Kinase inhibitor salts and compositions thereof

Abstract

To provide compositions which improve kinase inhibitor absorption following oral administration, reduce the absorption variation when the kinase inhibitor is orally administered with or without food, and / or reduce the absorption variation when co-administered with other drugs such as gastric acid reducing agents.SOLUTION: The present invention relates to kinase inhibitor C8-C16 aliphatic sulfate salts, compositions comprising kinase inhibitor C8-C16 aliphatic sulfate salts, and their use.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Application No. 62 / 685,411, filed Jun. 15, 2018; U.S. Provisional Application No. 62 / 791,356, filed Jan. 11, 2019; and U.S. Provisional Application No. 62 / 811,368, filed Feb. 27, 2019, each of which is incorporated herein by reference in its entirety.

[0002] (Technical Field) The present invention relates to salts of kinase inhibitors formed by the reaction of kinase inhibitors with C 8 -C 16 aliphatic sulfates. The salts of the kinase inhibitors may be orally administered to a subject in combination with at least one pharmaceutically acceptable additive.

[0003] The present invention also relates to pharmaceutically acceptable compositions and dosage forms comprising C 8 -C 16 aliphatic sulfate esters of kinase inhibitors, methods of preparing the compositions and dosage forms, and methods of treating various conditions such as cancer, including orally administering the compositions and dosage forms.

Background Art

[0004] Kinase inhibitors (KIs) are compounds that inhibit kinase enzymes, thereby preventing protein activation. KIs are commonly used in the treatment of cancer, but are also used in the treatment of inflammation and autoimmune diseases such as rheumatoid arthritis and Crohn's disease.

[0005] KIs often exhibit pH-dependent solubility and thus have unstable bioavailability upon oral administration.

[0006] KIs are administered in the presence of a high-fat meal or with a gastric acid inhibitor, i.e., an antacid, H 2It is known that absorption varies greatly during fasting administration compared to when administered with an antagonist or other drugs such as a proton pump inhibitor. For example, for some KIs, pharmacokinetic values such as C max (maximum plasma concentration) and AUC (area under the plasma concentration curve) are known to increase significantly during oral administration in the presence of a high-fat meal compared to administration during fasting. Similarly, co-administration of a gastric acid inhibitor or an agent that raises gastric pH with a KI is known to reduce the absorption of the KI. Since it can vary greatly, restrictions on the timing and conditions of KI administration are required, which are inconvenient for patients and may result in undesirable side effects or loss of efficacy if not administered correctly.

Summary of the Invention

Problems to be Solved by the Invention

[0007] Accordingly, an object of the present invention is to provide a novel salt of KI and a composition containing the salt of KI that improve the absorption of KI after oral administration, reduce the variation in absorption when KI is orally administered with or without food, and / or reduce the variation in absorption when co-administered with other agents such as gastric acid inhibitors.

[0008] The present invention achieves the above and other objects.

Means for Solving the Problems

[0009] The present invention includes a salt of KI, and the salt is formed by the reaction of KI with C 8 -C 16 an aliphatic sulfate. In certain embodiments, the salt of KI is formed by the reaction of KI with a lauryl sulfate of an alkali metal or alkaline earth metal, or a tetradecyl sulfate of an alkali metal or alkaline earth metal.

[0010] The present invention also relates to the C 8 -C 16Compositions and dosage forms comprising an aliphatic sulfate salt and at least one pharmaceutically acceptable additive, preferably for oral administration to a subject.

[0011] The present invention further includes a method of reducing or eliminating the effect of food on the oral administration of KI. More specifically, the present invention includes the oral administration of the composition and / or dosage form of the present invention to a subject, where the subject may be in a fed or fasting state. The plasma profile of KI is obtained in the oral administration of the composition or dosage form of the present invention, and the difference in at least one pharmacokinetic parameter under fed and fasting conditions is less than about 40%. In various embodiments, the pharmacokinetic parameters under fed and fasting conditions may vary by less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5%. The food-independent pharmacokinetic parameters may be C max , AUC, T max , or a combination thereof, but are not limited thereto. In one embodiment, the C 8 -C 16 One or more dosage forms comprising an aliphatic sulfate salt and at least one pharmaceutically acceptable additive are orally administered to cancer patients with or without food, and the C 8 -C 16 The dose of the aliphatic sulfate salt does not require adjustment of the dose or change of the administration time.

[0012] The present invention also includes a method for reducing or eliminating drug interactions by oral administration of KI and co-administration of other drugs, such as gastric acid suppressants or drugs that increase gastric pH. More specifically, the present invention includes oral administration of the compositions and / or dosage forms of the present invention to a subject, who may also be administered a drug that reduces gastric acid secretion or increases gastric acid pH. Upon oral administration of the compositions or dosage forms of the present invention, a plasma profile of KI is obtained, in which at least one pharmacokinetic parameter differs by less than about 40% when the compositions or dosage forms of the present invention are administered with or without a drug that reduces gastric acid secretion or increases gastric acid pH. In various embodiments, the pharmacokinetic parameters may vary by less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5% when the compositions or dosage forms of the present invention are administered with or without a drug that reduces gastric acid secretion or increases gastric acid pH. The pharmacokinetic parameters that are independent of co-administration with a drug that reduces gastric acid secretion or increases gastric acid pH are C max ,A.U.C.,T. max In one embodiment, the C of the KI may be 8 -C 16 One or more dosage forms comprising an aliphatic sulfate salt and at least one pharma- ceutical acceptable excipient are administered to a cancer patient who is co-administered with a gastric acid suppressant, and the C of the administered KI is 8 -C 16 The dosage of the aliphatic sulfate does not require adjustment in dosage or alteration of time of administration.

[0013] The present invention also includes a method for reducing the total daily oral dose of KI. More specifically, the present invention includes oral administration of a composition and / or dosage form prepared according to the present invention, wherein the total daily oral dose of KI is a KI free base or non-C currently approved by the U.S. Food and Drug Administration (FDA). 8 -C 16 At least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% less than the total daily amount of aliphatic sulfates.

[0014] In certain embodiments of the present invention, a composition or dosage form for oral administration is a hard or soft capsule, or a tablet, comprising a C 8 -C 16 aliphatic sulfate and a pharmaceutically acceptable carrier, preferably fully mixed. In certain aspects of this embodiment, the hard or soft capsule may be a gelatin-based or non-gelatin-based capsule. In certain aspects of this embodiment, the pharmaceutically acceptable carrier is liquid under ambient conditions, i.e., 25°C, standard atmospheric pressure, or the pharmaceutically acceptable carrier is solid under ambient conditions but has a melting point higher than 25°C and less than 120°C, preferably less than 100°C, more preferably less than 80°C. When the pharmaceutically acceptable carrier is liquid under ambient conditions, the C 8 -C 16 aliphatic sulfate and the liquid carrier are mixed and the resulting mixture is filled or formed into a hard or soft capsule. The liquid mixture may further contain one or more pharmaceutically acceptable additives such as stabilizers, which will be described in detail below. When the carrier is solid under ambient conditions, before filling or forming into a hard or soft capsule, or forming into a tablet, the carrier is heated to melt, and the melted carrier and the C 8 -C 16 aliphatic sulfate may be mixed. Alternatively, the carrier is dissolved or dispersed in a solvent, and the C 8 -C 16 aliphatic sulfate alone and in combination with at least one additional pharmaceutically acceptable additive may be combined with the carrier to make a complete admixture of the C 8 -C 16 aliphatic sulfate. Once a complete admixture of the C 8 -C 16 aliphatic sulfate and the carrier is made, it may be dried and filled or formed into a hard or soft capsule, or a complete admixture and at least one additional pharmaceutically acceptable additive may be combined and the resulting combination filled or formed into a hard or soft capsule, or formed into a tablet.

[0015] In another embodiment of the present invention, the composition and / or dosage form comprises a C of KI 8 -C 16 aliphatic sulfate and a carrier having an HLB value of 10 or more, and the carrier having an HLB value of 10 or more is selected from the group consisting of a wetting agent, an emulsifying agent, a solubilizing agent, a surfactant, or a combination thereof. In a preferred embodiment, the C of KI 8 -C 16 The aliphatic sulfate and the carrier having an HLB value of 10 or more are completely mixed. In a further embodiment, the composition may be a liquid composition for oral administration to a subject, or the liquid composition may be filled into hard or soft capsules for oral administration to a subject. The liquid mixture may further contain one or more pharmaceutically acceptable additives such as stabilizers described in detail below. Alternatively, the composition may be a solid or semi-solid composition such as a powder or granule that may be orally administered to a subject, or the solid or semi-solid composition may be formed into tablets or filled into capsules for oral administration to a subject.

[0016] The present invention also relates to the preparation, formation, and manufacturing method of a composition and dosage form comprising a C of KI 8 -C 16 aliphatic sulfate and at least one pharmaceutically acceptable additive, preferably for oral administration to a subject.

[0017] The present invention also further includes a method of treating a patient, which comprises orally administering a composition and dosage form comprising a therapeutic amount of a C of KI 8 -C 16 aliphatic sulfate and at least one pharmaceutically acceptable additive.

[0018] The present invention also includes a novel polymorph of a C of KI 8 -C 16 aliphatic sulfate, a method for producing the novel polymorph, a composition and dosage form containing the novel polymorph, and a method for treating a patient using the novel polymorph. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

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Mode for Carrying Out the Invention

[0020] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described. It should also be understood that the terms used herein are for the purpose of describing only the specific embodiments and are not intended to be limiting.

[0021] It should be noted that as used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0022] When a range of values is provided, each intermediate value between the upper and lower limits of that range and any indicated value or intermediate value within that range, to one tenth of the unit of the lower limit, is included within the scope of the present invention unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are included in the present invention subject to specifically excluded limitations within the described range. When the described range includes one or both of the upper and lower limit values, ranges excluding either or both of the included upper and lower limit values are also included in the present invention.

[0023] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, but the preferred methods and materials are described herein. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials related to the cited publications.

[0024] As used herein, the term "ordinary storage conditions" refers to room temperature, approximately 25 °C And it means storing at approximately 60% relative humidity for at least 3 months, preferably at least 6 months, and most preferably at least 1 year. The dosage forms according to the present invention should be stored in a pharmaceutically acceptable container such as a glass bottle, a plastic bottle, a metal foil sachet, or a blister pack, regardless of the presence or absence of a desiccant.

[0025] As used herein, the term "accelerated storage conditions" means storing at approximately 40 °C and approximately 75% relative humidity for at least 2 weeks or more, 1 month or more, 2 months or more, 3 months or more, 4 months or more, 5 months or more, or 6 months or more. The dosage forms according to the present invention should be stored in a pharmaceutically acceptable container such as a glass bottle, a plastic bottle, a metal foil sachet, or a blister pack, regardless of the presence or absence of a desiccant.

[0026] The term "HLB" means the "hydrophilic-lipophilic balance" of a surfactant or emulsifier, and is an index of the degree of hydrophilicity or lipophilicity determined by calculating the values of various regions of the molecule, as described in Griffin WC, "Calculation of HLB Values of Non-Ionic Surfactants", Journal of the Society of Cosmetic Chemists, 5:259 (1954). The HLB value ranges from 0 to 20, with an HLB value of 0 corresponding to a completely lipophilic molecule and an HLB value of 20 corresponding to a completely hydrophilic molecule. The HLB values are generally known and are reported in literature such as the manufacturer's technical data.

[0027] The term "C max " means the maximum plasma concentration obtained during the dosing interval.

[0028] The term "T max " means the time until the maximum plasma concentration (C max ) is reached.

[0029] The term "AUC" means the area under the drug concentration-time curve (AUC) calculated using the sum of linear trapezoids over a specific time interval. For example, AUC 0-12 means the area under the drug concentration-time curve from just before dosing to 12 hours after dosing, and AUC 0-24 means the area under the drug concentration-time curve from just before dosing to 24 hours after dosing, and AUC 0-∞ means the area under the drug concentration-time curve from just before dosing to infinity, and AUC 0-t means the area under the drug concentration-time curve from just before dosing to specified time points such as 2 hours, 8 hours, 18 hours, etc. after dosing. In some embodiments, the specified time point is the last blood sampling time point.

[0030] The pharmacokinetic values described herein are generally determined according to methods commonly described in publications such as the U.S. Food and Drug Administration (U.S. FDA) industry guidance "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products--General Considerations" (March 2003), the U.S. Food and Drug Administration (U.S. FDA) industry guidance "Statistical Approaches to Establishing Bioequivalence" (January 2001), and the U.S. Food and Drug Administration (U.S. FDA) industry guidance "Food-Effect Bioavailability and Fed Bioequivalence Studies" (December 2002), which are known and understood by those skilled in the art and incorporated herein by reference.

[0031] As used herein, unless otherwise defined, the term "subject" means a mammal such as a human, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, or guinea pig, preferably a human, and includes healthy mammals and mammals suffering from a disease that may be treatable with KI. A subject suffering from a disease that may be treatable with KI may also be referred to as a "patient".

[0032] As used herein, unless otherwise defined, when used in connection with a pharmaceutical composition or dosage form containing a salt of KI, the phrase "therapeutically effective amount" means an amount of KI or a salt thereof that is effective for the treatment of a disease or disorder disclosed herein such as cancer.

[0033] As used herein, unless otherwise defined, terms such as "completely mixed" and "complete mixture" refer to a combination of a salt of KI of the present invention and at least one pharmaceutically acceptable additive such as a wetting agent, emulsifier, solubilizer, surfactant, or a combination thereof, preferably a carrier having an HLB value of about 10 or more, preferably an HLB value of about 11 or more, and most preferably an HLB value of about 12 or more, and the salt of KI and at least one pharmaceutically acceptable additive are in close contact or are closely associated with each other. The complete mixture may be prepared by any means that enables blending of the salt of KI of the present invention and at least one pharmaceutically acceptable additive, preferably a carrier having an HLB value of about 10 or more. Examples of suitable methods for achieving a complete mixture include dissolving, suspending, or dispersing the salt of KI in a solution or suspension containing at least one pharmaceutically acceptable additive, preferably a carrier having an HLB value of about 10 or more, and optionally at least one further pharmaceutically acceptable additive such as a pharmaceutically acceptable solvent. The pharmaceutically acceptable solvent may or may not be removed. Another example of a suitable method for achieving a complete mixture is to use a liquid additive containing at least one pharmaceutically acceptable additive having an HLB value of about 10 or more, or to melt one or more solid additives containing at least one pharmaceutically acceptable additive having an HLB value of about 10 or more to form a composition of the melted additive or liquid additive containing at least one additive having an HLB value of about 10 or more, and dissolving, suspending, or dispersing the salt of KI in the composition of the melted additive or liquid additive. The liquid additive containing at least one additive having an HLB value of about 10 or more may further contain one or more pharmaceutically acceptable additives, which will be described in more detail below. Another method used to achieve a complete mixture of the salt of KI and at least one pharmaceutically acceptable additive preferably having an HLB value of about 10 or more includes co-blending, co-screening, co-condensing, co-compressing, or a combination thereof.Once a complete mixture of a salt of KI and at least one pharmaceutically acceptable additive, preferably having an HLB value of about 10 or more, is prepared, the completely mixed composition may be combined with at least one further pharmaceutically acceptable additive or carrier. The complete mixture may preferably contain a salt of KI and one, two or three additives before being combined with further additives.

[0034] As used herein, unless otherwise defined, the term "anti-acid agent" refers to an additive and / or agent that raises the pH of the stomach or neutralizes gastric acid, such as an antacid or a compound that reduces gastric acid secretion, such as an H 2 antagonist or a proton pump inhibitor. Examples of common antacids include, but are not limited to, sodium bicarbonate, sodium citrate, magnesium trisilicate, aluminum trisilicate, calcium carbonate, and commercial products such as TUMS and ALKA-SELTZER. H 2 Examples of H antagonists include, but are not limited to, antihistamines, cimetidine, ranitidine, famotidine, nizatidine, roxatidine, and raf tidine. Examples of proton pump inhibitors include, but are not limited to, omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, and dexlansoprazole.

[0035] As used herein, unless otherwise defined, the terms "co-administered," "co-administering," and "co-administer" mean a subject who is receiving one or more non-KI drugs or therapeutic agents during KI treatment. The one or more non-KI drugs or therapeutic agents can be administered simultaneously or sequentially with the KI composition or dosage form of the present invention. Simultaneous administration as used in the present invention means a non-KI drug or therapeutic agent that is administered within 2 hours before or after administration of the KI composition or dosage form of the present invention, preferably within 1 hour before or after administration of the KI composition or dosage form of the present invention, more preferably within 30 minutes before or after administration of the KI composition or dosage form of the present invention. Sequential administration as used herein means the administration of a non-KI drug or therapeutic agent at any time before or after administration of the KI composition or dosage form of the present invention, and may include the administration of a non-KI drug 4, 6, 8, 12, or 14 hours before or after administration of the KI composition or dosage form, etc.

[0036] As used herein, unless otherwise defined, the term "KI(s)" means one or more optional compounds that are pharmaceutically active and inhibit a kinase enzyme, preferably a tyrosine kinase enzyme. Preferably, the KI is a small molecule generally having the suffix "nib" in its name, a tyrosine kinase inhibitor (TKI) generally having the suffix "tinib" in its name, an angiogenesis inhibitor generally having the suffix "anib" in its name, and a Raf (rapidly accellerated fibrosarcoma) kinase inhibitor generally having the suffix "rafinib" in its name. Also included are focal adhesion kinase (FAK) inhibitors.

[0037] Examples of KI that can be used in the present invention include acalabrutinib (commercially available under the trade name CALQUENCE), afatinib (commercially available under the trade name GILOTRIF), alectinib (commercially available under the trade name ALECENSA), apatinib, axitinib (commercially available under the trade name INLYTA), bafetinib, baricitinib, bosutinib (commercially available under the trade name BOSULIF), brigatinib (commercially available under the trade name ALUNBRIG), cabozantinib (commercially available under the trade name COMETRIQ), canertinib, cediranib, ceritinib (commercially available under the trade name ZYKADIA), cobimetinib (commercially available under the trade name COTELLIC), crinolanib, crizotinib (commercially available under the trade name XALKORI), dabrafenib (commercially available under the trade name TAFINLAR), dasatinib (commercially available under the trade name SPRYCEL), defactinib (VerastemCommercially available from Oncology,enasidenib (commercially available under the trade name IDHIFA),entrectinib,erlotinib (commercially available under the trade name TARCEVA),filgotinib,foretinib, fostamatinib (commercially available under the trade name TAVALISSE),gefitinib (commercially available under the trade name IRESSA),glesatinib,ibrutinib (commercially available under the trade name IMBRUVICA),icotinib,imatinib (commercially available under the trade name GLEEVEC),lapatinib (commercially available under the trade name TYKERB),lestaurtinib,lenvatinib (commercially available under the trade name LENVIMA),linifanib,lusitanib,momelotinib,motesanib,mubritinib,neratinib (commercially available under the trade name NERLYNX),nilotinib (commercially available under the trade name TASIGNA),nintedanib (commercially available under the trade name OFEV),oclacitinib (commercially available under the trade name APOQUEL),olmutinib,osimertinib (commercially available under the trade name TAGRISSO),pacritinib,pazopanib (commercially available under the trade name VOTRIENT),ponatinib (commercially available under the trade name ICLUSIG),quizartinib,radotinib,regorafenib (commercially available under the trade name STIVARGA),roscovitine,ruxolitinib (commercially available under the trade name JAKAFI),saracatinib,saxagliptinib,semaxanib, sitravatinib,sorafenib (commercially available under the trade name NEXAVAR),sunitinib (commercially available under the trade name SUTENT),taselisib,tesevatinib, tibiozanib,toceranib,tofacitinib (commercially available under the trade name XELJANZ),trametinib (commercially available under the trade name MEKINIST),upadacitinib,batalanib, vandetanib (commercially available under the trade name CAPRELSA),and vemurafenib (commercially available under the trade name ZELBORAF),but not limited to these.

[0038] More preferred KIs useful in the present invention include, but are not limited to, acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, octreotide acetate, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib.

[0039] Further examples of KIs useful in the present invention are (i) a phenylcarboxamide moiety having the following structure

Chemical formula

Chemical formula

Chemical formula

[0040] Examples of KIs that include the phenylcarboxamide moiety (i) include, but are not limited to, afatinib, cabozantinib, dasatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, ponatinib, regorafenib, and trametinib.

[0041] Examples of KIs that include one of the aminopyrimidine moieties (ii) or (iii) include, but are not limited to, afatinib, brigatinib, ceritinib, dabrafenib, dasatinib, defactinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, nilotinib, osimertinib, pazopanib, luxitinib, tofacitinib, and vandetanib.

[0042] In certain preferred embodiments, the KIs used in the present invention include, as described above, (a) the phenylcarboxamide moiety (i) and the aminopyrimidine moiety (ii), or (b) the phenylcarboxamide moiety (i) and the aminopyrimidine moiety (iii). Examples of KIs that include the phenylcarboxamide moiety (i) and one of the aminopyrimidine moieties (ii) or (iii) include, but are not limited to, afatinib, dasatinib, imatinib, nilotinib, and osimertinib.

[0043] The C of the KI of the present invention 8 -C 16 The aliphatic sulfate salt can be formed by the reaction of the KI molecule with C 8 -C 16 The aliphatic sulfate. In certain embodiments, the C of the KI 8 -C 16The aliphatic sulfate salt is formed by the reaction of KI with a lauryl sulfate of an alkali metal or alkaline earth metal, or a tetradecyl sulfate of an alkali metal or alkaline earth metal. Preferred examples of the lauryl sulfate of an alkali metal or alkaline earth metal, or the tetradecyl sulfate of an alkali metal or alkaline earth metal include, but are not limited to, sodium or potassium lauryl sulfate, and sodium or potassium tetradecyl sulfate. The most preferred anion compound used in the preparation of the salt of KI of the present invention is sodium lauryl sulfate or potassium lauryl sulfate.

[0044] The C of KI of the present invention 8 -C 16 The aliphatic sulfate salt is prepared by dissolving a KI compound (either in the form of the free base or in the form of a salt such as the HCl salt of KI, the citrate salt of KI, the phosphate salt of KI, the mesylate salt of KI, the maleate salt of KI, or the tosylate salt of KI) in a suitable solvent such as water, a branched or straight-chain C 1 -C 6 alcohol, ether, ester or ketone, or a mixture thereof, a branched or straight-chain C 3 -C 12 alkane, or a mixture thereof, or a mixture of water and an organic solvent, and adding an aliphatic sulfate to the KI solution and mixing the resulting reactants. Alternatively, the aliphatic sulfate can be dissolved in a suitable solvent and the KI compound (either in the form of the free base or in the form of a salt) can be added to the aliphatic sulfate solution and the resulting reactants can be mixed. The C of KI of the present invention 8 -C 16 The aliphatic sulfate salt can also be formed by dissolving a KI compound (either in the form of the free base or in the form of a salt) in a suitable solvent, dissolving an aliphatic sulfate in a suitable solvent, and mixing the KI compound solution and the C 8 -C 16 aliphatic sulfate solution. The C of KI of the present invention 8 -C 16 The aliphatic sulfate salt can also be prepared by dissolving a KI compound (either in the form of the free base or in the form of a salt) in a suitable solvent, dissolving an aliphatic sulfate in a suitable solvent, and mixing the KI compound solution and the C 8 -C 16 aliphatic sulfate solution. The aliphatic sulfate salt of the present invention can also be prepared by dissolving a KI compound (either in the form of the free base or in the form of a salt) in a suitable solvent, dissolving an aliphatic sulfate in a suitable solvent, and mixing the KI compound solution and the C 8 -C 16 aliphatic sulfate solution. 8 -C 16It may also be formed by combining the aliphatic sulfate solution and mixing the resulting reactants. By conventional techniques such as evaporation and filtration, the solvent is removed from the resulting reactants, and the C of KI 8 -C 16 The aliphatic sulfate salt is separated. The separated C of KI of the present invention 8 -C 16 The aliphatic sulfate salt can be used in the compositions and dosage forms described herein.

[0045] In some embodiments of the present invention, the dissolved KI compound may be reacted with an acid, preferably a strong acid, most preferably an inorganic acid, to protonate one or more nitrogen atoms. When KI is protonated, it is C 8 -C 16 It mixes with the aliphatic sulfate to form the C of KI 8 -C 16 The aliphatic sulfate salt.

[0046] The C in the reactant 8 -C 16 The molar ratio of the aliphatic sulfate to the KI compound is about 0.5 mol to C of the aliphatic sulfate per 1 mol of the KI base present in the reactant 8 -C 16 It may range from about 6 mol of the aliphatic sulfate, preferably about 0.75 mol to C of the aliphatic sulfate per 1 mol of the KI base present in the reactant 8 -C 16 It may range from about 5 mol of the aliphatic sulfate, most preferably about 0.85 mol to C of the aliphatic sulfate per 1 mol of the KI base present in the reactant 8 -C 16 It is about 4 mol of the aliphatic sulfate. The C of KI 8 -C 16 The aliphatic sulfate salt may be formed during or as part of the manufacture of the composition or dosage form of the present invention. The mono C of KI 8 -C 16 It may range from about 0.85 mol to C of the aliphatic sulfate 8 -C 16 It is about 4 mol of the aliphatic sulfate. The C of KI 8 -C 16 The aliphatic sulfate salt may be formed during or as part of the manufacture of the composition or dosage form of the present invention. The mono C of KI 8 -C 16In some embodiments of the aliphatic sulfate salt, C in the reactants 8 -C 16 The molar ratio of the aliphatic sulfate to the KI compound may be from about 0.8 mole to about 1.3 moles of aliphatic sulfate per mole of KI base present in the reactants. In some embodiments of the KI di 8 -C 16 aliphatic sulfate salt, the molar ratio of the aliphatic sulfate to the KI compound may be from about 1.6 moles to about 2.5 moles of aliphatic sulfate per mole of KI base present in the reactants. The KI 8 -C 16 aliphatic sulfate salt of the present invention may be the mono 8 -C 16 aliphatic sulfate salt of KI, or the di 8 -C 16 aliphatic sulfate salt of KI, the tri 8 -C 16 aliphatic sulfate salt of KI, the tetra 8 -C 16 aliphatic sulfate salt of KI, or the penta 8 -C 16 aliphatic sulfate salt of KI, such as multi 8 -C 16 aliphatic sulfate salts of KI. Unless otherwise indicated, the term KI 8 -C 16 aliphatic sulfate salt as used herein includes mono and multi aliphatic sulfate salts, and similarly the term KI lauryl sulfate salt includes mono and multi lauryl sulfate salts. 8 -C 16 8 16 -C 8 16 8 -C 16 8 16 -C 8 16

[0047] The present invention also relates to the KI

[0047] aliphatic sulfate salt. 8 -C 16Compositions and dosage forms comprising an aliphatic sulfate salt and at least one pharmaceutically acceptable additive, preferably for oral administration to a subject. The compositions and dosage forms may be solid, semi-solid, or liquid, and the C of KI 8 -C 16 The aliphatic sulfate salt is combined with pharmaceutically acceptable additives such as fillers, diluents, binders, stabilizers, lubricants, disintegrants, wetting agents / solubilizers / emulsifiers or mixtures thereof. Pharmaceutically acceptable additives are well known to those skilled in the art and are described in Remington, The Science and Practice of Pharmacy, 21st ed. (2006), pp. 1058-1092, and Handbook of Pharmaceutical Excipients, 6th ed. (2009). Representative examples of various pharmaceutically acceptable additives used in embodiments of the present invention are shown below.

[0048] Solid and semi-solid compositions and dosage forms include powders, granules, pellets, mini-tablets, tablets, capsules, and are manufactured by methods known in the art such as direct compression, wet or dry granulation, and extrusion spheronization.

[0049] Liquid compositions and dosage forms include solutions, suspensions, or dispersions, which are also manufactured by methods known in the art.

[0050] In certain embodiments of the present invention, the composition or dosage form for oral administration is a tablet, or a hard or soft gelatin capsule, comprising an aliphatic sulfate salt of KI and a pharmaceutically acceptable carrier, preferably fully mixed. In certain aspects of this embodiment, the pharmaceutically acceptable carrier is liquid at ambient conditions, i.e., 25°C, normal atmospheric pressure, or the pharmaceutically acceptable carrier is solid at ambient conditions but has a melting point above 25°C and below 120°C, preferably below 100°C, more preferably below 80°C, most preferably below 60°C. When the pharmaceutically acceptable carrier is liquid at ambient temperature, the C of KI 8 -C 16 In certain embodiments of the present invention, the composition or dosage form for oral administration is a tablet, or a hard or soft gelatin capsule, comprising an aliphatic sulfate salt and a pharmaceutically acceptable carrier, preferably fully mixed. In certain aspects of this embodiment, the pharmaceutically acceptable carrier is liquid at ambient conditions, i.e., 25°C, normal atmospheric pressure, or the pharmaceutically acceptable carrier is solid at ambient conditions but has a melting point above 25°C and below 120°C, preferably below 100°C, more preferably below 80°C, most preferably below 60°C. When the pharmaceutically acceptable carrier is liquid at ambient temperature, the C of KI 8-C 16 The aliphatic sulfate salt and the liquid carrier are mixed, and the resulting mixture is filled or formed into hard or soft gelatin capsules. The liquid mixture may also contain one or more additional pharmaceutically acceptable additives, such as stabilizers, which are described in more detail below.

[0051] When the carrier is solid or semi-solid under ambient conditions, the carrier is heated to melt it before being formed into tablets or filled or formed into hard or soft gelatin capsules. 8 -C 16 The aliphatic sulfate salt is mixed or granulated with one or more additional pharmaceutically acceptable additives, if any. Alternatively, when the carrier is solid or semi-solid under ambient conditions, the carrier is heated to melt it before being formed into tablets or filled or formed into hard or soft gelatin capsules. 8 -C 16 The aliphatic sulfate salt is mixed with one or more additional pharmaceutically acceptable additives, if any.

[0052] In certain embodiments, 8 -C 16 The aliphatic sulfate salt is dissolved in the liquid carrier or in the melted carrier. Alternatively, 8 -C 16 The aliphatic sulfate salt is dispersed or suspended in the liquid carrier or in the melted carrier.

[0053] Examples of liquid carriers used in the preparation of oral dosage forms of the present invention include, but are not limited to, fatty acids, medium-chain triglycerides, fatty acid esters, fatty alcohols, vegetable oils such as corn oil, soybean oil, olive oil, sunflower oil, peanut oil, or mixtures thereof. In certain embodiments, the liquid carrier comprises about 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% (w / w) of the composition, or all ranges included in these values, preferably about 15% (w / w) to about 90% (w / w), most preferably about 20% (w / w) to about 85% (w / w) of the composition filled in capsules.

[0054] Examples of solid carriers having a melting point of from 25°C to less than 120°C include aliphatic alcohols, polyethylene glycols such as polyethylene glycol 1000 having a melting point of 37 to 40°C and polyethylene glycol 1500 having a melting point of 44°C to 48°C, hardened oils (also known as hydrogenated vegetable glycerides), hydrogenated vegetable oils, vitamin E polyethylene glycol succinate (also known as TPGS), poloxamers (nonionic polyoxyethylene-polyoxypropylene copolymers such as poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), polyoxyglycerides, polyoxyethylene stearate, and waxes such as carnauba wax, cetyl ester wax, microcrystalline wax, white wax, and yellow wax, and combinations of the aforementioned solid carriers. In certain embodiments, the solid carrier should comprise about 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, 50%, 52.5%, 55%, 57.5%, 60%, 62.5%, 65%, 67.5%, 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 92.5%, 95% (w / w), or all ranges included within these values of a composition filled into capsules or formed into tablets, preferably from about 5% (w / w) to about 90%, most preferably from about 7.5% (w / w) to about 85%.

[0055] Further examples of solid, semi-solid, and liquid carriers used in the preparation of solid, semi-solid, or liquid dosage forms of the present invention, including but not limited to hard gelatin capsules, soft gelatin capsules, and tablets of the present invention, include wetting agents, emulsifying agents, solubilizing agents, surfactants, or combinations thereof having an HLB value of about 10 or greater, preferably an HLB value of about 11 or greater, more preferably an HLB value of about 12 or greater, and most preferably an HLB value of about 14 or greater, as detailed below.

[0056] In another embodiment of the present invention, the composition or dosage form is C of KI 8 -C 16Aliphatic sulfate salts and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, having an HLB value of about 10 or more, preferably about 11 or more, more preferably about 12 or more, and most preferably about 14 or more, and further comprising at least one additional pharmaceutically acceptable additive. C of KI 8 -C 16 The aliphatic sulfate salts may be present in the composition at a weight of about 1% to about 80% by weight, preferably about 2% to about 70% by weight, more preferably about 2.5% to about 60% by weight, and most preferably about 3% to about 50% by weight, based on the total weight of the composition or dosage form. In certain embodiments, C of KI 8 -C 16The aliphatic sulfate salt may be present in the composition in a weight of about 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, or any range of weights included in these values. One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or more, preferably about 11 or more, more preferably about 12 or more, and most preferably about 14 or more should be present in the composition or dosage form in a weight of 1 wt% or more based on the total weight of the composition or dosage form, preferably about 2 wt% or more, and most preferably about 5% or more based on the total weight of the composition or dosage form. In certain embodiments, one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or more, preferably about 11 or more, more preferably about 12 or more, and most preferably about 14 or more should be present in the composition or dosage form in a weight of about 1 wt% to about 90 wt%, preferably about 2 wt% to about 80 wt%, and most preferably about 3 wt% to about 70 wt%.In some embodiments, one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of about 10 or greater may be present in the composition at a weight of about 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, or any range of weights included within these values.

[0057] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of about 10 or greater may be nonionic surfactants, ionic surfactants, or combinations thereof, preferably nonionic surfactants. Examples of nonionic surfactants that can be used include polyethoxylated castor oil, polyoxyethylene alkyl esters, polyglycolated glycerides, sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty alcohol polyglycol ethers, acetylene glycol, acetylene alcohol, oxyalkylene block polymers, polyoxyethylene alkyl ethers, polyoxyethylene alkyl aryl ethers, polyoxyethylene styryl aryl ethers, polyoxyethylene glycol alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid esters, polyoxyl glycerides, polyoxyethylene stearate, or mixtures thereof. A further list of possible nonionic surfactants is described on pages 1243 - 1249 of Martindale, The Extra Pharmacopoeia, 29th ed., which is incorporated herein by reference.

[0058] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of about 10 or greater may also be nonionic surfactants such as fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, and mixtures thereof. Examples of nonionic surfactants include, but are not limited to, polyoxyethylene derivatives of polyol esters such as polysorbate 20 (commercially available under the trade name TWEEN® 20), polysorbate 40 (commercially available under the trade name TWEEN® 40), polysorbate 60 (commercially available under the trade name TWEEN® 60), and polysorbate 80 (commercially available under the trade name TWEEN® 80).

[0059] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of about 10 or more may be polyoxyl castor oil or polyoxyethylene hydrogenated castor oil, or combinations thereof, such as polyoxyl castor oil. Examples of these surfactants include, but are not limited to, polyoxyl 35 castor oil (commercially available under the trade name CREMAPHOR EL or KOLLIPHOR EL), polyoxyl 40 hydrogenated castor oil (commercially available under the trade name CREMOPHOR RH40), and polyoxyl 60 hydrogenated castor oil.

[0060] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of about 10 or more may be polyoxyethylene alkyl ethers such as polyoxyl cetostearyl ether, polyoxyl cetyl ether, polyoxyl lauryl ether, polyoxyl oleyl ether, polyoxyl stearyl ether, or mixtures thereof.

[0061] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of about 10 or more may be nonionic polyoxyethylene-polyoxypropylene copolymers such as tyloxapol, poloxamer, i.e., poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, or combinations thereof.

[0062] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that exhibit an HLB value of about 10 or more may be fatty acid esters or fatty alcohols of polyglycerides such as caprylic / capric triglyceride (commercially available under the trade name MYIGLYOL).

[0063] In some embodiments of the present invention, the composition is C of KI 8 -C 16An aliphatic sulfate, and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or more, preferably being completely mixed, and having a low or no HLB value, may further include at least one additional second carrier. The second carrier may be a wetting agent, emulsifier, solubilizer, surfactant, or combination thereof having an HLB value of less than about 10, more preferably an HLB value of about 9 or less or about 8 or less, and most preferably an HLB value of about 7 or less. Examples of at least one additional second carrier having a low HLB value include polyethoxylated castor oil, polyoxyethylene alkyl ester, polyglycolated glyceride, sorbitan fatty acid ester, glycerin fatty acid ester, fatty acid polyglyceride, fatty acid alcohol polyglycol ether, acetylene glycol, acetylene alcohol, oxyalkylene block polymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene styryl aryl ether, polyoxyethylene glycol alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid ester, or a mixture thereof, including but not limited to, nonionic surfactants. A further list of nonionic surfactants having a low HLB value is described on pages 1243-1249 of Martindale, The Extra Pharmacopoeia, 29th ed., which is incorporated herein by reference.

[0064] In certain embodiments, the second carrier having an HLB value of less than about 10 is a medium-chain (i.e., about 4 to about 20 carbon atoms, preferably about 6 to about 18 carbon atoms, most preferably about 6 to about 14 carbon atoms) monoglyceride or diglyceride such as glyceryl caprylate / caprate (commercially available under the trade name CAPMUL MCM), glyceryl caprylate (commercially available under the trade name CAPMUL MCM C8), glyceryl caprate (commercially available under the trade name CAPMUL MCM C10), glyceryl monocaprylate / caprate (commercially available under the trade name CAPMUL471), or mixtures thereof.

[0065] In certain embodiments, the second carrier having an HLB value of less than about 10 is a polyoxylglyceride such as caprylocapryloyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, stearoyl polyoxylglyceride, and mixtures thereof.

[0066] In certain embodiments, the second carrier having an HLB value of less than about 10 is a sorbitan ester or sorbitan fatty acid ester such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, tyloxapol, and mixtures thereof.

[0067] In certain embodiments, the second carrier having an HLB value of less than about 10 is a phospholipid or lecithin.

[0068] In certain embodiments, the second carrier is an oil, medium-chain triglyceride, hydrogenated vegetable oil, suppository base, or combinations thereof.

[0069] In certain embodiments, the second carrier having an HLB value of less than about 10 is liquid at ambient temperature or exhibits a melting point of about 75 °C or less, about 70 °C or less, about 65 °C or less, about 60 °C or less, about 55 °C or less, about 50 °C or less, about 45 °C or less, or about 40 °C or less.

[0070] In an embodiment using a second carrier having an HLB value of less than about 10, the amount of the second carrier having an HLB value of less than about 10 may be about 1 wt% to about 90 wt% based on the total weight of the composition, preferably about 5 wt% to about 85 wt%, and most preferably about 10 wt% to about 80 wt%. The aforementioned weight percentages may be based on one second carrier or a combination of second carriers. In certain embodiments, one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of less than about 10 are about 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt%, or any range of weights included within these values may be present in the composition.

[0071] The compositions and dosage forms of the present invention may also optionally contain additional pharmaceutically acceptable additives such as stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavors, and combinations thereof.

[0072] In certain embodiments, the dosage forms of the present invention are (i) from about 1% to about 60% by weight, preferably from about 2% to about 55% by weight, most preferably from about 5% to about 50% by weight of KI, based on the total weight of the solid composition or dosage form, and C 8 -C 16 aliphatic sulfate salts, (ii) from about 1% to about 60% by weight, preferably from about 2% to about 50% by weight, most preferably from about 3% to about 40% by weight of one or more wetting agents, emulsifying agents, solubilizing agents, surfactants, or combinations thereof having an HLB value of about 10 or greater, preferably an HLB value of about 11 or greater, more preferably an HLB value of about 12 or greater, most preferably an HLB value of about 14 or greater, and (iii) at least one additional pharmaceutically acceptable additive selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavors, and combinations thereof, comprising a solid or semi-solid oral dosage form, preferably a capsule or tablet.

[0073] In further embodiments, such as semi-solid embodiments, the oral dosage form may further comprise (iv) a thickener that is solid at ambient temperature but has a melting point of less than 120°C, preferably less than 100°C, more preferably less than 80°C, most preferably less than 60°C. When the dosage form comprises (iv) a thickener that is solid at ambient temperature but has a melting point of less than 120°C, the agent of (iv) should comprise from about 0.5% to about 60% by weight of the total weight of the composition, preferably from about 1% to about 55% by weight, most preferably from about 5% to about 50% by weight.

[0074] Examples of stabilizers used in the present invention include, but are not limited to, antioxidants, desiccants, buffers, pH adjusters, or combinations thereof. When included in a dosage form, the stabilizer should be less than about 20% of the total weight of the composition, preferably less than about 15% of the total weight of the composition, and most preferably less than about 10% of the total weight of the composition. In certain embodiments, the stabilizer is present in the composition at about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, 4.0 wt%, 4.1 wt%, 4.2 wt%, 4.3 wt%, 4.4 wt%, 4.5 wt%, 4.6 wt%, 4.7 wt%, 4.8 wt%, 4.9 wt%, 5.0 wt%, or at any weight within all ranges encompassed by these values.

[0075] Examples of antioxidants used in the present invention include, but are not limited to, ascorbic acid, ascorbyl palmitate (AP), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, ethyl oleate, fumaric acid, hypophosphorous acid, malic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, tocopherol, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzyl benzoate, pyridoxine, ethyl vanillin, and mixtures thereof. Preferred antioxidants for use in accordance with the present invention include BHT, BHA, AP, propyl gallate, α-tocopherol, or any mixture thereof. Generally, the amount of antioxidant present in the composition of the present invention is from about 0.0001 wt% to about 5 wt%, preferably from about 0.01 wt% to about 2 wt%, most preferably from about 0.05 wt% to about 1 wt% based on the total weight of the composition.

[0076] As used herein, unless otherwise defined, the term "desiccant" means a pharmaceutically acceptable additive capable of binding or absorbing water present in the composition. Examples of desiccants useful in the present invention include, for example, magnesium oxide (MgO), aluminum oxide, attapulgite, bentonite, kaolin, pectin, saponite, colloidal silicon dioxide, and mixtures thereof. Depending on the particular dosage form, the thickeners described hereinafter can also be used as desiccants. When present, the amount of desiccant in the composition of the present invention can range from about 0.05 wt% to about 10 wt% of the total weight of the composition, preferably from about 0.1 wt% to about 5 wt% of the total weight of the composition, most preferably from about 0.5 wt% to about 2.5 wt% of the total weight of the composition.

[0077] Examples of buffers used in the present invention include, but are not limited to, acetic acid, adipic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium phosphate, sodium acetate, sodium citrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium lactate, sodium phosphate, succinic acid, and combinations thereof. Typically, the buffer is included in a combination of the above to create a buffer system such as citric acid and sodium citrate or acetic acid and sodium acetate.

[0078] Examples of pH adjusters used in the present invention include, but are not limited to, any pharmaceutically acceptable acid or base used for adjusting the pH of a pharmaceutical composition. Examples of typical compounds used for adjusting the pH of a pharmaceutical composition include hydrochloric acid, citric acid, lactic acid, tartaric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, arginine, lysine, meglumine, triethanolamine, or combinations thereof.

[0079] When used, the buffer and / or pH adjuster may be included in an amount of about 0.01% to about 20% by weight of the composition, preferably about 0.1% to about 10% by weight, and most preferably about 0.5% to about 5% by weight.

[0080] Fillers, sometimes referred to as diluents, may also be used in the present invention and include water; saccharides such as lactose, glucose, sucrose, maltose, or microcrystalline cellulose; clays, and mixtures thereof. Generally, the amount of filler present in the composition of the present invention is included in an amount of about 0% to about 90% by weight, preferably about 0.01% to about 80% by weight, and most preferably about 1% to about 70% by weight based on the total weight of the composition.

[0081] Thickeners that can be used in the present invention include natural or synthetic waxes, C 12 -C 60 alcohol, C 12 -C 60Organic materials such as acids, α-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and metal ester complexes containing zinc, calcium, aluminum or magnesium, fumed silica, and inorganic / organic materials such as organic clay are included. Further thickeners include polyol polyesters, glyceryl esters, polyglyceryl esters, and polysiloxanes.

[0082] Waxes are also suitable for use as thickeners in the compositions of the present invention. Natural waxes include, but are not limited to, carnauba, ozokerite, beeswax, candelilla, paraffin, ceresin, esparto, ouricury, resin wax, and other known mined and mineral waxes. Synthetic waxes include, but are not limited to, paraffin wax and microcrystalline wax.

[0083] Further thickeners that may be included in the composition of the present invention are gelling agents. A gelling agent is a material that swells or expands upon contact with water. Examples of gelling agents that may be used in the present invention include swellable polymers, also known as osmotic polymers or hydrogels. The swellable polymer may be non-crosslinked or lightly crosslinked. Crosslinking can be a covalent or ionic bond with a polymer that has the ability to swell in the presence of a fluid, and when crosslinked, it does not dissolve in the fluid. The polymer may be of plant, animal, or synthetic origin. Polymer gelling agents useful for this purpose include polyhydroxyalkylcelluloses having a molecular weight greater than 50,000 such as hydroxypropylmethylcellulose (METHOCEL K100M available from Dow Chemical); poly(hydroxyalkyl methacrylate) having a molecular weight of 5,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight of 100,000 to 3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinyl alcohol) with a low acetate residual; a swellable mixture of agar and carboxymethylcellulose; a swellable composition containing methylcellulose mixed with sparsely crosslinked agar; polyethers having a molecular weight of 10,000 to 6,000,000; a water-swellable copolymer produced by dispersion of a finely divided copolymer of maleic anhydride and styrene, ethylene, propylene, or isobutylene; water-swellable polymers of N-vinyl lactam, etc.

[0084] Other gelling agents useful in the present invention include pectin having a molecular weight of 30,000 to 300,000; polysaccharides such as agar, acacia, karaya, tragacanth, algin, and guar; a polymer of acrylic acid cross-linked with a polyallyl ether of sucrose as described in U.S. Patent Nos. 2,798,053 and 2,909,462, which is an acrylic acid polymer, a carboxyvinyl polymer, also called carboxypolymethylene, CARBOPOL® available as CARBOPOL® 934, 940, and 941, and salts thereof; polyacrylamide; a water-swellable indene maleic anhydride polymer; GOOD-RITE® which is a polyacrylic acid having a molecular weight of 80,000 to 200,000; POLYOX which is a polyethylene oxide polymer having a molecular weight of 100,000 to 7,000,000 TM ; starch graft copolymers; AQUA-KEEP which is an acrylate polymer capable of absorbing about 400 times its own weight of water TM ; diesters of polyglucan; a mixture of cross-linked polyvinyl alcohol and poly(N-vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecular weight of 4,000 to 100,000 is included. Representative polymers having gelling properties are described in U.S. Patent Nos. 6,419,954, 4,915,949, 4,327,725, 4,207,893, and in Scott and Roff, Handbook of Common Polymers, published by the Cleveland Rubber Company, Cleveland, Ohio

[0085] Generally, the amount of the thickener present in the composition of the present invention is about 0 wt% to about 30 wt%, preferably about 0.01 wt% to about 25 wt%, most preferably about 1 wt% to about 15 wt% based on the total weight of the composition. In the semi-solid embodiments of the present invention, a thickener that is solid at ambient temperature but exhibits a melting point of less than 120°C, preferably less than 100°C, more preferably less than 80°C, and most preferably less than 60°C as described above may be included in an amount of about 7.5 wt% to about 75 wt%, preferably about 10 wt% to about 60 wt%, most preferably about 12 wt% to about 50 wt% of the total weight of the composition. Examples of thickeners include natural or synthetic waxes such as carnauba wax, cetyl ester wax, microcrystalline wax, white wax, yellow wax, beeswax, ozokerite, paraffin, ceresin, esparto, ouoricry, rezowax, hardened oils (also known as hydrogenated vegetable glycerides), hydrogenated vegetable oils, C 12 -C 60 alcohols, C 12 -C 60 acids, α-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and combinations of the foregoing, but not limited thereto.

[0086] Examples of binders that can be used in the solid dosage forms of the present invention include acacia, povidone, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, polyethylene oxide, polymethacrylate, methylcellulose, ethylcellulose, pregelatinized starch, gelatin, tragacanth, zein, or mixtures thereof. Preferably, the binder is selected from povidone, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, polymethacrylate, methylcellulose, gelatin, and ethylcellulose, or combinations thereof. Particularly preferred binders include povidone, hypromellose, hydroxypropylcellulose, gelatin, and mixtures thereof. When the binder is a polymer binder, the binder preferably has a low molecular weight and / or a viscosity of less than 200 mPa·s, preferably less than 100 mPa·s, and most preferably less than 50 mPa·s when tested in an aqueous formulation at a concentration of 2% (w / v) at 20°C.

[0087] Generally, the amount of binder present in the composition of the present invention is from about 0 wt% to about 30 wt%, preferably from about 0.01 wt% to about 25 wt%, and most preferably from about 1 wt% to about 15 wt% based on the total weight of the composition.

[0088] Examples of disintegrants that can be used in the solid dosage forms of the present invention include croscarmellose sodium, starch, crospovidone, sodium starch glycolate, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, powdered cellulose, chitosan, guar gum, magnesium aluminum silicate, methylcellulose, sodium alginate, and mixtures thereof. Generally, the amount of disintegrant present in the composition of the present invention is from about 0 wt% to about 40 wt%, preferably from about 1 wt% to about 25 wt%, and most preferably from about 2 wt% to about 20 wt% based on the total weight of the composition.

[0089] Examples of lubricants that can be used in the solid dosage forms of the present invention include magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, polyethylene glycol (preferably, the polyethylene glycol has a molecular weight of 6000 or more), polyoxyethylene stearate, magnesium lauryl sulfate, sodium oleate, and mixtures thereof. The lubricant may be in the range of about 0.1% to about 10% by weight, preferably about 0.2% to about 7% by weight, most preferably about 0.5% to about 5% by weight based on the total weight of the dosage form.

[0090] Glidants that can be used in the solid dosage forms of the present invention include colloidal silicon dioxide, corn starch, talc, and mixtures thereof. The glidant may be in the range of about 0.1% to about 10% by weight, preferably about 0.2% to about 7% by weight, most preferably about 0.5% to about 5% by weight based on the total weight of the dosage form.

[0091] Flavors that can be used in the solid dosage forms of the present invention include artificial sweeteners such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, and flavoring agents such as citric acid, peppermint oil, wintergreen oil, menthol, lemon, lime, orange, grape, cherry, vanilla extract, etc. Further taste enhancers are described in U.S. Patent No. 6,027,746, which is incorporated herein by reference.

[0092] Embodiment A of the present invention is (i) C of KI at about 1% to about 80% by weight, preferably about 2% to about 70% by weight, more preferably about 3% to about 60% by weight, most preferably about 5% to about 50% by weight 8 -C 16An aliphatic sulfate salt, preferably the KI is selected from the group consisting of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, preferably the C of KI 8 -C 16 The aliphatic sulfate salt is the lauryl sulfate salt of KI, most preferably the mono- or dilauryl sulfate salt of KI, (ii) about 1 wt% to about 95 wt%, preferably about 5 wt% to about 90 wt%, most preferably about 10 wt% to about 80 wt% of a liquid carrier selected from the group consisting of fatty acids, medium-chain triglycerides, fatty acid esters, fatty alcohols, vegetable oils such as corn oil, soybean oil, olive oil, sunflower oil, peanut oil, or mixtures thereof, and (iii) optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavors, and combinations thereof, in a liquid dosage form, preferably filled in hard or soft capsules.

[0093] Embodiment B of the present invention is (i) about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, most preferably about 5 wt% to about 50 wt% of C of KI 8 -C 16An aliphatic sulfate salt, preferably the KI is selected from the group consisting of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, preferably the C of KI 8 -C 16 The aliphatic sulfate salt is the lauryl sulfate salt of KI, most preferably the mono- or dilauryl sulfate salt of KI, (ii) A solid carrier having a melting point between 25°C and less than 120°C, preferably less than 100°C, more preferably less than 80°C, most preferably less than 60°C, from about 1 wt% to about 90 wt%, preferably from about 2.5 wt% to about 80 wt%, more preferably from about 3 wt% to about 70 wt%, most preferably from about 5 wt% to about 60 wt%, and the solid carrier is preferably selected from the group consisting of polyethylene glycol, hardened oil, hydrogenated vegetable oil, vitamin E polyethylene glycol succinate, wax, poloxamer, and combinations thereof, and, (iii) Optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavors, and combinations thereof, A solid or semi-solid oral dosage form which may be a tablet or a soft or hard capsule.

[0094] Embodiment C of the present invention is (i) About 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt% of KI in C 8 -C 16 an aliphatic sulfate salt, preferably the KI is selected from the group consisting of afatinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, and bemrafeinib, most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, preferably the C of KI 8 -C 16 the aliphatic sulfate salt is the lauryl sulfate salt of KI, most preferably the mono- or dilauryl sulfate salt of KI, (ii) From about 1% to about 60% by weight, preferably from about 2% to about 50% by weight, most preferably from about 3% to about 40% by weight of at least one wetting agent, emulsifier, solubilizer, surfactant, or combination thereof having an HLB value of about 10 or more, preferably 11 or more, more preferably 12 or more, most preferably 14 or more, wherein the at least one wetting agent, emulsifier, solubilizer, surfactant, or combination thereof having an HLB value of about 10 or more is preferably selected from the group consisting of fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamers, tyloxapol, fatty acid esters or fatty alcohols of polyglycerides, or combinations thereof, and most preferably selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamers, caprylic / capric triglyceride, or combinations thereof. (iii) From about 5% to about 90% by weight, preferably from about 10% to about 85% by weight, most preferably from about 15% to about 80% by weight of a second carrier having an HLB value of less than about 10, preferably 9 or less, more preferably 8 or less, most preferably 7 or less, wherein the second carrier is selected from the group consisting of wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of less than about 10, more preferably selected from the group consisting of medium-chain monoglycerides, medium-chain diglycerides, polyoxyl glycerides, sorbitan esters, sorbitan fatty acid esters, phospholipids, and combinations thereof, and most preferably selected from the group consisting of medium-chain monoglycerides, medium-chain diglycerides, lecithin, and combinations thereof, and (iv) Optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavors, and combinations thereof. It is a solid or semi-solid oral dosage form such as a soft or hard capsule.

[0095] In certain embodiments of the capsule dosage form, at least one wetting agent, emulsifier, solubilizer, surfactant, or combination thereof having an HLB value of about 10 or greater, and a second carrier having an HLB value of less than about 10, which is liquid at 25°C, are completely mixed with a salt of KI, at least one wetting agent, emulsifier, solubilizer, surfactant, or combination thereof having an HLB value of about 10 or greater, and a second carrier having an HLB value of less than about 10.

[0096] Embodiment D of the present invention is a solid oral dosage form such as a tablet or capsule, and the contents of the tablet or capsule are (i) about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt% of KI in C 8 -C 16 an aliphatic sulfate salt, preferably the KI is selected from the group consisting of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, and bemrafenib, most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and preferably the KI in C 8 -C 16 the aliphatic sulfate salt is the lauryl sulfate salt of KI, most preferably the mono- or dilauryl sulfate salt of KI, (ii) from about 1% to about 60% by weight, preferably from about 2% to about 50% by weight, most preferably from about 3% to about 40% by weight of one or more wetting agents, solubilizing agents, emulsifying agents, surfactants or combinations thereof having an HLB value of about 10 or more, preferably 11 or more, more preferably 12 or more, most preferably 14 or more, wherein the one or more wetting agents, emulsifying agents, solubilizing agents, surfactants, or combinations thereof having an HLB value of about 10 or more are preferably selected from the group consisting of fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters or fatty alcohols of polyglycerides, or combinations thereof, and most preferably selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride, or combinations thereof, (iii) from about 0% to about 40% by weight, preferably from about 1% to about 25% by weight, most preferably from about 2.5% to about 20% by weight of a disintegrant, (iv) from about 5% to about 90% by weight, preferably from about 15% to about 85% by weight, most preferably from about 20% to about 80% by weight of a filler, and (v) optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, thickeners, binders, lubricants, glidants, fragrances, and combinations thereof, comprising.

[0097] In certain embodiments of Embodiment D, the C of KI 8 -C 16 aliphatic sulfate salts, and at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% by total weight of one or more wetting agents, emulsifying agents, solubilizing agents, surfactants, or combinations thereof having an HLB value of about 10 or more are present in a complete mixture within a solid tablet or solid capsule, preferably formed prior to mixing with components (iii), (iv) and / or (v).

[0098] Embodiment E of the present invention is (i) C of KI at about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt% 8 -C 16 is an aliphatic sulfate, preferably the KI is from the group consisting of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxolutinib, sorafenib, sunitinib, trametinib, vandetanib, and bemrafe nib, most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, preferably C of KI 8 -C 16 the aliphatic sulfate is the lauryl sulfate of KI, most preferably the mono- or dilauryl sulfate of KI, (ii) from about 1% to about 70% by weight, preferably from about 2% to about 60% by weight, most preferably from about 5% to about 50% by weight of one or more wetting agents, solubilizing agents, emulsifying agents, surfactants, or combinations thereof having an HLB value of about 10 or more, preferably 11 or more, more preferably 12 or more, and most preferably 14 or more, wherein the one or more wetting agents, emulsifying agents, solubilizing agents, surfactants, or combinations thereof having an HLB value of about 10 or more are selected from the group consisting of fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters or fatty alcohols of polyglycerides, or combinations thereof, and most preferably are selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride, or combinations thereof, (iii) from about 1% to about 70% by weight, preferably from about 2% to about 60% by weight, most preferably from about 5% to about 50% by weight of a second carrier having an HLB value of less than about 10, preferably 9 or less, more preferably 8 or less, and most preferably 7 or less, wherein the second carrier is selected from the group consisting of wetting agents, emulsifying agents, solubilizing agents, surfactants, or combinations thereof having an HLB value of less than about 10, more preferably medium-chain monoglycerides, medium-chain diglycerides, polyoxyl glycerides, sorbitan esters, sorbitan fatty acid esters, phospholipids, and combinations thereof, and most preferably is selected from the group consisting of medium-chain monoglycerides, medium-chain diglycerides, lecithin, and combinations thereof, (iv) Solid at ambient temperature but having a melting point of less than 120°C, preferably less than 100°C, more preferably less than 80°C, and most preferably less than 60°C, and being a thickener in an amount of about 0.5 wt% to about 70 wt%, preferably about 1 wt% to about 60 wt%, and most preferably about 2.5 wt% to about 50 wt%. The thickener is a natural or synthetic wax such as carnauba wax, cetyl ester wax, microcrystalline wax, white wax, yellow wax, beeswax, ozokerite, paraffin, ceresin, esparto, ouricury, resin wax, hardened oil (also known as hydrogenated vegetable glyceride), hydrogenated vegetable oil, C 12 -C 60 alcohol, C 12 -C 60 acid, α-hydroxy fatty acid, polyhydroxy fatty acid ester, polyhydroxy fatty acid amide, and a thickener selected from the group consisting of combinations thereof, and (v) Optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, binders, lubricants, flow promoters, fragrances, and combinations thereof, A semi-solid oral composition comprising The C of KI 8 -C 16 Aliphatic sulfate salts and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of 10 or more are present as a complete mixture.

[0099] Embodiment F of the present invention is a solid oral dosage form such as a tablet or capsule, and the contents of the tablet or capsule are (i) About 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt% of KI's C 8 -C 16An aliphatic sulfate salt, preferably the KI is selected from the group consisting of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, preferably the C of KI 8 -C 16 The aliphatic sulfate salt is the lauryl sulfate salt of KI, most preferably the mono- or dilauryl sulfate salt of KI, (ii) about 1 wt% to about 60 wt%, preferably about 2 wt% to about 50 wt%, most preferably about 3 wt% to about 40 wt% of one or more wetting agents, solubilizing agents, emulsifying agents, surfactants or combinations thereof having an HLB value of about 10 or more, preferably 11 or more, more preferably 12 or more, most preferably 14 or more, wherein the one or more wetting agents, emulsifying agents, solubilizing agents, surfactants, or combinations thereof having an HLB value of about 10 or more are selected from the group consisting of fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters or fatty alcohols of polyglycerides, or combinations thereof, most preferably selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride, or combinations thereof, and, (iii) About 1% to about 60% by weight, preferably about 2% to about 50% by weight, most preferably about 3% to about 45% by weight of one or more polymer agents, wherein the polymer agent is preferably a water-soluble polymer agent such that when tested in an aqueous formulation at a concentration of 2% (w / v) at 20°C, the clay has a viscosity of less than 200 mPa·s, preferably less than 100 mPa·s, most preferably less than 50 mPa·s, and most preferably is a polymer agent selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, gelatin, and mixtures thereof. comprising a solid dispersant.

[0100] The solid dispersant form of Embodiment F may further comprise, within the solid dispersion or mixed with the solid dispersion, i.e., the following additional granules. (iv) About 0% to about 40% by weight, preferably about 1% to about 25% by weight, most preferably about 2.5% to about 25% by weight of a disintegrant. (v) About 0% to about 90% by weight, preferably about 15% to about 85% by weight, most preferably about 20% to about 80% by weight of a filler, and (vi) Optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, thickeners, binders, lubricants, glidants, flavors, and combinations thereof.

[0101] Embodiment G of the present invention is a sustained-release or extended-release solid oral dosage form such as a tablet or capsule, and the contents of the tablet or capsule are (i) About 1% to about 80% by weight, preferably about 2% to about 70% by weight, more preferably about 3% to about 60% by weight, most preferably about 5% to about 50% by weight of C of KI 8 -C 16An aliphatic sulfate salt, preferably the KI is selected from the group consisting of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, preferably the C of KI 8 -C 16 The aliphatic sulfate salt is the lauryl sulfate salt of KI, most preferably the mono- or dilauryl sulfate salt of KI, the C of KI 8 -C 16 aliphatic sulfate salt, (ii) about 1 wt% to about 60 wt%, preferably about 2 wt% to about 50 wt%, most preferably about 3 wt% to about 40 wt% of one or more wetting agents, solubilizing agents, emulsifying agents, surfactants or combinations thereof having an HLB value of about 10 or more, preferably about 11 or more, more preferably 12 or more, most preferably about 14 or more, wherein the one or more wetting agents, emulsifying agents, solubilizing agents, surfactants, or combinations thereof having an HLB value of about 10 or more are preferably selected from the group consisting of fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters or fatty alcohols of polyglycerides, or combinations thereof, most preferably selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride, or combinations thereof, (iii) About 0.5% to about 50% by weight, preferably about 1% to about 40% by weight, most preferably about 2% to about 35% by weight of a sustained or controlled release agent, wherein the sustained or controlled release agent releases KI from the dosage form over a period of time exceeding 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours 8 -C 16 An additive that sustains or controls the release of the aliphatic sulfate salt, preferably selected from the aforementioned thickeners, more preferably the aforementioned gelling agents, such as polyhydroxyalkylcellulose having a molecular weight greater than 50,000 (METHOCEL K100M available from Dow Chemical), poly(hydroxyalkyl methacrylate) having a molecular weight of 5,000 to 5,000,000, poly(vinylpyrrolidone) having a molecular weight of 100,000 to 3,000,000, pectin having a molecular weight of 30,000 to 300,000, polysaccharides such as agar, acacia, karaya, tragacanth, algin, and guar, acrylic acid polymers (CARBOPOL®), polyethylene oxide polymers (POLYOX TM ) having a molecular weight of 100,000 to 7,000,000, and combinations thereof, (iv) Optionally, about 5% to about 90% by weight, preferably about 15% to about 85% by weight, most preferably about 20% to about 80% by weight of a filler, and (v) Optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, binders, lubricants, glidants, flavors, and combinations thereof, are included.

[0102] In certain embodiments of Embodiment G, the C of KI 8 -C 16An aliphatic sulfate salt and at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the total amount of one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or greater are present in a solid tablet or solid capsule as a complete mixture, preferably formed prior to mixing with components (iii), (iv) and / or (v).

[0103] In certain embodiments of Embodiment G, a sustained release or extended release solid oral dosage form, when tested using the USP Type II Apparatus (Paddle) (900 ml of an aqueous medium at pH 6.8 and 0.1% sodium lauryl sulfite, 75 rpm, with or without a sinker), the C of KI 8 -C 16 The aliphatic sulfate salt is released as follows. [Table 1]

[0104] In certain embodiments of the present invention, particularly Embodiments A - F, a solid oral dosage form, when tested using the USP Type II Apparatus (Paddle) (500 ml of 0.1 N HCl, 75 rpm, with or without a sinker, 37°C), the C of KI 8 -C 16 The aliphatic sulfate salt is released as follows. [Table 2]

[0105] In certain embodiments of the present invention, particularly a liquid oral dosage form, when tested using the USP Type II Apparatus (Paddle) (500 - 900 ml of 0.1 N HCl, 75 rpm, with or without a sinker, 37°C), the C of KI 8 -C 16 The aliphatic sulfate salt is released as follows. [Table 3]

[0106] Alternatively, certain embodiments of the present invention, particularly liquid oral dosage forms, when tested using the USP Type II Apparatus (Paddle) (900 ml of 0.1 N HCl and 0.1% Tween® 80, 75 rpm, with or without a sinker, 37°C), the C of KI 8 -C 16 The aliphatic sulfate ester salt is released as follows. [Table 4]

[0107] The compositions and dosage forms of the present invention, particularly the compositions and dosage forms described in Embodiments A - G above, are stable when prepared and stored under normal and accelerated conditions. More specifically, the dosage forms of the present invention, in a sealed bottle, preferably a sealed plastic bottle such as a high - density polyethylene bottle (with or without a desiccant), at about 25°C, relative humidity of about 60%, for at least 3 months, preferably 6 months, most preferably 1 year and / or at about 40°C, relative humidity of about 75% for 1 month, 2 months, or 3 months, contain individual degradation products of about 1% or less, preferably about 0.75% or less, most preferably about 0.5% or less.

[0108] The compositions and dosage forms of the present invention, particularly the compositions and dosage forms described in Embodiments A - G above, also, in a sealed bottle, preferably a sealed plastic bottle such as a high - density polyethylene bottle (with or without a desiccant), at about 25°C, relative humidity of about 60%, for at least 3 months, preferably 6 months, most preferably 1 year and / or at about 40°C, relative humidity of about 75% for 1 month, 2 months, or 3 months, the total amount of degradation products should be contained at about 2% or less, preferably about 1.5% or less, most preferably about 1.0% or less.

[0109] The C of KI 8 -C 16Aliphatic sulfate salts, particularly the lauryl sulfate salt of KI used in the compositions and dosage forms of the present invention, particularly the compositions and dosage forms described in Embodiments A - G above, may be amorphous or crystalline. The C of KI 8 -C 16 The lauryl sulfate salt of KI used in the aliphatic sulfate salt, particularly the solid dispersion dosage form of Embodiment F, is preferably amorphous.

[0110] Table 1 shows the amount of the lauryl sulfate salt of KI present in the dosage forms of the present invention, particularly the dosage forms described in Embodiments A - G above.

Table 5

[0111] Table 2 shows the C of KI 8 -C 16 The approved indications by the US FDA for the preferred KI compounds and symptoms for which the aliphatic sulfate salt of KI, particularly the lauryl sulfate salt of KI of the present invention, can be used for treatment are shown.

Table 6

[0112] The present invention includes a method for treating various symptoms confirmed in Table 2 by oral administration of one or more dosage forms containing the aliphatic sulfate salt of KI's C 8 -C 16 -C aliphatic sulfate salt, preferably one or more dosage forms containing the lauryl sulfate salt of KI. In certain embodiments, (i) oral administration may be with or without food, and in oral administration, as detailed below, it exhibits substantially constant pharmacokinetic values or is not affected by food, (ii) as detailed below, oral administration allows for maintaining similar pharmacokinetics while reducing the total daily dose of the KI compound compared to currently US FDA - approved KI compositions, (iii) oral administration may or may not be co - administered with an acid suppressant, and as detailed below, oral administration is not affected by the acid suppressant, or (iv) oral administration exhibits a combination of (i), (ii), and / or (iii).

[0113] In certain embodiments, the present invention includes a method of treating the symptoms identified in Table 2 by oral administration of one or more dosage forms described in Embodiments A - G and containing the lauryl sulfate salt of KI in the amounts listed in FIG. 1. In these embodiments, (i) oral administration may be with or without food and, in oral administration, exhibits substantially constant pharmacokinetic values or is not affected by food, as detailed below; (ii) oral administration allows for maintaining similar pharmacokinetics while reducing the total daily dose of the KI compound, as compared to currently US FDA - approved KI compositions, as detailed below; (iii) oral administration may or may not be co - administered with an acid suppressant and, as detailed below, oral administration is not affected by an acid suppressant; or (iv) oral administration exhibits a combination of (i), (ii), and / or (iii).

[0114] For example, dosage forms described in Embodiments A - G and containing 10 - 400 mg, preferably 15 - 350 mg, more preferably 25 - 300 mg of nilotinib sulfate can be orally administered to a patient to treat chronic myelogenous leukemia. (i) Oral administration may be with or without food and is not affected by food; (ii) oral administration allows for maintaining similar pharmacokinetics to oral administration of currently approved nilotinib hydrochloride while reducing the total daily dose of the nilotinib free base; (iii) oral administration may or may not be co - administered with an acid suppressant and is not affected by an acid suppressant.

[0115] Similarly, dosage forms described in Embodiments A - G and containing 5 - 250 mg, preferably 10 - 175 mg, more preferably 15 - 150 mg of dasatinib sulfate can be orally administered to a patient to treat chronic myelogenous leukemia and / or acute lymphoblastic leukemia. (i) Oral administration may be with or without food and is not affected by food; (ii) oral administration may or may not be co - administered with an acid suppressant and is not affected by an acid suppressant.

[0116] The compositions and dosage forms of the present invention, including but not limited to Embodiments A - G, can be administered to a subject, where the subject can be in either a fed or a fasting state, and when administered under either fed conditions or fasting conditions, substantially constant pharmacokinetic values are obtained, or there is no effect of food. Generally, the fed state is defined as a state in which food has been ingested within about 30 minutes prior to administration of the composition or dosage form. The meal can be a high - fat meal, a low - fat meal, a high - calorie meal, or a low - calorie meal. The fasting state can be defined as a state in which no food has been ingested for at least 10 hours prior to administration of the composition or dosage form. In some embodiments, the subject can be defined as fasting for at least 10 hours prior to administration and refraining from food intake for about 30 minutes to 2 hours, preferably about 1 hour, after administration. In another embodiment, the subject fasting should not ingest food for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours prior to administration of each dose of the composition or dosage form.

[0117] The method of orally administering the compositions and / or dosage forms of the present invention, including but not limited to Embodiments A - G, to a patient or a healthy subject, regardless of whether the composition is administered with a meal, T max , C max , and pharmacokinetic values such as AUC are substantially constant. Substantially constant pharmacokinetic values mean that when the compositions and dosage forms, including but not limited to Embodiments A - G, are administered to a patient or a healthy subject once or multiple times under fasting conditions as described in the US FDA guidance document, the measured pharmacokinetic values obtained are such that there is no change exceeding 40%, preferably no change exceeding 30%, and most preferably no change exceeding 20% when the same composition is administered to the same patient or healthy subject under fed conditions as described in the US FDA guidance document. For example, if a T max of 3 hours is obtained after a single administration to a patient under fed conditions, a T max in the range of 1.8 hours to 4.2 hours is considered substantially constant, i.e., 3 hours ± 40%.

[0118] In certain preferred embodiments of the present invention, a single oral administration of a composition or dosage form prepared according to the present invention, including but not limited to embodiments A - G, is biologically equivalent or shows no effect of food when administered under fed and fasted conditions. The terms "biologically equivalent" and "no effect of food" are used based on the guidance documents of the US FDA.

[0119] In certain embodiments of the present invention, a single oral administration of a composition or dosage form prepared according to the present invention, including but not limited to embodiments A - G, for KI administered with food, the C max and for KI administered without food, the C max ratio is from about 0.60 to about 2.5, preferably from about 0.70 to about 2.0, more preferably from about 0.75 to about 1.5, and most preferably from about 0.8 to about 1.25. Similarly, in certain embodiments of the present invention, a single oral administration of a composition or dosage form prepared according to the present invention, including but not limited to embodiments A - G, for the AUC of KI in a pharmaceutical composition administered with food, the 0-∞ and for the AUC of KI in a pharmaceutical composition administered without food, the 0-∞ ratio (AUC 0-∞ fed / AUC 0-∞ fast ) is from about 0.60 to about 2.5, preferably from about 0.70 to about 2.0, more preferably from about 0.75 to about 1.5, and most preferably from about 0.8 to about 1.25.

[0120] When an oral administration of a composition or dosage form of the present invention, including but not limited to embodiments A - G, is carried out, a plasma profile is obtained in which at least one pharmacokinetic parameter has a difference of less than 40% under fed and fasted conditions. In various embodiments, the pharmacokinetic parameter may change by less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5% under fed and fasted conditions. The food - independent pharmacokinetic parameters can be, but are not limited to, C max , AUC, T max , or combinations thereof.

[0121] In certain embodiments of the present invention, the method includes the step of orally administering to a patient one or more dosage forms described in Embodiments A - G, and the oral administration may be with food or without food, and the C of KI 8 -C 16 The dosage of the aliphatic sulfate ester salts and in particular the lauryl sulfate salt of KI includes a method of treating cancer in a human patient that does not require adjustment of the dosage or change of the administration time.

[0122] In certain embodiments, administration of a composition or dosage form prepared according to the present invention can reduce the amount of free KI base currently approved by the US FDA and achieve an equivalent therapeutic level. More specifically, the compositions of the present invention can reduce the daily amount of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% and achieve an equivalent therapeutic level, i.e., an equivalent plasma concentration.

[0123] Table 3 shows some suitable currently US FDA - approved dosages of KI.

Table 7

[0124] In certain embodiments, the C of KI of the present invention 8 -C 16Aliphatic sulfate salts, particularly the lauryl sulfate salt of KI, can reduce the recommended total daily dose of the free base of KI shown in Table 3 by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%, while maintaining similar pharmacokinetics. For example, the recommended total daily dose of nilotinib hydrochloride is 600 - 800 mg based on the free base of nilotinib. In the oral administration of nilotinib lauryl sulfate salt, the daily dose can be reduced by at least 25%, i.e., to 450 - 600 mg, while maintaining pharmacokinetics such as C max , T max and / or AUC similar or substantially similar to the original. Alternatively, a patient receiving 800 mg of nilotinib (as the hydrochloride) can be administered 600 mg of nilotinib (as the lauryl sulfate) while maintaining a similar plasma concentration of nilotinib.

[0125] The solubility of many KI drugs is pH-dependent. The solubility of many KIs decreases as the pH increases. Patients taking KI drugs may also be administered, or co-administered with, antacids, H 2 antagonists, proton pump inhibitors and other gastric acid suppressants to reduce gastric acid secretion or increase the gastric pH. Gastric acid suppressants increase the gastric pH of the patient, resulting in a decrease in the solubility of co-administered KI drugs in the patient's stomach, thereby reducing absorption. To avoid a decrease in absorption or the effects of gastric acid suppressants, patients are cautioned to take antacids at least 2 hours before or 2 hours after taking KI drugs, or to discontinue the use of H 2 antagonists, or proton pump inhibitors during treatment with KI drugs. According to the present invention, there is no need to shift the administration time of antacids or discontinue the use of H 2 antagonists or proton pump inhibitors during treatment with KI drugs of the present invention. The C 8 -C 16 Aliphatic sulfate salts, particularly the lauryl sulfate salt of KI, can be orally administered to patients or healthy subjects, and regardless of whether they are administered with gastric acid suppressants, C max , Tmax Pharmacokinetic values such as and AUC are the same or substantially constant. Substantially constant pharmacokinetic values are measured pharmacokinetic values obtained after administering the compositions and dosage forms of the present invention, including but not limited to Embodiments A - G, to patients or healthy subjects, either once or multiple times, together with an antacid under fasting conditions, such that there is no change exceeding 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% when the same composition is administered to the same patient or healthy subject without an antacid under fasting conditions.

[0126] In certain embodiments of the present invention, for a single oral administration of a composition or dosage form prepared according to the present invention, including but not limited to Embodiments A - G, the C of KI administered with an antacid max and the C of KI administered without an antacid max The ratio of (C max w / gastric acid reducing / C max w / o gastric acid reducing ) is from about 0.60 to about 2.5, preferably from about 0.70 to about 2.0, more preferably from about 0.75 to about 1.5, and most preferably from about 0.8 to about 1.25. Similarly, in certain embodiments of the present invention, for a single oral administration of a composition or dosage form prepared according to the present invention, including but not limited to Embodiments A - E, the AUC of KI of the pharmaceutical composition administered with an antacid 0-∞ and the AUC of KI of the pharmaceutical composition administered without an antacid 0-∞ The ratio of (AUC 0-∞ w / gastric acid reducing / AUC 0-∞ w / o gastric acid reducing ) is from about 0.60 to about 2.5, preferably from about 0.70 to about 2.0, more preferably from about 0.75 to about 1.5, and most preferably from about 0.80 to about 1.25.

[0127] Certain embodiments of the present invention employ the dosage forms of Embodiments A - G for the amounts of bosutinib, dasatinib, erlotinib, gefitinib, neratinib, nilotinib, and pazopanib described in Table 1 to treat the symptoms described in Table 2. Administration is oral, with or without co - administration of an antacid. Regardless of whether an antacid is co - administered or not, C max 、T maxPharmacokinetic values such as AUC are substantially constant.

[0128] Certain embodiments of the present invention include the step of orally administering to a patient one or more dosage forms described in Embodiments A - G and co - administering an acid suppressant to the patient, with C of KI 8 -C 16 The dosage of the aliphatic sulfate ester salt, particularly the lauryl sulfate salt of KI, does not require adjustment of the dosage or change in the administration time, and includes a method of treating cancer in a human patient. Examples of KI that are particularly useful in this embodiment are bosutinib, dasatinib, erlotinib, gefitinib, neratinib, nilotinib, and pazopanib, which treat specific cancers described in Table 2 in the amounts described in Table 1.

[0129] (Description of Embodiments) The following is provided only by way of example and is not intended to be limiting.

[0130] (Example 1) Nilotinib lauryl sulfate was prepared by dissolving 2.48 g of nilotinib hydrochloride monohydrate in 1900 mL of 0.1 N hydrochloric acid solution and 1.16 g of sodium lauryl sulfate in 100 mL of 0.1 N hydrochloric acid solution. After the nilotinib hydrochloride monohydrate and sodium lauryl sulfate were dissolved, the two solutions were mixed well and allowed to stand for 24 hours. The supernatant was removed to recover the precipitated nilotinib lauryl sulfate, which was dried at 40 °C for 18 hours.

[0131] (Example 2) The lauryl sulfate salts of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, or bemrafenib are formed in the same manner as described in Example 1 by dissolving in a suitable solvent such as a combination of 0.1N HCl or 0.1N HCl and an alcohol such as methanol, ethanol, isopropanol, etc., and adding sodium lauryl sulfate or an aqueous solution of sodium lauryl sulfate to the solution of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, or bemrafenib. 1 -C 6 (Example 3)

[0132] (Example 3) The capsule formulation of nilotinib lauryl sulfate was prepared by mixing the nilotinib lauryl sulfate (dry precipitate) of Example 1 with CAPMUL® MCM (glyceryl caprylate / caprate) and KOLLIPHOR® EL (polyoxyl 35 castor oil), and filling the liquid mixture into size 00 hard gelatin capsules.

[0133] The composition of the capsule contents is as follows. [Table 8]

[0134] (Example 4) The nilotinib lauryl sulfate capsules were prepared by dissolving 1940 mg of nilotinib lauryl sulfate (dry precipitate) and 1040 mg of poloxamer 188 in 5 mL of ethanol. The solution was manually mixed with AVICEL PH 101 (microcrystalline cellulose) and 3100 mg of lactose. The resulting granules were dried, powdered through a 60-mesh screen, and blended with 210 mg of colloidal silicon dioxide, 1040 mg of sodium glycolate starch, and 100 mg of magnesium stearate. The dry solid blend was filled into size 00 hard gelatin capsules.

[0135] The composition of the capsule contents is as follows. [Table 9]

[0136] (Example 5) Similar to those prepared in Examples 3 and 4, capsules adjusted to contain a weight that provides about 50 mg of nilotinib free base were administered to 6 healthy adult beagle dogs in a fasting state in a single-dose study at a single facility, together with capsules obtained by dividing 4 commercially available TASIGNA 200 mg capsules (each containing the equivalent of 50 mg of nilotinib free base). Plasma samples were collected before dosing and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after dosing. The mean values of nilotinib in plasma were calculated as follows.

Table 10

[0137] A graph of the average plasma profile is shown in Figure 1.

[0138] The individual data in this study are shown in the following table.

Table 11-1

Table 11-2

Table 11-3

Table 11-4

Table 11-5

[0139] (Example 6) The capsule dosage form may be prepared using the lauryl sulfate salts of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, or bemrafenib prepared in Examples 1 and 2 using the procedures described in Example 3.

[0140] The composition of the capsule contents is as follows. [Table 12]

[0141] (Example 7) The capsule dosage form may be prepared using the lauryl sulfate salts of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, or bemrafenib prepared in Examples 1 and 2 using the procedures described in Example 4.

[0142] The composition of the capsule contents is as follows. [Table 13]

[0143] (Example 8) The capsule dosage form may be prepared using the lauryl sulfate salts of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, or bemrafenib prepared in Examples 1 and 2 using the procedure described in Example 3.

[0144] The composition of the capsule contents is as follows. [Table 14]

[0145] (Example 9) Nilotinib lauryl sulfate was prepared by dissolving 2.92 g of nilotinib hydrochloride monohydrate in 2900 mL of 0.1 N hydrochloric acid solution and 1.50 g of sodium lauryl sulfate in 100 mL of 0.1 N hydrochloric acid solution. After the nilotinib hydrochloride monohydrate and sodium lauryl sulfate were dissolved, the two solutions were combined, mixed well, and allowed to stand for 24 hours. The supernatant was removed to recover the precipitated nilotinib lauryl sulfate, and the recovered precipitate was dried at 40 °C for 18 hours.

[0146] The nilotinib lauryl sulfate capsule dosage form was prepared by mixing nilotinib lauryl sulfate (dried precipitate) with CAPMUL® MCM (glyceryl caprylate / caprate) and KOLLIPHOR® EL (polyoxyl 35 castor oil) and filling the liquid mixture into size 00 hard gelatin capsules.

[0147] The composition of the capsule contents is as follows. [Table 15]

[0148] (Example 10) The capsules prepared according to Example 9 were administered to 9 healthy subjects under fed and fasted conditions. The administration was randomized, non-blinded, single-dose, 3-treatment, 3-group, 3-period crossover, with at least a 5-day washout period between administrations. The reference drug (Ref) is TASIGNA capsules containing 200 mg (free base) of nilotinib HCl. The test drug (Test) was prepared according to the procedure of Example 9 and is a capsule containing approximately 50 mg of nilotinib free base. Based on the results described in Example 5 herein, the amount of the test capsules was 100 mg (2 capsules each containing 50 mg of nilotinib free base). The 9 healthy subjects participating in this study were randomly assigned to one of the groups as shown in the following table.

[0149] [Table 16]

[0150] During each treatment period, blood samples were collected at 0 (before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. The AUC 0-48 , AUC 0-∞ , C max , T max , and T 1 / 2 of each subject were determined based on non-compartmental analysis. The test results were normalized to a 200 mg dose and summarized in Table 1. The AUC 0-t , AUC 0-∞ , C max transformed to Ln were analyzed by ANOVA. The model includes group, subject (group), period, and treatment effect. A comparison of the data obtained from the administration of the test drug and the reference drug is shown in Table 2. The data show that the composition of the present invention has 3.4 times the C max compared to nilotinib HCl approved by the US FDA.It has been shown to exhibit an increase and a 2.3-fold increase in AUC. The data also show that the composition of the present invention does not exhibit a food effect, i.e., the composition of the present invention exhibits equivalent pharmacokinetics under fasting and fed conditions.

[0151]

Table 17

[0152]

Table 18

[0153] The individual data of the subjects standardized at a dose of 200 mg obtained in this study are as follows.

Table 19-1

Table 19-2

Table 19-3

[0154] A graph of the standardized average plasma profile is shown in Figure 2.

[0155] (Example 11) Dasatinib lauryl sulfate was prepared by dissolving 253.0 mg of dasatinib monohydrate in 1000 mL of 0.1 N hydrochloric acid solution and dissolving 432.0 g of sodium lauryl sulfate in 100 mL of 0.1 N hydrochloric acid solution. After the dasatinib monohydrate and sodium lauryl sulfate were dissolved, the two solutions were combined, mixed well, and allowed to stand for 20 hours. The supernatant was removed to recover the precipitated dasatinib lauryl sulfate, and the recovered precipitate was dried at 50 °C for 20 hours.

[0156] Approximately 10.44 mg of the precipitate was dissolved in 50 mL of methanol, sonicated for 5 minutes, stirred for 5 minutes, and analyzed by high performance liquid chromatography (HPLC). As a result of the analysis, dasatinib dilauryl sulfate was contained in the precipitate.

[0157] (Example 12) Dasatinib monolauryl sulfate was prepared by the following general procedure. a. 13 g of dasatinib monohydrate (dasatinib·H 2 2O) and 650 mL of methanol (50V) were combined and stirred at 50 - 55 °C. b. 7.4 g of sodium lauryl sulfate (SLS) (1 molar equivalent relative to dasatinib·H 2 2O) was combined with 39 mL of methanol (3V) and 25.7 mL of 1N HCl (1 molar equivalent relative to SLS). c. The composition of step (b) was added to the composition of step (a), stirred for 30 minutes while maintaining the temperature at 50 - 55 °C, and then cooled at room temperature for about 1 hour. d. 650 mL of purified water (50V) was added to the reactant of step (c) and stirred at room temperature for 30 minutes. e. The solvent was removed from the reactant of step (d) and the residue was recovered. f. 260 mL of ethyl acetate (20V) was added to the residue of step (e), and the resulting reactant was washed three times with 130 mL of purified water (10V×3). g. The organic extracts were combined and 130 mL of methanol (10V) was added. h. The reactant of step (g) was dried in vacuo at 40 °C for 6 hours to obtain a crude product of dasatinib monolauryl sulfate (dasatinib - 1LS). i. The crude product of dasatinib - 1LS was combined with 130 mL of hexane (10V), stirred for 30 minutes, the solid was separated by filtration, washed with hexane, and dried in vacuo at 40 °C for 16 hours to obtain dasatinib - 1LS as a white powder showing a chromatographic purity of over 99%.

[0158] The powder X-ray diffraction pattern (XRPD) of dasatinib monolauryl sulfate salt white powder is shown in Figure 3. XRPD was obtained using a D8 Discover with GADDS (Bruker AXS Gmbh, Karlsruhe, Germany) (GADDS: General Area Diffraction Detection System) under the following test conditions. Cukα 1+2 =1.54184 Å 40 kV, 40 mA Beam size: 1.0 mm (analysis of surface area of 1000 μm possible by collimator system) 2 is possible) Detector type: Vantec-2000 (area 14×14 cm2, pixel density 2048×2048) Distance between sample and detector: 15.05 cm 300 seconds / frame (exposure time is 300 seconds per frame)

[0159] The above synthesis was carried out multiple times, and the results were summarized in the following table.

Table 20

[0160] (Example 13) Dasatinib dilauryl sulfate salt was prepared by the following general procedure. a. 10 g of dasatinib·H 2 O and 500 mL of methanol (50 V) were combined and stirred at 50 - 55 °C. b. 11.4 g of SLS (2 molar equivalents relative to dasatinib·H 2 O) was combined with 30 mL of methanol (3 V) and 79 mL of 1N HCl (2 molar equivalents relative to SLS). c. The composition of step (b) was added to the composition of step (a), stirred for 30 minutes while maintaining the temperature at 50 - 55 °C, and then cooled to room temperature for about 1 hour. d. 500 mL of purified water (50 V) was added to the reaction product of step (c), and stirred at room temperature for 30 minutes. e. The solvent was removed from the reactant of step (d), and the residue was recovered. f. 200 mL of ethyl acetate (20 V) was added to the residue of step (e), and the resulting reactant was washed three times with 100 mL of purified water (10 V × 3). g. The organic extracts were combined, and 100 mL of methanol (10 V) was added. h. The reactant of step (g) was dried under vacuum at 40 °C for 6 hours to obtain the dasatinib dilauryl sulfate (dasatinib-2LS) crude product. i. The dasatinib-2LS crude product was combined with 100 mL of hexane (10 V), stirred for 30 minutes, the solid was separated by filtration, washed with hexane, and dried under vacuum at 40 °C for 16 hours to obtain dasatinib dilauryl sulfate as a white powder showing a chromatographic purity of over 99%.

[0161] The XRPD of the dasatinib dilauryl sulfate white powder is shown in Figure 4. XRPD was obtained using a D8 Discover with GADDS (Bruker AXS Gmbh, Karlsruhe, Germany) (GADDS: General Area Diffraction Detection System) under the following test conditions. Cukα 1+2 = 1.54184 Å 40 kV, 40 mA Beam size: 1.0 mm (Analysis of the surface area of 1000 μm is possible by the collimator system) 2 Detector type: Vantec-2000 (area 14 × 14 cm2, pixel density 2048 × 2048) Distance between sample and detector: 15.05 cm 300 seconds / frame (Exposure time is 300 seconds per frame)

[0162] The above synthesis was carried out multiple times, and the results were summarized in the following table.

Table 21

[0163] (Example 14) Dasatinib lauryl sulfate was prepared by dissolving 1.012 g of dasatinib monohydrate in 1800 mL of 0.1N hydrochloric acid (HCl) solution and 1.728 g of sodium lauryl sulfate in 200 mL of 0.1N hydrochloric acid (HCl) solution. After the dasatinib monohydrate and sodium lauryl sulfate were dissolved, the two solutions were thoroughly mixed, diluted with 0.1N NCl to a total volume of 5330 mL, and stirred for 2 hours. The supernatant was removed to recover the precipitated dasatinib lauryl sulfate, which was dried at 50 °C for 20 hours.

[0164] (Example 15) The capsule formulation of dasatinib lauryl sulfate was prepared by mixing 522.0 g of dasatinib lauryl sulfate (dry precipitate) prepared in Example 14 with 2100.0 g of CAPMUL® MCM (glyceryl caprylate / caprate) and 525.0 g of KOLLIPHOR® EL (polyoxyl 35 castor oil), and filling the suspension mixture into size 00 hard gelatin capsules.

[0165] The composition of the capsule contents is as follows. [Table 22]

[0166] (Example 16) Pazopanib monolauryl sulfate was prepared by the following general procedure. a. 20 g of pazopanib hydrochloride (PZB·HCl), 200 mL of methanol (10V), and 400 mL of purified water (20V) were combined and stirred at 50 - 55 °C. b. 12.17 g of sodium lauryl sulfate (SLS) (1 molar equivalent to PZB·HCl) was combined with 60 mL of methanol (3V) and 60 mL of purified water (3V). c. The composition of step (b) was added to the composition of step (a), stirred for 30 minutes while maintaining the temperature at 50 - 55 °C, and then cooled to room temperature for about 1 hour. d. 400 mL of purified water (20 V) was added to the cooled reactant of step (c), and the mixture was stirred at room temperature for 1 hour. e. The precipitate (white crystals) of step (d) was collected by filtration and washed with 100 mL of purified water (5 V) to obtain a crude product of pazopanib monolauryl sulfate (PZB-1LS). f. The crude product of PZB-1LS was combined with 200 mL of purified water (10 V), stirred for 30 minutes, the solid was collected by filtration, washed with 100 mL of purified water (5 V), dried in vacuo, and 28 g of PZB-1LS was obtained as a white powder with a chromatographic purity of 100% and a yield of 94%.

[0167] The solubility of the pazopanib monolauryl sulfate prepared above and commercially available pazopanib hydrochloride was measured by adding the sample to 300 mL of the specified solvent at 37 °C and shaking or stirring for at least 18 hours to reach saturation. The reactant was filtered and the filtrate was measured by HPLC.

[0168]

Table 23

[0169] (Example 17) The PZB-1LS salt was prepared according to the procedure of Example 16 using 17.4 g of PZB·HCl and 10.58 g of SLS as starting materials. By this method, 20.5 g of PZB-1LS was obtained (yield 80%), and the chromatographic purity was 99.99%.

[0170] (Example 18) The capsule formulation of pazopanib lauryl sulfate was prepared by mixing 1009.7 g of PZB-1LS prepared according to the procedures of Examples 16 and 17 with 4981.0 g of CAPMUL® 808G glyceryl monocaprylate, 1.25 mg of butylated hydroxytoluene, 281.8 mg of PURAC® FCC88 (lactic acid), and 960.1 of KOLLIPHOR® ELP (polyoxyl 35 castor oil), and filling the liquid mixture into size 0 hard gelatin capsules.

[0171] The composition of the capsule contents is as follows. [Table 24]

[0172] The test of the above pazopanib monolauryl sulfate capsules was conducted using the following high performance liquid chromatography (HPLC) method. [Table 25]

[0173] Mobile phase A is water / trifluoroacetic acid with a volume ratio of 100 / 0.1. Mobile phase B is acetonitrile / trifluoroacetic acid with a volume ratio of 100 / 0.1.

[0174] Approximately 8.0 mg of pazopanib monolauryl sulfate was weighed into a 25 mL brown volumetric flask, 20 mL of a diluent containing acetonitrile / water / trifluoroacetic acid with a volume ratio of 50 / 50 / 0.1 was added, sonicated for about 5 minutes, and stirred at about 800 rpm for about 5 minutes until the pazopanib monolauryl sulfate was dissolved to prepare a test sample. Further diluent was added so that there was approximately 0.20 mg of pazopanib per 1 mL of the test sample.

[0175] The results of the HPLC test are as follows. [Table 26]

[0176] The capsules were stored in high-density polyethylene (HDPE) bottles (126 c.c., containing 2 - 3 g of silica gel) that were closed so that children could not open them and were induction-sealed with foil.

[0177] The above table indicates that the individual impurities contained in the capsules should not exceed 0.5% (「below」), preferably the individual impurities should be 0.35% or less, most preferably the individual impurities should be 0.25% or less, and the total amount of impurities should be 1.0% or less, preferably 0.75% or less, and most preferably 0.60% or less.

[0178] In an in vitro test using USP Type II Apparatu (Paddle) (500 ml of 0.1N HCl, 75 rpm, with or without a sinker, 37 °C), pazopanib monolauryl sulfate capsules release 90% or more, preferably 85% or more, and most preferably 80% or more of pazopanib within 45 minutes.

[0179] (Example 19) The capsule formulation of pazopanib lauryl sulfate was prepared by dissolving 226 mg of poloxamer 188 in 1.2 g of ethanol. The solution was manually mixed with 2421 mg of PZB-1LS prepared according to the procedures of Examples 16 and 17, 1398.3 mg of lactose monohydrate, and 238.9 mg of polyvinylpyrrolidone. The resulting granules were dried, powdered through a 60-mesh screen, and blended with 28.1 mg of colloidal silicon dioxide, 216.2 mg of sodium starch glycolate, 1259.1 mg of lactose monohydrate, and 29.2 mg of magnesium stearate. The dry solid blend was filled into size 0 hard gelatin capsules.

[0180] The composition of the capsule contents is as follows.

Table 27

[0181] The test of the above pazopanib monolauryl sulfate capsules was conducted using the HPLC method described in Example 18, and the following results were obtained. [Table 28]

[0182] The capsules were closed so that children could not open them and stored in high-density polyethylene (HDPE) bottles (126 c.c., containing 2 - 3 g of silica gel) induction-sealed with foil.

[0183] The above table indicates that the individual impurities contained in the capsules should be 0.5% or less, preferably 0.35% or less, most preferably 0.25% or less, and the total amount of impurities should be 1.0% or less, preferably 0.75% or less, most preferably 0.60% or less.

[0184] In an in vitro test using USP Type II Apparatu (Paddle) (500 ml of 0.1N HCl, 75 rpm, with or without a sinker, 37°C), the pazopanib monolauryl sulfate capsules release 90% or more, preferably 85% or more, most preferably 80% or more of pazopanib within 45 minutes.

[0185] (Example 20) The capsules prepared in Examples 18 and 19 containing PZB-1LS equivalent to 50 mg of pazopanib free base were administered to six (6) healthy adult beagle dogs in a fasting state in a single-dose study at a single facility together with capsules obtained by dividing four commercially available 200 mg VOTRIENT FILM COATED tablets (containing 216.7 mg of pazopanib HCl) (each capsule contains pazopanib hydrochloride equivalent to 50 mg of pazopanib free base). Blood samples were collected before administration and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. The average plasma values of pazopanib were calculated as follows.

Table 29

[0186] A graph of the average plasma profile is shown in Figure 5.

[0187] The individual data in this test are shown in the following table.

Table 30-1

Table 30-2

Table 30-3

Table 30-4

Table 30-5

[0188] (Example 21) Nintedanib lauryl sulfate was prepared by the following general procedure. a. 15 g of nintedanib ethylate was added to a co-solvent of ethyl acetate / 10% NaHCO 3 aqueous solution (450 ml / 150 ml) (30 V / 10 V), and the mixture was stirred at 40 °C for 1 hour. b. The organic layer of the reaction mixture in step (a) was separated and washed twice with 150 mL of purified water (10 V × 2). c. The organic extracts from step (b) were combined and concentrated to obtain nintedanib free base as a yellow powder (12.3 g, yield 98.7%). d. 738 mL of methanol (60 V) was added to 12.3 g of nintedanib free base, and the mixture was stirred at 50 - 55 °C. e. 13.1 g of SLS (2 molar equivalents relative to nintedanib) was dissolved in a co-solvent of 36.9 mL of methanol / 90 mL of 1N HCl (3 V) to prepare an SLS solution. f. Add the SLS solution from step (e) to the mixture from step (d) and stir at 50 - 55 °C for 30 minutes. g. Add 246 mL of purified water to the reaction mixture from step (f) and stir at room temperature for 1 hour. h. Recover the precipitate (crystals) from step (g) by filtration, wash with 61.5 mL of purified water (5V) to obtain the crude product of nintedanib dilauryl sulfate. i. Combine the crude product of nintedanib dilauryl sulfate with 123 mL of purified water (10V), stir for 30 minutes, recover the solid by filtration, wash with 61.5 mL of purified water (5V), and dry in vacuo to obtain nintedanib dilauryl sulfate as a golden powder with a chromatographic purity of 100% and a yield of 89.3%.

[0189] (Example 21A) The tablet formulation of nintedanib dilauryl sulfate was prepared by the following wet granulation process. (i) Mix 9.940 g of nintedanib dilauryl sulfate prepared by the procedure of Example 21 with 1.800 g of poloxamer 407 and 1.575 g of poloxamer 188. (ii) Granulate the mixture from step (i) with a solution containing 1.500 g of alcohol (95%) and 1.500 g of purified water. (iii) Pass 6.000 g of anhydrous lactose and 8.278 g of microcrystalline cellulose through a 40 - mesh sieve, add to the granules from step (ii), and blend the resulting composition. (iv) Dry the blend from step (iii) in an oven at 50 °C to evaporate the alcohol and water, and pass through a 40 - mesh sieve after drying. (v) Mix the dried and sieved material from step (iv) with 0.600 g of colloidal silicon dioxide passed through a 40 - mesh sieve and 1.500 g of polyethylene oxide (Polyox WSR303) with an average molecular weight of 7,000,000. (vi) Pass 0.007 g of butylated hydroxytoluene (BHT) through a 40 - mesh sieve, add to and mix with the composition from step (v). (vii) 0.300 g of magnesium stearate was sieved through a 40-mesh sieve, added to the composition of step (vi), and blended to obtain a final blend. (viii) The final blend was compressed using a capsule-shaped punch (length 17.5 mm, width 7.1 mm) into tablets with a target hardness of approximately 10 kp.

[0190] The composition of the tablets is as follows.

Table 31

[0191] (Example 21B) The tablet dosage form of nintedanib dilauryl sulfate was prepared according to the procedure described in Example 21A, and the composition of the tablets is as follows.

Table 32

[0192] (Example 21C) The dosage forms prepared in Examples 21A and 21B (n = 2) were tested using a USP Type II Apparatus (Paddle) with 675 ml of 0.1 N HCl for 2 hours, followed by changing the pH to 6.8 (final volume: 900 ml) at 37 °C using 0.1% sodium lauryl sulfate at 100 rpm with a sinker. The results of this dissolution test are as follows.

Table 33

[0193] The dosage forms prepared in Examples 21A and 21B (n = 2) were also tested using a USP Type II Apparatus (Paddle) (900 mL of aqueous solvent at pH 6.8 and 0.1% sodium lauryl sulfate, 100 rpm, with sinker, 37 °C). The results of this dissolution test are as follows.

Table 34

[0194] The in vitro dissolution data described above indicate that the dosage forms prepared according to the present invention may exhibit sustained release enabling once-daily or twice-daily administration. For example, when tested using the USP Type II Apparatus (Paddle) (900 mL of aqueous solvent at pH 6.8 and 0.1% sodium lauryl sulfate, 75 rpm), the nintedanib lauryl sulfate salt is released as follows. [Table 35]

[0195] The dosage forms prepared in Examples 21A and 21B were also subjected to impurity testing using the following HPLC method. [Table 36]

[0196] Mobile phase A is 100% acetonitrile. Mobile phase B is 0.0075 M diammonium hydrogen phosphate (pH 6.4 ± 0.2).

[0197] The test sample was prepared in triplicate by crushing the tablets, transferring the crushed material to a 100 mL brown volumetric flask, adding 80 mL of methanol, stirring for at least about 120 minutes until the material dissolved, sonicating for an additional 15 minutes, and stirring at about 800 rpm for about 10 minutes. The resulting composition was filtered through a 0.45 μm nylon filter, and the first 3 mL of filtrate was discarded.

[0198] It was found that the tablet dosage forms of nintedanib dilauryl sulfate prepared in Examples 21A and 21B have the following impurity profiles. [Table 37]

[0199] The above data indicates that the nintedanib dilauryl sulfate dosage form of the present invention should have individual impurities of 0.5% or less, preferably individual impurities of 0.35% or less, and most preferably individual impurities of 0.25% or less, and the total amount of impurities should be 1.0% or less, preferably 0.75% or less, and most preferably 0.60% or less.

[0200] (Example 21D) Tablets prepared in Example 21A (Test Formulation 1 or T1) and Example 21B (Test Formulation 2 or T2) containing nintedanib dilauryl sulfate (equivalent to 100 mg of nintedanib free base) were administered to 6 (six) healthy subjects in a single-dose study at a single facility, in a fasting state, together with a commercially available OFEV (registered trademark) capsule (reference) containing 120.4 mg of nintedanib etilsulfate (equivalent to 100 mg of nintedanib free base). This administration was a bioavailability study conducted on healthy subjects under fasting conditions in a non-blind, randomized, 3-treatment, 3-group, 3-period crossover method. All subjects were randomly assigned to the groups shown in the following table, and a 7-day washout period was provided between periods.

Table 38

[0201] During each formulation period, blood samples were collected at 0 (before dosing), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 48 hours after dosing. AUC 0-24 、AUC 0-∞ 、C max 、T max 、and T 1 / 2 were determined for each subject based on non-compartmental analysis. The test results are summarized in the following table. AUC 0-t 、AUC 0-∞ 、C max were analyzed by ANOVA. The model included group, subject (group), period, and treatment effect. A comparison of the data obtained from the administration of the test drug and the reference drug is shown in the following table.

Table 39-1

Table 39-2

[0202] The data for each individual subject obtained in this test are as follows.

Table 40-1

Table 40-2

Table 40-3

[0203] A graph of the average plasma profile obtained in this example is shown in Figure 6.

[0204] (Example 22) Nintedanib lauryl sulfate capsules were prepared by manually blending 2386 mg of nintedanib lauryl sulfate (powder) prepared by the procedure of Example 21 with 468 mg of croscarmellose sodium and 2122 mg of anhydrous lactose. The blend was passed through a 40-mesh screen. 2122 mg of microcrystalline cellulose (PH102), 390 mg of poloxamer 188, and 234 mg of hydroxypropyl cellulose (HPC-H) were passed through a 40-mesh screen and mixed with the blend. 78 mg of magnesium stearate was passed through a 40-mesh screen and added to the blend. The dry solid blend was filled into size 1 hard gelatin capsules.

[0205] The composition of the capsule contents is as follows.

Table 41

[0206] (Example 23) The capsule formulation of nintedanib lauryl sulfate was prepared by mixing 2386 mg of nintedanib lauryl sulfate (powder passed through an 80-mesh screen), prepared according to the procedure of Example 21, with a mixture of 4649 mg of medium-chain triglyceride (Miglyol 812N), 1920 mg of diethylene glycol monoethyl ether (Transcutol HP), 10 mg of butylated hydroxytoluene (BHT), and 1200 mg of lecithin to obtain a uniform dispersion. 1836 mg of hard fat (Gelucire 43 / 01) was melted in a constant temperature water bath (50 °C) and added to the dispersion to obtain a uniform suspension (semi-solid). The semi-solid suspension was filled into hard gelatin capsules of size 1.

[0207] The composition of the capsule contents is as follows. [Table 42]

[0208] (Example 24) Capsules containing nintedanib lauryl sulfate (equivalent to 30 mg of nintedanib free base), prepared in Examples 22 and 23, were administered to six (6) healthy adult beagle dogs in a fasting state in a single-dose study at a single facility, together with capsules equivalent to 30 mg prepared from OFEV (registered trademark) capsules of 100 mg (obtained by recovering the contents from commercially available 100 mg OFEV (registered trademark) capsules containing 120.40 mg of nintedanib esylate and refilling new capsules with contents equivalent to 30 mg of nintedanib free base each). Blood samples were collected before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 36 hours after dosing. The average values of nintedanib in plasma were calculated as follows. [Table 43]

[0209] A graph of the average plasma profile is shown in Figure 7.

[0210] The individual data of this test are shown in the following table. [Table 44-1] [Table 44-2] [Table 44-3] [Table 44-4] [Table 44-5]

[0211] (Example 25) Nintedanib monolauryl sulfate was prepared by the following general procedure. a. 17 g of nintedanib ethylate was added to a co-solvent of ethyl acetate / 10% NaHCO 3 aqueous solution (210 mL / 170 mL) (30V / 10V), and the mixture was stirred at 40 °C for 1 hour. b. The organic layer of the reaction product in step (a) was separated and washed twice with 170 mL of purified water (10V×2). c. The organic extracts from step (b) were combined and concentrated to obtain nintedanib free base as a yellow powder (13.4 g, yield 95%). d. 1340 mL of absolute ethanol (100V) was added to 13.4 g of nintedanib free base, and the mixture was stirred at 60 °C. e. 7.16 g of SLS (1 molar equivalent to nintedanib) was added to 40.2 mL of methanol (3V) and 2.3 mL of 12N HCl (1.1 molar equivalent), stirred at room temperature for 10 minutes, and 10 mL of 10% NaHCO 3 aqueous solution was added, and the SLS solution was prepared by stirring at room temperature for 5 minutes. f. The SLS solution from step (e) was added to the mixture from step (d), and the mixture was stirred at 60 °C for 1 hour. g. Concentrate the reactants of step (f), add 268 mL of ethyl acetate (20 V), and wash the resulting reaction mixture with 134 mL of purified water (10 V × 3). h. Combine and concentrate the organic extracts of step (g) to recover the solid, and vacuum dry at 40 °C for 16 hours to obtain 16.3 g of nintedanib monolauryl sulfate as a yellow powder with a chromatographic purity of 100% and a yield of 81.5%.

[0212] Nintedanib monolauryl sulfate may be used to prepare oral dosage forms as described in Examples 22 and 23.

[0213] (Example 25A) Samples were added to 5 - 20 mL of the designated solvent at room temperature and shaken or stirred for at least 18 hours to saturation to measure the solubility of the nintedanib lauryl sulfate salts prepared in Examples 21 and 25, and samples of commercially available nintedanib esylate. The reactants were filtered and the filtrate was measured by HPLC. The solubility measurement results are as follows. [Table 45]

[0214] (Example 25B) Using the HPLC method outlined in Example 21C, the impurities and stability of the nintedanib lauryl sulfate salts prepared in Examples 21 and 25 were measured.

[0215] Weigh 29.88 mg of nintedanib monolauryl sulfate or 39.76 mg of nintedanib dilauryl sulfate (equivalent to 20 mg of nintedanib) respectively and transfer to a 20 mL brown volumetric flask, add 16 mL of diluent (methanol), sonicate for about 5 minutes, and stir at 800 rpm for about 5 minutes until completely dissolved to prepare the test samples respectively. Additional diluent was added so that each mL of the test sample contained approximately 1.0 mg of nintedanib.

[0216] The following results were obtained.

Table 46

[0217] The above data show that nintedanib lauryl sulfate is more stable than monolauryl sulfate, and both the monolauryl and dilauryl sulfate salts of the present invention should have individual impurities of 0.5% or less, preferably individual impurities of 0.35% or less, most preferably individual impurities of 0.30% or less, and the total amount of impurities should be 1.0% or less, preferably 0.75% or less, most preferably 0.60% or less.

[0218] (Example 26) Nilotinib dilauryl sulfate was prepared by the following general procedure. a. 100 mL of methanol (10V) was added to 10 g of nilotinib HCl, and the mixture was stirred at room temperature. b. 1.57 mL of 12N HCl (1.1 molar equivalents) was added to the mixture of step (a), and the mixture was stirred at 50 - 55 °C for 2 hours. c. The mixture of step (b) was distilled under vacuum, and the residue was stirred with 100 mL of hexane (10V) for 30 minutes. d. The solid of step (c) was separated by filtration, washed with hexane, and dried under vacuum at 40 °C for 3 hours to obtain 10.8 g of nilotinib dihydrochloride as a golden powder (yield 98%). e. 216 mL of methanol (20V) was added to 10.8 g of nilotinib dihydrochloride of step (d), and the mixture was stirred at 50 - 55 °C. f. 9.76 g of SLS (2 molar equivalents) was added to 54 mL of methanol (5V), and the resulting mixture was added to the mixture of step (e), and the mixture was stirred at 50 - 55 °C for 3 hours. g. The reaction mixture of step (f) was concentrated, 324 mL of ethyl acetate (30V) was added, and the resulting reaction mixture was washed 3 times with 216 mL of purified water (20V × 3). h. Combine the organic extracts from step (g), concentrate them, and dry them under vacuum at 40 °C for 6 hours to obtain a crude product of nilotinib dilauryl sulfate. i. Combine the crude product of nilotinib dilauryl sulfate with 108 mL of hexane (10 V) and stir for 30 minutes. j. Separate the solids of the reaction mixture from step (i) by filtration, wash them with hexane, and dry them under reduced pressure at 40 °C for 16 hours to obtain 10.6 g of nilotinib dilauryl sulfate as a yellow powder with a chromatographic purity of 99.98% and a yield of 91%.

[0219] (Example 27) The nilotinib dilauryl sulfate ester salt was prepared according to the procedure of Example 26. Using 30 g of nilotinib HCl and 4.71 mL of 12N NCl, 32.4 g of nilotinib dihydrochloride was obtained (yield 98%). Combine 32.4 g of nilotinib dihydrochloride with 29.3 g of SLS to obtain 48.5 g of nilotinib dilauryl sulfate with a chromatographic purity of 99.97% (yield 90%).

[0220] (Example 28) The nilotinib dilauryl sulfate ester salt was prepared according to the following general procedure. a. Add 768 mL of methanol (30 V) to 25.6 g of nilotinib HCl and stir at room temperature. b. Add 4.02 mL of 12N HCl (1.1 molar equivalents) to the mixture from step (a) and stir at 50 - 55 °C for 2 hours. c. Distill the mixture from step (b) under vacuum and stir the residue with 256 mL of hexane (10 V) for 30 minutes. d. Separate the solids from step (c) by filtration, wash them with hexane, and dry them under vacuum at 40 °C for 3 hours to obtain 25.7 g of nilotinib dihydrochloride as a golden powder (yield 92%). e. Add 514 mL of methanol (20 V) to 25.7 g of nilotinib dihydrochloride from step (d) and stir the mixture at 50 - 55 °C. Add 2 molar equivalents of SLS of f.23.2g to 128.5 mL of methanol (5V), add the resulting mixture to the mixture of step (e), and stir at 50 - 55 °C for 3 hours. g. Concentrate the reaction mixture of step (f), add 771 mL of ethyl acetate (30V), and wash the resulting reaction mixture three times with 514 mL of purified water (20V × 3). h. Combine and concentrate the organic extracts, and dry under vacuum at 40 °C for 6 hours to obtain a crude product of nilotinib dilauryl sulfate. i. Combine the crude product of nilotinib dilauryl sulfate with 257 mL of hexane (10V) and stir for 30 minutes. j. Separate the solid of the reaction mixture of step (i) by filtration, wash with hexane, and dry at 40 °C under reduced pressure for 16 hours to obtain 36.5 g of nilotinib dilauryl sulfate as a golden powder with a chromatographic purity of 99.93% and a yield of 85%.

[0221] (Example 29) The nilotinib dilauryl sulfate prepared in Examples 26, 27, and 28 may be used to prepare oral dosage forms as described in Examples 3, 4, 9, 15, 18, 19, 22, 23, 30, 31, 33, 34, 37, or 39.

[0222] (Example 30) The capsule formulation of nintedanib monolauryl sulfate was prepared by wet granulation in a container of 1,793 mg of nintedanib monolauryl sulfate prepared by the procedure of Example 25, together with 600 mg of poloxamer 407, 480 mg of poloxamer 188 and 1,600 mg of absolute alcohol, heating at 70 °C and mixing for 10 minutes. A powder mixture of 600 mg of anhydrous lactose, 1,747 mg of microcrystalline cellulose PH102 (Part I) and 300 mg of sodium starch glycolate (Part I) was sieved through a 40-mesh sieve, added to the nintedanib monolauryl sulfate granules and mixed. The resulting mixture was dried in an oven at 70 °C to evaporate the alcohol. The dried mixture was combined with 300 mg of sodium starch glycolate (Part II), 120 mg of colloidal silicon dioxide, and 800 mg of microcrystalline cellulose PH102 (Part II) sieved through a 40-mesh sieve, and dry mixed. The resulting dry mixture was sieved through a 40-mesh sieve and collected in a suitable container. 60 mg of magnesium stearate was sieved through a 40-mesh sieve, added to the container and mixed to obtain the final blend. The final blend, which was a dry solid, was filled into size 1 hard gelatin capsules.

[0223] The composition of the capsule contents is as follows.

Table 47

[0224] (Example 31) The capsule formulation of nintedanib monolauryl sulfate was prepared by mixing 2,441 mg of medium-chain triglycerides (Miglyol 812N), 680 mg of diethylene glycol monoethyl ether (Transcutol HP), 6 mg of butylated hydroxytoluene (BHT), and 680 mg of lecithin to obtain a homogeneous dispersion. 1200 mg of hard fat (Gelucire 43 / 01) was melted in a water bath (50 °C) and added to the homogeneous dispersion to obtain a homogeneous suspension (semi-solid). 1.793 mg of nintedanib monolauryl sulfate prepared according to the procedure of Example 25 was sieved through an 80-mesh sieve, added to the suspension to obtain a homogeneous suspension, and / or solidified into a semi-solid. The semi-solid suspension was filled into size 1 hard gelatin capsules.

[0225] The composition of the capsule contents is as follows. [Table 48]

[0226] (Example 32) Capsules containing nintedanib monolauryl sulfate (equivalent to 30 mg of nintedanib free base) prepared in Examples 30 and 31 were administered to six (6) healthy adult beagle dogs in a fasting state in a single-dose study at a single facility, together with capsules equivalent to 30 mg prepared from OFEV (registered trademark) capsules 100 mg (obtained by recovering the contents from commercially available 100 mg OFEV (registered trademark) capsules containing 120.40 mg of nintedanib ethylic acid salt and refilling new capsules with each content equivalent to 30 mg of nintedanib free base). Blood samples were collected before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 36 hours after dosing. The mean values of nintedanib in plasma were calculated as follows. [Table 49]

[0227] A graph of the mean plasma profile is shown in Figure 8.

[0228] The individual data of this test are shown in the following table.

Table 50-1

Table 50-2

Table 50-3

Table 50-4

Table 50-5

[0229] (Example 33) The capsule formulation of dasatinib monolauryl sulfate was prepared by wet granulation of 1,865 mg of dasatinib monolauryl sulfate prepared according to the procedure of Example 12 in a suitable container with 750 mg of poloxamer 407, 600 mg of poloxamer 188 and 2,000 mg of absolute alcohol, heating to 70 °C and stirring for 10 minutes. 600 mg of anhydrous lactose, 1,405 mg of microcrystalline cellulose PH102 and 300 mg of sodium starch glycolate (Part I) were sieved through a 40-mesh sieve, added to the dasatinib monolauryl sulfate granules and mixed. The resulting mixture was dried in an oven at 50 °C to evaporate the alcohol. The dried mixture was combined with 300 mg of sodium starch glycolate (Part II) sieved through a 40-mesh sieve and 120 mg of colloidal silicon dioxide, and mixed. The resulting mixture was sieved through a 40-mesh sieve and collected in a suitable container. 60 mg of magnesium stearate was sieved through a 40-mesh sieve, added to the container and mixed to obtain the final blend. The final blend, which is a dry solid, was filled into size 1 hard gelatin capsules.

[0230] The composition of the capsule contents is as follows.

Table 51

[0231] (Example 34) The capsule formulation of dasatinib lauryl sulfate was prepared by wet granulation in a suitable container of 2,520 mg of dasatinib lauryl sulfate prepared by the procedure of Example 13, together with 750 mg of poloxamer 407, 600 mg of poloxamer 188 and 1,000 mg of absolute alcohol. 300 mg of anhydrous lactose, 1,050 mg of microcrystalline cellulose PH102 and 300 mg of sodium starch glycolate (Part I) were sieved through a 40-mesh sieve, added to the dasatinib lauryl sulfate granules and mixed. The resulting mixture was dried in an oven at 50 °C to evaporate the alcohol. The dried mixture was combined and mixed with 300 mg of sodium starch glycolate (Part II) sieved through a 40-mesh sieve and 120 mg of colloidal silicon dioxide. The resulting mixture was sieved through a 40-mesh sieve and collected in a suitable container. 60 mg of magnesium stearate was sieved through a 40-mesh sieve, added to the container and mixed to obtain the final blend. The final blend, which was a dry solid, was filled into size 1 hard gelatin capsules.

[0232] The composition of the capsule contents is as follows. [Table 52]

[0233] (Example 35) The capsules prepared in Examples 33 and 34 containing dasatinib monolauryl sulfate or dasatinib dilauryl sulfate were administered to six (6) healthy adult beagle dogs in a single-dose study at a single facility in a fasting state, together with capsules equivalent to 25 mg obtained by dividing the contents of a commercially available 50 mg Spycel® film-coated tablet (containing 50 mg of dasatinib) into two capsules. Blood samples were collected before administration and at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. In this example, the doses in the analysis were standardized such that the test drug was 25 mg of dasatinib monohydrate and Sprycel® was 25 mg of dasatinib. The average values of dasatinib in plasma standardized to 25 mg are as follows. [Table 53]

[0234] A graph of the average of the standardized plasma profiles is shown in Figure 9.

[0235] The standardized individual data in this study are shown in the following table. [Table 54-1] [Table 54-2] [Table 54-3] [Table 54-4] [Table 54-5]

[0236] (Example 36) Nilotinib lauryl sulfate salt was prepared by mixing 43 g of nilotinib hydrochloride monohydrate and 1,935 mL of absolute alcohol at 50 - 55 °C. 21.23 g of sodium lauryl sulfate (in 63.7 mL of alcohol (95%) and 42.5 mL of purified water) was added to the solution. The mixture was stirred at 50 - 55 °C for 30 minutes, at room temperature for 1 hour, and at 0 - 10 °C for 30 minutes. 1,505 mL of purified water was added to the mixture, and it was stirred at 0 - 10 °C for 30 minutes. The white crystals obtained by filtration were collected, washed with 215 mL of 85.5% aqueous ethanol solution to obtain crude product 1 of nilotinib monolauryl sulfate. 430 mL of purified water was added to crude product 1 of nilotinib monolauryl sulfate, stirred for 30 minutes, collected by filtration, and washed with 430 mL of purified water to obtain crude product 2 of nilotinib monolauryl sulfate. 430 mL of hexane was added to crude product 2 of nilotinib monolauryl sulfate, stirred for 30 minutes, collected by filtration, and washed with 215 mL of hexane to obtain 48 g of nilotinib lauryl sulfate salt (yield 82%) as an off - white powder with a chromatographic purity of 99.92%.

[0237] (Example 37) The capsule formulation of nilotinib monolauryl sulfate was prepared by mixing 3.754 g of nilotinib monolauryl sulfate prepared according to the procedure of Example 36, 12.528 g of CAPMUL® MCM (glyceryl caprylate / caprate), and 3.133 g of KOLLIPHOR® EL (polyoxyl 35 castor oil), and filling the mixture into soft gelatin capsules.

[0238] The composition of the capsule contents is as follows.

Table 55

[0239] (Example 38) Nilotinib dilauryl sulfate salt was prepared by mixing 25.6 g of nilotinib hydrochloride monohydrate and 768 mL of methanol at room temperature. 4.02 mL of hydrochloric acid solution (12 N) was added to the solution. The mixture was completely distilled under vacuum. 256 mL of hexane was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solid was separated by filtration, washed with hexane, and dried under vacuum at 40 °C for 3 hours to obtain nilotinib dihydrochloride as a golden powder. 25.7 g of nilotinib dihydrochloride and 514 mL of methanol were mixed at 50 - 55 °C. 23.2 g of sodium lauryl sulfate (in 116 mL of methanol) was added to the solution. The mixture was stirred at 50 - 55 °C for 3 hours. The mixture was concentrated, 771 mL of ethyl acetate was added, and the resulting reaction product was washed with 514 mL of purified water. The organic extract was concentrated and dried under vacuum at 40 °C for 6 hours to obtain a crude product of nilotinib dilauryl sulfate salt. 257 mL of hexane was added to the crude product of nilotinib dilauryl sulfate salt, and the mixture was stirred for 30 minutes. The solid was separated by filtration, washed with hexane, and dried under vacuum at 40 °C for 16 hours to obtain 36.5 g of nilotinib dilauryl sulfate salt as a golden powder with a chromatographic purity of 99.93% (yield 85%).

[0240] The XRPD of the nilotinib dilauryl sulfate salt golden powder is shown in Figure 10. The XRPD was obtained using a D8 Discover with GADDS (Bruker AXS Gmbh, Karlsruhe, Germany) (GADDS: General Area Diffraction Detection System) under the following test conditions. CuKα 1+2 = 1.54184 Å 40 kV, 40 mA Beam size: 1.0 mm (Analysis of the surface area of 1000 μm is possible by the collimator system) 2 Detector type: Vantec - 2000 (area 14×14 cm2, pixel density 2048×2048) Distance between sample and detector: 15.05 cm 300 seconds / frame (Exposure time is 300 seconds per frame)​

[0241] (Example 38A) The solubility of nilotinib monolauryl sulfate prepared in Example 36 and nilotinib hydrochloride monohydrate of a commercially available sample was measured by adding the sample to 300 mL of a specified solvent at 37°C and shaking or stirring for at least 18 hours to reach a saturated state. The solubility of nilotinib dilauryl sulfate prepared in Example 38 was measured by adding the sample to 5 - 20 mL of a specified solvent at room temperature and shaking or stirring for at least 18 hours to reach a saturated state. The reactants were filtered, and the filtrate was measured by HPLC. The measurement results of the solubility are as follows.

Table 56

[0242] (Example 39) The capsule formulation of nilotinib dilauryl sulfate was prepared by mixing 8.022 g of nilotinib dilauryl sulfate prepared according to the procedure of Example 38, 20.042 g of CAPMUL® MCM (glyceryl caprylate / caprate), 5.010 g of KOLLIPHOR® EL (polyoxyl 35 castor oil), and 0.667 g of sodium hydrogen carbonate, and filling the mixture into soft gelatin capsules.

[0243] The composition of the capsule contents is as follows.

Table 57

[0244] (Example 40) The same as those prepared in Examples 37 and 39, capsules adjusted to contain a weight approximately corresponding to about 50 mg of nilotinib free base were administered to six (6) adult healthy beagle dogs in a single-dose study at a single facility in a fasting state, together with capsules obtained by dividing four commercially available TASIGNA 200 mg capsules (each containing the equivalent of 50 mg of nilotinib free base). Blood samples were collected before administration and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration. The average plasma values of nilotinib were calculated as follows. [Table 58]

[0245] A graph of the average plasma profile is shown in Figure 11.

[0246] The individual data in this study are shown in the following table. [Table 59-1] [Table 59-2] [Table 59-3] [Table 59-4] [Table 59-5]

[0247] (Example 41) Cabozantinib monolauryl sulfate was prepared by the following general procedure. a. 37 g of cabozantinib S-malate was added to a co-solvent of 1850 mL / 740 mL of ethyl acetate / 10% NaHCO 3 aqueous solution (50 V / 20 V), and the mixture was stirred at 45 °C for 2 hours. b. The organic layer of the reaction mixture in step (a) was separated and washed twice with 740 mL of purified water (20V × 2). c. The organic extracts from step (b) were combined and concentrated to obtain cabozantinib free base as a white powder (29.2 g, 100% yield). d. 1022 mL of methanol (35V) was added to 29.2 g of cabozantinib free base, and the mixture was stirred at 50 - 55 °C. e. 16.8 g of SLS (1 molar equivalent to cabozantinib) was dissolved in a co - solvent of 87.6 mL of methanol (3V) / 58.26 mL of 1N HCl (1 molar equivalent) to prepare an SLS solution. f. The SLS solution from step (e) was added to the mixture from step (d), stirred at 50 - 55 °C for 30 minutes, and then adjusted to room temperature for 1 hour. g. 1460 mL of purified water (50V) was added to the reaction mixture from step (f), and the mixture was stirred at room temperature for 30 minutes. h. The precipitate (crystals) from step (g) was collected by filtration, washed with 292 mL of purified water (10V) to obtain a crude product of cabozantinib monolauryl sulfate. i. The crude product of cabozantinib monolauryl sulfate was combined with 584 mL of purified water (20V), stirred for 30 minutes, the solid was collected by filtration, washed with 146 mL of purified water (5V), and 41 g of cabozantinib monolauryl sulfate was obtained as a white powder with a UPLC chromatography purity of 100% and a yield of 91.7%.

[0248] The solubility of the cabozantinib monolauryl sulfate prepared above was measured by adding the sample to 50 mL of the designated solvent at 37 °C and shaking or stirring for at least 1 hour to reach saturation. The reactant was filtered, and the filtrate was measured by HPLC. The measurement results of the solubility are as follows.

Table 60

[0249] (Example 42) The cabozantinib monolauryl sulfate prepared in Example 41 may be used to prepare oral dosage forms as described in Examples 3, 4, 9, 15, 18, 19, 22, 23, 30, 31, 33, 34, 37 or 39.

[0250] (Example 42A) The capsule dosage form of cabozantinib monolauryl sulfate was prepared by the following wet granulation process. (i) 3.0595 g of cabozantinib monolauryl sulfate, 6.10 g of poloxamer 407, and 3.05 g of poloxamer 188 prepared according to the procedure of Example 41 were dissolved in 300 mL of 95% alcohol to prepare a granulation liquid. (ii) 1.75 g of anhydrous lactose, 3.6405 g of microcrystalline cellulose PH112, 1.00 g of croscarmellose sodium (Part I), and 0.20 g of colloidal silicon dioxide (Part I) were sieved through a 40-mesh sieve, blended, and granulated with the granulation liquid of step (i). (iii) The wet granules were sieved through a 20-mesh sieve, dried in an oven at 55 °C to evaporate the alcohol, and the dried granules were sieved through a 24-mesh sieve. (iv) The dried granules of step (iii) were mixed with 1.00 g of croscarmellose sodium (Part II) and 0.10 g of colloidal silicon dioxide (Part II). (v) 0.10 g of magnesium stearate was added to the mixture of step (iv) and blended well to obtain a final blend. (vi) The final mixture, which was a dry solid, was filled into size 1 hard gelatin capsules.

[0251] The composition of the capsule contents is as follows.

Table 61

[0252] (Example 42B) The capsule dosage form of cabozantinib monolauryl sulfate was prepared by the following process. (i) 8 mg of butylated hydroxytoluene (BHT) was dissolved in a mixture of 14.6856 g of CAPMUL® MCM (glyceryl caprylate / caprate) and 5.2112 g of KOLLIPHOR® EL (polyoxyl 35 castor oil). (ii) 4.8952 g of cabozantinib monolauryl sulfate prepared according to the procedure of Example 41 was sieved through a 60-mesh sieve and added to the solution of step (i) to obtain a uniform dispersion. (iii) 2.40 g of hardened oil (Gelucire 43 / 01) was melted using a 55 °C water bath, and the melted hardened oil was added to the dispersion of step (ii) while maintaining the temperature at 55 °C and homogenized to obtain a uniform suspension. (iv) The suspension of step (iii) was filled into size 3 hard gelatin capsules.

[0253] The composition of the capsule contents is as follows.

Table 62

[0254] (Example 42C) The tablet formulation of cabozantinib malate was prepared by the following steps. (i) 2.0276 g of cabozantinib malate was sieved through a 60-mesh sieve and blended with 2.4864 g of microcrystalline cellulose PH102, 1.2428 g of anhydrous lactose, and 0.192 g of croscarmellose sodium (Part I) that had been sieved through a 40-mesh sieve four times in advance. (ii) The mixture of step (i) was wet granulated with a granulation solution prepared by dissolving 0.192 g of hydroxypropylcellulose EXF in 1.28 g of purified water. (iii) The wet granules were sieved through a 20-mesh sieve, dried in an oven at 60 °C to evaporate the purified water, and the dried granules were sieved through a 24-mesh sieve. (iv) The dried and sieved granules were mixed with 0.192 g of croscarmellose sodium (Section II) and 0.0192 g of magnesium stearate. (v) 0.048 g of colloidal silicon dioxide was added to the mixture of step (iv) and blended well to obtain the final blend. (vi) The final blend was compressed using a 6 mm circular punch into tablets with a target hardness of about 4 kp.

[0255] The composition of the tablet contents is as follows.

Table 63

[0256] (Example 42D) The following capsule formulation was prepared according to the procedure of Example 42B. The composition of the capsule is as follows.

Table 64

[0257] (Example 42E) The dosage forms (n = 3) prepared in Examples 42A - 42D were tested using the USP Type II Apparatus (Paddle) (900 mL of 0.1 N HCl (with 0.5% Triton X - 100 added), 75 rpm, using a sinker, 37°C). The results of this dissolution test are as follows.

Table 65

[0258] The in vitro dissolution data described above indicate that the dosage form prepared according to the present invention releases (i) at least 40%, preferably at least 45%, most preferably 50% of cabozantinib after 30 minutes of the test, (ii) at least 55%, preferably at least 60%, most preferably 65% of cabozantinib after 45 minutes of the test, and (iii) at least 70%, preferably at least 75%, most preferably 80% of cabozantinib after 60 minutes of the test.

[0259] (Example 42F) The impurities and stability of the dosage forms prepared in Examples 42A to 42D were tested using the following HPLC method. [Table 66]

[0260] Mobile phase A is a buffer solution prepared by dissolving 2.72 g of potassium dihydrogen phosphate and 1 mL of triethylamine in 1000 mL of water and adjusting the pH to 3.20 ± 0.05 with phosphoric acid. Mobile phase B is acetonitrile / methanol / water with a volume ratio of 60 / 30 / 10.

[0261] The test results are as follows. [Table 67]

[0262] The capsules were closed so that children could not open them and stored in high-density polyethylene (HDPE) bottles (126 c.c., containing 2 - 3 g of silica gel) sealed by induction with foil.

[0263] Using the HPLC method described above, it was found that the cabozantinib monolauryl sulfate dosage form should have individual impurities of 0.5% or less, preferably individual impurities of 0.35% or less, most preferably individual impurities of 0.25% or less, and the total amount of impurities should be 1.0% or less, preferably 0.75% or less, most preferably 0.60% or less.

[0264] (Example 42G) Capsules prepared in Examples 42A (Test Preparation 1 or T1) and 42B (Test Preparation 2 or T2) containing cabozantinib monolauryl sulfate (equivalent to 20 mg of free cabozantinib base) were administered to six (6) healthy adult beagle dogs in a single-dose study at a single facility in a fasting state, together with 20 mg equivalent of cabozantinib malate tablets (equivalent to 20 mg of free cabozantinib base) prepared in Example 42C. Blood samples were collected before dosing and at 0.25, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after dosing. The mean plasma levels of cabozantinib were calculated as follows. [Table 68]

[0265] A graph of the mean plasma profiles is shown in Figure 12.

[0266] The individual data for this study are shown in the following table. [Table 69-1] [Table 69-2] [Table 69-3] [Table 69-4] [Table 69-5]

[0267] (Example 43) Liquid dosage forms may be prepared using the mono- or dilauryl sulfate salts of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, or bemrafenib prepared in Examples 1, 11-14, 16-17, 21, 25-27, 33-34, 36, 38 and 41, using the procedures described in Examples 3, 9, 15, 18, 37 and 39.

[0268] The composition of the capsule contents includes the following. [Table 70]

[0269] (Example 44) Solid dosage forms such as tablets or capsules may be prepared using the mono- or dilauryl sulfate salts of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, or bemrafenib prepared in Examples 1, 11-14, 16-17, 21, 25-27, 33-34, 36, 38 and 41, using the procedures described in Examples 4, 19, 22, 30, 33, and 34.

[0270] The composition of the solid dosage form includes the following. [Table 71]

[0271] (Example 45) The semi-solid dosage form may be prepared using the mono- or dilauryl sulfate salts of afatinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxitinib, sorafenib, sunitinib, trametinib, vandetanib, or bemrafenib prepared in Examples 1, 11 to 14, 16 to 17, 21, 25 to 27, 33 to 34, 36, 38 and 41, using the procedure described in Example 23 or 31.

[0272] The composition of the semi-solid dosage form comprises the following. [Table 72]

[0273] (Example 46) Nilotinib monolauryl sulfate was prepared by the following general procedure. a. Nilotinib free base (3 g) was suspended in MeOH (30 V), and the mixture was stirred at less than 60 °C, preferably about 55 ± 5 °C for about 20 minutes. b. Sodium lauryl sulfate (1 equivalent) and 1N HBr (1 equivalent) in 3V of MeOH and 3V of purified water (containing purified water in 1N HBr) were combined, and the resulting mixture was stirred at room temperature for 10 ± 5 minutes. c. When the solid in step (b) was dissolved, the nilotinib suspension in step (a) was added to the sodium lauryl sulfate / HBr solution in step (b), and the resulting mixture was stirred at less than 60 °C, preferably 55 ± 5 °C for 30 ± 10 minutes. d. Once all solids in the reaction mixture prepared in step (c) had dissolved, the temperature was adjusted to room temperature and stirred for 60 ± 10 minutes. e. After stirring, purified water (30V) was added to the reaction mixture of step (d), and the mixture was further stirred at room temperature for about 30 minutes. f. The resulting off-white crystals formed in step (e) were collected by filtration, washed with purified water (5V), and nilotinib monolauryl sulfate (3.747 g) was obtained (yield: 88.81%) (HPLC purity: 99.52%).

[0274] (Crystallization method A) The crude product of nilotinib monolauryl sulfate prepared according to steps (a) to (f) was recrystallized according to the following procedure. 1. To the crude product of nilotinib monolauryl sulfate (2 g), MeOH (15V) was added, and the mixture was stirred at a temperature below 60 °C, preferably at about 55 ± 5 °C, until the nilotinib monolauryl sulfate dissolved (for approximately 10 ± 5 minutes). 2. Purified water (15V) was added to the solution of step (1), and the temperature was maintained below 60 °C, preferably at about 55 ± 5 °C, for 30 ± 10 minutes to obtain a precipitate, and then the temperature of the reaction mixture was adjusted to room temperature. 3. The precipitate formed in step (2) was collected by filtration and washed with purified water (2 × 2V). 4. The precipitate recovered in step (3) was dried under high vacuum to obtain white crystalline nilotinib monolauryl sulfate (1.7846 g) (yield: 89.2%) (HPLC purity: 99.89%).

[0275] The XRPD of the white crystalline nilotinib monolauryl sulfate prepared by the method outlined above is shown in Figure 13. The XRPD was obtained using Rigaku, D / MAX2200 under the following test conditions. · Cukα 1+2 = 1.54184 Å · Output: 40 kV 30 mA · Beam size: 1.0 mm · Scan axis: 2 theta / theta · Angle: 5 - 40 ° ·DivH.L. slit: 5 mm ·Rec slit: 1.0 mm

[0276] The crystalline nilotinib monolauryl sulfate prepared by crystallization method A exhibits one or more of the following 2θ peaks: 5.6 ± 0.2, 8.5 ± 0.2, 9.4 ± 0.2, 13.0 ± 0.2, 13.6 ± 0.2, 17.1 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 21.5 ± 0.2, 22.0 ± 0.2, 22.8 ± 0.2, 24.8 ± 0.2, 25.8 ± 0.2, 26.1 ± 0.2 and / or 26.6 ± 0.2.

[0277] (Crystallization method B) The crude product of nilotinib monolauryl sulfate prepared by steps (a) to (f) was recrystallized according to the following procedure. 1. To the crude product of nilotinib monolauryl sulfate (3.747 g) was added MeOH (15V), and the mixture was stirred at a temperature below 60°C, preferably about 55 ± 5°C, until the nilotinib monolauryl sulfate dissolved (for approximately 10 ± 5 minutes). 2. The solution from step (1) was filtered at a high temperature to remove dust or other particulate matter and washed with MeOH (5V). 3. The resulting filtrate was heated to a temperature below 60°C, preferably about 55 ± 5°C. 4. While maintaining a temperature of about 55 ± 5°C, purified water (30V) was added dropwise to the solution from step (3) over approximately 30 ± 10 minutes. 5. Once the purified water was added to form a precipitate, the reaction mixture was cooled to room temperature and then further cooled to 0 - 5°C to precipitate further. 6. The precipitate formed in step (5) was collected by filtration and washed with purified water (2 × 2V). 7. The precipitate collected in step (6) was dried under high vacuum to obtain white crystalline nilotinib monolauryl sulfate (3.4201 g) (yield: 91.3%) (HPLC purity: 99.93%).

[0278] (Crystallization method C) The crude product of nilotinib monolauryl sulfate prepared by steps (a) to (f) was recrystallized according to the following procedure. 1. Ethanol (35 V) was added to the crude product (2 g) of nilotinib monolauryl sulfate, and the mixture was stirred at a temperature below 60 °C, preferably about 55 ± 5 °C, until the nilotinib monolauryl sulfate dissolved (for approximately 10 ± 5 minutes). 2. Purified water (60 V) was added to the solution of step (1), and the mixture was maintained at a temperature below 60 °C, preferably about 55 ± 5 °C, for 30 ± 10 minutes to obtain a precipitate, and then the temperature of the reaction product was adjusted to room temperature. 3. The precipitate formed in step (2) was collected by filtration and washed with purified water (2 × 2 V). 4. The precipitate collected in step (3) was dried under high vacuum to obtain white crystalline nilotinib monolauryl sulfate (1.7695 g) (yield: 88.5%) (HPLC purity: 99.88%).

[0279] The XRPD pattern of the white crystalline nilotinib monolauryl sulfate prepared by crystallization method C was obtained by the procedure outlined in crystallization method A and is shown in Figure 14.

[0280] The crystalline nilotinib monolauryl sulfate prepared by crystallization method C shows one or more of the following 2θ peaks: 5.6 ± 0.2, 8.5 ± 0.2, 9.2 ± 0.2, 9.4 ± 0.2, 13.1 ± 0.2, 13.7 ± 0.2, 17.1 ± 0.2, 17.8 ± 0.2, 19.1 ± 0.2, 20.2 ± 0.2, 21.5 ± 0.2, 22.0 ± 0.2, 22.8 ± 0.2, 24.9 ± 0.2, 25.8 ± 0.2, 26.5 ± 0.2, 27.7 ± 0.2 and / or 29.0 ± 0.2.

[0281] (Crystallization method D) The crude product of nilotinib monolauryl sulfate prepared by steps (a) to (f) was recrystallized according to the following procedure. 1. Add IPA (100 V) to the crude product (2 g) of nilotinib monolauryl sulfate, and stir the mixture at a temperature below 60 °C, preferably about 55 ± 5 °C, until the nilotinib monolauryl sulfate dissolves (about 10 ± 5 minutes). 2. Add purified water (265 V) to the solution of step (1), maintain at a temperature below 60 °C, preferably about 55 ± 5 °C for 30 ± 10 minutes to obtain a precipitate, and then adjust the temperature of the reaction mixture to room temperature. 3. Collect the precipitate formed in step (2) by filtration and wash with purified water (2 × 2 V). 4. Dry the precipitate collected in step (3) under high vacuum to obtain white crystalline nilotinib monolauryl sulfate (1.6742 g) (yield: 83.7%) (HPLC purity: 99.88%).

[0282] The XRPD pattern of the white crystalline nilotinib monolauryl sulfate prepared by crystallization method D was obtained by the procedure outlined in crystallization method A and is shown in Figure 15.

[0283] The crystalline nilotinib monolauryl sulfate prepared by crystallization method D exhibits one or more of the following 2θ peaks: 5.6 ± 0.2, 8.5 ± 0.2, 9.1 ± 0.2, 9.6 ± 0.2, 13.1 ± 0.2, 13.9 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 23.0 ± 0.2, 24.1 ± 0.2, 24.7 ± 0.2, 25.8 ± 0.2, 27.7 ± 0.2, 29.0 ± 0.2, 30.0 ± 0.2, 30.7 ± 0.2, 33.8 ± 0.2, 34.6 ± 0.2 and / or 38.7 ± 0.2.

[0284] (Example 47) Dasatinib monolauryl sulfate was prepared by the following general procedure. a. Add MeOH (25 V) to dasatinib monohydrate (6 g), and stir the mixture at reflux temperature. b. Sodium lauryl sulfate (1 equivalent), 3V of MeOH, and 1N HCl (1 equivalent) in 3V of purified water (purified water is included in 1N HCl) were combined, and the resulting mixture was stirred at room temperature for 10 ± 5 minutes. c. Once all solids in step (b) had dissolved, the sodium lauryl sulfate / HCl solution from step (b) was added to the dasatinib mixture from step (a), and the resulting mixture was stirred at reflux temperature (65 - 70 °C) for approximately 30 ± 10 minutes, and then the temperature was adjusted to room temperature for 60 ± 10 minutes. d. The reaction mixture from step (c) was concentrated by a rotary evaporator (T = 45 °C) under vacuum until dry. e. The concentrated reaction product from step (d) was extracted with ethyl acetate (20V) and water (10V). f. The organic layer from step (e) was separated and washed with water (2 × 10V). g. The washed organic layer from step (f) was concentrated under vacuum by a rotary evaporator (T = 45 °C). h. The product from step (g) was dried under high vacuum to obtain white crystalline dasatinib monolauryl sulfate (8.7659 g) (yield: 98.0%) (HPLC purity: 99.61%). i. IPA (10V) was added to the dasatinib monolauryl sulfate from step (h), and the mixture was stirred at room temperature for 30 ± 10 minutes. j. The white solid precipitate in the reaction product from step (i) was collected by filtration and washed with IPA (2 × 2V). k. The washed solid precipitate from step (j) was dried under high vacuum to obtain white crystalline dasatinib monolauryl sulfate (7.89 g) (yield: 90.0%) (HPLC purity: 99.82%).

[0285] (Crystallization Method A) The crude product of dasatinib monolauryl sulfate prepared by steps (a) - (k) was recrystallized according to the following procedure. 1. MeOH (5V) was added to the crude product of dasatinib monolauryl sulfate (3 g), and the mixture was stirred at approximately 60 °C for about 10 ± 5 minutes. 2. Add isopropyl alcohol (IPA) (40 V) and hexane (40 V) to the solution of step (1), maintain the temperature at about 60 °C until a precipitate is formed, and then adjust the temperature of the reaction mixture to room temperature. 3. Adjust the temperature of the reaction mixture of step (2) to 0 - 5 °C for 30 ± 10 minutes, collect the precipitate by filtration, and wash it with hexane (2 × 2 V). 4. Dry the precipitate collected in step (3) under high vacuum to obtain white crystalline dasatinib monolauryl sulfate salt (2.7196 g) (yield: 88.8%) (HPLC purity: 99.94%).

[0286] The XRPD pattern of the dasatinib monolauryl sulfate sample prepared by crystallization method A was obtained by the procedure outlined in Example 46 and is shown in Figure 16.

[0287] The crystalline dasatinib monolauryl sulfate prepared by crystallization method A exhibits one or more of the following 2θ peaks: 6.9 ± 0.2, 8.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 12.6 ± 0.2, 13.1 ± 0.2, 14.7 ± 0.2, 15.8 ± 0.2, 16.3 ± 0.2, 17.1 ± 0.2, 17.2 ± 0.2, 17.4 ± 0.2, 18.4 ± 0.2, 19.4 ± 0.2, 20.1 ± 0.2, 21.5 ± 0.2, 22.6 ± 0.2, 23.5 ± 0.2, 24.4 ± 0.2, 25.0 ± 0.2, 26.0 ± 0.2, 26.5 ± 0.2, 26.9 ± 0.2, 27.4 ± 0.2, 27.8 ± 0.2, 28.7 ± 0.2, 29.1 ± 0.2, 30.4 ± 0.2, 31.6 ± 0.2, 34.6 ± 0.2, 37.5 ± 0.2, and / or 39.2 ± 0.2.

[0288] (Crystallization method B) The crude product of dasatinib monolauryl sulfate prepared by steps (a) - (k) was recrystallized according to the following procedure. 1. Add MeOH (5 V) to the crude product of dasatinib monolauryl sulfate (3 g), stir the mixture at about 60 °C for approximately 10 ± 5 minutes, and then adjust the temperature to room temperature. 2. While maintaining the temperature at about 60 °C, ether (60 V) was added to the solution of step (1). 3. The temperature of the reactants in step (2) was adjusted to 0 - 5 °C for 30 ± 10 minutes, and the precipitate was collected by filtration and washed with ether (2 × 2 V). 4. The precipitate recovered in step (3) was dried under high vacuum to obtain white crystalline dasatinib monolauryl sulfate salt (2.8910 g) (yield: 94.5%) (HPLC purity: 99.85%).

[0289] The XRPD pattern of the dasatinib monolauryl sulfate sample prepared by crystallization method B was obtained by the procedure outlined in Example 46 and is shown in Figure 17.

[0290] The crystalline dasatinib monolauryl sulfate prepared by crystallization method B exhibits one or more of the following 2θ peaks: 6.6 ± 0.2, 8.1 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 10.7 ± 0.2, 12.4 ± 0.2, 12.8 ± 0.2, 14.4 ± 0.2, 15.5 ± 0.2, 16.0 ± 0.2, 17.1 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.8 ± 0.2, 20.5 ± 0.2, 21.3 ± 0.2, 22.3 ± 0.2, 23.2 ± 0.2, 24.1 ± 0.2, 24.8 ± 0.2, 25.8 ± 0.2, 26.1 ± 0.2, 26.7 ± 0.2, 27.2 ± 0.2, 27.5 ± 0.2, 28.4 ± 0.2, 28.8 ± 0.2, 30.8 ± 0.2, 31.4 ± 0.2, 32.5 ± 0.2, 33.3 ± 0.2, 34.1 ± 0.2, 34.4 ± 0.2, and / or 39.5 ± 0.2.

[0291] (Example 47A) The solubility of crystalline dasatinib monolauryl sulfate prepared by Method A of Example 47, amorphous dasatinib monolauryl sulfate prepared by Example 12, amorphous dasatinib dilauryl sulfate prepared by Example 13, and the free base of dasatinib monohydrate of a commercially available sample was measured by adding the sample to 500 mL of the designated solvent at 37 °C and shaking or stirring for at least 18 hours to reach saturation. The reactants were filtered and the filtrate was measured by HPLC. The results of the solubility measurement are as follows.

Table 73

[0292] As a result of the solubility test, it was found that the aqueous solubility of dasatinib varies depending on the pH.

[0293] (Example 48) The dasatinib monolauryl sulfate ester salt was prepared by the following general procedure. a. Methanol (25 V) was added to dasatinib monohydrate (3 g), and the mixture was stirred at reflux temperature. b. Sodium lauryl sulfate (1 equivalent), 1N HCl (1 equivalent) in 3 V of methanol and 3 V of purified water (including purified water in 1N HCl) were combined, and the resulting mixture was stirred at room temperature for 10 ± 5 minutes. c. When the solid in step (b) was dissolved, the sodium lauryl sulfate / HCl solution in step (b) was added to the dasatinib mixture in step (a), and the resulting mixture was stirred at reflux temperature (65 - 70 °C) for 30 ± 10 minutes, and then the temperature was adjusted to room temperature for 60 ± 10 minutes. d. The reaction mixture in step (c) was concentrated in vacuo by a rotary evaporator (T = 45 °C) until dry. e. The concentrated reaction product in step (d) was extracted with ethyl acetate (20 V) and water (10 V). f. The organic layer in step (e) was washed separately with water (2 × 10 V). g. The washed organic layer in step (f) was concentrated in vacuo by a rotary evaporator (T = 35 °C). h. To the product of step (g), MeOH (10V) was added and heated to 60 °C until dissolved. i. The solution of step (h) was filtered under high-temperature conditions to remove dust or other particulate matter and washed with MeOH (5V). j. The filtrate of step (i) was concentrated in vacuo using a rotary evaporator (T = 45 °C) until dry. k. The product of step (j) was dried under high vacuum to obtain white crystalline dasatinib monolauryl sulfate (4.419 g) (yield: 98.8%) (HPLC purity: 99.66%).

[0294] (Crystallization method C) The crude product of dasatinib monolauryl sulfate prepared by steps (a) to (k) was recrystallized according to the following procedure. 1. To the crude product of dasatinib monolauryl sulfate (3 g), MeOH (5V) was added and the mixture was stirred at about 60 °C for approximately 10 ± 5 minutes. 2. IPA (5V) and hexane (25V) were added to the solution of step (1), the temperature was maintained at about 60 °C until a precipitate formed, and then the temperature of the reaction mixture was adjusted to room temperature. 3. The temperature of the reaction mixture of step (2) was adjusted to 0 - 5 °C for 30 ± 10 minutes, the precipitate was collected by filtration and washed with hexane (2 × 2V). 4. The precipitate collected in step (3) was dried under high vacuum to obtain white crystalline dasatinib monolauryl sulfate (2.81 g) (yield: 93.7%) (HPLC purity: 99.90%). 5. Steps 1 - 4 were repeated to obtain white crystalline dasatinib monolauryl sulfate (2.68 g) (yield: 95.4%) (HPLC purity: 99.96%).

[0295] The XRPD pattern of the dasatinib lauryl sulfate sample prepared by crystallization method C was obtained by the procedure outlined in Example 46 and is shown in Figure 18.

[0296] The crystalline dasatinib monolauryl sulfate prepared by crystallization method C exhibits one or more of the following 2θ peaks: 5.9±0.2, 6.5±0.2, 7.9±0.2, 9.5±0.2, 10.2±0.2, 12.3±0.2, 12.7±0.2, 14.4±0.2, 14.9±0.2, 16.0±0.2, 16.8±0.2, 17.1±0.2, 18.1±0.2, 19.1±0.2, 19.8±0.2, 21.1±0.2, 22.2±0.2, 23.2±0.2, 24.1±0.2, 24.7±0.2, 25.6±0.2, 26.6±0.2, 27.6±0.2, 28.1±0.2, 28.5±0.2, 28.9±0.2, 30.0±0.2, 30.8±0.2, 31.3±0.2, 34.2±0.2, 35.4±0.2, 37.2±0.2 and / or 38.9±0.2.

[0297] (Crystallization method D) The crude product of dasatinib monolauryl sulfate ester salt was prepared by steps (a) to (k), and this process produced white crystalline dasatinib monolauryl sulfate (4.4373 g) (yield: 99.2%) (HPLC purity: 99.58%), and was recrystallized according to the following procedure. 1. IPA (6V) was added to the crude product of dasatinib monolauryl sulfate (3 g), and the mixture was stirred at room temperature for about 30±10 minutes. 2. The precipitated white solid was filtered and washed with IPA (2V). 3. The precipitate recovered in step (2) was dried under high vacuum to obtain white crystalline dasatinib monolauryl sulfate ester salt (2.83 g) (yield: 94.3 g) (HPLC purity: 99.75%). 4. Steps 1 to 3 were repeated to obtain white crystalline dasatinib monolauryl sulfate ester salt (2.70 g) (yield: 95.4 g) (HPLC purity: 99.81%).

[0298] The XRPD pattern of the dasatinib lauryl sulfate sample prepared by crystallization method D was obtained by the procedure outlined in Example 46 and is shown in Figure 19.

[0299] The crystalline dasatinib monolauryl sulfate prepared by crystallization method D exhibits one or more of the following 2θ peaks: 6.6 ± 0.2, 8.0 ± 0.2, 9.5 ± 0.2, 10.2 ± 0.2, 10.6 ± 0.2, 12.3 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 15.5 ± 0.2, 16.0 ± 0.2, 17.1 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 19.7 ± 0.2, 21.2 ± 0.2, 22.2 ± 0.2, 23.1 ± 0.2, 24.0 ± 0.2, 24.7 ± 0.2, 25.7 ± 0.2, 26.6 ± 0.2, 27.1 ± 0.2, 28.4 ± 0.2, 28.7 ± 0.2, 30.9 ± 0.2, 31.3 ± 0.2, 32.4 ± 0.2, 37.2 ± 0.2, and / or 39.2 ± 0.2.

[0300] (Example 48A) The dasatinib monolauryl sulfate ester salt was prepared by the following general procedure. a. MeOH (25V, 1980 g) was added to dasatinib monohydrate (1 equivalent, 100 g), and the mixture was stirred at reflux temperature (60 °C ± 5 °C). b. Sodium lauryl sulfate (1 equivalent, 57 g), and 1N HCl (1 equivalent, 197 ml) and purified water (1.03V, 103 g) in MeOH (3V, 327 g) were combined, and the resulting mixture was stirred at room temperature for 10 ± 5 minutes. c. Once the solid in step (b) had dissolved, the sodium lauryl sulfate / HCl solution from step (b) was added to the dasatinib mixture from step (a), and the resulting mixture was stirred at reflux temperature (60 °C ± 5 °C) for about 30 ± 10 minutes, and then the temperature was adjusted to room temperature over 60 ± 10 minutes. d. The reaction mixture from step (c) was concentrated in vacuo using a rotary evaporator (T = 40 °C) until dry. e. The concentrated reaction product from step (d) was extracted with ethyl acetate (20V, 1804 g) and stirred at room temperature for 10 ± 5 minutes. f. The organic layer from step (e) was separated and washed with water (3 × 10V, 3 × 1000 g). g. The washed organic layer from step (f) was concentrated in vacuo using a rotary evaporator (T = 35 °C) until dry. h. MeOH (5 V, 589 g) was added to the product from step (g) and heated to 60 °C until dissolved. i. The filtrate from step (h) was concentrated in vacuo using a rotary evaporator (T = 45 °C) until dry to obtain a crude product of dasatinib monolauryl sulfate salt.

[0301] (Crystallization Method E) The crude product of dasatinib monolauryl sulfate salt prepared by steps (a) to (i) was recrystallized according to the following procedure. 1. MeOH (3 V, 353 g) was added to the crude product of dasatinib monolauryl sulfate and the mixture was stirred at 60 °C ± 5 °C for 10 ± 5 minutes. 2. IPA (2 V, 234 g) was slowly added to the methanol solution of the crude product and the mixture was stirred at 60 °C ± 5 °C for 10 ± 5 minutes. 3. Hexane (40 V, 4000 g) was slowly added to the crude product at 45 °C ± 5 °C for 10 ± 5 minutes (addition time: 30 ± 10 minutes) to obtain a precipitate of the pure product, and then adjusted to room temperature for 30 ± 5 minutes. 4. The temperature of the reaction product from step (3) was adjusted to 0 - 5 °C for about 30 ± 10 minutes, and the precipitate was collected by filtration and washed with hexane (2 × 2 V, 2 × 200 g). 5. The precipitate collected in step (4) was dried under high vacuum to obtain white crystalline dasatinib monolauryl sulfate salt (yield: 79.5%, 118.5 g) (HPLC purity: 100.00%, pH value: 4.38).

[0302] The XRPD pattern of the dasatinib lauryl sulfate salt sample prepared by Crystallization Method E was obtained by the procedure outlined in Example 46 and is shown in Figure 20.

[0303] The crystalline dasatinib monolauryl sulfate prepared by crystallization method E exhibits one or more of the following 2θ peaks: 6.3±0.2, 9.5±0.2, 10.1±0.2, 12.2±0.2, 12.7±0.2, 14.4±0.2, 15.9±0.2, 16.7±0.2, 17.0±0.2, 18.0±0.2, 19.0±0.2, 21.0±0.2, 22.2±0.2, 23.1±0.2, 23.9±0.2, 24.6±0.2, 25.6±0.2, 27.5±0.2, 28.5±0.2, 28.7±0.2, 31.2±0.2, 34.2±0.2, 37.2±0.2, and / or 38.7±0.2.

[0304] (Example 49) The capsule formulation of dasatinib monolauryl sulfate was prepared by wet granulating 2,982 mg of dasatinib monolauryl sulfate prepared according to the procedure of Example 12 with 1,500 mg of poloxamer 407 (Kolliphor® P407) and poloxamer 188 (Kolliphor® P188) in alcohol (95%) in a suitable container for at least 2 minutes.

[0305] 1,800 mg of anhydrous lactose (SuperTab® 21AN, anhydrous), 2,958 mg of microcrystalline cellulose (Comprecel® M102D+), 600 mg of sodium starch glycolate (Part I), and 120 mg of colloidal silicon dioxide (AD101) (Part I) were passed through a 40-mesh screen and added to the granules of dasatinib monolauryl sulfate and mixed. The resulting blend was dried in an oven at 50°C to evaporate the alcohol.

[0306] 600 mg of sodium glycolate starch (Part II) and 120 mg of colloidal silicon dioxide (AD101) (Part II) were passed through a 40-mesh screen and added to a dry blend containing granules of dasatinib monolauryl sulfate and mixed well. After mixing, the resulting mixture was passed through a 40-mesh screen and collected in a suitable container. 120 mg of magnesium stearate was passed through a 40-mesh screen, added to the container, and blended with the dasatinib monolauryl sulfate mixture to obtain the final blend. The final blend was filled into size 2 hard gelatin capsules.

[0307] The composition of the capsules is as follows. [Table 74]

[0308] (Example 50) The capsules prepared in Example 49 containing dasatinib monolauryl sulfate were administered to 9 healthy subjects under fasting, fed, and fasting conditions pre-treated with omeprazole. Omeprazole is a commercially available proton pump inhibitor (PPI). This is a two-part study. In Part 1, it is a bioavailability study in healthy subjects under fasting and fed conditions with single-dose, open-label, randomized, 3-treatment, 3-group, 3-period crossover method. All subjects were randomly assigned to groups as shown in the following table, and a 7-day washout period was provided between periods. Part 2 is a drug-drug interaction study in healthy subjects with continuous 2 treatments. All subjects were orally administered 40 mg of omeprazole QD for 5 days to reach a steady state, and approximately 22 hours after the last omeprazole administration, 20 mg of dasatinib capsules were orally administered. The reference drug (Ref) is Sprycel® which is dasatinib monohydrate at a dose of 50 mg, and the test drug (Test) is a capsule prepared by the procedure of Example 49 and containing an amount of dasatinib monolauryl sulfate corresponding to approximately 20 mg of dasatinib monohydrate. The 9 healthy subjects participating in this study were randomly assigned to one of the groups as shown in the following table.

[0309]

Table 75

[0310] During each prescription period, blood samples were collected at 0 (before administration), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. The AUC of each subject 0-24 , AUC 0-∞ , C max , T max , and T 1 / 2 were determined based on non-compartmental analysis. The test results were standardized to a 50 mg dose and summarized in the following table.

Table 76

[0311] The Ln-transformed AUC 0-t , AUC 0-∞ , and C max were analyzed by ANOVA. The model includes group, subject (group), period, and treatment effect. The comparison of data obtained from the administration of the test drug and the reference drug is shown in the following table.

Table 77

[0312] The data indicate that the composition of the present invention increases C max by 1.01-fold and decreases the AUC by 0.88-fold compared to dasatinib monohydrate approved by the US FDA. The data also indicate that the composition of the present invention is not affected by acid suppressants or PPIs, i.e., the composition of the present invention shows equivalent pharmacokinetics under fasting conditions and under fasting conditions with co-administration of omeprazole.

[0313] The data of individual subjects in this test standardized to a 50 mg dose are as follows.

Table 78-1

Table 78-2

Table 78-3

Table 78-4

[0314] The graph of the average of the standardized plasma profiles provided in Example 50 is shown in Figure 21.

[0315] (Example 51) 7730 mg of dasatinib monolauryl sulfate sieved through a 60-mesh sieve prepared according to the procedure of crystallization method E of Example 48A was mixed with 2500 mg of anhydrous lactose passed through a 40-mesh screen, 6770 mg of microcrystalline cellulose, 3000 mg of poloxamer 407, 2500 mg of poloxamer 188, 750 mg of hydroxypropylcellulose (HPC-H), 500 mg of sodium glycolate starch (Part I), and 250 mg of colloidal silicon dioxide (Part I) for 2 minutes to prepare a capsule dosage form of dasatinib monolauryl sulfate.

[0316] The resulting mixture was wet granulated with 2500 mg of an alcohol solution prepared by mixing alcohol (95%) and purified water at a weight ratio of 1:1. The obtained granules were dried in an oven at 50 °C to evaporate alcohol and water.

[0317] The dried granules were sieved through a 40-mesh sieve and mixed with 500 mg of sodium glycolate starch (Part II) and 250 mg of colloidal silicon dioxide (Part II) sieved through a 40-mesh sieve. 250 mg of magnesium stearate sieved through a 40-mesh sieve was added to the resulting mixture and blended to obtain a final blend. The final blend was filled into size 1 hard gelatin capsules.

[0318] The composition of the capsule is as follows.

Table 79

[0319] (Example 51A) The capsules prepared in Example 51 containing dasatinib monolauryl sulfate were administered to healthy subjects under fasting, fed, and fasting conditions pre - administered with omeprazole. Omeprazole is a commercially available proton pump inhibitor (PPI). This is a two - part study. In the first part, it is a bioavailability study in 10 (ten) healthy subjects under fasting and fed conditions, single - dose, open - label, randomized, 4 - treatment, 4 - group, 4 - period crossover method. All subjects were randomly assigned to groups as shown in the following table, and a wash - out period of 3 or 4 days was provided between periods. The second part is a drug - drug interaction study with two consecutive treatments in 9 (nine) healthy subjects. All subjects were orally administered 40 mg QD of omeprazole for 5 days to reach a steady state, and approximately 22 hours after the last omeprazole administration, 50 mg dasatinib capsules were orally administered. The reference drug (Ref) is Sprycel® which is dasatinib monohydrate at a strength of 50 mg (free base), and the test drug (Test) is a capsule prepared according to the procedure of Example 51 and containing approximately 50 mg of dasatinib (free base). The 10 (ten) or 9 (nine) healthy subjects participating in the first or second part of this study were randomly assigned to one of the groups as shown in the following table.

[0320]

Table 80 - 1

Table 80 - 2

[0321] During each dosing period, blood samples were collected at 0 (before dosing), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. The AUC of each subject 0-24 、AUC0-∞ , C max , T max , and T 1 / 2 were determined based on non-compartmental analysis. The test results are summarized in the following table.

Table 81

[0322] Log-transformed AUC 0-t , AUC 0-∞ , and C max were analyzed by ANOVA. The model includes group, subject (group), period, and treatment effect. A comparison of the data obtained from the administration of the test drug and the reference drug is shown in the following table.

Table 82

[0323] The data indicate that the composition of the present invention reduces C max to 0.79-fold and reduces the AUC to 0.84-fold compared to dasatinib monohydrate approved by the US FDA under fasting conditions. The data indicate that the composition of the present invention reduces C max to 0.76-fold and reduces the AUC to 0.98-fold compared to dasatinib monohydrate approved by the US FDA under fed conditions. The data also indicate that the composition of the present invention has a positive effect of an acid suppressant or PPI, i.e., the composition of the present invention, under fasting conditions with co-administration of omeprazole, increases C max to 1.17-fold and increases the AUC to 1.13-fold compared to under fasting conditions.

[0324] A graph of the average plasma profile under fasting conditions in this example is shown in FIG. 22A.

[0325] A graph of the average plasma profile under fed conditions in this example is shown in FIG. 22B.

[0326] The graph of the mean plasma profile under fasting conditions with co - administered 40 mg omeprazole in this example is shown in Figure 22C.

[0327] Data for individual subjects at the 50 mg dose obtained from the study are shown below.

Table 83 - 1

Table 83 - 2

Table 83 - 3

Table 83 - 4

Table 83 - 5

Table 83 - 6

[0328] (Example 52) 9276 mg of dasatinib monolauryl sulfate passed through a 325 - mesh sieve and prepared according to the procedure of Example 12 was blended with 1440 mg of croscarmellose sodium and 6000 mg of anhydrous lactose in a suitable container for about 1 minute to prepare a capsule formulation of dasatinib monolauryl sulfate. 6342 mg of microcrystalline cellulose passed through a 40 - mesh sieve and 720 mg of hydroxypropyl cellulose (HPC - H) were added to the blend in the container and blended for an additional 2 minutes.

[0329] 240 mg of magnesium stearate passed through a 40 - mesh sieve was added to the blend and blended further to obtain the final blend. The final blend was filled into size 1 hard gelatin capsules.

[0330] The composition of the capsule is as follows.

Table 84

[0331] (Example 52A) The capsules prepared in Example 52 containing dasatinib monolauryl sulfate were administered to 6 healthy subjects under fasting conditions. This administration was a single-dose, non-blind, randomized, two-treatment, two-group, two-period crossover study, which was a bioavailability study in healthy subjects under fasting conditions. All subjects were randomly assigned to the groups shown in the following table, and a 3-day washout period was provided between periods. The reference drug (Ref) is Sprycel® which is dasatinib monohydrate at a strength of 50 mg (free base), and the test drug (Test) is the capsule prepared in Example 52, which contains approximately 50 mg of dasatinib (free base). The 6 healthy subjects participating in this study were randomly assigned to one of the groups shown in the following table.

[0332]

Table 85

[0333] During each dosing period, blood samples were collected at 0 (before dosing), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. The AUC 0-24 , AUC 0-∞ , C max , T max , and T 1 / 2 were determined based on non-compartmental analysis. The test results were summarized in the following table.

Table 86

[0334] The ln-transformed AUC 0-t , AUC 0-∞ , and C max were analyzed by ANOVA. The model included group, subject (group), period, and treatment effect. A comparison of the data obtained from the administration of the test drug and the reference drug is shown in the following table.

Table 87

[0335] The data indicate that the composition of the present invention reduces C by 0.46-fold and AUC by 0.79-fold compared to dasatinib monohydrate approved by the US FDA. max

[0336] The graph of the average plasma profile in this example is shown in Figure 23.

[0337] The data of individual subjects at a 50 mg dose obtained from the test are shown below.

Table 88-1

Table 88-2

[0338] (Example 53) The capsule formulation of dasatinib monolauryl sulfate was prepared as follows. (i) Dissolve 6 mg of butylated hydroxytoluene (BHT) in 9756 mg of medium-chain triglycerides. (ii) Using a water bath (60 °C), melt 3600 mg of lauroyl polyoxyl glyceride (Gelucire 44 / 14). (iii) Add the melted material from step (ii) to the solution from step (i) to obtain a homogeneous solution. (iv) Add 4638 mg of 60-mesh sieved dasatinib monolauryl sulfate prepared by the procedure of Example 48A (Crystallization Method E) to the solution from step (iii) to obtain a homogeneous semi-solid suspension. The semi-solid suspension was filled into size 1 hard gelatin capsules.

[0339] The composition of the capsule contents is as follows.

Table 89

[0340] (Example 53A) The capsules prepared in Example 53 containing dasatinib monolauryl sulfate were administered to 4 healthy subjects under fasting conditions. This administration was a bioavailability test in healthy subjects under fasting conditions using a single-dose, non-blind, randomized, 2-treatment, 2-group, 2-period crossover method. All subjects were randomly assigned to the groups shown in the following table, and a 3-day washout period was provided between periods. The reference drug (Ref) is Sprycel® which is dasatinib monohydrate with a strength of 50 mg (free base), and the test drug (Test) is the capsule prepared according to the procedure of Example 53 and contains approximately 20 mg of dasatinib (free base). The 4 healthy subjects participating in this test were randomly assigned to the groups shown in the following table.

[0341]

Table 90

[0342] During each treatment period, blood samples were collected at 0 (before dosing), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. The AUC 0-24 , AUC 0-∞ , C max , T max , and T 1 / 2 were determined based on non-compartmental analysis. The test results were summarized in the following table.

Table 91

[0343] The ln-transformed AUC 0-t , AUC 0-∞ , and C max were analyzed by ANOVA. The model included group, subject (group), period, and treatment effect. The comparison of the data obtained from the administration of the test drug and the reference drug is shown in the following table.

Table 92

[0344] The data shows that the composition of the present invention reduces C by 0.99-fold and AUC by 0.98-fold compared to dasatinib monohydrate approved by the US FDA. max as shown by indicating that it shows a decrease.

[0345] A graph of the average plasma profile in this example is shown in FIG. 24.

[0346] Data for individual subjects at a 50 mg dose obtained from the study are shown below.

Table 93-1

Table 93-2

[0347] (Example 54) It was confirmed that the following impurities are present in the dasatinib monolauryl sulfate prepared according to Examples 12 and 47.

[0348]

Table 94

[0349] RRT was measured using HPLC with the following parameters.

Table 95

[0350] Mobile phase A is an aqueous solution of 0.05 M ammonium acetate (pH 5.25) / acetonitrile / methanol with a volume ratio of 90 / 5 / 5. Mobile phase B is an aqueous solution of 0.05 M ammonium acetate (pH 5.25) / acetonitrile / methanol with a volume of 10 / 85 / 5.

[0351] The dosage forms prepared in Examples 49, 51 to 52 and the dasatinib lauryl sulfate prepared in Examples 12 to 13 were tested for impurities and stability using the above HPLC method.

[0352] Weighed approximately 30.92 mg of dasatinib monolauryl sulfate or 41.84 mg of dasatinib dilauryl sulfate (equivalent to 20 mg of dasatinib) into a 100 mL brown volumetric flask respectively, added approximately 80 mL of methanol, sonicated for about 5 minutes, and stirred at 800 rpm for 5 minutes until completely dissolved to prepare the test samples. Methanol was further added so that each milliliter of the test sample contained approximately 0.2 mg of dasatinib.

[0353] The test results are as follows.

Table 96-1

Table 96-2

[0354] For the capsules of dasatinib lauryl sulfate, each of the individual impurities 1, 2, 3, 4, or 5 should be 0.5% or less, preferably each individual impurity should be 0.35% or less, and most preferably each individual impurity should be 0.25% or less, and the total amount of impurities should be 1.0% or less, preferably 0.75% or less, and most preferably 0.60% or less.

[0355] In an in vitro test using a USP Type II Apparatus (Paddle) (500 mL of 0.1 N HCl, 75 rpm, with or without a sinker, 37 °C), the capsules of dasatinib lauryl sulfate should release 90% or more, preferably 85% or more, and most preferably 80% or more of dasatinib within 45 minutes.

[0356] (Example 55) The capsule dosage form of dasatinib monolauryl sulfate was prepared by blending dasatinib monolauryl sulfate prepared according to the procedure of Example 48A (Crystallization Method E) with specific additives and filling hard gelatin capsules in the following amounts.

Table 97

[0357] (Example 55E) The capsule dosage form of dasatinib monolauryl sulfate was prepared by adding dasatinib monolauryl sulfate prepared according to the procedure of Example 48A (Crystallization Method E) to molten Type I polyoxyl stearate (Gelucire 48 / 16). The composition was cooled and mixed with microcrystalline cellulose, hydrogenated vegetable oil (LUBRITAB), and colloidal silicon dioxide, and filled into size 2 hard gelatin capsules with a capsule content having the following composition.

Table 98

[0358] (Example 55F) The capsule dosage form of dasatinib monolauryl sulfate was prepared according to the procedure of Example 55, except that lauroyl polyoxyl glyceride was replaced with Type I polyoxyl stearate (Gelucire 48 / 16). The composition of the capsule is as follows.

Table 99

[0359] (Example 56) The dosage forms prepared in Examples 49, 51, 52, 53, and 55 were tested using a USP Type II Apparatus (Paddle) (500 mL of 0.1 N HCl, 75 rpm, using a sinker, 37 °C). The results of this dissolution test are as follows.

Table 100

[0360] (Example 57) The content of the capsule of dasatinib monolauryl sulfate prepared by dissolving dasatinib monolauryl sulfate (by the procedure of Example 48A (Crystallization Method E)) in specific additives and solvents, evaporating the solvent to form granules, and blending the granules with additional granular additives to form a blend for filling into hard gelatin capsules is described in the following table. [Table 101]

[0361] The dosage form prepared in Example 57 was tested using a USP Type II Apparatus (Paddle) (500 mL of 0.1 N HCl, 75 rpm, using a sinker, 37 °C). The results of this dissolution test are as follows. [Table 102]

[0362] (Example 58) In the same manner as the procedures described in Examples 33, 49, and 55, dasatinib monolauryl sulfate (Example 48A, by the procedure of Crystallization Method E) was dissolved in specific additives and solvents and wet granulated, the solvent was evaporated to form granules, and the granules were blended with additional granular additives to form a blend for filling into hard gelatin capsules. The content of the capsule of dasatinib monolauryl sulfate thus prepared is described in the following table. [Table 103-1] [Table 103-2]

[0363] The dosage form prepared in Example 58 was tested using a USP Type II Apparatus (Paddle) (0.1 N HCl of 500 mL, 75 rpm, using a sinker, 37°C). The results of this dissolution test are as follows.

Table 104

[0364] (Example 59A) 2319 mg of dasatinib monolauryl sulfate prepared according to the procedure of Example 48, crystallization method E, was pulverized, and 1500 mg of polyoxyl stearate type I (Gelucire 48 / 16), 375 mg of poloxamer 407, 1806 mg of microcrystalline cellulose, and 150 mg of sodium glycolate starch (Part I) were mixed with a small mixer for 15 seconds to prepare a capsule dosage form of dasatinib monolauryl sulfate. 600 mg of purified water was added to the mixer and granulated for 15 seconds. The mixture was dried in an oven at 50°C to evaporate water, pulverized into a powder, and sieved through a 40-mesh sieve. 750 mg of microcrystalline cellulose, 375 mg of sodium glycolate starch (Part II), and 150 mg of colloidal silicon dioxide were sieved through a 40-mesh sieve and mixed well with the mixture. 75 mg of sodium stearyl fumarate was sieved through a 40-mesh sieve and placed in a container, and blended with the powder to obtain a final blend. The dry solid blend was filled into size 1 hard gelatin capsules.

[0365] The composition of the capsule contents is as follows.

Table 105

[0366] (Example 59B) A capsule dosage form of dasatinib monolauryl sulfate with the following composition was prepared by the same procedure as described in Example 59A. The composition of the capsule contents is as follows.

Table 106

[0367] (Example 59C) The capsule formulation of dasatinib monolauryl sulfate with the following composition was prepared by the same procedure as described in Example 59A. The composition of the capsule contents is as follows.

Table 107

[0368] The dosage forms prepared in Examples 59A - 59C were tested using USP Type II Apparatus (Paddle) (500 mL of 0.1 N HCl, 75 rpm, using a sinker, 37 °C). The results of this dissolution test are as follows.

Table 108

[0369] (Example 60) The capsules of nilotinib monolauryl sulfate were prepared with the following composition according to the procedure outlined in Example 36.

Table 109

[0370] The dosage forms prepared in Examples 60A - 60I were tested using USP Type II Apparatus (Paddle) (675 mL of 0.1 N HCl, 75 rpm, using a sinker, 37 °C), or USP Type II Apparatus (Paddle) (900 mL of 0.1 N HCl and 0.1% Tween® 80, 75 rpm, using a sinker, 37 °C). The results of this dissolution test are as follows.

Table 110 - 1

Table 110 - 2

[0371] (Example 61A) The capsules prepared in Example 60A containing nilotinib monolauryl sulfate were administered to 9 healthy subjects under fed and fasted conditions. The study was conducted in a randomized, open-label, single-dose, 3-treatment, 3-group, 3-period crossover design with at least a 5-day washout period between administrations. The reference drug (Ref) was TASIGNA® capsules, nilotinib HCl at a strength of 200 mg (free base). The test drug (Test) was a capsule prepared according to the procedure of Example 60A and containing approximately 80 mg of nilotinib free base. The 9 healthy subjects participating in this study were randomly assigned to one of the groups as shown in the following table.

Table 111

[0372] During each dosing period, blood samples were collected at 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. The AUC 0-48 , AUC 0-∞ , C max , T max , and T 1 / 2 were determined based on non-compartmental analysis. The study results were normalized to the 200 mg dose and summarized in the following table.

Table 112

[0373] The ln-transformed AUC 0-t , AUC 0-∞ , and C max were analyzed by ANOVA. The model included group, subject (group), period, and treatment effect. The comparison of the data obtained from the administration of the test drug and the reference drug is shown in the following table.

Table 113

[0374] The data indicate that the composition of the present invention increases C by 2.5-fold and increases the AUC by 2.0-fold compared to nilotinib HCl approved by the US FDA. The data also indicate that the composition of the present invention shows no food effect, i.e., the composition of the present invention shows equivalent pharmacokinetics under fasting and fed conditions. max The individual subject data (normalized at a 200 mg dose) obtained from the study are shown below.

[0375] Table 114-1 Table 114-1 Table 114-2 Table 114-3

[0376] A graph of the mean plasma profile in Example 61A is shown in Figure 25.

[0377] (Example 61B) Capsules prepared in Example 60F containing nilotinib monolauryl sulfate were administered to 9 healthy subjects under fasting and fed conditions. The administration was a single-dose, open-label, randomized, 3-treatment, 3-group, 3-period crossover study, a bioavailability study in healthy subjects under fasting and fed conditions. All subjects were randomly assigned to the groups shown in the following table, and a washout period of at least 5 days was provided between periods. The reference drug (Ref) is TASIGNA® capsules, nilotinib HCl at a strength of 200 mg (free base), and the test drug (Test) is a capsule prepared by the procedure of Example 60F and containing approximately 80 mg of nilotinib free base. The 9 healthy subjects participating in this study were randomly assigned to one of the groups as shown in the following table.

[0378]

Table 115

[0379] During each prescription period, blood samples were collected at 0 (before administration), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after administration. The AUC 0-48 , AUC 0-∞ , C max , T max , and T 1 / 2 of each subject were determined based on non-compartmental analysis. The test results were summarized in the following table.

Table 116

[0380] The ln-transformed AUC 0-t , AUC 0-∞ , and C max were analyzed by ANOVA. The model included group, subject (group), period, and treatment effect. The comparison of data obtained from the administration of the test drug and the reference drug is shown in the following table.

Table 117

[0381] The individual data of the subjects obtained in this study (standardized at a dose of 200 mg) are as follows.

Table 118-1

Table 118-2

Table 118-3

[0382] A graph of the mean plasma profile in Example 61B is shown in Figure 26.

[0383] (Example 61C) The capsules prepared in Example 60G containing nilotinib monolauryl sulfate were administered to 9 healthy subjects under fasting and fed conditions. This administration was a single-dose, non-blind, randomized, 3-treatment, 3-group, 3-period crossover study, a bioavailability study in healthy subjects under fasting and fed conditions. All subjects were randomly assigned to the groups shown in the following table, with a washout period of at least 5 days between periods. The reference drug (Ref) is TASIGNA® capsules, nilotinib HCl at a strength of 200 mg (free base), and the test drug (Test) is a capsule prepared according to the procedure of Example 60G and containing approximately 80 mg of nilotinib free base. The 9 healthy subjects participating in this study were randomly assigned to one of the groups as shown in the following table.

[0384]

Table 119

[0385] During each treatment period, blood samples were collected at 0 (before dosing), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. The AUC 0-48 , AUC 0-∞ , C max , T max , and T 1 / 2 for each subject were determined based on non-compartmental analysis. The test results are summarized in the following table.

Table 120

[0386] The ln-transformed AUC 0-t , AUC 0-∞ , and C max were analyzed by ANOVA. The model included group, subject (group), period, and treatment effect. A comparison of the data obtained from the administration of the test drug and the reference drug is shown in the following table.

Table 121

[0387] The individual data of the subjects obtained in this test (standardized at a dose of 200 mg) are as follows.

Table 122-1

Table 122-2

Table 122-3

[0388] The graph of the average plasma profile in Example 61C is shown in Figure 27.

[0389] (Example 62) In the dosage forms of nilotinib lauryl sulfate salt and nilotinib lauryl sulfate prepared according to the present invention, the following impurities were confirmed to be present.

Table 123

[0390] The above RRT, nilotinib lauryl sulfate salt and dosage forms prepared in Examples 60F and 60G were measured using HPLC with the following parameters, or tested for impurities and stability.

Table 124

[0391] Mobile phase A is 0.25% formic acid / acetonitrile in a volume ratio of 90 / 10. Mobile phase B is 0.1% formic acid / acetonitrile in a volume ratio of 10 / 90.

[0392] Weigh 7.5 mg of nilotinib monolauryl sulfate (equivalent to 5 mg of nilotinib), transfer it to a 50 mL brown volumetric flask, add 40 mL of diluent (ethanol), perform ultrasonic treatment for 5 minutes, and stir at 800 rpm for about 5 minutes until nilotinib monolauryl sulfate dissolves, thereby preparing a test sample of nilotinib monolauryl sulfate prepared in Example 46 (crystallization method B). Further add diluent so that there is about 0.10 mg of nilotinib per 1 mL of the test sample.

[0393] Test samples of the dosage forms prepared in Examples 60F and 60G were prepared by the following procedure. 1. Cut the tip of the capsule with scissors, squeeze out the contents through the hole and put them into a 100 mL volumetric flask. Cut the capsule into two pieces and add them to the flask. Add 80% ethanol, perform ultrasonic treatment for 10 minutes, and stir at 800 rpm for 30 minutes to completely dissolve the contents. 2. Dilute to the volume with ethanol, invert the flask more than 10 times to mix well. 3. Pipette 3 mL and put it into a 25 mL brown volumetric flask, add ethanol, invert the flask more than 10 times to mix well. The test sample contains about 0.096 mg of nilotinib per 1 mL.

[0394] The nilotinib dilauryl sulfate prepared in Example 26 was tested for impurities and stability using HPLC with the following parameters. [Table 125]

[0395] Weigh 10 mg of nilotinib dilauryl sulfate (equivalent to 5 mg of nilotinib), transfer it to a 25 mL brown volumetric flask, add 20 mL of diluent (ethanol), sonicate for about 5 minutes, and stir at 800 rpm for about 5 minutes until the nilotinib dilauryl sulfate dissolves, thereby preparing a test sample of the nilotinib dilauryl sulfate prepared in Example 26. Further add diluent so that the test sample contains about 0.20 mg of nilotinib per 1 mL.

[0396] The test sample was tested according to the above procedure, and the following results were obtained.

Table 126-1

Table 126-2

[0397] The capsules were closed so that children could not open them and stored in high-density polyethylene (HDPE) bottles (126 c.c., containing 2 - 3 g of silica gel) induction-sealed with foil.

[0398] The above data indicate that nilotinib monolauryl sulfate is more stable than dilauryl sulfate, and that the individual impurities of both the monolauryl sulfate salt and the dilauryl sulfate salt of the present invention should be 0.5% or less, preferably 0.35% or less for individual impurities, most preferably 0.30% or less for individual impurities, and the total amount of impurities should be 1.0% or less, preferably 0.75% or less, most preferably 0.60% or less.

[0399]

Table 127

[0400] The capsules were closed so that children could not open them and stored in high-density polyethylene (HDPE) bottles (126 c.c., containing 2 - 3 g of silica gel) induction-sealed with foil.

[0401] Using the HPLC method described above, the nilotinib monododecyl sulfate dosage form should have individual impurities of 0.5% or less, preferably individual impurities of 0.35% or less, most preferably individual impurities of 0.25% or less, and the total amount of impurities should be 1.0% or less, preferably 0.75% or less, and most preferably 0.60% or less.

[0402] Example 63A 7730 mg of dasatinib monododecyl sulfate prepared according to the procedure of Example 48A, crystallization method E, was pulverized and mixed with 4800 mg of type I polyoxyl stearate in a small mixer for 15 seconds to prepare tablets of dasatinib monododecyl sulfate. 1000 mg of purified water was added to the mixer and granulated for 15 seconds. The granules were dried in an oven at 50 °C to evaporate the water. The dried granules were pulverized into a powder and passed through a 30-mesh sieve. 16695 mg of microcrystalline cellulose, 1400 mg of sodium starch glycolate, 3500 mg of croscarmellose sodium, and 700 mg of colloidal silicon dioxide, which had been pre-screened through a 40-mesh sieve, were dried, pulverized, and mixed with the granulated material that had been sieved to obtain a pre-blend. 175 mg of sodium stearyl fumarate, which had been pre-screened through a 40-mesh sieve, was added to the pre-blend and blended to obtain a final blend. The final blend was compressed using a 9.5-mm circular punch to form tablets with a target hardness of approximately 5 kp.

[0403] The composition of the tablet contents is as follows.

Table 128

[0404] Example 63B 2319 mg of dasatinib monolauryl sulfate prepared according to the procedure of Example 48A, crystallization method E, was pulverized and mixed with 1800 mg of polyoxyl stearate type I and 1800 mg of microcrystalline cellulose (Part I) in a small mixer for 15 seconds to prepare tablets of dasatinib monolauryl sulfate. 450 mg of purified water was added to the mixer and granulated for 15 seconds. The granules were dried in an oven at 50 °C to evaporate the water. The dried granules were pulverized into a powder and sieved through a 40-mesh sieve. 2638.5 mg of microcrystalline cellulose (Part II) previously sieved through a 40-mesh sieve, 420 mg of sodium starch glycolate, 1260 mg of croscarmellose sodium, and 210 mg of colloidal silicon dioxide were dried, pulverized, and mixed with the granulated material that had been sieved to obtain a pre-blend. 52.5 mg of sodium stearyl fumarate previously sieved through a 40-mesh sieve was added to the pre-blend and blended to obtain a final blend. The final blend was compressed using a 9.5-mm circular punch to form tablets with a target hardness of approximately 5 kp.

[0405] The composition of the tablet contents is as follows. [Table 129]

[0406] Example 63C Tablets of dasatinib monolauryl sulfate prepared in Examples 60A and 63B were tested using a USP Type II Apparatus (Paddle) (500 mL of 0.1 N HCl, 75 rpm, using a sinker, 37 °C). The results of this dissolution test are as follows. [Table 130]

[0407] The invention illustratively described in this specification can be practiced without one or more elements or one or more limitations not specifically disclosed herein. Thus, for example, in each embodiment of this specification, any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced by either of the other two terms. The terms and expressions employed are used as terms of description and not of limitation, and there is no intention, in the use of such terms and expressions, to exclude equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as defined by the claims. Accordingly, the invention is specifically illustrated by preferred embodiments and optional features, and modifications and variations of the concepts disclosed herein can be made by those skilled in the art, and it should be understood that such modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

[0408] (Appendix) (Appendix 1) (i) C of kinase inhibitor (KI) 8 -C 16 aliphatic sulfate salt, and (ii) at least one pharmaceutically acceptable additive, A pharmaceutical composition for oral administration comprising the same.

[0409] (Appendix 2) A pharmaceutical composition which is a hard or soft gel capsule, wherein the at least one pharmaceutically acceptable additive is a liquid carrier, a solid carrier having a melting point between 25°C and less than 120°C, or a combination thereof, the pharmaceutical composition according to Appendix 1.

[0410] (Appendix 3) The pharmaceutical composition according to appended note 2, wherein the carrier is a liquid carrier selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, polyoxyl castor oil, glycerin, polysorbate, fatty acids, medium-chain triglycerides and related esters, fatty acid esters, vegetable oils, or mixtures thereof.

[0411] (Appended note 4) The pharmaceutical composition according to appended note 2, wherein the carrier is a solid carrier selected from the group consisting of aliphatic alcohols, polyethylene glycols, hard fats, hydrogenated vegetable oils, vitamin E polyethylene glycol succinate, waxes, poloxamers, and combinations thereof, and having a melting point between 25°C and less than 120°C.

[0412] (Appended note 5) (i) C of KI 8 -C 16 Aliphatic sulfate salts, (ii) A carrier having an HLB value of about 10 or more, and, (iii) Optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, flow promoters, fragrances, and combinations thereof. The pharmaceutical composition according to appended note 1, comprising.

[0413] (Appended note 6) (i) C of KI 8 -C 16 Aliphatic sulfate salts, (ii) A carrier having an HLB value of less than about 10, and, (iii) Optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, flow promoters, fragrances, and combinations thereof. The pharmaceutical composition according to appended note 1, comprising.

[0414] (Appended note 7) (i) C of KI 8 -C 16 Aliphatic sulfate salts, (ii) a carrier with an HLB value of about 10 or more, (iii) a carrier with an HLB value of less than about 10, and (iv) optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavors, and combinations thereof, The pharmaceutical composition according to Supplementary Note 1, comprising the same.

[0415] (Supplementary Note 8) A pharmaceutical composition in the form of a tablet or capsule, wherein the content of the tablet or the capsule is (i) The C 8 -C 16 aliphatic sulfate salt of KI, (ii) a carrier with an HLB value of about 10 or more, (iii) a filler, and (iv) optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of disintegrants, stabilizers, thickeners, binders, lubricants, glidants, flavors, and combinations thereof, The pharmaceutical composition according to Supplementary Note 1, comprising the same.

[0416] (Supplementary Note 9) The C 8 -C 16 The pharmaceutical composition according to Supplementary Note 1, wherein the aliphatic sulfate salt of KI is the lauryl sulfate salt of KI.

[0417] (Supplementary Note 10) The pharmaceutical composition according to Supplementary Note 1, wherein the KI is selected from the group consisting of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, luxolutinib, sorafenib, sunitinib, trametinib, and vandetanib.

[0418] (Supplementary Note 11) The pharmaceutical composition according to Supplementary Note 5, wherein the carrier having an HLB value of about 10 or more is selected from the group consisting of a wetting agent, an emulsifier, a solubilizer, a surfactant, or a combination thereof.

[0419] (Supplementary Note 12) The pharmaceutical composition according to Supplementary Note 6, wherein the carrier having an HLB value of less than about 10 is selected from the group consisting of a wetting agent, an emulsifier, a solubilizer, a surfactant, or a combination thereof.

[0420] (Supplementary Note 13) The pharmaceutical composition according to Supplementary Note 7, wherein the carrier having an HLB value of about 10 or more is selected from the group consisting of a wetting agent, an emulsifier, a solubilizer, a surfactant, or a combination thereof, and the carrier having an HLB value of less than about 10 is selected from the group consisting of a wetting agent, an emulsifier, a solubilizer, a surfactant, or a combination thereof.

[0421] (Supplementary Note 14) The pharmaceutical composition according to Supplementary Note 8, wherein the carrier having an HLB value of about 10 or more is selected from the group consisting of a wetting agent, an emulsifier, a solubilizer, a surfactant, or a combination thereof.

[0422] (Supplementary Note 15) (i) C of about 1 wt% to about 80 wt% of KI 8 -C 16 aliphatic sulfate (ii) about 1 wt% to about 90 wt% of a carrier having an HLB value of about 10 or more (iii) about 1 wt% to about 90 wt% of a carrier having an HLB value of less than about 10, and (iv) optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of a stabilizer, a filler, a thickener, a binder, a disintegrant, a lubricant, a flow promoter, a fragrance, and combinations thereof The pharmaceutical composition according to Supplementary Note 1, comprising

[0423] (Supplementary Note 16) A pharmaceutical composition in the form of a tablet or capsule, wherein the contents of the tablet or the capsule are (i) about 1% to about 80% by weight of KI in C 8 -C 16 an aliphatic sulfate salt, (ii) about 1% to about 60% by weight of a carrier having an HLB value of 10 or more, (iii) about 5% to about 90% by weight of a filler, and (iv) optionally, one or more additional pharmaceutically acceptable additives selected from the group consisting of disintegrants, stabilizers, thickeners, binders, lubricants, flow accelerators, fragrances, and combinations thereof, The pharmaceutical composition according to Supplementary Note 1, comprising

[0424] (Supplementary Note 17) The pharmaceutical composition according to Supplementary Note 5, further comprising about 0.1% to about 60% by weight of a thickener that is solid at ambient temperature but exhibits a melting point below 120°C.

[0425] (Supplementary Note 18) The pharmaceutical composition according to Supplementary Note 6, further comprising about 1% to about 60% by weight of the carrier that is solid at ambient temperature but exhibits a melting point below 120°C.

[0426] (Supplementary Note 19) The pharmaceutical composition according to Supplementary Note 7, further comprising about 0.1% to about 60% by weight of a thickener that is solid at ambient temperature but exhibits a melting point below 120°C.

[0427] (Supplementary Note 20) The pharmaceutical composition according to Supplementary Note 8, further comprising about 1% to about 60% by weight of the carrier that is solid at ambient temperature but exhibits a melting point below 120°C.

[0428] (Supplementary Note 21) The KI in the pharmaceutical composition according to Supplementary Note 1 is selected from the group consisting of acalabrutinib, afatinib, alectinib, apatinib, axitinib, bafetinib, baricitinib, bosutinib, brigatinib, cabozantinib, canertinib, cediranib, ceritinib, cobimetinib, clenolanib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, entrectinib, erlotinib, filgotinib, foretinib, fostamatinib, gefitinib, glesatinib, ibrutinib, icotinib, imatinib, lapatinib, lestaurtinib, lenvatinib, linifanib, lucitanib, momelotinib, motesanib, mubritinib, neratinib, nilotinib, nintedanib, octreotide, olmutinib, osimertinib, pacritinib, pazopanib, ponatinib, quizartinib, radotinib, regorafenib, rociletinib, luxitinib, saracatinib, savolitinib, semaxanib, sitravatinib, sorafenib, sunitinib, taselisib, tesevatinib, tiboxanib, toceranib, trametinib, upadacitinib, batatinib, vandetanib, and bemrafenib.

[0429] (Supplementary Note 22) The KI is (i) a phenylcarboxamide moiety having the following structure

Chemical formula

Chemical formula

Chemical formula

Claims

1. Cabozantiniblauric sulfate.

2. 13. An oral dosage form comprising a therapeutic amount of the salt of claim 1 and one or more excipients.

3. The cabozantiniblauric sulfate ester salt is (a) amorphous, (b) crystalline, or (c) a combination of amorphous and crystalline; 3. The oral dosage form of claim 2.

4. The oral dosage form of claim 3 , wherein the dosage form is a tablet.

5. The oral dosage form of claim 3 , wherein the dosage form is a capsule.

6. (i) about 3% to about 50% by weight of cabozantinib sulfate; and (ii) from about 1% to about 90% by weight of one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, each having an HLB value of about 10 or greater; 6. The oral dosage form of claim 5, comprising:

7. 7. The oral dosage form of claim 6, wherein the one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof exhibiting an HLB value of about 10 or greater are selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylate alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene alkyl esters, polyglycerides, sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty acid alcohol polyglycol ethers, acetylenic glycols, acetylenic alcohols, oxyalkylene block polymers, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyoxyethylene styrylaryl ethers, polyoxyethylene glycol alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid esters, polyoxylglycerides, polyoxylethylene stearates, or combinations thereof.

8. (i) from about 10% to about 33% by weight of cabozantiniblauric sulfate; and (ii) from about 19% to about 90% by weight of at least one pharma- ceutically acceptable nonionic surfactant having a hydrophilic-lipophilic balance (HLB) value of 10 or greater, selected from the group consisting of vitamin E polyethylene glycol succinate, poloxamer, polyethoxylated castor oil, polyoxyethylene hydrogenated castor oil, polyoxylglyceride, polyoxyethylene stearate, and combinations thereof; 6. The oral dosage form of claim 5, comprising:

9. 7. The oral dosage form of claim 6, wherein the one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, exhibiting an HLB value of about 10 or greater, are solids having a melting point between 25° C. and 120° C.

10. 10. The oral dosage form of claim 2, further comprising at least one pharma- ceutically acceptable excipient having a hydrophilic-lipophilic balance (HLB) value of less than 10.

11. 11. The oral dosage form of claim 10, wherein the at least one pharma- ceutically acceptable excipient having an HLB value of less than 10 is selected from the group consisting of a wetting agent, an emulsifier, a solubilizer, a surfactant, or a combination thereof.

12. 12. The oral dosage form of claim 11, wherein the at least one pharma- ceutically acceptable excipient having an HLB value of less than 10 is selected from medium chain monoglycerides, medium chain diglycerides, polyoxylglycerides, sorbitan esters, sorbitan fatty acid esters, phospholipids, and combinations thereof.

13. 13. The oral dosage form of any one of claims 2 to 12, wherein the dosage form further comprises one or more pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof.

14. 14. The oral dosage form of any one of claims 2 to 13, wherein the dosage form exhibits (i) about 35% to about 100% dissolution after 45 minutes, or (ii) at least 70% dissolution after 60 minutes, when tested using a USP Type II Apparatus (Paddle) (0.1 N HCl, 75 rpm, with or without a sinker, 37°C).

15. 15. The oral dosage form of any one of claims 2 to 14, wherein the dosage form comprises cabozantinib uril sulfate equivalent to about 5 mg to about 200 mg of cabozantinib free base.

16. The oral dosage form of any one of claims 2 to 15, used in an effective amount for the treatment of thyroid cancer, renal cell carcinoma and / or hepatocellular carcinoma.

17. In an effective amount for the treatment of thyroid cancer, renal cell carcinoma and / or hepatocellular carcinoma in a subject, administration of the dosage form provides a C of about 0.6 to about 2.

5. ｍａｘ ｆｅｄ / C ｍａｘ ｆａｓｔ The ratio is represented by C ｍａｘ ｆｅｄ is the maximum cabozantinib plasma concentration obtained by administering a single dose of said oral dosage form to one or more human patients or healthy human subjects under fed conditions, and said C ｍａｘ ｆａｓｔ is the maximum cabozantinib plasma concentration obtained by administering a single dose of said oral dosage form to one or more of said patients or subjects under fasting conditions.

18. Said C ｍａｘ ｆｅｄ / C ｍａｘ ｆａｓｔ 18. The oral dosage form of claim 17, wherein the ratio is a geometric mean ratio.

19. In an effective amount for the treatment of thyroid cancer, renal cell carcinoma and / or hepatocellular carcinoma in a subject, administration of the dosage form provides an AUC of about 0.6 to about 2.

5. ０－∞ ｆｅｄ / A.U.C. ０－∞ ｆａｓｔ The ratio is shown in Table 1. ０－∞ ｆｅｄ is the AUC from the time of administration of a single dose of the oral dosage form to one or more human patients or healthy human subjects under fed conditions to infinity, ０－∞ ｆａｓｔ 16. The oral dosage form of claim 15, wherein AUC is the AUC from administration of a single dose of the oral dosage form to one or more of the patients or subjects under fasting conditions to infinity.

20. The AUC ０－∞ ｆｅｄ / A.U.C. ０－∞ ｆａｓｔ 20. The oral dosage form of claim 19, wherein the ratio is a geometric mean ratio.

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