New pharmaceutical compositions

Abstract

To provide a novel pharmaceutical composition and a process for preparing the same.SOLUTION: There are provided a novel pharmaceutical composition containing 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine) (eltrombopag olamine) and a process for preparing the same.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a compound represented by the following formula (I): [ka] (Compound B) and hereinafter referred to as "eltrombopagulamine" or compound B. (2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5- Oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1 '-biphenyl]-3-carboxylic acid bis-(monoethanolamine), granules and It relates to solid oral pharmaceutical dosage forms. [Background technology]

[0002] 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1, 5-Dihydropyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl- 3-Carboxylic acid (hereinafter, Compound A) is a pharma- ceutical acceptable salt, hydrate, solvate, and the like thereof. and esters, as disclosed in Patent Document 1 (filed internationally on May 24, 2001; It was published internationally on January 29th (Patent Document 2); it was published in the United States on January 29th, 2004 ( Patent Document 3); currently, Patent Document 4 (issued January 9, 2007) (by citing the source, In particular, the present invention relates to the enhancement of platelet production and and compounds useful as agonists of the TPO receptor in the treatment of thrombocytopenia. .

[0003] The bis-(monoethanolamine) salt of this compound is disclosed in Patent Document 5 (May 21, 2003). International application filed on the same day; International publication on December 4, 2003 (Patent Document 6); August 2006 This is disclosed in Patent Document 7, published in the United States on the 10th of this month (with the source indicated). (3'-[(2Z)-[1-(3,4-dimethylphenyl (1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene) hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (also referred to as Compound A).

[0004] Compound A is disclosed in US Pat. No. 5,399,433 issued on Apr. 29, 2004 to the U.S. Patent Application Publication No. 2004 / 0123669 for the treatment of degenerative diseases / injuries. Patent application filed on November 11, 2004; published internationally on May 1, 2007 (Patent Document 9). This is disclosed in Patent Document 10, published in the United States on the 0th (by citation, (which is incorporated herein in its entirety).

[0005] Compositions which may contain compound A and / or compound B are disclosed in U.S. Pat. No. 5,399,433 and U.S. Pat. No. 5,499,443. 2 and U.S. Pat. No. 5,399,433.

[0006] Solid oral pharmaceutical dosage forms are a common and useful form of drug therapy for dispensing pharmacologic active compounds. It is available in a wide range of forms including tablets, capsules, pellets, lozenges and powders. Such forms are known.

[0007] However, the formulation of acceptable solid oral pharmaceutical dosage forms on a commercial scale usually requires straightforward The product recipe and manufacturing process must be completely consistent and maintain their integrity until use. The solid dosage form must be such that it provides a satisfactory solid dosage form that satisfies the desired characteristics during use. The drug must have acceptable dissolution and disintegration properties to provide have low solubility and / or Pharmaceutically active compounds that may react with commonly used excipients must be prepared in high quality solid dosage forms. Formulators must develop solid dosage forms that are safe, effective, and easy to use. To be formulated, the properties of each excipient must be balanced with the specific properties of the drug.

[0008] Eltrombopagolamine has desirable pharmacokinetic properties, especially at commercial scale. The compound is formulated into a suitable solid oral pharmaceutical dosage form, suitably a tablet, suitably a capsule, These concerns include: However, if it comes into contact with excipients that contain coordinating metals, it may cause The tendency of the compound to form soluble metal complexes, slowing the dissolution of the compound from solid dosage forms; reduction One example is the tendency of compounds to undergo the Maillard reaction when exposed to sugar-containing excipients. A significant realization of these concerns is the in vivo administration of eltrombopagulamine. would have a detrimental effect on [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Application No. PCT / US01 / 16863 [Patent Document 2] International Publication No. WO01 / 89457 [Patent Document 3] US Publication No. US2004 / 0019190 A1 [Patent Document 4] U.S. Patent No. 7,160,870 [Patent Document 5] International Application No. PCT / US03 / 16255 [Patent Document 6] International Publication No. WO03 / 098002 [Patent Document 7] US Publication No. US2006 / 0178518 A1 [Patent Document 8] International Application No. PCT / US04 / 013468 [Patent Document 9] International Publication No. WO 04 / 096154 [Patent Document 10] US Publication No. US2007 / 0105824 A1 [Patent Document 11] International Application No. PCT / US01 / 16863 [Patent Document 12] International Application No. PCT / US03 / 16255 [Patent Document 13] International Application No. PCT / US04 / 013468 Summary of the Invention [Problem to be solved by the invention]

[0010] Eltron in a commercial solid oral pharmaceutical dosage form with desirable pharmacokinetic properties It is desirable to provide bopagolamine. [Means for solving the problem]

[0011] The present invention relates to granules and solid oral pharmaceutical dosage forms comprising eltrombopagolamine, Suitably the solid dosage form is a tablet, suitably the solid dosage form is a tablet, suitably the solid dosage form is a tablet, suitably the solid dosage form is a tablet, The dosage forms are manufactured on a commercial scale.

[0012] The present invention provides granules and solid oral pharmaceuticals comprising a therapeutically effective amount of eltrombopagolamine. The present invention also relates to a dosage form comprising eltrombopagolamine, a granule, and a solid oral dosage form. The present invention relates to a method for producing a pharmaceutical dosage form.

[0013] Another aspect of the present invention is a diluent that is substantially free of reducing sugars (as defined herein and in the claims). and diluents containing no reducing sugars, and substantially free of coordination metals. As used herein and in the claims, diluents that do not contain a coordinated metal are Granules and solid tablets containing eltrombopagolamine, formulated using The present invention relates to an oral pharmaceutical dosage form, suitably a tablet, suitably a capsule. Such granules and solid oral The pharmaceutical dosage forms exhibit improved properties. Such improved properties are essential for safe and effective treatment. This helps to ensure that:

[0014] Another aspect of the present invention is a film-coated tablet comprising eltrombopagolamine. For pharmaceutical tablets, the film coating does not contain a coordination metal or 0.1% of compound B. Contains approximately equal to or less than 0.025 moieties of coordinated metal. Such tablets exhibit improved properties. Such improved properties contribute to safe and effective treatment. This helps to ensure proper placement.

[0015] Another aspect of the present invention is a method for preparing a drug product comprising administering to a patient a drug product comprising administering to said patient a drug product having a particle size of about 90% of said drug product in the range of 10 to 90 microns. Granules and solid oral dosage forms containing eltrombopagolamine, formulated in a range of particle sizes. Such tablets exhibit improved properties. helps ensure safe and effective treatment.

[0016] Another embodiment of the invention is a high percentage, suitably equal to or greater than 4%. A granule and solid oral pharmaceutical dosage form comprising eltrombopagolamine, the granule and solid pharmaceutical dosage form comprising a disintegrant in an amount of Such tablets exhibit improved properties. Such improved properties include safety, and helps to ensure effective treatment.

[0017] Another aspect of the present invention is to administer a therapeutically effective amount of the granule or solid oral pharmaceutical dosage form of the present invention to a patient suffering from thrombocytopenia. The present invention relates to a method for treating thrombocytopenia, comprising administering to a subject in need thereof a do.

[0018] Another aspect of the present invention is to administer a therapeutically effective amount of the granule or solid oral pharmaceutical dosage form of the present invention to a patient receiving TPO. The present invention relates to a method for stimulating a TPO receptor, comprising administering to a subject in need of said stimulation do.

[0019] The present invention also relates to a method for the preparation of a granule or solid oral pharmaceutical dosage form of the present invention, comprising administering the granule or solid oral pharmaceutical dosage form of the present invention simultaneously with a further active ingredient. Methods of administration are also included. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 shows a comparison of the dissolution of tablets containing eltrombopagulamine and a metal-containing diluent with tablets containing eltrombopagulamine and a non-metal-containing diluent. [Diagram 2] FIG. 2 shows the effect of API particle size on the dissolution of eltrombopagolamine from 75 mg tablets. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] As used herein, the term "coordination metal" and its derivatives refer to the Metal or metal-containing compounds that form complexes, such as chelate complexes, in the presence of olamines. This means excipients, suitably diluents, or tablet coating materials, including metals. Examples of such metals are aluminum, calcium, copper, cobalt, gold, iron, magnesium, Examples of zinc include arsenic, manganese and zinc.

[0022] As used herein, the term "reducing sugar" refers to a sugar that, when mixed together, reduces the A sugar or sugar-containing excipient that reacts with guanidine to form Maillard products, as appropriate By "diluents" is meant reducing sugars. Examples of such reducing sugars are lactose, maltose, glucose, and the like. These include cose, arabinose and fructose.

[0023] The term Maillard reaction is known in the art and is used herein in its standard sense. In general, the term Maillard reaction refers to the reaction that produces one or more pigments, suitably brown pigments. The present invention relates to a formulation, suitably in a granular or solid dosage form, comprising eltrombopagulamine. As used herein to mean the reaction of reducing sugars as defined herein. The pigments are Maillard products. The formation of such Maillard products is chemically unstable. It is a sign of sexuality.

[0024] As used herein, the term "improved properties" and its derivatives suitably refers to a formulation that When produced on a commercial scale, formulations using aspects of the invention are more effective than formulations not using aspects of the invention. The formulation, suitably granulated or non-granular, will vary depending on the particular embodiment of the invention being used. or the pharmacokinetic characteristics of in vivo release of Compound B from solid oral pharmaceutical dosage forms. Several advantages are intended. Examples of improved properties include increased oral bioavailability. Additives, reduced formation of insoluble metal complexes, improved chemical stability, consistent pharmacokinetic properties and and consistent dissolution rate.

[0025] As used herein, the term "drug" or "active ingredient" and its derivatives refer to Compound B or or eltrombopagulamine.

[0026] As used herein, the term "commercial scale" and its derivatives refers to any amount of food produced in a quantity greater than about 20 kg. Batch scale of granulated mixture is preferably more than 50 kg, and more preferably more than 75 kg. or at least about 50,000 tablets, suitably at least 75,000 A suitable batch size is required to prepare tablets, suitably at least 100,000 tablets. It is meant.

[0027] The diluent used in the specification and claims is substantially free of coordinated metals; and / or substantially free of reducing sugars, e.g., a small amount, e.g., about 5% or less of the diluent component is It is contemplated that the reducing sugar may contain multiple reducing sugars. The amount of coordinating metal and / or reducing sugar can be diluted without detrimental effects on tablet performance. The stabilizer may be incorporated into the stabilizer composition.

[0028] The term "effective amount" and its derivatives are explored, for example, by researchers and clinicians. Drugs that may produce biological or medical responses in tissues, systems, animals or humans and the amount of active ingredient. Moreover, the term "therapeutically effective amount" refers to the amount of active ingredient that is The ability to treat, cure, prevent, or administer a therapeutically effective amount of the compound to a patient in need of treatment, cure, or treatment of a disease, disorder, or adverse event, when compared to a non-treated control. "Any amount that results in improved or improved remission of a disease or disorder, or a decrease in the rate of progression of a disease or disorder" means any amount that results in improved or improved remission of a disease or disorder, or a decrease in the rate of progression of a disease or disorder. The term also includes within the range of amounts effective to enhance normal physiological function.

[0029] As used herein, the term "formulation" and its derivatives, unless otherwise defined, refers to an The term "granules and / or solid oral pharmaceutical dosage forms of the present invention containing thrombopaguolamine" refers to the granules and / or solid oral pharmaceutical dosage forms of the present invention containing thrombopaguolamine. .

[0030] As used herein, the term "co-administration" and its derivatives refer to the administration of granules and and / or solid oral pharmaceutical dosage forms, and chemotherapy-induced thrombocytopenia, and platelet production It is known to treat thrombocytopenia, including bone marrow transplantation and other conditions involving the suppression of Any manner of simultaneous administration or separate sequential administration of one or more further active ingredients. As used herein, the one or more additional active ingredients are TP Are there any known beneficial properties when administered with TPO or TPO mimetics? Preferably, if administration is not simultaneous, the compound or therapeutic agent is The compounds are administered close to each other. In addition, whether the compounds are administered in the same dosage form or not It does not matter, for example, one compound may be administered topically and another orally. It may be administered in

[0031] Examples of one or more additional active ingredients for use in combination with the formulations of the present invention include, but are not limited to, Although not specific, G-CSF, BB10010 (Clemons et al., Breast Cancer Research Treatment, 1999, 57, 127), amifostine (Ethyol) (Fetscher et al., Current Opi nion in Hemat., 2000, 7, 255-60), SCF, IL-11, MCP-4, IL-1-base AcSDKP (Gaudron et al., Stem Cells, 1999, 17, 100-6), TNF-a, TG Fb, MIP-1a (Egger et al., Bone Marrow Transpl., 1998, 22 (Suppl. 2), 34 -35) as well as chemoprotective or myeloprotective agents, such as anti-apoptotic, survival or proliferation specific agents. Other molecules that are known to have this property include:

[0032] As used herein, the term "granule" and its derivatives refer to particles prepared into a solid oral pharmaceutical dosage form. The eltrombopagulamine, the coordination metal, is substantially a diluent which is substantially free of reducing sugars and / or substantially free of reducing sugars, and suitably A pharmaceutical product is a formulated particle containing a compound and / or a lubricant and / or a disintegrant. It is also possible to administer the granules directly to a subject in need thereof. It is expected that the composition will be most suitably used in the preparation of the above solid oral pharmaceutical dosage forms.

[0033] As used herein, the terms "solid oral dosage form" and "solid dosage form" and their derivatives are intended to mean , tablets, capsules, pellets, lozenges and powders suitable for in vivo administration A final pharmaceutical preparation containing eltrombopagolamine, such as "Coated versions" refers to any coated version of the material.

[0034] Suitably, the granules and solid oral pharmaceutical dosage forms of the present invention comprise eltrombopagolamine, Diluents (also known as fillers or extenders) and, suitably, binders and and / or lubricants and / or disintegrants. Those skilled in the art will appreciate that certain materials are essential for tablet formulations. Although the material serves one or more functions within the product, it is typically included for its primary function. It will be recognized that the diluents, binders, lubricants and the like provided in the specification and claims are The percentages of lubricant and disintegrant are based on the weight of the tablet.

[0035] Diluents provide bulk, for example to make tablets into a particle size for processing. Also, by providing improved physical properties such as flow, compressibility and tablet hardness. The relatively high percentage of diluent in a typical pharmaceutical formulation and and the amount of direct contact between the diluent and the active compound, which may result in interactions of the diluent with the active compound. Use is a particular concern for formulators. Examples of suitable diluents for general use include: Calcium phosphates (e.g., di- and tribasic, hydrated or anhydrous), calcium sulfate , calcium carbonate, magnesium carbonate, kaolin, spray dried or anhydrous lactose, cell cellulose (e.g., microcrystalline cellulose, powdered cellulose), pregelatinized starch, starch, Lactitol, mannitol, sorbitol, maltodextrin, powdered sugar, compressed sugar, sugar Water-soluble and water-insoluble fillers such as cellulose, dextrose, and inositol Diluents that do not contain a coordination metal and diluents that are not reducing sugars are suitable for use in the tablet formulation of the present invention. Suitable diluents for use in the present invention include crystalline cellulose, powdered cellulose, starch, pregelatinized starch, starch, lactitol, mannitol, sorbitol and and maltodextrin. Unsuitable diluents include calcium phosphates (e.g. For example, di- and tribasic, hydrated or anhydrous), calcium sulfate, calcium carbonate, Examples of the lactose-containing additives of the present invention include magnesium sulfate, kaolin and spray dried or anhydrous lactose. In an embodiment, the diluent is one or both of mannitol and crystalline cellulose. Or it will be.

[0036] The granules and solid oral pharmaceutical dosage forms of the present invention typically comprise from about 25% to about 89% of one or Contains multiple diluents.

[0037] One embodiment of the invention is a method for preparing a glycerol-based ... The term "granules" includes granules formulated with one or more diluents that do not include glycerol.

[0038] One embodiment of the invention is a method for preparing a glycerol-based ... The term "solid oral pharmaceutical dosage form" includes solid oral pharmaceutical dosage forms formulated with one or more diluents that do not contain

[0039] One embodiment of the invention is a method for preparing a glycerol-based ... This includes pharmaceutical tablets that are formulated with one or more diluents that do not contain glycerin.

[0040] One embodiment of the invention is a method for preparing a glycerol-based ... The present invention includes pharmaceutical capsules formulated with one or more diluents that do not contain glycerol.

[0041] Binders provide cohesive properties to the powder material. Examples of binders suitable for use in the present invention include: Starches (e.g., pastes, pregelatinized, mucilages), gelatins, sugars (e.g., sucrose , glucose, dextrose, molasses, lactose, dextrin, xylitol, sol bitol), polymethacrylic acid, natural and synthetic rubbers (e.g., acacia, alginate and and its salts such as sodium alginate, gum tragacanth, Irish moss extract, Panwar gum, ghatti gum, guar gum, zein, se cellulose derivatives (e.g., carboxymethylcellulose and its salts, methylcellulose (MC), Hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose cellulose (HPC), hydroxyethyl cellulose (HEC) and ethyl cellulose (E C), polyvinylpyrrolidone, Veegum, larch arab galactan ogalactan), polyethylene glycol, wax, water, alcohol, aluminum silicate In an embodiment of the present invention, the binder contains polyvinylpyrrolidone (PVP).

[0042] Granules and solid oral pharmaceutical dosage forms of the invention typically contain up to about 8% binder. The article suitably contains up to about 5%, suitably up to 2%, of a binder.

[0043] Lubricants enhance processing, for example by preventing formulation materials from sticking to manufacturing equipment. , reduce interparticle friction, improve flow rate of formulations, and / or improve the flow rate of manufacturing equipment. Suitable lubricants for use in the present invention include Examples of such agents include talc, stearates (e.g., magnesium stearate, stearic acid salts, etc.). Calcium phosphate, zinc stearate, palmitostearate, Thearic acid, hydrogenated vegetable oil, glyceryl betaine, polyethylene glycol, ethylene oxide Side polymers (e.g., CARBOWAXes), liquid paraffin, sodium lauryl sulfate , Magnesium lauryl sulfate, Sodium oleate, Sodium stearyl fumarate , DL-leucine, and silica derivatives (e.g., colloidal silicon dioxide, colloidal Examples of the silica used in the present invention include crystalline silica, pyrogenic silica and sodium silicoaluminate hydrate. In some embodiments, the lubricant comprises magnesium stearate.

[0044] The granules and solid oral pharmaceutical dosage forms of the invention typically contain up to about 2% of a lubricant. The article suitably contains up to about 1.5%, suitably up to 1%, of a binder.

[0045] Disintegrants are used to facilitate the breakup or disintegration of the formulation after administration. Examples of disintegrants suitable for use in the present invention include starches, celluloses, gums, cross-linked polymers, and and corn starch, potato starch, pregelatinized starch, modified corn starch, etc. effervescent agent, croscarmellose sodium, crospovidone, starch glycolate Sodium, Veegum HV, Methylcellulose, Microcrystalline Cellulose, Cellulose, Modified Decorated cellulose gum (e.g., Ac-Di-Sol R), agar, bentonite, monoxide Morillonite clay, natural sponges, cation exchange resins, ion exchange resins (e.g. Potassium polyacrylamide), alginic acid and alginates, guar gum, citrus pulp , sodium lauryl sulfate, and other carboxymethylcellulose and salts thereof, aluminum silicate Magnesium stearate, hydrated aluminum silicate, acidulants such as tartaric acid or citric acid In some embodiments of the present invention, the present invention includes sodium bicarbonate in a mixture with Binders include sodium starch glycolate.

[0046] The granules and solid oral pharmaceutical dosage forms of the present invention typically contain a disintegrant in an amount of from 4% to about 12%. The formulation suitably comprises from about 6% to about 10%, suitably from about 7% to 9%, of a disintegrant.

[0047] The solid oral pharmaceutical dosage form of the present invention, suitably a tablet, suitably a capsule, typically contains about 1 gram For example, the size of these solid dosage forms may range from about 0.01 grams to about 0.8 grams. Typically, each dosage form contains about 5 mg to about 900 mg of eltrombopagulone. In a suitable embodiment, the solid dosage form contains about 5 to about 200 mg of eltrombopag. olamine (e.g., in a dosage form of about 100-800 mg). The spheres may have a variety of shapes, including diamonds, modified capsules, modified ovals, and hexagons, and may optionally be obliquely shaped. The surface may have a surface.

[0048] tablet The specific types and amounts of excipients, as well as the choice of tableting technique, are important considerations in determining the efficacy and safety of eltrombopagulone. Further properties of the components and excipients, such as compressibility, flowability, particle size, compatibility and density Tablets can be manufactured by any method known in the art including direct compression, dry granulation, fluid bed granulation and wet granulation. It can be prepared according to known methods, so the excipients used will vary. The formula granulation method produces a relatively high concentration of eltrombopagolamine ( For example, about 40% or more) of tablets at a suitable commercial manufacturing scale. A suitable wet granulated tablet of the present invention is eltrombopag. granules comprising olamine and one or more fillers, binders and disintegrants, The granules are mixed with additional fillers, binders, disintegrants and / or lubricants to form tablets. The mixture is compressed to form a compressed mixture.

[0049] The present invention includes eltrombopagulamine, suitably prepared on a commercial scale. the pharmaceutical composition is in tablet form, the tablet being substantially free of coordinated metals; and / or By a wet granulation process using one or more diluents that are substantially free of reducing sugars. The present invention also includes such pharmaceutical compositions that include a film coat. The film coat contains no or approximately equal to 0.025 parts of the coordinated metal. or less of coordinated metal.

[0050] The present invention also includes a pharmaceutical composition comprising eltrombopagolamine, the tablet comprising: One or more compounds that are substantially free of coordinating metals and / or substantially free of reducing sugars It is suitably manufactured by a wet granulation process on a commercial scale using a diluent, and is approximately 90% Eltrombopagolamine particles are larger than 10 microns but smaller than 90 microns. It has a small particle size.

[0051] The present invention also includes a pharmaceutical composition comprising eltrombopagolamine, the tablet comprising: One or more compounds that are substantially free of coordinating metals and / or substantially free of reducing sugars It is suitably manufactured by a wet granulation process on a commercial scale using a diluent, and is approximately 90% Eltrombopagolamine particles are larger than 10 microns but smaller than 90 microns. Suitably then, it has a particle size greater than 20 microns but less than 50 microns.

[0052] The present invention also includes a pharmaceutical composition comprising eltrombopagolamine, the tablet comprising: One or more compounds that are substantially free of coordinating metals and / or substantially free of reducing sugars It is suitably manufactured by a wet granulation process on a commercial scale using a diluent, and contains approximately 50% Eltrombopagolamine particles are larger than 5 microns but smaller than 50 microns. Suitably, the particle size is greater than 5 microns but less than 20 microns.

[0053] In one embodiment of the present invention, the tablet of the present invention comprises: (i) about 2% to about 65% eltrombopagolamine; (ii) from about 25% to about 89% diluent; (iii) up to about 8%, suitably up to about 5%, suitably up to about 4% binder; (iv) up to about 2%, suitably up to about 1.5%, suitably up to about 1% of a lubricant; and (v) 4% to about 12%, suitably 6% to 10%, suitably 7% to 9%, of a disintegrant. Includes.

[0054] A suitable wet granulated tablet will contain from about 10% to about 95% eltrombopag by tablet weight. Contains olamine active inner granules and about 5% to about 90% of external excipients, The effective amount of pagolamine in the inner granule is calculated by weight of the inner granule. (i) about 2% to about 88% eltrombopagolamine; (ii) from about 10% to about 96% diluent; (iii) about 2% to about 5% of a binder; and (iv) optionally, 0% to about 4% of a disintegrant; The external excipients comprise, by weight of the tablet: (i) 0% to about 70% diluent; (ii) from about 0.25% to about 2%, suitably from 0.25% to about 1.25%, of a lubricant; and (iii) about 4% to about 10% of a disintegrant Includes.

[0055] In the above embodiment, the diluent is suitably a combination of mannitol and microcrystalline cellulose. wherein the non-reducing sugar is suitably mannitol and the binder is suitably polyvinyl pyrrolidone, the lubricant is suitably magnesium stearate, and the disintegrant is suitably sodium starch glycolate. Suitably the inner granular filler is A mixture of mannitol and microcrystalline cellulose, with the external filler being microcrystalline cellulose. .

[0056] In one embodiment of the invention, the tablet is formed from an aqueous film coat composition. Aqueous film coat compositions suitable for use in the present invention The composition comprises a film-forming polymer, water as a vehicle, and, optionally, a film coat. The film coat may include one or more adjuvants known in the coating art. When a coordination metal is used in the present specification, the amount of coordination metal is approximately equal to 0.025 parts of compound B. Equal to or less than.

[0057] The film-forming polymer should be selected based on the intended environment of use (e.g., dissolution characteristics in gastrointestinal fluids) and / or Mechanical properties (e.g., viscosity of solution) that meet the performance requirements dictated by the material or use. For example, the material is selected to form a coating having mechanical strength and flexibility. Examples of film-forming polymers include cellulose polymers (e.g., HPMC, HPC, M C, EC, HEC, CAP, sodium ethyl cellulose sulfate, carboxymethyl cellulose cellulose ethers, polyvinylpyrrolidone; zein; and acrylic poly polymers (e.g., methacrylic acid / methyl methacrylic acid copolymers, acrylate copolymers, etc. Cellulose polymers, especially cellulose Preferred in the present invention are the polyethers, more particularly HPMC and HPC. are typically provided in either aqueous or organic solvent based solutions or aqueous dispersions. However, the polymer may be in dry form, alone or with other components (e.g., plasticizers and and / or coloring agents) and may be mixed by the user with an aqueous vehicle. A solution or dispersion is prepared by mixing.

[0058] The aqueous film coat composition further comprises water as a vehicle for the other ingredients. The vehicle can optionally contain an alcohol (e.g., methacrylate), which facilitates delivery of the active ingredient to the tablet surface. ethanol, isopropanol, propanol) and ketones (e.g., acetone). One skilled in the art can select appropriate vehicle components. Select a film-forming polymer that provides good interaction between the film-forming polymer and the vehicle to achieve good flowability. In general, the polymer-vehicle interaction is important for the maximum polymer The filler is designed to produce polymer chain extensions with maximum bond strength and mechanical properties. The organism is designed to provide good deposition of the film-forming polymer onto the tablet surface. A selective, cohesive and adhesive film is obtained.

[0059] The aqueous film coating composition may optionally contain a plasticizer, a colorant, a detackifier, ifiers), secondary film-forming polymers, flow aids, surfactants (e.g., to aid in spreading) dextrin and polydextrose, which are known in the art. One or more adjuvants may be included.

[0060] Plasticizers provide flexibility to the film, reducing film cracking and improving adhesion to the tablet. Suitable plasticizers generally have a high compatibility with the film-forming polymer. The coating properties are generally stable and have sufficient performance. Examples include glycerin, propylene glycol, polyethylene glycol (e.g., Molecular weight of 200~20000, Union Carbide PEG 400, 4000 , 6000, 8000 and 20,000), Glycerin, Glycerin Triacetate Acetyl monoglyceride (aka triacetin), acetylated monoglyceride, citrate Stearyl citrate (e.g., triethyl citrate, acetyl triethyl citrate, tributyi citrate) phthalates (e.g., diethyl phthalate), Mineral oil and hydrogenated glucose syrup. The plasticizers are polyethylene glycol, triacetin, propylene glycol, and glycol. serine and mixtures thereof.

[0061] The aqueous film coat composition suitably comprises one or more colorants. The colorants are: Provides product identity while enhancing appearance. Suitable coloring agents include those listed in FD&C and D Contains FDA approved dyes, lakes, and pigments, and titanium dioxide There are some that are guaranteed, but the film coat must not contain any coordinated metals or or contains an amount of coordinated metal equal to or less than about 0.025 parts of compound B. do not have.

[0062] Suitably the colouring agents include red iron oxide, red dyes and lakes, iron oxide, yellow dyes and lakes, dioxane, One or more colorants selected from the group consisting of titanium oxide and indigo carmine For example, the coloring agent may be, for example, a) red iron oxide, red dye and / or red lake; ) A light pigment essentially consisting of iron yellow, yellow dye and / or yellow lake, and titanium dioxide The colorant may be selected to provide a beige color. Alternatively, the colorant may be selected to provide a peach color (e.g., dioxide). Titanium and red iron oxide, red dye and / or red lake), pale green ( For example, yellow iron oxide, yellow dyes and / or yellow lakes, indigo carmine and titanium dioxide. tan), pale blue (e.g., consisting essentially of titanium dioxide and indigo carmine) ), or orange (e.g., from titanium dioxide and sunset yellow ) can be selected to provide

[0063] The colorant containing a coordinated metal is about equal to or greater than 0.025 parts of Compound B. Levels below this are acceptable.

[0064] In another suitable embodiment, an aqueous film coating composition for use in the present invention The objects include: (i) a cellulose film-forming polymer; and (ii) Plasticizers.

[0065] Suitably, such compositions further comprise a colouring agent. These include one or more of the following: detackifiers, flow aids, surfactants and secondary film-forming polymers. further comprises a plurality of additional adjuvants.

[0066] Examples of optional detackifying agents include lecithin, stearic acid, mineral oil, modified derivatized starch, Optional secondary fillers include cellulose, tapioca dextrin and polyethylene glycol. Examples of lamella-forming polymers include alginate, propylene glycol alginate, and glycerol. Examples of optional surfactants include dioctyl, diphenyl ether, and polyvinylpyrrolidone. Examples of suitable fluid supplements include sodium sulphosuccinate and polysorbate 80. Examples of auxiliaries include talc, fumed silica, bentonite, hydrogenated vegetable oil, and stearin. and waxes.

[0067] The aqueous film coat composition typically comprises from about 5% to about 25%, suitably about The solids for the coating comprise from 5% to about 20%. In a suitable embodiment, the solids are Typically, about 25% to about 70% by weight, suitably about 60% to about 70% by weight of the filler. a polymer forming the polymer, from about 5% to about 10%, suitably from about 6% to about 8%, by weight of a plasticizer; and about 20% to about 35% by weight of a colorant.

[0068] Many suitable aqueous film coating compositions are commercially available. The composition may be provided in the form of a solution or dispersion. Alternatively, the composition may be applied as a coating to a tablet. A dry form that can be combined with the vehicle components according to the manufacturer's instructions just prior to dosing. Suitably the aqueous film coating composition may be provided in the form of OPADRY and O Colorcon, Inc. (West Point, PA) under the trademark PADRY II Commercially available products include, but are not limited to, Opadry YS-1-7706- G White, Opadry Yellow 03B92357, Opadry Blue These compositions are diluted with water immediately prior to use. OPADRY and OPADRY are available as dry film coating compositions that can be applied to any surface. The ADRY II formulation contains a cellulose film-forming polymer (e.g., HPMC and / or or HPC), polydextrose, maltodextrin, plasticizers (e.g., Riacetin, polyethylene glycol), polysorbate 80, colorants (e.g., dioxide titanium, one or more dyes and lakes), and / or other suitable film forms Suitable OPAs may include synthetic polymers such as acrylic acid-methacrylic acid copolymers. DRY and OPADRY II formulations contain a plasticizer and one or more maltodextrins. a) triacetin and polydextrose polydextrose or maltodextrin or lactose, or b) polyethylene The sugar may include glycerol and polydextrose or maltodextrin.

[0069] The tablets are also suitably coated to provide a uniform coating without staining. The tablets are typically formulated with a dry tablet weight gain of about 2 to about 5%, suitably about 3 to 4%. The uncoated tablet cores are coated to provide a desired dosage. Thomas Accela-Cota, Vector Hi-Coater, Co The aqueous film-coated polymer was prepared by methods known in the art using the mpu-Lab 36 Generally, the process involves rolling the tablets in a pan. or a step of turning over, or suspending the tablets on a cushion of air (fluid bed); Then, immediately or successively (preferably successively), the coating composition is sprayed onto the tablets. A fine mist of droplets is sprayed, causing the droplets to wet, spread and coalesce over the tablet surface, creating a sticky The tablet is typically heated to about 75° C. to form a coherent film coating. The temperature of the air is about 65 to 70 degrees Celsius, and the temperature is about 40 to 50 degrees Celsius, and the temperature of the air is about 45 to Heat to 50°C.

[0070] Tablet manufacturing method The wet granulated pharmaceutical tablet of the present invention may be prepared by a process comprising the steps of: I) preparing a granule comprising: a) Mix eltrombopagolamine, diluent, and binder together for a period of time sufficient to homogenize the materials. mixing together the combination drug and, optionally, a disintegrant; b) adding the granulating liquid to the dry ingredient mixture, preferably while mixing; c) Sufficient water to thoroughly and uniformly wet the dry ingredients to form wet granules. Granulation time, mixing the dry ingredients mixture with the granulation liquid; d) Milling the wet granules thoroughly; e) drying the well-milled granules to form dry granules; and f) dry crushing the dried granules to form granules of desired size; II) preparing a tablet, comprising: a) Mix the granules and outer excipients with fillers, lubricants and disintegrants for a period of time sufficient to homogenize the granules and outer excipients. mixing the granules prepared in step I) with an outer excipient containing a disintegrant; and b) Compressing the mixture of granules and external excipients to form tablets.

[0071] Suitably the tablet is further provided with a film coating, in particular an aqueous film coating. will be done. In preparing the wet granulation, the dry ingredients are mixed with any suitable blend of water and water-soluble organic solvents known in the art. Equipment (e.g. Niro-Fielder Blender / Granulator, B ear Varimixer, Key High Shear Mixer / Granu lator) for a sufficient time to homogenize the material (e.g., about 3 minutes). It is possible.

[0072] The granulation liquid is then added to the dry mix, preferably with mixing. The preferred binder is water, or alternatively water and one or more binders such as PVP and HPMC. (Based on the total wet granulation mixture, about 10 v / w% to about 30 v Granulation liquids and dry materials (w / w %) may be suitably used. Granulation liquids and dry materials are known in the art. Suitable equipment (e.g. Niro-Fielder Blender / Granul ator, Bear Varimixer, Key High Shear Mixer Dry ingredients are generally mixed using a mixing machine (such as a granulator) so that wet granules are formed. Mixing may be performed for a total time sufficient to achieve uniform wetting (approximately 3 to 15 minutes). The binder is added to the dry ingredients with mixing for about 1 to about 15 minutes, and then the entire batch is , and mixed for an additional period of time (an additional period of time after the granulation liquid, about 0.5 minutes to about 6 minutes).

[0073] In a suitable embodiment, about 10% v / w to about 30% v / w of granulation liquid, and for about 6 minutes A granulation time of about 24 v / w % after addition of the granulation liquid or less is used. granulation liquid, and granulation time after addition of granulation liquid for about 3 minutes or less (e.g., about 2.5 minutes ) is used. Suitably, about 16 v / w % of granulation liquid and granulation for longer than about 2.5 minutes. A granulation time after liquid addition (eg, 4 minutes) is used.

[0074] The wet granules are then mixed together to provide a generally uniformly sized wet mass (if the granules are relatively The powder is then wet-milled (so as to dry the powder evenly) by methods known in the art. Appropriate wet comminution techniques include sieving (e.g., manual sieving), comminution milling, ing mill) (including but not limited to 0.375" screen, Co-mil, etc. Wet milled granules are generally uniformly dried with a small amount of residual granulation liquid (preferred). or from about 0.5% to about 1.0%) by methods known in the art. A fluid bed dryer is a suitable dryer.

[0075] The dried granules are then dry crushed using known methods to produce generally uniformly sized particles. Granules (unimodal distribution, suitably with an average particle size of less than 240 microns (improved content It is found that the present invention provides uniformity. As a suitable drying and crushing equipment, Examples include, but are not limited to, Co-mil with a 0.094" screen. do.

[0076] Suitably, the granules and dry ingredients of the compaction mixture are generally of a composition suitable for facilitating the formulation of a homogenous mixture. However, the sizes are unimodal in distribution to reduce possible separation of the mixture after mixing. If necessary, the dry material is pre-sieved to provide the desired particle size distribution. Screening may be useful in dispersing the lubricant.

[0077] In preparing the compression mixture, mix the granules, fillers and Then, add the lubricant and mix for an appropriate time, about 1 to 4 minutes. The mixture is then tableted using a press known in the art (e.g., a rotary tablet press). Compress the mixture into a powder.

[0078] The above granulation liquid levels, granulation times and excipients have been found to provide improved processing. It has been done.

[0079] capsule The particular types and amounts of excipients, as well as the choice of encapsulation technique used, are important considerations in determining whether eltrombopag is a medicament for use in an eltrombopag formulation. Further properties of the guanidine and excipients (e.g., compressibility, flowability, particle size, compatibility, and The capsules may be prepared by any method known in the art, suitably a commercial method. The mixture is mixed with excipients and packed into two standard hard gelatin capsules at a scale suitable for production. Fill the capsule with eltrombopagolamine, suitably in two standard hard gelatin capsules. The capsules can be filled with the granules prepared according to the present invention. A suitable capsule of the present invention comprises eltrombopagolamine and one or more fillers, Granules containing a binder and a disintegrant, the granules further containing a filler, a binder, a disintegrant and and / or mixed with a lubricant to form a granular mixture which is filled into a capsule.

[0080] Suitably, a capsule form containing eltrombopagolamine is prepared on a commercial scale. The present invention includes pharmaceutical compositions comprising the above-mentioned capsules, which are substantially free of coordination metals, and / or is prepared using one or more diluents that are substantially free of reducing sugars.

[0081] Pharmaceutical compositions containing eltrombopagolamine are also included in the present invention, suitably One or more dilute soluble fertilizers that are substantially free of reducing metals and / or substantially free of reducing sugars. Eltrombopagolamine particles were produced on a commercial scale using a dilution agent, with approximately 90% of the particles It has a particle size greater than 10 microns but less than 90 microns.

[0082] Pharmaceutical compositions containing eltrombopagolamine are also included in the present invention, suitably One or more dilute soluble fertilizers that are substantially free of reducing metals and / or substantially free of reducing sugars. Eltrombopagolamine particles were produced on a commercial scale using a dilution agent, with approximately 90% of the particles Greater than 10 microns but less than 90 microns, suitably greater than 20 microns has a particle size less than 50 microns.

[0083] Pharmaceutical compositions containing eltrombopagolamine are also included in the present invention, suitably One or more dilute soluble fertilizers that are substantially free of reducing metals and / or substantially free of reducing sugars. Eltrombopagolamine particles were produced on a commercial scale using a dilution agent, with approximately 50% of the particles Greater than 5 microns but less than 50 microns, suitably greater than 5 microns but less than 2 It has a particle size smaller than 0 microns.

[0084] The granules and solid oral pharmaceutical dosage forms of the present invention can be prepared, for example, as described in PCT / US01 / 1686, supra. 3. PCT / US03 / 16255 and PCT / US04 / 013468 (with reference to the source) Thus, the compounds are therapeutically effective for treating or preventing the conditions described in Those skilled in the art will appreciate that the eltrombopagulamine formulations of the present invention can be administered in an amount of The exact amount and interval of individual doses will depend on the nature and severity of the condition being treated and the severity of the treatment. The optimal conditions will be determined by the particular patient in question, and such optimal conditions may vary. It will be appreciated that the above-mentioned parameters can be determined by conventional techniques. The optimal therapeutic dose, i.e., the amount of eltrombopag given per day for the specified number of days. To determine the frequency of pagolamine administration using conventional therapeutic units in treatment decision trials. Those skilled in the art will appreciate that it is possible to

[0085] The method of the present invention for producing TPO agonist activity in humans is the administration of a solid oral pharmaceutical agent of the present invention. The method includes administering a therapeutically effective amount of the compound of the formula (I) to a subject in need of such activity. The present invention also relates to the use of eltrombopagulone in the manufacture of the solid oral pharmaceutical dosage form of the present invention. Provides for the use of min.

[0086] The present invention also relates to a solid oral pharmaceutical composition of the present invention for use in enhancing platelet production. The use of eltrombopagolamine in the manufacture of a pharmaceutical form is provided. The present invention also provides a solid oral composition of the present invention for use in treating thrombocytopenia. The use of eltrombopagolamine in the manufacture of a pharmaceutical dosage form is provided.

[0087] The present invention also provides a pharmaceutical composition comprising eltrombopagulamine of the present invention and a pharma- ceutical acceptable carrier. The present invention provides a solid oral pharmaceutical dosage form for use as a TPO mimetic comprising: The present invention also provides a pharmaceutical composition comprising eltrombopagulamine of the present invention and a pharma- ceutical acceptable carrier. The present invention provides a solid oral pharmaceutical dosage form for use in treating thrombocytopenia, comprising

[0088] The present invention also provides a pharmaceutical composition comprising eltrombopagulamine of the present invention and a pharma- ceutical acceptable carrier. The present invention provides a solid oral pharmaceutical dosage form for use in enhancing platelet production, comprising The present invention also provides a method for the preparation of a composition that is substantially free of coordinated metals and / or substantially free of reducing sugars. A method for producing a solid oral pharmaceutical dosage form comprising one or more diluents is provided, the method comprising: includes combining eltrombopagolamine with one or more diluents.

[0089] No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. stomach. Without further elaboration, it is believed that one skilled in the art can, using the above description, fully utilize the present invention. Therefore, the following examples are merely illustrative and should not be construed as limiting the scope of the present invention. It is composed without any determination. All excipients used herein are available from a variety of manufacturers known to those skilled in the art. are standard pharmaceutical grade excipients available. EXAMPLES

[0090] Examples 1-7 --Tablet Preparation Wet granulation tablets were prepared containing eltrombopagolamine and the ingredients in Table 1.

[0091] [Table 1] Mannitol, microcrystalline cellulose and povidone were weighed separately and sieved. Thus, granules were prepared.

[0092] The general procedure is to mix the ingredients with the active ingredient and then wet granulate them with purified water. The wet granules were then wet milled and then dried in a fluid bed dryer. It was dried and the dried granules were milled.

[0093] The outer granule components (crystalline cellulose, optionally sodium starch glycolate) are Weighed out separately, sieved and mixed with the granules. Magnesium stearate was added to the mixture. The mixture was compressed and then the tablet cores were film coated. The films were coated with an aqueous suspension of the OPADRY film coating formulation.

[0094] Example 8 Tablet Preparation Eltrombopag containing a diluent containing calcium phosphate dibasic anhydrous acid coordination metal Guolamine tablets were prepared in the same manner as above. The tablet composition is provided in Table 2.

[0095] [Table 2] In FIG. 1, the diluent containing no coordinated metal (shown as non-coordinated metal diluent) was used. The tablets prepared were eltrombopag 50 mg tablets prepared generally as described in Table 1 above. A tablet of calcium anhydrous dibasic phosphate prepared with a coordination metal diluent. The ruthenium-(represented as the coordinated metal diluent) was prepared using eluents generally prepared as described in Table 2 above. Thrombopag 50mg tablets. USP Apparatus II, 50 rp Comparison of dissolution in phosphate buffer pH 6.8 containing 0.5% Tween 80 using m was carried out.

[0096] Example 9 FIG. 2 shows the effect of API particle size distribution on the dissolution of eltrombopagolamine. Eltrombopagolamine 75 mg tablets were administered at different doses in the manner described in Example 5. The particle size refers to the particle size of the drug granules used in the formulation. .

[0097] Dissolution comparisons were performed in phosphate buffer pH 6.8 containing 0.5% Tween 80 using a USP Apparatus II, 50 rpm. The invention as originally claimed in the present application is set forth below. [1] A pharmaceutical tablet comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), prepared using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars. [2] A pharmaceutical tablet comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), produced on a commercial scale by a wet granulation process using one or more diluents that are substantially free of coordinating metals and / or substantially free of reducing sugars. [3] The pharmaceutical tablet of [1], wherein approximately 90% of the drug particles have a particle size greater than 10 microns but less than 90 microns. [4] The pharmaceutical tablet of [2], wherein approximately 90% of the drug particles have a particle size greater than 10 microns but less than 90 microns. [5] The pharmaceutical tablet of [2], wherein approximately 90% of the drug particles have a particle size greater than 20 microns but less than 50 microns. [6] The pharmaceutical tablet of [2], wherein about 50% of the drug particles have a particle size greater than 5 microns but less than 50 microns. [7] The pharmaceutical tablet of [2], wherein about 50% of the drug particles have a particle size greater than 5 microns but less than 20 microns. [8] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) 4% to about 12% of a disintegrant The pharmaceutical tablet according to [1], [9] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) about 6% to about 10% of a disintegrant The pharmaceutical tablet according to [1],

[10] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) about 7% to about 9% of a disintegrant The pharmaceutical tablet according to [1],

[11] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) 4% to about 12% of a disintegrant The pharmaceutical tablet according to any one of [2], [4] or [5], comprising:

[12] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) about 6% to about 10% of a disintegrant The pharmaceutical tablet according to any one of [2], [4] or [5], comprising:

[13] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) about 7% to about 9% of a disintegrant The pharmaceutical tablet according to any one of [2], [4] or [5], comprising:

[14] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) 4% to about 12% of a disintegrant The pharmaceutical tablet according to [6] or [7],

[15] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) about 6% to about 10% of a disintegrant The pharmaceutical tablet according to [6] or [7],

[16] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) about 7% to about 9% of a disintegrant The pharmaceutical tablet according to [6] or [7],

[17] The pharmaceutical tablet of [8], wherein the diluent component comprises a non-reducing sugar and crystalline cellulose.

[18] The pharmaceutical tablet according to

[17] , wherein the non-reducing sugar is mannitol, the binder is polyvinylpyrrolidone, the disintegrant is sodium starch glycolate, and the lubricant is magnesium stearate.

[19] The pharmaceutical tablet of

[11] , wherein the diluent component comprises a non-reducing sugar and crystalline cellulose.

[20] The pharmaceutical tablet according to

[19] , wherein the non-reducing sugar is mannitol, the binder is polyvinylpyrrolidone, the disintegrant is sodium starch glycolate, and the lubricant is magnesium stearate.

[21] The pharmaceutical tablet of

[14] , wherein the diluent component comprises a non-reducing sugar and crystalline cellulose.

[22] The pharmaceutical tablet according to

[21] , wherein the non-reducing sugar is mannitol, the binder is polyvinylpyrrolidone, the disintegrant is sodium starch glycolate, and the lubricant is magnesium stearate.

[23] A pharmaceutical tablet according to

[18] , produced on a commercial scale.

[24] A pharmaceutical tablet comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), produced by a wet granulation process using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars.

[25] A method for treating thrombocytopenia in a human in need of treatment, comprising a step of administering a therapeutically effective amount of the pharmaceutical tablet according to any one of [1] to

[24] to the human in need of treatment for thrombocytopenia.

[26] A method for stimulating a TPO receptor in a human in need of stimulation of a TPO receptor, comprising the step of administering a therapeutically effective amount of the pharmaceutical tablet according to any one of [1] to

[24] to the human in need of stimulation of a TPO receptor.

[27] The method of

[25] , further comprising the step of co-administering a therapeutically effective amount of an agent selected from the group consisting of a colony-stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist or antagonist, a soluble receptor, a receptor agonist or antagonist antibody, or a small molecule or peptide that acts by the same mechanism as one or more of the agents.

[28] A solid oral pharmaceutical dosage form comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), wherein the solid oral pharmaceutical dosage form is manufactured using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars.

[29] A solid oral pharmaceutical dosage form comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), wherein the solid oral pharmaceutical dosage form is manufactured on a commercial scale using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars.

[30] The solid oral pharmaceutical dosage form of

[28] , wherein about 90% of the drug particles have a particle size greater than 10 microns but less than 90 microns.

[31] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) 4% to about 12% of a disintegrant The solid oral pharmaceutical dosage form according to

[28] , comprising:

[32] A solid oral pharmaceutical dosage form according to

[31] , produced on a commercial scale.

[33] A method for treating thrombocytopenia in a human in need of treatment, comprising the step of administering a therapeutically effective amount of a solid oral pharmaceutical dosage form according to any one of

[28] to

[32] to the human in need of treatment for thrombocytopenia.

[34] A method for stimulating a TPO receptor in a human in need of stimulation of a TPO receptor, comprising the step of administering to the human a therapeutically effective amount of a solid oral pharmaceutical dosage form according to any one of

[28] to

[32] .

[35] The method of

[33] , further comprising the step of co-administering a therapeutically effective amount of an agent selected from the group consisting of a colony-stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist or antagonist, a soluble receptor, a receptor agonist or antagonist antibody, or a small molecule or peptide that acts by the same mechanism as one or more of the agents.

[36] A pharmaceutical capsule comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), wherein the pharmaceutical capsule is manufactured using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars.

[37] A pharmaceutical capsule comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), produced on a commercial scale using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars.

[38] The pharmaceutical capsule of

[36] , wherein approximately 90% of the drug particles have a particle size greater than 10 microns but less than 90 microns.

[39] a) Approximately 2% to approximately 65% ​​eltrombopagulamine; b) about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% lubricant; and e) 4% to about 12% of a disintegrant The pharmaceutical capsule according to

[36] ,

[40] A pharmaceutical capsule according to

[39] , produced on a commercial scale.

[41] A method for treating thrombocytopenia in a human in need of treatment for thrombocytopenia, comprising the step of administering a therapeutically effective amount of the pharmaceutical capsule according to any one of

[36] to

[40] to the human in need of treatment for thrombocytopenia.

[42] A method for stimulating a TPO receptor in a human in need of stimulation of a TPO receptor, comprising the step of administering a therapeutically effective amount of the pharmaceutical capsule according to any one of

[36] to

[40] to the human in need of stimulation of the TPO receptor.

[43] The method of

[41] , further comprising the step of co-administering a therapeutically effective amount of an agent selected from the group consisting of a colony-stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist or antagonist, a soluble receptor, a receptor agonist or antagonist antibody, or a small molecule or peptide that acts by the same mechanism as one or more of the agents.

[44] A pharmaceutical granule comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), wherein the pharmaceutical granule is produced using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars.

[45] A pharmaceutical granule comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine), the pharmaceutical granule being produced on a commercial scale using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars.

[46] A method for preparing a solid oral therapeutic dosage form comprising a therapeutically effective amount of 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine) as described in [1] and one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars, comprising the step of combining a compound as described in [1] with one or more diluents.

Claims

[Claim 1] A pharmaceutical tablet comprising 5 to 200 mg of eltrombopagolamine particles, The diluent contained in the pharmaceutical tablet is substantially free of coordination metals; The eltrombopagolamine particles have an X90 particle size of 10 to 90 microns. Pharmaceutical tablets.

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