KR20060076319A - Therapeutic regimens for administering drug combinations - Google Patents

Abstract

The invention features dosing regimens for the administration of combination therapies, wherein one of the drugs of the combination is formulated for sustained release, or administered repeatedly, and compositions related thereto.

Description

Treatment regimens for administering drug combinations {THERAPEUTIC REGIMENS FOR ADMINISTERING DRUG COMBINATIONS}

The present invention relates to dosing regimens for drug administration of combination therapy.

Combination therapy refers to the administration of two or more drugs for the treatment of a disease or condition or two or more comorbid conditions. In some cases each component of the concomitant drugs acts separately from the other (s), but in other cases the two drugs act in a combinatorial manner, for example by synergism, Administration of two drugs in a non-overlapping manner may result in unacceptable results.

Notwithstanding the above, combination therapies falling within the latter category may include drugs with different pharmacokinetic properties (eg, different T _max times). In these cases, the full benefit of the combination therapy is not achieved.

Therefore, there is a desire to develop better methods for combination therapy.

Summary of the Invention

In a first aspect, the invention features a method of enhancing the efficacy of a drug combination. The method comprises i) administering the first drug in an amount sufficient to produce an effective plasma concentration of the first drug over a period of T _l , and ii) a second time period of at least 70% of T _l Administering said second drug in a manner sufficient to produce an effective plasma concentration of the drug. Preferably, the second drug is administered in a manner sufficient to produce an effective plasma concentration of the second drug for at least 75%, 80%, 85%, or even 90% of the time period T _l . Optionally, some or all of the second drug is formulated for sustained release and / or the second drug is administered at least once during the period T _l .

The invention also features a method of administering a drug combination. The method comprises administering the first drug not formulated for sustained release and the second drug formulated for sustained release simultaneously, or within 30 minutes of each other, wherein a) the first drug has a maximum plasma at T _max1 . Concentration and b) the second drug _produces a maximum plasma concentration at T _max2 , c) T _max2 is greater than or equal to T _maxl , and if the second drug is not formulated for sustained release, T _maxl > T _max2 to be.

The invention further comprises a first drug selected from tricyclic compounds, SSRI, SNRI, NsIDI, antihistamines, and tetra-substituted pyrimidopyrimidines; And a unit dosage form comprising a second drug formulated for sustained release.

The present invention comprises: (a) a first drug not formulated for sustained release, (b) a second drug formulated for sustained release, and (c) the first drug and the second drug simultaneously or within 30 minutes of each other. And a kit comprising instructions for administration.

In the above methods, compositions, and kits, the first or second drug is preferably a tricyclic compound, SSRI, SNRI, NsIDI, antihistamine, corticosteroid, or tetra-substituted pyrimidopyrimidine.

In any one of the methods, compositions, and kits, the first drug and the second drug are optionally formulated together in a unit dose form. Unit dosage forms include, for example, bilayer tablets having a first layer comprising the first drug not formulated for sustained release and a second layer comprising the second agent formulated for sustained release. The unit dosage form also includes a tablet having an inner core comprising the second drug formulated for sustained release and an outer coating comprising the first drug formulated for sustained release. Can be. Furthermore, the unit dosage form may be a capsule having beads comprising the second drug formulated for sustained release and beads comprising the first drug formulated for sustained release.

Any of the unit dose forms described herein may further comprise the second drug not formulated for sustained release.

In any one of the methods, compositions, and kits, the first drug may be a tricyclic compound and the second drug may be a cortico compound, such as a combination of amoxapine and prednisolone or a combination of nortriptyline and budesonide. Can be a steroid; Like the combination of paroxetine and prednisolone, the first drug may be an SSRI and the second drug may be a corticosteroid; The first drug may be dipyridamole and the second drug may be a corticosteroid, such as prednisolone; Like the combination of cyclosporin A and loratadine, the first drug may be NsIDI and the second drug may be an antihistamine; Alternatively, the first drug may be dipyridamole and the second drug may be an antihistamine, such as loratadine.

The compositions can be formulated for any route of administration. For example, the combination of nortriptyline and budesonide can be formulated for inhalation. Preferably the combination is formulated for oral administration.

Compounds useful in the present invention include isomers, salts, esters, solvents, and the like, such as diastereomers and enantiomers, described herein, in any of their pharmaceutically acceptable forms. Polymorphs, as well as racemic compounds and pure isomers of the compounds described herein.

The invention features a method of promoting investment in a company that conducts or plans in vivo studies on a composition or kit described herein, or sells or plans to sell or sell a composition or kit described herein.

The method includes disseminating information about the identity, therapeutic use, toxicity, efficacy, or anticipated date of government approval of the composition or kit.

The invention also features a method for promoting investment in a company that conducts or plans in vivo studies on the treatment methods described herein. The method of promoting investment includes disseminating information about the dosage regimen, toxicity, efficacy, or anticipated date of government approval of the therapeutic method.

As used herein, "identity" refers to an identifier intended to convey the identity of a composition, kit, or therapy described herein. The distinguished name can be, for example, a structure, diagram, drawing, chemical name, common name, trademark, formula, reference label, or any other distinguished name that conveys the identity of the composition, kit, or therapy to a human. It may include.

“In vivo studies” means, without limitation, compositions, kits of the invention, including, for example, non-clinical studies to collect data related to toxicity and efficacy, and clinical studies, Or any study in which the therapy is administered to a mammal.

"Expected date of government approval" means the date on which a company receives approval from a government agency that, for example, can sell a composition, kit, or therapy of the present invention to patients, doctors, or hospitals. Means any estimate of. Government approval includes, in particular, approval of drug use, for example by the Food and Drug Administration.

"SSRI" means (i) inhibition of serotonin uptake by neurons of the central nervous system, (ii) an inhibition constant (Ki) of 10 nM or less, and (iii) greater than 100 for serotonin than norepinephrine By any member of the class of compounds having selectivity (ie, the proportion of Ki (norepinephrine) outperforms Ki (serotonin)). Typically, SSRIs are administered at doses greater than 10 mg per day when used as an antidepressant. Typical SSRIs used in the present invention have been described herein.

By "corticosteroid" is meant a natural or synthetic compound characterized by a hydrogenated cyclopentanoperhydrophenanthrene ring system and having immunosuppressive and / or anti-inflammatory activity. Natural corticosteroids are usually produced by the adrenal cortex. Synthetic corticosteroids can be halogenated. Examples of corticosteroids are described herein.

"Nonsteroidal immunophilin-dependent immunosuppressant", or "NsIDI", refers to any agent that reduces proinflammatory cytokine production or secretion, binds to immunophilin, or causes down regulation of the proinflammatory response. By nonsteroidal drugs. NsIDIs are cyclosporine, tacrolimus, ascomycin, pimecrolimus, as well as other drugs that inhibit the phosphatase activity of calcineurin (peptides, peptide segments, chemically modified peptides, or peptide mimetics). Calcineurin inhibitors such as; NsIDIs also include rapamycin and everolimus and bind to the FK506-binding protein, FKBP-12, to block proliferation and cytokine secretion of antigen-induced leukocytes.

"Treat" means administering or prescribing a pharmaceutical composition for the treatment or prevention of a disease or condition.

"Patient" means any animal (eg, human).

By "effective plasma concentration" is meant, in the combination of the present invention, the concentration of drug in the plasma of the patient is the range required for treating or preventing a disease or condition in a clinically relevant method. For example, a sufficient amount of active compound used in the practice of the present invention for the treatment of abnormalities caused by or caused by an immunoinflammatory disease depends on the method of administration, the age, weight, and general health of the patient. . Eventually, the prescriber will determine the appropriate amount and dose regimen. In addition, the effective amount is determined by the regulatory authority (such as the US Food and Drug Administration) in the treatment of a patient with a disease or condition, and the effective amount of the compound in the combination of the present invention is safer and more effective than using each drug approved alone. Can be positive.

"Improve" or "enhance" means that the treatment shows excellent efficacy or is less toxic, i.e., safer than treatment using the same active ingredient but without the compositions or methods of the present invention. do. Efficacy can be measured by a skilled practitioner using any standard method appropriate for a given condition.

The term "immune inflammatory disease" encompasses a variety of abnormalities, including autoimmune diseases, proliferative skin diseases and inflammatory skin diseases. Inflammatory progression as a result of immunoinflammatory diseases results in the destruction of healthy tissue, dysregulation of the immune system, and the unnecessary proliferation of cells. Examples of immunoinflammatory diseases include vulgar acne; Acute respiratory syndrome; Edison's disease; Allergic rhinitis; Allergic intraocular inflammation, ANCA-associated small-vessel vasculitis; Ankylosing spondylitis; Arthritis, asthma; Atherosclerosis; Atopic dermatitis; Autoimmune hemolytic anemia; Autoimmune hepatitis; Behcet's disease; Bell facial nerve palsy; Bullous whey; Cerebral infarction; Hardening; Chronic obstructive pulmonary disease; Nasal liver syndrome; Allergic contact dermatitis; Chronic obstructive pulmonary disease; Crohn's disease; Cushing's syndrome; Dermatitis; diabetes; Discoid lupus erythematosus; Eosinophilic fasciitis; Nodule erythema; Deciduous dermatitis; Fibromyalgia; Local glomeruli; Giant cell arteritis; ventilation; Gouty arthritis; Graft-versus-host disease; Hand eczema; Henohoteline purple plaque; Herpes zoster; Hirsutism; Idiopathic cerato-scleritis; Idiopathic pulmonary fibrosis; Idiopathic thrombocytopenic erythema; Inflammatory bowel or gastrointestinal disease, inflammatory skin disease; Lichen planus; Lupus nephritis; Lymphoma bronchitis; Macular edema; Multiple sclerosis; Myasthenia gravis; Myositis; Osteoarthritis; Pancreatitis; Pseudomolar pregnancy; Plain cloth spear; Nodular polyarteritis; Rheumatic polymyalgia; Scrotum itching; Pruritis / inflammation, psoriasis; Psoriatic arthritis; Rheumatoid arthritis; Recurrent multiple chondritis; Rosacea caused by sarcoidosis; Rosacea caused by scleroderma; Rosacea caused by Sweet syndrome; Rosacea caused by systemic lupus erythematosus; Rosacea caused by urticaria; Rosacea caused by shingles-related pain; Sarcoidosis; Scleroderma; Segmental glomerulosclerosis; Septic shock syndrome; Shoulder tendinitis or bursitis; Sjogren's syndrome; Still's disease; Stroke-induced brain cell death; Sweet bottles; Systemic lupus erythematosus; Systemic sclerosis; Takayasu's arteritis; Temporal arteritis; Toxic Table Destruction; Tuberculosis; Type 1 diabetes; Ulcerative colitis; Uveitis; Vasculitis; And Wegener's granulomatosis.

"Non-dermal inflammatory disorders" include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.

"Dermal inflammatory disorders" or "inflammatory dermatoses" include, for example, psoriasis, acute febrile neutropenia, eczema (e.g., dry eczema, sweating eczema, bullous) Hand, plantar eczema), localized plasma cell blepharitis, scleroderma, Behcet's disease, central centripetal lupus erythema, persistent pigmentation erythema, polymorphic erythema, ring granulomas, glossy thyroid, squamous thyroid, percutaneous atrophic thyroid, chronic simple thymus, polar state Molecular dermatitis, necrosis, sarcoidosis, necrosis, urticaria, and transient visible cell dissociation dermatosis.

By "proliferative skin disease" is meant a benign or malignant disease characterized by accelerated cell division in the epidermis or dermis. Examples of proliferative dermatosis include psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, skin and squamous cell carcinoma, plaque gonads, epidermal exfoliation, malignant bulb keratosis, acne, and seborrheic dermatitis to be.

As will be appreciated by one of ordinary skill in the art to which this invention pertains, an individual disease, disorder, or condition may be characterized as both proliferative and inflammatory dermatoses. An example of such a disease is psoriasis.

"Sustained release" means the time when the effective plasma concentration of the drug is not formulated for sustained release when administered to humans; By a drug formulated to release at a slow rate to remain for more than 150%, 200%, 300%, 400%, or even 500% of the time.

"Not formulated for sustained use" does not alter more than 50% of the length of time that an effective plasma concentration of the drug is maintained when administered to a human with any formulation from which one of the excipients in the formulation has been removed. It means not done.

“C _max ” means the maximum measured plasma concentration for the administered drug.

“T _max ” means the time at which C _max occurs after administration of the drug at time = 0.

As used herein, "duration of T _l " means the length of time that the drug maintains an effective plasma concentration. Since bioavailability depends on the amount administered and the half-life of the individual drug, T ₁ can be at least 30 minutes or at most 7 days. Typically, T ₁ will be between 30 minutes and 24 hours.

As used herein, “administering in a sufficient manner” means changing the dosage, dosage regimen, or formulation of the drug to better match the pharmacokinetic behavior of the other drugs administered together.

The compositions and methods of the present invention are useful for enhancing the efficacy of drug combinations with pharmacokinetic behaviors in which each drug does not overlap. The methods and compositions of the present invention are such that each of the drugs administered for a combination treatment increases the length of time that is simultaneously present in the patient's plasma in an amount such that both drugs are more therapeutically effective. It was intended.

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

1 is a diagram showing the pharmacokinetic behavior of prednisolone and amoxapine administered orally to humans. The data shows a slight match of the pharmacokinetic curves for the two drugs.

2 is a chart showing the pharmacokinetic behavior of prednisolone and paroxetine administered orally to humans. The data shows a slight match of the pharmacokinetic curves for the two drugs.

The present invention provides methods, compositions, and kits for enhancing the efficacy of a drug combination. Administration of a drug combination in which one of the drugs is formulated or administered repeatedly is useful when the pharmacokinetic behavior of each drug must be modified to enhance the efficacy of the combination. In the formulations of the present invention, for example, pharmacokinetic behavior is such that each of the drugs is present simultaneously in the patient's plasma in an amount such that both drugs are more therapeutically effective than when both drugs are administered alone. It is modified to increase the length of time. Sustained release formulations can be used to prevent frequent dosing required to maintain the plasma concentration of both drugs at a therapeutic concentration.

For example, bilayer tablets are SSRI / steroids in which the custom granules are prepared for each drug in the SSRI / steroid combination, and then the two drugs are compressed by a bi-layer press to form one tablet. It may be formulated for. For example, 12.5 mg, 25 mg, 37.5 mg, or 50 mg paroxetine, formulated with sustained release formulation such that paroxetine t _{l / 2} is 15-20 hours, may be supported in the same tablet with 3 mg prednisolone Such tablets are formulated such that the half-life (t _{l / 2} ) is close to the half-life of paroxetine. Examples of paroxetine extended-release formulations, including those used in bilayer tablets, can be found in US Pat. No. 6,548,084. In addition to controlling the prednisolone release rate in vivo, enteric or delayed release coatings may be included that delay the onset of drug release such that the T _maX of prednisolone is _{close to} that of paroxetine (ie, 5 to 10 hours). .

Hereinafter, the present invention will be described in more detail.

Combination Therapy Combination Therapy )

SSRI  or SNRI With corticosteroids

Selective serotonin reuptake inhibitors (SSRIs) or selective serotonin norepinephrine reuptake inhibitors (SNRIs) refer to "methods and reagents for the treatment of diseases and conditions associated with increased concentrations of proinflammatory cytokines." In the name of the invention, it may be administered in combination with corticosteroids for the treatment of immunoinflammatory diseases, as described in US patent application Ser. No. 10 / 670,488, filed September 24, 2003. This application is incorporated herein by reference in its entirety.

NsIDI With antihistamines

Nonsteroidal immunophilin-dependent immunosuppressive agents (NsIDI) are described in US Patent Application No. 10 / 777,518, filed Feb. 12, 2004, entitled “Combination Therapy for Immune Inflammatory Disease”. And in combination with antihistamines for the treatment of immunoinflammatory diseases. This application is incorporated herein by reference in its entirety.

Tricyclic  Combination of compounds and corticosteroids

Tricyclic compounds are described in Provisional Patent Application No. 60 / 520,446, filed Nov. 13, 2003, entitled “Methods and Reagents for the Treatment of Diseases and Conditions Associated with Increased Concentration of Proinflammatory Cytokines”. As described, it may be administered in combination with a corticosteroid for the treatment of an immunoinflammatory disease. This application is incorporated herein by reference in its entirety.

Combination of dipyridamole with corticosteroids

Dipyridamole and other tetra-substituted pyrimidopyrimidines are described in US Patent Application No. 10 / 264,991, filed Oct. 4, 2002, entitled “Combinations for the Treatment of Immune Inflammatory Diseases”. As can be seen, it can be administered in combination with a corticosteroid for the treatment of an immunoinflammatory disorder. This application is incorporated herein by reference in its entirety.

Combination of dipyridamole with antihistamines

Dipyridamole and tetra-substituted pyrimidopyrimidines are filed on October 15, 2003, entitled "Methods and Reagents for the Treatment of Diseases and Conditions Associated with Increased Concentration of Proinflammatory Cytokines" It can be administered in combination with antihistamines for the treatment of immunoinflammatory diseases as described in Provisional Patent Application No. 60 / 512,415. This application is incorporated herein by reference in its entirety.

The T _max and disappearance half-life data for the types of drugs useful in the methods, compositions, and kits of the present invention are shown in Table 1 below. Excluding paroxetine / prednisolone and amoxapine / prednisolone, these data represent the pharmacokinetic parameters for each drug administered in monotherapy.

SSRI  And SNRI

The methods, compositions, and kits of the invention may employ SSRIs, or structural or functional analogs thereof. Suitable SSRIs include ericclamine (eg, glyceryl hydrochloride); Citalopram (eg, citalopram hydrobromide); Cloboxamine; Cyanodothipine; Dapoxetine; Escitalopram (escitalopram oxalate); Pemoxetine (eg, pemoxetine hydrochloride); Fluoxetine (eg, fluoxetine hydrochloride); Fluvoxamine (eg, fluvoxamine maleate); Ipoxetine; Indalpin (eg, indalpin hydrochloride); Inderogazine (eg, inderogin hydrochloric acid); Ritoxetine; Milnacipran (eg milnacifur hydrochloride); Paroxetine (eg, paroxetine hemihydrate; paroxetine maleate; paroxetine mesylate); Sertraline (eg, sertraline hydrochloride); Tamatrine hydrochloride; Viqualine; And gimeldine (eg, gimeldine hydrochloride).

Functional analogs of SSRIs can also be used in the methods, compositions, and kits of the invention. Typical SSRI functional analogs are shown below. One class of SSRI analogs is SNRIs comprising venlafaxine, duloxetine, and 4- (2-fluorophenyl) -6-methyl-2-piperazinothieno [2,3-d] pyrimidine (optional Serotonin norepinephrine reuptake inhibitors).

Standard recommended doses of typical SSRIs are shown in Table 2 below. Other standard doses are described, for example, in Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians'Desk Reference 2003 (57 ^th Ed. Medical Economics Staff et al., Medical Economics Co., 2002).

In general, when administered orally to humans, the dosage of SSRIs is typically from about 0.001 mg to 200 mg per day, preferably from about 1 mg to 100 mg per day, more preferably from about 5 mg per day 50 mg. Doses up to 200 mg may be needed per day. For SSRI administration by injection, the dose is typically about 1 mg to 250 mg per day, preferably about 5 mg to 200 mg per day, more preferably about 10 mg to 150 mg per day . Injection is preferably given once to four times a day. When administered systemically to humans, the dose of corticosteroid used in combination with SSRIs is typically from about 0.1 mg to 1500 mg per day, preferably about 0.5 mg to 10 mg per day, more preferably about 0.5 per day mg to 5 mg.

Corticosteroids Corticosteroids )

The methods, compositions, and kits of the invention may employ corticosteroids. Suitable corticosteroids include 1 l-alpha, 17-alpha, 21-trihydroxypresent-4-ene-3,20-dione; 11-beta, 16-alpha, 17,21-tetrahydroxypresent-4-ene-3,20-dione; 11-beta, 16-alpha, 17,21-tetrahydroxypresent-1,4-diene-3,20-dione; 11-beta, 17-alpha, 21-trihydroxy-6-alpha-methylpresen-4-ene-3,20-dione; 11-dihydrocorticosterone; 11-dioxycortisol; 11-hydroxy-1,4-amdrosadiene-3,17-dione; 11-ketotestosterone; 14-hydroxyamdro-4-ene-3,6,17-trione; 15,17-dihydroxyprogesterone; 16-methylhydrocortisone; 17,21-dihydroxy-16-alpha-methylpresna-1,4,9 (11) -triene-3,20-dione; 17-alpha-hydroxypresent-4-ene-3,20-dione; 17-alpha-hydroxypregnenolone; 17-hydroxy-16-beta-methyl-5-beta-presence-9 (11) -ene-3,20-dione; 17-hydroxy-4,6,8 (14) -prenatriene-3,20-dione; 17-hydroxypresna-4,9 (11) -diene-3,20-dione; 18-hydroxycorticosterone; 18-hydroxycortisone; 18-oxocortisol; 21-dioxy aldosterone; 21-dioxycortisone; 2-dioxyexidone; 2-methylcortisone; 3-dihydroexidone; 4-presene-17-alpha, 20-beta, 21-triol-3,11-dione; 6,17,20-trihydroxypresent-4-en-3-one; 6-alpha-hydroxycortisol; 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone 21-hemisuccinate sodium salts, 6-beta-hydroxycortisol, 6-alpha 9-alpha-difluoroprednisolone 21-acetate 17-butyrate, 6-hydroxycorticosterone; 6-hydroxydexamethazone; 6-hydroxyprednisolone; 9-fluorocortisone; Alclomethasone dipropionate; Aldosterone; Alghero; Alphaderm; Amadinone; Amcinononide; Anageston; Androstenedione; Ancortape acetate; Beclomethasone; Difluticasone acid beclomethasone; Difluticasone beclomethasone monohydrate; Betamethasone 17-valorate; Betamethasone sodium acetate; Betamethasone sodium phosphate; Betamethasone balerate; Borosterone; Budesonide; Calusosterone; Chlormadinone; Chloroprednisone; Chloroprednisone acetate; cholesterol; Clobetasol; Clobetasol propionate; Clobetason; Clocortolone; Clocortolone pivalate; Clogestone; Clopredinol; Corticosterone; Cortisol; Cortisol acetate; Cortisol butyrate; Cortisol cypionate; Cortisol octanoate; Cortisol sodium phosphate; Cortisol sodium succinate; Cortisol valerate; Cortisone; Cortisone acetate; Cortodoxone; Daturalone; Deplazacort, 21-dioxycortisol, dihydroepiamdrosterone; Delmadinone; Deoxycorticosterone; Deprodon; Descinolone; Desonide; Desoximetason; Dexafen; Dexamethasone; Dexamethasone 21-acetate; Dexamethasone acetate; Dexamethasone sodium phosphate; Dichlorisone; Dipulason; Diflorasone diacetate; Diflucortolone; Dihydroelatericin a; Domofredate; Doxybetasol; Ecdysone; Ecsterone; Endlison; Enoxonon; Flusinolone; Fludrocortisone; Fludrocortisone acetate; Flugestone; Flumetasone; Flumethasone pivarate; Flumoksonide; Flunisolide; Fluorocinolone; Fluorocinolone acetonoids; Fluorinide; 9-fluorocortisone; Fluorocortolone; Fluorohydroxyamdrostenedione; Fluorometholone; Fluorometholone acetate; Fluoxymesterone; Flufreddene; Fluprednisolone; Fluandrenolide; Fluticasone; Propionic acid fluticasone; Formmebolone; Formestane; Formocortal; Gestonolone; Glycerinin; Halogeninide; Hycanocanoside; Halomethasone; Halopredone; Haloprogesterone; Hydrocortioson cypionate; Hydrocortisone; Hydrocortisone 21-butyrate; Hydrocortisone acenate; Hydrocortisone acetate; Hydrocortisone butyrate; Hydrocortisone butyrate; Hydrocortisone cypionate; Hydrocortisone hemisuccinate; Hydrocortisone probutate; Hydrocortisone sodium phosphate; Hydrocortisone sodium succinate; Hydrocortisone valerate; Hydroxyprogesterone; Inocosterone; Isoflupredone; Isoflupredone acetate; Isoprenide; Mechlorisone; Mecortolone; Medrogestone; Methoxyprogesterone; Medridone; Megestrol; Megestrol acetate; Melengestrol; Meprednisone; Methanedrostenolone; Methylprednisolone; Methylprednisolone acenate; Methylprednisolone acetate; Methylprednisolone hemisuccinate; Methylprednisolone sodium succinate; Methyltestosterone; Metribolone; Mometasone; Mometasone furoate; Mometasone furoate monohydrate; Nison; Nomegestrol; Norgestomer; Norbinosterone; Oxymesterone; Paramethasone; Paramethasone acetate; Ponasterone; Prednisolamate; Prednisolone; Prednisolone 21-hemisuccinate; Prednisolone acetate; Prednisolone farnesylate; Prednisolone hemisuccinate; Prednisolone-21 (beta-D-glucuronide); Prednisolone metasulfobenzoate; Prednisolone sodium phosphate; Prednisolone steaglate; Prednisolone tebutate; Prednisolone tetrahydrophthalate; Prednisone; Prednisbal; Prednylidene; Pregnenolone; Prosnonide; Tralonide; Progesterone; Promegestone; Lafontisterone; Limexolone; Oxybolone; Lubrosterone; Styzophylline; Thixocotol; Topteron; Triamcinolone; Triamcinolone acetonide; Triamcinolone acetonide 21-palmitate; Triamcinolone diacetate; Triamcinolone hexaacetonide; Trimegesdon; Turkesterone; And orthomannin.

Standard recommended doses of various steroid / disease combinations are shown in Table 3 below (standard recommended corticosteroid doses).

Other standard recommended doses for corticosteroids are described, for example, in Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physician's Desk Reference 2003 (57 ^th Ed. Medical Economics Staff et al. , Medical Economics Co., 2002). In one embodiment, the dose of corticosteroid administered is the same dose as the prednisolone dose defined herein. For example, a low dose of corticosteroid can be thought of as a low dose of prednisolone.

Steroid receptor modulators (eg, antagonists and agents) may be used in addition to or in addition to corticosteroids in the methods, compositions, and kits of the invention. Thus, in one embodiment, the invention features a combination of SSRI (or an analog or metabolite thereof) and a glucocorticoid receptor modulator or other steroid receptor modulator, thereby treating an immunoinflammatory disease.

Glucocorticoid receptor modulators that can be used in the methods, compositions, and kits of the present invention are described in US Pat. Nos. 6,380,207, 6,380,223, 6,448,405, 6,506,766, and 6,570,020, US Patent Application Publication 20030176478 Nos. 20030171585, 20030120081, 20030073703, 2002015631, 20020147336, 20020107235, 20020103217, and 20010041802, and International Patent Publication No. WO00 / 66522, each of which is incorporated herein by reference. It is incorporated by. Other steroid receptor modulators that may also be used in the methods, compositions, and kits of the invention include U.S. Pat.Nos. 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, 5,693,647, 5,693,646, 5,688,810, 5,688,808, and 5,696,130, each of which is incorporated herein by reference.

NsIDIs

The methods, compositions, and kits of the present invention may use nonsteroidal immunophilin-dependent immunosuppressive agents (NsIDI).

NsIDIs include calcineurin inhibitors (eg cyclosporin, tacrolimus, pimecrolimus), and rapamycin.

Cyclosporine ( cyclosporines )

Cyclosporins are fungal metabolites that contain a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporin A, and its deuterated analog ISAtx247, is a hydrophobic cyclic polypeptide consisting of 11 amino acids. Cyclosporin A binds to the intracellular receptor cyclophylline to form a complex. Cyclosporine / cycle pilrin complex is Ca ^{2 +} - inhibits calcineurin binds to a specific protein phosphatase calcineurin-calmodulin-dependent serine-threonine. Calcineurin mediates signaling events that require T-cell activity (reviewed in Schreiber et al., Cell 70: 365-368, 1991). Cyclosporins and their functional and structural analogs inhibit T cell-dependent immune responses by inhibiting antigen-triggered signal transduction. This inhibition reduces the expression of proinflammatory cytokines such as IL-2.

Many cyclosporins (eg, cyclosporins A, B, C, D, E, F, G, H, and I) are produced by fungi. Cyclosporin A is marketed under the NEORAL trademark of Novartis. Cyclosporine A structural and functional analogs include cyclosporines having one or more fluorinated amino acids (eg, described in US Pat. No. 5,227,467); Cyclosporines with modified amino acids (eg described in US Pat. Nos. 5,122,511 and 4,798,823); And deuterated cyclosporines, such as described in US Pat. No. 20020132763, such as ISAtx247. Additional cyclosporine analogs are described in US Pat. Nos. 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporine analogs include D-Sar (α-SMe) ³ Val ² -DH-Cs (209-825), Allo-Thr-2-Cs, norvaline-2-Cs, D-AIa (3-acetylamino) -8 -Cs, Thr-2-Cs, and D-MeSer-3-Cs, D-Ser (O-CH ₂ CH ₂ -OH) -8-Cs, and D-Ser-8-Cs, but not necessarily these It is not limited to, it is Cruz et al. (Antimicrob. S drug Chemother . 44: 143-149, 2000).

Cyclosporins are very hydrophobic and readily precipitate in the presence of water (eg, in contact with body fluids). Methods of providing cyclosporin formulations with improved bioavailability are described in US Pat. Nos. 4,388,307, 6,468,968, 5,051,402, 5,342,625, 5,977,066, and 6,022,852. Cyclosporine microemulsion compositions are described in US Pat. Nos. 5,866,159, 5,916,589, 5,962,014, 5,962,017, 6,007,840, and 6,024,978.

Cyclosporines may be administered intravenously or orally, but oral administration is preferred. To neutralize the hydrophobicity of cyclosporin A, intravenous cyclosporin A is typically provided in an ethanol-polyoxyethylated castor oil vehicle that must be diluted prior to administration. Cyclosporin A can be provided, for example, as a microemulsion in a 25 mg or 100 mg tablet, or as a 100 mg / ml oral solution (NEORAL ^™ ).

Typically, patient doses of oral cyclosporin vary with the patient's condition, but some standard recommended doses in the prior art treatment regimens are described herein. Patients undergoing organ transplants typically receive an initial dose of oral cyclosporin A in amounts between 12 mg / kg / day and 15 mg / kg / day. The dose is then reduced by 5% per week until slowly reaching a 7-12 mg / kg / day maintenance dose. Intravenous administration of 2-6 mg / kg / day is preferred for most patients. In patients diagnosed with Crohn's disease or ulcerative colitis, a 6-8 mg / kg / day dose is generally administered. In patients diagnosed with systemic lupus erythematosus, a 2.2-6.0 mg / kg / day dose is generally administered. For psoriasis or rheumatoid arthritis, a 0.5-4 mg / kg / day dose is typical. Other useful doses include 0.5-5 mg / kg / day, 5-10 mg / kg / day, 10-15 mg / kg / day, 15-20 mg / kg / day, or 20-25 mg / kg / day. Include. Often cyclosporines are administered with other immunosuppressive agents, such as glucocorticoids.

Additional information is provided in Table 4 (NsIDIs).

Legend

CsA = cyclosporin A

RA = rheumatoid arthritis

UC = ulcerative colitis

SLE = systemic lupus erythematosus

Tacrolimus Tacrolimus )

Tacrolimus (PROGRAF, Fujisawa), also known as FK506, is an immunosuppressive agent that targets T cell intracellular signaling pathways. Tacrolimus is known as cyclophilin (Harding et al. Nature 341: 758-7601, 1989; Siekienka et al. Nature 341: 755-757, 1989; and Soltoff et al., J. Biol. Chem. 267: 17472-17477 , 1992) to the intracellular protein FK506 binding protein (FKBP-12) which is not structurally related. The FKBP / FK506 complex binds to calcineurin and inhibits phosphatase activity of calcineurin. This inhibition blocks the dephosphorylation and nuclear potential of NFAT, a nuclear component that initiates gene transcription requiring lymphokine (eg, IL-2, gamma interferon) production and T cell activity. Thus, tacrolimus inhibits T cell activity.

Tacrolimus is a macrolide antibiotic (macrolide antibiotic) produced by my process, Tsukuba-N-Sys (Streptomyces tsukubaensis) Streptomyces. It suppresses the immune system and prolongs the survival of transplanted organs. It is generally available in oral and injection formulations. Tacrolimus capsules contain 0.5 mg, 1 mg, or 5 mg of anhydrous tacrolimus in a gelatin capsule shell. Injectable formulations include 5 mg anhydrous tacrolimus in castor oil and alcohol diluted with 9% sodium chloride or 5% glucose prior to injection. Oral administration is preferred, but injectable tacrolimus is administered to patients who cannot take oral capsules. The initial dose should be administered by continuous intravenous infusion 6 hours after transplantation.

Tacrolimus and tacrolimus analogs are described by Tanaka et al., (J. Am. Chem. Soc., 109: 5031, 1987) and described in US Pat. Nos. 4,894,366, 4,929,611, and 4,956,352. It is. FK506-related compounds including FR-900520, FR-900523, and FR-900525 are described in US Pat. No. 5,254,562; O-aryl, O-alkyl, O-alkenyl, and O-alkynyl macrolides are described in US Pat. Nos. 5,250,678, 532,248, 5,693,648; Amino O-aryl macrolides are described in US Pat. No. 5,262,533; Alkylidene macrolides are described in US Pat. No. 5,284,840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, and N-alkynylheteroaryl macrolides are described in US Pat. No. 5,208,241; Aminomacrolides and derivatives thereof are described in US Pat. No. 5,208,228; Fluoromacrolides are described in US Pat. No. 5,189,042; Amino O-alkyl, O-alkenyl, and O-alkynyl macrolides are described in US Pat. No. 5,162,334; And halo macrolides are described in US Pat. No. 5,143,918.

The suggested doses will vary depending on the condition of the patient, but standard recommended doses and therapies are described below. Patients diagnosed with Crohn's disease or ulcerative colitis are administered 0.1-0.2 mg / kg / day oral tacrolimus. Patients transplanted with organs are typically given oral tacrolimus at a dose of 0.1-0.2 mg / kg / day. Patients being treated for rheumatoid arthritis typically receive 1-3 mg / day oral tacrolimus. For psoriasis treatment, oral tacrolimus at 0.01-0.15 mg / kg / day is administered to the patient. Atopic dermatitis can be treated by applying a cream containing 0.03-0.1% tacrolimus twice a day to the affected area. Patients taking oral tacrolimus capsules typically receive their first dose 6 hours after transplant, or 8 to 12 hours after intravenous tacrolimus infusion is discontinued. Other suggested tacrolimus doses are 0.005-0.01 mg / kg / day, 0.01-0.03 mg / kg / day, 0.03-0.05 mg / kg / day, 0.05-0.07 mg / kg / day, 0.07-0.10 mg / kg / Day, 0.10-0.25 mg / kg / day, or 0.25-0.5 mg / kg / day.

Tacrolimus is actively metabolized by a mixed-function oxidase system, particularly the cytochrome P-450 system. The primary mechanism of metabolism is demethylation and hydroxylation. While various tacrolimus metabolites are likely to exhibit immunosuppressive biological activity, 13-dimethyl metabolites are reported to have the same activity as tacrolimus.

Pimecrolimus  And Ascomyeira  derivative( Pimecrolimus and Ascomyeira derivatives )

Ascomycin is a similar structural analog of FK506 and a potent immunosuppressive agent. It binds to FKBP-12 and inhibits its proline rotamase activity. The ascomycin-FKBP complex inhibits calcineurin, a type 2B phosphatase.

Pimecrolimus (also known as SDZ ASM-981) is a 33-epi-chloro derivative of ascomycin. It is a strain Streptomyces Hygroscopius bar. Ascomysetus ( streptomyces hygroscopicus var . ascomyceitus ) . Like tacrolimus, pimecrolimus (ELIDEL ^™ , Novartis) binds to FKBP-12, inhibits calcineurin phosphatase activity, and inhibits T-cell activity by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits IL-2 production and the release of other proinflammatory cytokines.

Pimecrolimus structural and functional analogs are described in US Pat. No. 6,384,073. Pimecrolimus is particularly useful for the treatment of atopic dermatitis. Pimecrolimus is generally available in 1% cream. Individual dose adjustments will vary depending on the condition of the patient, but some standard recommended doses are described below. Oral pimecrolimus may be administered in an amount of 40-60 mg / day for the treatment of psoriasis or rheumatoid arthritis. Pimecrolimus may be administered in an amount of 80-160 mg / day for the treatment of Crohn's disease or ulcerative colitis. Patients who have undergone organ transplants can be administered pimecrolimus at 160-240 mg / day. Patients diagnosed with systemic lupus erythematosus may be administered pimecrolimus at 40-120 mg / day. Other useful pimecrolimus doses are 0.5-5 mg / day, 5-10 mg / day, 10-30 mg / day, 40-80 mg / day, 80-120 mg / day, or even 120-200 mg / Includes work.

Rapamycin ( Rapamycin )

Rapamycin (Rapamune® sirolimus, Wyeth) is a click between lactone produced by Scorpion kusu (Streptomyces hygroscopicus) thereof Streptomyces high. Rapamycin is an immunosuppressive agent that inhibits T lymphocyte activity and proliferation. Like cyclosporins, tacrolimus, and pimecrolimus, rapamycin complexes with immunophilin FKBP-12, but rapamycin-FKBP-12 complex does not inhibit calcineurin phosphatase activity. The rapamycin immunophilin complex binds to and inhibits the mammalian target (mTOR) of rapamycin, a kinase that requires cell cycle progression. Inhibition of mTOR kinase activity blocks T lymphocyte activity and lymphokine secretion.

And functional analogs of rapamycin structure include mono- and diacylated rapamycin derivatives (US Pat. No. 4,316,885); Rapamycin water soluble prodrugs (US Pat. No. 4,650,803); Carboxylic acid esters (WO 92/05179); Carbamate (US Pat. No. 5,118,678); Amide esters (US Pat. No. 5,118,678); Biotin esters (US Pat. No. 5,504,091); Fluorinated esters (US Pat. No. 5,100,883); Acetal (US Pat. No. 5,151,413); Silyl ethers (US Pat. No. 5,120,842); Bicyclic derivatives (US Pat. No. 5,120,725); Rapamycin dimers (US Pat. No. 5,120,727); O-aryl, O-alkyl, 0-alkenyl and 0-alkynyl derivatives (US Pat. No. 5,258,389); And deuterated rapamycin (US Pat. No. 6,503,921). Additional rapamycin analogs are described in US Pat. Nos. 5,202,332 and 5,169,851.

Everolimus (40-0- (2-hydroxyethyl) rapamycin; CERTICAN ^™ ; Novartis) is an immunosuppressive macrolide structurally related to rapamycin, which is an organ transplant when administered in combination with cyclosporin A It has been shown to be particularly effective in preventing acute rejection of patients.

Rapamycin is generally marketed for oral administration in liquid form and in tablet formulations. RAPAMUNE ^™ liquid contains 1 mg / mL rapamycin diluted with water or orange juice prior to administration. Tablets containing 1 or 2 mg of rapamycin may also be used. Rapamycin is administered once daily as soon as possible after transplantation. It is quickly absorbed completely after oral administration. Typically, the patient dose of rapamycin will vary with the patient's condition, but some standard recommended doses are given below. The initial loading dose of rapamycin is 6 mg. Subsequent maintenance doses of 2 mg / day are typical. Instead, a loading dose of 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg may be used with a 1 mg, 3 mg, 5 mg, 7 mg, or 10 mg maintenance dose per day. . In patients weighing less than 40 kg, rapamycin doses are typically adjusted based on body surface area; Typically a 3 mg / m ² / day loading dose and a 1-mg / m ² / day maintenance dose is used.

Tricyclic  compound( Tricyclic Compounds )

The methods, compositions, and kits of the invention may employ tricyclic compounds. Tricyclic compounds are amitriptyline, amoxapine, clomipramine, decipramin, dothipine, doxepin, imipramine, lofepramine, maprotiline, myanserine, mirtazapine, nortriphytline , Octriphthylline, oxaprotiline, protriphthylline, trimipramine, 10- (4-methylpiperazin-1-yl) pyrido (4,3-b) (1,4) benzothiazepine; 11- (4-methyl-1-piperazinyl) -5H-dibenzo (b, e) (1,4) diazepine; 5,10-dihydro-7-chloro-10- (2- (morpholino) ethyl) -11H-dibenzo (b, e) (1,4) diazepine-ll-one; 2- (2- (7-hydroxy-4-dibenzo (b, f) (1,4) thiazepin-11-yl-1-piperazinyl) ethoxy) ethanol; 2-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo (b, e) (1,4) diazepine; 4- (11H-dibenz (b, e) azin-6-yl) piperazine; 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo (b, e) (1,4) diazepin-2-ol; 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo (b, e) (1,4) diazepine monohydrochloride; (Z) -2-butenedioate 5H-dibenzo (b, e) (1,4) diazepine; Adinazolam; Amineftine; Amitriptyline oxide; Butriftyline; Clothiapine; Clozapine; Demexifyline; 11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine; 11- (4-methyl-1-piperazinyl) -2-nitro-dibenz (b, f) (1,4) oxazepine; 2-chloro-11- (4-methyl-1-piperazinyl) -dibenz (b, f) (1,4) oxazepine monohydrochloride; Dibenzepine; 11- (4-methyl-1-piperazinyl) -dibenzo (b, f) (1,4) thiazepine; Dimethacrine; Fluasizin; Fluperlapine; Imipramine N-oxide; Ifrindol; Lofepramine; Melitracene; Metapramine; Methiapine; Metallindol; Sorry serine; Mirtazapine; 8-chloro-6- (4-methyl-1 -piperazinyl) -morphanetridine; N-acetylamoxapine; Nomifensine; Norclomipramine; Norclozapine; Naxiftiline; Opiramol; Oxaprotiline; Perlapine; Piezotiline; Propizine; Quatiapine; Quinupramine; Tianeptin; Civil cepin; Flufenticol; Cloopenticol (clopenthixol); Piflutixol; Chlorproticsen; And thiotices. Other tricyclic compounds are described, for example, in US Pat. No. 2,554,736; 3,046,283; 3,310,553; 3,177,209; 3,205,264; 3,244,748; 3,244,748; 3,271,451; 3,272,826; 3,282,942; 3,282,942; 3,299,139; 3,312,689; 3,389,139; 3,389,139; 3,399,201; 3,399,201; 3,409,640; 3,419,547; 3,438,981; 3,454,554; 3,454,554; 3,467,650; 3,505,321; 3,505,321; 3,527,766; 3,534,041; 3,539,573; 3,574,852; 3,574,852; 3,622,565; 3,622,565; 3,637,660; 3,637,660; 3,663,696; 3,758,528; 3,366,499; 3,922,305; 3,963,778; 3,963,778; 3,978,121; 3,978,121; 3,981,917; 4,017,542; 4,017,542; No. 4,017,621; 4,020,096; 4,045,560; 4,045,560; 4,045,580; 4,045,580; 4,048,223; 4,048,223; No. 4,062,848; 4,088,647; 4,088,647; 4,128,641; 4,128,641; 4,148,919; 4,148,919; No. 4,153,629; 4,224,321; 4,224,321; 4,224,344; 4,224,344; 4,250,094; No. 4,284,559; 4,333,935; 4,358,620; 4,548,933; 4,691,040; 4,691,040; 4,879,288; 5,238,959; 5,238,959; 5,266,570; 5,266,570; 5,399,568; 5,399,568; 5,464,840; 5,464,840; 5,455,246; 5,455,246; 5,512,575; 5,512,575; 5,550,136; 5,550,136; No. 5,574,173; 5,681,840; 5,681,840; 5,688,805; 5,688,805; 5,916,889; 5,916,889; No. 6,545,057; And 6,600,065, and phenothiazine compounds corresponding to formula (I) in US Patent Application Nos. 10 / 617,424 or 60 / 504,310.

Typically, patient doses of maprotiline vary depending on the condition of the patient, but some standard recommended doses are indicated herein. Maprotiline, which is generally available in 25, 50, alc 100 mg tablets, may contain 1-25 mg / day, 25-100 mg / day, 100-150 mg / day, 150-225 mg / day, or 225 Although standard recommended doses of -350 mg / day may be administered, the highest dose is administered at a dose of 100-150 mg / day. Most antidepressants are well absorbed when administered orally, although some TCAs (eg, amitriptyline, clomipramine) can be administered intramuscularly.

Dipyridamole and related Tetrasubstituted Pyrimidopyrimidine

The methods, compositions, and kits of the invention may employ dipyridamole or tetra-substituted pyrimidopyrimidines. Dipyridamole (2,6-bis (diethanolamino) -4,8-dipiperidinopyrimido (5,4-d) pyrimidine) is, for example, a clot following heart valve surgery Tetra-substituted pyrimidopyrimidines to prevent blood clot formation and to be used as platelet inhibitors to alleviate deaths associated with coagulation diseases, including myocardial and cerebral infarction. Typically, anticoagulant therapy (prevention or treatment) is effected by administering about 75-200 mg of dipyridamole twice a day, three times a day, or four times a day alone or in combination with aspirin . In the present invention, low doses, eg, 20-80 mg, can be generally used and administered by any prior art route.

Tetra-substituted pyrimidopyrimidines are structural analogs that can replace dipyridamole in the methods and compositions of the present invention. Tetra-substituted pyrimidopyrimidines are generally formulated in US patent application Ser. No. 10 / 264,991, filed Oct. 4, 2002, entitled “Combinations for the Treatment of Immune Inflammatory Diseases”. All of (I) are incorporated herein by reference.

Typical tetra-substituted pyrimidopyrimidines useful in the methods and compositions of the present invention include 2,6-2 group substituted 4,8-dibenzylaminopyrimido [5,4-d] pyrimidines. Particularly useful tetra-substituted pyrimidopyrimidines are dipyridamole (also known as 2,6-bis (diethanolamino) -4,8-dipiperidinopyrimido (5,4-d) pyrimidine), Mordamol, dipyridamole monoacetate, NU3026 (2,6-di- (2,2-dimethyl-1,3-dioxolan-4-yl) -methoxy-4,8-di-piperidinopyrimi Dopyrimidine), NU3059 (2,6-bis- (2,3-dimethoxypropoxy) -4,8-di-piperidinopyrimidopyrimidine), NU3060 (2,6-bis [N, N-di (2-methoxy) ethyl] -4,6-di-piperidinopyrimidopyrimidine), and NU3076 (2,6-bis (diethanolamino) -4,8-di-4- Methoxybenzylaminopyrimidopyrimidines).

For oral, intramuscular, subcutaneous, topical, inhalation, rectal, vaginal and ocular administration of said tetra-substituted pyrimidopyrimidines, the dose used according to the invention is about 0.5-800 mg / day, preferably about 5-600 mg / day, 10-100 mg / day, more preferably 0.5-50 mg / day. Administration can be 1 to 4 times a day for 1 to 1 year, and even for the lifetime of the patient. Chronic, long term administration can occur in many cases. In some serious cases, up to 1600 mg / day may be needed. For intravenous administration of said tetra-substituted pyrimidopyrimidines, the dose used is about 0.1-200 mg / day, preferably about 0.5-150 mg / day, 1-100 mg / day, more preferably Is about 0.5-50 mg / day. Administration can be 1 to 4 times a day. The systemic dose will preferably be a steady state plasma concentration of 0.1-7.0 μM, more preferably 0.5-5.0 μM, most preferably 1.0-2.0 μM.

Antihistamines Antihistamines )

The methods, compositions, and kits of the invention may employ an antihistamine. Antihistamines are compounds that block the activity of histamine. Classes of antihistamines are:

(1) ethanolamines (eg, bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, diphenylpyraline, and doxyramine);

(2) ethylenediamines (eg, peniramine, pyrilamine, tripelinamine, and triprolidine);

(3) phenothiazines (eg diethazine, etopropazine, metdilazine, promethazine, chiethylperazine, and trimetaprazine);

(4) alkylamines (eg, acrivastin, brompheniramine, chlorpheniramine, desbrom peniramine, dexchlorpheniramine, pyrobutamine, and triprolidine);

(5) piperazines (eg, buclizine, cetrizine, chlorcycline, cyclizine, meclizin, hydroxyzine);

(6) piperidines (eg, astemizol, azatadine, ciproheptadine, desloratadine, fexofenadine, loratadine, ketotifen, olopatadine, phenindamin, and terpenadine);

(7) atypical antihistamines (eg azelastine, levocarbastine, metapyriline, and phenyltoxamine)

It includes.

In the methods, compositions, and kits of the invention, two non-sedating and sedating antihistamines may be used. Particularly preferred antihistamines for use in the methods, compositions, kits of the invention are non-sedative antihistamines such as loratadine and desloratadine. Genuine antihistamines may also be used in the methods, compositions, and kits of the invention. Preferred antihistamines for the methods, compositions, and kits of the invention include azatadine, bromodiphenhydramine; Chlorpheniramine; Cremisol; Ciproheptadine; Dimenhydrinate; Diphenhydramine; Doxyramamine; Meclizin; Promethazine; Pyrilamine; Chiethylperazine; And tripyleneamine.

Other antihistamines suitable for use in the methods and compositions of the present invention include acrivastin; Ahistan; Antazoline; Astimazole; Azelastine (eg, azelatin hydrochloride); Bamipine; Bepotastine; Bietanautine; Brompheniramine (eg, brompheniramine maleate); Carbinoxamine (eg, carbinoxamine maleate); Cetrizine (eg, cetrizine hydrochloride); Setoxime; Chlorocycline; Chloropyramine; Chlorodene; Chlorphenoxamine; Cinnarizine; Clemastine (eg clemastine fumarate); Clobenzepam; Clobenztropine; Clocinizine; Cyclazine (eg, cyclic acid hydrochloride; lactic acid cyclazine); Deptropine; Dexchlorpheniramine; Dexchlorpheniramineminate; Diphenylpyralline; Doxepin; Evastin; Embramine; Emedastine (eg, emedastine difumarate); Efinastin; Ethimethazine hydrochloride; Fexofenadine (eg, fexofenadine hydrochloride); Histapyrrodine; Hydroxyzin (eg, hydroxyzine hydrochloride; pamo hydroxyzine); Isopromethazine; Isothipendyl; Levocavastin (eg, levocavastin); Mebhydroline; Mequitazine; Metafurylene; Metapyrylene; Metron; Mizolastine; Olopatadine (eg, olopatadine hydrochloride); Orfenadrin; Penindamin (eg, penindamine tartarate); Peniamine; Phenyltolooxamine; p-methyldiphenhydramine; Pyrobutamine; Ceastine; Tarastine; Terpenadine; Tenyldiamine; Thiazinium (eg, thiazinium methylsulfate); Tonzylamine hydrochloride; Tolpropamine; Triprolidine; And tritoqualine.

Structural analogs of antihistamines may also be used in accordance with the present invention. Antihistamine analogues include, without limitation, 10-piperazinylpropylphenothiazine; 4- (3- (2-chlorophenothiazin-10-yl) propyl) -1-dihydrochloride piperazineethanol; 1- (10- (3- (4-methyl-1-piperazinyl) propyl) -lOH-phenothiazin-2-yl)-(9CI) 1-propanone; 3-methoxycyproheptadine; 4- (3- (2-chloro-10H-phenothiazin-10-yl) propyl) piperazin-1-hydrochloride ethanol; 10,11-dihydro-5- (3- (4-ethoxycarbonyl-4-phenylpiperidino) propylidene) -5H-dibenzo (a, d) cycloheptene; Acepromethazine; Acetophenazine; Alimethazine (eg, alimethazine hydrochloride); Aminopromazine; Benzimidazole; Butaperazine; Carfenazine; Chlorphenetazine; Chlormidazole; Synprazole; Desmethyl astemizol; Desmethylcyproheptadine; Diethazine (eg, diethazine hydrochloride); Etopropazine (eg, etopropazine hydrochloride); 2- (p-bromophenyl- (p'-tolyl) methoxy) -N, N-dimethyl-ethylamine hydrochloride; N, N-dimethyl-2- (diphenylmethoxy) -ethylamine methylbromide; EX-10-542A; Penetazine; Fuprazole; Methyl 10- (3- (4-methyl-l-piperazinyl) propyl) phenothiazin-2-yl ketone; Lerisetron; Medrillamine; Buckthorn chopped; Methylpromazine; N-desmethylpromethazine; Nilprazole; Northioridazine; Perphenazine (eg perphenazine enanthate); 10- (3-dimethylaminopropyl) -2-methylthio-phenothiazine; 4- (dibenzo (b, e) thiefin-6 (11H) -ylidene) -1-methyl-piperidine hydrochloride; Prochlorperazine; Pro margin; Propiomazine (eg, propiomazine hydrochloride); Rotoxamine; Lupatadine; Sch 37370; Sch 434; Tecastemizol; Thiazinamium; Thiopropazate; Thiolidazine (eg, thiolidazine hydrochloride); And 3- (10,11-dihydro-5H-dibenzo (a, d) cyclohepten-5-ylidene) -tropane.

Other compounds suitable for use in the present invention include AD-0261; AHR-5333; Alinastine; Arpromidine; ATI-19000; Bermastine; Bilastin; Bron-12; Carebastin; Chlorphenamine; Clofurenadine; Corsym; DF-1105501; DF-11062; DF-1111301; EL-301; Elbanizine; F-7946T; F-9505; HE-90481; HE-90512; Hivenyl; HSR-609; Icotidine; KAA-276; KY-234; Lamiakast; LAS-36509; LAS-36674; Levocetrizine; Levoprotiline; Metoclopramide; NIP-531; Noberastine; Oxatomide; PR-881-884A; Quisultazine; Rocastine; Selenotifen; SK &F-94461;SODAS-HC;Tagorizine;TAK-427;Temelastin;UCB-34742;UCB-35440;VUF-K-8707;Wy-49051; And ZCR-2060.

Still other compounds suitable for use in the present invention include US Pat. No. 3,956,296; 4,254,129; 4,254,129; 4,254,130; No. 4,282,833; 4,283,408; 4,283,408; 4,362,736; 4,362,736; 4,394,508; No. 4,285,957; 4,285,958; 4,285,958; 4,440,933; 4,510,309; 4,510,309; No. 4,550,116; 4,692,456; No. 4,742,175; No. 4,833,138; 4,908,372; 4,908,372; 5,204,249; No. 5,375,693; 5,578,610; 5,578,610; 5,581,011; 5,581,011; 5,589,487; 5,589,487; 5,663,412; 5,663,412; 5,994,549; 5,994,549; No. 6,201,124; And 6,458,958.

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

Loratadine (CLARITIN ^® ) is a tricyclic piperidine that acts as a selective peripheral histamine H-receptor antagonist. Applicants note that loratadine and its structural and functional analogues, such as piperidine, tricyclic piperidine, histamine H1-receptor antagonists, can be used to treat immunoinflammatory diseases, transplanted organ rejection, and graft-versus-host disease. It is reported herein as useful for use in anti-immune combinations.

Loratadine functional and / or structural analogues are AHR-11325, acribastin, antazoline, astemizol, azatadine, azelastine, bromopheniramine, carevastin, setrizine, chlorpheniramine, chlorcycline, clema Stin, ciproheptadine, descarboethoxyloratadine, dexchlorpheniramine, dimenhydrinate, diphenylpyrroline, diphenhydramine, evastin, fexofenadine, hydroxyzin ketotifen, rodoxamide, Levocavastin, metdilazine, mequitazine, oxatomide, phenyramine pyrilamine, promethazine, pyrilamine, cetastine, tajiphylline, temelastin, terpenadine, trimetaprazine, tripelinamine, tripe Other H 1 -receptor antagonists and similar compounds such as lollidine, utrizine (e.g., U.S. Pat.Nos. 3,956,296, 4,254,129, 4,254,130, 4,283,408, 4,362,736, 4,394,508, 4,285,957, 4,285,958 No. 4,440,933, 4,510,309, 4,550,116, 4,692,456, 4,742,175, 4,908,372, 5,204,249, 5,375,693, 5,578,610, 5,581,011, 5,589,661 5,994,549, 6,201,124, and 6,458,958).

Loratadine, setrizine, and fexofenadine are secondary-produced Hl-receptor antagonists that lack the soothing effects of many first generation H1-receptor antagonists. Piperidine H-receptor antagonists include loratadine, ciproheptadine hydrochloride (PERIACTIN), and phenindiamine tartrate (NOLAHIST). Piperazine H1-receptor antagonists include hydroxyzine hydrochloride (ATARAX), hydroxy hydroxyazine (VISTARIL), cyclic acid hydrochloride (MAREZINE), cyclic acid hydrochloride, and mecrizine hydrochloride.

Loratadine oral formulations include tablets, reditabs, and syrups. Loratadine tablets include 10 mg of micronized loratadine. Loratadine syrup contains 1 mg / ml finely divided loratadine, and readytap (easy-disintegrating tablets) contains 10 mg of micronized loratadine in tablets that disintegrate rapidly in the mouth. The suggested doses will vary depending on the condition of the patient, but the standard recommended doses are described below. Loratadine, although other daily doses useful for use in the anti-immunoinflammatory combination of the present invention, is 0.01-0.05 mg, 0.05-1 mg, 1-3 mg, 3-5 mg, 5-10 mg, 10- 15 mg, 15-20 mg, 20-30 mg, and 30-40 mg, but are typically administered in a 10 mg dose once daily.

Loratadine is rapidly absorbed after oral administration. It is metabolized to descarboethoxyloratadine by the cytochrome P450 3A4 and cytochrome P450 2D6 in the liver. Loratadine metabolites are also useful for the anti-immune combinations of the invention.

administration( Administration )

In using the methods of the invention, the drugs are administered within 30 minutes or simultaneously with each other. The drugs may be formulated together in a single composition or administered separately. It is said that the patient is treated with NSAIDs (e.g., sodium naproxen, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisac, pyricampam, indomethacin, ibuprofen, nabumetone, magnesium salicylate, sodium salicylate, Salicylic salicylic acid, phenopropene, flurbiprofen, ketoprofen, sodium meclofenamate, meloxycamp, oxaprozin, suldocak, and tolmetin), COX-2 inhibitors (e.g., Ropecoxib, celecoxib, valdecoxib, and luminacoxib), glucocorticoid receptor modulators, or other compounds such as DMARD may be desirable. Combination therapies of the present invention are drugs that modulate an immune response that acts positively on a disease, such as other anti-cytokine drugs or drugs that affect cell adhesion, ie biological agents (ie, Immunity with drugs that block the activity of IL-6, IL-1, IL-2, IL-12, IL-15 or TNFα (eg, etanercept, adelimumab, infliximab, or CDP-870) It is particularly useful for use in the treatment of inflammatory diseases. In this embodiment (drugs that block the effects of TNFα), the combination therapy reduces the production of cytokines, etanercepts or infliximab that act on the remainder of the inflammatory cytokine, enhancing the therapeutic effect.

The therapy according to the invention may be carried out alone or in combination with other therapies and may be provided at home, a doctor's office, a clinic, an outpatient office of a hospital, or a hospital. Treatment may optionally be initiated in a hospital to closely observe the effectiveness of the therapy and to make any necessary adjustments, or may be initiated in an outpatient clinic. The duration of the therapy depends on the type of disease or condition being treated, the age and condition of the patient, the condition and type of disease of the patient, and how the patient responds to the treatment. In addition, people at greater risk of developing inflammatory diseases (eg, those suffering from age-related hormonal changes) may be treated to inhibit or slow the onset of symptoms.

Routes of administration in the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (intravenous, intramuscular, subcutaneous, inhaled, rectal, oral, vaginal, intraperitoneal, intraarticular, ocular or oral Such as administration). As used herein, "systemic administration" refers to all routes of non-dermal administration, in particular excluding routes of topical and transdermal administration.

In combination therapy, the dose and frequency of administration of each component of the combination can be individually adjusted. For example, one compound may be administered three times a day, unlike other compounds may be administered once a day. Combination therapy may be given in on-and-off cycles including rest periods to allow the patient's body to have changes that overcome any unexpected side effects that have not yet occurred. The compounds may also be formulated together to deliver all of the compounds in one administration.

Formulations of pharmaceutical compositions ( Formulation of Pharmaceutical Compositions )

Administration of the drug combination of the present invention may be by any suitable means to achieve a desired therapeutic outcome. The components, or a combination thereof, can be included in any suitable amount in any suitable vehicle material, and is generally present in an amount of 1-95% of the total weight of the composition. The composition may be provided in a dosage form suitable for use in oral, parenteral (eg intravenous, intramuscular), rectal, skin, nasal, vaginal, inhalant, patch or ocular routes of administration. Thus, the composition may include, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drinks , Osmotic delivery devices, suppositories, enemas, injections, implants, nebulizers, or nebulizers. Pharmaceutical compositions may be prepared using conventional pharmaceutical practice (eg, Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. AR Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. And Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York).

Each compound of the drug combination can be formulated in a variety of ways well known in the art. For example, the first and second drugs can be formulated together or separately. Preferably, the first and second drugs are formulated for administering the drug simultaneously or nearly simultaneously. Such coformulated compositions may include, for example, SSRIs and steroids formulated together in the same pill, capsule, liquid, or the like. By using different formulation methods for different drugs, the pharmacokinetic behaviors of each drug can be matched appropriately.

Independently or individually formulated drugs may be packaged together in one kit. Unlimited embodiments include, for example, kits containing two pills, pills and powders, liquids in suppositories and vials, two topical creams, and the like.

The kit may include any component such as a powdered modal vial, an infusion syringe, a customized IV delivery system, an inhaler, or the like, which assists the patient in administering a unit dose. In addition, the unit dose kit may contain instructions for the preparation and administration of the compositions. The kit may be prepared in a single use unit dose for one patient, in multiple uses for a particular patient (individual compounds that may vary in efficacy with a given dose or regimen of treatments); Or the kit may contain multiple doses (“large doses”) suitable for administration to multiple patients. The kit components can be collected in a carton, blister pack, bottle, tube, and the like.

Ji Hyo Sung  Formulation ( Sustained Release Formulations )

Administration of any combination of the present invention, which is one of the active drugs formulated for sustained release, may result in (i) a narrow therapeutic index (e.g., plasma concentrations that cause deleterious side effects or toxic reactions and cause therapeutic effects). there is little difference between the plasma concentration; generally, the therapeutic index, i.e., TI is defined as the ratio of the medium lethal dose (LD ₅₀₎ for an intermediate amount (ED _50)); (ii) narrow absorption windows in the gastrointestinal liver; (iii) short biological half-life; Or (iv) any one of the drugs having the property that the pharmacokinetic behavior of each component must be modified to enhance the efficacy of the combination. In the formulations of the present invention, the pharmacokinetic behavior is, for example, of the patient in an amount such that administering the two drugs together is more therapeutically effective than administering the two drugs alone. It can be modified to increase the length of time that is simultaneously present in the plasma. Thus, sustained release formulations of one of the drugs may be used to prevent frequent dosing that may be required to maintain the plasma concentration of both drugs at a therapeutic concentration. For example, in preferred oral pharmaceutical compositions of the present invention, the half-life and mean residency times of 10-20 hours for one or two drugs of the combination of the present invention were measured.

Many methods can be pursued to obtain sustained release rates where the release rate is greater than the metabolic rate of the therapeutic compound. For example, sustained release can be obtained by appropriate selection of formulation parameters and components (appropriate sustained release compositions and coatings). Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches ), And liposomes. The release mechanism may be adjusted such that the drugs of the combination are released at intervals of time , wherein the release occurs simultaneously, or if the initial release of one particular drug precedes another. Delayed release can be affected.

Sustained release formulations may include degradable or non-degradable polymers, hydrogels, organogels, or other physical configurations that modify the bioabsorption, half-life or biodegradation of the drug. Sustained release formulations may be substances that are applied or applied to internal or external afflicted sites. In one embodiment, the present invention provides a biodegradable bolus or implant that is surgically inserted at or near the critical site (eg, proximal arthritis joint). In another embodiment, the sustained release formulation implant can be inserted into an organ, such as inside the intestine, for the treatment of inflammatory bowel disease.

Hydrogels can be used in sustained release formulations for the drug combinations of the present invention. Such polymers include those described in US Pat. No. 5,626,863. For example, hydrogels are encapsulated in a biodegradable network that can be used to capture combinations of the present invention and deliver them to the same tissue for slow delivery.

Chitosan and mixtures of carboxymethylcellulose sodium (CMC-Na) and chitosan are described in Inouye et al., Drug Design and Delivery 1: 297-305, 1987, has been used as a sustained release vehicle for drugs. When compressed below 200 kg / cm ² , mixtures of these compounds and the drugs of the combination of the present invention form tablets that are slowly released therefrom when administered to a patient. Release properties can be changed by changing the ratio of chitosan, CMC-Na, and active drug (s). The tablets may also contain lactose, CaHP0 ₄ dihydrate, sucrose, crystalline cellulose, or other additives including croscarmellose sodium. Some examples are shown in Table 6.

Baichwal, in US Pat. No. 6,245,356, discloses agglomerated particles, gelling agents, ionizing gel strength enhancers, and inert diluents of therapeutically active agents (eg, combinations or components thereof) in an amorphous form. Sustained release oral solid dosage forms comprising are described. The gelling agent can be a mixture of xanthan gum and locust bean gum crosslinkable with xanthan gum when the gums are exposed to the surrounding fluid. Preferably, the ionization gel strength enhancer acts to enhance the strength of crosslinking between xanthan gum and locust bean gum to prolong the release of the pharmaceutical component of the formulation. Gelling agents usable in addition to xanthan gum and locust bean gum include gelling agents well known in the art. Examples include alginate, carrageenan, pectin, guar gum, modified starch, hydroxypropylmethylcellulose, methylcellulose, and for example sodium carboxymethylcellulose and hydroxypropyl cellulose And natural or modified natural gums such as other cellulosic materials or polymers such as mixtures of the foregoing.

In other formulations useful in the combination of the present invention, Baichwal and Staniforth in US Pat. No. 5,135,757 refer to heteropolysaccharides (e.g., gallates) in the presence of heteropolysaccharides (e.g., xanthan gum or derivatives thereof) and aqueous solutions. About 20 to about 70 or more weight percent of hydrophilic material, including polysaccharide material capable of crosslinking with galactomannans, and most preferably such as locust bean gum, and inert pharmaceutical fillers (e.g., For free-flowing sustained-release granules for use as pharmaceutical excipients, including about 30 to about 80 weight percent (such as lactose, glucose, sucrose, sorbitol, xylitol, fructose or mixtures thereof) It is describing. After mixing the excipient with the combination of the present invention, ie the combination drug, the mixture is then compressed into a solid dosage form such as a tablet. The tablets thus formed slowly release the drug when digested and exposed to gastric fluid. Sustained release behavior can be obtained by varying the amount of excipient for the drug.

Combinations of the present invention may be formulated as set forth in US Pat. No. 5,007,790, which describes sustained release oral drug-dose forms that release the drug in solution at a rate controlled by the solubility of the drug. Dosage forms comprise a plurality of particles of a dispersion of a hydrophilic, water-swellable, low-solubility drug in a crosslinked polymer and retain their physical form during the dosing period, but thereafter rapidly decompose Contains capsules. Upon digestion, the particles swell to promote gastric retention, and gastric fluid penetrates the particles to dissolve the drug and filter the drug out of the particles, resulting in a solution that damages the stomach less than solid drugs. Let the drug reach the stomach Programmed final degradation of the polymer depends on the state of the polymer and the degree of crosslinking. The polymer is not microfibers and is substantially water soluble in the non-crosslinked state, and the degree of crosslinking is at least about 4 hours up to 8 hours by the choice according to the drug and the therapy, which is usually supported during the period for which the polymer is intended. It is sufficient to maintain the insoluble state from time to 12 hours. Suitable examples of crosslinked polymers that can be used in the present invention are gelatin, albumin, sodium alginate, carboxymethyl cellulose, polyvinyl alcohol, and chitin. Depending on the polymer, crosslinking can be achieved by thermal or radiotherapy or through the use of crosslinking agents such as aldehydes, polyamino acids, metal ions and the like.

Silicone microspheres for pH-regulated gastrointestinal drug delivery useful in the formulation of drug combinations of the present invention are described in Carelli et al., Int . J. Pharmaceutics 179: 73-83, 1999. The microspheres as described above were in various proportions of poly (methacrylic acid-co-methylmethacrylate) (Eudragit L100 or Eudragit S100) and crosslinked polyethylene glycol 8000 encapsulated with silicone microspheres in the 500-1000 μm size band. It is a pH-sensitive semi-interpenetrating polymer hydrogel made.

Sustained release formulations may include a coating that is not readily soluble in water and is slowly attacked by water to be removed or slowly penetrated by water. Thus, the combinations of the present invention can be spray-coated by a solution of a binder under continuously fluidized conditions as described in Kitamori et al., US Pat. No. 4,036,948. Examples of water soluble binders include pregelatinized starch (eg pregelatinized corn starch, pregelatinized white potato starch), pregelatinized modified starch, water soluble cellulose ( For example, hydroxypropyl-cellulose, hydroxymethyl-cellulose, hydroxypropylmethyl-cellulose, carboxymethyl-cellulose), polyvinyl pyrrolidone, polyvinyl alcohol, dextrin, gum arabicum And organic solvent-soluble binders such as gelatin, cellulose derivatives (eg cellulose acetate phthalate, hydroxypropylmethyl-cellulose phthalate, ethylcellulose).

Combinations of the invention, or components thereof, having sustained release properties can also be formulated by spray drying techniques. In one embodiment, Espositio et al., Pharm . Dev . Technol . As described in 5: 267-78, 2000, prednisolone was encapsulated in methacrylate microparticles (Eudragit RS) using a Mini Spray Dryer, model 190 (Buchi, Laboratorium Technik AG, Flawil, Germany). do. The optimal conditions for particulate formation are the pumping rate of the solution containing 50 mg prednisolone in 10 mL of acetonitrile is 0.5 mL / min, the flow rate of the sprayed air is 600 L / hr, It was found that the drying temperature heated at 80 ° C., and the flow rate of the sucked dry air was 28 m ³ / hr.

Another form of sustained release combinations can be prepared by microencapsulation of combination drug particles in a membrane that acts as microdialysis cells. In such formulations, gastric fluid allows penetration of the microcapsule walls to swell the microcapsules and to dialysis the active drug (s) (see, eg, Tsuei et al., US Pat. No. 5,589,194). ). One commercially available sustained release system of this kind consists of microcapsules with a membrane of acacia gum / gelatin / ethyl alcohol. This product is marketed by Eurand Limited (France) under the Diffucaps ^™ trademark. The microcapsules so formulated can be delivered or tableted in conventional gelatin capsules.

Sustained-release and / or sustained release formulations of SSRIs and corticosteroids are known. For example, as marketed by GlaxoSmithKline, Paxil CR ^® is an exploded sustained release form of the hydrochloric acid paroxetine of falls in the polymer matrix (extended release form) (GEOMATRIX ^TM, also U.S. Patent No. 4,839,177, 1 - 5,102,666 arc, and a 5,422,123 number It also has an enteric coating that delays the onset of drug release until the tablets pass through the stomach. For example, U. S. Patent No. 5,102, 666 discloses (1) fibrous cross-linked carboxy- water-swellable but water-insoluble fibrous cross-linked carboxy- in the presence of an active drug selected from the group consisting of SSRIs such as paroxetine. functional polymer), wherein the polymer comprises (a) at least about 80% of multiple repeat units containing at least one carboxyl group, and (b) substantially free of polyalkenyl polyethers A polymer sustained-release composition containing 0.05 to about 1.5% crosslinking agent, the percentage comprising components based on the weight of the unpolymerized repeat units and the crosslinking agent, respectively, and (2) a reaction complex formed by the interaction of water. It is described. The amount of polycarbophilcalcium present is from about 0.1 to about 99% by weight, for example about 10%. The amount of active drug present is from about 0.0001 to about 65% by weight, for example between about 5 and 20%. The amount of water present is from about 5 to about 200% by weight, for example between about 5 and 10%. The interaction is carried out at a pH between about 3 and about 10, for example between about 6 and 7. The polycarbophylcalcium is present in the form of a calcium salt comprising from about 5 to about 25% calcium from the outset.

Other sustained release formulation examples are described in US Pat. No. 5,422,123. Such formulations comprise (a) a deposit-core comprising an effective amount of active substance and having a defined geometric form, and (b) a support-platform applied to the precipitate-core. Wherein the precipitation-core is at least one active material, and (1) a polymer material and a gelable polymer material that expand when contacted with water or an aqueous solution, wherein the gelable polymer material to the expandable polymer material The ratio is in the range of 1: 9 to 9: 1 and (2) contains at least one member selected from the group consisting of a single polymeric material having both swelling and gelling properties, wherein the support-platform is the surface of the precipitation-core Is partially covered and follows changes due to the hydration of the precipitate-core and slowly dissolves in the aqueous solution and / or is slowly gelled to the precipitate-core Applied elastic support. The support-platform may be a polymer such as hydroxypropylmethylcellulose, plasticizers such as glycerides, binders such as polyvinylpyrrolidone, hydrophilic drugs such as lactose and silicon dioxide, and / or Hydrophobic drugs such as magnesium stearate and glycerides. The polymer (s) typically comprise 30 to 90% by weight of the support-platform, for example about 35 to 40%. Plasticizers comprise at least 2% by weight of the support-platform, for example about 15-20%. The binder (s), hydrophilic drug (s) and hydrophobic drug (s) typically add up to about 50% by weight of the support-platform, for example up to about 40-50%.

In another embodiment, the sustained release formulation for Venlafaxine (Effexor XR ^® ) is marketed by Wyeth Pharmaceuticals. Such formulations include venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose (see US Pat. Nos. 6,403,120 and 6,419,958).

Sustained-release formulations of budesonide (3 mg capsule) to treat inflammatory bowel disease are sold by AstraZeneca (sold as "Entocort ^™ "). Sustained-release formulations useful for corticosteroids are also described in U.S. Patent No. 5,792,476, which formulations begin about 1-3 hours after the glucocorticoid is injected into the small intestine of the patient, with about 40-80 minutes of glucocorticoids of 90% or more weight. Active substances having sustained release adjusted for release during the period of time include 2.5-7 mg of glucocorticoids. To enable this low dose concentration of the active substance, the active substance, i.e. the glucocorticoid, such as prednisolone or prednisone, is micronized and suitably mixed with known diluents such as starch and lactose, resulting in PVP (poly Vinylpyrrolidone). In addition, the granules are laminated with a slow release inner layer resistant to a pH of 6.8 and a slow release outer layer resistant to a pH of 1.0. The inner layer is made of Eudragit ^® RL (a copolymer of low content of quaternary ammonia groups and acryl and methacrylic esters) and the outer layer is made of Eudragit ^® L (anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester) .

Bilayer tablets may be formulated for any combination of the present invention in which custom granules are prepared for each drug of the combination, and then the two drugs are compressed by a bilayer press to form one tablet. For example, 12.5 mg, 25 mg, 37.5 mg, or 50 mg paroxetine, formulated with sustained release formulation such that paroxetine t _{l / 2} is 15-20 hours, may be supported in the same tablet with 3 mg prednisolone Such tablets are formulated such that the half-life (t _{l / 2} ) is close to the half-life of paroxetine. Examples of paroxetine sustained release formulations, including those used in bilayer tablets, can be found in US Pat. No. 6,548,084. In addition to controlling the prednisolone release rate in vivo, an enteric coating or delayed release coating may be included that delays the onset of drug release such that the T _maX of prednisolone is _{close to} that of paroxetine (ie, 5 to 10 hours).

Cyclodextrins are cyclic polysaccharides containing α- (1,4) linked natural D (+)-glucopyranose (glucopyranose) units. Alpha-, beta- and gamma-cyclodextrins containing 6, 7 or 8 glucopyranose units, respectively, are most commonly used and suitable examples are described in W091 / 11172, W094 / 02518 and W098 / 55148. It is. Structurally, the cyclic nature of the cyclodextrin forms a torus or donut-like form with an inner apolar or hydrophobic cavity, wherein the secondary hydroxyl group is one of the cyclodextrin toruss. Located on the side and the primary hydroxyl group is located on the other side. The side where the secondary hydroxyl group is located has a larger diameter than the side where the primary hydroxyl group is located. The hydrophobicity of the cyclodextrin inner cavity enables inclusion of various compounds (Comprehensive Supramolecular Chemistry, Volume 3, JL Atwood et al., Eds., Pergamon Press (1996); Cserhati, Analytical Biochemistry 225: 328-32, 1995; Husain et al., Applied Spectroscopy 46: 652-8, 1992). Cyclodextrins may be formed of various therapeutic compounds by forming inclusion complexes with various drugs that fit the hydrophobic cavity of the cyclodextrin or by forming non-covalent association complexes with other biologically active molecules. It was used as the delivery vehicle. US Pat. No. 4,727,064 describes a pharmaceutical formulation consisting of a drug having substantially low water solubility and an amorphous, water soluble cyclodextrin-based mixture in which the drug forms an inclusion complex with the cyclodextrins of the mixture.

Formation of the drug-cyclodextrin complex can alter the solubility, dissolution rate, bioavailability, and / or stability of the drug. For example, cyclodextrins are described in Uekama et al., J. Pharm Dyn. 6: 124-7, 1983 has been described as improving the bioavailability of prednisolone. The cyclodextrin / prednisolone complex can be prepared by adding all ingredients to water and stirring at 25 ° C. for 7 days. The resultant treated precipitate is the 1: 2 prednisolone / cyclodextrin complex.

Sulfonate ether -β- cyclodextrin (SBE-β-CD, CyDex , Inc, is sold by Overland Park, KA, USA sold as CAPTISOL ^®) may also aid in the manufacture of sustained release formulations of the combination of the drugs of the present invention Can be used as For example, sustained-release tablets have been prepared containing prednisolone and SBE-β-CD compressed in a hydroxypropyl methylcellulose matrix (see Rao et al., J. Pharm . Sci . 90: 807-16, 2001). ). In another embodiment using various cyclodextrins, European Patent 1109806 B1 describes cyclodextrin complexes of paroxetine and anhydrous or hydrated forms in which the complex ratio of drug to cyclodextrin is formed from 1: 0.25 to 1:20. Α-, γ-, or β-cyclodextrins in the [eptakis (2-6-di-O-methyl) -β-cyclodextrin, (2,3,6-tri-0-methyl)- [beta] -cyclodextrin, monosuccinyl epthakis (2,6-di-O-methyl)-[beta] -cyclodextrin, or 2-hydroxypropyl- [beta] -cyclodextrin.

Polymeric cyclodextrins have also been prepared as described in US Patent Application Nos. 10 / 021,294 and 10 / 021,312. The cyclodextrin polymers so formed may be useful for formulating drugs of the combinations of the present invention. Such multifunctional polymeric cyclodextrins are commercially available from Insert Therapeutics, Inc., Pasadena, CA, USA.

As an alternative to direct compounding with drugs, cyclodextrins can be used as auxiliary additives, such as vehicles, diluents or solubilisers. Formulations comprising cyclodextrins and other drugs of the combinations of the invention (eg, tricyclic compounds, SSRIs, SNRIs, NsIDIs, antihistamines, corticosteroids, and / or tetra-substituted pyrimidopyrimidines) are described herein. It may be prepared by methods similar to the preparation of the cyclodextrin formulations described.

Liposome  Formulations ( Liposomal Formulations )

One or two components of the combinations of the present invention, or mixtures of both components, may be incorporated into a liposome vehicle for administration. The liposome vehicles consist of three general types of vehicle-forming lipid components. The first includes vehicle-forming lipids that will form most of the vehicle structure in liposomes. In general, such vehicle-forming lipids have hydrophobic and polar head group moieties and (a) can spontaneously form bilayer vehicles in water, as exemplified by phospholipids (b) Amphipathic lipids that are stably incorporated into a lipid bilayer having a hydrophobic portion that contacts the inner hydrophobic region of the bilayer membrane and a polar head group portion thereof that faces the outer polar surface of the membrane.

Said vehicle-forming lipids of this type are preferably those having two hydrocarbon chains, typically acyl chains and a polar head group. As this class includes phospholipids such as phosphatidylcholine (PC), PE, phosphadidic acid (PA), phosphatidylinositol (PI), and sphingomyelin (SM), two hydrocarbon chains are typically about long in length. It is between 14-22 carbon atoms and has varying degrees of unsaturation. The lipids and phospholipids described above in which the acyl chains have varying degrees of saturation can be obtained commercially or prepared according to published methods. Other lipids that may be included in the present invention are sterols such as glycolipids and cholesterol.

The second common component includes vehicle-forming lipids derived from polymer chains forming the polymer layer in the composition. Vehicle-forming lipids that can be used as the second general vehicle-forming lipid component are any of those described in the first general vehicle-forming lipid component.

Vehicles that form lipids with diacyl chains such as phospholipids are preferred. One typical phospholipid is phosphatidylethanolamine (PE), which provides a reactive amino group that is convenient for coupling to activated polymers. Typical PE is distearyl PE (DSPE).

Preferred polymers in the derivatized lipids are polyethylene glycols (PEG), preferably PEG chains having a molecular weight between 1,000-15,000 Daltons, more preferably between 2,000 and 10,000 Daltons, most preferably between 2,000 and 5,000 Daltons . Other hydrophilic polymers that may be suitable include polyvinylpyrrolidone, polymethylloxazoline, polyethylloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide and polydimethylacrylamide, polylactic acid, polyglycolic acid, And derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.

In addition, it may be suitable to include block copolymers or random copolymers of such polymers, in particular the PEG component. Methods for preparing derivatized lipids and hydrophilic polymers such as PEG are well known, for example as described in US Pat. No. 5,013,556.

A third common vehicle-forming lipid component that is selectable is a lipid anchor in which the targeting moiety is anchored to the liposome through a polymer chain in an anchor. In addition, the targeting group is located at the distal end of the polymer chain in order not to lose the biological activity of the targeting moiety. The lipid anchor is liberated (outer) that can be activated or activated to covalently couple to a hydrophobic moiety that provides for anchoring lipids to the outer layer surface of the liposome bilayer, a covalently bonded polar head group of the polymer, and a targeting moiety. ) Polymer ends. The methods are described below for preparing lipid anchor molecules of this type.

The lipid components used to form the liposomes are preferably present in the vehicle forming lipid at a molar ratio of about 70-90 percent of the vehicle forming lipid, lipid derived 1-25 percent polymer, and 0.1-5 percent lipid anchor. . One typical formulation is 50-70 mole percent uninduced PE, 20-40 mole percent cholesterol, 0.1-1 mole percent of PE-PEG (3500) polymer with a chemical reactor for coupling from its free end to the targeting moiety. 5 to 10 mole percent PEG derived with PEG 3500 polymer chains, and 1 mole percent alpha-tocopherol.

The liposomes are preferably prepared to have substantially the same size within a substantially selected size range, typically between about 0.03 and 0.5 microns. One effective quantitative method for REV and MLV processes the aqueous suspension of liposomes through a series of polycarbonate membranes having a selected constant pore size, typically in the range of 0.03 to 0.2 microns, typically 0.05, 0.08, 0.1, or 0.2 microns. Forming. The pore size of the membrane corresponds approximately to the largest size of the liposomes produced by processing formation through the membrane, in particular wherein the preparation is processed and formed two or more times through the same membrane. Methods for down-sizing homogenization of liposomes down to 100 nm in size are also useful.

Other established liposome formulation techniques can be applied as needed. For example, the use of liposomes to promote cell uptake is described in US Pat. Nos. 4,897,355 and 4,394,448.

Administration of each drug in any one of the combinations described herein may be made, individually, one to four times a day for one to one year, and even for the lifetime of the patient. Chronic, long term administration will appear in many cases.

Other implementation Example

All publications, patent applications, and patents mentioned in this specification are incorporated herein by reference.

Although the present invention has been described in terms of specific embodiments, it should be understood that further variations are possible. Accordingly, the present application is not described herein but includes any variations, uses, or modifications of the present invention that generally conform to the principles of the present invention, including known or conventional practice in the art to which this invention pertains. Intended to.

Other embodiments are within the scope of the claims.

Claims (55)

A method for improving the efficacy of a combination of first and second drugs, the method comprising: i) administering the first drug to the patient in an amount sufficient to produce an effective plasma concentration for a period of T _l , and ii) administering said second drug to said patient in a manner sufficient to produce an effective plasma concentration for at least 70% of T _l . The method of claim 1, wherein some or all of the second drug is formulated for sustained release. The method of claim 1, wherein the second drug is the time T _l Administering at least once during. The method of claim 1, wherein the second drug is administered in a manner sufficient to produce an effective plasma concentration of the second drug for at least 80% of the time T ₁ . A method of administering a combination of a first and a second drug to a patient, the method comprising administering simultaneously, or within 30 minutes of each other, wherein the first drug is not formulated for sustained release and the second drug. Is formulated for sustained release, wherein: a) the first drug produces a maximum plasma concentration at T _maxl , b) the second drug _produces a maximum plasma concentration at T _max2 , and c) T _max2 is greater than or equal to T _maxl, ten thousand and one if not formulated wherein the drug is sustained for 2 _maxl T> T _max2 manner. 6. The method of claim 1, wherein the first drug and the second drug are formulated together in unit dosage form. 7. The method of claim 6, wherein the unit dosage form is a bilayer tablet having a first layer comprising the first drug not formulated for sustained release and a second layer comprising the second agent formulated for sustained release. How to. 7. The unit dosage form of claim 6, wherein the unit dosage form is a tablet having an inner core comprising the second drug formulated for sustained release and an outer coating comprising the first drug formulated for sustained release. Way. 7. The method of claim 6, wherein said unit dosage form is a capsule having beads comprising said second drug formulated for sustained release and beads comprising said first drug unformulated for sustained release. 10. The method of claim 9, wherein said capsule further comprises a bead comprising said second drug not formulated for sustained release. The method of claim 1 or 5, wherein the first drug or the second drug is a tricyclic compound, SSRI, SNRI, NsIDI, antihistamine, corticosteroid, or tetra-substituted pyrimidopyrimidine. . 12. The method of claim 11, wherein said second drug is a corticosteroid. 12. The method of claim 11, wherein the first drug is a tricyclic compound and the second drug is a corticosteroid. The method of claim 13, wherein the first drug is amoxapine and the second drug is prednisolone. 12. The method of claim 11, wherein said first drug is SSRI and said second drug is corticosteroid. 16. The method of claim 15, wherein said first drug is paroxetine and said second drug is prednisolone. 12. The method of claim 11, wherein said first drug is tetra-substituted pyrimidopyrimidine and said second drug is a corticosteroid. 18. The method of claim 17, wherein the first drug is dipyridamole and the second drug is prednisolone. 12. The method of claim 11, wherein said first drug is NsIDI and said second drug is an antihistamine. 20. The method of claim 19, wherein said first drug is cyclosporin A and said second drug is loratadine. 12. The method of claim 11, wherein the first drug is a tricyclic compound and the second drug is a corticosteroid. 22. The method of claim 21, wherein said first drug is nortriptyline and said second drug is budesonide. 23. The method of claim 22, wherein said nortriptyline and budesonide are formulated for inhalation. 12. The method of claim 11, wherein said first drug is tetra-substituted pyrimidopyrimidine and said second drug is an antihistamine. The method of claim 24, wherein the first drug is dipyridamole and the second drug is loratadine. A first drug selected from tricyclic compounds, SSRI, SNRI, NsIDI, antihistamines, and tetra-substituted pyrimidopyrimidines; And a unit dosage form comprising a second agent formulated for sustained release. 27. The method of claim 26, wherein the unit dosage form is a bilayer tablet having a first layer comprising the first drug not formulated for sustained release and a second layer comprising the second agent formulated for sustained release. Composition. 27. The method of claim 26, wherein the unit dosage form is a tablet having an inner core comprising the second drug formulated for sustained release and an outer coating comprising the first drug formulated for sustained release. Composition. 29. The composition of claim 27 or 28, wherein said tablet further comprises said second drug not formulated for sustained release. 27. The composition of claim 26, wherein said unit dosage form is a capsule having beads comprising said second drug formulated for sustained release and beads comprising said first drug unformulated for sustained release. 31. The composition of claim 30, wherein said capsule further comprises a bead comprising said second drug formulated for sustained release. 27. The composition of claim 26, wherein the first drug is a tricyclic compound and the second drug is a corticosteroid. 33. The composition of claim 32, wherein said first drug is amoxapine and said second drug is prednisolone. 33. The composition of claim 32, wherein said first drug is nortriptyline and said second drug is budesonide. 35. The composition of claim 34, wherein said nortriptyline and said budesonide are formulated for inhalation. 27. The composition of claim 26, wherein the first drug is SSRI and the second drug is a corticosteroid. 37. The composition of claim 36, wherein said first drug is paroxetine and said second drug is prednisolone. 27. The composition of claim 26, wherein said first drug is tetra-substituted pyrimidopyrimidine and said second drug is a corticosteroid. 39. The composition of claim 38, wherein the first drug is dipyridamole and the second drug is prednisolone. 27. The composition of claim 26, wherein the first drug is NsIDI and the second drug is an antihistamine. 41. The composition of claim 40, wherein said first drug is cyclosporin A and said second drug is loratadine. 27. The composition of claim 26, wherein the first drug is tetra-substituted pyrimidopyrimidine and the second drug is an antihistamine. 43. The composition of claim 42, wherein the first drug is dipyridamole and the second drug is loratadine. (a) a first drug not formulated for sustained release, (b) said second drug formulated for sustained release; And (c) a kit comprising instructions for administering the first drug and the second drug simultaneously or within 30 minutes of each other. 45. The kit of claim 44, wherein said first drug is a tricyclic compound and said second drug is a corticosteroid. 46. The kit of claim 45, wherein said first drug is amoxapine and said second drug is prednisolone. 46. The kit of claim 45, wherein said first drug is notriphthylline and said second drug is budesonide. 45. The kit of claim 44, wherein said first drug is SSRI and said second drug is corticosteroid. 49. The kit of claim 48, wherein said first drug is paroxetine and said second drug is prednisolone. 45. The kit of claim 44, wherein said first drug is tetra-substituted pyrimidopyrimidine and said second drug is a corticosteroid. 51. The kit of claim 50, wherein said first drug is dipyridamole and said second drug is prednisolone. 45. The kit of claim 44, wherein said first drug is NsIDI and said second drug is an antihistamine. 53. The kit of claim 52, wherein said first drug is cyclosporin A and said second drug is loratadine. 45. The kit of claim 44, wherein said first drug is tetra-substituted pyrimidopyrimidine and said second drug is an antihistamine. 55. The kit of claim 54, wherein said first drug is dipyridamole and said second drug is loratadine.

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