Novel pharmaceutical composition

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 the following formula (I):

Chem.

Background Art

[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), together with its pharmaceutically acceptable salts, hydrates, solvates and esters, is disclosed and claimed in Patent Document 1 (internationally filed on May 24, 2001; internationally published on January 29, 2001 (Patent Document 2); published in the United States on January 29, 2004( Patent Document 3); currently, Patent Document 4 (issued on January 9, 2007)) (by express reference, the entirety of which is incorporated herein by reference), and is particularly useful as an agonist of the TPO receptor in enhancing platelet production and treating thrombocytopenia.

[0003] The bis-(monoethanolamine) salt of this compound is described 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 Since the physical properties of affect the properties of the solid dosage form, pharmaceutical active compounds having low solubility and / or that can react with commonly used excipients present particular challenges in formulating high-quality solid dosage forms. Formulators must balance the properties of each excipient with the drug-specific properties in order to prepare a safe, effective, and easy-to-use solid dosage form. When attempting to formulate eltrombopag olamine, particularly on a commercial scale, into a suitable solid oral pharmaceutical dosage form, suitably a tablet, suitably a capsule, that has the desired pharmacokinetic properties, particular concerns are presented to the formulator. Such concerns include, but are not limited to, the tendency of the compound to form insoluble metal complexes when in contact with excipients containing coordinating metals, which can slow the dissolution of the compound from the solid dosage form, and the tendency of the compound to undergo the Maillard reaction when in contact with excipients containing reducing sugars. A significant manifestation of these concerns would have an adverse effect on the in vivo administration of eltrombopag olamine.

[0008] [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 Published Application No. US2004 / 0019190 A1 [Patent Document 4] US 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] U.S. Published Patent Application 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] U.S. Published Patent Application 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] [Problems to be Solved by the Invention]

[0010] Providing eltrombopag olamine in a solid oral pharmaceutical dosage form at commercial scale with desirable pharmacokinetic properties It is desirable to provide bopagololamine. [Means for Solving the Problems]

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

[0012] The present invention relates to granules and solid oral pharmaceutical dosage forms containing a therapeutically effective amount of eltrombopag olamine. The present invention also relates to a method for manufacturing granules and solid oral pharmaceutical dosage forms containing eltrombopag olamine.

[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 It relates to. Such tablets exhibit improved properties. Such improved properties help to ensure a safe and effective treatment.

[0017] Another aspect of the present invention relates to a method for treating thrombocytopenia, comprising the step of administering a therapeutically effective amount of the granules or solid oral pharmaceutical dosage form of the present invention to a subject in need of treatment for thrombocytopenia.

[0018] Another aspect of the present invention relates to a method for stimulating the TPO receptor, comprising the step of administering a therapeutically effective amount of the granules or solid oral pharmaceutical dosage form of the present invention to a subject in need of stimulation of the TPO receptor.

[0019] The present invention also includes a method of co-administering the granules or solid oral pharmaceutical dosage form of the present invention together with a further active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS

[0020]

Figure 1

Figure 2

[0021] As used herein, the term "coordinating metal" and its derivatives mean a metal or excipient containing a metal, suitably a diluent, or a tablet coating material containing a metal, which forms a complex such as a chelate complex in the presence of eltrombopag olamine. Examples of such metals include aluminum, calcium, copper, cobalt, gold, iron, magnesium ​ Examples include um, manganese, and zinc.

[0022] As used herein, the term "reducing sugar" refers to a sugar or sugar-containing excipient that, when mixed together, reacts with eltrombopag guanamine to form a Maillard product, and appropriately includes diluents. Examples of such reducing sugars include lactose, maltose, glucose, arabinose, and fructose. and appropriately includes diluents. Examples of such reducing sugars include lactose, maltose, glucose, arabinoside, and fructose. Examples of such reducing sugars include lactose, maltose, glucose, arabinose, and fructose.

[0023] The term Maillard reaction is known in the art and is used herein in its standard meaning. Generally, the term Maillard reaction refers to the reaction of a reducing sugar as defined herein in a formulation, appropriately a granule or solid dosage form, containing eltrombopag guanamine that produces one or more pigments, appropriately brown pigments. As used herein, the pigment refers to a Maillard product. The formation of such Maillard products is a sign of chemical instability. produces one or more pigments, appropriately brown pigments. in a formulation, appropriately a granule or solid dosage form, containing eltrombopag guanamine as defined herein. As used herein, the pigment refers to a Maillard product. The formation of such Maillard products is a sign of chemical instability. in a formulation, appropriately a granule or solid dosage form, containing eltrombopag guanamine as defined herein. As used herein, the pigment refers to a Maillard product. The formation of such Maillard products is a sign of chemical instability.

[0024] As used herein, the terms "improved properties" and derivatives thereof are intended to refer, appropriately, to several advantages over formulations that do not use aspects of the present invention, when the formulation is manufactured on a commercial scale, to the pharmacokinetic properties of the in vivo release of Compound B from a formulation, appropriately a granule or solid oral pharmaceutical dosage form, that varies depending on the specific aspect of the invention being used. Examples of improved properties include increased oral bioavailability, reduced formation of insoluble metal complexes, improved chemical stability, consistent pharmacokinetic properties, and consistent dissolution rates. when the formulation is manufactured on a commercial scale, to the pharmacokinetic properties of the in vivo release of Compound B from a formulation, appropriately a granule or solid oral pharmaceutical dosage form, that varies depending on the specific aspect of the invention being used. Examples of improved properties include increased oral bioavailability, reduced formation of insoluble metal complexes, improved chemical stability, consistent pharmacokinetic properties, and consistent dissolution rates. Examples of improved properties include increased oral bioavailability, reduced formation of insoluble metal complexes, improved chemical stability, consistent pharmacokinetic properties, and consistent dissolution rates. Examples of improved properties include increased oral bioavailability, reduced formation of insoluble metal complexes, improved chemical stability, consistent pharmacokinetic properties, and consistent dissolution rates. Examples of improved properties include increased oral bioavailability, reduced formation of insoluble metal complexes, improved chemical stability, consistent pharmacokinetic properties, and consistent dissolution rates. Examples of improved properties include increased oral bioavailability, reduced formation of insoluble metal complexes, improved chemical stability, consistent pharmacokinetic properties, and consistent dissolution rates.

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

[0026] As used herein, the term "commercial scale" and derivatives thereof refer to a batch scale of a granulation mixture greater than about 20 kg, preferably greater than 50 kg, preferably greater than 75 kg, or a batch size suitable for preparing at least about 50,000 tablets, preferably at least 75,000 tablets, preferably at least 100,000 tablets. When it is indicated that the diluent used herein and in the claims substantially does not contain a coordinated metal and / or substantially does not contain a reducing sugar, for example, a small amount, for example, about

[0027] 5% or less of the diluent component may contain one or more coordinated metals and / or one or more reducing sugars. In this aspect of the invention, very small amounts of coordinated metals and / or reducing sugars can be incorporated into the diluent component without having a detrimental effect on the performance of the tablets. 5% or less of the diluent component may contain one or more coordinated metals and / or one or more reducing sugars. In this aspect of the invention, very small amounts of coordinated metals and / or reducing sugars can be incorporated into the diluent component without having a detrimental effect on the performance of the tablets. amounts of coordinated metals and / or reducing sugars can be incorporated into the diluent component without having a detrimental effect on the performance of the tablets. amounts of coordinated metals and / or reducing sugars can be incorporated into the diluent component without having a detrimental effect on the performance of the tablets.

[0028] The term "effective amount" and derivatives thereof refer to an amount of a drug and active ingredient that will produce a biological or medical response in a tissue, system, animal or human being, for example, being sought by a researcher or clinician. Further, the term "therapeutically effective amount" means any amount that, when administered to a subject as compared to a corresponding subject not receiving such amount, results in the treatment, cure, prevention or amelioration of a disease, disorder or side effect, or a decrease in the rate of progression of a disease or disorder. The term also includes amounts effective for enhancing normal physiological functions. The term "effective amount" and derivatives thereof refer to an amount of a drug and active ingredient that will produce a biological or medical response in a tissue, system, animal or human being, for example, being sought by a researcher or clinician. Further, the term "therapeutically effective amount" means any amount that, when administered to a subject as compared to a corresponding subject not receiving such amount, results in the treatment, cure, prevention or amelioration of a disease, disorder or side effect, or a decrease in the rate of progression of a disease or disorder. The term also includes amounts effective for enhancing normal physiological functions. The term "effective amount" and derivatives thereof refer to an amount of a drug and active ingredient that will produce a biological or medical response in a tissue, system, animal or human being, for example, being sought by a researcher or clinician. Further, the term "therapeutically effective amount" means any amount that, when administered to a subject as compared to a corresponding subject not receiving such amount, results in the treatment, cure, prevention or amelioration of a disease, disorder or side effect, or a decrease in the rate of progression of a disease or disorder. The term also includes amounts effective for enhancing normal physiological functions. The term "effective amount" and derivatives thereof refer to an amount of a drug and active ingredient that will produce a biological or medical response in a tissue, system, animal or human being, for example, being sought by a researcher or clinician. Further, the term "therapeutically effective amount" means any amount that, when administered to a subject as compared to a corresponding subject not receiving such amount, results in the treatment, cure, prevention or amelioration of a disease, disorder or side effect, or a decrease in the rate of progression of a disease or disorder. The term also includes amounts effective for enhancing normal physiological functions. The term "effective amount" and derivatives thereof refer to an amount of a drug and active ingredient that will produce a biological or medical response in a tissue, system, animal or human being, for example, being sought by a researcher or clinician. Further, the term "therapeutically effective amount" means any amount that, when administered to a subject as compared to a corresponding subject not receiving such amount, results in the treatment, cure, prevention or amelioration of a disease, disorder or side effect, or a decrease in the rate of progression of a disease or disorder. The term also includes amounts effective for enhancing normal physiological functions. The term "effective amount" and derivatives thereof refer to an amount of a drug and active ingredient that will produce a biological or medical response in a tissue, system, animal or human being, for example, being sought by a researcher or clinician. Further, the term "therapeutically effective amount" means any amount that, when administered to a subject as compared to a corresponding subject not receiving such amount, results in the treatment, cure, prevention or amelioration of a disease, disorder or side effect, or a decrease in the rate of progression of a disease or disorder. The term also includes amounts effective for enhancing normal physiological functions.

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

[0030] As used herein, the terms "co - administration" and its derivatives mean either co - administration of one or more additional active ingredients with the granules and / or solid oral pharmaceutical dosage forms of the present invention, or any mode of separate and sequential administration. One or more additional active ingredients used herein include any compound or therapeutic agent known or shown to exhibit advantageous properties when administered with TPO or a TPO mimetic. Preferably, when the administration is not simultaneous, the compounds are administered without an interval between them. Further, it does not matter whether the compounds are administered in the same dosage form; for example, one compound may be administered topically and another compound may be administered orally.

[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, G - CSF, BB10010 (Clemons et al., Breast Cancer Res. Treatment, 1999, 57, 127), amifostine (Ethyol) (Fetscher et al., Current Opinion in Hemat., 2000, 7, 255 - 60), SCF, IL - 11, MCP - 4, IL - 1 - beta Thrombopoietin, AcSDKP (Gaudron et al., Stem Cells, 1999, 17, 100-6), TNF-a, TG F-b, MIP-1a (Egger et al., Bone Marrow Transpl., 1998, 22 (Suppl. 2), 34 -35) and other chemical or bone marrow protecting agents, as well as other molecules alleged to have anti-apoptotic, survival or proliferative properties are included.

[0032] As used herein, the term "granule" and its derivatives refer to eltrombopag olamine, a diluent substantially free of coordinating metal and / or substantially free of reducing sugar, and, appropriately, a formulated particle containing a binder and / or a lubricant and / or a disintegrant, which is suitable for use in the preparation of a solid oral pharmaceutical dosage form. It is also possible to administer the granules directly to a subject in need of the pharmaceutical. However, the

[0033] granules are expected to be most appropriately used in the preparation of the above-mentioned solid oral pharmaceutical dosage forms. As used herein, the terms "solid oral dosage form" and "solid dosage form" and their derivatives refer to final pharmaceutical preparations containing eltrombopag

[0034] olamine, such as tablets, capsules, pellets, medicated candies and powders, which are suitable for administration in vivo (including any coated versions of such preparations). while providing one or more functions therein, the materials are usually included for the main function will recognize this. The percentages of diluents, binders, lubricants and disintegrants provided in this specification and the claims are based on the weight of the tablets.

[0035] The diluent provides bulk, for example, to bring the tablets to a particle size suitable for processing. The diluent also serves in processing, for example, by providing improvements in physical properties such as flow, compressibility and tablet hardness. The relatively high percentage of diluent in typical pharmaceutical formulations and the direct contact of the diluent with the active compound are a particular concern for the formulator. Examples of diluents suitable for general use include calcium phosphates (e.g., dibasic and tribasic, hydrated or anhydrous), calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, spray-dried or anhydrous lactose, celluloses (e.g., crystalline cellulose, powdered cellulose), pregelatinized starch, starch, lactitol, mannitol, sorbitol, maltodextrin, powdered sugar, compressed sugar, sucrose, dextrose and inositol, including both water-soluble and water-insoluble fillers. Diluents that do not contain coordinated metals and that are not reducing sugars are suitable for the tablets of the present invention. Diluents suitable for use in the present invention include crystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol and maltodextrin. Unsuitable diluents include calcium phosphates (e.g., dibasic and tribasic, hydrated or anhydrous), calcium sulfate, calcium carbonate, carbon action with the active compound of the diluent is a particular concern for the formulator. Examples of diluents suitable for general use include calcium phosphate (e.g., dibasic and tribasic, hydrated or anhydrous), calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, spray-dried or anhydrous lactose, cellulose (e.g., crystalline cellulose, powdered cellulose), pregelatinized starch, starch, lactitol, mannitol, sorbitol, maltodextrin, powdered sugar, compressed sugar, sucrose, dextrose and inositol, including both water-soluble and water-insoluble fillers. Diluents that do not contain coordinated metals and that are not reducing sugars are suitable for the tablets of the present invention. Diluents suitable for use in the present invention include crystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol and maltodextrin. Unsuitable diluents include calcium phosphate (e.g., dibasic and tribasic, hydrated or anhydrous), calcium sulfate, calcium carbonate, carbon Magnesium acid, kaolin, and spray-dried or anhydrous lactose are included. In the embodiments of the present invention, the diluent is one or both of mannitol and crystalline cellulose.

[0036] The granules and solid oral pharmaceutical forms of the present invention typically contain about 25% to about 89% of one or

[0037] more diluents. One aspect of the present invention includes granules formulated using one or

[0038] more diluents that substantially do not contain coordinated metals and / or substantially do not contain reducing sugars.

[0039] One aspect of the present invention includes solid oral pharmaceutical forms formulated using one or more diluents that substantially do not contain

[0040] coordinated metals and / or substantially do not contain reducing sugars. One aspect of the present invention includes pharmaceutical tablets

[0041] formulated using one or more diluents that substantially do not contain coordinated metals and / or substantially do not contain reducing sugars. Examples of binders suitable for use in the present invention include starch (e.g., paste, pregelatinized, mucilage), gelatin, sugars (e.g., sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), Panwar gum, ghatti gum, guar gum, zein, cellulose derivatives (e.g., carboxymethyl cellulose and its salts, methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC) and ethyl cellulose (EC)), polyvinyl pyrrolidone, Veegum, larch arabinogalactan, polyethylene glycol, wax, water, alcohol, aluminum magnesium silicate and bentonite. In an embodiment of the present invention, the binder comprises polyvinyl pyrrolidone (PVP).

[0042] The granules and solid oral pharmaceutical dosage forms of the present invention typically contain up to about 8% binder. The formulation appropriately contains up to about 5%, appropriately up to 2% binder.

[0043] Lubricants are generally used to enhance processing, for example, to prevent adhesion of formulation materials to manufacturing equipment, reduce interparticle friction, improve the flow rate of the formulation, and / or facilitate the discharge of the formulation from manufacturing equipment. Examples of lubricants suitable for use in the present invention include talc, stearates (e.g., magnesium stearate, calcium stearate, zinc stearate, palmitostearate), stearic acid, hydrogenated vegetable oil, glyceryl behenate, polyethylene glycol, ethylene oxide polymers (e.g., CARBOWAXes), liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, stearyl sodium fumarate,​​​​​​ Mu, DL-leucine, and a silica derivative (e.g., colloidal silicon dioxide, colloidal silica, calcined silica, and sodium aluminosilicate hydrate) can be mentioned. In some embodiments of the present invention, the lubricant contains magnesium stearate.

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

[0045] Disintegrants are used to facilitate the decomposition or disintegration of the formulation after administration. Examples of disintegrants suitable for use in the present invention include starch, cellulose, rubber, cross-linked polymers, and also effervescent agents such as corn starch, potato starch, pregelatinized starch, modified corn starch, croscarmellose sodium, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, crystalline cellulose, cellulose, modified cellulose gum (e.g., Ac-Di-Sol R), agar, bentonite, mont morillonite clay, natural sponge, cation exchange resin, ion exchange resin (e.g., polyacrylic potassium), alginic acid and its salts, guar gum, citrus pulp sodium lauryl sulfate, carboxymethyl cellulose and its salts such as sodium bicarbonate in a mixture with an acidulant such as tartaric acid or citric acid, and sodium aluminosilicate magnesium, sodium aluminosilicate hydrate. In some embodiments of the present invention, the binder contains sodium starch glycolate.

[0046] The granules and solid oral pharmaceutical dosage forms of the present invention typically contain a disintegrant in an amount of 4% to about 12%.​​​ No. The pharmaceutical formulation suitably contains from about 6% to about 10%, suitably from about 7% to 9% of a disintegrant.

[0047] The solid oral pharmaceutical dosage forms of the present invention, suitably tablets, suitably capsules, will typically be sized up to 1 gram and, for example, from about 0.01 gram to about 0.8 gram. These solid dosage forms will typically contain from about 5 mg to about 900 mg of eltrombopag olamine per dosage form. In suitable embodiments, the solid dosage form contains from about 5 to about 200 mg of eltrombopag olamine (e.g., in a dosage form of about 100 - 800 mg). The tablet formulations of the present invention may have various shapes such as rhomboid, modified capsule, modified oval, and hexagonal, and may optionally have bevels.

[0048] Tablets The particular type and amount of excipients, as well as the choice of tabletting technique, will depend on the further properties of eltrombopag olamine and the excipients, such as compressibility, flowability, particle size, compatibility and density. Tablets can be prepared according to methods known in the art including direct compression, dry granulation, fluid bed granulation and wet granulation, and thus the excipients used will vary. Wet granulation is particularly suitable for providing tablets containing relatively high concentrations of eltrombopag olamine ( e.g., about 40% or more) with high strength and low breakage at a suitable commercial manufacturing scale. Suitable wet granulation tablets of the present invention contain granules comprising eltrombopag olamine and one or more fillers, binders and disintegrants, and the granules are mixed with further fillers, binders, disintegrants and / or lubricants to form a compression mixture which is compressed to form tablets. to form tablets. to form a compression mixture which is compressed to form tablets. to form tablets.

[0049] The present invention includes a pharmaceutical composition in tablet form, which contains eltrombopag olamine and is suitably prepared on a commercial scale. The tablets are produced by a wet granulation process using one or more diluents that substantially do not contain coordinated metals and / or substantially do not contain reducing sugars. The present invention also includes such a pharmaceutical composition comprising a film coat, wherein the film coat either does not contain coordinated metals or contains only a negligible amount of coordinated metals that is approximately equal to or less than 0.025 part of Compound B.

[0050] The present invention also includes a pharmaceutical composition containing eltrombopag olamine, wherein the tablets are substantially free of coordinated metals and / or substantially free of reducing sugars, and are produced by a wet granulation process using one or more diluents, suitably on a commercial scale, and about 90% of the eltrombopag olamine particles have a particle size greater than 10 microns but less than 90 microns.

[0051] The present invention also includes a pharmaceutical composition containing eltrombopag olamine, wherein the tablets are substantially free of coordinated metals and / or substantially free of reducing sugars, and are produced by a wet granulation process using one or more diluents, suitably on a commercial scale, and about 90% of the eltrombopag olamine particles have a particle size greater than 10 microns but less than 90 microns, suitably greater than 20 microns but less than 50 microns.

[0052] The present invention also includes a pharmaceutical composition containing eltrombopag olamine, wherein the tablets are substantially free of coordinated metals and / or substantially free of reducing sugars, and are produced by a wet granulation process using one or more ​​​​​Using a diluent, appropriately manufactured by a wet granulation process on a commercial scale, about 50% of the eltrombopag olamine particles are larger than 5 microns but smaller than 50 microns and appropriately have a particle size larger than 5 microns but smaller than 20 microns.

[0053] In one embodiment of the present invention, the tablets of the present invention are (i) about 2% to about 65% eltrombopag olamine; (ii) about 25% to about 89% diluent; (iii) up to about 8%, appropriately up to about 5%, appropriately up to about 4% binder; (iv) up to about 2%, appropriately up to about 1.5%, appropriately up to about 1% lubricant; and (v) 4% to about 12%, appropriately 6% to 10%, appropriately 7% to 9% disintegrant are included.

[0054] Tablets by appropriate wet granulation contain, by tablet weight, about 10% to about 95% eltrombopag olamine effective internal granules and about 5% to about 90% external excipients, and the eltrombopag olamine effective internal granules, by internal granule weight, (i) about 2% to about 88% eltrombopag olamine; (ii) about 10% to about 96% diluent; (iii) about 2% to about 5% binder; and (iv) optionally, 0% to about 4% disintegrant are included, and the external excipients, by tablet weight, (i) 0% to about 70% diluent; (ii) about 0.25% to about 2%, appropriately 0.25% to about 1.25% lubricant; and (iii) about 4% to about 10% disintegrant are included.

[0055] In the above embodiment, the diluent is appropriately a combination of mannitol and crystalline cellulose and the non-reducing sugar is suitably mannitol, the binder is suitably polyvinyl pyrrolidone, the lubricant is suitably magnesium stearate, and the disintegrant is suitably sodium starch glycolate. Suitably, the filler for the inner granules is a mixture of mannitol and crystalline cellulose, and the external filler is crystalline cellulose .

[0056] In one embodiment of the present invention, the tablet is formed from an aqueous film coating composition and is coated with a film coat. An aqueous film coating composition suitable for use in the present invention comprises a film-forming polymer, water as a vehicle, and optionally one or more adjuvants known in the film coating field. When the film coat contains a coordinated metal used in this specification, the amount of the coordinated metal is substantially equal to or less than 0.025 parts of Compound B.

[0057] The film-forming polymer is selected to form a coating having mechanical properties (e.g., mechanical strength, flexibility) that meet the performance requirements required by the intended use environment (e.g., dissolution characteristics in gastrointestinal fluids) and / or use (e.g., solution viscosity). Examples of suitable film forming polymers include cellulose polymers (e.g., cellulose ethers such as HPMC, HPC, MC, EC, HEC, CAP, sodium ethyl cellulose sulfate, carboxymethyl cellulose etc.), polyvinylpyrrolidone; zein; and acrylic polymers (e.g., methacrylic acid / methyl methacrylate copolymers such as methacrylic acid / meth acrylic acid ester copolymers, etc.). Cellulose polymers, in particular, cellulose ethers such as those mentioned above, polyvinylpyrrolidone, zein, and methacrylic acid / methacrylic acid ester copolymers are mentioned. Cellulose polymers, especially cellulose ​- Ethers, and more particularly, HPMC and HPC are preferred in the present invention. The polymer is typically provided in a solution or aqueous dispersion based on either an aqueous or organic solvent. However, the polymer can be provided in dry form, alone or as a powder mixture with other components (e.g., plasticizers and / or colorants), and prepared into a solution or dispersion by the user by mixing with an aqueous vehicle.

[0058] The aqueous film coating composition further contains water as a vehicle for other components to facilitate its delivery to the tablet surface. The vehicle can further contain one or more water-soluble solvents such as alcohols (e.g., methanol, isopropanol, propanol) and ketones (e.g., acetone) if desired. Those skilled in the art can select appropriate vehicle components to provide good interaction between the film-forming polymer and the vehicle, ensuring good film properties. Generally, the polymer-vehicle interaction is designed to cause maximum polymer chain extension to result in a film with maximum binding strength and mechanical properties. Organisms are selected to provide good film formation of the film-forming polymer on the tablet surface, resulting in a film that is adherent and tacky.

[0059] The aqueous film coating composition can contain, if desired, one or more adjuvants known in the art such as plasticizers, colorants, detackifiers, secondary film-forming polymers, flow aids, surfactants (e.g., those useful for spreading), maltodextrin, and polydextrose.

[0060] Plasticizers can impart flexibility to the film, reduce film cracking, and improve adhesion to tablets. Suitable plasticizers generally have a high affinity for the film-forming polymer and have sufficient performance for the coating properties to be generally stable. Examples of suitable plasticizers include glycerin, propylene, glycol, polyethylene glycol (e.g., molecular weights of 200 - 20000, PEG 400, 4000, 6000, 8000, and 20,000 from Union Carbide), glycerin, glycerin triacetate (aka triacetin), acetylated monoglyceride, citrate esters (e.g., triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate), phthalate esters (e.g., diethyl phthalate), mineral oil, and hydrogenated glucose syrup, etc. In one embodiment of the present invention, the plasticizer is selected from polyethylene glycol, triacetin, propylene glycol, glycerin, and mixtures thereof. The aqueous film coating composition suitably includes one or more colorants. Colorants enhance the appearance and provide product identity. Suitable colorants include FD&C and D&C approved dyes, lakes, and pigments, and those approved and guaranteed by the FDA, including titanium dioxide, provided that the film coating does not contain coordinated metals or contains an amount of coordinated metals approximately equal to or less than 0.025 parts of Compound B. Suitably, the colorants are valve handles, red dyes and lakes, iron yellow, yellow dyes and lakes, two For example, glycerin, propylene, glycol, polyethylene glycol (for example, Molecular weights of 200 - 20000, PEG 400, 4000 , 6000, 8000 and 20,000), glycerin, glycerin triacetate -rate (aka triacetin), acetylated monoglyceride, citrate ster (for example, triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate), phthalate esters (for example, diethyl phthalate), Mineral oil and hydrogenated glucose syrup and the like. In one embodiment of the present invention, The plasticizer is selected from polyethylene glycol, triacetin, propylene glycol, gly cerin and mixtures thereof.

[0061] The aqueous film coating composition suitably includes one or more colorants. Colorants enhance the appearance and provide product identity. Suitable colorants include FD&C and D &C approved dyes, lakes, and pigments, and those approved and guaranteed by the FDA, including titanium dioxide, provided that the film coating does not contain coordinated metals or contains an amount of coordinated metals approximately equal to or less than 0.025 parts of Compound B. &C approved dyes, lakes, and pigments, and those approved and guaranteed by the FDA, including titanium dioxide, provided that the film coating does not contain coordinated metals or contains an amount of coordinated metals approximately equal to or less than 0.025 parts of Compound B. Preferably, the film coating does not contain coordinated metals or contains an amount of coordinated metals approximately equal to or less than 0.025 parts of Compound B. Or contains an amount of coordinated metals approximately equal to or less than 0.025 parts of Compound B. Not included.

[0062] Preferably, the colorants are valve handles, red dyes and lakes, iron yellow, yellow dyes and lakes, two One or more colorants selected from the group consisting of titanium oxide and indigo carmine are included. For example, the colorant is, for example, a) valve stem, red dye and / or red lake, b ) iron yellow, yellow dye and / or yellow lake, and substantially consisting of titanium dioxide light beige color can be selected to provide. Alternatively, the colorant is peach (e.g., substantially consisting of titanium dioxide and valve stem, red dye and / or red lake), light green( e.g., iron yellow, yellow dye and / or yellow lake, indigo carmine and titanium dioxide substantially consisting of), light blue (e.g., substantially consisting of titanium dioxide and indigo carmine ), or orange (e.g., substantially consisting of titanium dioxide and sunset yellow ) can be selected to provide.

[0063] The above colorants containing a coordinated metal are acceptable at a level approximately equal to or less than 0.025 parts of Compound B.

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

[0065] Suitably, such a composition further comprises a colorant. Such a composition, if desired optionally, one or more additional adjuvants such as an anti-blocking agent, a flow aid, a surfactant and a secondary film-forming polymer are further included.

[0066] Examples of any anti-blocking agent include lecithin, stearic acid, mineral oil, modified derivatized starch Examples include dextrin, tapioca dextrin, and polyethylene glycol. Any secondary film Examples of forming polymers include sodium alginate, alginic acid pyrophylene glycol l, and polyvinylpyrrolidone. Examples of any surfactant include dioctyl sodium sulfosuccinate and polysorbate 80. Examples of any flow aid include talc, fumed silica, bentonite, hydrogenated vegetable oil, stearin and wax.

[0067] The aqueous film coating composition typically contains about 5% to about 25%, suitably about 5% to about 20% solids for the coating in the vehicle. In suitable embodiments, the solids typically include about 25 wt% to about 70 wt%, suitably about 60 wt% to about 70 wt% of the film forming polymer, about 5 wt% to about 10 wt%, suitably about 6 wt% to about 8 wt% of the plasticizer , and about 20 wt% to about 35 wt% of the colorant.

[0068] Many suitable aqueous film coating compositions are commercially available. The aqueous film coating composition can be provided in the form of a solution or dispersion. Alternatively, the composition can be provided in a dry form that is combined with the vehicle components according to the manufacturer's instructions immediately prior to coating the tablets. Suitably, the aqueous film coating composition is commercially available from Colorcon, Inc. (West Point, PA) under the trade names OPADRY and OPADRY II (non-limiting examples include Opadry YS-1-7706- G White, Opadry Yellow 03B92357, Opadry Blue such as 03B90842). These compositions can be used as dry film coating compositions that can be diluted with water immediately before use. OPADRY and OP ADRY II formulations contain a cellulose film-forming polymer (e.g., HPMC and / or HPC), polydextrose, maltodextrin, plasticizers (e.g., tri acetin, polyethylene glycol), polysorbate 80, colorants (e.g., titanium dioxide, one or more dyes and lakes), and / or other suitable film-forming polymers (e.g., acrylic acid-methacrylic acid copolymer). Suitable OP DRY and OPADRY II formulations can contain plasticizers and one or more maltodex trins, and polydextrose (including, but not limited to, a) triacetin and polydextrose or maltodextrin or lactose, or b) polyethylene glycol and polydextrose or maltodextrin). Tablets are also suitably coated to provide a uniform coating without staining. Tablets are typically coated to provide a dry tablet weight gain of about 2% to about 5%, suitably about 3% to 4%. Uncoated tablet cores are coated with an aqueous film coating composition by methods known in the art using commercially available equipment (e.g., Thomas Accela-Cota, Vector Hi-Coater, Co

[0069] mpu-Lab 36). Generally, the process usually involves rotating or tumbling the tablets in a pan or suspending the tablets on an air cushion (fluid bed), and then spraying the coating composition onto the tablets. Non-coated tablet cores are coated with an aqueous film coating composition by a method known in the art using commercially available equipment (e.g., Thomas Accela-Cota, Vector Hi-Coater, Co mpu-Lab 36). The process generally typically involves a step of rotating or turning the tablets in a pan or suspending the tablets on an air cushion (fluid bed) of the atmosphere, and then spraying the coating composition onto the tablets. or a step of suspending the tablets on an air cushion (fluid bed) of the atmosphere, And, immediately or continuously (preferably, continuously), spraying a fine mist of the coating composition onto the tablets, wetting the droplets, spreading and fusing them on the surface of the tablets to form an adhesive and interference film coating. The tablets are typically heated to about 75°C, suitably by air at a temperature of about 65 - 70°C, to about 40 - 50°C, suitably about 45 - 50°C. Spraying a fine mist of the droplet of the coating composition, wetting the droplets, spreading and fusing them on the surface of the tablets to form an adhesive and interference film coating. The process includes forming an adhesive and interference film coating. The tablets are typically heated to about 75°C, suitably by air at a temperature of about 65 - 70°C, to about 40 - 50°C, suitably about 45 - 50°C. And, immediately or continuously (preferably, continuously), spraying a fine mist of the coating composition onto the tablets, wetting the droplets, spreading and fusing them on the surface of the tablets to form an adhesive and interference film coating. The tablets are typically heated to about 75°C, suitably by air at a temperature of about 65 - 70°C, to about 40 - 50°C, suitably about 45 - 50°C. up to 50°C.

[0070] Method for manufacturing tablets The pharmaceutical tablets of the present invention prepared by wet granulation can be prepared by a method including the following steps: I) A step of preparing granules, including the following: a) Mixing eltron bopagolamine, a diluent, a binder, and, optionally, a disintegrant together for a sufficient time to homogenize the materials; b) Preferably, adding the granulating liquid to the mixture of the dried materials while mixing; c) Mixing the mixture of the dried materials and the granulating liquid for a sufficient granulation time to uniformly wet the dried materials throughout to form wet granules; d) Well pulverizing the wet granules; e) Drying the well pulverized granules to form dried granules; and f) Dry crushing the dried granules to form granules of a desired size; II) A step of preparing tablets, including the following: a) A step of mixing the granules prepared in step I) with an outer excipient containing a filler, a lubricant, and a disintegrant for a sufficient time to homogenize the granules and the outer excipient; and b) Compressing the mixture containing the granules and the outer excipient to form tablets.

[0071] Suitably, the tablets are further film coated, particularly with an aqueous film coating. ​​​​ When preparing the wet granulated particles, the dried material is subjected to appropriate equipment (e.g., Niro-Fielder Blender / Granulator, B ear Varimixer, Key High Shear Mixer / Granu lator) and mixed for a sufficient time (e.g., about 3 minutes) to homogenize the material.

[0072] Next, the granulating liquid is preferably added to the dry mixture while mixing. The granulating liquid is suitably water, or alternatively, a mixture of water and one or more binders such as PVP and HPMC in an amount (about 10 v / w% to about 30 v / w% of the granulating liquid based on the total wet granulation mixture) can be suitably used. The granulating liquid and the dry material are mixed for a total time (about 3 to 15 minutes) sufficient to generally wet the dry material uniformly so that wet granules are formed using appropriate equipment (e.g., Niro-Fielder Blender / Granul ator, Bear Varimixer, Key High Shear Mixer / Granulator) known in the art. Typically, the liquid is added to the dry material over about 1 to about 15 minutes while mixing, and then the entire batch is mixed for an additional time (additional time after the granulating liquid, about 0.5 minutes to about 6 minutes).

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

[0074] Next, the wet granules are wet milled by methods known in the art to provide wet masses of generally uniform size (so that the granules dry relatively uniformly). Appropriate wet milling techniques can include sieving (e.g., manual sieving), comminuting mill (including, but not limited to, a Co-mil with a 0.375” screen). The wet milled granules are then dried by methods known in the art to provide generally uniform drying to a small remaining amount of granulation liquid (preferably about 0.5% to about 1.0%). A fluid bed dryer is a suitable dryer. The dried granules are then dry milled using known methods to provide granules of generally uniform size (a unimodal distribution, appropriately with an average particle size smaller than 240 microns (which has been found to provide improved content uniformity)). Suitable dry milling equipment includes, but is not limited to, a Co-mil with a 0.094” screen. including, but not limited to, a Co-mil with a 0.375” screen The wet milled granules are then dried by methods known in the art to provide generally uniform drying to a small remaining amount of granulation liquid (preferably about 0.5% to about 1.0%). A fluid bed dryer is a suitable dryer. The dried granules are then dry milled using known methods to provide granules of generally uniform size (a unimodal distribution, appropriately with an average particle size smaller than 240 microns (which has been found to provide improved content uniformity)). Suitable dry milling equipment includes, but is not limited to, a Co-mil with a 0.094” screen. including, but not limited to, a Co-mil with a 0.094” screen

[0075] The dried granules are then dry milled using known methods to provide granules of generally uniform size (a unimodal distribution, appropriately with an average particle size smaller than 240 microns (which has been found to provide improved content uniformity)). Suitable dry milling equipment includes, but is not limited to, a Co-mil with a 0.094” screen. The dried granules are then dry milled using known methods to provide granules of generally uniform size (a unimodal distribution, appropriately with an average particle size smaller than 240 microns (which has been found to provide improved content uniformity)). Suitable dry milling equipment includes, but is not limited to, a Co-mil with a 0.094” screen. The dried granules are then dry milled using known methods to provide granules of generally uniform size (a unimodal distribution, appropriately with an average particle size smaller than 240 microns (which has been found to provide improved content uniformity)). Suitable dry milling equipment includes, but is not limited to, a Co-mil with a 0.094” screen. including, but not limited to, a Co-mil with a 0.094” screen is mentioned.

[0076] Appropriately, the granules of the compression mixture and the dry material generally have a unimodal size distribution to facilitate the formulation of a homogeneous mixture and reduce possible separation of the mixture after mixing. If necessary, the dry material is pre-screened to provide the desired particle size distribution. Screening of the lubricant can be useful for dispersing the lubricant. If necessary, the dry material is pre-screened to provide the desired particle size distribution. Screening of the lubricant can be useful for dispersing the lubricant. is mentioned.

[0077] When preparing the compression mixture, the granules, filler and disintegrant are mixed for an appropriate time, about 5 to 15 minutes. Then, a lubricant is added and mixed for an appropriate time, about 1 to 4 minutes. Next, using a press known in the art (e.g., a rotary tablet machine), the mixture is compressed into tablets.

[0078] The above granulation liquid level, granulation time and excipients have been found to provide improved processing.

[0079] Capsules The choice of the specific type and amount of excipient, and the encapsulation technique used, depends on the further properties of eltrombopag olamine and the excipient (e.g., compressibility, fluidity, particle size, compatibility and density). Capsules can be prepared according to methods known in the art (suitably, on a scale suitable for commercial production, suitably by filling two standard hard gelatin capsules with eltrombopag olamine mixed with an excipient, suitably by filling two standard hard gelatin capsules with the granules prepared according to the present invention). Suitable capsules of the present invention contain granules comprising eltrombopag olamine, and one or more fillers, binders and disintegrants, and the granules are mixed with further fillers, binders, disintegrants and / or lubricants to form a granule mixture filled into the capsules.

[0080] Suitably, a pharmaceutical composition in capsule form containing eltrombopag olamine, prepared on a commercial scale, is included in the present invention, and the capsules are manufactured using one or more diluents that are substantially free of coordinated metals and / or substantially free of reducing sugars.

[0081] ​​​​​​Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns, suitably greater than 20 microns but less than 50 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns.

[0082] Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns, suitably greater than 20 microns but less than 50 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns, suitably greater than 20 microns but less than 50 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 90% of the eltrombopag olamine particles greater than 10 microns but less than 90 microns, suitably greater than 20 microns but less than 50 microns.

[0083] Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 50% of the eltrombopag olamine particles greater than 5 microns but less than 50 microns, suitably greater than 5 microns but less than 20 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 50% of the eltrombopag olamine particles greater than 5 microns but less than 50 microns, suitably greater than 5 microns but less than 20 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 50% of the eltrombopag olamine particles greater than 5 microns but less than 50 microns, suitably greater than 5 microns but less than 20 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 50% of the eltrombopag olamine particles greater than 5 microns but less than 50 microns, suitably greater than 5 microns but less than 20 microns. Pharmaceutical compositions comprising eltrombopag olamine are also included in the present invention and are suitably manufactured on a commercial scale using one or more diluents substantially free of counter metals and / or substantially free of reducing sugars, and having a particle size of about 50% of the eltrombopag olamine particles greater than 5 microns but less than 50 microns, suitably greater than 5 microns but less than 20 microns.

[0084] The granules and solid oral pharmaceutical dosage forms of the present invention can be administered in a therapeutically effective amount, for example, to treat or prevent the medical conditions described in PCT / US01 / 16863, PCT / US03 / 16255, and PCT / US04 / 013468 (incorporated herein by reference). Those skilled in the art will appreciate the pharmaceutical formulations of eltrombopag olamine of the present invention. pharmaceutical formulations of eltrombopag olamine of the present invention. pharmaceutical formulations of eltrombopag olamine of the present invention. The dosage amounts and intervals for each administration will be determined by the nature and extent of the condition being treated and the particular patient being treated, and it will be recognized that such optimal conditions can be determined by the prior art. Also, one of ordinary skill in the art will understand that the optimal treatment unit for the treatment, i.e., the number of administrations of eltrombopag olamine given per day over a defined number of days, can be determined using the prior art treatment units of the treatment determination trials.

[0085] The method of the present invention that produces TPO agonist activity in humans comprises administering a therapeutically effective amount of the solid oral pharmaceutical form of the present invention to a subject in need of such activity. The present invention also provides for the use of eltrombopag olamine in the manufacture of the solid oral pharmaceutical form of the present invention.

[0086] The present invention also provides for the use of eltrombopag olamine in the manufacture of the solid oral pharmaceutical form of the present invention for use in enhancing platelet production. The present invention also provides for the use of eltrombopag olamine in the manufacture of the solid oral pharmaceutical form of the present invention for use in treating thrombocytopenia.

[0087] The present invention also provides a solid oral pharmaceutical form for use as a TPO mimetic comprising the eltrombopag olamine of the present invention and a pharmaceutically acceptable carrier. The present invention also provides a solid oral pharmaceutical form for use in the treatment of thrombocytopenia comprising the eltrombopag olamine of the present invention and a pharmaceutically acceptable carrier.

[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, and if desired, sodium starch glycolate) were separately weighed, sieved, and mixed with the granules. Magnesium stearate was added to the mixture and mixed. The mixture was compressed and then the tablet cores were film-coated. The tablets were coated with an aqueous suspension of an OPADRY film coating preparation.

[0094] Example 8 Tablet Preparation Elrombopag olamine tablets containing a diluent containing dibasic calcium phosphate anhydroarsite coordination metal were manufactured in the same manner as above. For the coordination metal diluent of the tablets The tablet composition is provided in Table 2.

[0095]

Table 2

[0096] Example 9 Figure 2 shows the effect of API particle size distribution on the dissolution of elrombopag olamine. Tablets of elrombopag olamine 75 mg were prepared in the manner described in Example 5, with different​​​​ It was generally prepared using a particle size, which refers to the particle size of the drug granules used in the formulation. .

[0097] Using USP Apparatus II at 50 rpm, the dissolution comparison was carried out in phosphate buffer pH 6.8 containing 0.5% Tween 80.

Claims

1. 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) A pharmaceutical tablet, the tablet being substantially free of coordinated metals and / or substantially free of reducing sugars. A pharmaceutical tablet manufactured using one or more diluents.

2. 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) A pharmaceutical tablet, the tablet being substantially free of coordinated metals and / or substantially free of reducing sugars. Pharmaceutical products manufactured on a commercial scale by a wet granulation process using one or more diluents. Medicine tablets.

3. Approximately 90% of the drug particles have a particle size greater than 10 microns but less than 90 microns. The pharmaceutical tablet according to claim 1.

4. Approximately 90% of the drug particles have a particle size greater than 10 microns but less than 90 microns. The pharmaceutical tablet according to claim 2.

5. Approximately 90% of the drug particles have a particle size greater than 20 microns but less than 50 microns. The pharmaceutical tablet according to claim 2.

6. Approximately 50% of the drug particles have a particle size greater than 5 microns but less than 50 microns; The pharmaceutical tablet according to claim 2.

7. Approximately 50% of the drug particles have a particle size greater than 5 microns but less than 20 microns; The pharmaceutical tablet according to claim 2.

8. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) 4% to about 12% of a disintegrant 2. The pharmaceutical tablet of claim 1, comprising:

9. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) about 6% to about 10% of a disintegrant 2. The pharmaceutical tablet of claim 1, comprising:

10. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) about 7% to about 9% of a disintegrant 2. The pharmaceutical tablet of claim 1, comprising:

11. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) 4% to about 12% of a disintegrant 6. The pharmaceutical tablet of claim 2, 4 or 5, comprising:

12. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) about 6% to about 10% of a disintegrant 6. The pharmaceutical tablet of claim 2, 4 or 5, comprising:

13. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) about 7% to about 9% of a disintegrant 6. The pharmaceutical tablet of claim 2, 4 or 5, comprising:

14. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) 4% to about 12% of a disintegrant 8. The pharmaceutical tablet of claim 6 or 7, comprising:

15. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) about 6% to about 10% of a disintegrant 8. The pharmaceutical tablet of claim 6 or 7, comprising:

16. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) about 7% to about 9% of a disintegrant 8. The pharmaceutical tablet of claim 6 or 7, comprising:

17. 9. The pharmaceutical tablet of claim 8, wherein the diluent component comprises a non-reducing sugar and microcrystalline cellulose.

18. The non-reducing sugar is mannitol, the binder is polyvinylpyrrolidone, and the disintegrant is dendrimer. The compound is sodium propylene glycolate, and the lubricant is magnesium stearate.

18. The pharmaceutical tablet according to claim 17.

19. 12. The pharmaceutical tablet of claim 11, wherein the diluent component comprises a non-reducing sugar and microcrystalline cellulose.

20. The non-reducing sugar is mannitol, the binder is polyvinylpyrrolidone, and the disintegrant is dendrimer. The compound is sodium propylene glycolate, and the lubricant is magnesium stearate.

20. The pharmaceutical tablet according to claim 19.

21. 15. The pharmaceutical tablet of claim 14, wherein the diluent component comprises a non-reducing sugar and microcrystalline cellulose.

22. The non-reducing sugar is mannitol, the binder is polyvinylpyrrolidone, and the disintegrant is dendrimer. The compound is sodium propylene glycolate, and the lubricant is magnesium stearate.

22. The pharmaceutical tablet according to claim 21.

23. 20. The pharmaceutical tablet of claim 18, which is manufactured on a commercial scale.

24. 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) A pharmaceutical tablet, the tablet being substantially free of coordinated metals and / or substantially free of reducing sugars. A pharmaceutical tablet manufactured by a wet granulation process using one or more diluents.

25. A therapeutically effective amount of the pharmaceutical tablet according to any one of claims 1 to 24 is administered to a patient who needs treatment for thrombocytopenia.

23. A method for treating thrombocytopenia in a human in need thereof, comprising the step of administering to said human a compound comprising the steps of:

26. A therapeutically effective amount of the pharmaceutical tablet according to any one of claims 1 to 24 is administered to stimulate the TPO receptor.

23. A method of stimulating a TPO receptor in a human in need thereof comprising the step of administering to said human a compound comprising the steps of:

27. Colony-stimulating factors, cytokines, chemokines, interleukins or cytokines Receptor agonists or antagonists, soluble receptors, receptor agonists or antagonists antagonist antibodies or small molecules that act by the same mechanism as one or more of the agents. or a peptide.

26. The method of claim 25, comprising:

28. 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) containing solid An oral pharmaceutical dosage form comprising: A solid oral pharmaceutical dosage form prepared using one or more diluents that do not contain

29. 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) containing solid An oral pharmaceutical dosage form comprising: A solid oral pharmaceutical dosage form manufactured on a commercial scale using one or more diluents that do not contain

30. Approximately 90% of the drug particles have a particle size greater than 10 microns but less than 90 microns.

29. The solid oral pharmaceutical dosage form of claim 28.

31. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) 4% to about 12% of a disintegrant 30. The solid oral pharmaceutical dosage form of claim 28, comprising:

32. 32. The solid oral pharmaceutical dosage form of claim 31, produced on a commercial scale.

33. A therapeutically effective amount of the solid oral pharmaceutical dosage form according to any one of claims 28 to 32 is administered to treat thrombocytopenia.

23. A method for treating thrombocytopenia in a human in need of such treatment comprising administering to said human a compound comprising the steps of:

34. A therapeutically effective amount of the solid oral pharmaceutical dosage form according to any one of claims 28 to 32 is administered to a TPO receptor. The method comprises administering to a human in need of stimulation of the TPO receptor. method.

35. Colony-stimulating factors, cytokines, chemokines, interleukins or cytokines Receptor agonists or antagonists, soluble receptors, receptor agonists or antagonists antagonist antibodies or small molecules that act by the same mechanism as one or more of the agents. or a peptide.

34. The method of claim 33, comprising:

36. 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) A drug capsule, substantially free of coordination metals and / or substantially free of reducing sugars.

2. A pharmaceutical capsule manufactured using one or more diluents that are free of glycerol.

37. 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) A drug capsule, substantially free of coordination metals and / or substantially free of reducing sugars. Pharmaceutical capsules manufactured on a commercial scale using one or more diluents that are not

38. Approximately 90% of the drug particles have a particle size greater than 10 microns but less than 90 microns.

37. The pharmaceutical capsule of claim 36.

39. a) from about 2% to about 65% eltrombopagolamine; b) from about 25% to about 89% diluent; c) up to about 8% binder; d) up to about 2% of a lubricant; and e) 4% to about 12% of a disintegrant 37. The pharmaceutical capsule of claim 36, comprising:

40. 40. The pharmaceutical capsule of claim 39, which is manufactured on a commercial scale.

41. A therapeutically effective amount of the pharmaceutical capsule according to any one of claims 36 to 40 is administered to treat thrombocytopenia.

23. A method for treating thrombocytopenia in a human in need thereof comprising administering to said human a therapeutically effective amount of the compound of formula (I).

42. A therapeutically effective amount of the pharmaceutical capsule according to any one of claims 36 to 40 is administered to stimulate a TPO receptor. A method for stimulating a TPO receptor in a human in need thereof comprising administering to said human a compound comprising the steps of: 。

43. Colony-stimulating factors, cytokines, chemokines, interleukins or cytokines Receptor agonists or antagonists, soluble receptors, receptor agonists or antagonists antagonist antibodies or small molecules that act by the same mechanism as one or more of the agents. or a peptide.

42. The method of claim 41 , comprising:

44. 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) A drug granule, the drug granule being substantially free of coordinated metals and / or substantially free of reducing sugars. Pharmaceutical granules prepared using one or more diluents.

45. 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) A drug granule, the drug granule being substantially free of coordinated metals and / or substantially free of reducing sugars. Pharmaceutical granules manufactured on a commercial scale using one or more diluents.

46. The 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-(monoethanol amine), and substantially free of coordinated metals and / or reducing sugars.

1. A method for producing a solid oral therapeutic dosage form substantially free of one or more diluents, comprising: A process comprising combining a compound of claim 1 with one or more diluents. 。

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