Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor

Abstract

Provided are prophylactic and therapeutic methods of treatment of subjects for the purpose of inhibiting vaso-occlusive events, including embolism, by administering agents, including anagrelide and anagrelide derivatives, which reduce the number of circulating platelets to low normal or to below normal levels. Methods and pharmaceutical preparations comprising such agents are provided.

1 . A composition, comprising:
 a solid support core of a substantially water soluble, swellable or insoluble material, wherein the solid support is from 85-95% by weight of the composition;   an optional preparatory coat, wherein the preparatory coat is from 0-5% by weight of the composition;   a substrate layer comprising a binder and a platelet number reducing agent in the form of microparticles, wherein:
 the platelet number reducing agent is present in a form that has a shelf stability of at least three months and is in an amount that is from 0.01-0.6% or 0.05-0.45% or 0.075-0.35% by weight of the composition or 10 ng to 10 mg or 50 μg to 10 mg or 50 μg to 1000 μg; 
 at least 90% of the microparticles are 25 microns or less; and 
 the binder is present at a weight of 0.1-5% by weight of the composition; 
   a release control component effective for controlled release of the platelet number reducing agent, wherein the release control component is present at a weight of 0-10% by weight of the composition; and   an optional finishing coat and/or enteric coating, wherein the finishing coat and/or enteric coating is present at a weight of 0.25-10% by weight of the composition.   
     
     
         2 . The composition of  claim 1 , wherein the solid support comprises one or a plurality of spheroid granules, pellets or beads. 
     
     
         3 . The composition of  claim 1 , wherein the amount of platelet number reducing agent is 50 μg to 10 mg. 
     
     
         4 . The composition of  claim 1  that is formulated as a tablet or capsule for single dosage administration. 
     
     
         5 . The composition of  claim 1 , wherein:
 the platelet number reducing agent is anagrelide hydrochloride monohydrate and is present at a weight of at or about 0.12% by weight of the formulation;   the solid support is in the form of a plurality of non-pareil sugar spheres and is present at a weight of at or about 89.42% by weight of the formulation;   the binding agent comprises hydroxypropyl methylcellulose and is present at a weight of at or about 7.43% by weight of the formulation;   the controlled release agent comprises ethylcellulose and is present in an amount of at or about 1.55% by weight of the formulation.   
     
     
         6 . The composition of  claim 1 , wherein the substrate layer includes an amount of platelet number reducing agent in a range selected from among at or about 10 ng to at or about 100 ng, at or about 10 ng to at or about 250 ng, at or about 10 ng to at or about 500 ng, at or about 10 ng to at or about 100 ng, at or about 10 ng to at or about 1000 ng, at or about 25 ng to at or about 250 ng, at or about 50 ng to at or about 500 ng, at or about 75 ng to at or about 750 ng, at or about 100 ng to at or about 1000 ng, at or about 250 ng to at or about 2500 ng, at or about 500 ng to at or about 5000 ng, at or about 750 ng to at or about 7500 ng, at or about 1 μg to at or about 10 μg, at or about 2 μg to at or about 20 μg, at or about 5 μg to at or about 25 μg, at or about 10 μg to at or about 100 μg, at or about 100 μg to at or about 500 μg, at or about 500 μg to at or about 750 μg, at or about 725 μg to at or about 1000 μg, at or about 750 μg to at or about 1125 μg, at or about 800 μg to at or about 1200 μg, at or about 1000 μg to at or about 1500 μg, at or about 1250 μg to at or about 2500 μg, 50 μg to 10 mg, 1000 μg to 1 mg, 5000 μg to 5 mg, 1 mg to 5 mg, 0.5 mg to 1.5 mg and 0.25 mg to 1.25 mg. 
     
     
         7 . The composition of  claim 1 , wherein:
 the optional preparatory coat when present is on the solid support;   the substrate layer is on the solid support or the optional preparatory coat when present;   the release control component is on the substrate layer;   the optional finishing coat when present is on the release control component; and   the enteric coating when present is on the release control component or the optional finishing coat when present.   
     
     
         8 . The composition of  claim 1 , further comprising a seal coat layer including a substantially water-soluble polymer on the substrate layer, wherein:
 the seal coat is disposed between the substrate layer and the release control component; and   the seal coat reduces chemical interaction between the platelet reducing agent and the release control component and/or the platelet reducing agent and the optional finishing coat.   
     
     
         9 . A composition in unit dosage form, comprising:
 the composition of  claim 8  in the form of spheroid granules, pellets or beads that include an amount from about 10 ng to about 10000 μg of a platelet-reducing agent that has a shelf stability of at least three months or is present in a form that has a shelf stability of at least 3 months; wherein:   the spheroid granules, pellets or beads include:
 a solid support core of a substantially water soluble, swellable or insoluble material; 
 the optional preparatory coat; 
 the substrate layer comprising the platelet number reducing agent; 
 the seal coat layer comprising a substantially water-soluble polymer on the substrate layer; 
 the release control component for controlled release of the platelet reducing agent; and 
 the optional finishing coat and/or enteric coating; 
   the unit dosage form provides a peak plasma level of the platelet number reducing agent at least 50% lower than produced by an immediate release formulation of the platelet number reducing agent; and   the seal coat is disposed between the substrate layer and the release control component and reduces chemical interaction between the platelet reducing agent and the release control component and/or the platelet reducing agent and the optional finishing coat.   
     
     
         10 . The composition of  claim 9 , wherein the amount of platelet number reducing agent is in a range selected from among at or about 10 ng to at or about 100 ng, at or about 10 ng to at or about 250 ng, at or about 10 ng to at or about 500 ng, at or about 10 ng to at or about 100 ng, at or about 10 ng to at or about 1000 ng, at or about 25 ng to at or about 250 ng, at or about 50 ng to at or about 500 ng, at or about 75 ng to at or about 750 ng, at or about 100 ng to at or about 1000 ng, at or about 250 ng to at or about 2500 ng, at or about 500 ng to at or about 5000 ng, at or about 750 ng to at or about 7500 ng, at or about 1 μg to at or about 10 μg, at or about 2 μg to at or about 20 μg, at or about 5 μg to at or about 25 μg, at or about 10 μg to at or about 100 μg, at or about 100 μg to at or about 500 μg, at or about 500 μg to at or about 750 μg, at or about 725 μg to at or about 1000 μg, at or about 750 μg to at or about 1125 μg, at or about 800 μg to at or about 1200 pg, at or about 1000 μg to at or about 1500 μg, at or about 1250 μg to at or about 2500 μg, 50 μg to 10 mg, 1000 μg to 1 mg, 5000 μg to 5 mg, 1 mg to 5 mg, 0.5 mg to 1.5 mg and 0.25 mg to 1.25 mg. 
     
     
         11 . The composition of  claim 9 , further comprising granules, pellets or beads that include an immediate release form of the platelet number reducing agent in an amount from at or about 10 ng to at or about 1000 μg. 
     
     
         12 . The composition of  claim 8 , wherein the seal coat is present at a weight of up to 10% by weight of the composition. 
     
     
         13 . The composition of  claim 1 , wherein the platelet number reducing agent is selected from among one or a combination of anagrelide, 3-hydroxy anagrelide, an analog or derivative of anagrelide, and a pharmaceutically acceptable salt thereof anagrelide. 
     
     
         14 . The composition of  claim 1 , wherein the form of the platelet number reducing agent is a hydrated crystal form. 
     
     
         15 . The composition of  claim 1 , wherein the platelet number reducing agent is anagrelide, which is in a monohydrate crystal form. 
     
     
         16 . The composition of  claim 15 , wherein the anagrelide is anagrelide hydrochloride monohydrate. 
     
     
         17 . The composition of  claim 14 , wherein the hydrated crystal form of the platelet-reducing agent is substantially maintained for a shelf period of at least six months. 
     
     
         18 . The composition of  claim 8 , wherein:
 the release control component and/or the optional finishing layer comprises a plasticizer; and   the seal layer reduces deleterious interactions between the platelet number reducing agent and the plasticizer.   
     
     
         19 . The composition of  claim 1 , wherein the substrate layer is formed by a process that substantially maintains the hydrated crystal form of the platelet number reducing agent. 
     
     
         20 . The composition of  claim 19 , wherein the platelet number reducing agent is spray dried onto the solid support. 
     
     
         21 . The composition of  claim 1  that has a moisture content of between at or about 0.05% and at or about 2% by weight. 
     
     
         22 . The composition of  claim 1 , wherein the platelet number reducing agent has an effective moisture of between at or about 3% and at or about 10% by weight or at least at or about 5% by weight. 
     
     
         23 . The composition of  claim 1 , wherein the platelet number reducing agent is anagrelide hydrochloride monohydrate, and the substrate layer further comprises an amount of hydroxyurea selected from among 5 μg to 500 mg. 
     
     
         24 . The composition of  claim 1 , wherein the substrate layer contains an amount of microparticles of a platelet number reducing agent selected from among 50 pg to 1000 μg, 150 μg to 500 μg, 200 μg to 400 μg and 1 μg to 10 μg. 
     
     
         25 . The composition of  claim 1 , wherein the binder in the substrate layer is selected from among polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, gelatin, gum arabic, gellan gum, xanthan gum, carrageenan, polyethylene oxide, a polymethacrylate, a dextrin, starch or starch derivatives and combinations thereof. 
     
     
         26 . The composition of  claim 1 , wherein the binder in the substrate layer is a low molecular weight hydroxypropyl methyl cellulose or povidone. 
     
     
         27 . The composition of  claim 1 , wherein at least 50% of the microparticles are 12 microns or less. 
     
     
         28 . The composition of  claim 1 , wherein the solid support core comprises a material selected from among sugar, starch or derivatives thereof, alginate, gellan gum, a polyol and combinations thereof. 
     
     
         29 . The composition of  claim 1 , wherein the solid support core is a non-pareil sugar sphere. 
     
     
         30 . The composition of  claim 8 , wherein the seal coat layer is present at a weight of 1-5% by weight of the composition. 
     
     
         31 . The composition of  claim 8 , wherein the water-soluble polymer of the seal coat is selected from among povidone, hydroxy-propyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxy methyl cellulose (CMC), gelatin, polyethylene oxide, gum arabic, dextrin, magnesium aluminum silicate, starch, a polymethacrylate and combinations thereof. 
     
     
         32 . The composition of  claim 8 , wherein the water-soluble polymer of the seal coat is low molecular weight hydroxypropyl methylcellulose (HPMC). 
     
     
         33 . The composition of  claim 8 , wherein the release control component is present at a weight of 1-5% by weight of the composition. 
     
     
         34 . The composition of  claim 1 , wherein the release control component comprises a film-forming polymer selected from among ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or a mixture of two or more of such cellulose derivatives, polyvinyl acetate, povidone, cross-linked starch, cross-linked chitosan, cross-linked gelatin, cross-linked hyaluronic acid, cross-linked polyvinyl alcohol, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, carboxypolymethylene, zein and combinations thereof. 
     
     
         35 . The composition of  claim 34 , wherein the film-forming polymer is a combination of polyvinyl acetate and povidone. 
     
     
         36 . The composition of  claim 1 , wherein the release control component further comprises a pore former, wherein upon exposure to a biological fluid, the pore former dissolves to form a channel or pore. 
     
     
         37 . The composition of  claim 36 , wherein the pore former is present at a weight of 0.1 to 10% by weight of the composition or is present at a weight of at or about 0.25% to at or about 10% by weight of the composition. 
     
     
         38 . The composition of  claim 36 , wherein the ratio of pore former to film-forming polymer in the release control component is selected from among a ratio of at or about 1:1 to at or about 1:12, at or about 1:2 to at or about 1:10, and 1:3. 
     
     
         39 . The composition of  claim 36 , wherein the pore former is a cellulose ether. 
     
     
         40 . The composition of  claim 1 , wherein the release control component includes at or about 60% to at or about 95% by weight of ethyl cellulose and at or about 40% to at or about 5% by weight of hydroxypropyl methylcellulose. 
     
     
         41 . The composition of  claim 1 , wherein:
 the substrate layer comprises a binder and 1 μg to 10 μg, 25 pg, 50 μg, 100 μg, 200 μg, 250 μg, 300 μg or 500 μg of microparticles of a platelet number reducing agent, wherein the platelet number reducing agent is anagrelide hydrochloride monohydrate;   the binder comprises hydroxypropyl methylcellulose;   the seal coat comprises hydroxypropyl methylcellulose and is present at a weight of at or about 5% to at or about 8% by weight of the composition; and   the release control component comprises ethylcellulose, hydroxypropyl methylcellulose and triethylcitrate.   
     
     
         42 . The composition of  41 , wherein the ethylcellulose is present in an amount to yield a ratio of ethylcellulose to the hydroxypropyl methylcellulose of 3:1 in the release control component. 
     
     
         43 . The composition of  41 , wherein the control release component is present at a weight of at or about 3% by weight of the composition. 
     
     
         44 . The composition of  claim 11 , wherein the immediate release form of the platelet number reducing agent comprises 50%, 25%, 10%, 3% or less by weight of the dosage form. 
     
     
         45 . A method for reducing platelet count in a subject, comprising:
 administering to a subject a controlled release composition of  claim 1 , wherein:   the composition delivers an amount of the platelet number reducing agent effective to reduce platelet count in the subject by at least 10% of pre-treatment levels.   
     
     
         46 . The method of  claim 45 , wherein the subject has a normal platelet count prior to treatment. 
     
     
         47 . The method of  claim 46 , wherein the platelet count is reduced to at least a low normal level. 
     
     
         48 . The method of  claim 45 , wherein the subject has an above normal platelet count prior to treatment. 
     
     
         49 . The method of  claim 48 , wherein the platelet count is reduced to at or about 600×103 platelets/μl or less or to a near normal level or to a high normal level of at or about 450×103 platelets/μl. 
     
     
         50 . The method of  claim 45 , wherein the subject is a mammal. 
     
     
         51 . The method of  claim 45 , wherein the subject is a human. 
     
     
         52 . The method of  claim 45 , wherein the subject has a disease selected from among vascular disease, hypercholesterolemia, hypertension, atherosclerosis, a thrombosis, a myeloproliferative disease, a condition or disorder resulting from a thrombotic event, diabetes mellitus, familial hypercholesterolemia, familial combined hyperlipidemia, familial dysbetalipoproteinemia, familial hypoalphalipo-proteinemia, hypothyroidism, cholesterol ester storage disease, systemic lupus erythematosus, homocysteinemia, chronic renal insufficiency, chronic vitamin D intoxication, pseudo-xanthoma elasticum, idiopathic arterial calcification, aortic valvular calcification, Werner's syndrome and elevated risk of experiencing a vaso-occlusive event. 
     
     
         53 . The method of  claim 52 , wherein:
 the subject has a vascular disease selected from among arteriosclerosis, atherosclerosis, accelerated atherosclerosis, atherosclerosis lesions, focal calcific arteriosclerosis (Mönckeberg's sclerosis), arteriolosclerosis, cardiovascular disease, cerebrovascular disease, renovascular disease, mesenteric vascular disease, pulmonary vascular disease, ocular vascular disease and peripheral vascular disease; or   the subject has a myeloproliferative disease or disorder selected from among polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis; or   the subject has a thrombosis selected from among an arterial thrombosis, a stent thrombosis, a graft thrombosis, a cardiac thrombosis, a coronary thrombosis, a heart valve thrombosis and a venous thrombosis; or   the subject has a thrombotic event selected from among a myocardial infarction, a stroke, a transient ischemic attack, amaurosis fugax, aortic stenosis, cardiac stenosis, coronary stenosis and pulmonary stenosis.   
     
     
         54 . The method of  claim 45 , wherein the controlled release composition is administered prior to or following a surgical procedure. 
     
     
         55 . The method of  claim 54 , wherein the surgical procedure is selected from among coronary angiography, coronary stent placement, coronary by-pass surgery, carotid artery procedure, peripheral stent placement, vascular grafting, thrombectomy, peripheral vascular surgery, vascular surgery, organ transplant, artificial heart transplant, vascular angioplasty, vascular laser therapy, vascular replacement and vascular stenting. 
     
     
         56 . The method of  claim 45 , wherein the controlled release composition is co-administered with another therapeutic agent selected from among an anti-inflammatory agent, an anti-thrombotic agent, an ADP receptor antagonist, a glycoprotein IIb/IIIa receptor inhibitor, an anti-coagulant agent, a thrombolytic agent, a cyclooxygenase-2 inhibitor, a PAR antagonist, a fibrinolytic agent, a lipid reducing agent, an angiotensin system inhibitor, an antihypertensive agent, a chemotherapeutic anti-cancer drug, an alkylating agent, a thromboxane synthetase inhibitor, a cell signaling molecule and a JAK-2 inhibitor. 
     
     
         57 . The method of  claim 56 , wherein the therapeutic agent is selected from among:
 an anti-inflammatory agent selected from among alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, aspirin, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate-sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methyl-prednisolone suleptanate, morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, salicylates, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, glucocorticoids and zomepirac sodium;   an ADP receptor antagonist selected from among clopidogrel, ticlopidine, prasugrel, sulfinpyrazone, AZD6140, AZD6933 and AR-C69931;   a glycoprotein IIb/IIIa receptor inhibitor selected from among abciximab, fradafiban, lamifiban, lotrafiban, orbofiban, roxifiban, sibrafiban, tirofiban and xemilofiban;   an anti-coagulant agent selected from among a vitamin K antagonist, coumarin and coumarin derivatives, warfarin sodium; a heparin; ardeparin sodium; bivalirudin; bromindione; coumarin dalteparin sodium; desirudin; dicumarol; lyapolate sodium; nafamostat mesylate; phenprocoumon sulfatide; and tinzaparin sodium;   a thrombolytic agent selected from among ancrod, anistreplase, bisobrin lactate, brinolase, Hageman factor (i.e., factor XII) fragments, molsidomine, plasminogen activators such as streptokinase, tissue plasminogen activators (TPA), urokinase, TFPI, plasmin and plasminogen and inhibitors of coagulation factors IIa, Va, VIIa, VIIIa, IXa, Xa, XIa, XIIa and XIIIa;   a lipid reducing agent selected from among bezafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemfibrozil, ronifibrate and simfibrate; a statin, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin; niacin or a niacin derivative, including acipimox, aluminium nicotinate, niceritrol (penta-erythritol tetranicotinate), nicofuranose and nicotinyl alcohol; a bile acid sequestrant, including colesevelam, colestyramine, colestipol and colextran; a CETP inhibitor, such as anacetrapib; benfluorex; cholestyramine; dextrothyroxine; ezetimibe; laropiprant; meglutol; omega-3-triglycerides; policosanol; probucol; and tiadenol;   a cyclooxygenase-2 (COX-2) inhibitor selected from among aspirin, celecoxib, lumiracoxib and etoricoxib;   an angiotensin system inhibitor selected from among an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an agent that activates the catabolism of angiotensin II, and an agent that prevents the synthesis of angiotensin I from which angiotensin II is ultimately derived;   an ACE inhibitor selected from among benazepril, captopril, cilazapril, delapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril and zofenopril;   an angiotensin II receptor antagonist selected from among azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan and valsartan;   a chemotherapeutic anti-cancer drug selected from among busulfan, carmustine, chlorambucil, cyclophosphamide, doxorubicin, estramustine, hepsulfan, hydroxy-carbamide, ifosfamide, lomustine, melphalan, methotrexate, pipobroman and thioTEPA;   a thromboxane synthetase inhibitor selected from among aspirin, β-[4-(2-carboxy-1-propenyl)benzyl]pyridine hydrochloride (OKY-1555) and 1-carboxyhexyl-, 1-carboxyheptyl, and 1-carboxy-octyl-imidazoles, 4(Z)-6-[(4RS,5SR)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl]hex-4-enoic acid, BM-573, camonagrel, CGS-12970, daltroban, dazmegrel, DTTX30, E-6700, FCE-27262, imitrodast (CS-518), isbogrel (CV-4151), ketoconazole, KK-505, KY-063, nafagrel (DP-1904), ozagrel (OKY-046), picotamide, pirmagrel (CGS-13080), ridogrel, SQ29548, rolafagrel (FCE-22178), satigrel (E-5510), sulotroban, terbogrel and UK 38485;   a cell signaling molecule selected from among a cytokine, a growth factor, an interleukin, α-interferon, γ-interferon, transforming growth factor-β, neutrophil activating peptide-2 and its analogs, macrophage inflammatory protein and its analogs, and platelet-factor 4 and transforming growth factor-beta, and combinations thereof; and   a JAK-2 inhibitor selected from among AT9283, VX-680, MK0457, TG101209, INCB018424, LS104, XLO19, TG101348, vorinostat, a 4-aryl-2-amino-pyridine and a 4-aryl-2-aminoalkyl-pyridine.   
     
     
         58 . The method of  claim 45 , wherein the controlled release composition is administered orally. 
     
     
         59 . The method of  claim 52 , wherein the disease is a myeloproliferative disease or disorder and platelet count is reduced by at least 20% or at least 50%. 
     
     
         60 . The method of  claim 59 , wherein platelet count is reduced to an amount above 200×103 platelets per μl or to an amount below 200×103 platelets per μl or is reduced from greater than 1,000×103 to at or about 600×103 platelets per μl or less or is reduced to near normal levels or is reduced to at or about 450×103 platelets per μl or less or is reduced to below 250×103 platelets per μl or is reduced to 150×103 platelets per μl. 
     
     
         61 . The method of  claim 45 , wherein the platelet-reducing agent is one or a combination of anagrelide, 3-hydroxy anagrelide, an analog or derivative of anagrelide or a pharmaceutically acceptable salt thereof. 
     
     
         62 . The method of  claim 45 , wherein the platelet number reducing agent is a combination of hydroxycarbamide and one or a combination of anagrelide, 3-hydroxy anagrelide, an analog or derivative of anagrelide or a pharmaceutically acceptable salt thereof. 
     
     
         63 . The method of  claim 45 , wherein the platelet number reducing agent is administered in an amount of from at or about 10 ng to at or about 2 mg daily or from at or about 100 μg to at or about 20 mg daily. 
     
     
         64 . The method of  claim 45 , wherein the controlled release composition releases the platelet number reducing agent in an amount and at a rate that:
 produces a W50 that is at or about 3 to at or about 5 times the W50 of an immediate release formulation; and/or   provides a Cmax that is 15% or less of an immediate release formulation of the platelet-reducing agent; and/or   delays Tmax by at or about 3 to at or about 6 hours as compared to an immediate release formulation; and/or   provides a maximum observed plasma concentration (Cmax) of the platelet number reducing agent that is 50% or less of an immediate release formulation of the platelet-reducing agent and does not cause clinical symptoms that prevent or limit therapeutic use of the platelet number reducing agent; and/or   inhibits megakaryocyte production of platelets without inhibiting phosphodiesterase (PDE) activity to a clinically significant extent thereby reducing observed side-effects and/or adverse reactions or clinical symptoms associated with inhibition of PDE activity; and/or   inhibits thrombopoietin (TPO)-induced platelet production without inhibiting phosphodiesterase (PDE) activity to a clinically significant extent thereby reducing observed side-effects and/or adverse reactions or clinical symptoms associated with inhibition of PDE activity; and/or   produces an area under the plasma concentration versus time curve (AUC) equal to or more than 55% of an immediate release formulation of the platelet number reducing agent; and/or   results in a delay in the time of maximum observed plasma concentration (Tmax) of at or about 1 hour to at or about 8 hours or at or about 4 hours to at or about 6 hours as compared to an immediate release formulation of the platelet number reducing agent; and/or   results in an exposure in serum of the platelet number reducing agent of from about 5-24 hours; and/or   reduces the number of circulating platelets in a subject and increases the apparent half life of the platelet number reducing agent by at least a factor of two with respect to an immediate release formulation; and/or   produces an effective duration of activity of the platelet number reducing agent of from at or about 5 hours to at or about 24 hours; and/or   inhibits reduces circulating platelet number without eliciting adverse reactions associated with modulation of cellular levels of cAMP and/or cGMP; and/or   produces a peak plasma level of the platelet number reducing agent of 50% or less of an immediate release formulation and produces a sustained exposure of the platelet number reducing agent of greater than 6 hours.   
     
     
         65 . An article of manufacture, comprising:
 a packaging material;   a composition of  claim 1  within the packaging material; and   
       a label that indicates that the composition is used for treatment, prevention or amelioration of one or more symptoms of a platelet mediated disease or disorder, or a disease or disorder in which platelet number is implicated.