CN1700921A - Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines - Google Patents

Abstract

The invention features a method for treating a patient diagnosed with, or at risk of developing, an immunoinflammatory disorder by administering an SSRI or analog or metabolite thereof and, optionally, a corticosteroid or other compound to the patient. The invention also features a pharmaceutical composition containing an SSRI or analog or metabolite thereof and a corticosteroid or other compound for the treatment or prevention of an immunoinflammatory disorder.

Description

Be used for the treatment of diseases related method and the medicine of proinflammatory cytokine level rising

Background of invention

The present invention relates to the immunoinflammatory treatment of diseases.

The feature of immunoinflammatory disease is the incorrect activation of immunity of organism defence.The immunne response targeting also damages body autologous tissue or transplanted tissue, rather than the infectious invador of targeting.With the difference of disease, organizing of immune system institute targeting is also different.For example, in multiple sclerosis, immunne response is at neuronal tissue, targeting digestive tract then in Crohn disease (Crohn ' s disease).The individuality that the immunoinflammatory affect is millions of, the disease that comprises be asthma, anaphylactic endophthalmitis disease, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatosis, inflammatory bowel or gastroenteropathy (for example Crohn disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritus/inflammation, psoriasis, rheumatoid arthritis and systemic lupus erythematosus (sle) for example.

Usually depend on immunosuppressant for immunoinflammatory treatment of diseases scheme at present.The curative effect difference of these medicines, and their application is often with toxic and side effects.Therefore, need can be used for treating the improved medicine and the method for immunoinflammatory disease.

Summary of the invention

On the one hand, of the present inventionly be characterized as a kind of compositions, described compositions comprises selectivity 5-hydroxy tryptamine reuptake inhibitor (SSRI) (or its analog or metabolite) and corticosteroid, and its total consumption is enough to treat the patient's of needs immunoinflammatory disease.If needed, described compositions can comprise one or more extra chemical compounds (for example glucocorticoid receptor modulator, NSAID, cox 2 inhibitor, DMARD, biological preparation, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid or 5-aminosalicylic acid).Described compositions can be mixed with for example for the topical or the usefulness that is administered systemically.

On the other hand, the method that is characterized as the interior proinflammatory cytokine secretion of a kind of patient's of minimizing body or produces of the present invention, described method comprises gives or gave respectively described patient SSRI (or its analog or metabolite) and corticosteroid simultaneously that in 14 days its consumption is enough to reduce the secretion or the generation of proinflammatory cytokine in described patient's body.

In a related aspect, of the present inventionly be characterized as a kind of method of suffering from the immunoinflammatory disease after diagnosing or the patient that the danger of immunoinflammatory disease takes place being arranged that is used for the treatment of, described method comprises gives or gave respectively described patient SSRI (or its analog or metabolite) and corticosteroid simultaneously that in 14 days its consumption is enough to treat described patient.

In arbitrary said method, also can give one or more extra chemical compounds of described patient (for example glucocorticoid receptor modulator, NSAID, cox 2 inhibitor, DMARD, biological preparation, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid or 5-aminosalicylic acid).

If needed, can give SSRI and/or corticosteroid by low dosage or high dose.Described medicine is adapted at giving respectively in 10 days, better gives respectively in 5 days, even better gives respectively in 24 hours or even give (promptly giving simultaneously) simultaneously.

In a related aspect, of the present inventionly be characterized as a kind of method that is used for the treatment of the patient's that needs are arranged immunoinflammatory disease, described method comprises and gives described patient SSRI (or its analog or metabolite) and corticosteroid simultaneously that its total amount ratio gives corticosteroid when not having SSRI more effective concerning treatment immunoinflammatory disease.

In another related fields, of the present inventionly be characterized as a kind of method that is used for the treatment of the patient's that needs are arranged immunoinflammatory disease, described method comprises and gives described patient SSRI (or its analog or metabolite) and corticosteroid simultaneously that its total amount ratio gives SSRI when not having corticosteroid more effective concerning treatment immunoinflammatory disease.

In related fields again, of the present inventionly be characterized as a kind of method that is used for the treatment of the patient's that needs are arranged immunoinflammatory disease, described method comprises and gives described patient's corticosteroid; With give described patient SSRI (or its analog or metabolite); Wherein: (i) give corticosteroid and SSRI and (ii) give described patient's corticosteroid and SSRI dosage separately gives corticosteroid or give SSRI when not having corticosteroid more effective concerning treatment immunoinflammatory disease than when not having SSRI simultaneously.

Feature of the present invention also is a kind of Pharmaceutical composition of unit dosage forms, and described compositions comprises corticosteroid; With SSRI or its analog or metabolite, wherein when giving described patient, the amount ratio of corticosteroid and SSRI gives corticosteroid or give SSRI when not having corticosteroid more effective concerning treatment immunoinflammatory disease when not having SSRI.

Feature of the present invention also is a kind of medicine box, and described medicine box comprises (i) compositions, and described compositions comprises SSRI or its analog or metabolite, and corticosteroid; (ii) description, this description indication gives described compositions to suffer from after diagnosing the patient of immunoinflammatory disease.

In a related aspect, of the present inventionly be characterized as a kind of medicine box, described medicine box comprises: (i) SSRI (or its analog or metabolite); (ii) corticosteroid; (iii) description, this description indication gives SSRI and corticosteroid to suffer from after diagnosing the patient of immunoinflammatory disease.

If needed, can substitute corticosteroid in method of the present invention, compositions and the medicine box with glucocorticoid receptor modulator or other steroid receptor modulator.

Therefore, on the other hand, of the present inventionly be characterized as a kind of compositions, described compositions comprises SSRI (or its analog or metabolite) and glucocorticoid receptor modulator, and its total consumption is enough to treat the patient's of needs immunoinflammatory disease.If needed, described compositions can comprise the chemical compound that one or more are extra.Described compositions can be mixed with for example for the topical or the usefulness that is administered systemically.

On the other hand, of the present inventionly be characterized as a kind of method that is used to reduce proinflammatory cytokine secretion in patient's body or produces, described method comprises gives or gave respectively described patient SSRI (or its analog or metabolite) and glucocorticoid receptor modulator simultaneously that in 14 days its consumption is enough to reduce the secretion or the generation of proinflammatory cytokine in described patient's body.

On the other hand, of the present inventionly be characterized as a kind of method that is used to reduce proinflammatory cytokine secretion in patient's body or produces, described method comprises gives or gave respectively described patient SSRI (or its analog or metabolite) and glucocorticoid receptor modulator simultaneously that in 14 days its consumption is enough to reduce the secretion or the generation of proinflammatory cytokine in described patient's body.

In a related aspect, of the present inventionly be characterized as a kind of method of suffering from the immunoinflammatory disease after diagnosing or the patient that the danger of immunoinflammatory disease takes place being arranged that is used for the treatment of, described method comprises gives or gave respectively described patient SSRI (or its analog or metabolite) and glucocorticoid receptor modulator simultaneously that in 14 days its consumption is enough to treat described patient.Described medicine is adapted at giving respectively in 10 days, better gives respectively in 5 days, even better gives respectively in 24 hours or even give (promptly giving simultaneously) simultaneously.

In a related aspect, of the present inventionly be characterized as a kind of method that is used for the treatment of the patient's that needs are arranged immunoinflammatory disease, described method comprises and gives described patient SSRI (or its analog or metabolite) and glucocorticoid receptor modulator simultaneously that its total amount ratio gives glucocorticoid receptor modulator when not having SSRI more effective concerning treatment immunoinflammatory disease.

In another related fields, of the present inventionly be characterized as a kind of method that is used for the treatment of the patient's that needs are arranged immunoinflammatory disease, described method comprises and gives described patient SSRI (or its analog or metabolite) and glucocorticoid receptor modulator simultaneously that its total amount ratio gives SSRI when not having glucocorticoid receptor modulator more effective concerning treatment immunoinflammatory disease.

In related fields again, of the present inventionly be characterized as a kind of method that is used for the treatment of the patient's that needs are arranged immunoinflammatory disease, described method comprises and gives described patient's glucocorticoid receptor modulator; And give described patient SSRI (or its analog or metabolite); Wherein: (i) give glucocorticoid receptor modulator and SSRI and (ii) give described patient's glucocorticoid receptor modulator and SSRI amount ratio separately gives glucocorticoid receptor modulator or give SSRI when not having glucocorticoid receptor modulator more effective concerning treatment immunoinflammatory disease when not having SSRI simultaneously.

Feature of the present invention also is a kind of Pharmaceutical composition of unit dosage forms, and described compositions comprises glucocorticoid receptor modulator; And SSRI (or its analog or metabolite), wherein when giving described patient, the amount ratio of glucocorticoid receptor modulator and SSRI gives glucocorticoid receptor modulator or give SSRI when not having glucocorticoid receptor modulator more effective concerning treatment immunoinflammatory disease when not having SSRI.

Feature of the present invention also is a kind of medicine box, and described medicine box comprises (i) compositions, and described compositions comprises SSRI (or its analog or metabolite) and glucocorticoid receptor modulator; (ii) description, this description indication gives described compositions to suffer from after diagnosing the patient of immunoinflammatory disease.

In a related aspect, of the present inventionly be characterized as a kind of medicine box, described medicine box comprises: (i) SSRI, or its analog or metabolite; (ii) glucocorticoid receptor modulator; (iii) description, this description indication gives SSRI and glucocorticoid receptor modulator to suffer from after diagnosing the patient of immunoinflammatory disease.

As described herein, when not having corticosteroid, SSRI or its analog or metabolite also have anti-inflammatory activity.Therefore, feature of the present invention also is the excretory method of one or more proinflammatory cytokines in a kind of patient's body that is used to suppress to have needs, and described method comprises and give described patient SSRI that its consumption is enough to suppress the secretion of the interior proinflammatory cytokine of described patient's body.

In a related aspect, of the present inventionly be characterized as a kind of method that is used for the treatment of the patient who suffers from the immunoinflammatory disease after diagnosing, described method comprises and gives described patient SSRI (or its analog or metabolite) that its consumption and persistent period are enough to treat described patient.

Feature of the present invention also is a kind of medicine box, and described medicine box comprises (i) SSRI (or its analog or metabolite) and (ii) description, and this description indication gives SSRI to suffer from after diagnosing the patient of immunoinflammatory disease.

On the other hand, of the present inventionly be characterized as a kind of Pharmaceutical composition, described compositions comprises SSRI (or its analog or metabolite) and is selected from the second following chemical compound: xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid or 5-aminosalicylic acid.

The authentication method that feature of the present invention also makes up for the excretory chemical compound of proinflammatory cytokine in a kind of patient's body that is used to suppress this treatment of needs, described method comprises: (a) make cell at external contact SSRI (or its analog or metabolite) and candidate compound; (b) with respect to contact SSRI but do not contact the cell of described candidate compound or contact described candidate compound but do not contact the cell of SSRI, whether the combination of determining SSRI and described candidate compound reduces the level of cytokine described in the hemocyte of irriate secrete cytokines, wherein identifies the patient's who can be used for treating this treatment of needs combination medicine from the reduction of described cytokine levels.

Be used for chemical compound of the present invention and comprise the chemical compound described herein that is any its pharmaceutically acceptable form, comprise isomer, salt, ester, solvate and polymorphs such as its diastereomer and enantiomer, and the racemic mixture of chemical compound described herein and pure isomer.

" SSRI " is meant any member of the chemical compound with following characteristic: (i) suppress the picked-up of central nervous system neurons to 5-hydroxy tryptamine, (ii) its suppress constant (Ki) be 10nM or below the 10nM and (iii) to the selectivity of 5-hydroxy tryptamine greater than the ratio of norepinephrine (being Ki (norepinephrine) and Ki (5-hydroxy tryptamine)) greater than 100.When SSRI was used as antidepressants, its dosage was usually greater than 10mg/ days.This paper has described and has been used for exemplary SSRI of the present invention.

" corticosteroid " is meant with the hydrogenation cyclopentanoperhydro-phenanthrene is any naturally occurring or synthetic chemical compound of feature, and it has immunosuppressant and/or anti-inflammatory activity.Naturally occurring corticosteroid is produced by adrenal cortex usually.Synthetic corticosteroid can be by halogenation.This paper provides the example of corticosteroid.

" non-steroidal immunophilin dependent immunity inhibitor " or " NsIDI " be meant the generation that reduces proinflammatory cytokine or secretion, in conjunction with immunophilin or cause any non-steroidal drug of short scorching reaction downward modulation.NsIDI comprises neurocalcin inhibitor such as cyclosporin, tacrolimus, ascosin, pimecrolimus, and the other medicines (peptide, fragments of peptides, chemical modification peptide or peptide mimics) that suppress the phosphatase activity of neurocalcin.NsIDI also comprises rapamycin (sirolimus) and everolimus, and these medicines are conjugated protein with FK506, FKBP-12 combines, and the antigen induction propagation of blocking leukocyte and the secretion of cytokine.

" low dosage " is meant than preparation and is used for the treatment of the minimum standards recommended dose of particular compound of specific administration approach of any human diseases or disease low at least by 5% (for example at least low 10%, 20%, 50%, 80%, 90% or even low 95%).For example, preparation is for oral administration different with the corticosteroid low dosage with corticosteroid low dosage and preparation for inhalation.

" high dose " is meant the highest standard recommended dose high at least by 5% (for example high at least 10%, 20%, 50%, 100%, 200% or even high by 300%) than the particular compound of the specific administration approach that is used for the treatment of any human diseases or disease.

" median dose " is meant the dosage between low dosage and high dose.

Dosage when " dosage that is equivalent to prednisolone dosage " is meant the SSRI of corticosteroid and given dose or its analog or metabolite coupling, this dosage produce identical anti-inflammatory effect during with the coupling of prednisolone dosage in patient's body.

" treatment " is meant and gives or specify Pharmaceutical composition to be used for the treatment of or the epidemic prevention inflammatory diseases.

" patient " is meant any animal (for example people).Other animal of available method of the present invention, compositions and medicine box treatment comprises horse, Canis familiaris L., cat, pig, goat, rabbit, hamster, monkey, Cavia porcellus, rat, mice, Eremiatis argi, Serpentis, sheep, cattle, fish and birds.In one embodiment of the invention, the patient who accepts treatment described herein does not have clinical depression, anxiety neurosis or Panic-stricken, obsession, alcoholism, eating disorders, ADHD, marginal personality's disease, sleep disorder, headache, premenstrual syndrome, irregular heart beating, schizophrenia, tourette's syndrome (Tourette ' s syndrome) or phobia.

" enough dosage " be meant in drug combination of the present invention, treats or the consumption of the needed chemical compound of epidemic prevention inflammatory diseases in clinical relevant mode.That the treatment of being used for the treatment of property is caused by the immunoinflammatory disease in practice of the present invention or cause that the enough dosage of reactive compound of the disease of immunoinflammatory disease will change with administering mode, patient's age, body weight and the different of general health situation.Finally, determine suitable dose and dosage regimen by the doctor that prescription power is arranged.In addition, effective dose can be the dosage of chemical compound during the present invention makes up, according to the definite and approval of cura legitima department (for example U.S. food and drug administration), described combination is safer, more effective when treatment suffers from the patient of immunoinflammatory disease than every kind of medicine list is used.

" more effective " is meant the other therapies for being compared, and treatment shows more large effect, and perhaps littler toxicity, safer, more convenient is perhaps more cheap.The technical staff can adopt any standard method that is suitable for given indication to measure effect.

Term " immunoinflammatory disease " comprises various diseases, comprises autoimmune disease, proliferative skin disorders and inflammatory dermatosis.The immunoinflammatory disease is owing to inflammatory process, immune system disorder and undesired cell proliferation cause health tissues destroyed.The example of immunoinflammatory disease is an acne vulgaris; Adult respiratory distress syndrome; Addison disease (Addison ' sdisease); Allergic rhinitis; The anaphylactic endophthalmitis disease, the little vascular vasculitis of ANCA dependency; Ankylosing spondylitis; Arthritis, asthma; Atherosclerosis; Atopic dermatitis; Autoimmune hemolytic anemia; Autoimmune hepatitis; Behcet syndrome (Behcet ' s disease); Facial paralysis (Bell ' s palsy); Bullous pemphigoid; Cerebral ischemia; Chronic obstructive disease of lung; Cogan syndrome (Cogan ' s syndrome); Contact dermatitis; COPD; Crohn disease; Hypercortisolism (Cushing ' s syndrome); Dermatomyositis; Diabetes; Discoid lupus erythematosus; Eosinophilic fasciitis; Erythema nodosum; Exfoliative dermatitis; Fibromyalgia; FGS; Giant cell arteritis; Gout; Gouty arthritis; Graft versus host disease; Hand eczema; Purpura,Henoch-Schonlein (Henoch-Schonlein purpura); Herpes gestationis; Hirsutism; Special inflammation corneal-scleral; Idiopathic pulmonary fibrosis; Idiopathic thrombocytopenic purpura; Inflammatory bowel or gastrointestinal disease, inflammatory dermatosis; Lichen planus; Lupus nephritis; The lymphoma tracheobronchitis; The speckle edema; Multiple sclerosis; Myasthenia gravis; Myositis; Osteoarthritis; Pancreatitis; Pemphigoid gestationis; Pemphigus vulgaris; Polyarteritis nodosa; Polymyalgia rheumatica; Scrotal pruritus; Pruritus/inflammation, psoriasis; Psoriasis arthropathica; Rheumatoid arthritis; Relapsing polychondritis; Rosacea due to the sarcoidosis; Rosacea due to the scleroderma; Rosacea due to the sweet's syndrome (Sweet ' s syndrome); The caused by systematic lupus erythematosus rosacea; Rosacea due to the urticaria; Rosacea due to the herpes zoster pain; Sarcoidosis; Scleroderma; Segmental glomerulosclerosis disease; The septic shock syndrome; Shoulder tendinitis or bursitis; Xerodermosteosis (Sjogren ' s syndrome); Still disease (Still ' s disease); The brain cell death that apoplexy causes; Sweet's syndrome; Systemic lupus erythematosus (sle); Systemic sclerosis; Pulseless (Takayasu ' s arteritis); Temporal arteritis; Toxicity epidermis necrolysis; Tuberculosis; Type i diabetes; Ulcerative colitis; Uveitis; Vasculitis; With wegener granulomatosis disease (Wegener ' s granulomatosis).

" non-skin inflammatory diseases " comprises for example rheumatoid arthritis, inflammatory bowel, asthma and chronic obstructive disease of lung.

" skin inflammatory diseases " or " inflammatory skin disease " comprises for example psoriasis, acute febrile neutrophilic dermatosis, eczema (dry eczema for example, pompholyx, brothers' vesicle eczema), balanitis circumscripta plasmacellularis, balanoposthitis, behcet disease, erythema annulare centrifugum, the erythema chromicum figuratum melanodermicum, erythema multiforme, granuloma annulare, lichen nitidus, lichen planus, lichen planus morphoeicus, simple chronic lichen, lichen spinulosus, coin shape dermatitis, PG, sarcoidosis, SPD, urticaria and transience acantholysis dermatosis.

" proliferative skin disorders " is meant that quickening cell division with epidermis or corium is the optimum or malignant disease of feature.The example of proliferative skin disorders is basaloma and squamous cell carcinoma, lamellar ichthyosis, epidermolytic hyperkeratosis, the preceding keratosis of deterioration, acne and the seborrheic dermatitis of psoriasis, atopic dermatitis, ergotropy dermatitis, stimulus object constitutional contact dermatitis, contact dermatitis, skin.

Just as understood by a person skilled in the art, a kind of specified disease, obstacle or disease can be feature with proliferative skin disorders and inflammatory dermatosis.The example of described disease is a psoriasis.

" slow release " or " controlled release " is meant that the therapeutic activity composition discharges from preparation with controllable rate, make the useful blood levels of this component for treating (but being lower than toxic level) keep one period long period, its time scope for example about 12 hours to about 24 hours, therefore, the dosage form of 12 hours or 24 hours for example is provided.

In the upper description of The compounds of this invention, the atomic number of concrete kind can provide scope usually in the substituent group, for example contains the alkyl or the C of 1-7 carbon atom _1-7Alkyl.Comprise as for the expection of described scope and to be specifically related to that each has the group of integer number atom in specified scope.For example, the alkyl of 1-7 carbon atom comprises C respectively ₁, C ₂, C ₃, C ₄, C ₅, C ₆And C ₇C _1-7Assorted alkyl for example except comprising one or more hetero atoms, also comprises 1-7 carbon atom.The atom of other atomic number and other kind can be represented by similar manner.

" acyl group " be meant have formula R-C (O)-chemical part, wherein R is selected from C _1-7Alkyl, C _2-7Thiazolinyl, C _2-7Alkynyl, C _2-6Heterocyclic radical, C _6-12Aryl, C _7-14Alkaryl, C _3-10Alkane heterocyclic radical or C _1-7Assorted alkyl.

" alkoxyl " is meant the chemical substituent group of formula-OR, and wherein R is selected from C _1-7Alkyl, C _2-7Thiazolinyl, C _2-7Alkynyl, C _2-6Heterocyclic radical, C _6-12Aryl, C _7-14Alkaryl, C _3-10Alkane heterocyclic radical or C _1-7Assorted alkyl.

" aryloxy group " is meant the chemical substituent group of formula-OR, and wherein R is C _6-12Aryl.

" C _6-12Aryl " be meant the aryl (for example phenyl) of ring system with the carbon atom that contains conjugated pi electron.Described aryl has 6-12 carbon atom.Aryl can be chosen wantonly and comprise monocycle, dicyclo or three rings, and wherein each encircles preferably 5 yuan of rings or 6 yuan of rings.Described aryl can be substituted or not be substituted.Exemplary substituent group comprises alkyl, hydroxyl, alkoxyl, aryloxy group, sulfydryl, alkylthio group, arylthio, halogen, fluoro-alkyl, carboxyl, hydroxy alkyl, carboxyalkyl, amino, aminoalkyl, a substituted-amino, disubstituted amido and quaternary ammonium group.

" acylamino-" is meant the chemical substituent group of formula-NRR ', and wherein nitrogen-atoms is the part (for example-C (O)-NRR ') of amido link, and wherein R and R ' independently are selected from C separately _1-7Alkyl, C _2-7Thiazolinyl, C _2-7Alkynyl, C _2-6Heterocyclic radical, C _6-12Aryl, C _7-14Alkaryl, C _3-10Alkane heterocyclic radical and C _1-7Assorted alkyl, perhaps-NRR ' formation as above defines but contains the C of at least one nitrogen-atoms _2-6Heterocyclic radical, for example piperidino, morpholino and azabicyclo base.

" halogen " or " halogen " is meant bromine, chlorine, iodine or fluorine.

Term " pharmaceutically acceptable salt " representative is applicable to contact tissue and lower animal tissue and does not have other problem such as over-drastic toxicity, zest, allergy and have the salt of quite rational interests/risk ratio in rational medication determination range.Pharmaceutically acceptable salt is well-known in the art.Can be during the final separation of The compounds of this invention and purification the described salt of in-situ preparing, perhaps by with its free alkali functional group and appropriate organic reaction through separating the described salt of preparation.Representational acid-addition salts comprises acetate, adipate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphorate, camsilate, citrate, cyclopentane propionate, glucosaccharic acid salt, lauryl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, the heptose hydrochlorate, caproate, hydrobromate, hydrochlorate, hydriodate, 2-hydroxyl-esilate, isethionate, the lactobiose hydrochlorate, lactate, laruate, lauryl sulfate, malate, maleate, malonate, mesylate (mesylate), mesylate (methanesulfonate), the 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalates, palmitate, embonate, pectate, persulfate, 3-phenylpropionic acid salt, phosphate, picrate, Pivalate, propionate, stearate, succinate, sulfate, tartrate, rhodanate, toluene fulfonate, the hendecane hydrochlorate, valerate etc.Representational alkali metal salt or alkali salt comprise sodium salt, lithium salts, potassium salt, calcium salt, magnesium salt etc., and nontoxic ammonium salt, quaternary ammonium salt and amine cation, include but not limited to the salt of ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethamine etc.

Be used for chemical compound of the present invention and comprise the chemical compound described herein that is any its pharmaceutically acceptable form, comprise isomer, salt, ester, amide, thioesters, solvate and polymorphs such as its diastereomer and enantiomer, and the racemic mixture of chemical compound described herein and pure isomer.As an example, " paroxetine " is meant free alkali and any pharmaceutically acceptable salt (for example maleic acid paroxetine, paroxetine hydrochloride semihydrate and methanesulfonic acid paroxetine) thereof.

From following detailed description and claims, can be well understood to other characteristics of the present invention and advantage.

Detailed Description Of The Invention

Of the present invention being characterized as is used to give independent SSRI or its analog or the metabolite of effective dose or unites give SSRI or its analog or metabolite and corticosteroid or other chemical compound method, compositions and medicine box with treatment immunoinflammatory disease.

In one embodiment of the invention, by patient SSRI (or its analog) and the corticosteroid that needs this treatment, treat the immunoinflammatory disease.

Below the present invention will be described in more detail.

Selectivity 5-hydroxy tryptamine reuptake inhibitor

Method of the present invention, compositions and medicine box use SSRI or its analog or functional analogue.Suitable SSRI comprises cericlamine (for example hydrochloric acid cericlamine); Citalopram (for example citalopram hydrobromate); Clovoxamine; Cyanogen dosulepin (cyanodothiepin); Dapoxetine; Escitalopram (oxalic acid escitalopram); Femoxetine (for example FG-4963); Fluoxetine (for example fluoxetine Hydrochloride); Fluvoxamine (for example fluvoxamine maleate); Ifoxetine; Indalpine (for example hydrochloric acid indalpine); Indeloxazine (for example hydrochloric acid indeloxazine); Litoxetine; Midalcipran (for example milnacipran hydrochloride); Paroxetine (paroxetine hydrochloride semihydrate for example; The maleic acid paroxetine; The methanesulfonic acid paroxetine); Sertraline (for example sertraline hydrochloride); The hydrochloric acid tametraline; Viqualine; And zimeldine (for example hydrochloric acid zimeldine).

Cericlamine

Cericlamine has following structure:

The cericlamine analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

R wherein ₁Be C ₁-C ₄Alkyl, R ₂Be H or C _1-4Alkyl, R ₃Be H, C _1-4Alkyl, C _2-4Thiazolinyl, phenylalkyl or have cycloalkyl-alkyl, alkanoyl, the octadecyloxy phenyl acyl group of 3-6 ring carbon atom or have the naphthene base carbonyl of 3-6 ring carbon atom, perhaps R ₂And R ₃Form heterocycle with the nitrogen-atoms that connects them, described heterocycle is saturated by 5-7 the chain link institute that it can have oxygen, sulfur or nitrogen, and second hetero atom is not directly connected on this nitrogen-atoms simultaneously, and the nitrogen heteroatom of back may carry C _2-4Alkyl.

Exemplary cericlamine analog is 2-methyl-2-amino-3-(3, the 4-Dichlorobenzene base)-propanol, 2-amyl group-2-amino-3-(3, the 4-Dichlorobenzene base)-propanol, 2-methyl-2-methylamino-3-(3, the 4-Dichlorobenzene base)-propanol, 2-methyl-2-dimethylamino-3-(3, the 4-Dichlorobenzene base)-propanol; And the pharmaceutically acceptable salt of all above-claimed cpds.

Citalopram

Citalopram has following structure:

The citalopram analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

R wherein ₁And R ₂Independently be selected from bromine, chlorine, fluorine, trifluoromethyl, cyano group and R-CO-separately, wherein R is C _1-4Alkyl.

Therefore exemplary citalopram analog (be SSRI analog of the present invention) is 1-(4 '-fluorophenyl)-1-(3-dimethylamino-propyl)-5-bromine phthalein alkane (phthalane); 1-(4 '-chlorphenyl)-1-(3-dimethylamino-propyl)-5-chlorine phthalein alkane; 1-(4 '-bromophenyl)-1-(3-dimethylamino-propyl)-5-chlorine phthalein alkane; 1-(4 '-fluorophenyl)-1-(3-dimethylamino-propyl)-5-chlorine phthalein alkane; 1-(4 '-chlorphenyl)-1-(3-dimethylamino-propyl)-5-trifluoromethyl-phthalein alkane; 1-(4 '-bromophenyl)-1-(3-dimethylamino-propyl)-5-trifluoromethyl-phthalein alkane; 1-(4 '-fluorophenyl)-1-(3-dimethylamino-propyl)-5-trifluoromethyl-phthalein alkane; 1-(4 '-fluorophenyl)-1-(3-dimethylamino-propyl)-5-fluorine phthalein alkane; 1-(4 '-chlorphenyl)-1-(3-dimethylamino-propyl)-5-fluorine phthalein alkane; 1-(4 '-chlorphenyl)-1-(3-dimethylamino-propyl)-5-phthalein alkane formonitrile HCN; 1-(4 '-fluorophenyl)-1-(3-dimethylamino-propyl)-5-phthalein alkane formonitrile HCN; 1-(4 '-cyano-phenyl)-1-(3-dimethylamino-propyl)-5-phthalein alkane formonitrile HCN; 1-(4 '-cyano-phenyl)-1-(3-dimethylamino-propyl)-5-chlorine phthalein alkane; 1-(4 '-cyano-phenyl)-1-(3-dimethylamino-propyl)-5-trifluoromethyl phthalein alkane; 1-(4 '-fluorophenyl)-1-(3-dimethylamino-propyl)-5-phthalein alkane formonitrile HCN; 1-(4 '-chlorphenyl)-1-(3-dimethylamino-propyl)-5-violet base phthalein alkane; 1-(4-(chlorphenyl)-1-(3-dimethylamino-propyl)-5-propionyl phthalein alkane; And the pharmaceutically acceptable salt of all above-claimed cpds.

Clovoxamine

Clovoxamine has following structure:

The clovoxamine analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

Wherein Hal is chloro, bromo or fluorine-based, and R is cyano group, methoxyl group, ethyoxyl, methoxy, ethoxyl methyl, methoxy ethoxy or cyano methyl.

Exemplary clovoxamine analog is 4 '-chloro-5-ethoxybenzene pentanone O-(2-aminoethyl) oxime; 4 '-chloro-5-(2-methoxy ethoxy) benzene pentanone O-(2-aminoethyl) oxime; 4 '-chloro-6 methoxybenzene hexanone O-(2-aminoethyl) oximes; 4 '-chloro-6-ethoxybenzene hexanone O-(2-aminoethyl) oxime; 4 '-bromo-5-(2-methoxy ethoxy) benzene pentanone O-(2-aminoethyl) oxime; 4 '-bromo-5-methoxybenzene pentanone O-(2-aminoethyl) oxime; 4 '-chloro-6-cyano group benzene hexanone O-(2-aminoethyl) oxime; 4 '-chloro-5-cyano group benzene pentanone O-(2-aminoethyl) oxime; 4 '-bromo-5-cyano group benzene pentanone O-(2-aminoethyl) oxime; And the pharmaceutically acceptable salt of all above-claimed cpds.

Femoxetine

Femoxetine has following structure:

The femoxetine analog has the following formula structure:

R wherein ₁Represent C _1-4Alkyl or C _2-4Alkynyl, or the optional phenyl that is replaced by following group: C _1-4Alkyl, C _1-4Alkylthio group, C _1-4Alkoxyl, bromine, chlorine, fluorine, nitro, acyl amino, methyl sulphonyl, methylene-dioxy or tetralyl, R ₂Represent C _1-4Alkyl or C _2-4Alkynyl, R ₃Represent hydrogen, C _1-4Alkyl, C _1-4Alkoxyl, trifluoroalkyl, hydroxyl, bromine, chlorine, fluorine, methyl mercapto or aralkoxy.

Exemplary femoxetine analog is disclosed in United States Patent (USP) the 3rd, 912, No. 743 embodiment 7-67, and described patent documentation is attached to herein by reference.

Fluoxetine

Fluoxetine has following structure:

The fluoxetine analog is chemical compound and the pharmaceutically acceptable salt thereof with following formula:

Each R wherein ₁Be hydrogen or methyl independently; R be naphthyl or

R wherein ₂And R ₃Be bromine, chlorine, fluorine, trifluoromethyl, C independently of one another _1-4Alkyl, C _1-3Alkoxyl or C _3-4Thiazolinyl; And n and m are 0,1 or 2 independently of one another.When R was naphthyl, it can be Alpha-Naphthyl or betanaphthyl.

Exemplary fluoxetine analog is 3-(to the isopropoxy phenoxy group)-3-phenylpropylamine methanesulfonates, 3-(3 ', 4 '-the dimethoxy phenoxy group)-3-phenylpropylamine P-hydroxybenzoic acid N, the N-dimethyl ester, bromination N, N-dimethyl 3-(alpha-naphthoxy base)-3-phenylpropylamine, iodate N, N-dimethyl 3-(β-naphthoxy)-3-phenyl-1-methyl propylamine, 3-(2 '-methyl-4 ', 5 '-dichlorophenoxy)-3-phenylpropylamine nitrate, 3-(to tert-butyl group phenoxy group)-3-phenylpropylamine glutarate, 3-(2 '-chloro-to toloxyl)-3-phenyl-1-methyl propylamine lactic acid N-methyl ester, 3-(2 ', 4 '-dichlorophenoxy)-3-phenyl-2-methyl propylamine citrate, 3-(an anisyl oxygen base)-3-phenyl-1-methyl propylamine maleic acid N, the N-dimethyl ester, 3-(to toloxyl)-3-phenylpropylamine sulphuric acid N-methyl ester, 3-(2 ', 4 '-two fluorophenoxies)-3-phenylpropylamine 2,4-dinitrobenzoic acid N, the N-dimethyl ester, 3-(adjacent ethyl phenoxy group)-3-phenylpropylamine dihydric phosphate, 3-(2 '-chloro-4 '-the isopropyl phenoxy group)-3-phenyl-2-methyl propylamine maleic acid N-methyl ester, 3-(2 ' alkyl-4 '-fluorophenoxy)-3-phenyl-propylamine succinic acid N, the N-dimethyl ester, 3-(adjacent isopropoxy phenoxy group)-3-phenyl-propylamine phenylacetic acid N, the N-dimethyl ester, 3-(adjacent bromine phenoxy group)-3-phenyl-propylamine β-Ben Jibingsuan N, the N-dimethyl ester, 3-(to the iodine phenoxy group)-3-phenyl-propylamine propanoic acid N-methyl ester and 3-(3-n-pro-pyl phenoxy group)-3-phenyl-propylamine capric acid N-methyl ester.

Fluvoxamine

Fluvoxamine has following structure:

The fluvoxamine analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

Wherein R is cyano group, cyano methyl, methoxy or ethoxyl methyl.

Indalpine

Indalpine has following structure:

The indalpine analog is those chemical compounds or its pharmaceutically acceptable salt with following formula structure:

R wherein ₁Be hydrogen atom, C ₁-C ₄Alkyl or its alkyl have the aralkyl of 1 or 2 carbon atom, R ₂Be hydrogen, C _1-4Alkyl, C _1-4Alkoxyl or C _1-4Alkylthio group, chlorine, bromine, fluorine, trifluoromethyl, nitro, hydroxyl or amino, the latter is optional to be replaced by one or two following group: C _1-4Alkyl, acyl group or C _1-4Alkyl sulphonyl; A representative-CO or-CH ₂-group; And n is 0,1 or 2.

Exemplary indalpine analog is indyl-3 (piperidyl-4 a methyl) ketone; (methoxyl group-5-indyl-3) (piperidyl-4 methyl) ketone; (chloro-5-indyl-3) (piperidyl-4 methyl) ketone; (indyl-3)-1 (piperidyl-4)-3 acetone, indyl-3 piperidyl-4 ketone; (methyl isophthalic acid indyl-3) (piperidyl-4 methyl) ketone, (benzyl-1 indyl-3) (piperidyl-4 methyl) ketone; [(methoxyl group-5 indyl-3)-2 ethyls]-piperidines, [(methyl isophthalic acid indyl-3)-2 ethyls]-4-piperidines; [(indyl-3)-2 ethyl-4 piperidines; (indyl-3 methyl)-4 piperidines, [(chloro-5 indyls-3)-2 ethyls]-4 piperidines; [(indyl-b 3)-3 propyl group]-4 piperidines; [(benzyl-1 indyl-3)-2 ethyls]-4 piperidines; And the pharmaceutically acceptable salt of all above-claimed cpds.

Indeloxazine

Indeloxazine has following structure:

The indeloxazine analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

R wherein ₁And R ₃Represent hydrogen, C separately _1-4Alkyl or phenyl; R ₂Represent hydrogen, C _1-4Alkyl, C _4-7Cycloalkyl, phenyl or benzyl; One in the dotted line is meant singly-bound, and another is meant the two keys or the mixture of its tautomer.

Exemplary indeloxazine analog is 2-(7-indenyl oxygen ylmethyl)-4-isopropyl morpholine; 4-butyl-2-(7-indenyl oxygen ylmethyl) morpholine; 2-(7-indenyl oxygen ylmethyl)-4-methyl morpholine; 4-ethyl-2-(7-indenyl oxygen ylmethyl) morpholine; 2-(7-indenyl oxygen ylmethyl)-morpholine; 2-(7-indenyl oxygen ylmethyl)-4-propyl group morpholine; 4-cyclohexyl-2-(7-indenyl oxygen ylmethyl) morpholine; 4-benzyl-2-(7-indenyl oxygen ylmethyl)-morpholine; 2-(7-indenyl oxygen ylmethyl)-4-phenylmorpholine; 2-(4-indenyl oxygen ylmethyl) morpholine; 2-(3-methyl-7-indenyl oxygen ylmethyl)-morpholine; 4-isopropyl-2-(3-methyl-7-indenyl oxygen ylmethyl) morpholine; 4-isopropyl-2-(3-methyl-4-indenyl oxygen ylmethyl) morpholine; 4-isopropyl-2-(3-methyl-5-indenyl oxygen ylmethyl) morpholine; 4-isopropyl-2-(1-methyl-3-phenyl-6-indenyl oxygen ylmethyl) morpholine; 2-(5-indenyl oxygen ylmethyl)-4-isopropyl-morpholine, 2-(6-indenyl oxygen ylmethyl)-4-isopropyl morpholine; With 4-isopropyl-2-(3-phenyl-6-indenyl oxygen ylmethyl) morpholine; And the pharmaceutically acceptable salt of all above-claimed cpds.

Midalcipran

Midalcipran has following structure:

The midalcipran analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

Wherein each R independently represents hydrogen, bromine, chlorine, fluorine, C _1-4Alkyl, C _1-4Alkoxyl, hydroxyl, nitro or amino; R ₁And R ₂Independent separately hydrogen, the C of representing _1-4Alkyl, C _6-12Aryl or C _7-14Alkylaryl, they are optional by bromine, chlorine or fluorine replacement (being preferably in para-orientation), perhaps R ₁And R ₂Form heterocycle with adjacent nitrogen atom with 5 yuan or 6 yuan; R ₃And R ₄Represent hydrogen or C _1-4Alkyl, perhaps R ₃And R ₄Form heterocycle with adjacent nitrogen atom, the optional hetero atom that is selected from nitrogen, sulfur and oxygen that also contains of this heterocycle with 5 yuan or 6 yuan.

Exemplary midalcipran analog is a 1-phenyl 1-amino carbonyl 2-dimethylamino methyl cyclopropane; 1-phenyl 1-dimethylamino carbonyl 2-dimethylamino methyl cyclopropane; 1-phenyl 1-B aminocarbonyl 2-dimethylamino methyl cyclopropane; 1-phenyl 1-diethylaminocarbonyl-2-amino methyl cyclopropane; 1-phenyl 2-dimethylamino methyl N-(4 '-chlorphenyl) cyclopropane carboxamide; 1-phenyl 2-dimethylamino methyl N-(4 '-the benzyl chloride base) cyclopropane carboxamide; 1-phenyl 2-dimethylamino methyl N-(2-phenethyl) cyclopropane carboxamide; (3,4-two chloro-1-phenyl) 2-dimethylamino methyl N, the N-dimethyl-cyclopropane carboxamide; 1-phenyl 1-pyrrolidinyl carbonyl 2-morpholinyl methyl cyclopropane; 1-rubigan 1-amino carbonyl 2-amino methyl cyclopropane; 1-Chloro-O-Phenyl 1-amino carbonyl 2-dimethylamino methyl cyclopropane; 1-p-hydroxybenzene 1-amino carbonyl 2-dimethylamino methyl cyclopropane; 1-p-nitrophenyl 1-dimethylamino carbonyl 2-dimethylamino methyl cyclopropane; 1-p-aminophenyl 1-dimethylamino carbonyl 2-dimethylamino methyl cyclopropane; 1-p-methylphenyl 1-amino-carbonyl 2-dimethylamino methyl cyclopropane; 1-p-methoxyphenyl 1-amino methyl carbonyl 2-amino methyl cyclopropane; And the pharmaceutically acceptable salt of all above-claimed cpds.

Paroxetine

Paroxetine has following structure:

The paroxetine analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

R wherein ₁Represent hydrogen or C _1-4Alkyl, and fluorine atom can be positioned on arbitrary available position.

Sertraline

Sertraline has following structure:

The Sertraline analog has the following formula structure:

R wherein ₁Be selected from hydrogen and C _1-4Alkyl; R ₂Be C _1-4Alkyl; X and Y are selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, C separately _1-3Alkoxyl and cyano group; W is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl and C _1-3Alkoxyl.Preferred Sertraline analog is cis-isomer configuration.Term " cis-isomer " is meant NR on the cyclohexene ring ₁R ₂Relative orientation (being the homonymy that they all are positioned at this ring) with phenyl moiety.Because 1-carbon and 4-carbon are all by asymmetric replacement,, be expressed as the enantiomer of enantiomer of (for 1-carbon) cis-(1R) and cis-(1S) so every kind of cis-compound all has two kinds of optical antimer forms.

Be (1S)-enantiomeric form or (1S) following compounds of the pharmaceutically acceptable salt of (1R) racemic modification form and they is particularly useful: cis-N-methyl-4-(3, the 4-Dichlorobenzene base)-1,2,3,4-tetrahydrochysene-naphthalidine; Cis-N-methyl-4-(4-bromophenyl)-1,2,3,4-tetrahydrochysene-naphthalidine; Cis-N-methyl-4-(4-chlorphenyl)-1,2,3,4-tetrahydrochysene-naphthalidine; Cis-N-methyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydrochysene-naphthalidine; Cis-N-methyl-4-(3-trifluoromethyl-4-chlorphenyl)-1,2,3,4-tetrahydrochysene-naphthalidine; Cis-N, N-dimethyl-4-(4-chlorphenyl)-1,2,3,4-tetrahydrochysene-naphthalidine; Cis-N, N-dimethyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydrochysene-naphthalidine; And cis-N-methyl-4-(4-chlorphenyl)-7-chloro-1,2,3,4-tetrahydrochysene-naphthalidine.Cis-N-methyl-4-(3, the 4-Dichlorobenzene base)-1,2,3, (the 1R)-enantiomer of 4-tetrahydrochysene-naphthalidine also is valuable.

Zimeldine

Zimeldine has following structure:

The zimeldine analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

Wherein said pyridine nucleus and adjacent carbon atom at the ortho position, a position or para-position combine, R wherein ₁Be selected from H, chlorine, fluorine and bromine.

Exemplary zimeldine analog be (e)-and (z)-3-(4 '-bromophenyl-3-(2 " pyridine radicals)-dimethyl allylamine; 3-(4 '-bromophenyl)-3-(3 " pyridine radicals)-dimethyl allylamine; 3-(4 '-bromophenyl)-3-(4 " pyridine radicals)-dimethyl allylamine; And the pharmaceutically acceptable salt of all above-claimed cpds.

This paper thinks that the analog of any above-mentioned SSRI all is the SSRI analog, therefore all can be used for any method of the present invention, compositions and medicine box.

Metabolite

The pharmacological activity metabolite of any above-mentioned SSRI also can be used for method of the present invention, compositions and medicine box.Exemplary metabolite is two Rac-Desmethylcitaloprams, Rac-Desmethylcitalopram, Desmethylsertraline and norfluoxetine.

Analog

The functional analogue of SSRI also can be used for method of the present invention, compositions and medicine box.Exemplary SSRI functional analogue is provided below.One class SSRI analog is SNRI (a selectivity 5-hydroxy tryptamine norepinephrine reuptake inhibitor), and it comprises venlafaxine and duloxetine.

Venlafaxine

Venlafaxine has following structure:

The venlafaxine analog is those chemical compounds and the pharmaceutically acceptable salt thereof with following formula structure:

Wherein A is the following formula part:

Or

What wherein dotted line was represented to choose wantonly is unsaturated; R ₁Be hydrogen or alkyl; R ₂Be C _1-4Alkyl; R ₄Be hydrogen, C _1-4Alkyl, formoxyl or alkanoyl; R ₃Be hydrogen or C _1-4Alkyl; R ₅And R ₆Be hydrogen, hydroxyl, C independently _1-4Alkyl, C _1-4Alkoxyl, C _1-4Alkanoyl oxygen base, cyano group, nitro, alkyl thiol, amino, C _1-4Alkyl amino, dialkyl amido, C _1-4Alkyl amido, halogen, trifluoromethyl, perhaps combining is methylene-dioxy; And n is 0,1,2,3 or 4.

Duloxetine

Duloxetine has following structure:

The duloxetine analog is a United States Patent (USP) the 4th, 956, disclosed chemical compound in No. 388, and described patent is attached to herein by reference.

Other SSRI analog is 1,2,3,4-tetrahydrochysene-N-methyl-4-phenyl-1-naphthylamine hydrochlorate; 1,2,3,4-tetrahydrochysene-N-methyl-4-phenyl-(E)-the naphthalidine hydrochlorate; N, N-dimethyl-1-phenyl-1-phthalein alkane propylamin hydrochloride; γ-(4-(trifluoromethyl) phenoxy group)-amfetamine hydrochlorate; BP554; CP53261; The O-desmethylvenlafaxine; WY 45,818; WY 45,881; N-(3-fluoropropyl) paroxetine; With Lu 19005.

Standard recommendation dosage

The standard recommendation dosage of exemplary SSRI sees the following form 1.Other standard dose provides in following document: Merck Manual of Diagnosis ﹠amp for example; Therapy (the 17th edition, MHBeers etc., Merck ﹠amp; Co.) and Physicians ' Desk Reference 2003 (the 57th edition, Medical Economics Staff etc., Medical Economics Co., 2002).

Table 1

Chemical compound	Standard dose
		Fluoxetine	20-80mg/ days
Sertraline	50-200mg/ days
		Paroxetine	20-50mg/ days
Fluvoxamine	50-300mg/ days
		Citalopram	10-80mg, every day 4 times
Escitalopram	10mg, every day 4 times

Corticosteroid

If needed, can give one or more corticosteroid in the method for the invention, perhaps can be in compositions of the present invention prepare with SSRI or its analog or metabolite.Suitable corticosteroid comprises 11-α, 17-α, and the 21-trihydroxy is pregnant-4-alkene-3, the 20-diketone; 11-β, 16-α, 17,21-four hydroxyls are pregnant-4-alkene-3, the 20-diketone; 11-β, 16-α, 17,21-four hydroxyls are pregnant-1,4-diene-3,20-diketone; 11-β, 17-α, 21-trihydroxy-6-Alpha-Methyl is pregnant-4-alkene-3, the 20-diketone; The 11-dehydrocorticosterone; Compd S 11-deoxycortisol; 11-hydroxyl-1,4-androstane diene-3,17-diketone; 11-ketone group testosterone; 14-hydroxy-androstane-4-alkene-3,6, the 17-triketone; 15, the 17-algestone; 16-hydrogenated methyl cortisone; 17,21-dihydroxy-16-Alpha-Methyl is pregnant-1,4,9 (11)-triolefins-3,20-diketone; The 17-Alpha-hydroxy is pregnant-4-alkene-3, and the 20-diketone; 17-Alpha-hydroxy pregnenolone; 17-hydroxyl-16-Beta-methyl-5-β-pregnant-9 (11)-alkene-3, the 20-diketone; 17-hydroxyl-4,6,8 (14)-pregnant triolefin-3,20-diketone; Pregnant-4,9 (11)-diene-3 of 17-hydroxyl, the 20-diketone; 18-hydroxyl corticosterone; 18-hydroxyl cortisone; 18-OXOF; 21-deoxidation aldosterone; The 21-desoxycortisone; 2-deoxidation ecdysone; 2-methyl cortisone; 3-dehydrogenation ecdysone; 4-pregnene-17-α, 20-β, 21-triol-3,11-diketone; 6,17, the 20-trihydroxy is pregnant-4-alkene-3-ketone; 6-Alpha-hydroxy hydrocortisone; 6-α-fluprednisolone, 6-α-methylprednisolone, 6-α-methylprednisolone 21-acetate, 6-α-methylprednisolone 21-hemisuccinic acid sodium salt, 6-beta-hydroxy hydrocortisone, 6-α, 9-α-two fluprednisolone 21-acetate 17-butyrate, 6-hydroxyl corticosterone; 6-hydroxyl dexamethasone; The 6-hydroxy prednisonlone; 9-fluorine cortisone; Alclometasone diproionate; Aldosterone; Algestone; 1% hydrocortisone emulsifiable paste; Amadinone; Amcinonide; Anagestone; Androstenedione; NSC 24345; Beclometasone; Beclomethasone; The beclomethasone monohydrate; The 17-betamethasone valerate; The betamethasone sodium acetate; Betamethasone sodium phosphate; Betamethasone valerate; Bolasterone; Budesonide; Calusterone; Chlormadinone; Chloroprednisone; Chloroprednisone acetate; Cholesterol; Clobetasol; Clobetasol propionate; Clobetasone; Clocortolone; The neopentanoic acid clocortolone; Clogestone; Cloprednol; Corticosterone; Hydrocortisone; The acetic acid hydrocortisone; The butanoic acid hydrocortisone; The cyclopentyl propionic acid hydrocortisone; Sad hydrocortisone; The hydrocortisone sodium phosphate; The hydrocortisone sodium succinate; The valeric acid hydrocortisone; Cortisone; Cortisone acetate; Cortodoxone; Daturaolone; Deflazacort, 21-deoxy-cortisol, dehydroepiandrosterone; Delmadinone; Deoxycorticosterone; Deprodone; Descinolone; Desonide; Desoximetasone; Dexafen; Dexamethasone; The 21-dexamethasone acetate; Dexamethasone acetate; Dexamethasone sodium phosphate; Dichlorisone; Diflorasone; Diflorasone diacetate; Diflucortolone; Dihydro elaterin a; Domoprednate; Doxibetasol; Ecdysone; Ecdysterone; Endrisone; Enoxolone; Flucinolone; Fludrocortisone; Fludrocortisone acetate; Flugestone; Flumetasone; The neopentanoic acid flumetasone; Flumoxonide; Flunisolide; Fluocinolone acetonide; Fluocinolone acetonide; Fluocinonide; 9-fluorine cortisone; Fluocortolone; Fluorine hydroxyl androstenedione; Fluorometholone; Fluorometholone acetate; Fluoxymesterone; Fluprednidene; Fluprednisolone; Flurandrenolide; Fluticasone; Fluticasone propionate; Formebolone; Formestane; Formocortal; Gestonorone; Glyderinine; Halcinonide; Hyrcanoside; Halometasone; Halopredone; Haloprogesterone; The cyclopentyl propionic acid hydrocortisone; Hydrocortisone; Hydrocortisone 21-butyrate; Hydrocortisone aceponate; The cellulose acetate hydrogen cortisone; The hydrocortisone buteprate; The hydrocortisone butyrate; The cyclopentyl propionic acid hydrocortisone; Hydrocortisone half amber ester; Hydrocortisone probutate; The hydrocortisone sodium phosphate; Hydrocortisone sodium succinate; The valeric acid hydrocortisone; Hydroxyprogesterone; Inokosterone; Isoflupredone; Isoflupredone acetate; Isoprednidene; The meclorisone; Mecortolon; Medrogestone; Medroxyprogesterone; Medrysone; Megestrol; Megestrol acetate; Melengestrol; Meprednisone; Metandienone; Methylprednisolone; Methylprednisolone aceponate; Methylprednisolone acetate; Methylprednisolone hemisuccinate; Methylprednisolone sodium succinate; Methyltestosterone; Metribolone; Mometasone; Mometasone furoate; The mometasone furoate monohydrate; Nisone; Nomegestrol; Norgestomet; Norvinisterone; Oxymesterone; Paramethasone; Paramethasone acetate; The pine sterone; Prednisolamate; Prednisolone; Prednisolone 21-hemisuccinic acid ester; Prednisolone acetate; Method Buddhist nun's acid prednisolone; Prednisolone hemisuccinate; Prednisolone-21 (β-D-glucosiduronic acid); Sulfosalicylic acid ester between prednisolone; Inflamase; Prednisolone steaglate; Prednisolone uncle fourth ethyl ester; Prednisolone tetrahydrophthalic acid ester; Prednisone; W-4869; Prednylidene; Pregnenolone; Procinonide; Tralonide; Progesterone; Promegestone; Rhapontisterone; Rimexolone; Roxibolone; Rubrosterone; Stizophyllin; Tixocortol; Topterone; Triamcinolone; Triamcinolone acetonide; Triamcinolone acetonide 21-cetylate; Triamcinolone diacetate; Triamcinolone hexacetonide; Trimegestone; Turkesterone; And wortmannin.

Various types of sterin/used standard recommendation dosage of disease combination sees the following form 2.

The corticosteroid dosage of table 2-standard recommendation

Indication	Approach	Medicine	Dosage	Timetable
					Psoriasis	Oral	Prednisolone	?????7.5-60mg	The every day or the every day of being divided into 2 times
	Oral	Prednisone	?????7.5-60mg	The every day or the every day of being divided into 2 times
Asthma	Suck	Beclomethasone	42 μ g/ spray into	Under each spray 4-8, every day 2 times
						Suck	Budesonide	(200 μ g/ suction)	Under each suction 1-2, every day 2 times
	Suck	Flunisolide	(250 μ g/ spray into)	Under each spray 2-4, every day 2 times
						Suck	Fluticasone propionate	44,110 or 220 μ g/ spray into	Under each spray 2-4, every day 2 times
	Suck	Triamcinolone acetonide	100 μ g/ spray into	Under each spray 2-4, every day 2 times
?COPD	Oral	Prednisone	?????30-40mg	Every day
Crohn disease	Oral	Budesonide	????????9mg	Every day
Ulcerative colitis	Oral	Prednisone	?????40-60mg	Every day
						Oral	Hydrocortisone	?????300mg(IV)	Every day
	Oral	Methylprednisolone	?????40-60mg	Every day
Rheumatoid arthritis	Oral	Prednisone	?????7.5-10mg	Every day

For example in following document, provide other standard recommendation dosage of corticosteroid: Merck Manual of Diagnosis ﹠amp; Therapy (the 17th edition, MH Beers etc., Merck ﹠amp; Co.) and Physicians ' Desk Reference 2003 (the 57th edition, Medical EconomicsStaff etc., Medical Economics Co., 2002).In one embodiment, as defined herein, the corticosteroid dosage that gives is equivalent to the dosage of prednisolone dosage.For example, the corticosteroid of low dosage is considered to be equivalent to the dosage of low dosage prednisolone.

Steroid receptor modulator

Steroid receptor modulator (for example antagonist and agonist) can be used as the succedaneum or the additives of corticosteroid in the inventive method, compositions and the medicine box.Therefore, in one embodiment, the drug combination that is characterized as SSRI (or its analog or metabolite) and glucocorticoid receptor modulator or other steroid receptor modulator of the present invention, and the method for using it for treatment immunoinflammatory disease is provided.

The glucocorticoid receptor modulator that can be used for method of the present invention, compositions and medicine box comprises the chemical compound of describing in the following document: United States Patent (USP) the 6th, 380,207,6,380,223,6,448,405,6,506,766 and 6,570, No. 020, U.S. Patent Application Publication No. 20030176478,20030171585,20030120081,20030073703,2002015631,20020147336,20020107235,20020103217 and 20010041802, and PCT publication No. WO00/66522, each described document all is attached to herein by reference.Following document description also can be used for other steroid receptor modulator of the inventive method, compositions and medicine box: United States Patent (USP) the 6th, 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, No. 130, each described document all is attached to herein by reference.

Other chemical compound

Can be used as the inventive method, other chemical compound of the succedaneum of corticosteroid or additives comprises A-348441 (Karo Bio) in compositions and the medicine box, adrenal cortex extract (GlaxoSmithKline), alsactide (Aventis), amebucort (Schering AG), Amelometasone (Taisho), ATSA (Pfizer), bitolterol (Elan), CBP-2011 (InKinePharmaceutical), cebaracetam (Novartis), CGP-13774 (Kissei), ciclesonide (Altana), ciclometasone (Aventis), clobetasone butyrate (Glaxo SmithKline), cloprednol (Hoffmann-La Roche), collismycin A (Kirin), cucurbatacin E (NIH), deflazacort (Aventis), propanoic acid deprodone (SSP), dexamethasone acefurate (Schering-Plough), decamethasone 21-linolete (GlaxoSmithKline), valeric acid dexamethasone (Abbott), difluprednate (Pfizer), domoprednate (Hoffmann-La Roche), ebiratide (Aventis), etiprednol dicloacetate (IVAX), Fluazacort (Vicuron), flumoxonide (Hoffmann-La Roche), fluocortin butyl (Schering AG), fluocortolone monohydrate (Schering AG), GR-250495X (GlaxoSmithKline), halometasone (Novartis), halopredone (Dainippon), HYC-141 (Fidia), vinegar fourth Ai Kemi (Hovione), itrocinonide (AstraZeneca), L-6485 (Vicuron), Lipocort (DraxisHealth), locicortolone dicibate (Aventis), meclorisone (Schering-Plough), naflocort (Bristol-Myers Squibb), NCX-1015 (NicOx), NCX-1020 (NicOx), NCX-1022 (NicOx), nicocortonide (Yamanouchi), NIK-236 (NikkenChemicals), NS-126 (SSP), Org-2766 (Akzo Nobel), Org-6632 (AkzoNobel), P16CM, propyl group mesterolone (Schering AG), RGH-1113 (GedeonRichter), rofleponide (AstraZeneca), Palmic acid rofleponide (AstraZeneca), RPR-106541 (Aventis), RU-26559 (Aventis), Sch-19457 (Schering-Plough), T25 (Matrix Therapeutics), TBI-PAB (Sigma-Tau), ticabesone propionate (Hoffmann-La Roche), tifluadom (Solvay), timobesone (Hoffmann-LaRoche), TSC-5 (Takeda) and ZK-73634 (Schering AG).

Treatment

Of the present invention being characterized as is used to suppress the excretory method of proinflammatory cytokine, and described method can be used as the method for the following disease of treatment: immunoinflammatory disease, proliferative skin disorders, organ-graft refection or graft versus host disease.By giving one or more SSRI, optional and one or more steroid combinations can suppress the secretion of cytokine.Although embodiment has described single SSRI of using and list uses steroid, people to know, usually expect the combination of multiple medicine.For example methotrexate, oxychloroquine and sulfasalazine are generally united and are used for the treatment of rheumatoid arthritis.Other therapies is described below.

Chronic obstructive disease of lung

In one embodiment, method of the present invention, compositions and medicine box are used for the treatment of chronic obstructive disease of lung (COPD).If needed, one or more medicines that are generally used for treating COPD can be used as the succedaneum or the additives of corticosteroid in the inventive method, compositions and the medicine box.Described medicine comprises xanthine (for example theophylline), anticholinergic compound (for example ipratropium, tiotropium) and beta receptor agonist/bronchodilator (for example sulphuric acid ibuterol, bitolterol mesilate, epinephrine, formoterol fumarate, isoproterenol, levalbuterol hydrochloride, orciprenaline sulfate, pirbuterol acetate (pirbuterol scetate), salmeterol xinafoate and terbutaline).Therefore, in one embodiment, the drug combination that is characterized as SSRI (or its analog or metabolite) and bronchodilator of the present invention, and the method for the treatment of COPD with it is provided.

Psoriasis

Method of the present invention, compositions and medicine box can be used for treating psoriasis.If needed, one or more are generally used for treating succedaneum or the additives that psoriatic antipsoriatic can be used as corticosteroid in the inventive method, compositions and the medicine box.Described medicine comprises biological preparation (alefacept for example, infliximab (inflixamab), adelimumab, efalizumab, Embrel and CDP-870), non-steroidal neurocalcin inhibitor (cyclosporin for example, tacrolimus, pimecrolimus and ISAtx247), novel vitamin D analogues (calcipotriene for example, calcipotriol), psoralen (for example methoxsalen), retinoid (acitretin for example, tazoretene), DMARD (for example methotrexate) and dithranol.Therefore, in one embodiment, the drug combination that is characterized as SSRI (or its analog or metabolite) and antipsoriatic of the present invention, and provide with it and treat psoriatic method.

Inflammatory bowel

Method of the present invention, compositions and medicine box can be used for treating inflammatory bowel.If needed, one or more medicines that are generally used for treating inflammatory bowel can be used as the succedaneum or the additives of corticosteroid in the inventive method, compositions and the medicine box.Described medicine comprises biological preparation (for example infliximab, adelimumab and CDP-870), non-steroidal neurocalcin inhibitor (for example cyclosporin, tacrolimus, pimecrolimus and ISAtx247), 5-aminosalicylic acid (for example mesalazine, sulfasalazine, balsalazide disodium and olsalazine sodium), DMARD (for example methotrexate and azathioprine) and alosetron.Therefore, in one embodiment, the drug combination that is characterized as SSRI (or its analog or metabolite) and any said medicine of the present invention, and the method for the treatment of inflammatory bowel with it is provided.

Rheumatoid arthritis

Method of the present invention, compositions and medicine box can be used for treating rheumatoid arthritis.If needed, one or more medicines that are generally used for treating rheumatoid arthritis can be used as the succedaneum or the additives of corticosteroid in the inventive method, compositions and the medicine box.Described medicine comprises NSAID (naproxen sodium for example, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, Choline magnesium trisalicylate, sodium salicylate, salicyl salicylate (salsalate) (two bigcatkin willow ester), fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam Evil promazine, sulindac and Tolmetin), cox 2 inhibitor (rofecoxib for example, celecoxib, valdecoxib and Prexige (lumiracoxib)), biological preparation (infliximab for example, adelimumab, Embrel and CDP-870), non-steroidal neurocalcin inhibitor (cyclosporin for example, tacrolimus, pimecrolimus and ISAtx247), 5-aminosalicylic acid (mesalazine for example, sulfasalazine, balsalazide disodium and olsalazine sodium), DMARD (methotrexate for example, leflunomide, minocycline, auranofin, sodium aurothiomalate, aurothioglucose and azathioprine), hydroxychloroquine sulfate and penicillamine.Therefore, in one embodiment, the drug combination that is characterized as SSRI (or its analog or metabolite) and any said medicine of the present invention, and the method for the treatment of rheumatoid arthritis with it is provided.

Asthma

Method of the present invention, compositions and medicine box can be used for treating asthma.If needed, one or more medicines that are generally used for treating asthma can be used as the succedaneum or the additives of corticosteroid in the inventive method, compositions and the medicine box.Described medicine comprises β2Ji Dongji/bronchodilator/leukotrienes regulator (for example zafirlukast, montelukast and zileuton), biological preparation (for example omalizumab), anticholinergic compound, xanthine, ephedrine, guaifenesin, disodium cromoglycate, sodium nedocromil and potassium iodide.Therefore, in one embodiment, the drug combination that is characterized as SSRI (or its analog or metabolite) and any said medicine of the present invention, and the method for the treatment of rheumatoid arthritis with it is provided.

Non-steroidal immunophilin dependent immunity inhibitor

In one embodiment, method, compositions and the medicine box that uses SSRI and non-steroidal immunophilin dependent immunity inhibitor (NsIDI), optional and corticosteroid or other medicines coupling described herein that be characterized as of the present invention.

In healthy individual, immune system utilizes cytological effect devices such as B cell and T cell to come targeting infective micro-organisms and abnormal cell kind, and can be at normal cell.Suffering from the individual of autoimmune disease or having in the individuality of transplant organ the activating T cell damage healthy tissues.Neurocalcin inhibitor (for example cyclosporin, tacrolimus, pimecrolimus) and rapamycin targeting comprise polytype immunity regulatory cell of T cell, and suppress the immunne response in organ transplantation and the autoimmune disease.

Cyclosporin

Cyclosporin is a fungal metabolite, and it comprises the cyclic oligopeptides of a class as immunosuppressant.The hydrophobicity ring type polypeptide that cyclosporin A and deuterate analog ISAtx247 thereof are made up of 11 aminoacid.Cyclosporin A and intracellular receptor cyclosporin be conjugated protein to combine and forms complex.The conjugated protein complex combination of cyclosporin/cyclosporin also suppresses neurocalcin (a kind of Ca ²⁺-calmodulin-dependent serine-threonine-specific protein phosphatase).The required signal transduction incident of neurocalcin mediation T cell activation (summary referring to Schreiber etc., Cell 70:365-368,1991).Cyclosporin and functional analogue thereof and analog be the suppressor T cell dependent immune response by the signal transduction that suppresses the antigen triggering.This inhibition reduces the expression of proinflammatory cytokines such as IL-2.

Fungus can produce multiple cyclosporin (for example cyclosporin A, B, C, D, E, F, G, H and I).Cyclosporin A is commercially available, and its commodity are called NEORAL, are produced by Novartis.Cyclosporin A analog and functional analogue comprise having one or more amino acid whose cyclosporin No. the 5th, 227,467, United States Patent (USP) (for example be described in) of fluoridizing; Cyclosporin (being described in for example United States Patent (USP) the 5th, 122,511 and 4,798, No. 823) with modified amino acid; With the deuterate cyclosporin, ISAtx247 (be described in U.S. Patent Publication number 20020132763) for example.Other cyclosporin analog is described in United States Patent (USP) the 6th, 136, and 357,4,384,996,5,284,826 and 5,709, No. 797.Cyclosporin analog includes but not limited to D-Sar (α-SMe) ³Val ²-DH-Cs (209-825), Allo-Thr-2-Cs, norvaline-2-Cs, D-Ala (3-acetylamino)-8-Cs, Thr-2-Cs and D-MeSer-3-Cs, D-Ser (O-CH ₂CH ₂-OH)-and 8-Cs and D-Ser-8-Cs, these analog are described in (Antimicrob.Agents Chemother.44:143-149,2000) such as Cruz.

The cyclosporin height is hydrophobic, easily precipitates under the situation of water is arranged (when for example touching body fluid).Following document description the method for the cyclosporin formulations with improved bioavailability is provided: United States Patent (USP) the 4th, 388,307,6,468,968,5,051,402,5,342,625,5,977,066 and 6,022, No. 852.The cyclosporin micro-emulsion composition is described in United States Patent (USP) the 5th, 866, and 159,5,916,589,5,962,014,5,962,017,6,007,840 and 6,024, No. 978.

Cyclosporin can be through intravenous or orally give, but the preferred oral administration.In order to reduce the hydrophobicity of cyclosporin A, before administration, vein is dissolved in ethanol-polyoxyethylated castor oil solvent with cyclosporin A usually.Cyclosporin A can be the microemulsion of 25mg or 100mg tablet for example, or 100mg/ml oral solution (NEORAL ^TM).

Usually, the dosage of patient's oral cyclosporin changes with described patient's disease.But this paper provides the standard recommendation dosage in some prior art therapeutic schemes.The patient of experience organ transplantation accepts the initial dose of oral cyclosporin A usually between 12mg/kg/ days and 15mg/kg days.Weekly dosage is reduced by 5% gradually then, until the maintenance dose that reaches 7-12mg/kg/ days.For intravenous administration, to the preferred 2-6mg/kg/ of Most patients days.For the patient who suffers from Crohn disease or ulcerative colitis after diagnosing, giving dosage usually is 6-8mg/kg/ days.For the patient who suffers from systemic lupus erythematosus (sle) after diagnosing, giving dosage usually is 2.2-6.0mg/kg/ days.For psoriasis or rheumatoid arthritis, common dosage is 0.5-4mg/kg/ days.Other effective dose comprises 0.5-5mg/kg/ days, 5-10mg/kg/ days, 10-15mg/kg/ days, 15-20mg/kg/ days or 20-25mg/kg/ days.Usually with other immunosuppressant combination such as cyclosporin and glucocorticoid.Other information see the following form 3.

Table 3-NsIDI

Chemical compound	Atopic dermatitis	Psoriasis	???????RA	??????Crohn′s	?????????UC	Transplant	?????SLE
								?????CsA ???(NEORAL)	????????N/A	0.5-4 mg/kg/ days	0.5-4 mg/kg/ days	6-8mg/kg/ days (oral-fistula)	6-8mg/kg/ days (oral)	～7-12 mg/kg/ days	2.2-6.0 mg/kg/ days
Tacrolimus	0.03-0.1% ointment/every day 2 times (30 and 60 gram/pipe)	Mg/kg/ days 0.05-1.15 (oral)	1-3 mg/kg/ days (oral)	Mg/kg/ days 0.1-0.2 (oral)	Mg/kg/ days 0.1-0.2 (oral)	0.1-0.2 mg/kg/ days	??????N/A
								Pimecrolimus	1% ointment/every day 2 times (15,30,100 gram/pipe)	40-60 mg/kg/ days (oral)	40-60 mg/kg/ days (oral)	80-160 mg/kg/ days (oral)	160-240 mg/kg/ days (oral)	40-120 mg/kg/ days (oral)	40-120 mg/kg/ days (oral)

Symbol description:

The CsA=cyclosporin A

The RA=rheumatoid arthritis

The UC=ulcerative colitis

SLE=systemic lupus erythematosus (sle)

Tacrolimus

(PROGRAF Fujisawa) is also referred to as FK506 to tacrolimus, is the immunosuppressant of targeting T cell born of the same parents inner cell transduction pathway.Tacrolimus is in conjunction with intracellular protein FK506 conjugated protein (FKBP-12), and described albumen and cyclosporin be conjugated protein not to have structural dependence (Harding etc., Nature 341:758-7601,1989; Siekienka etc., Nature 341:755-757,1989; With Soltoff etc., J.Biol.Chem.267:17472-17477,1992).The FKBP/FK506 complex combines and suppresses the phosphatase activity of neurocalcin with neurocalcin.This inhibition stops dephosphorylation and NFAT transfer in nuclear, and NFAT is the generation of a kind of initial lymphokine (for example IL-2, IFN-) and the nuclear composition of the required genetic transcription of T cell activation.Therefore, tacrolimus suppressor T cell activation.

Tacrolimus is the macrolide antibiotic that is produced by Streptomyces tsukubaensis.It suppresses immune system and prolongs the time-to-live of transplant organ.At present available have oral and ejection preparation.The tacrolimus capsule contains 0.5mg, 1mg or the anhydrous tacrolimus of 5mg in gelatine capsule shell.Ejection preparation contains and is dissolved in Oleum Ricini and the anhydrous tacrolimus of alcoholic acid 5mg, described preparation before injection with 9% sodium chloride or the dilution of 5% glucose.Although the preferred oral administration, patient that can not oral capsule can accept the injection tacrolimus.Transplanted back 6 hours, and just should give initial dose by continuous intravenous infusion

Tacrolimus and tacrolimus analog have description: Tanaka etc. (J.Am.Chem.Soc., 109:5031,1987) and United States Patent (USP) the 4th, 894,366,4,929,611 and 4,956, No. 352 in following document.Comprise the FK506 related compound of FR-900520, FR-900523 and FR-900525, be described in United States Patent (USP) the 5th, 254, No. 562; O-aryl, O-alkyl, O-thiazolinyl and O-alkynyl-macrolides are described in United States Patent (USP) the 5th, 250, and 678,532,248,5,693, No. 648; Amino O-aryl macrolide is described in United States Patent (USP) the 5th, 262, No. 533; The alkylidene macrolide is described in United States Patent (USP) the 5th, 284, No. 840; N-heteroaryl, N-miscellaneous alkyl aryl, N-thiazolinyl heteroaryl and N-alkynyl heteroaryl macrolide are described in United States Patent (USP) the 5th, 208, No. 241; Amino macrolide and derivant thereof are described in United States Patent (USP) the 5th, 208, No. 228; The fluoro macrolide is described in United States Patent (USP) the 5th, 189, No. 042; Amino O-alkyl, O-thiazolinyl and O-alkynyl-macrolides are described in United States Patent (USP) the 5th, 162, No. 334; With the halo macrolide, be described in United States Patent (USP) the 5th, 143, No. 918.

Although recommended dose changes with patient's disease, provide prior art therapeutic scheme accepted standard recommended dose below.Give to suffer from after diagnosing patient 0.1-0.2mg/kg/ days oral tacrolimuss of Crohn disease or ulcerative colitis.The common dosage of accepting of patient with transplant organ is 0.1-0.2mg/kg/ days oral tacrolimuss.The dosage that the patient of treatment rheumatoid arthritis accepts usually is 1-3mg/ days oral tacrolimuss.For the treatment psoriasis, give patient 0.01-0.15mg/kg/ days oral tacrolimuss.Smear the ointment that contains the 0.03-0.1% tacrolimus by one day twice at infected position, can treat atopic dermatitis.Accepting the administration first time that the capsular patient of oral tacrolimus accepts usually, is to give in back 6 hours in transplanting, perhaps stops the back at the intravenous infusion tacrolimus and gives in 8-12 hour.The tacrolimus dosage of other recommendation comprises 0.005-0.01mg/kg/ days, 0.01-0.03mg/kg/ days, 0.03-0.05mg/kg/ days, 0.05-0.07mg/kg/ days, 0.07-0.10mg/kg/ days, 0.10-0.25mg/kg/ days or 0.25-0.5mg/kg/ days.

The abundant metabolism of the oxidase system of the mixed function of tacrolimus, specifically, by the metabolism of cytochrome P-450 system.Metabolic main mechanism is demethylation and hydroxylating.Although various tacrolimus metabolite may demonstrate the immunosuppressant biological activity, it is reported that 13-demethyl metabolite has the activity identical with tacrolimus.

Pimecrolimus and ascomycin derivative

Ascosin is the analog of FK506, is effective immunosuppressant.It combines with FKBP-12 and suppresses its proline and rotate the different enzymatic activity of purchasing.Ascosin-FKBP complex suppresses neurocalcin (a class 2B phosphatase).

Pimecrolimus (being also referred to as SDZ ASM-981) is the 33-table-chlorine derivative of ascosin.It is produced by bacterial strain Streptomyces hygroscopicus var.ascomyceitus.Similar with tacrolimus, pimecrolimus (ELIDEL ^TM,, suppress the neurocalcin phosphatase activity and suppressor T cell activation by blocking-up cytokine early transcription Novartis) in conjunction with FKBP-12.Specifically, pimecrolimus suppresses the generation of IL-2 and the release of other proinflammatory cytokine.

Pimecrolimus analog and functional analogue are described in United States Patent (USP) the 6th, 384, No. 073.Pimecrolimus is particularly useful in the treatment atopic dermatitis.Present available pimecrolimus is 1% ointment.Although individual dose will change with described patient's disease difference, some standard recommendation dosage are provided below.Can give pimecrolimus by 40-60mg/ days oral dose, be used for the treatment of psoriasis or rheumatoid arthritis.For treatment Crohn disease or ulcerative colitis, the dosage that can give pimecrolimus is 80-160mg/ days.The patient 160-240mg/ days pimecrolimus that can have organ transplantation.The patient who suffers from systemic lupus erythematosus (sle) after diagnosing can give 40-120mg/ days pimecrolimus.Other effective dose of pimecrolimus comprises 0.5-5mg/ days, 5-10mg/ days, 10-30mg/ days, 40-80mg/ days, 80-120mg/ days or even 120-200mg/ days.

Rapamycin

(Rapamunet  sirolimus is the annular lactone that is produced by streptomyces hygroscopicus (Steptomyces hygroscopicus) Wyeth) to rapamycin, is the immunosuppressant that suppresses T lymphocyte activation and propagation.Similar with cyclosporin, tacrolimus and pimecrolimus, rapamycin and immunophilin FKBP-12 form complex, but rapamycin-FKBP-12 complex does not suppress the neurocalcin phosphatase activity.Rapamycin-immunophilin complex in conjunction with and suppress target (mTOR) combination of rapamycin in the mammalian body, this target is the required kinases of a kind of cell cycle progression.Suppress the mTOR kinase activity and then blocked the secretion of T lymphopoiesis and lymphokine.

Rapamycin analog and functional analogue comprise an acidylate and two acylation of rapamycin derivants (United States Patent (USP) the 4th, 316, No. 885); Rapamycin water-soluble prodrug (United States Patent (USP) the 4th, 650, No. 803); Formic acid esters (PCT publication No. WO 92/05179); Carbamate (United States Patent (USP) the 5th, 118, No. 678); Carboxylic acid amide esters (United States Patent (USP) the 5th, 118, No. 678); Biotin ester (United States Patent (USP) the 5th, 504, No. 091); Fluorinated esters (United States Patent (USP) the 5th, 100, No. 883); Acetal (United States Patent (USP) the 5th, 151, No. 413); Silyl ether (United States Patent (USP) the 5th, 120, No. 842); Bicyclic derivatives (United States Patent (USP) the 5th, 120, No. 725); Rapamycin dimer (United States Patent (USP) the 5th, 120, No. 727); O-aryl, O-alkyl, O-thiazolinyl and O-alkynyl derivatives (United States Patent (USP) the 5th, 258, No. 389); With deuterate rapamycin (United States Patent (USP) the 6th, 503, No. 921).Other forms of rapamycin analogs is described in United States Patent (USP) the 5th, 202, and 332 and 5,169, No. 851.

Everolimus (40-O-(2-ethoxy) rapamycin; CERTICAN ^TMNovartis) be inhibitive ability of immunity macrolide with the rapamycin structurally associated, and found when itself and cyclosporin A coupling effective especially in the prophylaxis of acute organ-graft refection.

The rapamycin of present usefulness for oral administration is liquid preparation or tablet formulation.RAPAMUNE ^TMLiquid preparation contains the 1mg/mL rapamycin, before administration, and water or orange juice dilution.Also can use the tablet that contains 1mg or 2mg rapamycin.Give rapamycin every day once as soon as possible after being preferably in transplanting.Behind the oral administration, it absorbs rapidly and fully.Although patient's rapamycin dosage with described patient's different change of disease, provides some standard recommendation dosage usually below.Be 6mg initial load dosage every day of rapamycin.Maintenance dose subsequently common every day is 2mg.Perhaps, spendable loading dose every day is 3mg, 5mg, 10mg, 15mg, 20mg or 25mg, and maintenance dose every day is 1mg, 3mg, 5mg, 7mg or 10mg.When weight in patients during less than 40kg, rapamycin dosage can be adjusted by body surface area usually; Be generally 3mg/m ²The loading dose and the 1mg/m in/sky ²The maintenance dose in/sky.

Peptide moiety

No matter peptide, peptide mimics, fragments of peptides are natural, synthetic or through chemical modification, as long as can reduce dephosphorylation and NFAT transfer in nuclear of neurocalcin mediation, just are suitable for practice of the present invention.Following document description by suppressing the example that NFAT activation and NFAT transcription factor play the peptide of neurocalcin inhibitor effect: Aramburu etc. for example, Science 285:2129-2133,1999 and Aramburu etc., Mol.Cell 1:627-637,1998.As a class neurocalcin inhibitor, these medicines can be used for method of the present invention.

Administration

In the specific embodiments of any the inventive method, in 10 days, in 5 days, in 24 hours, give or give simultaneously described chemical compound respectively.Described chemical compound can formulated togetherly become a kind of compositions, perhaps can prepare respectively and give.One or both chemical compounds can give by low dosage or high dose, and these two kinds of dosage as defined herein.It is desirable to give described patient other chemical compound, for example corticosteroid, NSAID (naproxen sodium for example, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, Choline magnesium trisalicylate, sodium salicylate, salicyl salicylate (salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam Evil promazine, sulindac and Tolmetin), cox 2 inhibitor (rofecoxib for example, celecoxib, valdecoxib and Prexige), glucocorticoid receptor modulator or DMARD.Conjoint therapy of the present invention is particularly useful to treatment immunoinflammatory disease with following other medicines coupling the time: the antibacterial agent medicine, or regulate immunne response so that the medicine of positive influences disease (for example influencing the medicine of cell adhesion), perhaps biological preparation (promptly blocking the medicine (for example Embrel, adelimumab, infliximab or CDP-870) of the effect of IL-6, IL-1, IL-2, IL-12, IL-15 or TNF α).In this example (effect of medicine blocking-up TNF α), conjoint therapy has reduced production of cytokines, and the Embrel or the infliximab that act on the inflammatory cytokine remainder provide enhanced curative effect.

Can carry out separately or carry out treatment of the present invention, and can stay at home, in doctor's office, clinic, hospital clinic or hospital, provide treatment with other therapies.Treatment is chosen wantonly in hospital and is begun, so that the doctor can examine therapeutic effect and make necessary adjustment, perhaps treatment can begin in out-patient department.The persistent period of treatment is depended on period of kind, patient age and disease, patient disease of disease to be treated or obstacle and kind and the patient response situation to described treatment.In addition, there is the patient (for example patient who changes through the chronological age associated hormone) that the big danger of inflammatory diseases takes place to receive treatment, to suppress or to postpone the outbreak of symptom.

The route of administration of different embodiments includes but not limited to part, percutaneous and is administered systemically (for example intravenous, intramuscular, subcutaneous, suction, rectum, buccal, vagina, intraperitoneal, intraarticular, eye or oral administration)." being administered systemically " used herein is meant all non-percutaneous drug delivery approach, specifically do not comprise topical approach and percutaneous dosing approach.

In conjoint therapy, can independently control the dosage and the frequency of every kind of composition in the drug combination.For example, but a kind of chemical compound give 3 times every day, but and second kind of chemical compound gives 1 time every day.Conjoint therapy can give in the cycle of being interrupted, and comprising the recuperation phase, makes described patient body have an opportunity to be restored from any unforeseen side effect.Described chemical compound also can be formulated together, so that once give 2 kinds of chemical compounds.

Pharmaceutical combination preparation

Conjoint therapy of the present invention can be by any suitable method administration that causes suppressing target site proinflammatory cytokine level.Described chemical compound can contain any proper dosage in any suitable carrier material, and accounts for the amount of the 1-95% (weight) of described composition total weight usually.Described compositions can be the dosage form that is fit to following approach: oral, parenteral (for example intravenous, intramuscular), rectum, skin, nasal cavity, vagina, suction, skin (patch) or dosing eyes approach.Therefore, described compositions can be following form: for example tablet, capsule, pill, powder, granule, suspensoid, Emulsion, solution, the gel that comprises hydrogel, paste, ointment, ointment, plaster, immersion (drench), etc. ooze medicament release device, suppository, enema, injection, implant, spray or aerosol.Described Pharmaceutical composition can be according to conventional pharmacy criterion preparation (referring to for example Remington:The Science and Practice ofPharmacy, the 20th edition, 2000, A.R.Gennaro, Lippincott Williams ﹠amp; Wilkins writes, Philadelphia, and and Encyclopedia of Pharmaceutical Technology, J.Swarbrick and J.C.Boylan write, 1988-1999, Marcel Dekker, New York).

Every kind of chemical compound in the conjoint therapy can be by different modes preparation known in the art.For example, first and second medicines can formulated together or separately preparation.Preferably be used for simultaneously or almost simultaneously giving described medicine with first and second medicines are formulated together.Described compositions formulated altogether can comprise SSRI and the steroid that is pill, capsule, liquid preparation etc. formulated together.People know that when relating to " combination of SSRI/ steroid " preparation, the formulations employed technology also can be used for preparing the single medicine in the drug combination, and other combination of the present invention (for example SSRI/ glucocorticoid receptor modulator combination).Along with different pharmaceutical is used different preparation strategies, can mate the pharmacokinetic properties of every kind of medicine aptly.

It is packaging together that separately or respectively the medicine of preparation can be used as medicine box.Limiting examples comprises and fills for example two kinds of pill, a kind of pill and a kind of powder, a kind of suppository and a kind of medicine boxs of containing the liquid preparation in bottle, two kinds of topical cream agent etc.Described medicine box can include the optional member that helps unit dose is given the patient, for example is used to rebuild the bottle of injectable powder form, the intravenously administrable system of the syringe that is used to inject, customization, inhaler etc.In addition, the unit dose medicine box can comprise described preparation of compositions and administration description.Described medicine box can be made be used for a nonrecoverable unit dose of patient, concrete patient repeatedly uses (by constant dosage, or wherein independent chemical compound can change effectiveness by the treatment process); Perhaps described medicine box can comprise the multiple dose (" big packing ") that is suitable for multidigit patient administration.The composition of described medicine box can be packed in carton, blister, bottle, the pipe etc.

Controlled release preparation

The administration of SSRI/ steroid of the present invention combination can be used for wherein one or both active medicines being mixed with slow releasing pharmaceutical when SSRI or steroid have following characteristics: (i) (difference that for example produces between the plasma concentration of the plasma concentration of toxic and side effects or toxic reaction and generation therapeutical effect is very little for narrower therapeutic index; Usually, therapeutic index TI is defined as half lethal dose (LD ₅₀) and median effective dose (ED ₅₀) ratio); (ii) has narrow absorbing window in the gastrointestinal tract; (iii) short biological halflife; Or (iv) every kind of composition must be adjusted to its pharmacokinetic properties the distribution of every kind of medicine of best performance when using together, makes the inhibition of its consumption pair cell factor have the treatment effectiveness.Therefore, slow releasing preparation can be used for avoiding for keep medicine in blood plasma treatment level and frequent drug administration.For example, in the preferred composition for oral liquid of the present invention, for one or both medicines of the present invention's combination, observed half life and mean residence time were from 10 hours to 20 hours.

Can take many strategies to obtain sustained release, wherein the rate of release of therapeutic compound surpasses its metabolic rate.For example, can be by suitably selecting formulation parameters and composition (for example suitable controlled release composition and coating), to reach sustained release.Example comprises single unit or many units tablet composition or capsule composition, oily solution agent, suspensoid, Emulsion, microcapsule, microsphere, nanoparticle, patch and liposome.Can sustained release mechanism, so that SSRI and/or steroid discharged at interval by cycle time, such release can be simultaneously, perhaps when preferred early stage when discharging a kind of concrete medicine earlier, can allow a kind of medicine in the combination postpone release.

Controlled release preparation can comprise that degradable or nondegradable polymer, hydrogel, organogel or other have changed bio-absorbable, half life or the biodegradable physical arrangement of medicine.Controlled release preparation can be a kind of material, and needed surface can be coated or be applied to this material, no matter is inner surface or outer surface.In an example, the invention provides a kind of biodegradable bolus or implant, it can be near surgical operation be embedded into target site or its (for example near the arthritis knuckle place).In another example, described controlled release preparation implant can be embedded in the organ, for example at the intestinal hypomere, is used for the treatment of inflammatory bowel.

In the controlled release preparation of SSRI/ steroid combination of the present invention, can use hydrogel.Described polymer is formed by macromonomer, has polymerizable, non-degradable district, and described district is separated by at least one degradable district.For example, water miscible non-degradable district can form the center of macromonomer, has at least two degradable districts that are connected with this center, and when degraded, non-degradable district (particularly polymeric gel) is separated out, and as United States Patent (USP) the 5th, 626, No. 863 described.Hydrogel can comprise acrylate, and it can be by for example some initiating systems such as Yihong dyestuff, ultraviolet or visible light, polymerization easily.Hydrogel also can comprise highly-hydrophilic and have the Polyethylene Glycol (PEG) of biocompatibility.Hydrogel also can comprise low polyglycolic acid, it be poly-('alpha '-hydroxy acids), its ester bond easily is hydrolyzed into glycolic (a kind of nontoxic metabolite).Other chain extension can comprise polylactic acid, polycaprolactone, poe, polyanhydride or polypeptide.Whole network can gelling become biodegradable network, is used to catch and homodisperse SSRI/ steroid combination of the present invention, and passs medicine with controllable rate.

Chitosan and chitosan and sodium carboxymethyl cellulose (CMC-Na) mixture is as the carrier of medicament slow release, as Inouye etc., and Drug Design and Delivery 1:297-305,1987 is described.The medicine of the mixture of these chemical compounds and SSRI/ steroid of the present invention combination is at 200kg/cm ²Under be pressed into tablet, give the patient after, active medicine can therefrom slowly release.Can change release characteristics by changing the ratio of chitosan, CMC-Na and active medicine.Described tablet also can contain other additive, comprises lactose, CaHPO ₄Dihydrate, sucrose, crystalline cellulose or cross-linking sodium carboxymethyl cellulose.Some examples see the following form 4.

Table 4

Material	Ingredient in tablets (mg)
													Active medicine	20	20	20	20	20	20	20	20	20	20	20	20
Chitosan	10	10	10	10	10	20	3.3	20	3.3	70	40	28
													Lactose		110				220	36.7
CMC-Na	60	60	60	60	60	120	20	120	20		30	42
													CaHPO 4*2H 2O			110					220	36.7	110	110	110
Sucrose	110
													Crystalline cellulose				110
Cross-linking sodium carboxymethyl cellulose			110

Baichwal is at United States Patent (USP) the 6th, 245, described the release oral solid dosage forms in No. 356, described dosage form comprises agglutinating particle, gellant, ionogenic gel strength reinforcing agent and the inert diluent of the therapeutic activity medicine (SSRI/ steroid combination for example of the present invention or its component) of amorphous forms.Described gellant can be xanthan gum and locust bean gum mixture, and locust bean gum can be crosslinked with xanthan gum when environmental liquids is touched in described splicing.Ionogenic gel strength reinforcing agent preferably can play the effect that strengthens cross-link intensity between xanthan gum and the locust bean gum, and the release that therefore prolongs the preparation of Chinese medicine composition.Except xanthan gum and locust bean gum, also spendable acceptable gellant comprises gellant well-known in the art.Example comprises natural gum or modified natural glue, for example alginate, carrageenin, pectin, guar gum, modified starch, hydroxypropyl emthylcellulose, methylcellulose and other cellulosic material or polymer, for example mixture of sodium carboxymethyl cellulose and hydroxypropyl cellulose and said components.

At another preparation that is used for the present invention's combination, Baichwal and Staniforth are at United States Patent (USP) the 5th, 135, free-pouring slow-releasing granules as pharmaceutical excipient has been described in No. 757, described excipient comprises about 20% hydrophilic material to (weight) more than about 70% or 70%, and about 30% (weight) is to the medicinal filler of inertia of about 80% (weight) (lactose for example, glucose, sucrose, sorbitol, xylitol, fructose or its mixture), described hydrophilic material comprise heteropolysaccharide (for example xanthan gum or derivatives thereof) and in the presence of aqueous solution can with the crosslinked polysaccharide material (for example galactomannan, most preferably locust bean gum) of this heteropolysaccharide.Excipient with after SSRI/ steroid of the present invention combination or composition of medicine mix, directly is pressed into described mixture solid dosage formss such as tablet.Therefore, when taking in and contact gastric juice, so the tablet that forms slowly discharges medicine.Change excipient with respect to amount of drug, can obtain slow release characteristic.

Be used for the preparation of the present invention combination at another, Shell is at United States Patent (USP) the 5th, 007, described the release oral pharmaceutical dosage form in No. 790, and described dosage form discharges medicine by the speed of this drug solubility control in solution.Described dosage form comprises tablet or capsule, described preparation comprise be dispersed in hydrophilic, water is swollen, the drug particles of a large amount of limited solubilities in the cross linked polymer (described medicine is any other medicines of prednisolone, paroxetine or SSRI/ steroid of the present invention combination for example), they are keeping physical integrity but stripping rapidly after the administration during the administration.In case be ingested, granule swelling then, to impel it at Entogastric lingering and allow gastric juice to be penetrated in the granule, dissolved substance and leaching from granule arrive in the stomach with dissolved state (infringement to stomach compared with solid-state of this state is littler) to guarantee these medicines.The character and the crosslinking degree of this polymer depended in the final stripping of polymer sequencing.Polymer when its non cross-linked state be non-fibrillation and be water miscible basically, its crosslinking degree is enough to guarantee to allow polymer keep insoluble in required time, the common time is at least about 4 hours to 8 hours, 12 hours at the most, medicine that mixes and the Drug therapy that relates to, were depended in its selection.Can be used for suitable cross linked polymer example of the present invention is gelatin, albumin, sodium alginate, carboxymethyl cellulose, polyvinyl alcohol and chitin.According to the difference of polymer, can be by heating or radiation treatment or crosslinked by using cross-linking agent to finish, described cross-linking agent is acetaldehyde, polyamino acid, metal ion etc. for example.

Following document description be used for the silicone microsphere with the administration of pH control gastrointestinal of SSRI/ steroid combination preparation of the present invention: Carelli etc., Int.J.Pharmaceutics 179:73-83,1999.Described microsphere is a pH sensitivity semi-interpenetrating polymer hydrogel, be to make, their magnitude range with 500-1000 μ m are wrapped in the silicone microsphere by the methacrylic acid/methacrylate copolymer (Eudragit L100 or Eudragit S100) and the cross-linked polyethylene glycol 8000 of different proportion.

Slow releasing preparation can comprise the coatings that one deck is not soluble in water but can be removed by the slow etch of water, and perhaps water can the slowly infiltration by coating.Therefore, for example can be described under the continuous fluid condition of following document, SSRI/ steroid combination of the present invention is being used binder solution spray coating: Kitamori etc., United States Patent (USP) the 4th, 036, No. 948.The example of water-soluble binder comprises pregelatinized Starch (for example pregelatinized corn starch, pregelatinated white potato starch), pregelatinated modified starch, water-soluble cellulose (for example hydroxypropyl cellulose, hydroxy methocel, hydroxypropyl emthylcellulose, carboxymethyl cellulose), polyvinylpyrrolidone, polyvinyl alcohol, dextrin, arabic gum and gelatin, dissolve in the binding agent of organic solvent, for example cellulose derivative (for example cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose).

Also can pass through spray drying technology, preparation has the present invention's combination or its component of slow release characteristic.In an example, according to Espositio etc., Pharm.Dev.Technol.5:267-78,2000 is described, with 190 type mini spray exsiccator (Buchi, Laboratorium TechnikAG, Flawil, Germany), prednisolone is encased in the methacrylate microparticle (EudragitRS).The optimum condition of microparticle preparation is: charging (pump) speed that contains the 10mL acetonitrile solution of 50mg prednisolone is 0.5mL/min, and vaporific air velocity is 600L/hr, and drying air temperature is 80 ℃ of heating, and the flow velocity of bleeding of dry air is 28m ³/ hr.

Can prepare another form of slow release SSRI/ steroid combination by with the microencapsulation of composition of medicine granule on film, described film is as the microdialysis cell.In such preparation, gastric juice permeates this microcapsule wall and makes the microcapsule swelling, allows active medicine ooze out (referring to for example Tsuei etc., United States Patent (USP) the 5th, 589, No. 194).A kind of this type of commercially available slow-released system comprises having arabic gum/gelatin/microcapsule of ethanol film.This product derives from Eurand Limited (France), and commodity are called Diffucaps ^TMSo the microcapsule of preparation can wrap in the normal gelatin capsule or make tablet.

The slow release of SSRI and corticosteroid and/or controlled release preparation are known.PaxilCR for example ^, be the commercially available prod of GlaxoSmithKline, be the slow release form (GEOMATRIX of the paroxetine hydrochloride in degradable polymerization substrate ^TM, also referring to United States Patent (USP) the 4th, 839,177,5,102,666 and 5,422, No. 123), it also can have enteric coating, to postpone the beginning of drug release, after this tablet passes through stomach.For example United States Patent (USP) the 5th, 102, polymeric controlled release composition has been described in No. 666, described compositions comprises the reaction complex that interacts and form by following chemical compound, described being reflected in the presence of the active medicine that is selected from SSRI (for example paroxetine) carried out: (1) polycarbophil calcium component, described composition is water-soluble bloated but water-insoluble, the polymer of fibrous crosslinked carboxyl functional group, described polymer contains (a) at least about 80% a large amount of repetitives that contain at least one carboxyl functional group, (b) about 0.05%-about 1.5% is substantially free of the cross-linking agent of polyalkenyl polyether, this percentage ratio is benchmark and (2) water with the weight of polymer repeating unit and cross-linking agent not respectively.The consumption of WL-140 is about 0.1% to about 99% (weight), for example about 10%.The consumption of active medicine is about 0.0001% to about 65% (weight), for example between about 5% and 20%.The consumption of water is about 5% to about 200% (weight), for example between about 5% and 10%.This interaction (for example about 6-7) between pH is about 3 to about 10 is carried out.At first WL-140 is calcium salt forms, and it contains 5% to about 25% the calcium of having an appointment.

The case description of other slow releasing preparation is in United States Patent (USP) the 5th, 422, No. 123.Therefore, the controlled release system that is used for SSRI active substance (for example paroxetine) comprises (a) storage storehouse sheet heart, described pericardium contains the active substance of effective dose and has definite geometric format, (b) be used to store the supporting platform of the storehouse sheet heart, the wherein said storage storehouse sheet heart contains active substance and at least one at least and is selected from following film: (1) but polymeric material and gelling polymeric material, described polymeric material is swellable when contact water or waterborne liquid, wherein but the swellable polymeric material is 1: 9 to 9: 1 with the scope of the ratio of gelling polymeric material, (2) single polymeric material, described material not only has swellable but also have gelling characteristic, and wherein supporting platform is the elasticity support that is used for the described storage storehouse sheet heart, make it partly to cover sheet heart surface, described storage storehouse and because of the hydration of the storage storehouse sheet heart changes thereupon, and slowly dissolving and/or slow gelling in waterborne liquid.Described supporting platform can comprise hydrophilic agent and/or hydrophobic agents such as magnesium stearate and glyceride such as binding agents such as plasticizers such as polymer, glyceride, polyvinylpyrrolidone, lactose and Silicon stone such as hydroxypropyl emthylcellulose.Described polymer is usually by 30-90% (weight), for example the supporting platform of about 35-40% is formed.Plasticizer can be by at least 2% (weight), for example the supporting platform of about 15-20% is formed.Binding agent, hydrophilic agent and hydrophobic agents add up to about 50% (weight) that accounts for supporting platform, for example about 40-50% usually.

In another example, a kind of slow releasing preparation of venlafaxine (Effexor XR ^) be the commercially available prod of Wyeth Pharmaceuticals.Said preparation comprises VENLAFAXINE HCL, microcrystalline Cellulose and hydroxypropyl emthylcellulose with ethyl cellulose and hydroxypropyl methylcellulose mixtures coating (referring to United States Patent (USP) the 6th, 403,120 and 6,419, No. 958).The commercially available prod that a kind of budesonide controlled release preparation (3mg capsule) that is used for the treatment of inflammatory bowel is AstraZeneca is (as " Entocort ^TM" sell).United States Patent (USP) the 5th, 792, a kind of slow releasing preparation that is used for corticosteroid has also been described in No. 476, wherein said preparation comprises the controlled release preparation of 2.5-7mg as the glucocorticoid of active substance, feasible beginning in about 1-3 hour after described glucocorticoid enters patient's small intestinal, the glucocorticoid of at least 90% (weight) discharged in about 40-80 minute time.In order to prepare the active substance of these low dosage levels, with active substance (being glucocorticoids such as prednisolone or prednisone) micronization, suitably mix with known diluent such as starch and lactose, and with PVP (polyvinylpyrrolidone) pelletize.Then, with the slow release internal layer and the slow release of tolerance pH1.0 outer coating of described granule with tolerance pH6.8.Internal layer is by Eudragit ^RL (copolymer of acrylic acid and methacrylate and a small amount of quaternary ammonium group) constitutes, and outer by Eudragit ^L (by methacrylic acid and the synthetic anionic polymer of methyl methacrylate) constitutes.

Can prepare the bilayer tablet that is used for SSRI/ steroid combination of the present invention, wherein can prepare the different conventional granulates of every kind of medicine of this combination, and two kinds of medicines can be compressed on double-deck going up to form a kind of tablet.For example 12.5mg, 25mg, 37.5mg or the 50mg paroxetine of making controlled release preparation (can be made the t of paroxetine _1/2Be 15-20 hour) with the same tablet combination of 3mg prednisolone, prednisolone is mixed with its t _1/2The t that is about paroxetine _1/2At United States Patent (USP) the 6th, 548, in No. 084, can find to comprise the paroxetine slow release examples of formulations that is used for bilayer tablet.In the body of control prednisolone, the rate of release, can also comprise enteric coating and delayed release coating, begin to discharge, make the T of prednisolone to postpone medicine _MaxThe T that is about paroxetine _Max(promptly 5 to 10 hours).

Cyclodextrin is the cyclic polysaccharide that natural D (+)-glucopyranose units of containing connects with α-(1,4) key.The α that the most frequently used is contains 6,7 or 8 glucopyranose units respectively-, β-and gamma-cyclodextrin, its suitable case description is in WO91/11172, WO94/02518 and WO98/55148.On structure, the cyclic nature of cyclodextrin forms has inner nonpolarity or the anchor ring of hydrophobic cavities or the shape of irregular ring, and its secondary hydroxyl is positioned at a side of cyclodextrin anchor ring, and primary hydroxyl is positioned at opposite side.One side at secondary hydroxyl place is compared with a side at primary hydroxyl place, and diameter is wideer.The hydrophobicity of cyclodextrin inner cavity makes the multiple chemical compound of its energy enclose.(J.L Atwood etc. writes Pergamon Press (1996) for Comprehensive Supramolecular Chemistry, the 3rd volume; Cserhati, Analytical Biochemistry 225:328-32,1995; Husain etc., Applied Spectroscopy 46:652-8,1992.By forming inclusion complex with the various medicines that are suitable for the cyclodextrin hydrophobic cavities, perhaps by forming non-covalent association coordination compound with other bioactive molecule, cyclodextrin has been used for the drug carrier of passing as various therapeutic compounds.United States Patent (USP) the 4th, 727 has been described medicine and the pharmaceutical preparation of forming based on the mixture of amorphism, water soluble Beta-cyclodextrin by poorly water-soluble for No. 064, the cyclodextrin formation inclusion complex in wherein said medicine and the mixture.

The formation of drug-cyclodextrin complex can change dissolubility, dissolution rate, bioavailability and/or the stability of medicine.For example, following document description be used to improve the cyclodextrin of prednisolone bioavailability: Uekama etc., J.Pharm Dyn.6:124-7,1983.By with beta-schardinger dextrin-with prednisolone is added to the water and stirred preparation beta-schardinger dextrin-/prednisolone complex 7 days in 25 ℃.The gained precipitation that reclaims is 1: 2 prednisolone/cyclodextrin complexes.

Sulfobutyl ether-beta-cyclodextrin (SBE-β-CD is CyDex, Inc, and Overland Park, KA, the commercially available prod of USA is with CAPTISOL ^Trade name sell), also can be used as the auxiliary agent for preparing composition of medicine slow releasing preparation of the present invention.For example, can prepare and comprise the prednisolone that is compressed in the hydroxypropyl methylcellulose matrix and the slow releasing tablet (referring to Rao etc., J.Pharm.Sci.90:807-16,2001) of SBE-β-CD.In another example that uses the different rings dextrin, EP1109806 B1 has described the complex of cyclodextrin and paroxetine, the ratio that wherein can obtain medicine and cyclodextrin is 1: 0.25-1: 20 α-, γ-or beta-schardinger dextrin-[comprise eptakis (2-6-two-O-methyl)-beta-schardinger dextrin-, (2,3,6-three-O-methyl)-beta-schardinger dextrin-, single succinyl eptakis (2,6-two-O-methyl)-cyclodextrin or 2-HP-] anhydrous form or the complex of hydrated form.

Also can be described by following document, preparation polymeric cyclodextrins: U.S. Patent application serial number 10/021,294 and 10/021,312.So the cyclodextrin that forms can be used for preparing the medicine of the present invention's combination.These multifunctional polymeric cyclodextrins are Insert Therapeutics, Inc., Pasadena, CA, the commercially available prod of USA.

As with the direct compound alternative method of medicine, cyclodextrin can be used as auxiliary additive, for example as carrier, diluent or solubilizing agent.Can be by the similar approach of preparation cyclodextrin formulations described herein, preparation comprises the preparation of the other medicines of cyclodextrin and the present invention's combination (being SSRI and/or steroid).

Liposomal formulation

One or both compositions or this two kinds of mixture of ingredients of SSRI/ steroid combination of the present invention can be incorporated in the administrable liposome vectors.Described liposome vectors forms lipid components by the general vesicle of 3 classes and forms.The first kind is included in the vesicle that forms a large amount of vesicle structures in the liposome and forms lipid.Usually, these vesicles form lipid and comprise any amphipathic lipids with hydrophobicity and polar head group part, and described lipid (a) is example with phospholipid, the double-deck vesicle of can be in water spontaneous formation, or (b) stable being incorporated in the double-layer of lipoid, its hydrophobic part contact is inner, i.e. hydrophobic region of duplicature, and its polar head group part is towards the outside, i.e. the polar surfaces of film.

This type of vesicle forms the lipid that lipid preferably has two hydrocarbon chains (normally acyl chain) and a polar head group.This lipoids comprises phospholipid, for example phosphatidylcholine (PC), PE, phosphatidic acid (PA), phosphatidylinositols (PI) and sphingomyelin (SM), and wherein the length of these two hydrocarbon chains is about 14-22 carbon atom usually, and has various degrees of unsaturation.Above-mentioned lipid and phospholipid that its acyl chain has different saturation can be commercially available, perhaps can prepare according to disclosed method.Can comprise that other lipid in the present invention is glycolipid and sterin, for example cholesterol.

The second class universaling component comprises that vesicle forms lipid, and described lipid and polymer chain are derived, and makes in it is formed and forms polymeric layer.The vesicle formation lipid that can be used as the general vesicle formation of second class lipid components is that the general vesicle of any first kind forms the described composition of lipid.The vesicle that preferably has diacyl chain forms lipid, for example phospholipid.A kind of exemplary phospholipid is PHOSPHATIDYL ETHANOLAMINE (PE), and it provides is convenient to and the link coupled active amino of activated polymer.A kind of exemplary PE is distearyl PE (DSPE).

Deriving, preferred polymer is Polyethylene Glycol (PEG) in the lipid, and the molecular weight of preferred PEG chain is between 1,000 dalton and 15,000 dalton, more preferably between 2,000 dalton and 10,000 dalton, most preferably between 2,000 dalton and 5,000 dalton.Other hydrophilic polymer that is fit to comprises polyvinylpyrrolidone, Ju Jia oxazolin, Ju ethyl oxazoline base, poly-hydroxypropyl methyl acrylamide, PMAm and polydimethylacrylamiin, polylactic acid, polyglycolic acid and derivative fibre element, for example hydroxy methocel or hydroxyethyl-cellulose.

In addition, the block copolymer or the random copolymer of these polymer (particularly comprising the PEG fragment) are suitable.Preparation method with the deutero-lipid of hydrophilic polymer (for example PEG) is well-known, for example is described in United States Patent (USP) the 5th, 013, No. 556.

It is the lipid anchor that the general vesicle of the 3rd optional class forms lipid components, by this lipid anchor, targeting moiety is anchored on the described lipid through the polymer chain on the anchor.In addition, the targeting group is positioned at the far-end of polymer chain, makes the biological activity of targeting moiety can not lose in this way.This lipid ground tackle has hydrophobic part, polar head group and free (outside) polymer end; Described hydrophobic part is anchored on the double-deck surperficial outer field lipid of liposome it, described polymer inner with polar head group be covalently bound, and (outside) polymer end of dissociating activates or can activate because of the covalent coupling of targeting moiety because of the covalent coupling of targeting moiety.The method of this lipoids anchor molecule of preparation is described below.

The preferably about 70-90% vesicle of mol ratio that is used to form the lipid components of liposome forms lipid, 1-25% polymer-derived lipid and 0.1-5% lipid anchor.An exemplary formulation comprises the PE that do not derive of 50-70 mole percent, the cholesterol of 20-40 mole percent, PE-PEG (3500) polymer (its chemical active radical is used for the free-end of coupling targeting moiety at it) of 0.1-1 mole percent, the deutero-PE of usefulness PEG 3500 polymer chains of 5-10 mole percent, and 1 mole percent alpha-tocopherol.

The liposome that preferably prepares the basic homogeneous of size in selected magnitude range is usually between about 0.03-0.5 micron.The method of a kind of effective measure R EV and MLV size comprises to be extruded the waterborne suspension of described liposome from a series of polycarbonate membranes with selected same apertures, described selected same apertures scope is the 0.03-0.2 micron, is generally 0.05 micron, 0.08 micron, 0.1 micron or 0.2 micron.The aperture of film roughly is equivalent to extrude the full-size of the liposome that produces by crossing film, particularly extrudes twice by same film or repeatedly the time when preparation.The homogenate method also can be used for the size reduction of liposome to 100nm or below the 100nm.

Liposomal formulation of the present invention comprises at least a surfactant.The suitable surfactant that is used for SSRI/ steroid combination preparation described herein comprises the chemical compound that belongs to following kind: the polyethoxylated fatty acid, PEG-fatty acid diester, PEG-fatty-acid monoester and two ester admixtures, the polyethylene glycol glycerol fatty acid ester, alcohol-grease exchange product, polyglycerol fatty acid ester, methyl glycol fatty acid ester, propylene glycol ester and glyceride mixture, monoglyceride and two glyceride, sterin and steroid derivatives, the Polyethylene Glycol fatty acid esters of sorbitan, polyethylene glycol alkyl ether, sugar ester, polyalkylene glycol alkyl phenol, polyox-yethylene-polyoxypropylene block copolymer, fatty acid esters of sorbitan, lower alcohol fatty acid esters and ionic surfactant.The example of commercially available all kinds of excipient is provided below.

The polyethoxylated fatty acid can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available polyethoxylated fatty-acid monoester surfactant comprises: PEG 4-100 monolaurate (Crodet L series, Croda), PEG 4-100 monoleate (Crodet O series, Croda), PEG 4-100 monostearate (Crodet S series, Croda and Myrj series, Atlas/ICI), PEG 400 distearates (Cithrol 4DS series, Croda), PEG100,200 or 300 monolaurates (Cithrol ML series, Croda), PEG 100,200 or 300 monoleates (Cithrol MO series, Croda), PEG 400 dioleates (Cithrol4DO series, Croda), PEG 400-1000 monostearate (Cithrol MS series, Croda), PEG-1 stearate (Nikkol MYS-1EX, Nikko and Coster K1, Condea), PEG-2 stearate (Nikkol MYS-2, Nikko), PEG-2 oleate (NikkolMYO-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 (Nikkol TMGO-5, Nikko), PEG-6 oleate (Algon OL 60, AuschemSpA, PEG-7 oleate (Algon OL 70, Auschem SpA), PEG-6 laurate (Kessco  PEG300 ML, Stepan), (Lauridac 7 for the PEG-7 laurate, Condea), PEG-6 stearate (Kessco  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-12 oleate (Kessco  PEG 600 MO, Stepan), PEG-12 ricinoleate ester (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 (Kessco  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), (Ariacel 165 for the PEG-100 stearate, ICI), PEG-200 oleate (Albunol200 MO, Taiwan Surf), PEG-400 oleate (LACTOMUL, Henkel) and PEG-600 oleate (Albunol 600 MO, Taiwan Surf).The preparation of one or both compositions can comprise above-mentioned one or more polyethoxylated fatty acids in the SSRI/ steroid combination of the present invention.

The polyethylene glycol fatty acid diester also can be used as the excipient of SSRI/ steroid combination described herein.The example of commercially available polyethylene glycol fatty acid diester comprises: 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  PEG300 DL, Stepan), PEG-6 dioleate (Kesseo  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  PEG1000 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  PEG1540 DO, Stepan), PEG-32 distearate (Kessco  PEG 1540 DS, Stepan), PEG-400 dioleate (Cithrol 4DO series, Croda) and the PEG-400 distearate (Cithrol 4DS series, Croda).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more polyethylene glycol fatty acid diester.

PEG-fatty-acid monoester and two ester admixtures can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available PEG-fatty-acid monoester and two ester admixtures comprises: PEG 4-150 monolaurate, dilaurate (Kessco  PEG 200-6000 monolaurate, dilaurate, Stepan), PEG 4-150 monoleate, dioleate (Kessco  PEG 200-6000 monoleate, dioleate, Stepan) and PEG 4-150 monostearate, distearate (Kessco  200-6000 monostearate, distearate, Stepan).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more PEG-fatty-acid monoesters and two ester admixtures.

In addition, the polyethylene glycol glycerol fatty acid ester can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available polyethylene glycol glycerol fatty acid ester comprises: PEG-20 glycerol monolaurate (Tagat  L, Goldschmidt), PEG-30 glycerol monolaurate (Tagat  L2, Goldschmidt), PEG-15 glycerol monolaurate (Glycerox L series, Croda), PEG-40 glycerol monolaurate (Glycerox L series, Croda), PEG-20 glyceryl stearate (Capmul  EMG, ABITEC) and Aldo  MS-20 KFG, Lonza), PEG-20 glyceryl oleate (Tagat  O, Goldschmidt) and the PEG-30 glyceryl oleate (Tagat  O2, Goldschmidt).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more polyethylene glycol glycerol fatty acid esters.

Alcohol-grease exchange product also can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available alcohol-grease exchange product comprises: PEG-3 Oleum Ricini (Nikkol CO-3, Nikko), PEG-5,9 and 16 Oleum Ricini (ACCONON CA series, ABITEC), PEG-20 Oleum Ricini (Emalex C-20, Nihon Emulsion), PEG-23 Oleum Ricini (EmulganteEL23), (Incrocas 30 for the PEG-30 Oleum Ricini, Croda), PEG-35 Oleum Ricini (Incrocas-35, Croda), PEG-38 Oleum Ricini (Emulgante EL 65, Condea), PEG-40 Oleum Ricini (Emalex C-40, Nihon Emulsion), PEG-50 Oleum Ricini (Emalex C-50, NihonEmulsion), PEG-56 Oleum Ricini (Eumulgin  PRT 56, Pulcra SA), PEG-60 Oleum Ricini (Nikkol CO-60TX, Nikko), the PEG-100 Oleum Ricini, PEG-200 Oleum Ricini (Eumulgin  PRT 200, Pulcra SA), PEG-5 castor oil hydrogenated (Nikkol HCO-5, Nikko), PEG-7 castor oil hydrogenated (Cremophor WO7, BASF), PEG-10 castor oil hydrogenated (Nikkol HCO-10, Nikko), PEG-20 castor oil hydrogenated (Nikkol HCO-20, Nikko), PEG-25 castor oil hydrogenated (Simulsol  1292, Seppic), PEG-30 castor oil hydrogenated (Nikkol HCO-30, Nikko), PEG-40 castor oil hydrogenated (Cremophor RH 40, BASF), PEG-45 castor oil hydrogenated (Cerex ELS 450, Auschem Spa), PEG-50 castor oil hydrogenated (Emalex HC-50, Nihon Emulsion), PEG-60 castor oil hydrogenated (Nikkol HCO-60, Nikko), PEG-80 castor oil hydrogenated (Nikkol HCO-80, Nikko), PEG-100 castor oil hydrogenated (Nikkol HCO-100, Nikko), PEG-6 Semen Maydis oil (Labrafil  M 2125 CS, Gattefosse), PEG-6 almond oil (Labrafil  M 1966CS, Gattefosse), PEG-6 almond oil (Labrafil  M 1944 CS, Gattefosse), PEG-6 olive oil (Labrafil  M 1980 CS, Gattefosse), PEG-6 Oleum Arachidis hypogaeae semen (Labrafil  M 1969 CS, Gattefosse), PEG-6 hydrogenated palm kernel oil (Labrafil  M2130 BS, Gattefosse), PEG-6 palm-kernel oil (Labrafil  M 2130 CS, Gattefosse), PEG-6 glycerol trioleate (Labrafil  M 2735 CS, Gattefosse), PEG-8 Semen Maydis oil (Labrafil  WL 2609 BS, Gattefosse), PEG-20 corn glyceride (Crovol M40, Croda), PEG-20 Semen Armeniacae Amarum glyceride (Crovol A40, Croda), PEG-25 trioleate (TAGAT  TO, Goldschmidt), PEG-40 palm-kernel oil (Crovol PK-70), PEG-60 corn glyceride (Crovol M70, Croda), PEG-60 Semen Armeniacae Amarum glyceride (Crovol A70, Croda), PEG-4 three (caprylic/capric) glyceride (Labrafac  Hydro, Gattefosse), PEG-8 caprylic/capric glyceride (Labrasol, Gattefosse), PEG-6 caprylic/capric glyceride (SOFTIGEN  767, Huls), (GELUCIRE 44/14 for lauroyl Polyethylene Glycol-32 glyceride, Gattefosse), (GELUCIRE 50/13 for the stearoyl polyethyleneglycol glyceride, Gattefosse), the list of vegetable oil and sorbitol, two, three, four ester (SorbitoGlyceride, Gattefosse), pentaerythritol tetraoctyl stearate (Crodamol PTIS, Croda), pentaerythritol stearic acid ester 2 (Albunol DS, Taiwan Surf), tetramethylolmethane four oleates (Liponate PO-4, Lipo Chem.), pentaerythritol tetrastearate (LiponatePS-4, Lipo Chem.), tetramethylolmethane four sad four decanoin (LiponatePE-810, LipoChem.) and tetramethylolmethane four caprylates (Nikkol Pentarate 408, Nikko).This class surfactant also comprise as oil be fatsoluble vitamin, for example vitamin A, D, E, K etc.Therefore, the derivant of these vitamin for example tocopherol PEG-1000 succinate (TPGS, the commercially available prod of Eastman) also be suitable surfactant.SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more alcohol-grease exchange product.

Polyglycerol fatty acid ester also can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available polyglycerol fatty acid ester comprises: stearic acid polyglycereol (2) ester (NikkolDGMS, Nikko), oleic acid polyglycereol (2) ester (Nikkol DGMO, Nikko), isostearic acid polyglycereol (2) ester (Nikkol DGMIS, Nikko), oleic acid polyglycereol (3) ester (Caprol  3GO, ABITEC), oleic acid polyglycereol (4) ester (Nikkol Tetraglyn 1-O, Nikko), stearic acid polyglycereol (4) ester (Nikkol Tetraglyn 1-S, Nikko), oleic acid polyglycereol (6) ester (Drewpol 6-1-O, Stepan), lauric acid polyglycereol (10) ester (Nikkol Decaglyn 1-L, Nikko), oleic acid polyglycereol (10) ester (Nikkol Decaglyn 1-O, Nikko), stearic acid polyglycereol (10) ester (Nikkol Decaglyn 1-S, Nikko), castor oil acid polyglycereol (6) ester (Nikkol Hexaglyn PR-15, Nikko), linoleic acid polyglycereol (10) ester (Nikkol Decaglyn 1-LN, Nikko), five oleic acid polyglycereol (6) ester (Nikkol Hexaglyn 5-O, Nikko), two oleic acid polyglycereol (3) ester (Cremophor GO32, BASF), distearyl acid polyglycereol (3) ester (Cremophor GS32, BASF), five oleic acid polyglycereol (4) ester (Nikkol Tetraglyn 5-O, Nikko), two oleic acid polyglycereol (6) ester (Caprol  6G20, ABITEC), two oleic acid polyglycereol (2) ester (Nikkol DGDO, Nikko), three oleic acid polyglycereol (10) ester (Nikkol Decaglyn 3-O, Nikko), five oleic acid polyglycereol (10) ester (Nikkol Decaglyn 5-O, Nikko), seven oleic acid polyglycereol (10) ester (NikkolDecaglyn 7-O, Nikko), four oleic acid polyglycereol (10) ester (Caprol  10G4O, ABITEC), ten isostearic acid polyglycereol (10) ester (Nikkol Decaglyn 10-IS, Nikko), ten oleic acid polyglycereol (101) ester (Drewpol 10-10-O, Stepan), single oleic acid polyglycereol (10) ester, two oleic acid polyglycereol (10) ester (Caprol  PGE 860, ABITEC) and poly-castor oil acid polyglycerin ester (Polymuls, Henkel).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more polyglycerol fatty acid ester.

In addition, methyl glycol fatty acid ester can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available methyl glycol fatty acid ester comprises: (Capryol 90 for Capryol 90, Gattefosse), (Lauroglycol 90 for PGML, Gattefosse), propylene glycol oleate (Lutrol OP2000, BASF), propylene glycol myristinate (Mirpyl), propylene glycol monostearate (LIPO PGMS, Lipo Chem.), the propylene glycol hydroxy stearic acid ester, propylene glycol ricinoleate ester (PROPYMULS, Henkel), the propylene glycol isostearate, propylene glycol mono-oleate (Myverol P-O6, Eastman), propylene glycol two sad dicaprate (Captex  200, ABITEC), propylene glycol dicaprylate (Captex  800, ABITEC), the sad decanoin of propylene glycol (LABRAFAC PG, Gattefosse), the propylene glycol dilaurate, propylene glycol distearate (Kessco  PGDS, Stepan), propylene glycol dicaprylate (Nikkol Sefsol228, Nikko) and propylene glycol dicaprate (Nikkol PDD, Nikko).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more methyl glycol fatty acid esters.

Propylene glycol ester and glyceride mixture also can be used as the excipient of SSRI/ steroid combination preparation described herein.A kind of preferred mixture is made up of the oleate (Arlacel 186) of propylene glycol and glycerol.The example of these surfactants comprises: and oleate (ATMOS 300, ARLACEL186, ICI) and stearate (ATMOS 150).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more propylene glycol esters and glyceride mixture.

In addition, monoglyceride and two glyceride can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available monoglyceride and two glyceride comprises: single palmitoleic acid glyceride (C16:1) (Larodan); single trielaidin (C18:1) (Larodan); MONOTRICAPROIN (C6) (Larodan); single caprylin (Larodan); single caprin (Larodan); glyceryl monolaurate (Larodan); single myristin (C14) (NikkolMGM; Nikko); glyceryl monooleate (C18:1) (PECEOL; Gattefosse); glyceryl monooleate (Myverol; Eastman); single oleic acid/glyceryl linoleate (OLICINE; Gattefosse); single glyceryl linoleate (Maisine; Gattefosse); castor oil acid glyceride (Sofdgen  701; Huls); glyceryl monolaurate (ALDOL  MLD; Lonza); monopalmitin (Emalex GMS-P; Nihon); glyceryl monostearate (Capmul  GMS; ABITEC); single oleic acid and glyceryl dioleate (Capmul  GMO-K; ABITEC); Palmic acid/tristerin (CUTINA MD-A; ESTAGEL-G18); acetin (Lamegin  EE; Grunau GmbH); glyceryl laurate ester (Imwitort  312; Huls); citric acid/lactic acid/oleic acid/glyceryl linoleate (Imwitor  375; Huls); caprylin (Imwitor  308; Huls); caprylic/capric glyceride (Capmul  MCM; ABITEC); sad monoglyceride and two glyceride (Imwitor  988; Huls); caprylic/capric glyceride (Imwitor  742; Huls); one acetylation and diacetylation monoglyceride (Myvacet  9-45; Eastman); glyceryl monostearate (Aldo  MS; Arlacel 129; ICI); lactic acid esters of mono and two glyceride (LAMEGIN GLP; Henkel); two caproins (C6) (Larodan); two caprins (C10) (Larodan); two caprylins (C8) (Larodan); two myristin (C14) (Larodan); glycerol-1,3-dipalmitate (C16) (Larodan); distearin (Larodan); GLYCERYL DILAURATE (C12) (Capmul  GDL ABITEC); glyceryl dioleate (Capmul  GDO; ABITEC); (GELUCIRE 39/01 for fatty glyceride; Gattefosse); two palmitoleic acid glyceride (C16:1) (Larodan); 1; 2 and 1,3-glyceryl dioleate (C18:1) (Larodan); two trielaidins (C18:1) (Larodan) and dilinoleic acid glyceride (C18:2) (Larodan).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more monoglycerides and two glyceride.

Sterin and steroid derivatives also can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available sterin and steroid derivatives comprises: cholesterol, sitosterol, lanosterol, PEG-24 cholesterol ethers (Solulan C-24, Amerchol), PEG-30 Dihydrocholesterol (Phytosterol GENEROL series, Henkel), PEG-2 5 plant sterol (NikkolBPSH-25, Nikko), PEG-5 soyasterol (Nikkol BPS-5, Nikko), PEG-10 soyasterol (Nikkol BPS-10, Nikko), PEG-20 soyasterol (Nikkol BPS-20, Nikko) and the PEG-30 soyasterol (Nikkol BPS-30, Nikko).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more sterin and steroid derivatives.

The Polyethylene Glycol fatty acid esters of sorbitan also can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available Polyethylene Glycol fatty acid esters of sorbitan comprises: PEG-10 sorbitan laurate (Liposorb L-10, Lipo Chem.), PEG-20 Arlacel-20 (Tween  20, Atlas/ICI), PEG-4 Arlacel-20 (Tween  21, Atlas/ICI), PEG-80 Arlacel-20 (HodagPSML-80, Calgene), PEG-6 Arlacel-20 (Nikkol GL-1, Nikko), PEG-20 Arlacel-40 (Tween  40, Atlas/ICI), PEG-20 Arlacel-60 (Tween  60, Atlas/ICI), PEG-4 Arlacel-60 (Tween  61, Atlas/ICI), PEG-8 Arlacel-60 (DACOL MSS, Condea), PEG-6 Arlacel-60 (NikkolTS-106, Nikko), PEG-20 Arlacel-65 (Tween  65, Atlas/ICI), PEG-6 anhydro sorbitol tetrastearate (Nikkol GS-6, Nikko), PEG-60 anhydro sorbitol tetrastearate (Nikkol GS-460, Nikko), PEG-5 Arlacel-80 (Tween  81, Atlas/ICI), PEG-6 Arlacel-80 (NikkolTO-106, Nikko), PEG-20 Arlacel-80 (Tween  80, Atlas/ICI), PEG-40 sorbitan oleate (Emalex ET 8040, NihonEmulsion), PEG-20 sorbitan trioleate (Tween  85, Atlas/ICI), PEG-6 anhydro sorbitol four oleates (Nikkol GO-4, Nikko), PEG-30 anhydro sorbitol four oleates (Nikkol GO-430, Nikko), PEG-40 Isosorbide Dinitrate four oleate (NikkolGO-440, Nikko), PEG-20 anhydro sorbitol list isostearate (Tween  120, Atlas/ICI), PEG sorbitol six oleates (Atlas G-1086, ICI), polyoxyethylene sorbitan monoleate (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 six stearates (Nikkol GS-6, Nikko).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more Polyethylene Glycol fatty acid esters of sorbitan.

In addition, polyethylene glycol alkyl ether can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available polyethylene glycol alkyl ether comprises: the PEG-2 oleyl ether is that (Brij 92/93 for oil base polyoxyethylene (2) ether, Atlas/ICI), the PEG-3 oleyl ether is that (Volpo 3 for oil base polyoxyethylene (3) ether, Croda), the PEG-5 oleyl ether is that (Volpo 5 for oil base polyoxyethylene (5) ether, Croda), the PEG-10 oleyl ether is that (Volpo 10 for oil base polyoxyethylene (10) ether, Croda), the PEG-20 oleyl ether is that (Volpo 20 for oil base polyoxyethylene (20) ether, Croda), the PEG-4 lauryl ether is that (Brij 30 for lauryl polyoxyethylene (4) ether, Atlas/ICI), the PEG-9 lauryl ether, the PEG-23 lauryl ether is that (Brij 35 for lauryl polyoxyethylene (23) ether, Atlas/ICI), (Brij 52 for the PEG-2 cetyl ether, ICI), (Brij 56 for the PEG-10 cetyl ether, ICI), (BriJ 58 for the PEG-20 cetyl ether, ICI), (Brij 72 for the PEG-2 stearyl ether, ICI), PEG-10 stearyl ether (Brij76, ICI), (Brij 78 for the PEG-20 stearyl ether, ICI) and the PEG-100 stearyl ether (Brij 700, ICI).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more polyethylene glycol alkyl ethers.

Sugar ester also can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available sugar ester comprises: sucrose distearate (SUCRO ESTER 7, Gattefosse), sucrose distearate/monostearate (SUCRO ESTER 11, Gattefosse), sucrose dipalmitate, sucrose monostearate (Crodesta F-160, Croda), sucrose palmitic acid ester (SUCRO ESTER 15, Gattefosse) and sucrose monolaurate (sucrose monolaurate 1695, Mitsubisbi-Kasei).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more sugar esters.

Polyalkylene glycol alkyl phenol also can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available polyalkylene glycol alkyl phenol comprises: PEG-10-100 nonyl phenol series (TritonX series, Rohm ﹠amp; Haas) and PEG-15-100 octylphenol ether series (Triton N series, Rohm ﹠amp; Haas).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more polyalkylene glycol alkyl phenol.

Polyox-yethylene-polyoxypropylene block copolymer also can be used as the excipient of SSRI/ steroid combination preparation described herein.These surfactants are commercially available, have different trade names, comprise one or more Synperonic PE series (ICI), Pluronic  series (BASF), Lutrol (BASF), Supronic, Monolan, Pluracare and Plurodac.The adopted name of these copolymers is " poloxamer (poloxamer) " (CAS 9003-11-6).These polymer have following formula (X) structure:

HO(C ₂H ₄O) _a(C ₃H ₆O) _b(C ₂H ₄O) _aH

(X)

Wherein " a " and " b " represents polyoxyethylene unit number and polyoxypropylene unit number respectively.These copolymer molecule weight ranges are available 1000-15000 dalton, and wherein the ethylene oxide/propylene oxide ratio between 0.1 and 0.8 (weight).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more polyox-yethylene-polyoxypropylene block copolymers.

Polyoxyethylene such as PEG 300, PEG 400 and PEG 600 can be used as the excipient of SSRI/ steroid combination preparation described herein.

Fatty acid esters of sorbitan also can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of commercially available fatty acid esters of sorbitan comprises: Arlacel-20 (Span-20, Atlas/ICI), Arlacel-40 (Span-40, Atlas/ICI), Arlacel-80 (Span-80, Atlas/ICI), Arlacel-60 (Span-60, Atlas/ICI), sorbitan trioleate (Span-85, Atlas/ICI), Arlacel-83 (Arlacel-C, ICI, Arlacel-65 (Span-65, Atlas/ICI), (Crill 6 for anhydro sorbitol list isostearate, Croda) and the anhydro sorbitol sesquistearate (Nikkol SS-15, Nikko).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more fatty acid esters of sorbitan.

Lower alcohol (C ₂-C ₄) and fatty acid (C ₈-C ₁₈) ester be to be applicable to surfactant of the present invention.The example of these surfactants comprises: ethyl oleate (Crodamol EO, Croda), isopropyl myristate (Crodamol IPM, Croda), isopropyl palmitate (Crodamol IPP, Croda), Ethyl linoleate (Nikkol VF-E, Nikko) and the linoleic acid isopropyl ester (Nikkol VF-IP, Nikko).SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more lower alcohol fatty acid esters.

In addition, ionic surfactant can be used as the excipient of SSRI/ steroid combination preparation described herein.The example of useful ionic surfactant comprises: Sodium caproate; sodium caprylate; Capric acid sodium salt; sodium laurate; Sodium myristate; myristoleic acid sodium; sodium palmitate; palmitoleic acid sodium; enuatrol; sodium ricinoleate; linoleic acid sodium; linolenic acid sodium; sodium stearate; lauryl (dodecyl) sodium sulfate; sodium tetradecyl sulfate; sarcosyl; sodium dioctyl sulfosuccinate; sodium cholate; sodium taurocholate; sodium glycocholate; NaTDC; the deoxidation sodium taurocholate; glycocholeic acid sodium; ursodesoxycholic acid sodium; chenodeoxy cholic acid sodium; goose deoxidation sodium taurocholate; goose glycocholeic acid sodium; sodium cholylsarcosinate; N-methyl sodium taurocholate; Ovum Gallus domesticus Flavus lecithin; hydrogenated soy phosphatidyl choline; two myristoyl lecithin; lecithin; hydroxylated lecithin; LYSO-PHOSPHATIDYLCHOLINE LYSOPC; cuorin; sphingomyelin; phosphatidylcholine; PHOSPHATIDYL ETHANOLAMINE; phosphatidic acid; phosphatidyl glycerol; Phosphatidylserine; diethanolamine; phospholipid; polyoxyethylene-10 oleyl ether phosphate ester; the esterification products of aliphatic alcohol or alcohol ethoxylate and phosphoric acid or anhydride; ether carboxylate (by the oxidation of the terminal OH group of ethoxylized fatty alcohol); succinylated monoglycerides; sodium stearyl fumarate; stearoyl propylene glycol succinic acid hydrogen salt; tartaric monoglyceride of list/diacetylization and two glyceride; the monoglyceride of citric acid and two glyceride; the glyceride lactate of fatty acid; acyl lactylates; the lactate of fatty acid; stearoyl-2-sodium lactate; sodium stearoyl lactate; alginate; propanediol alginate; ethoxylation alkyl sodium sulfate ester; the alkylbenzene sulfone; the alpha-olefin sulphonic acid ester; the isethionic acid acyl ester; the taurine acyl ester; the glycerin ether alkyl sulfonate esters; the octyl group sodium sulfosuccinate; hendecene amide-MEA-sodium sulfosuccinate; six decyl brominations, three ammoniums; the decyl trimethylammonium bromide; the cetyl trimethylammonium bromide; undecyl ammonium chloride; the alkyl benzyl dimethyl ammonium salt; diisobutyl phenoxy group ethyoxyl dimethyl benzyl ammonium salt; Fixanol; betanin (trialkyl glycine); lauryl betaine (N-lauryl; N, N-two sarcosines) and amine ethoxylate (polyoxyethylene-15 coconut amine).Say simply, counter ion counterionsl gegenions commonly used more than are provided.Yet, one skilled in the art will appreciate that and can use biological acceptable any counter ion counterionsl gegenions.For example, although shown fatty acid is a sodium-salt form, also can use other cation counterbalancing ion, for example alkali metal cation or ammonium.SSRI/ steroid combination preparation of the present invention can comprise above-mentioned one or more ionic surfactants.

The consumption of excipient makes carrier form the clarification or the milky aqueous dispersion of SSRI, steroid or the combination of SSRI/ steroid in liposome in the preparation of the present invention.Adopt known method to determine the relative consumption of preparation liposome or the required surface activity excipient of solid-liquid nano particle preparations.For example, can prepare liposome, for example be described in Szoka etc., 1980 by various technology.Can form multilamellar vesicle (MLV) by simple fat-film hydration technology.In the method, above-mentioned liposome is formed lipid mixture be dissolved in appropriate organic solvent, evaporation forms thin film in container, is covered by aqueous medium then.The adipose membrane hydrate forms MLV, and size is between about 0.1-10 micron usually.

Can adopt other fixed liposome preparation technology on demand.For example, liposome promotes the application of cellular uptake to be described in United States Patent (USP) the 4th, 897,355 and 4,394, and No. 448.

Dosage

Usually, when oral administration of human, the dosage of SSRI is about 0.001mg-200mg/ days common every day, preferably about 1mg-100mg, more preferably every day about 5mg-50mg.In case of necessity, dosage can be up to 200mg/ days.For the drug administration by injection of SSRI, dosage is about 1mg-250mg common every day, preferred every day about 5mg-200mg, more preferably every day about 10mg-150mg.Preferably every day, injection gave 1-4 time.

When system's administration of human, be used for being about 0.1mg-1500mg common every day with the dosage of the corticosteroid of SSRI coupling, preferred every day about 0.5mg-10mg, more preferably every day about 0.5mg-5mg.

But every kind of medicine in the combination independently gives patient 1-4 time every day, continue 1 day to 1 year, even the patient needs lifelong administration.In many cases, need long term administration.

Other application

Adopt mensuration well-known in the art (example is as described herein), chemical compound of the present invention can be used for immunomodulating or mechanism is measured, to determine that other combination or independent medicine are in the secretion that suppresses proinflammatory cytokine or in producing or whether effectively equally with described combination regulating in the immunne response.For example, candidate compound can with SSRI (or its metabolite or analog) or corticosteroid coupling, and be used for stimulating PBMC.Spend one suitable period, checked cytokine secretion or generation or other suitable immunne response of cell.Comparative drug single with the relative effect of coupling each other, identify compounds effective and combination thereof then.

It is of the present invention that to be combined in the information of setting forth the relevant biological approach mechanism aspect that participates in inflammation also be useful instrument.Such information can instruct people to develop to be used to new medicine and the combination thereof that suppresses the inflammation that caused by proinflammatory cytokine.Can adopt the method that is used to measure biological approach known in the art, determine the network of biological approach or approach, described method comprises the cell that makes The compounds of this invention contact irriate and produce proinflammatory cytokine, thereby influences the network of biological approach or approach.Described method can comprise: with after The compounds of this invention contacts, analyze and express or downtrod cellular component, and itself and untreated cell, positive or negative control compound and/or new medicine and combination thereof compared, perhaps analyze some other metabolic activities of described cell, for example enzymatic activity, nutrient picked-up and propagation.The cellular component of being analyzed can comprise genetic transcription thing and protein expression thing.Suitable method can comprise the standard biological chemical technology, chemical compound of the present invention (is for example carried out radioactive label ¹⁴C or ³The H labelling), and observes described chemical compound and combine, for example use 2d gel, gene expression type analysis with proteic.In case identified out that then described chemical compound can be used for the body inner model of further method for building up, perhaps be used to develop new anti-inflammatory drug.

The following examples are used to illustrate the present invention, and limit the present invention anything but by any way.

Embodiment 1: proinflammatory cytokine suppresses active mensuration

As described below, measure of the inhibition of diluted chemical compound liquid matrix to IFN γ, IL-1 β, IL-2, IL-4, IL-5 and TNF α.

IFNγ

By with final concentration being 10ng/mL phorbol 12-myristinate 13-acetas (Sigma, P-1585) and 750ng/mL ionomycin (Sigma, I-0634) handle, secrete IFN γ with the human leukocyte suspension that the 100 μ L that stimulate each hole of polystyrene 384 orifice plates (NalgeNunc) to hold dilute.When stimulating, add every kind of test compound of variable concentrations.In humidified incubator in 37 ℃ hatch 16-18 hour after, this plate is centrifugal, supernatant transfer to the bag by anti-IFN gamma antibodies (Endogen, White-opalescent polystyrene 384 orifice plates #M-700A-E) (NalgeNunc, Maxisorb) in.After hatching in 2 hours, this plate is washed (Tecan PowerWasher 384) with the phosphate buffered saline(PBS) (PBS) that contains 0.1% polysorbas20 (polyoxyethylene sorbitan monolaurate), and with the biotin labeled anti-IFN gamma antibodies (Endogen of other usefulness, M701B) and the horseradish peroxidase of coupling streptavidin (HRP) (PharMingen #13047E) was hatched 1 hour together again.After this plate washed with 0.1% polysorbas20/PBS, every hole added the HRP-luminous substrate, measured light intensity with LJL Analyst plate luminometer.

IL-1β

By being that 2 μ g/mL lipopolysaccharide (Sigma L-4130) are handled with final concentration, secrete IL-1 β with the human leukocyte suspension that the 100 μ L that stimulate each hole of polystyrene 384 orifice plates (NalgeNunc) to hold dilute.When stimulating, add every kind of test compound of variable concentrations.In humidified incubator in 37 ℃ hatch 16-18 hour after, this plate is centrifugal, supernatant transferred to the bag by anti-il-i-beta antibody (R﹠amp; D, White-opalescent polystyrene 384 orifice plates #MAB-601) (NalgeNunc, Maxisorb) in.After hatching in 2 hours, with this plate with the PBS washing (Tecan PowerWasher 384) that contains 0.1% polysorbas20, and with the biotin labeled anti-il-i-beta antibody of other usefulness (R﹠amp; D, BAF-201) and the HRP of coupling streptavidin (PharMingen #13047E) was hatched 1 hour together again.After this plate washed with 0.1% polysorbas20/PBS, every hole added the HRP-luminous substrate, measured light intensity with LJL Analyst plate luminometer.

IL-2

By with final concentration being 10ng/mL phorbol 12-myristinate 13-acetas (Sigma, P-1585) and 750ng/mL ionomycin (Sigma, I-0634) handle, secrete IL-2 with the human leukocyte suspension that the 100 μ L that stimulate each hole of polystyrene 384 orifice plates (NalgeNunc) to hold dilute.When stimulating, add every kind of test compound of variable concentrations.In humidified incubator in 37 ℃ hatch 16-18 hour after, this plate is centrifugal, supernatant transfer to the bag by anti-IL-2 antibody (PharMingen, White-opalescent polystyrene 384 orifice plates #555051) (NalgeNunc, Maxisorb) in.After hatching in 2 hours, this plate is washed (Tecan PowerWasher 384) with the PBS that contains 0.1% polysorbas20, and with the biotin labeled anti-IL-2 antibody (Endogen of other usefulness, M600B) and the HRP of coupling streptavidin (PharMingen #13047E) was hatched 1 hour together again.After this plate washed with 0.1% polysorbas20/PBS, every hole added the HRP--luminous substrate, measured light intensity with LJL Analyst plate luminometer.

IL4 and IL-5

With BD PharMingen Cytometric 6 Bead Array systems,, analyze IL-4 and IL-5 cytokine-expressing according to manufacturer's description.In brief, will hatch with the cytokine assay pearl mixture of labelling from the supernatant of the determined plate of light yellow bag.Washing sample, resuspension and reading on BD Pharmingen FACsCalibur flow cytometer then.Come analytical data with BD Pharmingen CBA 6 Bead analysis software then.

TNFα

By being that 2 μ g/mL lipopolysaccharide (Sigma L-4130) are handled with final concentration, to stimulate the human leukocyte suspension TNF secretion α of the 100 μ L dilution that each hole of polystyrene 384 orifice plates (NalgeNunc) holds.When stimulating, add every kind of test compound of variable concentrations.In humidified incubator in 37 ℃ hatch 16-18 hour after, this plate is centrifugal, supernatant transfer to the bag by anti-TNF alpha antibodies (PharMingen, White-opalescent polystyrene 384 orifice plates #551220) (NalgeNunc, Maxisorb) in.After hatching in 2 hours, this plate is washed (Tecan PowerWasher 384) with the PBS that contains 0.1% polysorbas20, and with the biotin labeled anti-TNF alpha antibodies (PharMingen of other usefulness, #554511) and the HRP of coupling streptavidin (PharMingen #13047E) was hatched 1 hour together again.After this plate washed with 0.1% polysorbas20/PBS, every hole added the HRP-luminous substrate, measured light intensity with LJL Analyst plate luminometer.

Embodiment 2: the preparation of chemical compound

Preparation is dissolved in the storage liquid that contains corticosteroid or SSRI in the dimethyl sulfoxine (DMSO), and its final concentration is between 0 μ M and 40 μ M.Preparation contains the mainboard of the diluent of above-claimed cpd storage liquid.With the mainboard sealing and in-20 ℃ of stored for future use.

By with Packard Mini-Trak liquid processor, from concrete mainboard, 1 μ L storage liquid transferred to and contain 100 μ L culture medium (RPMI; Gibco BRL, #11875-085), 10% hyclone (Gibco BRL, #25140-097), in the dilution plate of 2% penicillin/streptomycin (Gibco BRL, #15140-122)), produce final single medicine plate.Should dilute plate then mixes, and 5 μ L samples are transferred in the final assay plate, this final assay plate has been packed in advance and has been contained the 50 μ L/ hole RPMI culture medium that activate IFN γ, IL-1 β, IL-2 or the excretory suitable stimulus thing of TNF α (referring to embodiment 1, referring to above).

Embodiment 3:SSRI, analog and metabolite suppress active test to proinflammatory cytokine

The test single medicine suppresses the ability of irriate leukocyte secretion IFN γ, IL-1 β, IL-2 and TNF α, determines the inhibition percentage rate of the cytokine secretion with respect to unprocessed irriate leukocyte.The data 5-14 that sees the following form.

Table 5-fluoxetine

????(μM)	??TNFα ??(PI)	??TNFα ??(LPS)	??IL-2	?IL-1β	????(μM)	????IFNγ
							????29.00	???89	????72	????84	????47	????36.15	???90.28
????14.50	???77	????0	????70	????18	????18.08	???55.84
							????7.25	???53	????0	????25	????22	????9.04	???28.08
????3.63	???21	????0	????0	????11	????4.52	???9.59
							????1.81	???13	????0	????0	????7	????2.26	???-5.35
????0.91	???6	????0	????0	????5	????1.13	???-4.25
							????0.45	???7	????0	????0	????0	????0.56	???-4.67
????0.23	???12	????0	????0	????0	????0.28	???0.02
							????0.11	???10	????0	????0	????0	????0.14	???2.94
????0.06	???6	????0	????0	????0	????0.07	???1.01
							????0.03	???4	????0	????0	????0	????0.04	???-4.41
????0.01	???0	????0	????0	????0	????0.02	???-3.21

Table 6-fluvoxamine

??????μM	??TNFα ??(PI)	?TNFαLPS	??IL-2	?IL-1β	????μM	????IFNγ
							??????63	????90	????76	????90	????39	???39.27	????46.16
??????31.5	????55	????0	????33	????25	???19.64	????10.07
							??????15.75	????26	????0	????6	????7	???9.82	????5.6
??????7.875	????11	????0	????0	????6	???4.91	????-0.75
							??????3.938	????0	????0	????0	????0	???2.45	????-2.92
??????1.969	????0	????0	????0	????0	???1.23	????-1.66
							??????0.984	????0	????0	????0	????0	???0.61	????-0.05
??????0.492	????0	????0	????0	????0	???0.31	????1.61
							??????0.246	????0	????0	????0	????0	???0.15	????1.39
??????0.123	????0	????0	????0	????0	???0.08	????-0.45
							??????0.062	????0	????0	????0	????0	???0.04	????2.14
??????0.031	????0	????0	????0	????0	???0.02	????-3.52

Table 7-paroxetine

???μM	??TNFα ??(PI)	??TNFα ??(LPS)	??IL-2	???μM	?IL-1β	????μM	????IFNγ
								??27.00	???94	???80	???88	??53.00	????64	???33.35	???97.58
??13.50	???87	???13	???71	??26.50	????39	???16.68	???73.92
								??6.75	???66	???0	???21	??13.25	????24	???8.34	???52.8
??3.38	???44	???0	???6	??6.63	????0	???4.17	???27.93
								??1.69	???30	???0	???0	??3.31	????0	???2.08	???16.48
??0.84	???16	???0	???0	??1.66	????0	???1.04	???4.26
								??0.42	???13	???0	???0	??0.83	????0	???0.52	???2.42
??0.21	???11	???0	???0	??0.41	????0	???0.26	???-0.93
								??0.11	???5	???0	???0	??0.21	????0	???0.13	???3.96
??0.05	???0	???0	???0	??0.10	????0	???0.07	???3.29
								??0.03	???0	???0	???0	??0.05	????0	???0.03	???0.53

Table 8-Sertraline

????μM	???TNFα ???(PI)	???TNFα ???(LPS)	??IL-2	?IL-1β	?????μM	??IENγ
							???64.00	????95	????97	????71	????95	????37.43	????20
???32.00	????96	????84	????63	????55	????18.72	????9
							???16.00	????87	????20	????53	????11	????9.36	????8
???8.00	????66	????7	????36	????6	????4.68	????6
							???4.00	????38	????0	????9	????0	????2.34	????3
???2.00	????18	????0	????0	????0	????1.17	????4
							???1.00	????11	????0	????0	????0	????0.58	????7
???0.50	????0	????0	????0	????0	????0.29	????5
							???0.25	????0	????0	????0	????0	????0.15	????2
???0.13	????0	????0	????0	????0	????0.07	????1
							???0.06	????0	????0	????0	????0	????0.04	????3
???0.03	????0	????0	????0	????0	????0.02	????1

Table 9-venlafaxine

????μM	?????TNFα ?????(PI)	?????TNFα ?????(LPS)	?????IL-1β	?????IL-2	????IFNγ
						???39.83	?????-1.64	?????32.50	????18.79	????-19.45	????-4.73
???19.92	?????-0.61	?????24.15	????0.66	????-20.24	????-9.95
						???9.96	?????-7.73	?????1.20	????-6.19	????-17.89	????-6.69
???4.98	?????-13.51	?????-18.41	????-14.75	????-20.77	????-3.38
						???2.49	?????-12.83	?????0.10	????-18.84	????-14.09	????-4.00
???1.24	?????-12.55	?????8.77	????-1.13	????-18.48	????2.25
						???0.62	?????-7.21	?????14.65	????-14.89	????-16.48	????-1.52
???0.31	?????-2.52	?????3.33	????-15.56	????-17.67	????0.75
						???0.16	?????-6.08	?????-2.41	????-21.72	????-16.19	????0.61
???0.08	?????-7.55	?????3.33	????-21.22	????-12.90	????3.22
						???0.04	?????-7.81	?????9.79	????0.23	????-10.03	????0.01
???0.02	?????-5.18	?????11.85	????-9.54	????-8.07	????-1.27

Table 10-norfluoxetine

?????μM	?????TNα ?????PI	???TNFα ???LPS	??IL-2	?IL-1β
					????45.00	????96	????70	????77	????68
????22.50	????86	????0	????66	????0
					????11.25	????57	????0	????32	????0
????5.63	????22	????0	????14	????0
					????2.81	????0	????0	????7	????0
????1.41	????0	????0	????0	????0
					????0.70	????0	????0	????0	????0
????0.35	????0	????0	????0	????0
					????0.18	????0	????0	????0	????0
????0.09	????0	????0	????0	????0
					????0.04	????0	????0	????0	????0
????0.02	????0	????0	????0	????0

Table 11-R (+) fluoxetine

????μM	????TNFα ????(PI)	????TNFα ????(LPS)	???IL-2	???IL-1β
					????58	????97	????82	????72	????68
????29	????89	????0	????72	????0
					????14.5	????66	????0	????55	????0
????7.25	????22	????0	????11	????0
					????3.625	????3	????0	????15	????0
????1.813	????0	????0	????12	????0
					????0.906	????0	????0	????0	????0
????0.453	????0	????0	????0	????0
					????0.227	????0	????0	????0	????0
????0.113	????0	????0	????0	????0
					????0.057	????0	????0	????0	????0
????0.028	????0	????0	????0	????0

Table 12-S (+) fluoxetine

??????μM	?????TNFα ?????(PI)	???TNFα ???(LPS)	??IL-2	?IL-1β
					??????58	??????98	????72	????62	????76
??????29	??????94	????45	????66	????70
					??????14.5	??????70	????0	????55	????31
??????7.25	??????48	????0	????17	????0
					??????3.625	??????20	????0	????0	????0
??????1.813	??????18	????0	????0	????0
					??????0.906	??????12	????0	????0	????0
??????0.453	??????6	????0	????0	????0
					??????0.227	??????7	????0	????0	????0
??????0.113	??????0	????0	????0	????0
					??????0.057	??????0	????0	????0	????0
??????0.028	??????0	????0	????0	????0

Table 13-zimeldine

?????μM	???TNFα ???(PI)	??????TNFα ??????(LPS)	???IL-2	??IL-1β
					????51.00	????51	???????25	????0	????34
????25.50	????28	???????0	????0	????10
					????12.75	????9	???????0	????0	????3
????6.38	????4	???????0	????0	????0
					????3.19	????0	???????0	????0	????0
????1.59	????0	???????0	????0	????0
					????0.80	????0	???????0	????0	????0
????0.40	????0	???????0	????0	????0
					????0.20	????0	???????0	????0	????0
????0.10	????0	???????0	????0	????0
					????0.05	????0	???????0	????0	????0
????0.03	????0	???????0	????0	????0

Table 14-citalopram

?????μM	????TNFα ????(PI)	????TNFα ????(LPS)	???IL-2	???IL-1β
					????20.00	????20	????ND	????44	?????ND
????10.00	????0	????ND	????0	?????ND
					????5.00	????0	????ND	????0	?????ND
????2.50	????0	????ND	????0	?????ND
					????1.25	????0	????ND	????0	?????ND
????0.63	????0	????ND	????0	?????ND
					????0.31	????0	????ND	????0	?????ND
????0.16	????0	????ND	????0	?????ND
					????0.08	????0	????ND	????0	?????ND
????0.04	????0	????ND	????0	?????ND
					????0.02	????0	????ND	????0	?????ND
????0.01	????0	????ND	????0	?????ND

Embodiment 4:SSRI suppresses active test to TNF α

Test SSRI and corticosteroid combination suppress the ability of irriate leukocyte TNF secretion α, determine the inhibition percentage rate of the cytokine secretion with respect to unprocessed irriate leukocyte.The data 15-22 that sees the following form.

Table 15

		Prednisolone (μ M)
												??0.400	???0.200	??0.100	??0.050	??0.025	???0.013	??0.006	???0.003	??0.0015	??0.000
		(μ M) Ting Xiluopa	????6.000	??74.3	???73.2	??71.6	??70.7	??67.4	???65.2	??64.0	???62.4											???61.7	???57.7
????3.000	??55.4											???54.8	??50.1	??46.3	??39.5	???36.5	??30.4	???28.5	???26.4	???22.8
			????1.500	??48.9	???47.7	??40.0	??35.4	??31.6	???21.8	??18.8	???16.4										???13.1	???10.8
????0.750	??43.6											???43.2	??35.5	??31.0	??23.0	???17.7	??11.9	???9.4	???5.82	???4.0
			????0.375	??40.2	???38.7	??33.6	??26.6	??22.4	???15.2	??12.0	???5.5										???3.2	???1.4
????0.188	??38.1											???38.8	??32.1	??26.4	??19.8	???16.5	??9.3	???5.4	???1.5	???-0.2
			????0.094	??42.3	???38.5	??30.6	??25.8	??21.3	???14.4	??9.8	???4.1										???4.9	???-1.0
????0.047	??37.6											???37.5	??31.6	??28.2	??16.5	???12.1	??6.4	???3.8	???0.2	???-4.3
			????0.023	??37.1	???35.3	??32.1	??23.4	??18.5	???9.35	??4.5	???1.8										???-0.3	???-3.1
????0.000	??36.2											???34.1	??29.4	??23.4	??16.5	???11.5	??4.6	???-0.1	???-0.8	???-2.0

Table 16

		Prednisolone (μ M)
												??0.200	??0.100	???0.050	??0.025	??0.013	??0.006	??0.003	??0.0015	??0.0008	??0.000
		West, (μ M) spit of fland fluorine	????7.230	??64.0	??52.9	???54.7	??43.5	??43.9	??42.4	??36.1	???31.6											???31.4	??29.6
????3.615	??52.5											??44.5	???38.4	??30.9	??23.1	??22.7	??16.3	???14.9	???12.1	??10.8
			????1.808	??47.0	??42.0	???36.8	??31.5	??22.7	??19.8	??13.4	???19.3										???13.4	??12.6
????0.904	??43.7											??40.3	???28.0	??21.8	??13.4	??17.6	??6.8	???16.7	???9.3	??10.4
			????0.452	??41.0	??33.6	???30.0	??25.8	??13.3	??11.2	??10.9	???6.2										???9.3	??4.6
????0.226	??35.4											??28.9	???22.5	??19.9	??13.1	??8.6	??9.8	???0.0	???3.8	??0.1
			????0.113	??36.2	??30.0	???21.6	??14.6	??7.7	??4.7	??4.5	???3.2										???1.6	??2.3
????0.057	??38.5											??25.8	???22.8	??7.9	??3.5	??9.2	??6.7	???6.6	???5.7	??5.0
			????0.028	??31.0	??27.8	???24.7	??11.2	??9.1	??8.9	??6.7	???0.0										???5.5	??25.8
????0.000	??39.7											??31.6	???24.3	??18.3	??8.9	??7.0	??4.4	???-1.9	???3.8	??5.1

Table 17

		Budesonide (μ M)
								??0	????0.0005	????0.002	???0.009	???0.035	???0.140
		West, (μ M) spit of fland fluorine	????0	??0	????-2.4	????-8.9	???5.3							???-19.0	???-18.8
????0.002	??21.3							????40.1	????38.7	???33.7	???43.7	???31.2
			????0.009	??7.9	????32.0	????29.6	???43.6						???45.8	???33.3
????0.036	??10.5							????34.8	????35.6	???32.1	???39.1	???38.2
			????0.140	??10.4	????36.2	????38.2	???30.4						???29.7	???27.8
????0.580	??39.7							????38.1	????44	???43.4	???37.4	???49.5

Table 18

		Dexamethasone (μ M)
										????0	????0.0004	????0.0008	?????0.0016	???0.0031	???0.0063	???0.013	???0.025
		(μ M) Ting Xiluopa	???0	????-0.1	????2.1	????6.7	?????17.7	???21.2	???26.7									???35.0	???47.8
???0.023	????2.1									????5.5	????12.6	?????22.9	???15.4	???31.9	???30.6	???36.4
			???0.047	????-4.0	????-0.7	????-0.2	?????13.2	???16.4	???25.0								???35.6	???40.6
???0.094	????-12.2									????-1.3	????3.9	?????11.3	???19.6	???25.0	???40.3	???39.3
			???0.190	????-13.1	????-3.5	????5.2	?????4.8	???18.4	???29.6								???34.1	???41.0
???0.380	????-10.9									????1.8	????2.9	?????10.2	???14.9	???21.4	???31.8	???37.5
			???0.750	????-3.6	????0.5	????5.1	?????10.6	???22.6	???28.9								???42.1	???40.4
???1.500	????2.0									????11.8	????14.7	?????15.2	???23.4	???32.1	???38.7	???48.7
			???3.000	????9.9	????18.7	????20.0	?????29.3	???32.3	???42.0								???50.1	???53.4
???6.000	????40.6									????44.1	????47.0	?????51.6	???55.1	???63.4	???59.5	???68.3

Table 19

		Dexamethasone (μ M)
								???0	???0.0006	???0.0024	????0.0096	????0.0380	????0.1500
		West, (μ M) spit of fland fluorine	????0	???0	???-3.8	???0.25	????-11.4							????-16.2	????-20.0
????0.002	???14.0							???24.1	???31.7	????33.0	????30.4	????28.5
			????0.009	???16.9	???29.5	???29.0	????26.8						????25.8	????29.0
????0.036	???22.7							???30.5	???35.0	????35.7	????27.3	????32.4
			????0.140	???22.1	???29.9	???34.2	????34.5						????29.4	????31.6
????0.580	???22.2							???30.9	???34.0	????36.0	????29.4	????31.4

Table 20

		Prednisolone (μ M)
											????0	????0.0078	???0.0160	???0.0310	???0.0620	???0.1200	????0.2500	????0.500	????1.0000
		West, (μ M) spit of fland fluorine	????0	????-2.1	????1.1	???10.5	???16.4	???24.1	???27.2	????31.1										????39.0	????35.1
????0.23	????-1.4										????-1.4	???3.7	???9.8	???18.3	???24.7	????31.1	????34.0	????33.9
			????0.45	????-3.4	????5.5	???6.3	???10.6	???21.5	???28.2	????33.2									????34.1	????40.8
????0.90	????-4.6										????-6.4	???0.2	???15.2	???18.5	???18.7	????31.3	????34.0	????27.7
			????1.80	????5.5	????9.3	???19.4	???18.1	???27.0	???36.8	????48.1									????44.1	????44.9
????3.60	????9.7										????20.1	???20.5	???22.9	???33.5	???44.4	????46.0	????53.0	????48.1
			????7.20	????51.8	????54.0	???53.5	???51.2	???64.4	???63.4	????66.9									????67.7	????68.0
????14.00	????76.8										????78.1	???75.7	???82.5	???82.8	???83.1	????84.5	????86.7	????83.5
			????29.00	????93.4	????94.4	???93.6	???94.8	???93.8	???91.9	????95.6									????95.9	????95.5

Table 21

		Prednisolone (μ M)
											????0	??0.0078	??0.0160	?0.0310	??0.0620	??0.1200	?0.2500	?0.1500	??1.0000
		(μ M) Ting Xiluopa	????0	???-1.3	???12.9	???12.9	??22.7	???32.4	???33.2	??41.6										??35.4	???38.6
???0.21	???-8.9										???8.6	???8.1	??21.2	???27.6	???30.9	??36.1	??39.9	???40.5
			???0.42	???1.4	???4.0	???9.8	??17.5	???29.4	???34.6	??38.9									??38.3	???45.6
???0.83	???3.2										???83	???18.8	??26.2	???30.6	???33.8	??39.8	??42.2	???44.2
			???1.70	???13.8	???13.5	???24.7	??36.4	???33.2	???46.1	??55.3									??50.3	???49.5
???3.30	???29.1										???47.8	???50.3	??56.3	???55.2	???60.5	??62.3	??67.0	???66.2
			???6.70	???65.5	???69.2	???72.3	??74.9	???76.3	???77.8	??80.4									??80.4	???78.5
???13.00	???88.2										???88.3	???90.0	??89.0	???92.8	???92.3	??92.5	??88.5	???92.4
			???27.00	???96.9	???96.9	???95.3	??95.7	???91.4	???96.4	??97.7									??97.7	???97.4

Table 22

		Prednisolone (μ M)
											?????0	??0.0078	??0.0160	??0.0310	???0.0620	??0.1200	??0.2500	???0.500	??1.0000
		(μ M) Lin Qu house	?????0	???-3.2	????2.1	???6.3	????13.4	????17.5	????21.9	???263										????29.1	???34.0
????0.5	???-3.1										????-3.3	???3.5	????9.8	????19.0	????19.1	???26.1	????28.0	???27.5
			????1.0	???1.8	????2.0	???4.1	????7.4	????21.1	????20.9	???24.0									????31.2	???34.7
????2.0	???1.7										????3.7	???9.6	????7.8	????21.4	????19.2	???33.4	????28.6	???33.6
			????4.0	???19.4	????23.9	???29.0	????30.9	????34.2	????42.2	???47.7									????45.7	???46.5
????8.0	???49.1										????53.5	???54.5	????57.5	????59.0	????64.2	???66.6	????65.8	????68.3
			????16.0	???74.7	????76.5	???77.2	????80.2	????81.5	????80.5	???75.1									????83.8	????84.2
????32.0	???92.3										????92.3	???93.7	????93.5	????93.8	????94.4	???94.3	????95.0	????94.4
			????63.0	???96.8	????97.1	???97.0	????97.2	????97.7	????97.2	???97.2									????97.7	????97.0

Also tested the combination of prednisolone and paroxetine to vitro inhibition IL-4 and the excretory ability of IL-5.The results are shown in following table 23 and table 24.

Table 23-IL-4

	Suppress (%)
		Prednisolone 1.0 μ M	47.76
Paroxetine 28.0 μ M	97.06
		Its combination (1.0/28.0)	97.32
		Prednisolone 0.125 μ M	43.62
Paroxetine 3.5 μ M	43.64
		Its combination (0.125/3.5)	64.69
		Prednisolone 0.016 μ M	18.53
Paroxetine 0.44 μ M	14.04
		Its combination (0.016/0.44)	18.10

Table 24-IL-5

	Suppress (%)
		Prednisolone 1.0 μ M	75.49
Paroxetine 28.0 μ M	97.76
		Its combination (1.0/28.0)	98.45
		Prednisolone 0.125 μ M	73.19
Paroxetine 3.5 μ M	69.93
		Its combination (0.125/3.5)	85.91
		Prednisolone 0.016 μ M	36.76
Paroxetine 0.44 μ M	32.32
		Its combination (0.016/0.44)	44.10

Embodiment 5: cyclosporin A and Sertraline are combined in the secretion of external reduction IL-2

As mentioned above, after stimulating, measure the secretion of IL-2 with ELISA with phorbol 12-myristinate 13-acetas and ionomycin.Cyclosporin A, Sertraline and the Sertraline of variable concentrations and cyclosporin A effect of Combination and control wells are compared.Stimulate these holes with phorbol 12-myristinate 13-acetas and ionomycin, but do not give cyclosporin A or Sertraline.

Experimental result sees the following form 25.The medicine list is used and the effect of coupling is expressed as the excretory inhibition percentage rate of IL-2.

Table 25

The inhibition (%) of IL-2 PBMC PI
											Cyclosporin A (μ M)
(μ M) Lin Qu house		??????0	??0.008	???0.016	???0.031	???0.062	??0.125	???0.25	????0.5	???1.0
											?????0	????-0.4	???0.0	???-1.7	???18.6	???44.4	???68.5	???75.1	????80.6	???83.5
	????0.25	????2.3	???1.7	???3.4	???17.5	???46.4	???66.8	???77.9	????81.1	???83.2
											????0.5	????-2.9	???0.6	???13.1	???22.2	???48.5	???71.4	???79.5	????82.6	???84.2
	????1	????3.2	???-0.5	???8.3	???27.4	???50.1	???72.6	???79.8	????83.2	???85.9
											????2	????-0.8	???9.0	???6.4	???28.5	???64.4	???79.1	???83.8	????87.0	???87.4
	????4	????3.0	???11.0	???25.1	???56.8	???81.6	???88.3	???89.8	????91.0	???92.2
											????8	????20.8	???34.9	???55.7	???85.4	???92.4	???94.5	???95.2	????95.5	???95.4
	????16	????70.9	???81.6	???90.7	???93.6	???94.8	???95.7	???96.0	????96.3	???96.4
											????32	????86.3	???90.1	???89.2	???92.2	???90.1	???95.7	???96.2	????95.8	???91.5

Embodiment 6: cyclosporin A and Sertraline are combined in the secretion of external reduction IFN γ

As mentioned above, after stimulating, measure the secretion of IFN γ with ELISA with phorbol 12-myristinate 13-acetas and ionomycin.With cyclosporin A, Sertraline and the cyclosporin A of variable concentrations and Sertraline effect of Combination with compare without cyclosporin A or Sertraline stimulated control hole.Experimental result sees the following form 26.The medicine list is used and the effect of coupling is expressed as the excretory inhibition percentage rate of IFN γ.

Table 26

The inhibition (%) of IFN γ PBMC PI
											Cyclosporin A (μ M)
(μ M) Lin Qu house		?????0	???0.0077	???0.015	???0.031	???0.062	???0.12	???0.25	????0.5	????1.0
											?????0	???-6.3	????4.4	???12.9	???20.1	???47.0	???76.5	???93.1	???95.3	???95.5
	????0.25	???0.0	????5.6	???8.6	???18.6	???41.8	???78.1	???93.2	???95.3	???95.4
											????0.5	???0.0	????-10.5	???7.6	???22.3	???49.2	???80.5	???94.0	???95.6	???95.8
	????1	???4.5	????5.7	???11.4	???22.9	???47.4	???82.3	???93.9	???95.4	???95.7
											????2	???7.7	????10.9	???18.6	???34.0	???61.6	???89.4	???95.0	???96.0	???95.7
	????4	???26.0	????29.0	???33.5	???46.3	???71.4	???91.2	???95.7	???96.7	???96.8
											????8	???50.1	????54.2	???60.6	???69.5	???83.4	???94.2	???96.7	???97.0	???97.1
	????16	???78.2	????82.8	???80.9	???85.2	???91.9	???96.0	???97.3	???97.6	???96.6
											????32	???92.2	????94.0	???93.1	???95.3	???96.7	???96.7	???97.9	???97.8	???95.8

Embodiment 7: cyclosporin A and Sertraline are combined in the secretion of external reduction TNF α

As mentioned above, after stimulating, measure the secretion of TNF α with ELISA with phorbol 12-myristinate 13-acetas and ionomycin.With cyclosporin A, Sertraline and the cyclosporin A of variable concentrations and Sertraline effect of Combination with compare without cyclosporin A or Sertraline stimulated control hole.The results are shown in following table 27.The medicine list is used and the effect of coupling is expressed as the excretory inhibition percentage rate of TNF α.

Table 27

The inhibition (%) of TNF α PBMC PI
											Cyclosporin A (μ M)
(μ M) Lin Qu house		????0	??0.0077	???0.015	??0.031	???0.062	???0.12	???0.25	???0.5	???1.0
											????0	???-1.8	???10.9	???11.2	???38.4	???61.8	???82.0	???92.6	???94.0	???94.2
	???0.25	???-1.8	???10.6	???14.0	???32.0	???60.5	???81.1	???92.7	???94.1	???93.3
											???.5	???-6.4	???4.0	???23.7	???38.9	???70.0	???87.5	???93.1	???94.6	???95.0
	???1	???-0.4	???13.2	???22.7	???40.9	???63.9	???88.7	???92.3	???95.3	???95.4
											???2	???-0.6	???22.5	???33.1	???55.1	???72.0	???91.3	???95.0	???95.7	???95.5
	???4	???23.5	???37.8	???46.8	???62.0	???84.6	???94.6	???95.9	???96.4	???96.9
											???8	???59.1	???70.8	???73.5	???85.4	???93.5	???96.5	???97.0	???97.3	???97.1
	???16	???73.8	???93.4	???92.4	???95.7	???97.4	???97.6	???98.2	???95.0	???97.7
											???32	???96.0	???70.2	???97.4	???98.1	???98.0	???98.0	???97.5	???97.9	???74.5

Embodiment 8: cyclosporin A and fluoxetine are combined in the secretion of external reduction IL-2

As mentioned above, after stimulating, measure the secretion of IL-2 with ELISA with phorbol 12-myristinate 13-acetas and ionomycin.With cyclosporin A, fluoxetine and the cyclosporin A of variable concentrations and fluoxetine effect of Combination with compare without cyclosporin A or fluoxetine stimulated control hole.Experimental result sees the following form 28.The medicine list is used and the effect of coupling is expressed as the excretory inhibition percentage rate of IL-2.

Table 28

The inhibition of IL-2PBMC PI (%)
											Cyclosporin A (μ M)
West, (μ M) spit of fland fluorine		??????0	??0.0077	??0.015	??0.031	??0.062	??0.12	??0.25	????0.5	???1.0
											????0	???-0.8	????7.7	??20.2	??48.5	??72.4	??91.2	??94.7	???95.2	???100.3
	??0.65	???0.8	????12.7	??15.8	??47.3	??75.1	??86.7	??92.9	???94.6	???98.4
											??1.3	???-2.1	????11.2	??22.3	??49.5	??73.1	??78.7	??93.0	???93.1	???91.6
	??2.6	???0.6	????8.8	??28.3	??47.2	??71.3	??84.7	??91.5	???93.1	???92.2
											??5.2	???-0.2	????11.2	??25.5	??55.2	??77.1	??82.6	??89.1	???91.0	???92.6
	??10	???16.1	????24.3	??45.5	??66.5	??91.2	??91.3	??93.6	???92.4	???89.4
											??21	???47.4	????63.4	??74.7	??91.7	??98.8	??96.8	??94.0	???93.5	???106.3
	??42	???90.3	????94.2	??91.7	??105.2	??109.8	??109.3	??102.0	???107.0	???106.0
											??84	???103.4	????109.6	??110.0	??109.7	??110.8	??104.4	??103.9	???108.1	???105.2

Embodiment 9: tacrolimus and fluvoxamine are combined in the secretion of external reduction IL-2

As mentioned above, after stimulating, measure the secretion of IL-2 with ELISA with phorbol 12-myristinate 13-acetas and ionomycin.With tacrolimus, fluvoxamine and the tacrolimus of variable concentrations and fluvoxamine effect of Combination with compare without tacrolimus or fluvoxamine stimulated control hole.Experimental result sees the following form 29.The medicine list is used and the effect of coupling is expressed as the excretory inhibition percentage rate of IL-2.

Table 29

The inhibition of IL-2PBMC PI (%)
											Tacrolimus (μ M)
(μ M) Ming Shafu fluorine		?????0	??0.0004	???0.0008	??0.0016	??0.0031	??0.0062	??0.013	??0.025	??0.05
											?????0	????-6.7	????0.73	????-4.4	????8.1	????19	????44	????60	???76	???87
	???0.16	????1.1	????2	????-1.1	????13	????17	????39	????63	???79	???86
											???0.31	????3.6	????2.7	????7.8	????12	????26	????48	????64	???80	???91
	???0.62	????4.6	????1.7	????7.4	????8.8	????17	????43	????62	???80	???90
											???1.2	????-1.4	????-0.98	????5.4	????12	????23	????48	????70	???78	???90
	???2.5	????-2	????7.9	????2.9	????7.1	????30	????55	????68	???83	???91
											???5	????3.6	????4.6	????8	????15	????33	????53	????76	???88	???94
	???10	????8.1	????14	????10	????25	????48	????70	????85	???92	???97
											???20	????22	????31	????43	????54	????75	????92	????98	???103	???106

Embodiment 10: cyclosporin A and paroxetine are combined in the secretion of external reduction IL-2

As mentioned above, after stimulating, measure the secretion of IL-2 with ELISA with phorbol 12-myristinate 13-acetas and ionomycin.With cyclosporin A, paroxetine and the cyclosporin A of variable concentrations and paroxetine effect of Combination with compare without cyclosporin A or paroxetine stimulated control hole.Experimental result sees the following form 30.The medicine list is used and the effect of coupling is expressed as the excretory inhibition percentage rate of IL-2.

Table 30

The inhibition of IL-2PBMC PI (%)
											Cyclosporin A (μ M)
(μ M) Ting Xiluopa		????0	???0.0077	??0.015	??0.031	??0.062	???0.12	???0.25	????0.5	??1.0
											?????0	????1.0	????-1.7	???29.7	???43.9	???68.4	???86.2	???98.3	???96.8	??97.7
	????0.56	????-2.4	????5.0	???23.4	???47.6	???69.1	???85.1	???91.5	???97.9	??102.7
											????1.1	????-0.3	????2.7	???30.4	???39.9	???71.8	???89.5	???95.2	???97.9	??97.7
	????2.2	????4.8	????10.5	???26.8	???42.7	???69.6	???88.5	???95.4	???92.1	??100.4
											????4.4	????1.9	????31.2	???40.7	???57.6	???83.2	???94.4	???95.2	???94.0	??97.4
	????8.9	????21.6	????38.7	???61.3	???74.1	???90.7	???91.9	???92.5	???95.9	??92.2
											????18	????54.2	????71.0	???81.2	???88.2	???90.6	???93.4	???96.4	???98.1	??107.0
	????36	????83.5	????89.8	???94.3	???102.5	???100.5	???99.5	???99.1	???104.3	??100.7
											????72	????95.7	????98.3	???98.9	???99.9	???95.5	???97.8	???97.9	???105.8	??104.3

Other embodiment

Under the situation that does not depart from scope and spirit of the present invention, the various modifications and variations of the method and system that the present invention describes will be conspicuous to those skilled in the art.Although adopt concrete embodiment preferred to describe the present invention, people know, claimed the present invention should not think the inappropriate restriction that is subjected to described specific embodiments.In fact, be that the various modifications of the embodiment described of conspicuous the present invention all comprise within the scope of the present invention for medicine, immunology, pharmacology, endocrinology or those skilled in the relevant art.

Claims (77)

1. compositions, described compositions comprises selectivity 5-hydroxy tryptamine reuptake inhibitor (SSRI) and corticosteroid, and its total consumption is enough to reduce in vivo the secretion or the generation of proinflammatory cytokine.

2. the compositions of claim 1, wherein said SSRI is cericlamine, citalopram, clovoxamine, cyanogen dosulepin, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, litoxetine, midalcipran, paroxetine, Sertraline, tametraline, viqualine or zimeldine.

3. the compositions of claim 1, wherein said corticosteroid is prednisolone, cortisone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone or diflorasone.

4. the compositions of claim 1, wherein said SSRI is fluoxetine or paroxetine, and described corticosteroid is a prednisolone.

5. the compositions of claim 1, wherein said SSRI or described corticosteroid exist with low dosage in described compositions.

6. the compositions of claim 1, wherein said SSRI or described corticosteroid exist with high dose in described compositions.

7. the compositions of claim 1, described compositions also comprises NSAID, cox 2 inhibitor, biological preparation, DMARD, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid and 5-aminosalicylic acid.

8. the compositions of claim 7, wherein said NSAID is ibuprofen, diclofenac or naproxen.

9. the compositions of claim 7, wherein said cox 2 inhibitor is rofecoxib, celecoxib, valdecoxib or Prexige.

10. the compositions of claim 7, wherein said biological preparation is adelimumab, Embrel or infliximab.

11. the compositions of claim 7, wherein said DMARD is methotrexate or leflunomide.

12. the compositions of claim 7, wherein said xanthine is a theophylline.

13. the compositions of claim 7, wherein said anticholinergic compound are ipratropium or tiotropium.

14. the compositions of claim 7, wherein said beta receptor agonist is sulphuric acid ibuterol, bitolterol mesilate, epinephrine, formoterol fumarate, isoproterenol, levalbuterol hydrochloride, orciprenaline sulfate, pirbuterol acetate, salmeterol xinafoate or terbutaline.

15. the compositions of claim 7, wherein said non-steroidal neurocalcin inhibitor is cyclosporin, tacrolimus, pimecrolimus or ISAtx247.

16. the compositions of claim 7, wherein said novel vitamin D analogues are calcipotriene or calcipotriol.

17. the compositions of claim 7, wherein said psoralen is a methoxsalen.

18. the compositions of claim 7, wherein said retinoid are acitretin or tazoretene.

19. the compositions of claim 7, wherein said 5-aminosalicylic acid are mesalazine, sulfasalazine, balsalazide disodium or olsalazine sodium.

20. the compositions of claim 1, wherein said compositions are mixed with for topical and use.

21. the compositions of claim 1, wherein said compositions are mixed with for being administered systemically usefulness.

22. one kind is used to reduce the method that proinflammatory cytokine is secreted or produced in patient's body, described method comprises gives or gave respectively described patient SSRI and corticosteroid simultaneously that in 14 days its consumption is enough to reduce the secretion or the generation of proinflammatory cytokine in described patient's body.

23. one kind is used for the treatment of the method for suffering from the immunoinflammatory disease after diagnosing or the patient that the danger of immunoinflammatory disease takes place being arranged, described method comprises and gives simultaneously or gave described patient SSRI and corticosteroid respectively in 14 days that its consumption is enough to treat described patient.

24. the method for claim 23, wherein said immunoinflammatory disease is rheumatoid arthritis, Crohn disease, ulcerative colitis, asthma, chronic obstructive disease of lung, polymyalgia rheumatica, giant cell arteritis, systemic lupus erythematosus (sle), atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondylitis or psoriasis arthropathica.

25. the method for claim 23, wherein said SSRI is cericlamine, citalopram, clovoxamine, cyanogen dosulepin, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, litoxetine, midalcipran, paroxetine, Sertraline, tametraline, viqualine or zimeldine.

26. the method for claim 23, wherein said corticosteroid are prednisolone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone or diflorasone.

27. also comprising, the method for claim 23, described method give described patient NSAID, cox 2 inhibitor, biological preparation, DMARD, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid and 5-aminosalicylic acid.

28. the method for claim 27, wherein said NSAID is ibuprofen, diclofenac or naproxen.

29. the method for claim 27, wherein said cox 2 inhibitor are rofecoxib, celecoxib, valdecoxib or Prexige.

30. the method for claim 27, wherein said biological preparation are adelimumab, Embrel or infliximab.

31. the method for claim 27, wherein said DMARD is methotrexate or leflunomide.

32. the method for claim 27, wherein said xanthine is a theophylline.

33. the method for claim 27, wherein said anticholinergic compound are ipratropium or tiotropium.

34. the method for claim 27, wherein said beta receptor agonist is sulphuric acid ibuterol, bitolterol mesilate, epinephrine, formoterol fumarate, isoproterenol, levalbuterol hydrochloride, orciprenaline sulfate, pirbuterol acetate, salmeterol xinafoate or terbutaline.

35. the method for claim 27, wherein said non-steroidal neurocalcin inhibitor is cyclosporin, tacrolimus, pimecrolimus or ISAtx247.

36. the method for claim 27, wherein said novel vitamin D analogues are calcipotriene or calcipotriol.

37. the method for claim 27, wherein said psoralen is a methoxsalen.

38. the method for claim 27, wherein said retinoid are acitretin or tazoretene.

39. the method for claim 27, wherein said 5-aminosalicylic acid are mesalazine, sulfasalazine, balsalazide disodium or olsalazine sodium.

40. the method for claim 23, wherein said SSRI or described corticosteroid are to give with low dosage.

41. the method for claim 23, wherein said SSRI or described corticosteroid are to give with high dose.

42. the method for claim 23, wherein said SSRI and described corticosteroid are to give respectively in 10 days.

43. the method for claim 42, wherein said SSRI and described corticosteroid are to give respectively in 5 days.

44. the method for claim 43, wherein said SSRI and described corticosteroid are to give respectively in 24 hours.

45. the method for claim 44, wherein said SSRI and described corticosteroid are to give simultaneously.

46. a compositions, described compositions comprises SSRI and glucocorticoid receptor modulator, and its total consumption is enough to reduce the secretion or the generation of proinflammatory cytokine.

47. the compositions of claim 46, wherein said SSRI is cericlamine, citalopram, clovoxamine, cyanogen dosulepin, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, litoxetine, midalcipran, paroxetine, Sertraline, tametraline, viqualine or zimeldine.

48. also comprising, the compositions of claim 46, described compositions be selected from following chemical compound: NSAID, cox 2 inhibitor, biological preparation, DMARD, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid and 5-aminosalicylic acid.

49. one kind is used to reduce the method that proinflammatory cytokine is secreted or produced in patient's body, described method comprises gives or gave respectively described patient SSRI and glucocorticoid receptor modulator simultaneously that in 14 days its consumption is enough to reduce the secretion or the generation of proinflammatory cytokine in described patient's body.

50. one kind is used for the treatment of the method for suffering from the immunoinflammatory disease after diagnosing or the patient that the danger of immunoinflammatory disease takes place being arranged, described method comprises and gives simultaneously or gave described patient SSRI and glucocorticoid receptor modulator respectively in 14 days that its consumption is enough to treat described patient.

51. the method for claim 50, wherein said immunoinflammatory disease is rheumatoid arthritis, Crohn disease, ulcerative colitis, asthma, chronic obstructive disease of lung, polymyalgia rheumatica, giant cell arteritis, systemic lupus erythematosus (sle), atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondylitis or psoriasis arthropathica.

52. the method for claim 50, wherein said SSRI is cericlamine, citalopram, clovoxamine, cyanogen dosulepin, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, indeloxazine, litoxetine, midalcipran, paroxetine, Sertraline, tametraline, viqualine or zimeldine.

53. also comprising, the method for claim 50, described method give described patient's cox 2 inhibitor, NSAID, corticosteroid, DMARD, biological preparation, xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid or 5-aminosalicylic acid.

54. the method for claim 50, wherein said SSRI and described glucocorticoid receptor modulator are to give respectively in 10 days.

55. the method for claim 54, wherein said SSRI and described glucocorticoid receptor modulator are to give respectively in 5 days.

56. the method for claim 55, wherein said SSRI and described glucocorticoid receptor modulator are to give respectively in 24 hours.

57. the method for claim 56, wherein said SSRI and described glucocorticoid receptor modulator are to give simultaneously.

58. a Pharmaceutical composition, described compositions comprise (i) SSRI and (ii) are selected from the second following chemical compound: xanthine, anticholinergic compound, beta receptor agonist, bronchodilator, biological preparation, NSAID, DMARD, cox 2 inhibitor, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid and 5-aminosalicylic acid.

59. the compositions of claim 58, wherein said NSAID is ibuprofen, diclofenac or naproxen.

60. the compositions of claim 58, wherein said cox 2 inhibitor are rofecoxib, celecoxib, valdecoxib or Prexige.

61. the compositions of claim 58, wherein said biological preparation are adelimumab, Embrel or infliximab.

62. the compositions of claim 58, wherein said DMARD is methotrexate or leflunomide.

63. the compositions of claim 58, wherein said xanthine is a theophylline.

64. the compositions of claim 58, wherein said anticholinergic compound are ipratropium or tiotropium.

65. the compositions of claim 58, wherein said beta receptor agonist is sulphuric acid ibuterol, bitolterol mesilate, epinephrine, formoterol fumarate, isoproterenol, levalbuterol hydrochloride, orciprenaline sulfate, pirbuterol acetate, salmeterol xinafoate or terbutaline.

66. the compositions of claim 58, wherein said non-steroidal neurocalcin inhibitor is cyclosporin, tacrolimus, pimecrolimus or ISAtx247.

67. the compositions of claim 58, wherein said novel vitamin D analogues are calcipotriene or calcipotriol.

68. the compositions of claim 58, wherein said psoralen is a methoxsalen.

69. the compositions of claim 58, wherein said retinoid be acitretin or

70. interior excretory method of one or more proinflammatory cytokines of patient's body that is used to suppress to have needs, described method comprises and gives described patient (i) SSRI and (ii) be selected from the second following chemical compound: xanthine, anticholinergic compound, biological preparation, NSAID, DMARD, cox 2 inhibitor, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid and 5-aminosalicylic acid, its consumption are enough to reduce the secretion or the generation of proinflammatory cytokine in described patient's body.

Give described patient SSRI 71. the interior excretory method of one or more proinflammatory cytokines of patient's body that is used to suppress to have needs, described method comprise, its consumption is enough to suppress the secretion of proinflammatory cytokine in described patient's body.

Give described patient SSRI 72. a method that is used for the treatment of the patient who suffers from the immunoinflammatory disease after diagnosing, described method comprise, its consumption and persistent period are enough to treat described patient.

73. a medicine box, described medicine box comprises:

(i) comprise the compositions of SSRI and corticosteroid; With

(ii) description, this description indication gives to suffer from the immunoinflammatory disease after diagnosing with described compositions or the patient that the danger of immunoinflammatory disease takes place is arranged.

74. a medicine box, described medicine box comprises:

(i)SSRI；

(ii) corticosteroid; With

(iii) description, this description indication gives described SSRI and described corticosteroid system to suffer from the immunoinflammatory disease after diagnosing or the patient that the danger of immunoinflammatory disease takes place is arranged.

75. a medicine box, described medicine box comprises: (i) SSRI and (ii) description, this description indication gives described SSRI to suffer from after diagnosing the patient of immunoinflammatory disease.

76. a medicine box, described medicine box comprises:

(i)SSRI；

(ii) be selected from the second following chemical compound: glucocorticoid receptor modulator, xanthine, anticholinergic compound, biological preparation, NSAID, DMARD, cox 2 inhibitor, beta receptor agonist, bronchodilator, non-steroidal neurocalcin inhibitor, novel vitamin D analogues, psoralen, retinoid and 5-aminosalicylic acid; With

(iii) description, this description indication gives described SSRI and described second chemical compound to suffer from the immunoinflammatory disease after diagnosing or the patient that the danger of immunoinflammatory disease takes place is arranged.

77. an evaluation is used to suppress the method for the excretory chemical compound combination of proinflammatory cytokine in patient's body of this treatment of needs, described method comprises the steps:

(a) make cell at external contact SSRI and candidate compound; With

(b) with respect to the described SSRI of contact but do not contact the cell of described candidate compound or contact described candidate compound but do not contact the cell of SSRI, whether the combination of determining described SSRI and described candidate compound reduces the level of cytokine described in the hemocyte of irriate secrete cytokines, wherein identifies the patient's who can be used for treating this treatment of needs combination medicine from the reduction of described cytokine levels.