-methyl cyclopropane, 1- p-tolyl-1-methylaminocarbonyl-2- dimethylaminomethyl-cyclopropane, 1-p-methoxy-phenyl-1-aminomethylcarbonyl-2-aminomethyl-cyclopropane and their pharmaceutically acceptable salts.

Paroxetine

Paroxetine has the following structure:

[image]

Structural analogues of paroxetine are those with the formula:

[image]

as well as pharmaceutically acceptable salts, wherein each R 1 represents hydrogen or a C 1-4 alkyl group, and the fluorine atom may be in any available position.

Sertraline

Sertraline has the following structure:

[image]

Structural analogues of paroxetine are those with the formula:

[image]

where R1 is selected from the group consisting of hydrogen and C1-4alkyl, R2 is C1-4alkyl, X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, C1-3alkoxy and cyano, and W is trifluoromethyl and C1-3Alkoxy. Preferably, sertaline analogs are cis-configurational isomers. The term "cis-isomer" refers to the relative position of NR 1 R 2 and the phenyl group on the cyclohexane ring (ie, both are located on the same side of the ring). As the 1- and 4-carbons are asymmetrically substituted, each cis-compound has two optically active enantiomeric forms designated (according to carbon 1) as cis-(1R) and cis-(1S) enantiomers.

The following compounds are particularly useful as (1S)-enantiomeric or (1S)(1R) racemic forms, and their pharmaceutically acceptable salts: cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4 -tetrahydro-1-naphthalene-amine; cis-N-methyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine; cis-N-methyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine; cis-N-methyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4 tetrahydro-1-naphthaleneamine; cis-N-methyl-4-(3-trifluoromethyl-4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine; cis-N,N-dimethyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine; cis-N,N-dimethyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine; and cis-N-methyl-4-(4-chlorophenyl)-7-chloro-1,2,3,4-tetrahydro-1-naphthaleneamine. Also of interest is the (1R)-enantiomer cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine.

Zimeldin

Zimeldin has the following structure:

[image]

Structural analogues of paroxetine are those with the formula:

[image]

as well as its pharmaceutically acceptable salts, wherein the pyridine nucleus is attached in the ortho-, mea- or para-position to the adjacent carbon atom and R1 is selected from the group consisting of H, chlorine, fluorine and bromine.

Examples of zimeldin analogs are: (E)- and (Z)- 3-(4'-bromophenyl-3-(2"pyridyl)dimethylallylamine, 3-(4'-bromophenyl)-3-(3"-pyridyl)dimethylallylamine, 3-(4'-bromophenyl)-3-(4"-pyridyl)-dimethylallylamine, and their pharmaceutically acceptable salts.

Structural analogs of any of the above SSRIs are considered SSRI analogs herein and thus may be used in the methods, compositions, and kits of the invention.

Metabolites

Pharmacologically active metabolites of any of the foregoing SSRIs may also be used in the methods, compositions and kits of the invention. Examples of metabolites are didesmethylcitalopram, desmethylcitalopram, desmethylsertraline and norfluoxetine.

Analogues

Functional analogs of SSRIs can also be used in the methods, compositions and kits of the invention. Examples of functional SSRI analogs are shown below. One class of SSRI analogs are the SNRIs (selective serotonin norepinephrine reuptake inhibitors), which include velafaxine and duloxetine.

Velafaxine

Velafaxin has the following structure:

[image]

Structural analogues of velafaxine are those with the formula:

[image]

as well as its pharmaceutically acceptable salts, where A is a residue of the following formula:

[image] or [image]

in which the dashed line represents possible unsaturation, R1 is hydrogen or alkyl, R2 is C1-4alkyl, formyl or alkanoyl, R3 is hydrogen or C1-4alkyl, R5 and R6 are independently hydrogen, hydroxy, C1-4alkyl,, C1-4alkoxy, C1-4alkanoyloxy, cyano, nitro, alkylmercapto, amino, C1-4alkylamino, diallylamino, C1-4alanamido, halogen, trifluoromethyl or methylenedioxy taken together, and n is 0, 1, 2, 3, or 4.

Duloxetine

Duloxetine has the following structure:

[image]

Structural analogs of duloxetine are compounds described by the formula shown in U.S. Patent No. 4,956,388, incorporated herein by reference.

Other SSRI analogues are: 1,2,3,4-tetrahydro-N-methyl-4-phenyl-lnaphtylamine hydrochloride; 1,2,3,4-tetrahydro-N-methyl-4-phenyl-(E)-1-naphthylamine hydrochloride; N,N-dimethyl-1-phenyl-1-phthalanpropylamine hydrochloride; gamma-(4-(trifluoromethyl)phenoxy)-benzenepropanamine hydrochloride; BP 554; CP 53261; O-des-methylvenlafaxine; Wy 45,818; WY 45.88 1; N-(3-fluoropropyl)paroxetine; and Lu 19005

Standard recommended doses

Standard recommended doses of some SSRIs are shown below in Table 1. Other standard doses are shown, for example, in the Merck Manual of Diagnosis & Therapy (17, ed. Ed. MH Beers et al., Merck & Co.) and in the Physicians' Desk Reference 2003 (57th ed. Medical Economics Staff et al., Medical Economics Co., 2002).

Table 1

[image]

Corticosteroids

If it is desirable in the method of the invention, one or more corticosteroids can be given together with the SSRI, or in the preparation of the invention it can be formulated with an SSRI or its analog or metabolite. Suitable corticosteroids include the following: 11-alpha,17-alpha,21-trihydroxypregn-4-ene-3,20-dione, 11-beta,16-alpha,17,21-tetrahydroxypregn-4-ene-3,20-dione , 11-beta,16-alpha,17,21-tetrahydroxypregn-1,4-dien-3,20-dione, 11-beta,17-alpha,21-trihydroxy-6-alpha-methylpregn-4-ene-3 ,20-dione, 11-dehydrocorticosterone, 11-deoxycortisol, 11-hydroxy-1,4-androstadien-3,17-dione, 11-ketotestosterone, 14-hydroxy-androst-4-ene-3,6,17 -trione, 15,17-dihydroxyprogesterone, 16-methylhydrocortisone, 17,21-dihydroxy-16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione, 17-alpha-hydroxypregn-4- ene-3,20-dione, 17-alpha-hydroxy-roxypregnenolone, 17-hydroxy-16-beta-methyl-5-beta-pregn-9(11)-ene-3,20-dione, 17-hydroxy-4 ,6,8(14)-pregnatriene-3,20-dione, 17-hydroxypregna-4,9(11)-dien-3,20-dione, 18-hydroxycorticosterone, 18-hydroxycortisone, 18-oxocortisol, 21 -deoxyaldosterone, 21-deoxycortisone, 2-deoxy-ecdysone, 2-methylcortisone, 3-dehydroecdysone, 4-pregnene-17-alpha,20-beta,21-triol-3,11-dione, 6,17,20-trihydroxypregn -4-en-3-one, 6-alpha -hydroxycortisol, 6-alpha-fluoroprednisolone, 6-alpha-methyl-prednisolone, 6-alpha-methylprednisolone-21 acetate, 6-alpha-methylprednisolone-21-hemisuccinate sodium salt, 6-beta-hydroxycortisol, 6-alpha,9- alpha-difluoroprednisolone-21-acetate-17-butyrate, 6-hydroxycorti-costerone, 6-hydroxydexamethasone, 6-hydroxyprednisolone, 9-fluorocortisone, alclomethasone dipropionate, aldosterone, algestone, alfaderm, amadinone, amcinonide, anagestone, androstenedione, anecortav-acetate, beclomethasone, beclomethasone-dipropionate, beclomethasone-dipropionate mono-hydrate, betamethasone-17-valerate, betamethasone sodium acetate, betamethasone sodium phosphate, betamethasone-valerate, bolasterone, budesonide, calusterone, chlormadinone, chlorprednisone, chlorprednisone-acetate , cholesterol, clobetasol, clobetasol-propionate, clobetazone, clocortolone, clocortolone-pivalate, clogestone, cloprednol, corticosterone, cortisol, cortisol-acetate, cortisone-butyrate, cortisol-cypionate, cortisol-octanoate, cortisol sodium phosphate, cortisol sodium succinate , cortisol-va lerate, cortisone, cortisone-acetate, cortodoxone, daturaolone, deflazacort, 21-deoxycortisol, dehydroepian-drosterone, delmadinone, deoxycorticosterone, deprodone, descinolone, desonide, desoxymethasone, dexaphene, dexamethasone, dexamethasone-21-acetate, dexamethasone-acetate, dexamethasone sodium phosphate, dicklorison, diflorasone, diflorasone-diacetate, diflucortolone, dihydroelatericin a, domoprednate, doxibetazol, ecdysone, ecdysterone, endrisone, enoxolone, flucinolone, fludrocortisone, fludrocortisone-acetate, flugestone, flumetasone, flumetasone-pivalate, flumoxonide, flunisolide, fluocinolone , fluocinolone-acetonide, fluocinonide, 9-fluorocortisone, fluocortolone, fluorohydroxyandrostenedione, fluorometholone, fluorometholone-acetate, fluoxymesterone, flupredniden, fluprednisolone, flurandrenolide, fluticasone, fluticasone-propionate, formebolone, formestan, formocortal, gestonoron, gliderinin, halcinonide, hyrcanoside , halomethasone, halopredone, haloprogesterone, hydrocortisone-cypionate, hydrocortisone, hydrocortisone-21-bu tirate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone hemisuccinate, hydrocortisone probutate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone valerate, hydroxyprogesterone, inocosterone, isoflupredone, isoflupredone acetate , isopredniden, mechlorisone, mecortolone, medrogestone, medroxyprogesterone, medrizone, megestrol, megestrol-acetate, melengestrol, meprednisone, methandrostenolone, methylprednisolone, methylprednisolone-aceponate, methylprednisolone-acetate, methylprednisolone-hemisuccinate, methylprednisolone sodium succinate, methyltestosterone, metriboIon, mometasone, mometasone - furoate, mometasone furoate monohydrate, nison, nomegestrol, norgestomet, norvinisterone, oxymesterone, paramethasone, paramethasone-acetate, ponasterone, prednisolate, prednisolone, prednisolone-21-hemisuccinate, prednisolone-acetate, prednisolone-farnesylate, prednisolone-hemisuccinate, prednisolone-21( beta-D-glucuronide), prednisolone n-metasulfobenzoate, prednisolone sodium phosphate, prednisolone-steaglate, prednisonol-tebutate, prednisonol-tetrahydrophthalate, prednisone, prednival, predniliden, pregne-nolone, procinonide, tralonide, progesterone, promegestone, rapontisterone, rimexolone, roxibolone, rubrosterone, stizophiline, thixocortol, thopteron, triamcinolone, triamcinolone-acetonide, triamcinolone-acetonide-21-palmitate, triamcinolone-diacetate, triamcinolone-hexacetonide, trimegestone, turkesterone, and wortmannin.

Standard recommended doses for various steroid/disease combinations are shown below in Table 2.

Table 21 - Standard recommended doses of corticosteroids

[image]

Other standard recommended doses of corticosteroids are presented in, for example, the Merck Manual of Diagnosis & Therapy (17th ed. MH Beers et al., Merck & Co.) and in the Physicians' Desk Reference 2003 (57th ed. Medical Economics Staff et al ., Medical Economics Co., 2002). In one embodiment, the dose of corticosteroid is administered at a dose equivalent to a dose of prednisolone, as defined herein. For example, a low dose of corticosteroid can be considered as a dose equivalent to a low dose of prednisolone.

Modulators of steroid receptors

Steroid receptor modulators (eg, antagonists and agonists) can be used as a substitute for or in addition to corticosteroids according to the methods, kits and kits of the invention. Therefore, in one aspect, the invention presents a combination of an SSRI (or its analog or its metabolite) and a glucocorticoid receptor modulator and another steroid receptor modulator, and methods of treating inflammatory disorders with them.

Glucocorticoid receptor modulators that can be used in the methods, kits and kits of the invention include the compounds described in Patent no. 6,380,207, 6,380,223, 6,448,405, 6,506,766, and 6,570,020, U.S. Patent no. 20030176478, 20030171585, 20030120081, 20030073703,2 002015631, 20020147336, 20020107235, 20020103217, and 20010041802, and PCT publication no. WO 00/66522, all of which are incorporated herein by reference. Other steroid receptor modulators that can be used in the methods, kits and kits of the invention of U.S. Pat. Patent no. 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, 5,693,647, 5,693,646, 5,688,810, 5,688,808, and 5,696,130, all of which are incorporated herein by reference.

Other compounds

Other compounds that can be used as a substitute or addition to a corticosteroid according to the methods, patches and kits of the invention are: A34-8441 (KaroBio adrenal cortex extract (GlaksoSmithKIine), alsactide (Aventis), amebucort (Schering AG), amelomethasone (Taisho), ATSA (Pfizer), bitolterol (Elan), CBP-2011 (InKine Pharmaceutical), cebaracetam (Novartis) CGP-13774 (Kissei), ciclesonide (Altana), cyclomethasone (Avenfis), clobetasone-butyrate (GlaksoSmithKline), cloprednol (Hoffmann- La Roche), colismycin A (Kirin), cucurbitacin E (NIH), deflazacort (Aventis), deprodone propionate (SSP), dexamethasone acefurate (Schering-Plough), dexamethasone linoleate (GlaxoSmithKIine), dexamethasone valerate (Abbott) , difluprednate (Pfizer), domoprednate (Hoffmann-La Roche), ebiratide (Aventis), etiprednol-dicloacetate (IVAKS), fluazacort (Vicuron), flumoxonide (Hoffinann-La Roche), fluocortin-butyl (Schering AG), fluocortolone monohydrate ( Schering AG), GR-250495KS (GlaxoSmithKIine), halomethasone (Novartis), halo predone (Dainippon), HYC-141 (Fidia), icometasone-enbutate (Hovione), itrocinonide (AstraZeneca), L-6485 (Vicuron), Lipocort (Draksis Health), locickorton (Aventis), meclorizon (Schering-Plough), naflocort (Bristol-Myers Squibb), NCKS-1015 (NicOx), NCKS-1020 (NicOx), NCKS-1022 (NicOx), nicocortonide (Yamanouchi), NIK-236 (Nikken Chemicals), NS-126 (SSP), Org- 2766 (Akzo Nobel), Org-6632 (Akzo Nobel), P16CM, propylmesterolone (Schering AG), RGH-1113 (Gedeon Ricbter), rofleponide (AstraZeneca), rofleponide palmitate (AstraZeneca), RPR-106541 (Aventis), RU- 26559 (Aventis), Sch-19457 (Schering-Plough), T25 (Matriks Therapeutics), TBI-PAB (Sigma-Tau), ticabesone propionate (Hoffmann-La Roche), tifluadom (Solvay), timobesone (Hoffmann-La Roche) , TSC-5 (Takeda), and ZK-73634 (Schering AG).

Therapy

The invention provides methods for preventing the secretion of proinflammatory cytokines by treating an immunoinflammatory disorder, pre-inflammatory skin disease, organ transplant rejection, or transplant rejection disease. Prevention of cytokine secretion is achieved by administering one or more SSRIs in combination, and possibly with one or more steroids. While the examples describe one SSRI and one steroid, it is understood that a combination of multiple agents is preferred. For example, methotrexate, hydroxychloroquine, and sulfasalazine are commonly given to treat rheumatoid arthritis. Additional therapies are described below.

Chronic obstructive pulmonary disease

In one embodiment, the methods, compositions and kits of the invention were used for the treatment of chronic obstructive pulmonary disease (COPD). If desired, one or more typical agents for the treatment of COPD can be used as a substitute for or in addition to a corticosteroid in the methods, preparations and kits of the invention. Such agents include xanthines (eg, theophylline), anticholinergic compounds (eg, ipratropium, triotropium), and beta receptor agonists/bronchodilators (eg, ibutyerol sulfate, bioterol mesylate, epinephrine, formoterol fumarate, isoproterenol, levabuterol hydrochloride, metaproterenol sulfate, pirbuterol acetate, salmeterol xinafonate and terbutaline). Therefore, in one embodiment, the invention presents a combination of an SSRI (or its analog or its metabolite) and a bronchodilator and a method of treating COPD with them.

Psoriasis

The methods, compositions and kits of the invention can be used for the treatment of psoriasis. If desired, one or more antipsoriatic agents that are typically used in the treatment of psoriasis can be used as a substitute or in addition to the corticosteroid methods, preparations and kits of the invention. Such agents include biologics (eg, alefacept, inflixamab, adelimumab, efalizumab, etanercept, and CDP-870), nonsteroidal calcineurin inhibitors (eg, cilosporin, tacrolimus, pimecrolimus, and ISAtx247), vitamin D analogs (eg, calcipotriene, calcipotriol), psoralens (eg methoxalen), retinoids (eg acitretin, tazoreten), DMARDs (eg methotretaxate) and anthralin. Therefore, in one embodiment, the invention presents a combination of an SSRI (or its analog or its metabolite) and an anti-psoriasis agent, and a method of treating psoriasis with them.

Inflammatory bowel disease

The methods, compositions and kits of the invention can be used for the treatment of inflammatory bowel disease. If desired, one or more agents that are typically used in the treatment of inflammatory bowel disease can be used as a substitute or in addition to the corticosteroid methods, preparations and kits of the invention. Such agents include biologics (eg, inflixamab, adelimumab, and CDP-870), nonsteroidal calcineurin inhibitors (eg, cilosporin, tacrolimus, pimecrolimus, and ISAtx247), 5-aminosalicylic acid (eg, mesalamine, sulfasalazine, balsalazide disodium, or oxalazine sodium), DMARDs (eg methotretaxate and azathioprine) and allosterone. Therefore, in one embodiment, the invention presents a combination of an SSRI (or its analog or its metabolite) and any of the aforementioned agents, and a method of treating inflammatory bowel disease with them.

Rheumatoid arthritis

The methods, compositions and kits of the invention can be used for the treatment of rheumatoid arthritis. If desired, one or more agents that are typically used in the treatment of rheumatoid arthritis can be used as a substitute or in addition to the corticosteroid methods, preparations and kits of the invention. Such agents include: NSAIDs (eg, naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylic acid (salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, yr tolmetin), COX-2 inhibitors (eg rofecoxib, celecoxib, valdecoxib, and lumiracoxib), biological agents (eg inflixamab, adelimumab, etanercept and CDP-870), non-steroidal calcinerin inhibitors ( eg cyclosporine, tacrolimus, pimecrolimus and ISAtx247), 5-aminosalicylic acid (eg mesalamine, sulfasalazine, balsalazide disodium and olsalazine sodium), DMARDs (eg methotrexate, leflunomide, minocycline, auranofin, gold sodium thiomalate, aurothioglucose, azatrioprine), hydroxychloroquine sulfate and penicillinamine. Therefore, in one embodiment, the invention shows a combination of an SSRI (or its analog or its metabolite) and any of the aforementioned agents, and a method of treating rheumatoid arthritis with them.

Asthma

The methods, compositions and kits of the invention can be used for the treatment of asthma. If desired, one or more agents that are typically used in the treatment of asthma can be used as a substitute or in addition to the corticosteroid methods, preparations and kits of the invention. Such agents include beta 2 agonist/bronchodilator/leukotriene modulators (eg, zafirlukast, montelukast, and zileuton), biologic agents (eg, omalizumab), anticholinergic compounds, xanthines, ephedrine, guaifenesin, cromolyn sodium, nedoromolin sodium, and potassium iodide. Therefore, in one embodiment, the invention provides a combination of an SSRI (or its analog or its metabolite) and any of the aforementioned agents, and methods of treating asthma with them.

Nonsteroidal immunophilin-dependent immunosuppressant

In one embodiment, the invention provides methods, preparations and kits that use an SSRI and a non-steroidal immunophilin-dependent immunosuppressant (NsIDI) and can with a corticosteroid or other agent described here.

In healthy individuals, the immune system uses cellular effectors such as B-cells or T-cells to target infectious microbes and abnormal cell types while leaving healthy cells intact. In individuals with an autoimmune disorder or who have transplanted organs, activated T-cells damage healthy tissue. Calcineurin inhibitors (cyclosporins, tacrolimus, pimecrolimus) and rapamycin target many types of immunoregulatory cells including T-cells and prevent the immune response in the transplanted organ and the autoimmune response.

Cyclosporins

Cyclosporins are fungal metabolites that contain a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporin A and its deuterated analogue ISAtx247 are hydrophobic cyclic polypeptides containing eleven amino acids. Cyclosporin A binds and forms a complex with the intracellular cyclophilin receptor. The cyclosporin/cyclophilin complex binds to and inhibits calcineurin, which is a Ca2+-calmodulin-dependent serine-threonine-specific phosphotase. Calcineurin maintains the signal transduction required for T-cell activation (reviewed in Schreiber et al., Cell 70:365-368, 1991). Cyclosporins and their functional and structural analogs prevent the T-cell-dependent immune response by inhibiting antigen-triggered signal transduction. Inhibition reduces the expression of proinflammatory cytokines such as IL-2.

Many cyclosporins (eg, cyclosporin A, B, C, D, E, F, G, H, and I) are fungiform. Cyclosporin A is commercially available under the trade name NEORAL from Novartis. Structural and functional analogs include cyclosporins having one or more fluorinated amino acids (described, e.g., in U.S. Patent No. 5,227,467); cyclosporins having modified amino acids (described, e.g., in U.S. Patent Nos. 5,122,511 and 4,798,823); and deuterated cyclosporins such as ISAtx247 (described in U.S. Patent Publication No. 20020132763). Additional cyclosporine analogs are described in U.S. Pat. Patents no. 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporine analogs include, but are not limited to, D-Sar(�-SMe)3 Val2-DH-Cs (209-825), Allo-Thr-2-Cs, Norvaline-2-Cs, D-Ala (3- acetyl-amino)-8-Cs, Thr-2-Cs and D-MeSer-3-Cs, D-Ser(O-CH2CH2-OH)-8-Cs, and D-Ser-8-Cs, which are described in Cruz et al. (Antimicrob. Agents Cbemother. 44:143149,2000).

Many cyclosporins are highly hydrophobic and readily precipitate in the presence of water (eg after contact with body fluids). Methods showing ciclosporin formulations with improved bioavailability are described in U.S. Pat. Patents no. 4,388,307, 6,468,968, 5,051,402, 5,342,625, 5,977,066 and 6,022,852. Microemulsion preparations of cyclosporine are described in U.S. Pat. Patents no. 5,866,159, 5,916,589, 5,962,014, 5,962,017, 6,007,840 and 6,024,978.

Cyclosporins can be given intravenously or orally, but oral administration is preferred. To affect the hydrophobicity of cyclosporine A, intravenous cyclosporine A is usually encapsulated in an ethanol-polyoxyethylated castor oil vesicle that must be diluted before administration. Cyclosporine A can be, for example, as a microemulsion in tablets of 25 mg or 100 mg or in oral solutions of 100 mg/mL (NEORAL™).

Although the typical patient dose of oral ciclosporin varies according to the patient's condition, some previous standard recommendations for treatment regimens are presented here. Patients undergoing organ transplantation typically receive an initial dose of oral cyclosporine A in amounts between 12 and 15 mg/kg/day. The dose is then gradually reduced by 5% per week until a dose of 7-12 mg/kg/day is reached, which is maintained. For intravenous administration, 2-6 mg/kg/day is preferred in most patients. For patients diagnosed with Crohn's disease or ulcerative colitis, a dose of 6-8 mg/kg/day is generally given. For patients with systemic lupus erythematosus, the dose is 2.2-6.0 mg/kg/day. For psoriasis and rheumatoid arthritis, the typical dosage amount is 0.5-4 mg/kg/day. »ciclosporins are often given in combination with other immunosuppressive agents such as glucocorticoids. Additional information is shown in Table 3.

Table 3 - NsIDI

[image] Legend

CsA=cyclosporin A

RA=rheumatoid arthritis

UC=ulcerative colitis

SLE-systemic lupus erythematosus

Tacrolimus

Tacrolimus (PROGRAF, Fujisawa), also known as FK506, is an immunosuppressive agent that targets intracellular T-cell signal transduction. Tacrolimus binds to the intracellular protein FK506 (FKBP-12), which is structurally unrelated to cyclophilin (Harding et al. Nature 341:758-7601, 1989; Siekienka et al. Nature 341:755-757, 1989; and Soltoff et al. , J. Biol. Chem. 267:17472-17477,1992). The TFKBP/FK506 complex binds to calcineurin and inhibits calcineurin phosphatase activity. This inhibition prevents dephosphorylation of the nuclear translocation of NFAT, which is a nuclear component that initiates the transcription of genes required for lymphokine production (eg gamma interferon IL-2) and T-cell activation. Thus, tacrolimus inhibits T-cell activation.

Tacrolimus is a macrolide antibiotic produced by Streptomyces tsukbaensis. It inhibits the action of the immune system and prolongs the survival of transplanted organs. It is now available as an oral formulation or for injection. Tracholim capsules contain 0.5 mg, 1 mg or 5 mg of anhydrous tracholim inside the gelatin capsule. The injection formulation contains 5 mg of anhydrous tarcholim in castor oil and alcohol which is diluted with 9% sodium chloride or 5% dextrose before injection. Although oral administration is preferred, patients who cannot take oral capsules receive injectable tracholim. The initial dose should be given no earlier than six hours after transplantation under conditions of continuous infusion.

Tracholim or tracholim analogs are described in Tanaka et al., (J. Am. Chem. Soc. 109:5031, 1987), and in U.S. Pat. Patents no. 4,894,366, 4,929,611 and 4,956,352. Compounds corresponding to FK506, including FR-900520, FR-900523 and FR-900525 are described in U.S. Pat. Patent no. 5; 254,562; O-aryl, O-alkyl, O-alkenyl and O-alkyne macrolides are described in U.S. Pat. Patents no. 5,250,678, 532,248, 5,693,648; amino-O macrolides are described in U.S. Pat. Patent no. 5,262,533; Alkylidene macrolides are described in U.S. Pat. Patent No. 5,284,840; N-beteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl and N-alkynylheteroaryl macrolides are described in U.S. Pat. Patent No. 5,208,241; aminomacrolides and their derivatives are described in U.S. Patent no. 5,208,228; fluoromacrolides are described in the U.S. Patent no. 5,189,042; amino-O-alkyl, O-alkenyl and O-alkyl macrolides are described in U.S. Pat. Patent No. 5,162,334; and balomacrolides are described in the U.S. Patent No. 5,143,918.

Although recommended dosages will vary according to the patient's condition, standard dosages recommended for transitional treatments are shown below. For patients diagnosed with Crohn's disease or ulcerative colitis, a dose of 0.1-0.2 mg/kg/day of oral tacrolimus is generally given. For organ transplant patients, typical doses are 0.1-2 mg/kg/day of oral tacrolimus. Patients treated for rheumatoid arthritis typically receive 1-3 mg/day tacrolimus orally. For the treatment of sporiasis, the patient is given orally 0.01-0.15 mg/kg/day. Atopic dermatitis can be treated twice a day by applying a cream containing 0.01-0.1% tacrolimus to the affected areas. Patients receiving tacrolimus capsules typically receive their first dose no sooner than six hours after transplantation or eight or twelve hours after the intravenous infusion of tacrolimus has stopped. Other recommended doses of tacrolimus include 0.005-0.01 mg/kg/day, 0.01-0.03 mg/kg/day, 0.03-0.05 mg/kg/day, 0.05-0.07 mg/kg/day, 0.07-0.10 mg/kg/day, 0.10-0.25 mg/kg/day or 0.25-0. 5 mg/kg/day.

Derivatives of pimecrolimus and ascomycin

Ascomycin is a close structural analogue of FK506, which are potent immunosuppressants. It binds to FKBP-12 and prevents its proline rotamase activity. Askiomycin-FKBP complex inhibits calcineurin, a type 2B phosphatase.

Pimecrolimus (also known as SDZ ASM-981) is a 33-epi-chloro derivative of ascomycin. It is produced by Streptomyces hygroscopicus var. ascomycetus. Like tacrolimus, pimecrolimus (ELIDEL™, Novartis) binds FKBP-12, inhibits calcineurin phosphate activity, and inhibits T-cell activation by blocking early cytokine transcription. Thus, pimecrolimus inhibits the production of IL-2 and the release of other proinflammatory cytokines.

Structural and functional analogs of pimecrolimus are described in U.S. Pat. Patent no. 6,384,073. Pimecrolimus is now available as a 1% cream. Although recommended doses will vary according to the patient's condition, some standard recommended doses are shown below. Oral pimecroplim can be given for the treatment of psoriasis and rheumatoid arthritis in amounts of 40-60 mg/day. For the treatment of Crohn's disease or ulcerative colitis, amounts of pimecrolimus of 80-160 mg/day can be given.

Rapamycin

Rapamycin (Rapamune® sirolimus, Wyeth) is a cyclic lactone produced by Steptomyces hygroscopicus. Rapamycin is an immunosuppressive agent that inhibits the activation and proliferation of T-lymphocytes. Like cyclosporins, tacrolimus and pimecrolimus, rapamycin forms a complex with the immunophilin FKBP-12, but the rapamycin-FKBP-12 complex does not inhibit calcineurin phosphate activity. The rapamycin-immunophilin complex binds to and inhibits the mammalian target of rapamycin (mTOR), a kinase required for cell cycle progression. Inhibition of mTOR kinase activity blocks T-lymphocyte proliferation and lymphokine secretion.

Structural and functional analogs of rapamycin include mono- and diacetylated rapamycin derivatives (U.S. Patent No. 4,316,885); a water-soluble prodrug of rapamycin (U.S. Patent No. 4,650,803); carboxylic acid esters (PCT Publication No. WO 92/05179); carbamates (U.S. Patent No. 5,118,678); amide esters (U.S. Patent No. 5,118,678); biotin esters (U.S. Patent No. 5,504,091); fluorinated esters (U.S. Patent No. 5,100,883); acetals (U.S. Patent No. 5,151,413); ethers (U.S. Patent No. 5,120,842); bicyclic derivatives (U.S. Patent No. 5,120,725); dimeth rapamycin (U.S. Patent No. 5,120,727); O-aryl, O-alkyl, O-alkenic, and O-alkynyl derivatives (U.S. Patent No. 5,258,389); and deuterated rapamycin (U.S. Patent No. 6,503,921). Additional rapamycin analogs are described in U.S. Patents no. 5,202,332 and 5,169,851.

Everolimus (40-O-(2-hydroxyethyl)rapamycin; CERTICAIN™; Novartis) is an immunosuppressive macrolide structurally similar to rapamycin that has been found to be particularly effective in preventing acute transplant rejection when given in combination with cyclosporine A .

Rapamycin is now available for oral administration in a tablet and liquid formulation. RAPAMUNE™ liquid contains 1 mg/mL rapamycin which is diluted in water or orange juice before administration. Tablets containing 1 or 2 mg of rapamycin are also available. Rapamycin is preferably given once daily immediately after transplantation. It is quickly and completely absorbed after oral administration. Although the typical patient dose of rapamycin varies according to the patient's condition, some standard recommended doses are given below. The initial dose of rapamycin is 6 mg. A typical dose of 2 mg/day is then maintained. Alternatively, an initial dose of 3 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg can be used, and a maintenance dose of 1 mg, 3 mg, 5 mg or 10 mg per day can be used. If the patient weighs less than 40 kg, the dose of rapamycin is typically adjusted based on body surface area, generally using a 3 mg/m2/day starting dose and a 1 mg/m2/day maintenance dose.

Peptide parts

Peptides, peptidomimetics, peptide fragments, whether natural, synthetic, or chemically modified, that prevent calcineurin-mediated dephosphorylation and nucleolar translocation of NFAT are useful for use in the practice of the invention. Examples of peptides that act as clacineurin inhibitors by inhibiting activation of the NFAT transcription factor are illustrated in Aramburu et al. Scinece 285:2129-2133, 1999) and Aramburu et al. Mole. Cell 1:627-637, 1998). As a class of clacineurin inhibitors, these compounds are useful in the methods of the invention.

Giving

In a particular embodiment of any method of the invention, the compounds are administered 10 days apart, 5 days apart, 24 hours apart, or simultaneously. The compounds may be formulated together in a single preparation or may be formulated and administered separately. One or both compounds may be administered at a low dose or a high dose, each as defined herein. It may be desirable to give the patient some other compound such as a corticosteroid, NASID (eg, naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, imdomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylic acid, fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac and tolmetin), COX-2 inhibitors (eg rofecoxib, celecoxib, valdecoxib, and lumiracoxib), glucocorticoid receptor modulator or DMARD. The combination therapies of the invention are particularly useful for the treatment of immunoinflammatory disorders in combination with other anti-cytotoxic agents or agents that modulate the immune response to the positive effect of the disease, such as agents that act on cell adhesion or biologics (e.g. agents that block the action of IL- 6, IL-1, IL-2, IL-12, IL-15) or TNF� (eg, etanercept, adelimumab or CDP-870). In this example (in which the agent blocks the effect of TNF�), the combination therapy reduces cytokine production, etanercept or infliximab act on the rest of the inflammatory cytokines by linking the treatment.

The therapy according to the invention can be performed alone or together with other therapy and can be performed at home, in a doctor's office, in a clinic and in a hospital. The treatment can start in the hospital so that the doctor can closely monitor the therapeutic effect and make adjustments if necessary. The duration of therapy depends on the type of disease or disorder treated, the patient's age and condition, the degree and type of the patient's disease, and the patient's response to treatment. In addition, a person at higher risk of developing an inflammatory disease (eg, a person undergoing age-related hormonal changes) may receive treatment to inhibit or delay the onset of symptoms.

Methods of administration to various entities include, but are not limited to, topical, transdernal, and systemic administration (such as intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic, or oral administration). As used herein, "systemic administration" refers to a non-dermal route of administration and specifically excludes topical and transdermal routes of administration.

In combination therapy, the dosage, frequency and method of administration of each component of the combination can be independently controlled. For example, one compound can be given orally three times a day, while another compound can be given once a day. Combination therapy can be administered in on-off cycles that include rest periods so that the patient's body can recover from as-yet-unforeseen side effects. The compounds can also be formulated together so that the compounds are delivered in a single administration.

Formulation of pharmaceutical preparations

The administration of the combination of the invention can be carried out by any convenient means that results in a reduction of the levels of proinflammatory cytokines at the target site. The compound may contain any suitable amount of any suitable carrier which is generally present in an amount of 1-95% by weight of the total weight of the composition. The preparation can be in a dosage form suitable for oral, parenteral (eg intravenous, intramuscular), rectal, cutal, nasal, vaginal, inhalation, transdermal (patch) or ocular administration. Therefore, the preparation can be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, poultices, suitable for osmotic delivery devices, suppositories, enemas, implants which can be injected, sprayed or aerosolized. Pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: Science and Practice in Pharmacy, 20th ed., 2000, ed. A.R. Gennaro, Lippnicott Williams & Wlikins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekket, New York).

Each compound of the invention can be formulated in a variety of ways known in the art. For example, the first and second agents can be formulated together or separately. Preferably, the first and second agents are formulated together for simultaneous or near-simultaneous administration of the agents. Such a co-formulated preparation may contain an SSRI and a steroid formulated in the same pill, capsule, liquid, etc. It is also understood that stating the formulation "SSRI/steroid combination" is using a formulation technology that is also useful for formulating the individual agents in combination, as well as other combinations of the invention (eg SSRI/glucocorticoid receptor modulator combination). Using different formulation strategies for different agents favors the pharmacokinetic profile of each agent.

Individually and separately formulated products can be packaged in sets. Non-limiting examples include kits containing, for example, two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit may contain components that assist in the administration of a unit dose to a patient, such as vials for preparing powder forms, syringes for injection , common IV delivery systems, inhalers, etc. In addition, the unit dose kit may contain instructions for preparation and administration of the preparations. The kit can be prepared as a unit dose for a single patient, for multiple use for a specific patient (at a constant dose or in which the amount of an individual compound changes as therapy progresses), or the kit contains multiple doses suitable for administration to several patients ("bulk packaging") . Kit components can be placed in cartons, blisters, vials, test tubes and the like.

Controlled release formulations

Administration of an SSRI/steroid combination of the invention in which one or both active agents are formulated for controlled release is useful when the SSRI or steroid has (i) a narrow therapeutic index (eg, the difference between the plasma concentration leading to adverse side effects or a toxic reaction and the concentration in of plasma that has a therapeutic effect is small; in general, the therapeutic index, TI, is defined as the ratio of the median lethal dose (LD50) to the median effective dose (ED50)); (ii) narrow "window" of absorption in the gastro-intestinal tract; (iii) short biological half-life; or (iv) the pharmacokinetic profile of each component must be modified to obtain the effect of each agent when used together, and in an amount that is therapeutically effective to prevent cytokine secretion. According to Tom, delayed-release formulations can be used to avoid the frequent dosing that would be necessary to maintain therapeutic plasma levels of both agents. For example, it has been observed that the preferred pharmaceutical preparations in the invention have a half-life and mean retention time of 10 to 20 hours of one or both agents in combination from the invention.

Many strategies can be used to achieve a controlled release in which the rate of release overcomes the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by appropriate selection of formulation parameters and ingredients, (eg use of appropriate controlled release preparations and use of coating). Examples include single or multiple unit preparations of tablets or capsules, oily solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches and liposomes. The release mechanism can be controlled so that the SSRI and/or steroid is released at time intervals, and the release can be simultaneous or delayed release of one agent from the combination, where early release of a particular agent is preferred over another.

Controlled release formulations may contain degradable or non-degradable polymers, hydrogel, organogel, or other physical constructs that modify the bioabsorption, half-life, or biodegradation of the agent. A controlled-release formulation can be a material that is smeared or otherwise applied to the affected area internally or externally. In one example, the invention features a biodegradable veterinary preparation or implant that is operatively inserted at or near a site of interest (eg adjacent to an arthritic joint). In another example, implants with a controlled release formulation may be inserted into an organ, such as the lower digestive tract, for the treatment of inflammatory bowel disease.

The hydrogels of the present invention can be used in controlled release SSRI/steroid formulations. Such polymers are formed from macromers with a polymerizable, non-degradable region separated by at least one degradable region. For example, a water-soluble non-degradable region may form the core of a macromer and have at least two degradable regions attached to the core such that after degradation the non-degradable region (which is a polymerized gel) is separated as described in U.S. Patent no. 5,626,863. Hydrogels can contain acrylates that readily polymerize using several initiation systems such as eosin dye, ultraviolet, or visible light. Hydrogels can also contain polyethylene glycols (PEG), which are highly hydrophilic and biocompatible. Hydrogels may also include oligoglycolic acid which is a poly(�-hydroxy acid) that is readily degraded by hydrolysis of the ester bond to glycolic acid which is a non-toxic metabolite. Other chain extensions may include hemilactic acid, polycaprolactone, polyorthoesters, polyanhydrides, and polypeptides. The entire network can gel into a biodegradable network that can be used to propel and homogeneously disperse the SSTI/steroid combinations of the invention for rate-controlled delivery.

Chitosan and mixtures of chitosan with sodium carboxymethyl cellulose (CMC-Na) have been used as vesicles for sustained release of drugs, as described by Inouye et al., Drug Design and Delivery 1:297-305, 1987. Mixtures of these compounds and agents SSRI/steroid combinations, and when compressed under 200 kg/cm2, form tablets from which the active agent is released slowly after administration to the subject. The release profile can be modified by changing the ratio of chitosan. CMC-Na and active substance(s). Tablets may also contain other additives including lactose, CaHPO4 dihydrate, sucrose, crystalline cellulose or croscarmellose sodium. Some examples are given in Table 4.

Table 4

[image]

Baichwal in U.S. Patent No. 6,245,356 discloses a delayed-release oral dosage form containing agglomerated particles of a therapeutically effective active drug (eg, an SSRI/steroid combination or a component thereof in this invention) in an amorphous form, a gel-forming agent, an agent for increasing the ionization of the gel, and an inert solvent. The gelling agent can be a mixture of xanthan gum and carob seed gum, which can be cross-linked with xanthan gum, and when the gum is exposed to liquid from the environment. The preferred gelling agent acts to increase the strength of the crosslinking between the xanthan gum and the carob seed gum and thereby prolong the release of the drug component from the formulation. In addition to xanthan gum and locust bean gum, acceptable gelling agents that may also be used include those gelling agents well known in the art. Examples include natural and modified natural gums such as alginates, carrageenan, pectin, guas gum, modified starch, hydroxypropyl methylcellulose. Metocellulose and other cellulosic materials or polymers such as sodium carboxymethylcellulose and hydroxypropyl cellulose and mixtures of the aforementioned.

In the following formulation useful for the combination of the invention, Baichwal and Stainfort in U.S. Pat. Patent no. 5,135,757 described a free-flow slow-release granulation for use as a pharmaceutical excipient containing from about 20 to about 70 percent or more by weight of a hydrophilic material including heteropolysaccharides (such as, for example, xanthan gum or derivatives thereof) and polysaccharide material capable of cross-linking the heteropolysaccharides (such as, for example, galacromans, and the most preferred is carob seed gum in the presence of aqueous solutions and form from about 30 to about 80 percent by weight of the inert pharmaceutical filter (such as, for example, lactose, dextrose, sucrose, sorbitol, xylitol, fructose or mixtures thereof ). After mixing the excipient with the SSRI/steroid combination or combination agent of the invention, the mixture is directly compressed into a solid dosage form such as tablets. The resulting tablets slowly release the drug upon digestion when exposed to gastric fluid. By varying the amount of excipient relative to the drug, to achieve a slow release profile.

In the following formulation useful for the combination of the invention, Shell in the U.S. Patent no. 5,007,790 describes solubilized drug dosage forms in which drug release is controlled by drug solubility. The dosage form comprises a tablet or capsule containing multiple particles in a dispersion of limited solubility (such as, for example, prednisolone, paroxetine, or any of the SSRI/serroid combination agents of this invention) in a hydrophilic, water-swellable cross-linked polymer that maintains a disintegrated form for a longer period of time. from the lifetime of the dose, but then quickly dissolves. During digestion, the particles swell and promote retention in the stomach and allow gastric fluids to penetrate the particles, dissolving the drug that comes out of the particles, ensuring that the drug reaches the stomach in the form of a solution that is less harmful to the stomach than the drug in solid form. The programmed accelerated dissolution of the polymer depends on the nature of the polymer and the degree of crosslinking. The polymer has a non-fibrillar structure and is mostly soluble in water in an uncrosslinked state, and the degree of crosslinking is sufficient to allow the polymer to remain insoluble for the desired period of time, normally at least from 4 hours to 8 hours to 12 hours, and the choice depends on the incorporated drug and medical treatment . Examples of suitable cross-linked polymers that can be used in the invention are gelatin, albumin, sodium alginate, carboxymethyl cellulose, polyvinyl alcohol and chitin. Depending on the polymer, cross-linking can be achieved by thermal or radiation treatment using cross-linking agents such as aldehydes, polyamino acids, metal ions and the like.

Silicon drug microspheres for pH-controlled gastrointestinal drug delivery useful in the SSRI/steroid combination formulation of the invention are described in Carelli et al. Int. J. Pharmaceuutics 179: 73-83, 1999. pH-sensitive hydrogel proteins made of different proportions of poly(methacrylic acid-comethyl methacrylate) (Eudragit L1000 or Euragit S100) and cross-linked polyethylene glycol 8000 are semipermeable to the described microspheres, they are encapsulated in silicone microspheres size range from 500 to 1000 μm.

Sustained-release formulations contain a coating layer that is not readily soluble in water but is slowly attacked and removed by water or through which water can slowly penetrate. Therefore, an exemplary SSRI/steroid combination of the invention can be coated by spraying with a binder solution under continuous liquefaction conditions, as described by Kitamori et al. U.S. Patent No. 4,036,948. Examples of water-soluble binders include pregelatinized starch (eg, pregelatinized corn starch, pregelatinized white potato starch), pregelatinized modified starch, water-soluble cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose), polyvinylpyrrolidone, polyvinylalcohol, dextrin, gum arabica and gelatin, binders soluble in organic solvents such as cellulose derivatives (eg cellulose-acetate-phthalate, hydroxypropylmethyl-cellulose, phthalate, ethylcellulose).

The combinations of the invention or their components with delayed release properties can also be formulated using the spray drying technique. In one example, as described by Esposito et al., Pharm. Dev. Technol. 5: 267-78, 2000, prednisolone was encapsulated in methyl acrylate microparticles (Eudragit RS) using a Mini Spray Dryer, model 190 (Buchi, Laboratorium Technik AG, Flawil, Germany). It was found that the optimal conditions for the formation of microparticles are: introduction rate (pump) 0.5 mL/min of a solution containing 50 mg of prednisolone in 10 mL of acetonitrile, the air flow rate for spraying is 600 L/h, the temperature of dry air for heating is 80 °C and the flow rate of sucked dry air is 28 m3/h.

The following SSRI/sustained release steroid combination can be prepared by microencapsulating the combination of agents into membranes that act as microdialysis cells. By such formation, the gastric fluid penetrates the walls of the microcapsule and the kidney microcapsule, allowing the active agent(s) to exit by dialysis (see, for example, Tsuei et al., U.S. Patent No. 5,589,194). One commercially available sustained release system of this type contains microcapsules having a gum acacia/ethanol membrane. This product is available from Eurand Limited (France) under the trade name Diffucaps™. Microcapsules formulated in this way can be in a regular gelatin capsule or can be tableted.

Sustained or controlled delayed release formulations of SSRIs and corticosteroids are well known. For example, Paxil CR® commercially available from GlaxoSmithKline is an extended release form of paroxetine hydrochloride in a degradable polymeric matrix (GEOMATRIX™, see also U.S. Patent Nos. 4,839,177, 5,102,666 and 5,422,123) which also has an enteric coating to delay the onset of drug release until the tablet is came to the stomach. For example, U.S. Patent 5,102,666 describes a controlled-release polymer composition comprising a reaction complex formed by the interaction of (1) a water-swellable but water-insoluble calcium polycarbophilic component, a fibrous cross-linked polymer with carboxyl functional groups, and the polymer contains (a) a plurality of repeating units of which at least 80% contain at least one carboxyl functional group, and (b) about 0.05 to about 1.5% of a non-polyalkenyl polyether crosslinking agent, the percentage being based on the weight of the unpolymerized repeating unit and the crosslinking agent with (2) water in the presence of an active agent selected from an SSRI such as paroxetine. The amount of calcium polycarbonyl present is from about 0.1 to about 99% by weight, for example about 10%. The amount of active agent present is from about 0.0001 to about 65% by weight, for example between about 5 and 20%. The amount of water present is from about 5 to about 200% by mass, for example between 5 and 10%. The interaction is carried out at a pH between about 3 and about 10, for example about 6 to 7. Calcium polycarophil is originally present in the form of a calcium salt containing from about 5 to about 25% calcium.

Examples of other sustained release formulations are described in U.S. Pat. 5,422,123. Thus, a controlled release system in which an SSRI such as paroxerin comprises (a) a core containing an effective amount of the active ingredient in a defined geometrical shape and (b) a carrier applied to the core, the core comprising a material that swells in contact with with water or an aqueous liquid and a gel-forming polymer, wherein the ratio of swelling polymer to gel-forming polymer is in the range of 1:9 to 9:1, and (2) one polymer material that both swells and forms a gel, with carrier an elastic carrier applied to said core so that it partially covers the surface of the core and changes due to the hydration of the core and slowly dissolves or slowly forms a gel in an aqueous liquid. The carrier may contain a polymer such as polyhydroxymethyl cellulose, plasticizers such as glyceride, binders such as polyvinylpyrrolidone, hydrophilic agents such as lactose or silica gel and/or hydrophobic agents such as magnesium stearate and glycerides. The polymer(s) typically comprise 30 to 90% by weight of the carrier, for example 35 to 40%. The plasticizer is made up of at least 2% by weight of the carrier, for example around 15 to 20%. The binder(s), hydrophilic agent(s) and hydrophobic agent(s) are typically up to about 50% by weight of the carrier, for example about 40 to 50%.

In the following example, an extended release formulation of venlafaxine (Effexor XR®) is commercially available from Wyeth Pharmaceuticals. This formulation contains venaflaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose, coated with a mixture of ethylcellulose and hydroxypropylmethylcellulose (see U.S. Patent Nos. 6,403,120 and 6,419,958). Controlled-release formulations of buidesonide (3 mg capsules) for the treatment of inflammatory bowel disease are available from AstraZeneca (marketed as "Entocort™"). Sustained release formulations useful for corticosteroids are also described in U.S. Pat. 5,792,476 where the formulation includes 2.5-7 mg of glucocorticoid as an active substance with a regulated delayed release where at least 90% by mass of glucocorticoid is released during a period of about 40-80 min, starting about 1-3 h after the entry of said glucocorticoid into the patient's small digestive tract. To enable these low dose levels of the active substance possible, the active substance, i.e. a glucocorticoid such as prednisolone or prednisone is ground, suitably mixed with suitable diluents such as starch and lactose and granulated with PVP (polyvinylpyrrolidone). Furthermore, the granules are coated with an outer layer for delayed release that is resistant to a pH of 10. The inner layer is made of Eudragir®RL (a copolymer of acrylic and methacrylic ester with a low content of quaternary ammonium groups) and the outer layer is made of Eudragir®L (an anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester).

A double-layered tablet can be formulated for the SSRI/steroid combination of the invention in which the variously granulated individual agents in the combination of the two agents are compressed on a double-layered press, resulting in a single tablet. For example, 2.5 mg, 25 mg, 37.5 mg or 50 mg of paroxetine is formulated for controlled release, which gives a paroxetine t1/2 of 15 to 20 hours, which can be combined in the same talbet with 3 mg of prednisolone, which is formulated so that the t1/2 is approximately the same as that of paroxetine. Examples of sustained-release formulations of paroxetine include the bilayer tablets found in U.S. Patent No. 6,548,084. With rate-controlled release of prednisolone in vitro, an enteral or delayed-release coating can be designed to delay the onset of drug release so that the Tmax of prednisolone is approximately that of paroxetine (ie, 5 to 10 hours).

Cyclodextrins are cyclic polysaccharides containing natural D-(+)-glucopyranose units with a �-(1,4)-linkage. Alpha-, beta- and gamma-cyclodextrins containing six, seven or eight glucoripranose units are commonly used, suitable examples being given in WO 91/11172, WO 94/02518 and WO 98/55148. The structure of cyclic cyclodextrin has the shape of a donut that has an internal non-polar or hydrophobic cavity, the secondary hydroxyl groups are located at one end of the cyclodextrin structure, and the primary hydroxyl groups are located at the other side. The side on which the secondary hydroxyl groups are located has a larger diameter than the side on which the primary hydroxyl groups are located. The hydrophobicity of the inner cavity of cyclodextrin allows the incorporation of various compounds (Compreghensive Supramileculat Chemistry, vol. 3, J. Atwood et al. ed, Pergamon Press (1996), Cserhati, Analytical Biochemistry 225: 328-32, 1995, Husain et al., Applied Spectroscopy 46: 652-8, 1992. Cyclodextrins have been used as vesicles for the delivery of various therapeutic compounds, by forming inclusion complexes with various drugs that can fit into the hydrophobic cavity of the cyclodextrin or by forming noncovalent association complexes with other biologically active molecules. U.S. Patent No. 4,727,064 describes pharmaceutical preparations containing a drug that is very poorly soluble in water and is an amorphous, water-soluble cyclodextrin-based mixture in which the drug forms an inclusion complex with the cyclodextrin mixture.

The formation of a drug-cyclodexrin complex can modify drug solubility, degradation rate, bioavailability and/or stability. For example, cyclodextrins have been described to improve the bioavailability of prednisolone, as described by Uekama et al. J. Pharm. Dyn 6:124-7, 1983. The �-cyclodextine/prednisolone complex can be prepared by adding both components to water and stirring for 7 days at 25°C. The resulting precipitate is a 1:2 prednisolone/cyclodextrin complex.

Sulfobutylether-�-cyclodextrin (SBE-�-CD, commercially available from CyDex, Inc. Overland Park, Ka, USA and sold as CAPTISOL®) can also be used as an aid in the preparation of sustained release formulations of the combination agents of this invention . For example, a delayed-release tablet has been formulated to contain prednisolone and SBE-�-CD compressed into a hydroxypropylmethyl-cellulose matrix (see Rao et al. J. Pharm. Sci, 90: 807-16, 2001). In the following example of the use of different cyclodextrins, EP 1109806 B1 describes complexes of cyclodextrins and paroxetine, where �-, �- or �-cyclodextrins [including heptakis(2,6-di-O-methyl)-�-cyclodextrin, (2,3, 6-tri-O-methyl)-�-cyclodextrin, monosuccinyl-heptakis(2,6-di-O-methyl)-�-cyclodextrin or 2-hydroxypropyl-�-cyclodetrin] in anhydrous or hydrated form can be obtained in the ratio of the agent and cyclodextrin in a complex from 1:0.25 to 1:20.

Polymeric cyclodextrins have also been prepared, as described in U.S. Pat. To the patent application serial no. 10.21,294 and 10/021,312. The polymeric cyclodextrins thus formed may be useful for the combination formulation of the present invention. These multifunctional polymeric cyclodextrins are commercially available from Inset Therapeutics, Inc., Pasadena, CA, USA.

As an alternative to direct complexation with agents, cyclodextrins can be used as an additional additive, eg carrier, diluent or solubilizer. Formulations containing cyclodextrins and other combination agents of this invention (ie, SSRI and/or steroid) can be prepared according to methods similar to the preparation of cyclodextrin formulations described herein.

Liposomal formulations

One or both components of the SSRI/steroid combination of the invention or a mixture of the two components can be incorporated into liposomal delivery vehicles. Liposomal carriers are composed of three general types of lipid components that form vesicles. The first type contains vesicle-forming lipids that will form a bulky vesicle structure in the liposome. In general, vesicle-forming lipids may comprise any of the amphipathic lipids having a hydrophobic polar head and which (a) can spontaneously form bilayer vesicles in water, such as, for example, phospholipids, or (b) are stably incorporated into a lipid bilayer with a hydrophobic partly in contact with the inner hydrophobic region of the bilayer membrane, and its polar head is oriented towards the outer polar surface of the membrane.

Lipids that form vesicles of this type typically have two hydrocarbon chains, typically acyl chains, and a polar head. This class includes phospholipids such as phosphophthalidylcholine (PC), PE, phosphatidic acid (PA), phosphatidyl-inositol (PI) isphingomyelin (SM), while the typical length of the two hydrocarbon chains is between 14-22 carbon atoms, and they have different degrees of unsaturation. The lipids and phospholipids described above whose acyl chains have different degrees of saturation can be obtained commercially or prepared according to published methods. Other lipids included in the invention are glycolipids and sterols, such as cholesterol.

Another general component includes a vesicle-forming lipid that has been converted into a derivative with a polymer chain, which will fill the polymer layer in the formulation. The vesicle-forming lipids that can be used as the second general component of the vesicle-forming lipid are all those described for the first general component of the vesicle-forming lipid. Lipids that form vesicles with diclinic chains, such as phospholipids, are preferred. One example of a phospholipid is phosphatidylethanolamine (PE) which has a reactive amino group that is covalently attached to an activated polymer. Examples of PE are disteryl PE (DSPE).

Preferably the polymer in the derivatized lipid is polyethylene glycol (PEG), preferably a PEG chain having a molecular weight between 1000-15000 Daltons, more preferably between 2000 and 10000 Daltons, most preferably between 2000 and 5000 Daltons. Other hydrophilic polymers which may contain the following: polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide and polymethylacrylamide, polylactic acid, polyglycolic acid and derivatized cellulose such as hydroxymethylcellulose or hydroxyethylcellulose.

Additionally, block copolymers or random copolymers of these polymers, especially those containing PEG segments, may be suitable. Methods for attaching derivatized lipids to hydrophilic polymers such as PEG are well established, as described, for example, in U.S. Pat. Patent no. 5,013,556.

The third generation of the lipid component that forms the vesicle can be a lipid anchor that binds the target moiety to the liposome via the anchor polymer chain. In addition, the targeting group is located at the distal end of the polymer chain so that the biological activity of the targeting moiety is not lost. The lipid anchor contains a hydrophobic part that serves to bind the lipid in the outer layer of the liposome with a bilayer surface, a polar head to which the inner end of the polymer is covalently bound, and a free (outer) polymer end that can be activated for covalent binding to the target part. The methods of preparation of lipid molecules that are the anchor of this type are described below.

The lipid components used in the formation of liposomes are preferably present in the following molar ratios: from about 70-90 percent of lipids that form bridges, 1-25 percent of polymer derivatized lipids and 0.1-5 percent of lipid anchor. One example formulation contains 50-70 mole percent non-derivatized PE, 20-40 mole percent cholesterol, 0.1-1 mole percent PE-PEG (3500) polymer with a chemically reactive group at the free end for binding to the target moiety, 5-10 mole percent derivatized PE with PEG 3500 polymer and 1 molar percentage of alpha-tocopherol.

Liposomes are preferably prepared so that homogeneous sizes are selected in the range between 0.03 and 0.5 microns. One effective method of particle uniformity for REV and MVL involves squeezing an aqueous suspension of liposomes through a series of polycarbonate membranes having a selected pore size in the range of 0.03 and 0.2 microns, typically 0.05, 0.08, 0.1 or 0.2 microns. The pore size of the membrane roughly corresponds to the largest size of liposomes obtained by pushing through the same membrane two or more times. Homogenization methods are also useful for reducing the size of liposomes to 100 nm or less.

Liposomal formulations of the present invention contain at least one surfactant. Suitable surfactants useful for the SSRI/steroid combination formulations described here contain compounds belonging to the following classes: polyethoxylated fatty acids, diesters of polyethoxylated PEG-fatty acids, mixtures of mono-esters and diesters, polyethylene glycol-glycerol fatty acid esters, alcohol transesterification products and oils, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters and glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol-sorbitan and fatty acid esters, polyethylene glycol-alkyl ethers, sugar esters, polyethylene glycol-alkylphenols, block copolymers of polyoxyethylene-polyoxypropylene, esters of sorbitan and fatty acids, esters of lower alcohols and fatty acids, and ionic surfactants. Commercially available examples of each class of excipients are shown below.

Polyethoxylated fatty acids can be used as excipients for the SSRI/steroid combination formulation described herein. Examples of commercially available surfactants that are polyethoxylated fatty monoesters include: PEG 4400-monolaurate (Crodet L series, Croda), PEG 4-100 monooleate (Crodet O series, Croda), PEG 4-100 monostearate (Crodet S series, Croda, and Myrj Series, Atlas/ICI), PEG 400 distearate (Cithrol 4DS series, Croda), PEG 100, 200, or 300 monolaurate (Cithrol ML series, Croda), PEG 100, 200, or 300 monooleate (Cithrol MO series, Croda ), PEG 400 dioleate (Cithrol 4DO series, Croda), PEG 400-1000 monostearate (Cithrol MS series, Croda), PEG-1 stearate (Nikkol MYS1lEX, Nikko, and Coster KI, Condea), PEG-2 stearate (Nikkol MYS -2, Nikko), PEG-2 oleate (Nikkol MYO-2, Nikko), PEG-4 laurate (Mapeg® 200 ML, PPG), PEG-4 oleate (Mapeg® 200 MO, PPG), PEG-4 stearate ( Kessco® PEG 200 MS, Stepan), PEG-5 stearate (Nikkol TMGS-5, Nikko), PEG-5 oleate (Nikko] TMGO-5, Nikko), PEG-6 oleate (Algon OL 60, Auschem SpA), PEG -7 oleate (Algon OL 70, Auschem SpA), PEG-6 laurate (Kessco® PEG300 ML, Stepan), PEG-7 laurate (Lauridac 7, Condea), PEG-6 stearate (Kessco(O PEG300 MS, Stepan), PEG-8 laurate (Mapeg® 400 ML, PPG), PEG-8 oleate (Mapeg® 400 MO, PPG), PEG-8 stearate (Mapeg® 400 MS, PPG), PEG-9 oleate (Emulgante A9, Condea), PEG-9 stearate (Cremophor S9, BASF), PEG-10 laurate (Nikkol MYL-10, Nikko), PEG-10 oleate ( Nikkol MYO-10, Nikko), PEG-12 stearate (Nikkol MYS-10, Nikko), PEG-12 laurate (Kessco® PEG 600 ML, Stepan), PEG-2 oleate (Kessco® PEG 600 MO, Stepan), PEG -12 ricinoleate (CAS # 9004-97-1), PEG-12 stearate (Mapeg® 600 MS, PPG), PEG-15 stearate (Nikkol TMGS-15, Nikko), PEG-15 oleate (Nikkol TMGO-15, Nikko ), PEG-20 laurate (Kessco® PEG 1000 ML, Stepan), PEG-20 oleate (Kessco® PEG 1000 MO, Stepan), PEG-20 stearate (Mapeg® 1000 MS, PPG), PEG-25 stearate (Nikkol MYS -25, Nikko), PEG-32 laurate (Kessco® PEG 1540 ML, Stepan), PEG-32 oleate (Kessco® PEG 1540 MO, Stepan), PEG-32 stearate (Kesseo® PEG 1540 MS, Stepan), PEG- 30 stearate (Myrj 51), PEG-40 laurate (Crodet L40, Croda), PEG-40 oleate (Crodet O40, Croda), PEG-40 stearate (Emerest® 2715, Henkel), PEG-45 stearate (Nikkol MYS-45, Nikko), PEG-50 stearate (Myrj 53), PEG-55 stearate (Nikkol MYS-55, Nikko), PEG-100 oleate (Crodet O-100, Croda), PEG-100 stearate (Ariacel 165, ICI), PEG-200 oleate (Albunol 200 MO, Taiwan Surf.), PEG-400 oleate (LACTOMUL, Henkel), and PEG-600 oleate (Albunol 600 MO, Taiwan Surf.). Formulations of one or both components of the SSRI/steroid combination according to the invention may contain one or more of the above polyethoxylated fatty acids.

Fatty acid diesters of polyethylene glycol can also be used as excipients for the SSRI/steroid combinations described herein. Examples of commercially available polyethylene glycol and fatty acid diesters are as follows: PEG-4 dilaurate (Mapeg® 200 DL, PPG), PEG-4 dioleate (Mapeg® 200 DO, PPG), PEG-4 distearate (Kessco® 200 DS, Stepan), PEG-6 dilaurate (Kessco® PEG 300 DL, Stepan), PEG-6 dioleate (Kessco® PEG 300 DO, Stepan), PEG-6 distearate (Kessco® PEG 300 DS, Stepan), PEG-8 dilaurate (Mapeg® 400 DL, PPG), PEG-8 dioleate (Mapeg® 400 DO, PPG), PEG-8 distearate (Mapeg® 400 DS, PPG), PEG-10 dipalmitate (Polyaldo 2PKFG), PEG-12 dilaurate (Kessco® PEG 600 DL , Stepan), PEG-12 distearate (Kessco® PEG 600 DS, Stepan), PEG-12 dioleate (Mapeg® 600 DO, PPG), PEG-20 dilaurate (Kessco® PEG 1000 DL, Stepan), PEG-20 dioleate ( Kessco® PEG 1000 DO, Stepan), PEG-20 distearate (Kessco® PEG 1000 DS, Stepan), PEG-32 dilaurate (Kessco® PEG 1540 DL, Stepan), PEG-32 dioleate (Kessco® PEG 1540 DO, Stepan) , PEG-32 distearate (Kessco® PEG 1540 DS, Stepan), PEG-400 dioleate (Cithrol 4DO series, Croda), and PEG-400 distearate (Cithrol 4DS series, Croda). Formulations of SSRI/steroid combinations according to the invention may contain one or more of the above polyethylene glycol and fatty acid esters.

Mixtures of PEG-fatty acid mono- and diesters can be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available mono- and diester mixtures are: PEG 4-150 mono, dilaurate (Kessco® PEG 200-6000 mono, Dilaurate, Stepan), PEG 4-150 mono, dioleate (Kessco® PEG 200-6000 mono, Dioleate, Stepan ), and PEG 4-150 mono, distearate (Kessco® 200-6000 mono, Diostearate, Stepan). Formulations of the SSRI/steroid combination according to the invention may contain one or more of the above mixtures of PEG-fatty acid mono- and diesters.

Additionally, polyethylene glycol-glycerol and fatty acid esters can be excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available esters of polyethylene glycol-glycerol and fatty acids are as follows: PEG-20 glyceryl laurate (Tagatl® L, Goldschmidt), PEG-30 glyceryl laurate (Tagat® L2, Goldschmidt), PEG-15 glyceryl laurate (Glicerox L series, Croda), PEG-40 glyceryl laurate (Glicerox L series, Croda), PEG-20 glyceryl stearate (Capmul® EMG, ABITEC) and Aldo® MS-20 KFG, Lonza), PEG-20 glyceryl oleate ( Tagatg® O, Goldschmidt) and PEG-30 glyceryl oleate (Tagat® O2, Goldschmidt). The SSRI/steroid combination formulations of the invention may contain one or more of the above polyethylene glycol and fatty acid esters.

Transesterification products of alcohols and oils can also be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available transesterification products of alcohols and oils are as follows: PEG-3 castor oil (Nikkol CO-3, Nikko), PEG-5, 9, and 16 castor oil (ACCONON CA series, ABITEC), PEG-20 castor oil, ( Emalex C-20, Nihon Emulsion), PEG-23 castor oil (Emulgante EL23), PEG-30 castor oil (Incrocas-30, Croda), PEG-35 castor oil (Incrocas-35, Croda), PEG-38 castor oil (Emulgante EL 65, Condea), PEG-40 castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castor oil (Emalex C-50, Nihon Emulsion), PEG-56 castor oil (Eumulgin® PRT 56, Pulera SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castor oil, PEG-200 castor oil (Eumulgin® PRT 200, PuIcra SA), PEG-5 hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castor oil (Cremophor WO7, BASF), PEG-10 hydrogenated castor oil (Nikkol HCO-10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko), PEG-25 hydrogenated castor oil (Simulsol® 1292 , Seppic), PEG-30 hydrogenated castor oil (Nikkol HCO-30, Nikko), PEG-40 hydrogenated castor oil (Cremophor RH 40, BASF), PEG-45 hydrogenated castor oil (Gerex ELS 450, Auschem Spa), PEG -50 hydrogenated castor oil (Emalex HC-50, Nihon Emulsion), PEG-60 hydrogenated castor oil (Nikkol HCO-60, Nikko), PEG-80 hydrogenated castor oil (Nikkol HCO-80, Nikko), PEG-100 hydrogenated castor oil oil (Nikkol HCO-100, Nikko), PEG-6 corn oil (Labrafil® M 2125 CS, Gattefosse), PEG-6 almond oil (Labrafil® M 1966 CS, Gattefosse), PEG-6 apricot kernel oil (Labrafil® M 1944 CS, Gaftefosse), PEG-6 raspberry oil (Labrafil® M 2130 BS, Gattefosse), PEG-6 palm kernel oil (Labrafil® M 2130 CS, Gattefosse), PEG-6 triolein (Labrafil® M 2735 CS, Gattefosse), PEG-8 corn oil (Labrafil® WL 2609 BS, Gattefosse), PEG-20 corn glycerides (Crovol M40, Croda), PEG-20 almond glycerides (Crovol A40, Croda), PEG-25 trioleate (TAGAT® TO , Goldschmidt), PEG-40 palm oil ich stone (Crovol PK 70), PEG-60 corn glycerides (Crovol M70, Croda), PEG-60 almond glycerides (Crovol A70, Croda), PEG-4 caprylic/caprate triglycerides (Labrafac® Hydro, Gattefosse), PEG-8 caprylic/caprate glycerides (Labrasol, Gattefosse), PEG-6 caprylic/caprate glycerides (SOFTIGEN®767, Huls), lauroyl-macrogol-32 glyceride (GELUCIRE 44/14, Gattefosse), stearoyl-macrogol glyceride (GELUCIRE 50/13, Gattefosse), mono, di, tri, tetra esters of vegetable oils and sorbitol (SorbitoGliceride, Gattefosse), pentaerythritol tetraisostearate (Crodamol PTIS, Croda), pentaerythritol distearate (Albunol DS, Taiwan Surf), pentaerythritol tetraoleate (Liponate PO-4 , Lipo Chem.), pentaerythritol tetrastearate (Liponate-PS4, Lipo-Chem pentaerythritol tetracaprylate tetracaprate (Liponate PE-8 10, Lipo Chem.) and pentaerythritol tetraoctanoate (Nikkol Pentarate 408, Nikko). Also included as oil in this category of surfactants are oil-soluble vitamins such as vitamins A, D, E, K, etc. Therefore, derivatives of these vitamins, such as tocopheryl PEG-1000 succinate (TPGS, from Eastman) are also suitable surfactants. The SSRI/steroid combination formulations of the invention may contain one or more of the above transesterification products of alcohol and oil.

Polyglycerylated fatty acids can also be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available polyglyceryl fatty acids are as follows: polyglyceryl-2 stearate (Nikkol DGMS, Nikko), polyglyceryl-2 oleate (Nikkol DGMO, Nikko), polyglyceryl-2 isostearate (Nikkol DGMIS, Nikko), polyglyceryl-3 oleate (Caprol® 3GO , ABITEC), polyglyceryl-4 oleate (Nikkol Tetraglyn 1-O, Nikko), polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S, Nikko), polyglyceryl-6 oleate (Drewpol 6-1-O, Stepan), polyglyceryl-10 laurate (Nikkol Decaglyn 1-L, Nikko), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O, Nikko), polyglyceryl-10 stearate (Nikkol Decaglyn 1-S, Nikko), polyglyceryl-6 ricinoleate (Nikkol Hexaglyn PR-15, Nikko), polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN, Nikko), polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-O, Nikko), polyglyceryl-3 dioleate (Cremopbor GO32, BASF), polyglyceryl-3 distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-O, Nikko), polyglyceryl-6 dioleate (Caprol® 6G20, ABITEC), polyglyceryl-2 dioleate (Nikkol DGDO, Nikko), polyglyceryl aryl-10 trioleate (Nikkol Decaglyn 3-O, Nikko), polyglyceryl-10 pentaoleate (Nikkol Decaglyn 5-O, Nikko), polyglyceryl-10 septaoleate (Nikkol Decaglyn 7-O, Nikko), polyglyceryl-10 tetraolcate (CaproI® I OG4O, ABITEC), polyglyceryl-10 decaisostearate (Nikkol Decaglyn 10-IS, Nikko), polyglyceryl-101 decaoleate (Drewpol 10-10-O, Stepan), polyglyceryl-10 mono, dioleate (Caprol® PGE 860, ABITEC) and polyglyceryl polyricinoleate (Polymuls, Henkel). The SSRI/steroid combination formulations of the invention may contain one or more of the above polyglycerylated fatty acids.

Additionally, propylene glycol and fatty acid esters can be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available propylene glycol fatty acid esters are as follows: propylene glycol monocaprylate (Capryol 90, Gattefosse), propylene glycol monolaurate (Lauroglycol 90, Gattefosse), propylene glycol oleate (Lutrol OP2000, BASF), propylene glycol myristate (Mirpyl), propylene glycol monostearate (LIPO PGMS, Lipo Chem.), propylene glycol hydroxystearate, propylene glycol ricinoleate (PROPYMULS, Henkel), propylene glycol isostearate, propylene glycol monooleate (Myverol P-O6, Eastman), propylene glycol dicaprylate dicaprate (Captex® 200, ABITEC ), propylene glycol dioctanoate (Captex® 800, ABITEC), propylene glycol caprylate caprate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate, propylene glycol distearate (Kessco® PGDS, Stepan), propylene glycol dicaprylate (Nikkol Sefsol 228, Nikko) and propylene glycol dicaprate (Nikkol PDD, Nikko). The SSRI/steroid combination formulations of the invention may contain one or more of the above propylene glycol and fatty acid esters.

Mixtures of propylene glycol esters and glycerol esters can also be used as excipients for the SSRI/steroid combination formulations described herein. One preferred mixture is composed of oleic acid ester of propylene glycol and glycerol (Aralcel 186). Examples of these surfactants are: oleic (ATMOS 300, ARLACEL 186, ICI) and stearic (ATMOS 150). The SSRI/steroid combination formulations of the invention may contain one or more of the above mixtures of propylene glycol esters and glycerol esters.

Furthermore, mono- and diglycerides can be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available mixtures of mono- and diglycerides are: monopalmitolein (C16:1) (Larodan), monoelaidin (C18:1) (Larodan), monocaproin (C6) (Larodan), monocaprylin (Larodan), monocaprin (Larodan), monolaurin ( Larodan), glyceryl monomyristate (C14) (Nikkol MGM, Nikko), glyceryl monooleate (C18:1) (PECEOL, Gattefosse), glyceryl monooleate (Myverol, Eastman), glycerol monooleate/linoleate (OLICINE, Gattefosse), glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate (Soffigen® 701, Huls), glyceryl monolaurate (ALDO® MLD, Lonza), glycerol monopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul® GMS , ABITEC), glyceryl mono- and di-oleate (Capmul® GMO-K, ABITEC), glyceryl-palmityl/stearyl (CUTINA MD-A, ESTAGEL-G18), glyceryl-acetate (Lamegin® EE, Grunau-GmbH) glyceryl- laurate (Imwitor® 312, Huls), glyceryl citrate/lactate/oleate/linoleate (Imwitor® 375, Huls), glyceryl caprylate (Imwitor® 308, Huls), glyceryl caprylate/caprate (Capmul® MCM, ABITEC), caprylic acid and mono- and dig lycerides (Imwitor® 988, Huls), caprylic/capric glycerides (Imwitor® 742, Huls), mono- and diacetylated monoglycerides (Myvacet® 9-45, Eastman), glyceryl monostearate (Aldo® MS, Arlacel 129, ICI), mono and diglycerides of medicinal acid (LAMEGIN GLP, Henkel), dikaproin (C6) (Larodan), dicaprine (C10) (Larodan), dioctanoin (C8) (Larodan), dimyristin (C14) (Larodan), dipalmitin (C16) (Larodan ), distearin (Larodan), glyceryl dilaurate (C12) (Capmul® GDL, ABITEC), glyceryl dioleate (CapmuI® GDO, ABITEC), glycerol fatty acid esters (GELUCIRE 39/01, Gattefosse), dipalmitolein (C16:1 ) (Larodan), 1,2 and 1,3-diolein (C18:1) (Larodan), dielaidin (C18:1) (Larodan) and dilinolein (C 18:2) (Larodan). Formulations of the SSRI/steroid combination according to the invention may contain one or more of the above mono- and diglyceride mixtures.

Sterol and sterol derivatives can also be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available sterols and sterol derivatives are as follows: cholesterol, sitosterol, lanosterol, PEG-24-cholesterol-ether (Solulan C-24, Amerchol), PEG-30 cholestanol (Phytosterol GENEROL series, Henkel), PEG-25 phytosterol (Nikkol BPSH-25, Nikko), PEG-5 sojasterol (Nikkol BPS-5, Nikko), PEG-10 sojasterol (Nikkol BPS-10, Nikko), PEG-20 sojasterol (Nikkol BPS-5, Nikko), PEG-10 sojasterol (Nikkol BPS-20, Nikko) and PEG-30 soyasterol (Nikkol BPS-30, Nikko). The SSRI/steroid combination formulations according to the invention may contain one or more of the above sterols and sterol derivatives.

Polyethyleneglycol-sorbitan and fatty acid esters can also be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available polyethylene glycol-sorbitan fatty acid esters are as follows: PEG-10 sorbitan laurate (Liposorb L-10, Lipo Chem.), PEG-20 sorbitan monolaurate (Tween® 20, Atlas/ICI), PEG-4 sorbitan -monolaurate (Tween®-21, AtIas/lCl), PEG-80 sorbitan-menolaurate (Hodag PSML-80, Calgene), PEG-6 sorbitan-monolaurate (Nikkol GL-1, Nikko), PEG-20 sorbitan-monopalmitate ( Tween® 40, Atlas/ICI), PEG-20 sorbitan monostearate (Tween® 60, Atlas/ICI), PEG-4 sorbitan monostearate (Tween® 61, Atlas/ICI), PEG-8 sorbitan monostearate (DACOL MSS , Condea), PEG-6 sorbitan monostearate (Nikkol TS106, Nikko), PEG-20 sorbitan tristearate (Tween® 65, Atlas/ICI), PEG-6 sorbitan tetrastearate (Nikkol GS-6, Nikko), PEG-60 sorbitan tetrastearate (Nikkol GS-460, Nikko), PEG-5 sorbitan monooleate (Tween® 81, Atlas/ICI), PEG-6 sorbitan monooleate (Nikkol TO-106, Nikko), PEG-20 sorbitan monooleate (Tween ® 80, Atlas/ICI), PEG-40 sorbitan oleate (Emalex ET 8040, Nihon Emulsion), PEG-20 sorbitan trioleate (Tweeng 8 5, Atlas/ICI), PEG-6 sorbitan tetraoleate (Nikkol GO-4, Nikko), PEG-30 sorbitan tetraoleate (Nikkol GO-430, Nikko), PEG-40 sorbitan tetraoleate (Nikkol GO-440, Nikko ), PEG-20 sorbitan-monoisostearate (Tween® 120, Atlas/ICI), PEG sorbitol-hexaoleate (Atlas G-1086, ICI), polysorbate 80 (Tween® 80, Pharma), polysorbate 85 (Tween® 85, Pharma) , polysorbate 20 (Tween® 20, Pharma), polysorbate 40 (Tween® 40, Pharma), polysorbate 60 (Tween® 60, Pharma), and PEG-6 sorbitol-hexastearate (Nikkol GS-6, Nikko). Formulations of the SSRI/steroid combination according to the invention may contain one or more of the above polyethylene glycol sorbitan fatty acid esters.

Additionally, propylene glycol alkyl esters can be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available alkyl esters of propylene glycol are as follows: PEG-2 oleyl ether, olet-2 (Brij 92/93, Atlas/ICI), PEG-3 oleyl ether, olet-3 (Volpo 3, Croda), PEG-5 oleyl ether, olet-5 (Volpo 5, Croda), PEG-10 oleyl ether, olet-10 (Volpo 10, Croda), PEG-20 oleyl ether, olet-20 (Volpo 20, Croda), PEG- 4 lauryl ether, laureth-4 (Brij 30, Atlas/ICI), PEG-9 lauryl ether, PEG-23-lauryl ether, laureth-23 (Brij 35, Atlas/ICI), PEG-2 cetyl ether ( Brij 52, ICI), PEG-10 cetyl ether (Brij 56, ICI), PEG-20 cetyl ether (Brij 58, ICI), PEG-2 stearyl ether (Brij 72, ICI), PEG-10 stearyl- ether (Brij 76, ICI), PEG-20 stearyl ether (Brij 78, ICI) and PEG-100 stearyl ether (Brij 700, ICI). The SSRI/steroid combination formulations of the invention may contain one or more of the above propylene glycol alkyl esters.

Sugar esters can also be used as excipients for the SSRI/steroid combination formulations described herein. Examples of commercially available sugar esters are as follows: sucrose-distearate (SUCRO ESTER 7, Gattefosse), sucrose-distearate/monostearate (SUCRO ESTER 11, Gattefosse), sucrose-dipalmitate, sucrose-monostearate (Crodesta F-160, Croda), sucrose- monopalmitate (SUCRO ESTER 15, Gattefosse) and sucrose monolaurate (Saccharose monolaurate 1695, Mitsubishi-Kasei). Formulations of the SSRI/steroid combination according to the invention may contain one or more of the above sugar esters.

Polyethyleneglycol alkylphenols are also useful excipients for the formulation of the SSRI-steroid combination described herein. Examples of commercially available polyethylene glycol alkylphenols are as follows: PEG-15-100 nonylphenol series (Triton X series, Rohm & Haas). The SSRI/steroid combination formulations of the invention may contain one or more of the above polyethylene glycol alkylphenols.

Polyoxyethylene-polyoxypropylene block polymers are also useful excipients for the formulation of the SSRI-steroid combination described herein. These surfactants are available under various trade names including one or more of the Synperonic PE series (ICI), Pluornic® series (BASF), Lutrol (BASF), Supronic, Monolan, Pluracare and Pludorac. The generic term for copolymers is "poloxamer" (CAS 9003-11-6). These polymers have the formula (X):

HO(C2H4O)a(C3H6O)b(C2H4O)aH

(X)

where "a" and "b" indicate the number of polyoxyethylene and polyoxypropylene units. These copolymers have a molecular weight in the range of 1000 to 15000 dlatons, and the ratio of ethylene oxide/propylene/oxide is between 0.1 and 0.8 by mass. The SSRI/steroid combination formulations of the present invention may contain one or more of the above polyoxyethylene-polyoxypropylene block polymers.

Polyoxyethylenes such as PEG 300, PEG 400 and PEG 600 can be used as excipients for the formulation of the SSRI/steroid combinations described herein.

Sorbitan and fatty acid esters can also be used as excipients for the formulation of the SSRI-steroid combination described herein. Examples of commercially available esters of sorbitan and fatty acids are as follows: sorbitan monolaurate (Span-20, Atlas/ICI), sorbitan monopalmitate (Span-40, Atlas/ICI), sorbitan monooleate (Span-80, Atlas/ICI), sorbitan monostearate (Span-60, Atlas/ICI), sorbitan trioleate (Span-85, Atlas/ICI), sorbitan sesquioleate (Arlacel-C, ICI), sorbitan tristearate (Span-65, Atlas/ICI), sorbitan monoisostearate (Crill 6, Croda) and sorbitan sesquistearate (Nikkol SS-15, Nikko). Formulations of the SSRI/steroid combination according to the invention may contain one or more of the above sorbitan and fatty acid esters.

Esters of lower alcohols (C2 to C4) and fatty acids (C8 to C18) are suitable for use in the invention as surfactants. Examples of such surfactants are: ethyl oleate (Crodamol EO, Croda), isopropyl myristate (Crodamol IPM, Croda), isopropyl palmitate (Crodamol IPP, Croda), ethyl linoleate (Nikkol VF-E, Nikko) and isopropyl- linoleate (Nikkol VF-IP, Nikko). The SSRI/steroid combination formulations of the invention may contain one or more of the above lower alcohol and fatty acid esters.

In addition, ionic surfactants can be used as excipients for the SSRI/steroid combination formulation described herein. Examples of useful ionic surfactants are: sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristolate, sodium palmitate, sodium palmitoleate, sodium oleate, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl- sulfate (dodecyl), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium glyco- cheno-deoxycholate, sodium cholylsarkonizate, sodium N-methyltaurocholate, egg yolk phosphatides, hydrated soy lecithin, dimyristoyl-lecithin, lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl-ethanolamine, phosphatidic acid, phosphatidyl-glycerol, phosphatidyl-serine , diethanolamine, phosphol lipids, polyoxyethylene-10 oleyl-ether-phosphate, esterification products of fatty alcohols or ethoxylates of fatty alcohols with phosphoric acid or anhydride, ether-carboxylates (by oxidation of the terminal OH group of ethoxylates of fatty alcohols), succinylated monoglycerides, sodium stearyl fumarate, stearoyl-propylene glycol hydrogensuccinate , mono/diacetylated tartaric acid esters of mono- and diglycerides, citric acid esters of mono- and diglycerides, glyceryl-lacto esters of fatty acids, acyl lactylates, lactyl esters of fatty acids, sodium stearoyl-2-lactylate, sodium stearoyl-lactylate, alginate salts , propylene glycol-alginate, toxylated alkyl-sulfates, alkylbenzene-sulfones, �-olefin-sulfonates, acyl-isethionates, acyl-taurates, alkyl-glyceryl-ether sulfonates, sodium octyl-sulfosuccinate, sodium undecylenamideo-MEA-sulfosuccinate, hexadecyl-triammonium bromide, decyl-trimethyl ammonium bromide, cetyl-trimethyl ammonium bromide, dodecyl-ammonium chloride, alkyl-benzyldimethylammonium salts, diisobutyl -phenoxyethoxydimethylbenzylammonium salts, alkylpyridinium salts, betaines (trialkylglycine), lauryl betaine (N-lauryl-N,N-dimethylglycine) and ethoxylated amines (polyoxyethylene-15 coconut amines). For simplicity, typical counterions are shown above. It will be clear to one skilled in the art that, however, any bio-acceptable counterion can be used. For example, although fatty acids are shown as sodium salts, other cations as counterions can also be used, such as, for example, alkali metal cations or ammonium ion. The SSRI/steroid combination formulations of the invention may contain one or more of the above ionic surfactants.

The excipients present in the formulations of the invention are present in such amounts that the carrier forms a clear or cloudy aqueous dispersion of the SSRI, steroid or SSRI/steroid combination located within the liposomes. The relative amount of surface-active excipient required for a liposomal preparation or for a solid lipid nanoparticle formulation is determined using known methodology. For example, lyosomes can be assembled by various techniques such as those described in Szoka et al, 1980. Multilamellar Vesicles (MLV), and can be prepared by simple lipid film hydration techniques. In this procedure, a mixture of lipids forming a liposome of the type detailed above is dissolved in a suitable organic solvent and evaporated in a vessel so that a thin film is formed which is then covered with an aqueous medium. The lipid film hydrates and forms MLV, whose typical size is about 0.1 to 10 microns.

Other known techniques for creating liposomal formulations can be used as needed. For example, the use of liposomes to facilitate cellular uptake is described in U.S. Pat. Patents no. 4,897,355 and 4,394,448.

Dosage

Generally when administered orally to a human, the dose of an SSRI is normally about 0.01 mg to 200 mg per day, preferably about 1 mg to 100 mg per day, and more preferably about 5 mg to 50 mg per day. A dose of up to 200 mg per day may be necessary. For SSRI administration by injection, the dose is normally about 1 mg to 250 mg per day, preferably about 5 mg to 200 mg per day, and more preferably about 10 mg to 150 mg per day. It is preferable that the injections are given four times a day.

When administered systemically to a human, the dose of corticosteroid for use in combination with an SSRI is normally about 0.1 mg to 1500 mg per day, preferably about 0.5 mg to 10 mg per day, and more preferably about 0.5 mg to 5 mg per day.

Administration of each drug in combination can be independently four times a day for a year, or even for the entire life of the patient. Chronic, long-term administration is indicated in many cases.

Additional application

Compounds of the invention can be used in an immunomodulatory or mechanistic assay to determine whether another combination or single agent is effective as a combination to inhibit the secretion or production of proinflammatory cytokines or to modulate an immune response using commonly known assays, such as those described herein. For example, a candidate compound can be combined with an SSRI (or a metabolite or an analog thereof) or a corticosteroid and administered to stimulated PBMC. After a suitable time in the cells, the secretion of cytokines or the production of another suitable immune response is tested. The relative effects of one combination to another and to one agent are compared and the effective compound or combination is identified.

The combinations of the invention are also useful tools for elucidating mechanistic information. Such information may lead to the development of new combinations or a single agent for the inhibition of inflammation caused by proinflammatory cytokines. Methods known in the art can be used to determine the biological pathways or network of pathways that are acted upon by contacting cells stimulated to produce proinflammatory cytokines with the compounds of the invention. Such methods may include analysis of cellular constituents that are expressed or reduced upon exposure to compounds of the invention compared to untreated compounds as positive and negative controls and/or novel single agents and combinations or analysis of some other metabolic activity in the cell such as enzymatic activity, food intake and proliferation. Cellular components analyzed may include gene transcripts and protein expression. Suitable methods may include standard biochemical techniques, radiolabeling of the compounds of the invention (eg 14C or 3H labeling) and observing the binding of the compounds to proteins, eg using 2d gels, gene expression profiling. Once such a compound is identified it can be used in an in vivo model to further evaluate the tool or develop new anti-inflammatory agents.

The following examples are presented to illustrate the invention. They are not meant to limit the invention in any way.

Example 1: Test for reducing the activity of proinflammatory cytokines

Diluted arrays of the compounds were tested to reduce IFN�, IL-1�, IL-2, IL-4, IL-5 and TNFα, as described below.

INFα

A 100 μL suspension of diluted human white blood cells placed in each well of a 384-well polystyrene plate (NalgeNunc) was stimulated to secrete IFNα by treatment with a final concentration of 10 ng/mL phorbol-12-myristate-13-acetate (Sigma, P -1585) and 750 ng/mL ionomycin (Sigma, I-0634). Different concentrations of the test compound were added at the time of stimulation. After 16-18 hours of incubation at 37°C in a humidified incubator, the plates were centrifuged and the supernatant was transferred to a 384-well opaque polystyrene plate (NalgeNunc, Maxisorb) coated with anti-IFN� antibody (Endogen, #M-700A-E). After two hours of incubation, the plate was washed (Tecan Power Washer 384) with phosphonate-buffered saline (PBS) containing 0.1% Tween 20 (polyethylenesorbitan-monolaureate) and incubated for another hour with another anti-IFN� antibody that was labeled biotin (Endogen, M701B) and horseradish peroxidase (HRP) bound to steptavidin (PharMingen, #13047E). After washing the plate with 0.1% Tween20/PBS, HRP-luminescent substrate was added to each well and light intensity was measured using an LJL Analyst plate luminometer.

IL-1�

A 100 �L suspension of diluted human white blood cells placed in each well of a 384-well polystyrene plate (NalgeNunc) was stimulated to secrete IL-1� by a final concentration of 2 �g/mL lipopolysaccharide (Sigma, L-4130). . Different concentrations of the test compound were added at the time of stimulation. After 16-18 hours of incubation at 37°C in a humidified incubator, the plates were centrifuged and the supernatant was transferred to a 384-well opaque polystyrene plate (NalgeNunc, Maxisorb) coated with anti-IL-1� antibody (R&D, #MAB-601). After two hours of incubation, the plate was washed (Tecan Power Washer 384) with PBS containing 0.1% Tween 20 and incubated for another hour with another biotin-labeled anti-IL-1� antibody (R&D, #BAF-201) and HRP bound to steptavidin (PharMingen, #13047E). After washing the plate with 0.1% Tween20/PBS, HRP-luminescent substrate was added to each well and light intensity was measured using an LJL Analyst plate luminometer.

IL-2

A 100 �L suspension of diluted human white blood cells contained in each well of a 384-well polystyrene plate (NalgeNunc) was stimulated to secrete IL-2 by action with a final concentration of 10 ng/mL phorbol-12-myristate-13-acetate ( Sigma, P-1585) and 750 ng/mL ionomycin (Sigma, I-0634). Different concentrations of the test compound were added at the time of stimulation. After 16-18 hours of incubation at 37 °C in a humidified incubator, the plates were centrifuged and the supernatant was transferred to a 384-well opaque polystyrene plate (NalgeNunc, Maxisorb) coated with anti-IL-2 antibody (PharMingen #555051). After two hours of incubation, the plate was washed (Tecan Power Washer 384) with PBS containing 0.1% Tween 20 and incubated for another hour with another anti-IFN antibody labeled with biotin (Endogen, M701B) and horseradish peroxidase (HRP ) bound to steptavidin (PharMingen, #13047E). After washing the plate with 0.1% Tween20/PBS, HRP-luminescent substrate was added to each well and light intensity was measured using an LJL Analyst plate luminometer.

IL-4 and IL-5

Analysis of IL-4 and IL-5 cytokine expression was performed using the BD PharMingen Cytometric 6 Bead Array system according to the manufacturer's instructions. Briefly, the supernatant from the buffy layer from the plate was incubated with a labeled bead cocktail for cytokine detection. Samples were then washed, resuspended and read on a BD Pharmingen FACsCAlibur flow cytometer. Data were analyzed using the BD Pharmingen CBA 6 Bead Analysis program.

TNF�

A 100 �L suspension of diluted human white blood cells placed in each well of a 384-well polystyrene plate (NalgeNunc) was stimulated to secrete IL-1� by a final concentration of 2 �g/mL lipopolysaccharide (Sigma, L-4130). . Different concentrations of the test compound were added at the time of stimulation. After 16-18 hours of incubation at 37 °C in a humidified incubator, the plates were centrifuged and the supernatant was transferred to a 384-well opaque polystyrene plate (NalgeNunc, Maxisorb) coated with anti-TNF� antibody (PharMingen #551220). After two hours of incubation, the plate was washed (Tecan Power Washer 384) with PBS containing 0.1% Tween 20 and incubated for another hour with another anti-TNF antibody labeled with biotin (PharMingen #554511) and HRP bound to steptavidin ( PharMingen, #13047E). After washing the plate with 0.1% Tween 20/PBS, HRP-luminescent substrate was added to each well and light intensity was measured using an LJL Analyst plate luminometer.

Example 2: Preparation of compounds

Stock solutions containing the corticosteroid or SSRI were made in dimethylsulfoxide (DMSO) to a final concentration between 0 and 40 �M/ Plates were prepared to contain a dilution of the stock solution of the compound described above. The plates were stored at -20 °C until use of the compound.

The final plate media signal was generated by transferring 1 µL of stock solution from the specic plate to a dilution plate containing 100 µL of media (RPMI, Gibco BRL, #11875-085), 10% fetal bovine serum (Gibco BRL, #25140-097 ), 2% penicillin/streptomycin (Gibco BRL, #15140-122)) using a Packard Mini-Trak for liquid handling. The diluted plates were then mixed and a 5 �L aliquot was transferred to a test plate to which 10 �L/well of RPMI medium containing the appropriate stimulant to activate IFN�, IL-1�, IL-2 or TNG� had been previously added. (see Example 1, supra).

Example 3: Testing SSRIs, analogs and metabolites in preventing proinflammatory cytokine activity

The ability of certain agents to prevent the secretion of IFN�, IL-1�, IL-2 or TNG����� stimulated white blood cells and the percentage of inhibition of cytokine secretion, relative to untreated stimulated white blood cells, was tested. The data are presented below in Tables 5-14.

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Example 4: Testing SSRIs for Inhibition of TNFα Activity

Combinations of SSRIs and corticosteroids were tested for their ability to prevent the secretion of TNF� from stimulated white blood cells, and the percentage of inhibition of cytokine secretion in relation to stimulated white blood cells was determined. The data are presented in Tables 15-22.

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The ability of the combination of prednisolone and paroxetine to inhibit the secretion of IL-4 and IL-5 in vitro was also tested. The results are presented in Tables 23 and 24.

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Example 5: The combination of cyclosporin A and sertraline reduces the secretion of IL-2 in vitro

IL-2 secretion was measured by ELISA as described above after stimulation with phorbol-12-myristate-13-acetate and ionomycin. The effects of different concentrations of cyclosporine A, sertraline and the combination of sertraline and cyclosporine A were compared with control wells. These wells were stimulated with phorbol-12-myristate-13-acetate and ionomycin, but did not receive cyclosorin A or sertraline.

The results of this experiment are shown in Table 15. The effects of the agents themselves and the combination are shown as a percentage of inhibition of IL-2 secretion.

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Example 6: The combination of cyclosporin A and sertraline reduces the secretion of IFN� in vitro

IFN� secretion was measured by ELISA as described above after stimulation with phorbol-12-myristate-13-acetate and ionomycin. The effects of different concentrations of cyclosporine A, sertraline and the combination of sertraline and cyclosporine A were compared with control wells. These wells were stimulated with phorbol-12-myristate-13-acetate and ionomycin, but did not receive cyclosorin A or sertraline. The results of these studies are shown below in Table 26. The effects of the agents themselves and the combination are shown as a percentage of IFN� secretion inhibition.

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Example 7: The combination of cyclosporin A and sertraline reduces the secretion of TNF� in vitro

TNFα secretion was measured by ELISA as described above after stimulation with phorbol-12-myristate-13-acetate and ionomycin. The effects of different concentrations of cyclosporine A, sertraline and the combination of sertraline and cyclosporine A were compared with control wells. These wells were stimulated with phorbol-12-myristate-13-acetate and ionomycin, but did not receive cyclosorin A or sertraline. The results of these studies are shown below in Table 27. The effects of the agents themselves and the combination are shown as a percentage of TNF� secretion inhibition.

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Example 8: The combination of cyclosporin A and fluoxetine reduces the secretion of IL-2 in vitro

IL-2 secretion was measured by ELISA as described above after stimulation with phorbol-12-myristate-13-acetate and ionomycin. The effects of different concentrations of cyclosporine A, fluoxetine and the combination of cyclosporine A and fluoxetine were compared with control wells. These wells were stimulated with phorbol-12-myristate-13-acetate and ionomycin, but did not receive cyclosorin A or fluoxetine. The results of these studies are shown below in Table 28. The effects of the agents themselves and the combination are shown as a percentage of inhibition of IL-2 secretion.

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Example 9: The combination of tacrolimus and fcuoxetine reduces the secretion of IL-2 in vitro

IL-2 secretion was measured by ELISA as described above after stimulation with phorbol-12-myristate-13-acetate and ionomycin. The effects of different concentrations of tacrolimus, fluoxetine and the combination of tacrolimus and fluoxetine were compared with control wells. These wells were stimulated with phorbol-12-myristate-13-acetate and ionomycin, but did not receive tacrolimus or fluoxetine. The results of these studies are shown below in Table 29. The effects of the agents themselves and the combination are shown as a percentage of inhibition of IL-2 secretion.

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Example 10: The combination of cyclosporine A and paroxetine reduces the secretion of IL-2 in vitro

IL-2 secretion was measured by ELISA as described above after stimulation with phorbol-12-myristate-13-acetate and ionomycin. The effects of different concentrations of cyclosporine A, paroxetine and the combination of sretraline and paroxetine were compared with control wells. These wells were stimulated with phorbol-12-myristate-13-acetate and ionomycin, but did not receive cyclosorin A or paroxetine. The results of these studies are shown below in Table 30. The effects of the agents themselves and the combination are shown as a percentage of inhibition of IL-2 secretion.

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Other units

Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope of the invention. While the invention has been described in connection with specific embodiments desired, it is to be understood that the invention as claimed in the claims should not be unnecessarily limited to specific embodiments. Indeed, various modifications of the described methods of carrying out the invention, which are apparent to those skilled in the art of medicine, immunology, pharmacology, endocrinology, or related fields, are intended to be within the scope of the invention.

Claims (77)

1. The preparation, characterized by the fact that it contains a selective serotonin reuptake inhibitor (SSRI) and a corticosteroid, and in amounts that together are sufficient for in vivo reduction of secretion or production of a proinflammatory cytokine. 2. The preparation from patent claim 1, characterized in that said SSRI is ceriklamin citalopram, clovoxamine, cyanodothiepine, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazin, litoxetine, milnacipran, paroxetine, sertraline, tametraline, vicvalin or zimeldine . 3. The preparation from claim 1, characterized in that said corticosteroid is prednisolone, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone or diflorasone. 4. The preparation from claim 1, characterized in that said SSRI is fluoxetine or paroxetine, and said corticosteroid is prednisolone. 5. The composition of claim 1, characterized in that said SSRI and said corticosteroid are present in said composition in a low dose. 6. The preparation from claim 1, characterized in that said SSRI and said corticosteroid are present in said preparation in a high dose. 7. The preparation of patent claim 1, characterized in that it further contains NSAID, COX-2 inhibitor, DMARD, biologic, xanthine, anticholinergic compound, beta-receptor agonist, bronchodilator, non-steroidal clacineurin inhibitor, vitamin D analogue, psoralen, retinoid and 5- aminosalicylic acid. 8. The preparation from claim 7, characterized in that said NSAID is ibuprofen, diclofenac or naproxen. 9. The preparation from claim 7, characterized in that said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib or lumiracoxib. 10. The preparation from claim 7, characterized in that said biologic is adellimumab, etanercept or infliximab. 11. The preparation from claim 7, characterized in that said DMARD is methotrexate or leflunomide. 12. The preparation from patent claim 7, characterized in that said xanthine is theophylline. 13. The preparation from claim 7, characterized in that said anticholinergic compound is ipratropium or tiotropium. 14. The preparation from claim 7, characterized in that said beta-receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol acetate, salmaterol xinafoate or terbutaline. 15. The preparation from claim 7, characterized in that said non-steroidal calcineurin inhibitor is ciclosporin, tacrolimus, pimecrolimus or ISAtx247. 16. The preparation from patent claim 7, characterized in that said analog of vitamin D is calcipotriene or calcipotriol. 17. The preparation from patent claim 7, characterized in that said psoralen is methoxsalen. 18. The preparation from claim 7, characterized in that said retinoid is acitretin or tazoreten. 19. The preparation from claim 7, characterized in that said 3-aminosalicylic acid is mesalamine, sulfasalazine, disodium balsalazide or sodium oxalazine. 20. The preparation from patent claim 1, characterized in that said preparation is formulated for topical administration. 21. The preparation from patent claim 1, characterized in that said preparation is formulated for systemic administration 22. A method of reducing secretion or production of a proinflammatory cytokine in a patient, indicated by the fact that said method comprises administering to the patient an SSRI and a corticosteroid simultaneously or at a distance from each other within 14 days, in amounts sufficient for in vivo reduction of secretion or production of a proinflammatory cytokine in said to the patient. 23. A method of treating a patient who has been diagnosed with an immunoinflammatory disorder or is at risk for its development, indicated by the fact that said method includes giving the patient an SSRI and a corticosteroid simultaneously or at an interval of 14 days, in amounts sufficient for the treatment of said patient. 24. The method from patent claim 23, characterized in that said autoimmune disorder is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, polymyalgia rheumatica, large cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthemia gravis. , psoriasis, ankylosing spondylitis or arthritis caused by psoriasis. 25. The method of patent claim 23, characterized in that said SSRI is cericlamin citalopram, clovoxamine, cyanodothiepine, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazin, litoxetine, milnacipran, paroxetine, sertraline, tametraline, vicvalin or zimeldine . 26. The method from claim 23, characterized in that said corticosteroid is prednisolone, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone or diflorasone. 27. The method of claim 23, characterized in that it comprises administering to said patient an NSAID, COX-2 inhibitor, DMARD, biologic, xanthine, anticholinergic compound, beta-receptor agonist, bronchodilator, nonsteroidal clacineurin inhibitor, vitamin D analog, psoralen, retinoid and 5-aminosalicylic acid. 28. The method of claim 27, characterized in that said NSAID is ibuprofen, diclofenac or naproxen. 29. The method from claim 27, characterized in that said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib or lumiracoxib. 30. The method from patent claim 27, characterized in that said biologic is adellimumab, etanercept or infliximab. 31. The method of claim 27, characterized in that said DMARD is methotrexate or leflunomide. 32. The method of claim 27, characterized in that said xanthine is theophylline. 33. The method from claim 27, characterized in that said anticholinergic compound is ipratropium or tiotropium. 34. The method from claim 27, characterized in that said beta-receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol acetate, salmaterol xinafoate or terbutaline. 35. The method of claim 27, characterized in that said non-steroidal calcineurin inhibitor is ciclosporin, tacrolimus, pimecrolimus or ISAtx247. 36. The method from claim 27, characterized in that said vitamin D analogue is calcipotriene or calcipotriol. 37. The method of claim 27, characterized in that said psoralen is methoxalene. 38. The method of claim 27, characterized in that said retinoid is acitretin or tazoreten. 39. The method of claim 27, characterized in that said 3-aminosalicylic acid is mesalamine, sulfasalazine, disodium balsalazide or sodium oxalazine. 40. The method of claim 23, characterized in that said SSRI and said corticosteroid are present in said preparation in a low dose. 41. The method of claim 23, characterized in that said SSRI and said corticosteroid are present in said preparation in a high dose. 42. The method of claim 23, wherein said SSRI and said corticosteroid are administered within 10 days of each other. 43. The method of claim 42, wherein said SSRI and said corticosteroid are administered within five days of each other. 44. The method of claim 43, wherein said SSRI and said corticosteroid are administered within twenty-four hours of each other. 45. The method of claim 44, wherein said SSRI and said corticosteroid are administered simultaneously. 46. Preparation, characterized in that it contains an SSRI and a glucocorticoid receptor modulator, in amounts that are together sufficient to reduce the secretion or production of a proinflammatory cytokine. 47. The preparation from patent claim 46, characterized in that said SSRI is cericlamin citalopram, clovoxamine, cyanodothiepine, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazin, litoxetine, milnacipran, paroxetine, sertraline, tametraline, vicvalin or zimeldine . 48. The method of patent claim 46, characterized in that it further contains a compound selected from the group consisting of: NSAID, COX-2 inhibitor, DMARD, biologic, xanthine, anticholinergic compound, beta-receptor agonist, bronchodilator, nonsteroidal inhibitor of clacineurin, vitamin D analog , psoralen, retinoid and 5-aminosalicylic acid. 49. A method of reducing the secretion or production of a proinflammatory cytokine in a patient, characterized in that said method comprises administering to the patient an SSRI and a glucocorticoid receptor modulator at the same time or at an interval of 14 days, in amounts sufficient for in vivo reduction of the secretion or production of a proinflammatory cytokine cytokines in said patient. 50. A method of treating a patient who has been diagnosed with an immunoinflammatory disorder or is at risk for its development, indicated by the fact that said method includes giving the patient an SSRI and a glucocorticoid receptor modulator at the same time or at an interval of 14 days, in amounts sufficient for the treatment of said patient . 51. The method from patent claim 50, characterized in that said autoimmune disorder is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, polymyalgia rheumatica, large cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthemia gravis , psoriasis, ankylosing spondylitis or arthritis caused by psoriasis. 52. The method of patent claim 50, characterized in that said SSRI is ceriklamin citalopram, clovoxamine, cyanodothiepine, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazin, litoxetine, milnacipran, paroxetine, sertraline, tametraline, vicvalin or zimeldine . 53. The method of patent claim 50, characterized in that it comprises administering to said patient an NSAID, COX-2 inhibitor, DMARD, biologic, xanthine, anticholinergic compound, beta-receptor agonist, bronchodilator, nonsteroidal clacineurin inhibitor, vitamin D analog, psoralen, retinoid and 5-aminosalicylic acid. 54. The method of claim 50, wherein said SSRI and said glucocorticoid receptor modulator are administered within 10 days of each other. 55. The method of claim 54, wherein said SSRI and said glucocorticoid receptor modulator are administered within five days of each other. 56. The method of claim 55, wherein said SSRI and said glucocorticoid receptor modulator are administered within twenty-four hours of each other. 57. The method of claim 44, wherein said SSRI and said glucocorticoid receptor modulator are administered simultaneously. 58. Pharmaceutical preparation, characterized in that it contains (i) an SSRI and (ii) another compound selected from the group consisting of: xanthine, anticholinergic compound, beta-receptor agonist, bronchodilator, biologic, NSAID, DMARD, COX-2 inhibitor, non-steroidal clacineurin inhibitor, vitamin D analogue, psoralen, retinoid and 5-aminosalicylic acid. 59. The method of claim 58, characterized in that said NSAID is ibuprofen, diclofenac or naproxen. 60. The method from claim 58, characterized in that said COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib or lumiracoxib. 61. The method from patent claim 58, characterized in that said biologic is adellimumab, etanercept or infliximab. 62. The method of claim 58, characterized in that said DMARD is methotrexate or leflunomide. 63. The method of claim 58, characterized in that said xanthine is theophylline. 64. The method of patent claim 58, characterized in that said anticholinergic compound is ipratropium or tiotropium. 65. The method from patent claim 58, characterized in that said beta-receptor agonist is ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate, pirbuterol acetate, salmaterol xinafoate or terbutaline. 66. The method of claim 58, characterized in that said non-steroidal calcineurin inhibitor is ciclosporin, tacrolimus, pimecrolimus or ISAtx247. 67. The method of claim 58, characterized in that said vitamin D analog is calcipotriene or calcipotriol. 68. The method of claim 58, characterized in that said psoralen is methoxalene. 69. The method of claim 58, characterized in that said retinoid is acitretin or tazoreten. 70. A method of preventing the secretion of one or more proinflammatory cytokines in a patient who needs it, indicated by the fact that said method includes giving the patient (i) an SSRI and (ii) another compound selected from the group consisting of: xanthine, anticholinergic compound, agonist beta-receptor, bronchodilator, biologic, NSAID, DMARD, COX-2 inhibitor, non-steroidal clacineurin inhibitor, vitamin D analogue, psoralen, retinoid and 5-aminosalicylic acid, and in amounts sufficient for in vivo reduction of secretion or production of proinflammatory cytokines in said to the patient. 71. A method of preventing the secretion of one or more pro-inflammatory cytokines in a patient in need thereof, characterized in that said method comprises administration to the patient in an amount sufficient for in vivo reduction of the secretion or production of pro-inflammatory cytokines in said patient. 72. A method of treating a patient who has been diagnosed with an immunoinflammatory disorder or is at risk of developing it, characterized in that said method includes giving the patient an SSRI in an amount and for a duration that is sufficient for the treatment of said patient. 73. The set, indicated by the fact that it contains: (i) a preparation containing an SSRI and a corticosteroid, and (ii) instructions for administering said preparation to a patient diagnosed with an immunoinflammatory disorder. 74. The set, indicated by the fact that it contains: (i) SSRIs, (ii) corticosteroid, and (ii) instructions for systemic administration of said SSRI and said corticosteroid to a patient diagnosed with an immunoinflammatory disorder or at risk for its development. 75. A kit, comprising (i) an SSRI and (ii) instructions for administering said SSRI to a patient diagnosed with an immunoinflammatory disorder. 76. A set, indicated by the fact that it contains: (i) SSRIs, (ii) another compound selected from the group consisting of: glucocorticoid receptor modulator, xanthine, anticholinergic compound, beta-receptor agonist, biologic, NSAID, DMARD, COX-2 inhibitor, beta-receptor agonist, bronchodilator, nonsteroidal clacineurin inhibitor, vitamin D analog , psoralen, retinoid and 5-aminosalicylic acid, and (iii) instructions for administering said preparation to a patient who has been diagnosed with an immunoinflammatory disorder or is at risk for its development. 77. A method of identifying combinations of compounds useful for preventing the secretion of proinflammatory cytokines in a patient in need of such tremtan, characterized in that said method contains the following steps: (a) contacting the cells in vitro with the SSRI and the candidate compound, and (b) determining whether combinations of said SSRI and said candidate compound reduce cytokine levels in white blood cells stimulated to secrete cytokines, relative to cells that have been exposed to said SSRI but not exposed to said candidate compound or contacted with said candidate compound but not contacted with said SSRI, wherein a reduction in the level of said cytokine identifies the combination as useful for the treatment of a patient in need of such treatment.