WO2008021283A2 - Compositions and methods for increasing blood platelet levels in humans - Google Patents
Compositions and methods for increasing blood platelet levels in humans Download PDFInfo
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- WO2008021283A2 WO2008021283A2 PCT/US2007/017860 US2007017860W WO2008021283A2 WO 2008021283 A2 WO2008021283 A2 WO 2008021283A2 US 2007017860 W US2007017860 W US 2007017860W WO 2008021283 A2 WO2008021283 A2 WO 2008021283A2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention is directed to compositions and methods for increasing blood platelet levels in humans.
- thrombocytopenia is a potentially serious condition characterized by a deficiency of platelets in the circulatory system. It is associated with an increased risk of bleeding particularly from small capillaries resulting in thrombocytopenic purpura.
- the causes of thrombocytopenia are heterogeneous and include decreases in platelet production in the bone marrow and decreases in platelet survival in the blood.
- There are specific disease related thrombocytopenias such as Idiopathic Thrombocytopenic Purpura and thrombocytopenias caused by the indirect effect of other diseases on the bone marrow including malignancies and infections such as hepatitis.
- management of thrombocytopenia is primarily based on platelet transfusion.
- HLA human leukocyte antigen
- Thrombopoietin is the principal physiologic regulator of platelet production.
- TPO is produced constitutively in liver and other organs, circulates in the bloodstream, and is delivered to bone marrow, where it stimulates the early development of multiple hematopoietic lineages and megakaryocytopoiesis.
- TPO exerts its effect on megakaryocytopoiesis and thrombopoiesis through binding to and activation of the cytokine receptor, c-Mpl, which is express on hematopoietic stem sells (HSCs), on cells of the megakaryocyte lineage, and platelets.
- HSCs hematopoietic stem sells
- c-Mpl agonist that mimics the biological effects on thrombopoietin.
- This compound is disclosed in WO03/062233 (Example 16) and WO04/029049 (as the maleic acid salt), which are incorporated by reference in their entireties.
- the chemical name for Formula I is l-(3-chloro-5- ⁇ [4-(4-chlorothiophen-2-yl)- 5-(4-cyclohexylpi ⁇ erazin- 1 -yl)thiazol-2-yl] carbamoyl ⁇ pyridin-2-yl)piperadine-4- carboxylic acid.
- the present invention provides an oral dosage form for treatment of thrombocytopenia, comprising a therapeutically effective amount of l-(3- chlo ⁇ o-5- ⁇ [4-(4-chlorothiophen-2 yl)-5-(4-cyclohexylpiperazin-l-yl)thiazol-2-yl] carbamoyl ⁇ pyridm-2-yl)piperadine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient, wherein said therapeutically effective amount is a single dose ranging from about lmg to about lOOmg, said single dose providing an increase in platelet count from baseline in a human patient in need thereof of at least about 25%.
- the present invention provides n oral dosage form for treatment of thrombocytopenia, comprising a therapeutically effective amount of l-(3- chloro-5- ⁇ [4-(4-chlorothiophen-2 yl)-5-(4-cyclohexylpiperazin-l-yl)thiazol-2-yl] carbamoyl ⁇ pyridin-2-yl)piperadine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient, wherein said therapeutically effective amount is a single dose ranging from about lmg to about lOOmg, wherein said single dose achieves a mean maximum plasma concentration (C max ) of from about 5.7 ng/ml to about 475 ng/ml.
- C max mean maximum plasma concentration
- the present invention is directed to an oral pharmaceutical dosage form comprising a pharmaceutically acceptable excipient and aneffective amount of the drug of Formula I or a pharmaceutically acceptable salt thereof, to increaseplatelet levels in humans, the dosage form providing a mean maximum plasma concentration (Cmax) of from about 3 ng/ml to about 8 ng/ml for each 1 mg of the drug included in the dosage form, after single dose administration to human subjects.
- Cmax mean maximum plasma concentration
- the present invention is directed to an oral pharmaceutical dosage form comprising a pharmaceutically acceptable excipient and aneffective amount of the drug of Formula I or a pharmaceutically acceptable salt thereof, to increase platelet levels in humans, the dosage form providing a mean AUCO-24 of from about 50 ng*hr/ml to about 250 ng*hr/ml for each 1 mg of the drug included in the dosage form, after single dose administration to human subjects.
- the present invention is directed to an oral pharmaceutical dosage form comprising a pharmaceutically acceptable excipient and aneffective amount of the drug of Formula I or a pharmaceutically acceptable salt thereof, to increase platelet levels in humans, the dosage form providing an elimination half-life (T 1 / 2 ) of from about 10 hours to about 25 hours after single dose administration to human subjects.
- T 1 / 2 elimination half-life
- the present invention is also directed to methods of treating or preventing thrombocytopenia utilizing any of the formulations of Formula I disclosed herein.
- the invention is directed to a method of treating thrombocytopenia, comprising orally administering a single daily dose of l-(3-chloro-5- ⁇ [4-(4-chlorothiophen-2yl)-5-(4-cyclohexyIpiperazin- 1 -yl)thiazol-2-yl] carbamoyl ⁇ pyridin-2-yl)piperadine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof in an amount from about lmg to about lOOmg to achieve a mean maximum plasma concentration (C m _ ⁇ ) of from about 5.7 ng/ml to about 475 ng/ml.
- C m _ ⁇ mean maximum plasma concentration
- the term "provide a increase in platelet levels” shall mean an increase in a subject's or patient's platelets from baseline that is at least about 25%; preferably at least about 50%; more preferably greater than 50%.
- drug of Formula I shall mean l-(3-chloro-5 ⁇ [4-(4-chlorothiophen-2- yl)-5-(4-cyclohexylpiperazin-l -yl)thiazol-2-yl] carbamoyl ⁇ pyridin-2-yl)piperadine-4- carboxylic acid and any pharmaceutically acceptable salt, hydrate, solvate, polymorph, metabolite, derivative, pro-drug, free-base or any combination thereof.
- human subject shall mean a normal healthy male or female volunteer and/or any individual that presents with clinical signs and symptoms of thrombocytopenia or any disease or disorder that may cause thrombocytopenia.
- thrombocytopenia shall mean any and all disease related thrombocytopenias, which include, but are not limited to, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), disseminated intravascular coagulation (DIC), paroxysmal nocturnal hemoglobinuria (PNH), antiphospholipid syndrome, systemic lupus erythematosus (SLE), post transfusion purpura, neonatal alloimmune thrombocytopenia (NAITP), splenic sequestration of platelets due to hypersplenism, dengue fever, thrombocytopenia of myelodysplastic syndromes (MDS), and chemotherapy-induced thrombocytopenia) either as a substitute for, or in combination with s platelet transfusion, Hepatitis C.
- ITP idiopathic thrombocytopenic purpura
- TTP thrombotic
- thrombocytopenia also shall mean other disease processes that can cause decreased platelets such as, but are not limited to vitamin B12 or folic acid deficiency; leukemia; decreased production of thrombopoietin by the liver in liver failure; sepsis, systemic viral or bacterial infection; hereditary syndromes including, but not limited to, Congenital Amegakaryocytic Thrombocytopenia (CAMT), thrombocytopenia absent radius syndrome, Fanconi anemia, Bernard-Soulier syndrome, May-Hegglin anomaly; Grey platelet syndrome; and Alport syndrome.
- CNT Congenital Amegakaryocytic Thrombocytopenia
- Fanconi anemia Bernard-Soulier syndrome
- May-Hegglin anomaly May-Hegglin anomaly
- Grey platelet syndrome and Alport syndrome.
- bioequivalent or “bioequivalence” is a term of art and is intended to be defined in accordance with Approved Drug Products with Therapeutic Equivalence Evaluations, 15th Edition, pages vii-xvii, which is published by the U.S. Department of Health and Human Services, and is commonly known as the "Orange Book”.
- Bioequivalence of different formulations of the same drug substance involves equivalence with respect to the rate and extent of drug absorption. The extent and rate of absorption of the test formulation is compared to a reference formulation in order to determine whether the two formulations are bioequivalent.
- the standard bioequivalence study is conducted in crossover fashion by extensive testing which includes administering single doses of the test and reference drugs to a number of volunteers, usually 12 to 24 healthy normal adults, and then measuring the blood or plasma levels of the drug over time.
- Detailed guidelines for establishing the bioequivalence of a formulation with a reference formulation have been published by the FDA Office of Generic Drugs, Division of Bioequivalence.
- Figure 1 depicts a graph of the mean maximum change from baseline platelet count from Example 1.
- Figure 2 depicts a graph of the mean maximum change from baseline platelet count from Example 2.
- Figure 3 depicts a graph of the average concentration profiles of the three doses of drug administered in Example 3.
- the compound of Formula I did not promote the differentiation of human hematopoietic progenitor cells, other than those of megakaryocytic lineage.
- the compound of Formula I does not interfere with rhTPO binding to human platelets at concentrations up to lOO ⁇ M suggesting that the site of action of Formula I on human c-Mpl differs from that of rhTPO. It is highly species specific, showing activity only in the chimpanzee and man. While the compound of Formula I enhances human platelet proliferation and differentiation, it does not appear to effect platelet function as measured by platelet aggregation and activation. [0028] After single intravenous administration of drug of Formula I as the monomaleate salt to mice and dogs, plasma concentrations of Formula I decreased in a biphasic manner. The terminal elimination half-life (ti /2 ) was 2.7 hours in both species. Following oral administration, Formula I is well absorbed having an absolute bioavailability of 91% in the mouse and 52% in the dog.
- the in-vitro plasma protein binding of drug of Formula I was independent of concentration over the concentration range of 0.05 to 50 ⁇ g/mL and was 87.2 — 89.1% in mice; 87.6 - 89.2 % in rats; 88.3 - 92.0 % in rabbits; 97.3 - 97.9.6% in dogs; 97.0 - 97.6 in monkeys; and 96.3 - 96.6% in humans.
- the drug of Formula I does not appear to be metabolized by mouse, dog or human liver microsomal enzymes and did not inhibit the major human liver cytochrome P450 isoenzymes (CYPl A2, 2C9, 2C19, 2D6 and 3A4). Drug of Formula I does not appear to possess a liability for drug-drug interactions due to metabolic inhibition of cytochrome P450 liver enzymes.
- the present invention is directed to a method of treating thrombocytopenia, comprising orally administering a single daily dose of l-(3-chloro-5- ⁇ [4-(4-chlorothiophen-2yl)-5-(4-cyclohexylpiperazin-l-yl)thiazol-2-yl] carbamoyl ⁇ pyridin-2-yl)piperadine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof in an amount from about lmg to about lOOmg to achieve a mean maximum plasma concentration (C max ) of from about 5.7 ng/ml to about 475 ng/ml.
- C max mean maximum plasma concentration
- Administration of the single daily dose achieves a mean AUCo-i ast of from about 130 ng-hr/ml to about 10864 ng-hr/ml; a mean ti/ 2 of from about 18 to about 24 hours; and a mean time to maximum plasma concentration (T m ax) from about 4.7 to about 6.2 are achieved.
- a mean maximum plasma concentration (C max ) of about 25 ng/ml; a mean AUCo-iast of about 659 ng-hr/ml; and mean time to maximum plasma concentration (T ma ⁇ ) from about 6.0 are achieved.
- a mean maximum plasma concentration (C ma ⁇ ) of about 94 ng/ml; a mean AUCo-i ast of about 2364 ng-hr/ml; and a mean time to maximum plasma concentration (T max ) of about 4.4 are achieved.
- a mean maximum plasma concentration (C max ) of about 204 ng/ml; a mean AUCo-i ast of about 3610 ng-hr/ml; and a mean time to maximum plasma concentration (T max ) of about 5.5 are achieved.
- the present invention provides an oral dosage form for treatment of thrombocytopenia, comprising a therapeutically effective amount of l-(3- chloro-5- ⁇ [4-(4-chlorothiophen-2 yl)-5-(4-cydohexylpiperazin-l-yl)thiazol-2-yl] carbamoyl ⁇ pyridin-2-yl)piperadine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient, wherein said therapeutically effective amount is a single dose ranging from about lmg to about lOOmg, said single dose providing an increase in platelet count from baseline in a human patient in need thereof of at least about 25%.
- the dosage form of the present invention achieves: i) a mean maximum plasma concentration (Cmax) of from about 5.7 ng/ml to about 475 ng/ml; ii) a mean AUCo-iast of from about 130 ng «hr/ml to about 10864 ng*hr/ml; and iii) a mean t
- Cmax mean maximum plasma concentration
- the present invention is directed to an oral pharmaceutical dosage form comprising a pharmaceutically acceptable excipient and an effective amount of the drug of Formula I or a pharmaceutically acceptable salt thereof, to increase platelet levels in humans, the dosage form providing a mean maximum plasma concentration (Cmax) of from about 3 ng/ml to about 8 ng/ml for each 1 mg of the drug included in the dosage form, after single dose administration to human subjects.
- Cmax mean maximum plasma concentration
- the formulation comprises 3 mg of the drug and provides a mean maximum plasma concentration (C max ) of from about 9 ng/ml to about 24 ng/ml or from about 13 ng/ml to about 19 ng/ml, after single dose administration to human subject.
- C max mean maximum plasma concentration
- the formulation comprises 10 mg of the drug and provides a mean maximum plasma concentration (C m a x ) of from about 30 ng/ml to about 80 ng/ml or from about 50 ng/ml to about 75 ng/ml, after single dose administration to human subjects.
- C m a x mean maximum plasma concentration
- the formulation comprises 20 mg of the drug and provides a mean maximum plasma concentration (C max ) of from about 60.0 ng/ml to about 160.0 ng/ml or from about 130 ng/ml to about 155 ng/ml, after single dose administration to human subjects.
- C max mean maximum plasma concentration
- the formulation comprises 50 mg of the drug and provides a mean maximum plasma concentration (C m3x ) of from about 150.0 ng/ml to about 400 ng/ml or from about 250 ng/ml to about 350 ng/ml, after single dose administration to human subjects.
- C m3x mean maximum plasma concentration
- the formulation comprises 75 mg of the drug and provides a mean maximum plasma concentration (C max ) of from about 225 ng/ml to about 600 ng/ml or from about 400 ng/ml to about 500 ng/ml, after single dose administration to human subjects.
- C max mean maximum plasma concentration
- the formulation comprises 100 mg of the drug and provides a mean maximum plasma concentration (C m ax) of from about 300 ng/ml to about 800 ng/ml or from about 325 ng/ml to about 425 ng/ml, after single dose administration to human subjects.
- C m ax mean maximum plasma concentration
- the present invention is directed to an oral pharmaceutical dosage form comprising a pharmaceutically acceptable excipient and an effective amount of the drug of Formula I or a pharmaceutically acceptable salt thereof, to increase platelet levels in humans, the dosage form providing a mean AUCo- 24 of from about 50 ng-hr/ml to about 250 ng-hr/ml for each 1 mg of the drug included in the dosage form, after single dose administration to human subjects.
- the formulation comprises 3 mg of the drug and provides a mean AUCo-24 of from about 150 ng-hr/ml to about 750 ng-hr/ml or from about 400 ng-hr/ml to about 550 ng-hr/ml, after single dose administration to human subjects.
- the formulation comprises 10 mg of the drug and provides a mean AUCo-24 of from about 500 ng-hr/ml to about 2500 ng-hr/ml or from about 1500 ng-hr/ml to about 2400 ng-hr/ml, after single dose administration to human subjects.
- the formulation comprises 20 mg of the drug and provides a mean AUCo- 2 4 of from about 1000 nghr/ml to about 5000 ng-hr/ml or from about 3500 ng-hr/ml to about 4500 ng-hr/ml, after single dose administration to human subjects.
- the formulation comprises 50 mg of the drug and provides a mean AUCo- 24 of from about 2500 ng hr/ml to about 12500 ng-hr/ml or from about 8000 ng-hr/ml to about 10000 ng-hr/ml, after single dose administration to human subjects.
- the formulation comprises 75 mg of the drug and provides a mean AUCo- 24 of from about 3750 ng-hr/ml to about 18750 ng-hr/ml or from about 300 ng-hr/ml to about 635 ng-hr/ml, after single dose administration to human subjects.
- the formulation comprises 100 mg of the drug and provides a mean AUCo-24 of from about 5000 ng-hr/ml to about 25000 or from about 11000 ng-hr/ml to about 14000 ng-hr/ml, after single dose administration to human subjects.
- the present invention is directed to an oral pharmaceutical dosage form comprising a pharmaceutically acceptable excipient and an effective amount of the drug of Formula I or a pharmaceutically acceptable salt thereof, to increase platelet levels in humans, the dosage form providing an elimination half-life (T1/2) of from about 10 hours to about 25 hours, from about 12 hours to about 18 hours or from about 14 hours to about 16 hours, after single dose administration to human subjects.
- T1/2 elimination half-life
- the present invention is directed to formulations and methods as disclosed herein, wherein the mean change in platelet count from baseline is increased by at least about 25%, at least about 50%, at least about 75%, at least about 100% or at least about 150%; or from about 25% to about 200% or from about 75% to about 150%. In certain embodiments, the platelet count is increased from baseline by greater than 50%.
- the drug of Formula I may be in the form of the free base, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, metabolite, derivative or any combination of the foregoing.
- Pharmaceutically acceptable salts may include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like; salts with an inorganic base such as sodium, potassium, magnesium, calcium, and the like; salts with an organic base such as methylamine
- the drug of Formula I is in the form of the monomaleate salt.
- the drug of Formula I may be contained in an oral dosage form together with pharmaceutically acceptable excipients in an immediate release oral dosage form.
- the immediate release dosage forms of the present invention include, but are not limited to, tablets, soft or hard gelatin capsules, solutions or suspensions.
- compositions and dosage forms of the invention preferably contain one or more pharmaceutically acceptable excipients.
- excipients include, but are not limited to, carriers, diluents, fillers, lubricants and glidants.
- Carriers, diluents and fillers suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, cellulose (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, and cellulose acetate), dextrates, dextrin, dextrose (glucose), fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, matitol, maltodextrins, maltose, sorbitol, starch (e.g., pregelatinized starch), sucrose, sugar, and xylitol.
- calcium carbonate calcium phosphate
- dibasic calcium phosphate tribasic calcium sulfate
- calcium carboxymethylcellulose cellulose
- cellulose e.g., microcrystalline cellulose, silicified microcrystalline cellulose, and cellulose acetate
- Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil (e.g., com oil, cottonseed oil, olive oil, peanut oil, sesame oil, soybean oil, and sunflower oil), magnesium oxide, magnesium stearate, mannitol, poloxamer, glycols (e.g., polyethylene glycol), sodium benzoate, sodium lauryl sulfate, sodium stearyl, sorbitol, stearic acid, talc, zinc stearate, and mixtures thereof.
- agar calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate
- hydrogenated vegetable oil e.g., com oil, cottons
- Glidants include, for example, coagulated aerosols of synthetic silica colliodal silicon dioxide, magnesium trisilicate, powdered cellulose, pyrogenic silicon dioxide products (e.g., CAB-O-SIL sold by Cabot Co. of Boston, Mass.), starch, syloid silica gels (e.g., AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), talc, tribasic calcium phosphate, and mixtures thereof. If used, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
- Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form the compositions of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
- Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, algins (e.g., alginic acid), calcium carbonate, carboxmethylcellulose, cellulose (e.g., hydroxypropyl cellulose, microcrystalline cellulose, and silicified microcrystalline cellulose), clays, colloid silicon dioxide, croscarrnellose sodium, crospovidone, gums, magnesuim aluminium silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, starch (e.g., pregelatinized starch, potato starch, and tapioca starch), and mixtures thereof.
- algins e.g., alginic acid
- calcium carbonate e.g., carboxmethylcellulose
- cellulose e.g., hydroxypropyl cellulose, microcrystalline cellulose, and silicified microcrystalline cellulose
- clays e.g., colloid silicon dioxide,
- compositions and dosage forms can also contain wetting, emulsifying, and pH buffering agents.
- Other suitable fillers, binders, disintegrates, lubricants and additional excipients which may be used are described in Handbook of Pharmaceutical Excipients, 2nd Edition, American Pharmaceutical Association; The Theory and Practice of Industrial Pharmacy, 2nd Edition, Lachman, Leon, 1976; Pharmaceutical Dosage Forms: Tablets Volume 1, 2.sup.nd Edition, Lieberman, Hebert A., et al, 1989; Modern Pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 1979; and Remington's Pharmaceutical Sciences, 20 th Edition, 2000.
- compositions of the invention suitable for administration can be presented as discrete dosage forms, such as capsules (e.g., gelcaps), caplets, tablets, troches, lozenges, dispersions, and suppositories each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
- capsules e.g., gelcaps
- caplets e.g., caplets, tablets, troches, lozenges, dispersions, and suppositories each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
- Dosage forms of the present invention can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the excipient, which constitutes one or more necessary ingredients, hi general, the compositions are prepared by uniformly admixing the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping . the product into the desired presentation. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
- the pharmaceutical composition of the invention may be prepared, using standard techniques and manufacturing processes generally known in the art, for example by dry blending the components.
- the active agent, one or more fillers, one or more optional excipients e.g., binders and/or disintegrants, as well as other additional optional excipients
- the components of the blend prior to blending, or the blend itself may be passed through a mesh screen, for example a 400-700 um mesh screen.
- a lubricant which may also be screened, is then added to the blend and blending continued until a homogeneous mixture is obtained.
- the mixture is then compressed into tablets.
- a wet granulation technique can be employed.
- the active agent and excipient(s) are blended together, for example by using a granulator, and the powder blend is granulated with a small volume of purified water.
- the granulate is dried and passed though a mill.
- the remainder of the disintegrant and a lubricant are added to the milled granulation and after blending the resultant homogeneous mixture is compressed into tablets.
- modifications of the dry blending and wet granulation techniques including the order of addition of the components and their screening and blending prior to compression into tablets, may be carried out according to principles well known in the art.
- a tablet coating may then be applied, for example by spray-coating.
- a water- based film coating formulation may comprise, for example, lactose, hydroxypropyl methylcellulose, triacetin, titanium dioxide and ferric oxides.
- the drug of Formula I is contained in a liquid oral dosage form such an elixir, emulsion, syrup, solution or suspension. Initially, drug of Formula I may be dissolved prior to incorporation into a liquid dosage form by utilizing any pharmaceutically acceptable solvent.
- suitable solvents for use in the present invention may include, but are not limited to, alcohol, glycerin, propylene glycol, water (purified or sterile) and the like.
- the liquid dosage forms of the present invention may contain any pharmaceutically acceptable excipient suitable for use in liquid dosage forms.
- the liquid dosage forms of the present invention may optionally contain one or more antioxidants, if necessary, taste modifiers, flavors or flavoring agents, sweeteners, glidants, suspending agents, anti-caking agents, emulsifying agents, buffering agents, and preservatives.
- Suitable suspending agents include, but are not limited to, sodium and calcium carboxymethylcelluloses, microcrystalline cellulose, xanthan gum, carrageenan and any combinations and mixtures thereof.
- Suitable sweeteners may be any convenient agent(s) known in the art for this purpose and may be selected from any compatible sweetener groups such as natural sweeteners like sucrose, fructose, glucose, dextrose, xylitol, sorbitol, or manitol, as well as artificial sweeteners such as aspartame, saccharin, acesulfame K and sucrolose.
- natural sweeteners like sucrose, fructose, glucose, dextrose, xylitol, sorbitol, or manitol
- artificial sweeteners such as aspartame, saccharin, acesulfame K and sucrolose.
- Suitable flavors and flavoring agents may include, but are not limited to, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits, and so forth and combinations thereof.
- Suitable oils include, for example, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil.
- Additional suitable flavoring agents include, for example, vanilla, citrus oil (e.g., lemon, orange, grape, lime, grapefruit), citric acid, menthol, glycine, orange powder, cream, chocolate, mocha, spearmint, and cola.
- Suitable flavor essences include, for example, apple, apricot, banana, cherry, peach, pear, pineapple, plum, raspberry, strawberry, licorice flavor, orange vanilla flavor, creme de mint, cherry vanilla flavor, berry mix flavor, passion fruit flavor, mandarin orange flavor, bubble gum flavor, tropical punch flavor, juicy compound for grape, grape flavor, artificial grape flavor, grape bubble gum flavor, and tutti-frutti-flavor, and any combinations or mixtures thereof.
- Suitable anti-caking agents include, but are not limited to, colloidal silicon dioxide, talc, tribasic calcium phosphate and any combinations or mixtures thereof.
- Those skilled in the art will understand how to select a suitable amount of anti-caking agent.
- the amount of anti- caking agent should be such that a firm, difficult to resuspend (beyond mild physical agitation) cake does not form under normal conditions of transportation and storage, but not an amount which causes gelation.
- Suitable preservative for use in the present invention include, but are not limited to, parabens, benzyl alcohol, sodium benzoate, phenol, benzalkonium chloride, thimerosal, chlorobutanol, benzoic acid, sodium bisulfite, sodium proprionate and any combinations or mixtures thereof.
- benzyl alcohol sodium benzoate
- phenol benzalkonium chloride
- thimerosal chlorobutanol
- benzoic acid sodium bisulfite
- sodium proprionate sodium bisulfite
- any combinations or mixtures thereof any combinations or mixtures thereof.
- the amount of preservative used in any particular dosage form is a function of, in large part, the exact preservative used, the pH of the dosage form, and the other components comprising the liquid dosage form.
- Buffering agents suitable for use in the present invention include, but are not limited to, sodium phosphate dibasic anhydrous, sodium phosphate monobasic, and any combinations and mixtures thereof.
- Additional excipients suitable for use in the present invention can be found in the Handbook of Pharmaceutical Excipients, 4 th Edition 2003), the disclosure of which is hereby incorporated by reference.
- the liquid dosage forms of the present invention may be prepared using a pre-manufactured vehicle such as, but not limited to, Ora-Plus , Ora- Blend ® ; Ora-Blend ® SF; Suspendol-STM; Ora-Sweet ® ; Ora-Sweet ® SF (all manufactured by Paddock Laboratories, Inc.) and the like.
- a pre-manufactured vehicle such as, but not limited to, Ora-Plus , Ora- Blend ® ; Ora-Blend ® SF; Suspendol-STM; Ora-Sweet ® ; Ora-Sweet ® SF (all manufactured by Paddock Laboratories, Inc.) and the like.
- the drug substance in the form of the monomaleate salt was suspended in Ora-Plus® (purified water, microcrystalline cellulose, sodium carboxymethylcellulose, xanthan gum, citric acid, sodium phosphate, simethicone, potassium sorbate and methylparaben), a commercially available oral suspending vehicle manufactured by Paddock Laboratories, Inc. Minneapolis, MN.
- the Ora-Plus® was diluted with purified water, USP in a L:l suspension before being used to suspend the drug substance powder in preparation for oral administration. Prior to administration, 30 mL of the Ora-Plus®/ water vehicle was added to each bottle, shaken and then consumed by the subject for each of the 3, 10, 50 and 75mg dose cohorts.
- a minimum of 9 subjects male and female healthy volunteers were enrolled in each cohort.
- the active group within each cohort included male and female volunteers.
- Three subjects per cohort received placebo.
- Each successive dose cohort was treated no sooner than 10 days after the previous group had received the study drug.
- Dose escalation in succeeding groups did not proceed until all safety and pharmacodynamic parameters from Day 7 were reviewed by the Investigator and Sponsor.
- Each subject received only 1 dose of Formula I. Intra-subject dose escalation and treating previously treated subjects in any cohort expansions were not allowed. All subjects were followed until there platelet count returned to normal levels (defined as ⁇ 20% of baseline).
- PD limit dose limiting toxicity
- a double-blind, placebo-controlled, dose rising study was performed in healthy male and female volunteers. Each dose cohort received either placebo or active treatment as an oral suspension once daily for fourteen (14) consecutive days. The dose of study drug was prepared and administered as described in Example 1 above. The doses administered in this multiple dose study were based on the safety and tolerability assessment of the doses administered in Example 1. The dose level in this study always remained at least one dose level lower than the next highest dose level at which dose safety and tolerability were demonstrated in Example 1.
- Example 1 Based on the results of Example 1, the starting dose was 3 mg. Based on the safety and tolerability results from Example 1 , the dose was scheduled to be escalated to 10, 20, 50 and 100 mg per day for 14 consecutive days. Successive dose cohorts were not treated until the previous cohort completed 14 days of treatment and the safety follow-up visit on Day 21. Dose escalation from 50mg to lOOmg did not proceed as the study was discontinued after enrollment of the 20mg cohort due to the fact that all subjects had reached a PD limit platelelt count (> 500,000mm 3 ).
- the t)/2 of the drug was independent of dose and was estimated to be approximately 18 to 21 hours.
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Abstract
Description
Claims
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ES07811274.5T ES2452032T3 (en) | 2006-08-08 | 2007-08-08 | Compositions and methods to increase blood platelet levels in humans |
EP07811274.5A EP2056826B1 (en) | 2006-08-08 | 2007-08-08 | Compositions and methods for increasing blood platelet levels in humans |
AU2007284644A AU2007284644B2 (en) | 2006-08-08 | 2007-08-08 | Compositions and methods for increasing blood platelet levels in humans |
JP2009523867A JP2010500361A (en) | 2006-08-08 | 2007-08-08 | Compositions and methods for increasing human platelet levels |
CA2660283A CA2660283C (en) | 2006-08-08 | 2007-08-08 | 2-acylaminothiazole compositions and methods for increasing blood platlelet levels in humans |
IL196897A IL196897A (en) | 2006-08-08 | 2009-02-04 | Dosage forms of compositions based on 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl] carbamoyl} pyridin-2yl)piperadine-4-carboxylic acid or salts thereof, for increasing blood platelet levels in humans |
IL240322A IL240322A0 (en) | 2006-08-08 | 2015-08-03 | Dosage forms of compositions based on 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl). (4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyli}pyridin-2yl)piperadine- carboxylic acid or salts thereof, for increasing blood platelet levels in humans |
IL240323A IL240323A (en) | 2006-08-08 | 2015-08-03 | Dosage forms of compositions based on 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl). (4-cyclohexylpiperazin-1-yl)thiazol-2-yl] carbamoyl} pyridin-2yl)piperidine-carboxylic acid or salts thereof, for increasing blood platelet levels in humans |
IL245911A IL245911A0 (en) | 2006-08-08 | 2016-05-29 | Compositions and methods for increasing blood platelet levels in humans |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011019990A1 (en) * | 2009-08-14 | 2011-02-17 | Eisai, Inc. | Use of e5501 for stimulating platelet production |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4120586B2 (en) * | 2002-01-18 | 2008-07-16 | アステラス製薬株式会社 | 2-acylaminothiazole derivatives or salts thereof |
CN112022825B (en) * | 2020-08-24 | 2024-03-22 | 瑞阳制药股份有限公司 | Atorvastatin maleate tablet and preparation method thereof |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5330998A (en) * | 1988-03-08 | 1994-07-19 | Pfizer Inc. | Thiazolidinedione derivatives as hypoglycemic agents |
US5256675A (en) * | 1989-08-07 | 1993-10-26 | Fujisawa Pharmaceutical Co., Ltd. | Thiazole derivatives, processes for production thereof and pharmaceutical compositions comprising the same |
IE68593B1 (en) * | 1989-12-06 | 1996-06-26 | Sanofi Sa | Heterocyclic substituted acylaminothiazoles their preparation and pharmaceutical compositions containing them |
FR2677356B1 (en) * | 1991-06-05 | 1995-03-17 | Sanofi Sa | HETEROCYCLIC DERIVATIVES OF SUBSTITUTED ACYLAMINO-2 THIAZOLES-5, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
US5250732A (en) * | 1991-07-18 | 1993-10-05 | Genentech, Inc. | Ketamine analogues for treatment of thrombocytopenia |
GB9126677D0 (en) * | 1991-12-16 | 1992-02-12 | Johnson Matthey Plc | Improvements in chemical compounds |
DE59401177D1 (en) * | 1993-04-08 | 1997-01-16 | Abb Management Ag | Mixing and flame stabilization device in a combustion chamber with premix combustion |
EP0768311B1 (en) * | 1995-03-09 | 2003-08-06 | Kyowa Hakko Kogyo Co., Ltd. | Pyrrolocarbazole derivatives |
WO1996033973A1 (en) * | 1995-04-28 | 1996-10-31 | Banyu Pharmaceutical Co., Ltd. | 1,4-disubstituted piperidine derivatives |
BR9608587A (en) * | 1995-06-07 | 1999-01-05 | Glaxo Group Ltd | Compound that binds to the thrombopoietin receptor pharmaceutical composition and process for treating a patient suffering from a disorder |
US5963666A (en) * | 1995-08-18 | 1999-10-05 | International Business Machines Corporation | Confusion matrix mediated word prediction |
CA2207656A1 (en) * | 1995-10-17 | 1997-04-24 | Suntory Limited | Therapeutics for thrombocytopenia |
US5932546A (en) * | 1996-10-04 | 1999-08-03 | Glaxo Wellcome Inc. | Peptides and compounds that bind to the thrombopoietin receptor |
US6187797B1 (en) * | 1996-12-23 | 2001-02-13 | Dupont Pharmaceuticals Company | Phenyl-isoxazoles as factor XA Inhibitors |
JP2002526482A (en) * | 1998-09-18 | 2002-08-20 | バーテックス ファーマシューティカルズ インコーポレイテッド | inhibitors of p38 |
EP1133291B1 (en) * | 1998-11-17 | 2006-01-11 | Smithkline Beecham Corporation | Cyclic polyamines for treating thrombocytopenia |
TWI284639B (en) * | 2000-01-24 | 2007-08-01 | Shionogi & Co | A compound having thrombopoietin receptor agonistic effect |
GB0028383D0 (en) * | 2000-11-21 | 2001-01-03 | Novartis Ag | Organic compounds |
WO2002062792A1 (en) * | 2001-02-02 | 2002-08-15 | Takeda Chemical Industries, Ltd. | Jnk inhibitor |
EP1357116A4 (en) * | 2001-02-02 | 2005-06-01 | Yamanouchi Pharma Co Ltd | 2-acylaminothiazole derivative or its salt |
JP4120586B2 (en) * | 2002-01-18 | 2008-07-16 | アステラス製薬株式会社 | 2-acylaminothiazole derivatives or salts thereof |
MXPA05000130A (en) * | 2002-06-27 | 2005-02-17 | Novo Nordisk As | Aryl carbonyl derivatives as therapeutic agents. |
JP4317818B2 (en) | 2002-09-30 | 2009-08-19 | アステラス製薬株式会社 | Novel salt of 2-acylaminothiazole derivative |
EP1610793A2 (en) * | 2003-03-25 | 2006-01-04 | Vertex Pharmaceuticals Incorporated | Thiazoles useful as inhibitors of protein kinases |
US7361658B2 (en) * | 2003-07-17 | 2008-04-22 | Astellas Pharma Inc. | 2-acylaminothiazole derivative or salt thereof |
KR100776961B1 (en) * | 2003-08-12 | 2007-11-28 | 시오노기세이야쿠가부시키가이샤 | Compounds having thrombopoietin receptor agonism |
KR20080074166A (en) * | 2005-11-08 | 2008-08-12 | 아스테라스 세이야쿠 가부시키가이샤 | Compositions and methods for treating thrombocytopenia |
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- 2016-05-29 IL IL245911A patent/IL245911A0/en unknown
Non-Patent Citations (2)
Title |
---|
None |
See also references of EP2056826A4 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011019990A1 (en) * | 2009-08-14 | 2011-02-17 | Eisai, Inc. | Use of e5501 for stimulating platelet production |
JP2013501811A (en) * | 2009-08-14 | 2013-01-17 | エーザイ インコーポレーテッド | Use of E5501 to stimulate platelet production |
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AU2011253775A1 (en) | 2011-12-22 |
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