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Researchers Submit Patent Application, "Therapeutic Regimens for the Treatment of Immunoinflammatory Disorders", for Approval

No assignee for patent serial number 587503 has been made.

News editors obtained the following quote from the background information supplied by the inventors: "The combination of prednisolone and dipyridamole is an orally available synergistic drug candidate in Phase 2 clinical development for the treatment of immunoinflammatory disorders. A synergistic drug includes two compounds that are designed to act synergistically through multiple pathways to provide a therapeutic effect which neither component administered alone and at the same dosing levels can achieve. The combination of prednisolone with dipyridamole was designed to selectively amplify certain elements of prednisolone's anti-inflammatory and immunomodulatory activities, without replicating steroid side effects.

"Proper formulation is essential to maximize the therapeutic benefit of a synergistic drug combination."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent: "The invention provides methods, compositions, and kits for administering dipyridamole in combination with a corticosteroid. This combination is useful for the treatment of immunoinflammatory disorders.

"Accordingly, in a first aspect, the invention features a method for treating an immunoinflammatory disorder in a subject in need thereof by (i) administering to the subject a first dose of corticosteroid at time T.sub.0; and (ii) administering to the subject a second dose of corticosteroid 3 to 8 hours after time T.sub.0, wherein the ratio of the first dose to the second dose is 1.5-2.5:1. In certain embodiments, the ratio of the first dose to the second dose is 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, or even 2.5:1. In other embodiments, the first dose is administered in a unit dosage formulation including from 1 to 10 mg, desirably 1 to 8 mg, 1 to 5 mg, 1.25 to 3 mg, 1.4 to 2.3 mg, or 1.5 to 2.5 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid, and the second dose is administered in a unit dosage formulation including from 0.5 to 5 mg, desirably from 0.5 to 4 mg, 0.5 to 3 mg, 0.5 to 2 mg, 0.75 to 2 mg, 0.70 to 1.20 mg, or 0.75 to 1.25 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid. In still other embodiments, the first dose is administered in a unit dosage formulation including 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid, and the second dose is administered in a unit dosage formulation including 0.7, 0.8, 0.9, or 1.0 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid. In certain embodiments, the corticosteroid is formulated for immediate release. The method can further include administering to the subject dipyridamole in unit dosage form (e.g., 40 to 200 mg, 40 to 180 mg, 45 to 200 mg, 50 to 200 mg, 70 to 200 mg, 90 to 200 mg, 90 to 180 mg, or 120 to 180 mg) of dipyridamole. In certain embodiments 180 mg, 120 mg, 90 mg, 60 mg, or 45 mg of dipyridamole in unit dosage form is administered to the subject.

"In a related aspect the invention features a pharmaceutical composition in unit dosage form including (i) 1 to 10 mg, desirably 1 to 8 mg, 1 to 5 mg, 1.25 to 3 mg, 1.4 to 2.3 mg, or 1.5 to 2.5 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid; and (ii) 40 to 200 mg, 40 to 180 mg, 45 to 200 mg, 50 to 200 mg, 70 to 200 mg, 90 to 200 mg, 90 to 180 mg, or 120 to 180 mg of dipyridamole. In certain embodiments, the pharmaceutical composition includes 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid; and (ii) 180 mg, 120 mg, 90 mg, 60 mg, or 45 mg of dipyridamole. For example, the pharmaceutical composition can include 1.8 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid; and (ii) 180 mg, 90 mg, or 45 mg of dipyridamole.

"In invention further features a pharmaceutical composition in unit dosage form including (i) 0.5 to 5 mg, desirably from 0.5 to 4 mg, 0.5 to 3 mg, 0.5 to 2 mg, 0.75 to 2 mg, 0.70 to 1.20 mg, or 0.75 to 1.25 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid; and (ii) 40 to 200 mg, 40 to 180 mg, 45 to 200 mg, 50 to 200 mg, 70 to 200 mg, 90 to 200 mg, 90 to 180 mg, or 120 to 180 mg of dipyridamole. In certain embodiments, the pharmaceutical composition includes 0.7, 0.8, 0.9, or 1.0 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid; and (ii) 180 mg, 120 mg, 90 mg, 60 mg, or 45 mg of dipyridamole. For example, the pharmaceutical composition can include 0.9 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid; and (ii) 180 mg, 90 mg, or 45 mg of dipyridamole.

"In one embodiment, of the above aspects, each of the corticosteroid and the dipyridamole is formulated for immediate release. In another embodiment of the above aspects, the dipyridamole is formulated as a homogenous bead. In still another embodiment of the above aspects, the corticosteroid is formulated as a coated non-pareil bead.

"In invention features a pharmaceutical composition in unit dosage form including homogenous dipyridamole beads. In certain embodiments, the unit dosage form includes from 40 to 200 mg, 40 to 180 mg, 45 to 200 mg, 50 to 200 mg, 70 to 200 mg, 90 to 200 mg, 90 to 180 mg, or 120 to 180 mg of dipyridamole. In other embodiments, the unit dosage form comprises 180 mg, 120 mg, 90 mg, 60 mg, or 45 mg of dipyridamole.

"In another aspect, the invention features a kit including (i) a first pharmaceutical composition of the invention including prednisolone or an equivalent, equipotent amount of another corticosteroid, and dipyridamole; (ii) a second pharmaceutical composition of the invention including prednisolone or an equivalent, equipotent amount of another corticosteroid, and dipyridamole; and (iii) instructions for administering the second pharmaceutical composition 3 to 8 hours after the first pharmaceutical composition. In certain embodiments, the kit includes instructions for administering the second pharmaceutical composition 3 to 8, 3 to 7, 3 to 6, 4 to 8, 4 to 7, or 4 to 6 hours after the first pharmaceutical composition. In other embodiments, the kit includes instructions for administering the first pharmaceutical composition upon waking. In still other embodiments, the kit includes instructions for administering the first pharmaceutical composition and the second pharmaceutical composition for the treatment of an immunoinflammtory disease.

"In a related aspect, the invention features a kit including (i) a first pharmaceutical composition in a unit dosage formulation including from 1 to 10 mg, desirably 1 to 8 mg, 1 to 5 mg, 1.25 to 3 mg, 1.4 to 2.3 mg, or 1.5 to 2.5 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid; and (ii) a second pharmaceutical composition in a unit dosage formulation comprising from 0.5 to 4 mg, 0.5 to 3 mg, 0.5 to 2 mg, 0.75 to 2 mg, 0.70 to 1.20 mg, or 0.75 to 1.25 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid; and (iii) instructions for administering the second pharmaceutical composition 3 to 8 hours after the first pharmaceutical composition. In certain embodiments, the first pharmaceutical composition includes 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid, and the second pharmaceutical composition includes 0.7, 0.8, 0.9, or 1.0 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid. In certain embodiments, the corticosteroid is formulated for immediate release. Each of the first pharmaceutical composition and the second pharmaceutical composition can further include dipyridamole (e.g., 40 to 200 mg, 40 to 180 mg, 45 to 200 mg, 50 to 200 mg, 70 to 200 mg, 90 to 200 mg, 90 to 180 mg, or 120 to 180 mg). In certain embodiments each of the first pharmaceutical composition and the second pharmaceutical composition include 180 mg, 120 mg, 90 mg, 60 mg, or 45 mg of dipyridamole.

"In certain embodiments, the kits of the invention include instructions for administering the first pharmaceutical composition and the second pharmaceutical composition for the treatment of an immunoinflammtory disease.

"In any of the above methods, compositions, and kits the corticosteroid can be, without limitation, selected from prednisolone, prednisone, budesonide, methylprednisolone, fluticasone, betamethasone, and deflazacort.

"In any of the above methods and kits the first dose of corticosteroid can be, for example, administered to the subject upon waking (e.g., time T.sub.0), while the second dose is administered to the subject, for example, 3 to 8, 3 to 7, 3 to 6, 4 to 8, 4 to 7, or 4 to 6 hours after time T.sub.0.

"As used herein, the term 'treating' refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. To 'prevent disease' refers to prophylactic treatment of a subject who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease. To 'treat disease' or use for 'therapeutic treatment' refers to administering treatment to a subject already suffering from a disease to improve or stabilize the subject's condition. Thus, in the claims and embodiments, treating is the administration to a subject either for therapeutic or prophylactic purposes.

"The term 'immunoinflammatory disorder' encompasses a variety of conditions, including autoimmune diseases, proliferative skin diseases, and inflammatory dermatoses. Immunoinflammatory disorders result in the destruction of healthy tissue by an inflammatory process, dysregulation of the immune system, and unwanted proliferation of cells. Examples of immunoinflammatory disorders are acne vulgaris; acute respiratory distress syndrome; Addison's disease; allergic rhinitis; allergic intraocular inflammatory diseases, ANCA-associated small-vessel vasculitis; ankylosing spondylitis; arthritis, asthma; atherosclerosis; atopic dermatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; Bell's palsy; bullous pemphigoid; cerebral ischaemia; chronic obstructive pulmonary disease; cirrhosis; Cogan's syndrome; contact dermatitis; COPD; Crohn's disease; Cushing's syndrome; dermatomyositis; diabetes mellitus; discoid lupus erythematosus; eosinophilic fasciitis; erythema nodosum; exfoliative dermatitis; fibromyalgia; focal glomerulosclerosis; giant cell arteritis; gout; gouty arthritis; graft-versus-host disease; hand eczema; Henoch-Schonlein purpura; herpes gestationis; hirsutism; idiopathic cerato-scleritis; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; inflammatory bowel or gastrointestinal disorders, inflammatory dermatoses; lichen planus; lupus nephritis; lymphomatous tracheobronchitis; macular edema; multiple sclerosis; myasthenia gravis; myositis; osteoarthritis; pancreatitis; pemphigoid gestationis; pemphigus vulgaris; polyarteritis nodosa; polymyalgia rheumatica; pruritus scroti; pruritis/inflammation, psoriasis; psoriatic arthritis; rheumatoid arthritis; relapsing polychondritis; rosacea caused by sarcoidosis; rosacea caused by scleroderma; rosacea caused by Sweet's syndrome; rosacea caused by systemic lupus erythematosus; rosacea caused by urticaria; rosacea caused by zoster-associated pain; sarcoidosis; scleroderma; segmental glomerulosclerosis; septic shock syndrome; shoulder tendinitis or bursitis; Sjogren's syndrome; Still's disease; stroke-induced brain cell death; Sweet's disease; systemic lupus erythematosus; systemic sclerosis; Takayasu's arteritis; temporal arteritis; toxic epidermal necrolysis; tuberculosis; type-1 diabetes; ulcerative colitis; uveitis; vasculitis; and Wegener's granulomatosis.

"By 'corticosteroid' is meant any naturally occurring or synthetic steroid hormone which can be derived from cholesterol and is characterized by a hydrogenated cyclopentanoperhydrophenanthrene ring system. Naturally occurring corticosteroids are generally produced by the adrenal cortex. Synthetic corticosteroids may be halogenated. Functional groups required for activity include a double bond at .DELTA.4, a C3 ketone, and a C20 ketone. Corticosteroids may have glucocorticoid and/or mineralocorticoid activity. In preferred embodiments, the corticosteroid is either fludrocortisone or prednisolone. Exemplary corticosteroids are 11-alpha,17-alpha,21-trihydroxypregn-4-ene-3,20-dione; 11-beta,16-alpha,17,21-tetrahydroxypregn-4-ene-3,20-dione; 11-beta,16-alpha,17,21-tetrahydroxypregn-1,4-diene-3,20-dione; 11-beta,17-alpha,21-trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione; 11-dehydrocorticosterone; 11-deoxycortisol; 11-hydroxy-1,4-androstadiene-3,17-dione; 11-ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogesterone; 16-methylhydrocortisone; 17,21-dihydroxy-16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione; 17-alpha-hydroxypregn-4-ene-3,20-dione; 17-alpha-hydroxypregnenolone; 17-hydroxy-16-beta-methyl-5-beta-pregn-9(11)-ene-3,20-dione; 17-hydroxy-4,6,8(14)-pregnatriene-3,20-dione; 17-hydroxypregna-4,9(11)-diene-3,20-dione; 18-hydroxycorticosterone; 18-hydroxycortisone; 18-oxocortisol; 21-acetoxypregnenolone; 21-deoxyaldosterone; 21-deoxycortisone; 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17-alpha,20-beta, 21-triol-3,11-dione; 6,17,20-trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycortisol; 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone 21-hemisuccinate sodium salt, 6-beta-hydroxycortisol, 6-alpha, 9-alpha-difluoroprednisolone 21-acetate 17-butyrate, 6-hydroxycorticosterone; 6-hydroxydexamethasone; 6-hydroxyprednisolone; 9-fluorocortisone; alclomethasone dipropionate; aldosterone; algestone; alphaderm; amadinone; amcinonide; anagestone; androstenedione; anecortave acetate; beclomethasone; beclomethasone dipropionate; betamethasone 17-valerate; betamethasone sodium acetate; betamethasone sodium phosphate; betamethasone valerate; bolasterone; budesonide; calusterone; chlormadinone; chloroprednisone; chloroprednisone acetate; cholesterol; ciclesonide; clobetasol; clobetasol propionate; clobetasone; clocortolone; clocortolone pivalate; clogestone; cloprednol; corticosterone; cortisol; cortisol acetate; cortisol butyrate; cortisol cypionate; cortisol octanoate; cortisol sodium phosphate; cortisol sodium succinate; cortisol valerate; cortisone; cortisone acetate; cortivazol; cortodoxone; daturaolone; deflazacort, 21-deoxycortisol, dehydroepiandrosterone; delmadinone; deoxycorticosterone; deprodone; descinolone; desonide; desoximethasone; dexafen; dexamethasone; dexamethasone 21-acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichlorisone; diflorasone; diflorasone diacetate; diflucortolone; difluprednate; dihydroelatericin a; domoprednate; doxibetasol; ecdysone; ecdysterone; emoxolone; endrysone; enoxolone; fluazacort; flucinolone; flucloronide; fludrocortisone; fludrocortisone acetate; flugestone; flumethasone; flumethasone pivalate; flumoxonide; flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide; fluocortin butyl; 9-fluorocortisone; fluocortolone; fluorohydroxyandrostenedione; fluorometholone; fluorometholone acetate; fluoxymesterone; fluperolone acetate; fluprednidene; fluprednisolone; flurandrenolide; fluticasone; fluticasone propionate; formebolone; formestane; formocortal; gestonorone; glyderinine; halcinonide; halobetasol propionate; halometasone; halopredone; haloprogesterone; hydrocortamate; hydrocortiosone cypionate; hydrocortisone; hydrocortisone 21-butyrate; hydrocortisone aceponate; hydrocortisone acetate; hydrocortisone buteprate; hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisuccinate; hydrocortisone probutate; hydrocortisone sodium phosphate; hydrocortisone sodium succinate; hydrocortisone valerate; hydroxyprogesterone; inokosterone; isoflupredone; isoflupredone acetate; isoprednidene; loteprednol etabonate; meclorisone; mecortolon; medrogestone; medroxyprogesterone; medrysone; megestrol; megestrol acetate; melengestrol; meprednisone; methandrostenolone; methylprednisolone; methylprednisolone aceponate; methylprednisolone acetate; methylprednisolone hemisuccinate; methylprednisolone sodium succinate; methyltestosterone; metribolone; mometasone; mometasone furoate; mometasone furoate monohydrate; nisone; nomegestrol; norgestomet; norvinisterone; oxymesterone; paramethasone; paramethasone acetate; ponasterone; prednicarbate; prednisolamate; prednisolone; prednisolone 21-diethylaminoacetate; prednisolone 21-hemisuccinate; prednisolone acetate; prednisolone farnesylate; prednisolone hemisuccinate; prednisolone-21(beta-D-glucuronide); prednisolone metasulphobenzoate; prednisolone sodium phosphate; prednisolone steaglate; prednisolone tebutate; prednisolone tetrahydrophthalate; prednisone; prednival; prednylidene; pregnenolone; procinonide; tralonide; progesterone; promegestone; rhapontisterone; rimexolone; roxibolone; rubrosterone; stizophyllin; tixocortol; topterone; triamcinolone; triamcinolone acetonide; triamcinolone acetonide 21-palmitate; triamcinolone benetonide; triamcinolone diacetate; triamcinolone hexacetonide; trimegestone; turkesterone; and wortmannin. Desirably, the corticosteroid is fludrocortisone or prednisolone.

"By 'an effective amount' is meant the amount of a compound, in a combination of the invention, required to treat or prevent an immunoinflammatory disorder. The effective amount of active compound(s) used to practice the present invention for therapeutic treatment of conditions caused by or contributing to an inflammatory disease varies depending upon the manner of administration, the age, body weight, and general health of the patient. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an effective amount.

"By an 'equivalent, equipotent amount' is meant a dosage of a corticosteroid that produces the same anti-inflammatory effect in a patient as a recited dosage of prednisolone.

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

"The term 'pharmaceutically acceptable salt' represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well 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 function with a suitable organic acid. Representative acid addition salts include acetate, ascorbate, aspartate, benzoate, citrate, digluconate, ftimarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, lactate, malate, maleate, malonate, mesylate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic 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, such as a pill, tablet, caplet, hard capsule, or soft capsule, each unit containing a predetermined quantity of dipyridamole and/or corticosteroid.

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

"As used herein, the term 'coated' refers to a bead formulation including a corticosteroid, such as prednisolone, applied to the surface of a carrier, such as a non-pareil seed. Coated beads can be prepared as described in the examples.

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

For additional information on this patent application, see: Padval, Mahesh. Therapeutic Regimens for the Treatment of Immunoinflammatory Disorders. U.S. Patent Serial Number 587503, filed August 16, 2012, and posted December 13, 2012. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser'Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=2030&p=41&f=G&l=50&d=PG01&S1=20121206.PD.&OS=PD/20121206&RS=PD/20121206

Keywords for this news article include: Anions, Patents, Butyrates, Chemistry, Valerates, Succinates, Propionates, Dosage Forms, Acyclic Acids, Butyric Acids, Hydrocortisone, Succinic Acids, Phosphoric Acids, Sodium Phosphate, Organic Chemicals, Dicarboxylic Acids, Adrenal Cortex Hormones, 11-Hydroxycorticosteroids, 17-Hydroxycorticosteroids.

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