HK1150549A

HK1150549A - Therapeutic regimens for the treatment of immunoinflammatory disorders

Info

Publication number: HK1150549A
Application number: HK11104635.0A
Authority: HK
Inventors: Mahesh V. Padval
Original assignee: Combinatorx, Incorporated
Priority date: 2007-12-17
Filing date: 2008-12-17
Publication date: 2012-01-06

Description

Therapeutic regimens for treating immunoinflammatory disorders

Background

In the second clinical development of the treatment of immunoinflammatory disorders, the combination of prednisolone and dipyridamole is an orally available synergistic drug candidate. Synergistic agents include two compounds designed to act synergistically through multiple pathways to provide therapeutic effects that cannot be achieved with either component administered alone at the same dosage level. The combination of prednisolone and dipyridamole is designed to selectively enhance certain elements of the anti-inflammatory and immunomodulatory activity of prednisolone without repeating the side effects of steroids.

Proper formulation is essential to maximize the therapeutic effect of the synergistic drug combination.

Summary of The Invention

In one aspect, the invention features a method for treating an immunoinflammatory disorder in a subject in need thereof, the method including administering (e.g., once, twice, or three times daily) to the subject a unit dosage form comprising dipyridamole coated onto acid beads and formulated for controlled release. The unit dosage form may include between 40 and 400mg dipyridamole (e.g., 45mg, 90mg, 180mg, or 360 mg). In some embodiments, dipyridamole is coated onto tartaric acid beads in a weight ratio (dipyridamole: tartaric acid) of, for example, 1: 0.8, 1: 0.6, 1: 0.7, 1: 0.9, 1: 1, 1: 1.1, or 1: 1.2.

In certain embodiments, dipyridamole can be coated with a controlled release coating (e.g., hydroxypropylmethylcellulose phthalate 55, Surelease @)HPMC E5, or EudragitL100∶EudragitS100) coating.

In still other embodiments, the unit dosage form comprises dipyridamole formulated for immediate release. The percentage of dipyridamole that is formulated for controlled release is between 20% and 100% (e.g., from 50% to 80%, 55% to 85%, 60% to 90%, 65% to 95%, 45% to 75%, 45% to 55%, 50% to 60%, 55% to 65%, 70% to 80%, 75% to 85%, 80% to 90%, or 85% to 95%) of dipyridamole in the unit dosage form.

In another embodiment, the method further comprises administering a corticosteroid (e.g., prednisolone, prednisone, budesonide, methylprednisolone, fluticasone, betamethasone, or deflazacort) to the subject. The corticosteroid can be administered in two separate doses. For example, a first dose may be administered (e.g., upon waking) in a unit dose formulation containing from 0.75 to 3.75mg (e.g., 1.5 to 2.5mg, 0.75 to 2.0mg, 2.0 to 3.75mg, 0.9mg, or 1.8mg) of prednisolone or an equivalent (equivalent) thereof, an equivalent (equivalent) of an additional corticosteroid (e.g., an anticancer corticosteroid), and a second dose may be administered within 8 hours of the first dose (e.g., 4-6, 3-5, or 2-4 hours after the first dose) in a unit dose formulation containing from 0.75 to 3.75mg (e.g., 0.75 to 1.25mg, 1.5 to 2.5mg, 0.75 to 2.0mg, 2.0 to 3.75mg, 0.9mg, or 1.8mg) of prednisolone or an equivalent, an additional corticosteroid, thereof. The first and second doses of corticosteroid may be formulated for immediate release or controlled release, the first dose may be formulated for immediate release and the second dose for controlled release, or the first dose may be formulated for controlled release and the second dose for immediate release. In a particular embodiment, the first dose is administered in a unit dose formulation comprising from 1.0 to 2.5mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid, formulated for immediate release, and the second dose is administered in a unit dose formulation comprising from 0.75 to 2.0mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid, formulated for controlled release.

In a related aspect, the invention features a pharmaceutical composition in unit dosage form comprising dipyridamole coated onto tartaric acid beads and formulated for controlled release. The unit dosage form may contain between 40 and 400mg (e.g., 45mg, 90mg, 180mg, or 360mg) dipyridamole. In some embodiments, dipyridamole is coated onto tartaric acid beads in a weight ratio (dipyridamole: tartaric acid) of, for example, 1: 0.8, 1: 0.6, 1: 0.7, 1: 0.9, 1: 1, 1: 1.1, or 1: 1.2.

In still other embodiments, the unit dosage form comprises dipyridamole formulated for immediate release. The percentage of dipyridamole that is formulated for controlled release may be between 20% and 100% (e.g., from 50% to 80%, 55% to 85%, 60% to 90%, 65% to 95%, 45% to 75%, 45% to 55%, 50% to 60%, 55% to 65%, 70% to 80%, 75% to 85%, 80% to 90%, or 85% to 100%) of dipyridamole in the unit dosage form.

Such unit dosage forms may further comprise administering a corticosteroid (e.g., prednisolone, prednisone, budesonide, methylprednisolone, fluticasone, betamethasone, or deflazacort) to the subject. The formulation of corticosteroid may be from 0.75 to 3.75mg (e.g., 1.5 to 2.5mg, 0.75 to 2.0mg, 2.0 to 3.75mg, 0.9mg, or 1.8mg) of prednisolone or an equivalent, equivalent amount of additional corticosteroid. Corticosteroids may be formulated as controlled release or immediate release, or a combination of controlled release and immediate release. The percentage of corticosteroid formulated for controlled release may be between 20% and 100% (e.g., from 50% to 80%, 55% to 85%, 60% to 90%, 65% to 95%, 45% to 75%, 45% to 55%, 50% to 60%, 55% to 65%, 70% to 80%, 75% to 85%, 80% to 90%, or 85% to 100%). The corticosteroid formulated for controlled release may be formulated to release a major portion of the corticosteroid at, for example, 2-8 hours, 4-6 hours, or 3-5 hours after administration. In a particular embodiment, the unit dosage form comprises 0.75 to 3.75mg of prednisolone, wherein 30% to 60%, 40% to 70%, 50% to 80%, or 60% to 90% of the prednisolone is formulated for immediate release, and 10% to 40%, 20% to 50%, 30% to 60%, or 40% to 70% of the prednisolone is formulated for controlled release. In certain embodiments, dipyridamole is coated onto the acidic beads. In other embodiments, the dipyridamole is formulated as homogeneous beads.

In other aspects, the invention features pharmaceutical compositions in unit dosage form including 40 to 400mg of dipyridamole formulated for controlled release (e.g., 45mg, 90mg, 180mg, or 360mg), and 0.75 to 3.75mg of prednisolone formulated for controlled or immediate release (e.g., 1.5 to 2.5mg, 0.75 to 2.0mg, 2.0 to 3.75mg, 0.9mg, or 1.8mg) or an equivalent, equivalent amount of an additional corticosteroid.

In certain embodiments, the unit dosage form comprises dipyridamole formulated for immediate release. The percentage of dipyridamole that is formulated for controlled release may be between 20% and 100% (e.g., from 50% to 80%, 55% to 85%, 60% to 90%, 65% to 95%, 45% to 75%, 45% to 55%, 50% to 60%, 55% to 65%, 70% to 80%, 75% to 85%, 80% to 90%, or 85% to 95%) of dipyridamole in the unit dosage form.

In other embodiments, the unit dosage form comprises a corticosteroid formulated as a combination of controlled release and immediate release. The percentage of corticosteroid formulated for controlled release is between 20% and 100% (e.g., from 50% to 80%, 60% to 80%, 30% to 60%, 40% to 70%, 45% to 75%, or 80% to 100%). The corticosteroid formulated for controlled release may be formulated to release a major portion of the corticosteroid after administration, for example, 2-8 hours, 4-6 hours, or 3-5 hours. In a particular embodiment, the unit dosage form comprises 0.75 to 3.75mg of prednisolone, wherein 30% to 60%, 40% to 70%, 50% to 80%, or 60% to 90% of the prednisolone is formulated for immediate release and 10% to 40%, 20% to 50%, 30% to 60%, or 40% to 70% of the prednisolone is formulated for controlled release.

In certain embodiments, the pharmaceutical compositions of the present invention comprise an inner core comprising prednisolone formulated for controlled release and an outer coating comprising prednisolone formulated for immediate release. For example, the inner core can include 0.75 to 1.25mg (e.g., 0.75 to 1.1mg, 0.65 to 1.1mg, 0.80mg to 1.0mg, or 0.9mg) of prednisolone formulated for controlled release, and the outer coating comprises 1.25 to 2.25mg (e.g., 1.5 to 2.0mg, 1.6 to 2.0mg, 1.7mg to 2.0mg, or 1.8mg) of prednisolone formulated for immediate release. In other embodiments, the size of the pill is reduced and the dosage regimen is increased by having an inner core comprising 0.25 to 0.75mg (e.g., 0.35 to 0.65mg, 0.35 to 0.75mg, 0.25mg to 0.55mg, or 0.45mg) of prednisolone formulated for controlled release and an outer coating comprising 0.75 to 1.25mg (e.g., 0.75 to 1.1mg, 0.65 to 1.1mg, 0.80mg to 1.0mg, or 0.9mg) of prednisolone formulated for immediate release.

The invention also features a kit that includes any of the foregoing pharmaceutical compositions and instructions for administering (e.g., once, twice, or three times daily) the pharmaceutical compositions to treat an immunoinflammatory disorder.

In an embodiment of any of the above methods, compositions, and kits, the pharmaceutical compositions of the invention comprise a corticosteroid formulated in a unit dosage form having a dissolution release profile that releases at least 55%, 60%, 65%, 70%, or 75% of the corticosteroid within the first two hours of testing using USP dissolution apparatus No.1 at 37 ℃ ± 0.5 ℃ and 100rpm in 0.1N HCl as dissolution medium followed by phosphate buffer at ph6.8 as medium. Ideally, the corticosteroid formulated as a unit dose has a dissolution release profile under in vitro conditions of at least 50%, 55%, 60%, 65%, 70% or 75% release of the corticosteroid within the first 30, 45 or 60 minutes of testing, wherein the in vitro conditions are the first two hours in 0.1N HCl as dissolution medium and then in ph6.8 phosphate buffer as medium using USP dissolution apparatus No.1 and at 37 ℃ ± 0.5 ℃ and 100 rpm.

In still other embodiments of any of the above methods, compositions, and kits, the pharmaceutical compositions of the present invention comprise dipyridamole formulated in unit dosage form, which has a dissolution release profile under in vitro conditions of at least 10-55% (i.e. 15-55%, 20-55%, 25-45%, 35-55%, 30-45% or 40-55%) dipyridamole released within the first two hours of testing and not less than 80%, 82%, 84%, 86%, 88%, 90%, 91%, 93%, 95% or 97% dipyridamole released within 8 hours, wherein the in vitro conditions are the first two hours using USP dissolution apparatus No.1 and at 37 ℃. + -. 0.5 ℃ and 100rpm in 0.1N HCl as dissolution medium, and then in a phosphate buffer pH6.8 containing 0.25% sodium lauryl sulfate as the medium.

In further embodiments of any of the above methods, compositions, and kits, the pharmaceutical compositions of the invention comprise dipyridamole formulated in unit dosage form having an absorption rate constant of 0.20 to 0.40, 0.22 to 0.42, 0.24 to 0.44, 0.26 to 0.46, 0.28 to 0.48, 0.30 to 0.50, 0.32 to 0.52, 0.34 to 0.54, 0.36 to 0.56, 0.38 to 0.58, 0.40 to 0.60, 0.42 to 0.62, 0.44 to 0.64, 0.46 to 0.66, 0.48 to 0.68, 0.50 to 0.70, 0.52 to 0.72, 0.54 to 0.74, 0.56 to 0.76, 0.58 to 0.78, 0.60 to 0.82, 0.82 to 0.70, 0.84 to 0.72, 0.80 to 0.80, 0.72 to 0.80, 0.80 to 0.72, 0.80 to 0.72, 0.80, 0.72 to 0.72, 0.80 to 0.72 to 0.80, 0.72 to 0.72, 0.72 to 0.80, 0..

The term "absorption rate constant" refers to the average absorption rate constant observed for dipyridamole in a pharmacokinetic study involving 12 or more subjects after normal breakfast, as described in example 9. The absorption rate constant can be determined by measuring the circulating concentration of dipyridamole in each subject taking the drug after a meal and fitting the resulting data to each individual subject using commercially available algorithms, as described in example 9.

As used herein, the term "treating" refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. "preventing disease" refers to prophylactic treatment of a subject who has not yet suffered from, but is susceptible to or otherwise at risk of suffering from, a particular disease. "treating a disease" or for "therapeutic treatment" refers to administering a treatment to a subject already suffering from a disease, in order to improve or stabilize the condition of the subject. Thus, in the claims and embodiments, the treatment is administered to the subject for therapeutic or prophylactic purposes.

The term "immunoinflammatory disorder" includes a variety of conditions including autoimmune diseases, proliferative skin diseases and inflammatory skin diseases. Immunoinflammatory disorders lead to the destruction of healthy tissue through inflammatory processes, immune system dysregulation (dysregulation) and unwanted cell proliferation. Examples of immunoinflammatory disorders are acne vulgaris; acute respiratory distress syndrome; addison's disease; allergic rhinitis; allergic intraocular inflammatory diseases, anti-neutrophil cytoplasmic antibody (ANCA) associated small vessel vasculitis; ankylosing spondylitis; arthritis, asthma; atherosclerosis; atopic dermatitis; autoimmune hemolytic anemia; autoimmune hepatitis; behcet's disease; bell's paralysis; bullous pemphigoid; cerebral ischemia; chronic Obstructive Pulmonary Disease (COPD); cirrhosis of the liver; -the syndrome of calamus margaritae (Cogan's); contact dermatitis; crohn's disease; cushing's syndrome; dermatomyositis; diabetes mellitus; discoid lupus erythematosus; eosinophilic fasciitis; erythema nodosum; exfoliative dermatitis; fibromyalgia; local glomerulosclerosis; giant cell arteritis; gout; gouty arthritis; graft versus host disease; hand eczema; allergic purpura; herpes gestationis; hirsutism; idiopathic corneoscleritis; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; inflammatory bowel or gastrointestinal disorders, inflammatory skin diseases; lichen planus; lupus nephritis; lymphangiomatous tracheobronchitis; macular edema; multiple sclerosis; myasthenia gravis; myositis; osteoarthritis; pancreatitis; pemphigoid gestationis; pemphigus vulgaris; polyarteritis nodosa; polymyalgia rheumatica; pruritus scrotum; pruritus/inflammation, psoriasis; psoriatic arthritis; rheumatoid arthritis; recurrent polychondritis; rosacea (e.g., caused by sarcoidosis, scleroderma, sjogren's syndrome, systemic lupus erythematosus, urticaria, herpes zoster-associated pain, other diseases); sarcoidosis; scleroderma; segmental glomerulosclerosis; septic shock syndrome; tendonitis or bursitis; sjogren's syndrome; still's disease; stroke-induced brain cell death; swart's disease (Sweet's disease); systemic lupus erythematosus; systemic sclerosis; takayasu's arteritis; temporal arteritis; toxic epidermal necrolysis; tuberculosis; type I diabetes; ulcerative colitis; uveitis; vasculitis; and wegener's granulomatosis.

"corticosteroid" refers to any naturally occurring or synthetic steroid hormone that can be derived from cholesterol and that has the characteristics of a hydrogenated cyclopentane polyhydrophenanthrene ring system. Naturally occurring corticosteroids are typically produced by the adrenal cortex. Synthetic corticosteroids may be halogenated. Functional groups required for activity include double bonds at the Δ 4 position, C3 ketones, and C20 ketones. Corticosteroids may have glucocorticoid and/or mineralocorticoid activity. In a preferred embodiment, the corticosteroid is prednisolone. Exemplary corticosteroids are 11- α, 17- α, 21-trihydroxypregn-4-ene-3, 20-dione; 11- β, 16- α, 17, 21-tetrahydroxypregn-4-ene-3, 20-dione; 11- β, 16- α, 17, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione; 11- β, 17- α, 21-trihydroxy-6- α -methylpregn-4-ene-3, 20-dione; 11-dehydrocorticosterone; 11-deoxycorticosterol; 11-hydroxy-1, 4-androstadiene-3, 17-dione; 11-ketotestosterone; 14-hydroxyandrost-4-ene-3, 6, 17-trione; 15, 17-dihydroxyprogesterone; 16-methylcorticosterol; 17, 21-dihydroxy-16- α -methylpregna-1, 4, 9(11) -triene-3, 20-dione; 17- α -hydroxypregn-4-ene-3, 20-dione; 17-alpha-hydroxypregnanolone; 17-hydroxy-16-beta-methyl-5-beta-pregn-9 (11) -ene-3, 20-dione; 17-hydroxy-4, 6, 8(14) -gestriene-3, 20-dione; 17-hydroxypregna-4, 9(11) -diene-3, 20-dione; 18-hydroxycorticosterone; 18-hydroxy cortisone; 18-oxocortisol; 21-acetoxypregnenolone; 21-deoxyaldosterone; 21-deoxycorticosterone; 2-deoxyecdysone; 2-methyl cortisone; 3-dehydroecdysone; 4-pregnene-17-alpha, 20-beta, 21-triol-3, 11-dione; 6, 17, 20-trihydroxypregn-4-en-3-one; 6-alpha-hydroxycortinol; 6-alpha-methylprednisolone, 6-alpha-methylprednisolone-21-acetate, 6-alpha-methylprednisolone 21 sodium hemisuccinate, 6-beta-hydroxycortinol, 6-alpha, 9-alpha-diflupredone 21-acetate 17-butyrate and 6-hydroxycorticosterone; 6-hydroxydexamethasone; 6-hydroxy prednisolone; 9-flucortisone; alclometasone dipropionate; aldosterone; alestrol; alphaderm; amadone; amcinonide; anagesterone; androstenedione; anecortave acetate; beclomethasone; beclomethasone dipropionate; betamethasone 17-valerate; betamethasone sodium acetate; betamethasone sodium phosphate; betamethasone valerate; (ii) a dehydroepiandrosterone; budesonide; (ii) carpoterone; chlormadinone; prednisone; prednisolone acetate; cholesterol; ciclesonide; clobetasol; clobetasol propionate; clobetasol; (ii) a chlorocortolone; (ii) clocortolone valerate; progesterone chloride; (ii) prednisolone; corticosterone; cortisol; cortisol acetate; cortisol butyrate; cortisol cyclopentanepropionate; cortisol caprylate; cortisol sodium phosphate; cortisol sodium succinate; cortisol valerate; cortisone; cortisone acetate; (ii) a kovar; trutodo pine; daturalone (daturaolone); deflazacort, 21-deoxycorticosterol, dehydroepiandrosterone; demegestone; deoxycorticosterone; diprosone; a delphinidin derivative; (ii) donepezil; dexamethasone oxychloride (desoximethasone); dexafen; dexamethasone; dexamethasone 21-acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichloro pine; diflorasone; diflorasone diacetate; diflucortolone; difluprednate; dihydromomordica picrin a (dihydroelathericin a); a polyprednisole ester; a polypetaxole; ecdysone; ecdysterone; emoxolone; emthylosol; glycyrrhetinic acid; fluzacort; flucinolone; dichlorofluocinon; fludrocortisone; fludrocortisone acetate; fluoprogesterone; diflunisal; diflunisal pivalate; (ii) flumonade; flunisolide; fluocinolone (fluocinolone); fluocinolone acetonide (fluocinolone acetonide); fluocinonide (fluocinonide); a fluorocyclobutane group; 9-flucortisone; fluocortolone; (ii) fluoro hydroxyandrostenedione; fluorometholone; fluorometholone acetate; fluoxymesterone; fluoropolyether acetate; fluprednidene; fluprednidone; fluoro-hydrogen shrinkage; fluticasone; fluticasone propionate; formylboxolone; 2, fulvestrant; formocortah; pregnenolone; glyderinine; halcinonide; halobetasol propionate; halometasone; prednisone halide; a haloprogesterone; a hydrocortisone ester; hydrocortisone cypionate; hydrocortisone; hydrocortisone 21-butyrate; hydrocortisone acetate propionate; hydrocortisone acetate; hydrocortisone dipropionate; hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisuccinate; hydrocortisone propylbutyl ester (hydrocortisone probutate); hydrocortisone sodium phosphate; hydrocortisone sodium succinate; hydrocortisone valerate; hydroxyprogesterone; achyranthes bidentata sterone; isoflupredone; isoflupredone acetate; isoprednisone; loteprednol etabonate; (ii) meclosone; prednisolone valerate; medroxyprogesterone; medroxyprogesterone; (ii) medroxyprogesterone; megestrol; megestrol acetate; melengestrol; methylprednisolone; 1, meperidinone; methylprednisolone; methylprednisolone aceponate; methylprednisolone acetate; methylprednisolone hemisuccinate; methylprednisolone sodium succinate; methyltestosterone; metrobolone; mometasone; mometasone furoate; mometasone furoate monohydrate; 1-limonene (nisone); nomegestrol; norgestimate; (ii) a ketene dimer; hydroxymethyltestosterone; (ii) a palatasone; a parehasone acetate; a linasterone; prednisolone ester; prednisolone ester; prednisolone; prednisolone 21-diethylaminoacetate; prednisolone 21-hemisuccinate; prednisolone acetate; prednisolone farnesoate; prednisolone hemisuccinate; prednisolone 21(β -D-glucuronide); prednisolone metasenesulfonate; prednisolone sodium phosphate; prednisolone stearoyl glycolate; prednisolone tert-butyl acetate; prednisolone tetrahydrophthalate; prednisone; prednisolone valerate; prednisolone; pregnenolone; pracinonide; (ii) trilonene; progesterone; promegestrol; rhapontigenin; rimexolone; luoxibolone; amaranthone; stilzophyllin; alternative cortisone; tropanone; triamcinolone acetonide; triamcinolone acetonide; triamcinolone acetonide 21-palmitate; triamcinolone acetonide; triamcinolone diacetate; triamcinolone acetonide hexa; trimegestone; tacrolidone; and wortmannin. Desirably, the corticosteroid is prednisolone.

By "acidic beadlets" is meant beadlets having an acidic core which, when exposed to the intestine (gut), lowers the local pH sufficiently for the dipyridamole to dissolve. The acid beads may contain fumaric acid, malic acid, tartaric acid, citric acid, succinic acid and/or ascorbic acid. In a preferred embodiment, the acid beads are tartaric acid beads. Acid beads coated with dipyridamole are described in us patents 4,361,546 and 4,367,217.

By "effective amount" is meant the amount of a compound in the combination of the invention required for the treatment or prevention of an immunoinflammatory disorder. The effective amount of the active compound for use in the practice of the present invention in the therapeutic treatment of a condition caused by or contributing to an inflammatory disorder will vary depending on the mode of administration, the immunoinflammatory disorder being treated, the age, weight and general health of the patient. At the end of this period, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amounts are considered to be effective amounts.

By "equivalent, equivalent amount" is meant the amount of corticosteroid that produces the same anti-inflammatory effect in the patient as the recited dose of prednisolone.

By "immediate release" is meant that the therapeutically active component (e.g., corticosteroid) is released from the formulation immediately after oral administration such that 80%, 85%, 90%, or even 95% of the component in the formulation is absorbed into the patient's bloodstream in less than two hours. Whether a pharmaceutical composition is formulated for immediate release can be determined by measuring the pharmacokinetic properties of the formulation.

By "controlled release" is meant that the therapeutically active component is released from the formulation over a predetermined period of time, such that at a given dose, C is compared to the same dose of the therapeutically active component formulated for immediate release_maxIs reduced. In controlled release formulations, T_maxAnd may or may not be changed.

The term "pharmaceutically acceptable salt" denotes salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base groups with a suitable organic acid. Representative acid addition salts include acetate, ascorbate, aspartate, benzoate, citrate, digluconate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, lactate, malate, maleate, malonate, methanesulfonate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, valerate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The terms "unit dosage form" and "unit dosage formulation" refer to physically discrete units suitable as unitary dosages, for example, pills, tablets, caplets, hard or soft gelatin capsules, each unit containing a predetermined amount of dipyridamole and/or corticosteroid.

As used herein, the term "homogeneous beadlets" refers to a beadlet formulation that includes dipyridamole distributed throughout the beadlets along with other pharmaceutically acceptable excipients (e.g., diluents and binders). Homogeneous beads may be prepared as described in the examples.

As used herein, the term "coated" refers to a bead formulation that includes a corticosteroid, such as prednisolone, applied to the surface of a carrier, such as a non-pareil seed or tartaric acid bead. The coated beads may be prepared as described in the examples.

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

Drawings

Fig. 1 is a flow chart describing the process of preparing prednisolone beads.

Fig. 2 is a flow diagram depicting a process for the preparation of dipyridamole beadlets.

Fig. 3A and 3B are flow charts depicting the process for preparing hydroxypropyl methylcellulose phthalate 55-coated dipyridamole beads.

FIGS. 4A and 4B are diagrams describing SureleaseA flow chart of a process for preparing HPMC E5-coated dipyridamole beads.

FIGS. 5A and 5B are diagrams describing EudragitL100∶EudragitS100 flow chart of process for the preparation of coated dipyridamole beads.

Fig. 6 is a flow diagram depicting a process for preparing dipyridamole/prednisolone capsules.

FIG. 7 is a graph showing the percent drug release as a function of time for a controlled release formulation (variants B-D). These data show that differences in the controlled release coatings result in differences in the drug release characteristics.

Fig. 8 is a graph showing the in vitro dissolution profiles of dipyridamole from formulation variants D1 and D2.

Figure 9 is a graph showing the in vitro dissolution profile of prednisolone from formulation variants E and F.

Detailed Description

The invention provides pharmaceutical compositions in unit dosage form comprising dipyridamole, optionally together with a corticosteroid. The compositions are useful for treating, for example, immunoinflammatory disorders. Several formulations are known and described in the examples (example 1 (variant B), example 2 (variant C), example 3 (variant D), example 4 (variant D1), example 5 (variant D2), example 6 (variant E), example 7 (variant F)).

Corticosteroids

The combinations of the invention comprise a corticosteroid selected from the group of selective glucocorticoid receptor agonists (SEGRAs) including, but not limited to, 11-alpha, 17-alpha, 21-trihydroxy-4-pregnene-3, 20-dione; 11- β, 16- α, 17, 21-tetrahydroxy-4-pregnene-3, 20-dione; 11- β, 16- α, 17, 21-tetrahydroxy-1, 4-pregnadiene-3, 20-dione; 11- β, 17- α, 21-trihydroxy-6- α -methyl-4-pregnene-3, 20-dione; 11-dehydrocorticosterone; 11-deoxycorticosterol; 11-hydroxy-1, 4-androstadiene-3, 17-dione; 11-ketotestosterone; 14-hydroxyandrost-4-ene-3, 6, 17-trione; 15, 17-dihydroxyprogesterone; 16-methyl hydrocortisone; 17, 21-dihydroxy-16- α -methylpregna-1, 4, 9(11) -triene-3, 20-dione; 17- α -hydroxypregn-4-ene-3, 20-dione; 17-alpha-hydroxypregnanolone; 17-hydroxy-16-beta-methyl-5-beta-pregn-9 (11) -ene-3, 20-dione; 17-hydroxy-4, 6, 8(14) -gestriene-3, 20-dione; 17-hydroxypregna-4, 9(11) -diene-3, 20-dione; 18-hydroxycorticosterone; 18-hydroxy cortisone; 18-oxocortisol; 21-acetoxypregnenolone; 21-deoxyaldosterone; 21-deoxycorticosterone; 2-deoxyecdysone; 2-methyl cortisone; 3-dehydroecdysone; 4-pregnene-17-alpha, 20-beta, 21-triol-3, 11-dione; 6, 17, 20-trihydroxypregn-4-en-3-one; 6-alpha-hydroxycortinol; 6-alpha-methylprednisolone, 6-alpha-methylprednisolone-21-acetate, 6-alpha-methylprednisolone-21 sodium hemisuccinate, 6-beta-hydroxycortinol, 6-alpha, 9-alpha-diflupredone 21-acetate 17-butyrate and 6-hydroxycorticosterone; 6-hydroxydexamethasone; 6-hydroxy prednisolone; 9-flucortisone; alclometasone dipropionate; aldosterone; alestrol; alphaderm; amadone; amcinonide; anagesterone; androstenedione; anecortave acetate; beclomethasone; beclomethasone dipropionate; betamethasone 17-valerate; betamethasone sodium acetate; betamethasone sodium phosphate; betamethasone valerate; (ii) a dehydroepiandrosterone; budesonide; (ii) carpoterone; chlormadinone; prednisone; prednisolone acetate; cholesterol; ciclesonide; clobetasol; clobetasol propionate; clobetasol; (ii) a chlorocortolone; (ii) clocortolone valerate; progesterone chloride; (ii) prednisolone; corticosterone; cortisol; cortisol acetate; cortisol butyrate; cortisol cyclopentanepropionate; cortisol caprylate; cortisol sodium phosphate; cortisol sodium succinate; cortisol valerate; cortisone; cortisone acetate; (ii) a kovar; trutodo pine; daturalone (daturaolone); deflazacort, 21-deoxycorticosterol, dehydroepiandrosterone; demegestone; deoxycorticosterone; diprosone; a delphinidin derivative; (ii) donepezil; dexamethasone oxychloride (desoximethasone); dexafen; dexamethasone; dexamethasone 21-acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichloro pine; diflorasone; diflorasone diacetate; diflucortolone; difluprednate; dihydromomordica picrin a (dihydroelathericin a); a polyprednisole ester; a polypetaxole; ecdysone; ecdysterone; emoxolone; emthylosol; glycyrrhetinic acid; fluzacort; flucinolone; dichlorofluocinon; fludrocortisone; fludrocortisone acetate; fluoprogesterone; diflunisal; diflunisal pivalate; (ii) flumonade; flunisolide; fluocinolone (fluocinolone); fluocinolone acetonide (fluocinolone acetonide); fluocinonide (fluocinonide); a fluorocyclobutane group; 9-flucortisone; fluocortolone; (ii) fluoro hydroxyandrostenedione; fluorometholone; fluorometholone acetate; fluoxymesterone; fluoropolyether acetate; fluprednidene; fluprednidone; fluoro-hydrogen shrinkage; fluticasone; fluticasone propionate; formylboxolone; 2, fulvestrant; formocortah; pregnenolone; glyderinine; halcinonide; halobetasol propionate; halometasone; prednisone halide; a haloprogesterone; a hydrocortisone ester; hydrocortisone cypionate; hydrocortisone; hydrocortisone 21-butyrate; hydrocortisone acetate propionate; hydrocortisone acetate; hydrocortisone dipropionate; hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisuccinate; hydrocortisone propionate; hydrocortisone sodium phosphate; hydrocortisone sodium succinate; hydrocortisone valerate; hydroxyprogesterone; achyranthes bidentata sterone; isoflupredone; isoflupredone acetate; isoprednisone; loteprednol etabonate; (ii) meclosone; prednisolone valerate; medroxyprogesterone; medroxyprogesterone; (ii) medroxyprogesterone; megestrol; megestrol acetate; melengestrol; methylprednisolone; 1, meperidinone; methylprednisolone; methylprednisolone aceponate; methylprednisolone acetate; methylprednisolone hemisuccinate; methylprednisolone sodium succinate; methyltestosterone; metrobolone; mometasone; mometasone furoate; mometasone furoate monohydrate; 1-limonene (nisone); nomegestrol; norgestimate; (ii) a ketene dimer; hydroxymethyltestosterone; (ii) a palatasone; a parehasone acetate; a linasterone; prednisolone ester; prednisolone ester; prednisolone; prednisolone 21-diethylaminoacetate; prednisolone 21-hemisuccinate; prednisolone acetate; prednisolone farnesoate; prednisolone hemisuccinate; prednisolone-21 (β -D-glucuronide); prednisolone metasenesulfonate; prednisolone sodium phosphate; prednisolone stearoyl glycolate; prednisolone tert-butyl acetate; prednisolone tetrahydrophthalate; prednisone; prednisolone valerate; prednisolone; pregnenolone; pracinonide; (ii) trilonene; progesterone; promegestrol; rhapontigenin; rimexolone; luoxibolone; amaranthone; stilzophyllin; alternative cortisone; tropanone; triamcinolone acetonide; triamcinolone acetonide; triamcinolone acetonide 21-palmitate; triamcinolone acetonide; triamcinolone diacetate; triamcinolone acetonide hexa; trimegestone; tacrolidone; and wortmannin.

The standard recommended dosages for the different steroid/disease combinations are given in table 1 below, as follows.

TABLE 1 Standard recommended corticosteroid dosages

Other standard recommended dosages for corticosteroids are provided, for example, in the diagnostic & therapeutic merck manual (17 th edition MH Beers et al merck corporation) and in the physician's case reference 2003 (57 th edition Medical Economics Staff et al, Medical Economics co., 2002). In one embodiment, the dose of corticosteroid administered is a dose that is equivalent to the dose of prednisolone as defined herein. For example, a low dose of corticosteroid can be considered a dose comparable to a low dose of prednisolone. Two or more corticosteroids may be administered in the same treatment.

Equivalent potency (equivalent potency) in clinical doses is known and information relating to the dose equivalent to corticosteroid can be found in the British National Formulary (BNF), 37, month 3 1999, the contents of which are incorporated herein by reference.

The BNF guidelines are contained in table 2 below. More specifically, the dosages of corticosteroids provided in table 2 correspond to 5mg of prednisolone administered in accordance with the methods of the present invention and to 1mg of prednisolone administered in accordance with the methods of the present invention.

TABLE 2 equivalent dosages of prednisolone

Medicine	Equal to 5mg prednisolone	Equal to 1mg prednisolone
			Betamethasone	750μg	150μg
Cortisone acetate	25mg	5mg
			Deflazacort	6mg	1.2mg
Dexamethasone	750μg	150μg
			Hydrocortisone	20mg	4mg
Methylprednisolone	4mg	0.8mg
			Triamcinolone acetonide	4mg	0.8mg

From the clinical dose equivalence (BNF 37 at 3 months 1999), it is known that the nasal (110. mu.g, 100. mu.g and 200. mu.g) doses of triamcinolone, fluticasone and budesonide are approximately similar.

The two or more corticosteroids may be administered in the same therapy, or may be present in the same kit or unit dosage formulation.

Dipyridamole

The invention features unit dosage forms of dipyridamole between 20 and 400mg (e.g., 20, 30, 45, 90, 120, 180, 360, or 400 mg). These doses can be formulated for controlled release (e.g., delayed release and sustained release) or immediate release using the methods and compositions described herein.

Preparation

The combination of the invention may optionally be administered as a pharmaceutically acceptable salt, for example a non-toxic acid addition salt or a metal complex, as is commonly used in the pharmaceutical industry. Examples of the acid addition salts include organic acids such as acetic acid, lactic acid, pamoic acid, maleic acid, citric acid, malic acid, ascorbic acid, succinic acid, benzoic acid, palmitic acid, suberic acid, salicylic acid, tartaric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid and the like; polymeric acids such as tannic acid, carboxymethyl cellulose, and the like; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. The metal complex includes zinc, iron, and the like.

Formulations for oral use include tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, preferably from the GRAS catalogue. These excipients may be, for example, inert diluents or fillers (e.g. sucrose and sorbitol), lubricants, glidants and antiadherents (e.g. magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oils or talc).

Formulations for oral use may also be presented as unit dosage forms, such as chewable tablets, caplets or capsules (e.g., hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium).

The formulations of the present invention include diluents (e.g., lactose monohydrate, cellulose, glyceryl monostearate and/or dibasic calcium phosphate and others) and binders (e.g., polyvinylpyrrolidone, hypromellose, sucrose, guar gum and/or starch). Any diluent or binder known in the art may be used in the methods, compositions, and kits of the present invention.

The formulations of the present invention may also include a controlled release coating. Such coatings include EUDRAGIT RLEUDRAGIT RSCellulose derivatives such as aqueous ethylcellulose dispersions (AQUACOAT)SURELEASE) Hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone/vinyl acetate copolymer and OPADRY

Medicament box

The individually or separately formulated agents of the present invention may be packaged together or separately as a kit. Non-limiting examples include kits comprising, for example, two pills, pills and capsules, capsules comprising a plurality of bead formulations, and the like. In addition, the unit dosage kit may contain instructions for preparing and administering the composition.

The kit can be prepared as a single unit dose for one patient, for multiple uses for a particular patient (at a fixed dose or where individual compounds may vary in potency as the treatment progresses); or the kit may contain multiple doses ("bulk packaging") suitable for administration to multiple patients. The components of the kit may be assembled into cartons, blister packs, bottles, tubes, and the like. The kit may further comprise instructions to administer the pharmaceutical composition using any of the indications and/or dosage regimens described therein. Further description of the kit is provided in the examples.

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are carried out, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

Pharmaceutical product

Dipyridamole and prednisolone were formulated in bead form and encapsulated in standard '0' capsules. Six different capsule sizes (strength) were prepared to accommodate the administration of different amounts of prednisolone in the morning and midday, and to allow for dose adjustments. A dosage regimen comprising 1.8mg prednisolone +180mg dipyridamole at 0800 hours followed by 0.9mg prednisolone +180mg dipyridamole at 1300 hours has been shown to be effective in Rheumatoid Arthritis (RA) and Osteoarthritis (OA) subjects. In this previous study both active ingredients were formulated for immediate release. The specifications are shown in table 3.

TABLE 3 amounts of prednisolone and dipyridamole in capsules

The quantitative composition of the capsules is given in tables 4 and 5, wherein the first table gives the quantitative composition of three dosage specifications containing 0.9mg prednisolone and different amounts of dipyridamole, and the second table gives the quantitative composition of three dosage specifications containing 1.8mg prednisolone.

TABLE 4 composition of pharmaceutical dosage forms containing 0.9mg prednisolone

^bIs removed in the process

Abbreviations: EP ═ european pharmacopeia; NF is the national formulary; QS is sufficient; USP ═ united states pharmacopeia

TABLE 5 composition of pharmaceutical dosage forms containing 1.8mg prednisolone

^bIs removed in the process

Preparation process

The process for the preparation of the formulations for the combination of the invention comprises three preparation steps followed by packaging: preparing prednisolone beads, preparing dipyridamole beads, preparing capsules and packaging.

Preparation process of prednisolone beads

Prednisolone beads were prepared by coating elite seeds with prednisolone. This process is described in more detail below and is schematically illustrated in fig. 1. PVP (Kollidon 30) was dissolved in purified water using a Lightnin' mixer or other similar mixer. Prednisolone is then added to the solution of PVP and water and mixed until a homogeneous suspension is formed. The super seeds of MCC (Celphere CP-708) were charged into the drum (bowl) of a fluidized bed coater and preconditioned to a temperature of 40-50 ℃ by bed flow. The prednisolone suspension was sprayed onto the flowing, preconditioned, best-fit seeds at a constant rate of-100 g/min to ensure that the beads did not clump due to over-wetting. Care was taken to ensure that a suitable spray rate was maintained in order to prevent prednisolone from being spray dried. The product bed temperature was maintained in the range of 40-50 ℃ by maintaining the inlet air temperature in the range of 60-70 ℃. Once the spray process was complete, the prednisolone-loaded beads were dried to a moisture content of less than 2%. The dried beads were discharged and screened through a #20 mesh screen to remove any clumps. The screened beads were stored at room temperature 25 ℃ (15 to 30 ℃) in fiberboard drums double-lined with polyethylene bags. The potency (assay) of the prednisolone beads was analyzed to determine the appropriate fill weight for preparing the capsules. Table 6 summarizes the quantitative composition of the prednisolone capsules.

TABLE 6 composition of prednisolone capsules

^bIs removed in the process

Preparation process of dipyridamole homogeneous beads

Dipyridamole beads were prepared by extrusion spheronization. The preparation process for the preparation of dipyridamole beadlets is described in more detail below and is schematically illustrated in fig. 2. Dipyridamole was screened using a vibratory mill equipped with a #20 mesh screen and transferred to the barrel of a high shear granulator. MCC, pregelatinized starch, and PVP were added sequentially to the vibratory mill to wash out any remaining dipyridamole. The milled material was transferred to the barrel of a high shear granulator where it was dry blended for 5 minutes. Moisture samples of the dry blends were taken for information only. The dry dipyridamole mixture was then wet granulated at a spray rate of 1200 g/min using purified water as granulating agent until a dough was formed. The sampling is used to determine the water content. The wet mass of dipyridamole dough was passed through an extruder with a 0.8mm screen and spheronized at 800 revolutions per minute (rpm) for approximately 7 minutes until round beads were formed. The wet beads were dried in an oven set at 60 ℃ until the moisture content was less than 1.4%. The dried beads were stored at room temperature at 25 ℃ (15-30 ℃) in fiberboard drums with polyethylene bag double liners. The final beads were analyzed for titer (assay) to determine the appropriate fill weight for the capsules. Table 7 summarizes the quantitative composition of the dipyridamole capsules.

TABLE 7 composition of capsules comprising dipyridamole homogeneous beads

^bIs removed in the process

Preparation process of dipyridamole coated beads

Controlled release Dipyridamole (DP) beads are featured. Examples of such beadlets include tartaric acid beadlets coated with dipyridamole (e.g., a 1: 0.8 ratio of dipyridamole to tartaric acid). The beads are further coated with a controlled release coating. Suitable materials for the release control layer include EUDRAGIT RLEUDRAGIT RSCellulose derivatives such as aqueous ethylcellulose dispersions (AQUACOAT)SURELEASE) Hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone/vinyl acetate copolymer and OPADRYExamples of preparation processes for producing dipyridamole-coated acid beads (e.g. tartaric acid beads) are given in the examples below.

Capsule preparation process

The capsule preparation process is described below and schematically illustrated in fig. 6. The fill weight of each capsule was calculated based on the percent weight/weight effect values of prednisolone and dipyridamole beads. The amount of each type of bead for the desired numbered capsules was weighed and added to the Bosch GKF 400 capsule machine with empty capsules. Prednisolone and dipyridamole beads were filled into "0" gray/gray capsules. During the capsule-sealing process, the filling weight of the capsule is checked for changes at predetermined intervals and the capsule is sealed at appropriate times. If any deviation is found in the determined fill weight, the machine is adjusted. The filled capsules were stored at room temperature 25 ℃ (15-30 ℃) in fiberboard drums with polyethylene bag double liner. The final capsules were tested before shipment for the characteristics of the active ingredient, the potency of prednisolone and dipyridamole, the uniformity of content, dissolution rate, presence and amount of related substances and bioburden.

Package (I)

Dipyridamole/prednisolone capsules were packaged in blisters using an Uhlman packaging machine. The batches of capsules are placed on a tray of a Uhlman packer for overflow filling into blister cavities. The sealing layer was placed on each strip containing five capsules and heat sealed. The sealed strip was checked at the beginning and end of the process and every 30 minutes in the process for proper sealing and missing cavities, and if found satisfactory placed in the labeled holding container. The preservation container is placed in a warehouse for secondary packaging.

Example 1: variant B

The components used to prepare the dipyridamole beads with a controlled release coating of hydroxypropyl methylcellulose phthalate 55 are given in tables 8-11 (variation B). This manufacturing process is schematically depicted in fig. 3 and described in more detail below.

Preparation of Cellets or phthalate from coating solution consisting of tartaric acid, Pharmacoat 603, isopropanol and water^*hthalate) seed was subjected to fluid bed coating. Layering was continued until a total of 89.1% w/w tartaric acid was loaded onto the core. The 89.1% tartaric acid pellets were then coated in a fluidized bed with a protective seal coating consisting of Kollidon 30, talc, isopropanol and water to a 20% weight gain level.

Drug loading

A dispersion consisting of dipyridamole, Kollidon 30 and water was sprayed onto the seal-coated tartaric acid cores using a fluidized bed. The amount sprayed onto these cores was allowed to be 1: 0.8 (dipyridamole: tartaric acid) final ratio.

Modified release coating

A coating solution consisting of hydroxypropylmethylcellulose phthalate 55(HPMC P-55), triethyl citrate, ethanol and water was sprayed onto the dipyridamole-coated pellets. The theoretical weight gain of the modified release coating sprayed onto DP pellets was 20%. The coated pellets were then cured in a tray drying oven at 40 ℃ for 2 hours.

Scheme(s)

The following is an exemplary protocol for making hydroxypropyl methylcellulose phthalate 55 coated beads.

Preparation of drug dispersions

Kollidon 30 was dissolved in isopropanol using an overhead stirrer under vortexing to obtain a clear solution. Dipyridamole (passed through a #40 mesh screen) was dispersed in the above solution to obtain a homogeneous suspension. The suspension was filtered through a #60 mesh screen. A fluidized bed processor having a bottom spray and a wurster column was prepared. The hermetically coated tartaric acid beads were loaded onto wurster. The dipyridamole suspension was sprayed onto the tartaric acid beads using a peristaltic pump at the desired spray rate. Ensure that the suspension remains stirred throughout the coating process. Tartaric acid beads were coated with the drug suspension. After spraying is complete, the beads with the drug layer are dried in a fluidized bed.

Preparation of delayed Release coating suspensions

HPMC P-55 was dissolved in a mixture of ethanol and purified water using an overhead stirrer under vortex stirring. Triethyl citrate was added and the solution was stirred for 20 minutes. The solution was passed through a #80 mesh screen and used for coating.

Delayed release coating

A fluidized bed processor having a bottom spray and a wurster column was prepared. Drug-loaded beads were loaded into wurster. The polymer solution was sprayed onto the drug-loaded beads using a peristaltic pump at the desired spray rate. Ensure that the coating solution is stirred throughout the coating process. The polymer coated beads were dried and treated for 2 hours.

TABLE 8 auxiliary materials

^*Included in the process, but not in the final product

TABLE 9 amount of compound per capsule

		Amount per capsule (mg)
			I.	Drug loading

TABLE 10 percent weight of bead component

TABLE 11 percent weight of delayed release coating

Example 2: variant C

The components used to prepare dipyridamole beadlets with Sure are given in tables 12-14 (variation C)leaseAnd a controlled release coating of HPMC E5 (in a ratio of 80: 20). The manufacturing process is schematically depicted in fig. 4 and described in more detail below.

Preparation begins with fluid bed coating of the celets with a coating solution consisting of tartaric acid, Pharmacoat 603, isopropanol, and water. Layering was continued until a total of 89.1% w/w tartaric acid was loaded onto the core. Subsequently, 89.1% tartaric acid pellets were coated in a fluidized bed with a protective seal coating consisting of Kollidon 30, talc, isopropanol and water to a level of 20% weight gain.

Drug loading

Modified release coating

Will be expressed by SureleaseA coating solution of HPMC E5 (80: 20), glycerol and water was sprayed onto the dipyridamole-coated pellets. The theoretical weight gain of the modified release coating sprayed onto DP pellets was 15%. The coated pellets were then dried and cured for 2 hours.

Scheme(s)

Kollidon 30 was dissolved in isopropanol using an overhead stirrer under vortexing to obtain a clear solution. Dipyridamole (passed through a #40 mesh screen) was dispersed in the above solution to obtain a homogeneous suspension. The suspension was filtered through a #60 mesh screen. A fluidized bed processor having a bottom spray and a wurster column was prepared. The hermetically coated tartaric acid beads were loaded onto wurster. The dipyridamole suspension was sprayed onto the tartaric acid beads using a peristaltic pump at the desired spray rate. Ensure that the suspension remains stirred throughout the coating process. After spraying is complete, the beads with the drug layer are dried in a fluidized bed.

Preparation of modified Release coating suspensions

HPMC E5 was dissolved in water at 60-70 deg.C using an overhead stirrer. The solution was cooled until it reached room temperature and glycerol was added with stirring. The solution was diluted to the concentration required for Surelease by adding water. The solution was passed through a #80 mesh screen and used for coating. The solution was stirred continuously throughout the coating process, and the coated beads were dried and treated for 2 hours.

TABLE 12 adjuvants

^*Included in the process, but not in the final product

TABLE 13 amount of compound per capsule

4.	Ethyl cellulose	27.97
			5.	Hydroxypropyl methylcellulose 5 centipoise	7.0
6.	Glycerol	0.53
				Total up to	272.00

TABLE 14 percent weight of delayed release coating

Example 3: variant D

The components used to prepare dipyridamole beadlets with Eudragit are given in tables 15-17 (variation D)S100 and EudragitL100 (in a ratio of 75: 25). This manufacturing process is schematically depicted in fig. 5 and described in more detail below.

Preparation the fluidized bed coating of the Cellets was started using a coating solution consisting of tartaric acid, Pharmacoat 603, isopropanol and water. Layering (layering) was continued until a total of 89.1% w/w tartaric acid was loaded onto the core. The 89.1% tartaric acid pellets were then coated in a fluidized bed with a protective seal coating consisting of Kollidon 30, talc, isopropanol and water to a level of 20% weight gain.

Drug loading

A dispersion consisting of dipyridamole, Kollidon 30 and water was sprayed onto the seal-coated tartaric acid cores using a fluidized bed. The amount sprayed onto this core was allowed to be 1: 0.8 (dipyridamole: tartaric acid) final ratio.

Modified release coating

Will be composed of EudragitS100∶EudragitL100 (75: 25), triethyl citrate, talc, isopropanol and water were sprayed onto the dipyridamole-layered pellets. The theoretical weight gain of the modified release coating sprayed onto DP pellets was 20%. The coated pellets were then cured in a tray drying oven at 40 ℃ for 2 hours.

Scheme(s)

The following is used to prepare EudragitS100∶EudragitL100 (75: 25) exemplary protocol for coating beads.

Preparation of drug dispersions

Kollidon 30 was dissolved in isopropanol using an overhead stirrer under vortexing to obtain a clear solution. Dipyridamole (passed through a #40 mesh screen) was dispersed in the above solution to obtain a homogeneous suspension. The suspension was filtered through a #60 mesh screen. A fluidized bed processor having a bottom spray and a wurster column was prepared. The hermetically coated tartaric acid beads were loaded onto wurster. The dipyridamole suspension was sprayed onto the tartaric acid beads using a peristaltic pump at the desired spray rate. Ensure that the suspension remains stirred throughout the coating process. After the spraying was finished, the beads were dried in a fluidized bed.

Preparation of modified Release coating suspensions

Eudragit is transferred using a top stirrerL100 and EudragitS100 was dissolved in isopropanol. Purified water was added to the suspension and stirred to obtain a clear solution. Triethyl citrate and talc were added to the above solution under stirring. Pass through a #80 mesh screen and are used for coating. The coating solution was stirred continuously throughout the coating process. The coated beads were dried and treated for 2 hours.

TABLE 15 adjuvants

^*Included in the process, but not in the final product

TABLE 16 amount of compound per capsule

TABLE 17 percent weight of delayed release coating

Example 4: variant D1

The components used to prepare dipyridamole beads, which are given in tables 18-20 (variation D1), areThe granule carries EudragitS100 and EudragitL100 (in a ratio of 75: 25). The preparation process is described in more detail below.

Drug loading

Modified release coating

Will be composed of EudragitS100∶EudragitL100 (75: 25), triethyl citrate, talc, isopropanol and water were sprayed onto the dipyridamole-layered pellets. The theoretical weight gain of the modified release coating sprayed onto DP pellets was 10%. The coated pellets were then cured in a tray drying oven at 40 ℃ for 2 hours.

Scheme(s)

Preparation of drug dispersions

Kollidon 30 was dissolved in isopropanol using an overhead stirrer under vortexing to obtain a clear solution. Dipyridamole was dispersed in the above solution to obtain a homogeneous suspension. The suspension was filtered through a #100 mesh screen. A fluidized bed processor having a bottom spray and a wurster column was prepared. The hermetically coated tartaric acid beads were loaded onto wurster. The dipyridamole suspension was sprayed onto the tartaric acid beads using a peristaltic pump at the desired spray rate. Ensure that the suspension remains stirred throughout the coating process. After the spraying was finished, the beads were dried in a fluidized bed.

Preparation of modified Release coating suspensions

Eudragit is transferred using a top stirrerL100 and EudragitS100 was dispersed in water and 90% isopropyl alcohol. Purified water was added to the suspension and stirred to obtain a clear solution. Triethyl citrate was added to the suspension and mixed for at least 15 minutes. Water, 10% isopropanol and talc were added in separate containers and then homogenized for 10 minutes to form a dispersion. The talc dispersion and Eudragit solution were combined and mixed for at least 30 minutes before coating. The coating solution was stirred continuously throughout the coating process. The coated beads were dried and treated for 2 hours.

TABLE 18 adjuvants

Auxiliary materials	Chemical name	Function(s)
			Dipyridamole	-	API
Kollidon 30	Polyvinylpyrrolidone	Non-functional coating/binding agent
			Cellets	Microcrystalline cellulose spheres	Seeds of best quality
Tartaric acid	-	Solubilizer

^*Included in the process, but not in the final product

TABLE 19 amount of compound per capsule

TABLE 20 percent weight of delayed release coating

Example 5: variant D2

The components used to prepare dipyridamole beadlets carrying Eudragit are given in tables 21-23 (variation D2)S100 and EudragitL100 (in a ratio of 75: 25). The preparation process is described in more detail below.

Preparation begins with fluid bed coating of the celets with a coating solution consisting of tartaric acid, Pharmacoat 603, isopropanol, and water. Layering was continued until a total of 89.1% w/w tartaric acid was loaded onto the core. Subsequently, 89.1% tartaric acid pellets were coated in a fluidized bed with a protective seal coat consisting of HPMC phthalate PH-55, triethyl citrate, isopropanol and acetone to a 15% weight gain level.

Drug loading

A dispersion consisting of dipyridamole, Kollidon 30 and isopropanol was sprayed onto the seal-coated tartaric acid cores using a fluidized bed. The amount sprayed onto this core was allowed to be 1: 0.8 (dipyridamole: tartaric acid) final ratio.

Modified release coating

Scheme(s)

Preparation of drug dispersions

Preparation of modified Release coating suspensions

TABLE 21 auxiliary materials

Isopropanol (I-propanol)^*	-	Solvent(s)
			Acetone (II)^*	-	Solvent(s)
Purified water^*	-	Solvent(s)

^*Comprises in the processBut not in the final product

TABLE 22 amount of compound per capsule

TABLE 23 percent weight of delayed release coating

Example 6: variant E (Co-filling capsule)

The components used to prepare the prednisolone beads carrying Eudragit are given in tables 24-26 (variation E)S100 and EudragitL100 (in a ratio of 75: 25). The preparation process is described in more detail below.

Drug loading

A fluid bed was used to spray a solution consisting of prednisolone, Kollidon 30 and water onto the Cellets. The amount sprayed onto this core allowed the final prednisolone amount to be 2.0%. Some 2.0% prednisolone pellets were set aside for use as the IR portion, and some were used for further processing to prepare the delayed release portion.

Sealing coating

A solution consisting of Kollidon VA-64, Pharmacoat 603 and water was sprayed onto the prednisolone coated pellets using a fluidized bed. The amount sprayed onto these cores allowed the final prednisolone amount to be 1.9%. Subsequently, the 1.9% prednisolone pellets were further coated with a delayed release coating.

Delayed release coating

Will be composed of EudragitS100∶EudragitA coating solution of L100 (75: 25), triethyl citrate, talc, isopropyl alcohol and water was sprayed onto the prednisolone layered pellets. The theoretical weight gain of the modified release coating sprayed onto DP pellets was 25%. The coated pellets were then cured in a tray drying oven at 40 ℃ for 8 hours.

Scheme(s)

Preparation of drug dispersions

Kollidon 30 was dissolved in water using an overhead stirrer under vortex conditions to obtain a clear solution. Prednisolone is dispersed in the above solution to obtain a solution. A fluidized bed processor having a bottom spray and a wurster column was prepared. The Cellets were loaded onto wurster. The prednisolone solution was sprayed onto the Cellets using a peristaltic pump at the desired spray rate. Ensure that the solution remains stirred throughout the coating process. And (3) drying: after the spraying was finished, the beads were dried in a fluidized bed.

Preparation of seal coating solution

Kollidon VA-64 was dissolved in water and isopropanol using an overhead stirrer under a vortex to obtain a clear solution. Pharmacoat 603 was dispersed in the above solution and mixed until dissolved. A fluidized bed processor having a bottom spray and a wurster column was prepared. The prednisolone coated pellets were loaded onto wurster. The seal coat solution was sprayed onto the prednisolone pellets using a peristaltic pump at the desired spray rate. Ensure that the solution remains stirred throughout the coating process. And (3) drying: after the spraying was finished, the beads were dried in a fluidized bed.

Preparation of modified Release coating suspensions

Eudragit is transferred using a top stirrerL100 and EudragitS100 was dispersed in water and 90% isopropyl alcohol. Purified water was added to the suspension and stirred to obtain a clear solution. Triethyl citrate was added and mixed for at least 15 minutes. Water, 10% isopropanol and talc were added in separate containers and then homogenized for 10 minutes to form a dispersion. The talc dispersion and Eudragit solution were combined and mixed for at least 30 minutes before coating. The coating solution was stirred continuously throughout the coating process. The coated beads were dried and treated for 8 hours.

TABLE 24 adjuvants

Purified water^*

-

Solvent(s)

^*Included in the process, but not in the final product

TABLE 25 amount of compound per capsule

TABLE 26 percent weight of delayed release coating

Example 7: variant F (Combined pill)

The components used to prepare the prednisolone beads carrying Eudragit are given in tables 27-29 (variation F)S100 and EudragitL100 (in a ratio of 75: 25). The preparation process is described in more detail below.

Drug loading

A fluid bed was used to spray a solution consisting of prednisolone, Kollidon 30 and water onto the Cellets. The amount sprayed onto this core allowed the final prednisolone amount to be 2.5%. The 2.5% prednisolone pellets were then further coated to include immediate release and delayed release functions.

Sealing coating

A solution consisting of Kollidon VA-64, Pharmacoat 603 and water was sprayed onto the prednisolone coated pellets using a fluidized bed. The amount sprayed onto these cores allowed the final prednisolone amount to be 2.4%. The 2.4% prednisolone pellets were then further coated to include immediate release and delayed release functions.

Delayed release coating

Will be composed of EudragitS100∶EudragitA coating solution consisting of L100 (75: 25), triethyl citrate, talc, isopropyl alcohol and water was sprayed onto the seal-coated prednisolone layered pellets. The theoretical weight gain of the modified release coating sprayed onto DP pellets was 25%. The coated pellets were then cured (cure) in a tray drying oven at 40 ℃ for 8 hours.

Second drug Loading

A fluid bed was used to spray a solution consisting of prednisolone, Kollidon 30 and water onto DR coated prednisolone pellets. The amount sprayed onto these cores allowed the final prednisolone amount to be a total of 5.4%.

Scheme(s)

The following is used to prepare EudragitS100∶EudragitL100(75∶25) Exemplary protocol for coating the beads.

Preparation of drug dispersions

Preparation of seal coating solution

Preparation of modified Release coating suspensions

Eudragit is transferred using a top stirrerL100 and EudragitS100 was dispersed in water and 90% isopropyl alcohol. Purified water was added to the suspension and stirred to obtain a clear solution. Triethyl citrate was added and mixed for at least 15 minutes. Water, 10% isopropanol and talc were added in a separate vessel and then homogenized for 10 minutes to form a dispersion. The talc dispersion and Eudragit solution were combined and mixed for at least 30 minutes before coating. The coating solution is continuously stirred throughout the coating process. Dry matterThe coated beads were dried and treated for 8 hours.

TABLE 27 adjuvants

^*Included in the process, but not in the final product

TABLE 28 amount of compound per capsule

TABLE 29 percent weight of delayed release coating

Example 8 dissolution Properties

Fig. 7 is a graph depicting dissolution characteristics of variants B, C and D. FIG. 8 is a graph depicting dissolution characteristics of variants D1 and D2. FIG. 9 is a graph depicting dissolution characteristics of variants E and F. All of which are measured in simulated media as described herein.

For the prototype of variant B, there was an average release of 20% dipyridamole in 0.1N HCl over the first two hours. The media was replaced at a two hour time point, where the prototype was added to media containing phosphate buffer ph6.8 with 0.25% SLS. During this phase, dipyridamole was released over a period of 6 hours

For the prototype of variant C, there was an average release of 80% dipyridamole in 0.1N HCl over the first two hours. The media was replaced at a two hour time point, where the prototype was added to media containing acetate buffer ph5.5 with 0.25% sodium dodecyl sulfate. At this stage dipyridamole was released over a period of 22 hours.

For the prototype of variant D, there was an average release of 39% dipyridamole in the first two hours in 0.1N HCl. The media was replaced at a two hour time point, where the prototype was added to media containing phosphate buffer ph6.8 with 0.25% sodium dodecyl sulfate. At this stage dipyridamole was released over a period of 6 hours.

Example 9 headache relief and absorption Rate reduction

We have found that the headache, a side effect of dipyridamole treatment, can be alleviated by decreasing the rate of increase to Cmax. To minimize the risk of headache, the release of dipyridamole in the administered dosage form is modified to reduce the absorption rate constant (ka) in vivo (e.g., to between 0.2 and 0.90 l/hr). For comparative reasons, dipyridamole formulated for immediate release had an absorption rate constant (ka) in the range of 1.19 and 1.54 l/hr. Formulations that can reduce the incidence of headache include, for example, variant D. These conclusions are based on the results of the clinical studies described below.

Clinical trial

This trial was an open label, balanced, randomized, quadruped, quadruplicate, four-phase, single dose, cross-comparative oral bioavailability study of immediate release and modified release dipyridamole 100mg capsules made by M/s. rubicon Research PVT Ltd, Mumbai, India for combatorx in normal, healthy, adult, human subjects after a normal breakfast.

The formulations tested in this study were:

t1: dipyridamole modification a-dipyridamole immediate release capsules 100mg (prescription code X) (one 100mg capsule given in a single dose in the morning for each treatment period);

t2: dipyridamole modified form B-modified release capsules (one 100mg capsule administered in a single dose in the morning per treatment period);

t3: dipyridamole modified form C-modified release capsules (one 100mg capsule given in a single dose in the morning per treatment period); and

t4: dipyridamole modified form D-modified release capsules (one 100mg capsule was administered in a single dose in the morning per treatment period).

Subjects fasted overnight for at least 10 hours before the scheduled time for normal breakfast (approximately 500 calories, described below); administration was 30 minutes after the start of breakfast. The food or dessert is provided 4, 8, 12, 24, 28, 32 and 48 hours after administration in each stage. At each stage, 17 blood samples were taken from each subject. Venous blood samples (5 mL each) were drawn before dosing (within one and a half hours before normal breakfast) and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0 and 48.0 hours after dosing.

Plasma samples were analyzed using a validated LC/MS bioanalytical method to quantify dipyridamole concentrations. The (Ka) values of the DP data for IR and modified release were evaluated using PK Solutions 2.0TM Noncompartmental pharmaceutical data analysis software from Summit Research Services, which fit the two-chamber kinetics with first order (first order) absorption and elimination (best described using a three-level exponential curve fit).

Normal breakfast

Administration was performed 30 minutes after eating the following normal breakfast.

Meal menu

Content of meal ID

Note: the proportional size of the food items may vary depending on the amount of added water during cooking

Other embodiments

All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Other implementations are within the scope of the following claims.

Claims

1. A method for treating an immunoinflammatory disorder in a subject in need thereof, the method comprising administering to the subject a unit dosage form comprising dipyridamole coated onto acid beads and formulated for controlled release.

2. The method of claim 1, wherein said dipyridamole is coated with a controlled release coating.

3. The method of claim 2Characterized in that said controlled release coating comprises hydroxypropyl methylcellulose phthalate 55, SureleaseHPMC E5 and EudragitL100∶EudragitS100。

4. The method of any one of claims 1-3, wherein said unit dosage form further comprises dipyridamole formulated for immediate release.

5. The method of any one of claims 1-4, wherein said unit dosage form comprises between 40 and 400mg dipyridamole.

6. The method of claim 5, wherein said unit dosage form comprises 45mg of dipyridamole.

7. The method of claim 5, wherein said unit dosage form comprises 90mg of dipyridamole.

8. The method of claim 5, wherein said unit dosage form comprises 180mg of dipyridamole.

9. The method of claim 5, wherein said unit dosage form comprises 360mg of dipyridamole.

10. The method of any one of claims 5-9, wherein 50% to 80% of said dipyridamole is formulated for controlled release and 20% to 50% of said dipyridamole is formulated for immediate release.

11. A process according to any one of claims 1 to 10, characterised in that the acid beads are tartaric acid beads.

12. The method of claim 11, wherein the ratio of dipyridamole to tartaric acid is 1: 0.8.

13. The method of any one of claims 1-12, wherein said unit dosage form is administered once or twice daily.

14. The method of any one of claims 1-13, further comprising administering a corticosteroid to the subject.

15. The method of claim 14, wherein said corticosteroid is administered in two doses.

16. The method of claim 15, wherein said first dose is administered in a unit dosage formulation comprising 1.5 to 2.5mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid, and said second dose is administered in a unit dosage formulation comprising 0.75 to 1.25mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid.

17. The method of claim 16, wherein said first dose is administered in a unit dosage formulation comprising 1.8mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid, and said second dose is administered in a unit dosage formulation comprising 0.9mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid.

18. The method according to any one of claims 14 to 17, characterized in that the corticosteroid is selected from the group consisting of prednisolone, prednisone, budesonide, methylprednisolone, fluticasone, betamethasone and deflazacort.

19. The method of claim 18, wherein said corticosteroid is prednisolone.

20. The method of any one of claims 15-19, wherein said first dose is administered when said subject wakes.

21. The method of any one of claims 15-20, wherein said second dose is administered to said subject 4 to 6 hours after said first dose.

22. A method according to any of claims 14 to 21, characterised in that the corticosteroid is formulated for immediate release.

23. The method according to any one of claims 14-21, characterized in that the corticosteroid is formulated for controlled release.

24. The method of any one of claims 15-17, characterized in that said first dose is administered in a unit dose formulation comprising 1.0 to 2.5mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid formulated for immediate release, and said second dose is administered in a unit dose formulation comprising 0.75 to 2.0mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid formulated for controlled release.

25. The method of claim 14, wherein said corticosteroid is formulated into a unit dosage form having a dissolution release profile that releases at least 50% of the corticosteroid within the first 30 minutes of testing under in vitro conditions using USP dissolution apparatus No.1 at 37 ℃ ± 0.5 ℃ and 100rpm for the first two hours in 0.1N HCl as a dissolution medium followed by a phosphate buffer ph6.8 as a medium.

26. The method of claim 1, wherein said dipyridamole is formulated into a unit dosage form having a dissolution release profile that releases at least 10-55% of dipyridamole within the first two hours and no less than 80% of dipyridamole within 8 hours tested under in vitro conditions using USP dissolution apparatus No.1 at 37 ℃ ± 0.5 ℃ and 100rpm for the first two hours in 0.1N HCl as a dissolution medium followed by a phosphate buffer at pH6.8 with 0.25% sodium lauryl sulfate as a medium.

27. The method of claim 1, wherein said dipyridamole is formulated in a unit dosage form having an absorption rate constant of from 0.20 to 0.90l/hr once administered to a fed patient.

28. A pharmaceutical composition in unit dosage form comprising dipyridamole coated on acid beads and formulated for controlled release.

29. The pharmaceutical composition of claim 28, wherein said acidic beads are tartaric acid beads.

30. The pharmaceutical composition of claim 28, wherein said dipyridamole is coated with a controlled release coating.

31. The pharmaceutical composition according to claim 30, wherein said controlled release coating comprises hydroxypropyl methylcellulose phthalate 55, SureleaseHPMC E5 and EudragitL100∶EudragitS100。

32. The pharmaceutical composition according to any one of claims 28-31, wherein said unit dosage form further comprises dipyridamole formulated for immediate release.

33. The pharmaceutical composition according to any one of claims 28-32, characterized in that said unit dosage form comprises between 40 and 400mg dipyridamole.

34. The pharmaceutical composition of claim 33, wherein said unit dosage form comprises 45mg of dipyridamole.

35. The pharmaceutical composition of claim 33, wherein said unit dosage form comprises 90mg of dipyridamole.

36. The pharmaceutical composition of claim 33, wherein said unit dosage form comprises 180mg of dipyridamole.

37. The pharmaceutical composition of claim 33, wherein said unit dosage form comprises 360mg of dipyridamole.

38. The pharmaceutical composition according to any one of claims 33-37, wherein 50% to 80% of said dipyridamole is formulated for controlled release and 20% to 50% of said dipyridamole is formulated for immediate release.

39. Pharmaceutical composition according to any of claims 28-38, characterised in that the unit dosage form further comprises 0.75 to 2.5mg of prednisolone formulated for immediate release or an equivalent, equivalent amount of an additional corticosteroid.

40. The pharmaceutical composition according to one of claims 28-39, characterized in that said unit dosage form further comprises 0.75 to 2.5mg of prednisolone formulated for controlled release or an equivalent, equivalent amount of an additional corticosteroid.

41. The pharmaceutical composition of claim 39, comprising 1.8mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid.

42. The pharmaceutical composition of claim 40, comprising 0.9mg of prednisolone or an equivalent, equivalent amount of an additional corticosteroid.

43. Pharmaceutical composition according to claim 39 or 40, characterized in that the corticosteroid is selected from the group consisting of prednisolone, prednisone, budesonide, methylprednisolone, fluticasone, betamethasone and deflazacort.

44. A pharmaceutical composition according to claim 39 or 40, characterised in that the corticosteroid is formulated as coated superior beadlets.

45. The pharmaceutical composition of any one of claims 28-38, characterized in that said unit dosage form further comprises 0.75 to 3.75mg of prednisolone, wherein 50% to 80% of said prednisolone is formulated for immediate release and 20% to 50% of said prednisolone is formulated for controlled release.

46. The pharmaceutical composition of claim 45, wherein said unit dosage form comprises an inner core comprising prednisolone formulated for controlled release and an outer coating comprising prednisolone formulated for immediate release.

47. The pharmaceutical composition of claim 46, wherein the inner core comprises 0.9mg of prednisolone formulated for controlled release and the outer coating comprises 1.8mg of prednisolone formulated for immediate release.

48. The pharmaceutical composition of claim 46, wherein the inner core comprises 0.45mg of prednisolone formulated for controlled release and the outer coating comprises 0.9mg of prednisolone formulated for immediate release.

49. A pharmaceutical composition in unit dosage form comprising 40 to 400mg dipyridamole formulated for controlled release and 0.75 to 3.75mg prednisolone or an equivalent, equivalent amount of an additional corticosteroid formulated for controlled or immediate release.

50. The pharmaceutical composition of claim 49, wherein said unit dosage form further comprises dipyridamole formulated for immediate release.

51. The pharmaceutical composition of claim 50, wherein 50% to 80% of said dipyridamole is formulated for controlled release and 20% to 50% of said dipyridamole is formulated for immediate release.

52. The pharmaceutical composition of claim 49, wherein said unit dosage form further comprises prednisolone or an equivalent, equivalent amount of an additional corticosteroid formulated for controlled and immediate release.

53. The pharmaceutical composition of claim 52, wherein 50% to 80% of the prednisolone or an equivalent, equivalent amount of an additional corticosteroid is formulated for immediate release, and 20% to 50% of the prednisolone or an equivalent, equivalent amount of an additional corticosteroid is formulated for controlled release.

54. The pharmaceutical composition of claim 36, wherein said corticosteroid is formulated into a unit dosage form having a dissolution release profile that releases at least 50% of the corticosteroid within the first 30 minutes of testing under in vitro conditions using USP dissolution apparatus No.1 at 37 ℃ ± 0.5 ℃ and 100rpm for the first two hours in 0.1N HCl as a dissolution medium followed by a phosphate buffer ph6.8 as a medium.

55. The pharmaceutical composition of claim 28, wherein the dipyridamole is formulated into a unit dosage form having a dissolution release profile that releases at least 10-55% of the dipyridamole within the first two hours and no less than 80% of the dipyridamole within 8 hours when tested under in vitro conditions using USP dissolution apparatus No.1 at 37 ℃ ± 0.5 ℃ and 100rpm for the first two hours in 0.1N HCl as a dissolution medium followed by a phosphate buffer ph6.8 with 0.25% sodium lauryl sulfate as the medium.

56. The pharmaceutical composition of claim 28, wherein said dipyridamole is formulated in a unit dosage form having an absorption rate constant of 0.20 to 0.90l/hr after administration to a fed patient.

57. A kit comprising (i) the unit dosage form pharmaceutical composition of any one of claims 28-56; and (ii) instructions for administering the pharmaceutical composition to treat an immunoinflammatory disorder.

58. The kit of claim 57, further comprising instructions for administering said unit dosage form once or twice daily.