Salts of kinase inhibitors 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 June 15, 2018, U.S. Provisional Application No. 62 / 791,356, filed January 11, 2019, and U.S. Provisional Application No. 62 / 811,368, filed February 27, 2019, each of which is incorporated by reference in its entirety.

[0002] (Technical field) The present invention relates to a kinase inhibitor and a C8-C 16 The present invention relates to a salt of a kinase inhibitor formed by reaction with an aliphatic sulfate. The salt of a kinase inhibitor may be orally administered to a subject in combination with at least one pharma- ceutically acceptable excipient.

[0003] The present invention relates to a kinase inhibitor, C8-C 16 Also disclosed are pharma- ceutically acceptable compositions and dosage forms comprising the aliphatic sulfate salts, methods of preparing the compositions and dosage forms, and methods of treating various conditions, such as cancer, comprising orally administering the compositions and dosage forms. [Background technology]

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

[0005] KI often exhibits pH-dependent solubility and therefore variable oral bioavailability.

[0006] KIs are known to exhibit greater variability in absorption when administered in the fasting state than when administered in the presence of a high-fat meal or with other drugs such as gastric acid suppressants, i.e., antacids, H2 antagonists, and proton pump inhibitors. For example, some KIs exhibit a higher C max It is known that pharmacokinetic values ​​such as maximum plasma concentration (PTC) and area under the plasma concentration curve (AUC) are significantly increased. Similarly, coadministration of KI with gastric acid suppressants or drugs that increase gastric pH is known to decrease KI absorption. The large variability requires restrictions on the time and conditions of KI administration, resulting in inconvenience for patients and, if not administered correctly, undesirable side effects or ineffectiveness. Summary of the Invention [Problem to be solved by the invention]

[0007] Accordingly, it is an object of the present invention to provide novel salts of KI and compositions comprising salts of KI that improve the absorption of KI following oral administration, reduce the variability in absorption when KI is administered orally with or without food, and / or reduce the variability in absorption when co-administered with other drugs, such as gastric acid suppressants.

[0008] The present invention accomplishes the above and other objectives. [Means for solving the problem]

[0009] The present invention includes salts of KI, which are salts of KI and C8-C 16 In one embodiment, a salt of KI is formed by reaction of KI with an alkali or alkaline earth metal lauryl sulfate or an alkali or alkaline earth metal tetradecyl sulfate.

[0010] The present invention also relates to a method for the preparation of a compound comprising the steps of: 16Compositions and dosage forms comprising an aliphatic sulfate salt and at least one pharma- ceutically acceptable excipient are included, preferably for oral administration to a subject.

[0011] The present invention further includes a method of reducing or eliminating the food effect of oral administration of KI. More specifically, the present invention includes oral administration of the compositions and / or dosage forms of the present invention to a subject, which may be in a fed or fasted state. Oral administration of the compositions or dosage forms of the present invention results in a plasma profile of KI in which at least one pharmacokinetic parameter differs by less than about 40% under fed and fasted conditions. In various embodiments, the pharmacokinetic parameters under fed and fasted conditions may vary by less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5%. The food-independent pharmacokinetic parameters include C max ,A.U.C.,T. max In one embodiment, the KI may be, but is not limited to, C8-C 16 One or more dosage forms comprising an aliphatic sulfate ester salt and at least one pharma- ceutically acceptable excipient are orally administered to a cancer patient with or without food, and a C8-C KI administered with or without food. 16 The dosage of the aliphatic sulfate does not require adjustment in dosage or alteration of time of administration.

[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 C8-C 16 One or more dosage forms comprising an aliphatic sulfate salt and at least one pharma- ceutically acceptable excipient are administered to a cancer patient who is co-administered with a gastric acid suppressant, and the C8-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 less than or equal to 100 mg / kg of KI currently approved by the U.S. Food and Drug Administration (FDA) for use with KI free base or non-C8-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 one embodiment of the present invention, the composition or dosage form for oral administration comprises a C8-C 16 The capsule is a hard or soft capsule or tablet, preferably thoroughly mixed, containing an aliphatic sulfate salt and a pharma- ceutically acceptable carrier. In some aspects of this embodiment, the hard or soft capsule may be a gelatin-based or non-gelatin-based capsule. In some aspects of this embodiment, the pharma- ceutically acceptable carrier is liquid at ambient conditions, i.e., 25° C. and standard atmospheric pressure, or the pharma- ceutically 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. When the pharma- ceutically acceptable carrier is liquid at ambient conditions, the C8-C 16 The aliphatic sulfate salt 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 include one or more pharma- ceutically acceptable additives, such as stabilizers, which are described in detail below. If the carrier is solid at ambient conditions, the carrier is heated to melt it before filling or forming into a hard or soft capsule or forming into a tablet, and the C8-C of the molten carrier and KI are mixed. 16 Alternatively, the carrier may be dissolved or dispersed in a solvent, and the C8-C 16 The aliphatic sulfate salt alone or in combination with at least one further pharma- ceutically acceptable excipient is combined with a carrier and C8-C KI. 16 A complete mixture of aliphatic sulfates may be made. C8-C of KI 16 Once the intimate blend of the aliphatic sulfate salt and carrier is formed, it may be dried and filled or formed into a hard or soft capsule, or the intimate blend may be combined with at least one pharma- ceutically acceptable excipient and the resulting combination may be 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 C8-C 16The carrier includes an aliphatic sulfate salt and a carrier having an HLB value of 10 or more, the carrier having an HLB value of 10 or more being selected from the group consisting of a wetting agent, an emulsifier, a solubilizer, a surfactant, or a combination thereof. 16 The aliphatic sulfate salt and the carrier having an HLB value of 10 or more are thoroughly mixed. In a further embodiment, the composition is a liquid composition that may be orally administered to a subject, or the liquid composition may be filled into a hard or soft capsule for oral administration to a subject. The liquid mixture may further include one or more pharma- ceutically acceptable additives, such as stabilizers, which are described in detail below. Alternatively, the composition may be a solid or semi-solid composition, such as a powder or granules, that may be orally administered to a subject, or the solid or semi-solid composition may be formed into a tablet or filled into a capsule for oral administration to a subject.

[0016] The present invention also relates to a method for the preparation of a compound comprising the steps of: 16 Further included are methods of preparing, forming, and manufacturing compositions and dosage forms comprising an aliphatic sulfate salt and at least one pharma- ceutically acceptable excipient, preferably for oral administration to a subject.

[0017] The present invention also provides a therapeutic amount of C8-C 16 Further included are methods of treating a patient comprising orally administering compositions and dosage forms comprising an aliphatic sulfate salt and at least one pharma- ceutically acceptable excipient.

[0018] The present invention also relates to a method for the preparation of a compound comprising the steps of: 16 Included are novel polymorphs of the aliphatic sulfate ester salts, methods for making the novel polymorphs, compositions and dosage forms containing the novel polymorphs, and methods of treating patients with the novel polymorphs. [Brief description of the drawings]

[0019] [Figure 1] 1 is a graph showing the mean in vivo plasma data provided in Example 5. [Diagram 2]1 is a graph showing the mean in vivo plasma data provided in Example 10. [Diagram 3] FIG. 1 is an XRPD pattern of dasatinib monolauryl sulfate of Example 12. [Figure 4] 1 is an XRPD pattern of dasatinib dilauryl sulfate of Example 13. [Diagram 5] FIG. 2 is a graph showing the mean in vivo plasma data provided in Example 20. [Figure 6] FIG. 2 is a graph showing the mean in vivo plasma data provided in Example 21D. [Figure 7] FIG. 2 is a graph showing the mean in vivo plasma data provided in Example 24. [Figure 8] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 32. [Figure 9] FIG. 36 is a graph showing the mean in vivo plasma data provided in Example 35. [Figure 10] 1 is an XRPD pattern of nilotinib dilauryl sulfate of Example 38. [Figure 11] 1 is a graph showing the mean in vivo plasma data provided in Example 40. [Figure 12] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 42G. [Figure 13] FIG. 1 is an XRPD pattern of nilotinib monolauryl sulfate by crystallization method A of Example 46. [Figure 14] FIG. 1 is an XRPD pattern of nilotinib monolauryl sulfate by crystallization method C of Example 46. [Figure 15] FIG. 1 is an XRPD pattern of nilotinib monolauryl sulfate by crystallization method D of Example 46. [Figure 16] FIG. 1 is an XRPD pattern of dasatinib monolauryl sulfate by crystallization method A of Example 47. [Figure 17]FIG. 1 is an XRPD pattern of dasatinib monolauryl sulfate by crystallization method B of Example 47. [Figure 18] FIG. 1 is an XRPD pattern of dasatinib monolauryl sulfate by crystallization method C of Example 48. [Figure 19] FIG. 1 is an XRPD pattern of dasatinib monolauryl sulfate by crystallization method D of Example 48. [Figure 20] FIG. 1 is an XRPD pattern of dasatinib monolauryl sulfate by crystallization method E of Example 48A. [Figure 21] 5 is a graph showing the mean in vivo plasma data provided in Example 50. [Figure 22A] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 51A. [Figure 22B] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 51A. [Figure 22C] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 51A. [Diagram 23] FIG. 5 is a graph showing the mean in vivo plasma data provided in Example 52A. [Figure 24] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 53A. [Diagram 25] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 61A. [Figure 26] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 61B. [Figure 27] FIG. 13 is a graph showing the mean in vivo plasma data provided in Example 61C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Before the present invention is further described, it is to be understood that the invention is not limited to particular embodiments described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is 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, it is to be understood that each intermediate value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any stated or intermediate value within that range is included within the scope of the 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 invention, subject to any specifically excluded limits in the stated range. When the stated range includes one or both of the limits, ranges excluding either or both of the included limits are also included in the invention.

[0023] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled 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 preferred methods and materials are described herein.All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials related to the cited publications.

[0024] As used herein, the term "normal storage conditions" refers to room temperature, approximately 25°C. and approximately 60% relative humidity for at least 3 months, preferably at least 6 months, and most preferably at least 1 year. Dosage forms according to the present invention should be stored in a pharma- ceutically acceptable container, such as a glass bottle, a plastic bottle, a foil sachet, or a blister pack, with or without a desiccant.

[0025] As used herein, the term "accelerated storage conditions" means storage at approximately 40° C. and approximately 75% relative humidity for at least 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. Dosage forms according to the present invention should be stored in pharma- ceutically acceptable containers such as glass bottles, plastic bottles, foil sachets, or blister packs, with or without 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). HLB values ​​range 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. HLB values ​​are commonly known and reported in the literature, such as manufacturers' technical literature.

[0027] "C max The term "maximum plasma concentration achieved during the dosing interval" refers to the maximum plasma concentration achieved during the dosing interval.

[0028] "T max The term "maximum plasma concentration (C max ) means the time it takes for the

[0029] The term "AUC" refers to the area under the drug concentration-time curve (AUC) calculated using linear trapezoidal sums at specific time intervals, e.g., AUC 0-12 means the area under the drug concentration-time curve from immediately before administration to 12 hours after administration, and AUC 0-24 means the area under the drug concentration-time curve from immediately before administration to 24 hours after administration, and AUC 0-∞ means the area under the drug concentration-time curve from just before administration to infinity, and AUC 0-t means the area under the drug concentration-time curve from immediately before administration to a specified time point after administration, such as 2 hours, 8 hours, 18 hours, etc. In some embodiments, the specified time point is the time of the last blood draw.

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

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

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

[0033] As used herein, unless otherwise defined, phrases such as "thoroughly mixed", "complete mixture" and the like refer to a combination of the KI salt of the present invention with at least one pharma- ceutically acceptable additive, such as a wetting agent, emulsifier, solubilizer, surfactant, or 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, where the KI salt and the at least one pharma- ceutically acceptable additive are in intimate contact or intimate association with each other. The complete mixture may be prepared by any means that allows blending of the KI salt of the present invention with at least one pharma- ceutically 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 KI salt in a solution or suspension containing at least one pharma- ceutically acceptable additive, preferably a carrier having an HLB value of about 10 or more, and optionally at least one additional pharma- ceutically acceptable additive, such as a pharma- ceutically acceptable solvent. The pharmaceutical solvent may or may not be removed. Another example of a suitable method for achieving an intimate mixture includes using a liquid additive containing at least one pharma- ceutically acceptable additive with an HLB value of about 10 or more, or melting one or more solid additives containing at least one pharma- ceutically acceptable additive with an HLB value of about 10 or more to form a molten additive or liquid additive composition containing at least one additive with an HLB value of about 10 or more, and dissolving, suspending, or dispersing the KI salt in the molten additive or liquid additive composition. The liquid additive containing at least one additive with an HLB value of about 10 or more may further contain one or more pharma- ceutically acceptable additives, as described in more detail below. Another method used to achieve an intimate mixture of the KI salt and at least one pharma- ceutical acceptable additive, preferably with an HLB value of about 10 or more, includes co-blending, co-screening, co-condensation, co-compression, or a combination thereof.Once an intimate mixture of the KI salt and at least one pharma- ceutically acceptable excipient, preferably having an HLB value of about 10 or greater, is prepared, the intimately mixed composition may be combined with at least one additional pharma- ceutically acceptable excipient or carrier. The intimate mixture may preferably include the KI salt and one, two or three excipients prior to combination with the additional excipient.

[0034] As used herein, unless otherwise defined, the term "gastric acid suppressant" refers to additives and / or agents that increase gastric pH or neutralize gastric acid, such as antacids or compounds that reduce gastric acid secretion, such as H2 antagonists or proton pump inhibitors. 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. Examples of H2 antagonists include, but are not limited to, antihistamines, cimetidine, ranitidine, famotidine, nizatidine, roxatidine, and lafutidine. 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-administration," "co-administered," and "co-administer" refer to a subject receiving one or more non-KI drugs or therapeutic agents while undergoing KI therapy. 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. Concurrent administration as used herein refers to a non-KI drug or therapeutic agent 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 refers to administration of the 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 administration of the non-KI drug 4, 6, 8, 12, or 14 hours before or after administration of the KI composition or dosage form.

[0036] As used herein, unless otherwise defined, the term "KI(s)" refers to any compound or compounds that are pharmacologically active and inhibit kinase enzymes, preferably tyrosine kinase enzymes. Preferably, KIs are small molecules that generally use the suffix "nib" in their names, including tyrosine kinase inhibitors (TKIs), generally use the suffix "tinib" in their names, angiogenesis inhibitors, generally use the suffix "anib" in their names, and Raf (rapidly accelerated fibrosarcoma) kinase inhibitors, generally use the suffix "rafinib" in their names. Also included are focal adhesion kinase (FAK) inhibitors.

[0037] Examples of KIs that may 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 name COMETRIQ), canertinib, cediranib, ceritinib (commercially available under the name ZYKADIA), cobimetinib (commercially available under the name COTELLIC), crenolanib, crizotinib (commercially available under the name XALKORI), dabrafenib (commercially available under the name TAFINLAR), dasatinib (commercially available under the name SPRYCEL), defactinib (VerastemOncology), 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), cefotiamido (commercially available under the trade name CEKAI ... (commercially available under the name TYKERB), lestaurtinib, lenvatinib (commercially available under the name LENVIMA), linifanib, lucitanib, momelotinib, motesanib, mubritinib, neratinib (commercially available under the name NERLYNX), nilotinib (commercially available under the name TASIGNA), nintedanib (commercially available under the name OFEV), oclacitinib (commercially available under the name APOQUEL), olmutinib, Osimertinib (marketed under the name TAGRISSO), pacritinib, pazopanib (marketed under the name VOTRIENT), ponatinib (marketed under the name ICLUSIG), quizartinib, radotinib, regorafenib (marketed under the name STIVARGA), rociletinib, ruxolitinib, (marketed under the name JAKAFI), saracatinib, savolitinib, semaxanib, sitravtinib, sorafenib (NEXAV These include, but are not limited to, sunitinib (marketed under the trade name SUTENT), taselisib, tecevatinib, tivozanib, toceranib, tofacitinib (marketed under the trade name XELJANZ), trametinib (marketed under the trade name MEKINIST), upadacitinib, vatalanib, vandetanib (marketed under the trade name CAPRELSA), and vemurafenib (marketed under the trade name ZELBORAF).

[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, oclacitinib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib.

[0039] Further examples of KIs useful in the present invention include: (i) a phenylcarboxamide moiety having the structure [ka] (ii) an aminopyrimidine moiety having the structure [ka] (iii) an aminopyrimidine moiety having the structure [ka] or (iv) a combination of the moieties described in (i), (ii) or (iii). A KI comprising: A is H, C, N, O, S, P, halogen (F, Cl, Br, I), and / or A may be part of a larger moiety, such as a straight chain, branched or cyclic moiety, for example, alkyl, aryl, alkoxy, etc. In certain embodiments, the A substituent on the nitrogen of the phenylcarboxamide moiety (i) is preferably H or C1-C4 alkyl.

[0040] Examples of KIs containing a 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 containing 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, ruxolitinib, tofacitinib, and vandetanib.

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

[0043] C8-C of the KI of the present invention 16 Aliphatic sulfate ester salts are formed by combining KI molecules with C8-C 16 In one embodiment, the C8-C of KI can be formed by reaction with an aliphatic sulfate. 16Aliphatic sulfate salts are formed by the reaction of KI with alkali metal or alkaline earth metal lauryl sulfate or alkali metal or alkaline earth metal tetradecyl sulfate.Preferred examples of alkali metal or alkaline earth metal lauryl sulfate or alkali metal or alkaline earth metal tetradecyl sulfate 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 or potassium lauryl sulfate.

[0044] C8-C of the KI of the present invention 16 Aliphatic sulfate salts are prepared by dissolving a KI compound (either in the form of a free base or in the form of a salt such as KI HCl, KI citrate, KI phosphate, KI mesylate, KI maleate, or KI tosylate) in an organic solvent such as water, a branched or straight chain C1-C6 alcohol, ether, ester, or ketone, or mixtures thereof, a branched or straight chain C3 ... 12 The KI solution is dissolved in a suitable solvent, such as an organic solvent, such as an alkane or a mixture of these, or a mixture of water and an organic solvent, and the C8-C 16 It can be formed by adding an aliphatic sulfate ester and mixing the resulting reactants. Alternatively, C8-C 16 The aliphatic sulfate ester is dissolved in a suitable solvent, and the KI compound (either in the form of a free base or salt) is added to the C8-C 16 The resulting reactants may be mixed by adding the C8-C 16 Aliphatic sulfates can also be prepared by dissolving the KI compound (either in free base or salt form) in a suitable solvent and condensing the C8-C 16 Aliphatic sulfate ester is dissolved in a suitable solvent, and the KI compound solution and C8-C 16 The resulting reactant may be mixed with the aliphatic sulfate ester solution to form the reactant. The solvent may be removed from the resulting reactant by conventional techniques such as evaporation, filtration, etc., and the C8-C of KI may be removed. 16The aliphatic sulfate ester salt is separated. 16 Aliphatic sulfate esters 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 becomes a C8-C 16 Mixed with aliphatic sulfate esters to form C8-C 16 Forms aliphatic sulfate ester salts.

[0046] C8-C in the reactants 16 The molar ratio of aliphatic sulfate to KI compound is 1 mole of C8-C KI base present in the reaction mixture. 16 Aliphatic sulfate esters approx. 0.5 mol ~ C8-C 16 The aliphatic sulfate may range from about 6 moles, preferably C8-C10 per mole of KI base present in the reaction. 16 Aliphatic sulfate esters approx. 0.75 mol ~ C8-C 16 About 5 moles of aliphatic sulfate, most preferably C8-C for each mole of KI base present in the reaction 16 Aliphatic sulfate esters approx. 0.85 mol ~ C8-C 16 Aliphatic sulfate ester is about 4 moles. C8-C of KI 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. 16 In some embodiments of the aliphatic sulfate salt, the C8-C 16 The molar ratio of aliphatic sulfate to KI compound is 1 mole of C8-C KI base present in the reaction mixture. 16 Aliphatic sulfate esters approx. 0.8 mol ~ C8-C 16 Aliphatic sulfate esters may range from about 1.3 moles. 16 In some embodiments of the aliphatic sulfate salt, the C8-C 16The molar ratio of aliphatic sulfate to KI compound is 1 mole of C8-C KI base present in the reaction mixture. 16 Aliphatic sulfate esters approx. 1.6 mol ~ C8-C 16 The aliphatic sulfate ester may be in the range of about 2.5 moles. 16 Aliphatic sulfate ester salts are mono C8-C 16 Aliphatic sulfate ester salt or KI diC8-C 16 Aliphatic sulfate ester salt, KI triC8-C 16 Aliphatic sulfate ester salts, KI tetra C8-C 16 Aliphatic sulfate ester salt or KI penta C8-C 16 Aliphatic sulfates, etc., KI multi-C8-C 16 Unless otherwise indicated, the C8-C of KI as used herein may be an aliphatic sulfate salt. 16 The term aliphatic sulfate includes mono- and multi-aliphatic sulfates, similarly the term KI lauryl sulfate includes mono- and multi-lauryl sulfates.

[0047] The present invention also relates to a method for the preparation of a compound comprising the steps of: 16 The present invention includes compositions and dosage forms comprising an aliphatic sulfate salt and at least one pharma- ceutically acceptable excipient, preferably for oral administration to a subject. The compositions and dosage forms may be solid, semi-solid, or liquid, and may be selected from the group consisting of C8-C 16 The aliphatic sulfate salt is combined with a pharma- ceutically acceptable excipient such as a filler, diluent, binder, stabilizer, lubricant, disintegrant, wetting agent / solubilizer / emulsifier or mixtures thereof. Pharmaceutically acceptable excipients 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 pharma- ceutically acceptable excipients that may be used in embodiments of the present invention are given below.

[0048] Solid and semi-solid compositions and dosage forms include powders, granules, pellets, minitablets, tablets, capsules and are prepared 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 may also be prepared by methods known in the art.

[0050] In one embodiment of the present invention, the composition or dosage form for oral administration comprises a C8-C 16 The tablet or hard or soft gelatin capsule contains an aliphatic sulfate salt and a pharma- ceutically acceptable carrier, preferably thoroughly mixed. In some aspects of this embodiment, the pharma- ceutically acceptable carrier is liquid at ambient conditions, i.e., 25° C. and normal atmospheric pressure, or the pharma- ceutically acceptable carrier is solid at ambient conditions, but has a melting point greater than 25° C. and less than 120° C., preferably less than 100° C., more preferably less than 80° C., and most preferably less than 60° C. When the pharma- ceutically acceptable carrier is liquid at ambient temperature, the C8-C 16 The aliphatic sulfate salt and the liquid carrier are mixed and the resulting mixture is filled or molded into a hard or soft gelatin capsule. The liquid mixture may also contain one or more additional pharma- ceutically acceptable additives, such as stabilizers, which are described in more detail below.

[0051] If the carrier is a solid or semi-solid at ambient conditions, the carrier may be mixed with the C8-C KI prior to being formed into a tablet or filled or formed into a hard or soft gelatin capsule. 16 The carrier is mixed or granulated with the aliphatic sulfate salt and, optionally, one or more additional pharma- ceutically acceptable excipients. Alternatively, if the carrier is solid or semi-solid at ambient conditions, the carrier is heated to melt and the molten carrier, C8-C of KI, is added to the tablet or filled or formed into a hard or soft gelatin capsule. 16The aliphatic sulfate ester salt, and optionally any additional one or more pharma- ceutically acceptable excipients, are mixed.

[0052] In one embodiment, the C8-C 16 The aliphatic sulfate salt is dissolved in a liquid carrier or in a molten carrier. 16 The aliphatic sulfate salt is dispersed or suspended in a liquid carrier or dispersed or suspended in a molten carrier.

[0053] Examples of liquid carriers used in the preparation of the oral dosage form of the present invention include, but are not limited to, fatty acids, medium chain triglycerides, fatty acid esters, fatty acid alcohols, vegetable oils such as corn oil, soybean oil, olive oil, sunflower oil, peanut oil, and the like, or mixtures thereof. In one embodiment, 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 any range encompassed by these values, preferably about 15% (w / w) to about 90% (w / w) of the composition filled in the capsule, and most preferably about 20% (w / w) to about 85% (w / w).

[0054] Examples of solid carriers with a melting point of 25°C to less than 120°C include fatty alcohols, polyethylene glycols such as polyethylene glycol 1000 with a melting point of 37-40°C and polyethylene glycol 1500 with a melting point of 44°C to 48°C, hydrogenated 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 stearates, and waxes such as carnauba wax, cetyl ester wax, microcrystalline wax, white wax, yellow wax, and combinations of the aforementioned solid carriers. In certain embodiments, the solid carrier comprises 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%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 100%, 102%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%. %, 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 any range subsumed within these values, preferably from about 5% (w / w) to about 90%, and most preferably from about 7.5% (w / w) to about 85%.

[0055] Further examples of solid, semi-solid, and liquid carriers for use in preparing the solid, semi-solid, or liquid dosage forms of the present invention, including, but not limited to, the hard gelatin capsules, soft gelatin capsules, and tablets of the present invention, include wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, as detailed below, exhibiting 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.

[0056] In another embodiment of the present invention, the composition or dosage form comprises a C8-C 16The composition further comprises an aliphatic sulfate salt and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, each 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 at least one additional pharma- ceutically acceptable additive. 16 The aliphatic sulfate may be present in the composition in an amount 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. 16The aliphatic sulfate ester salts are about 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 20% by weight, 21% by weight, 22% by weight, 23% by weight, 24% by weight, 25% by weight, 26% by weight, 27% by weight, 28% by weight, 29% by weight, 30% by weight, 31% by weight, 32% by weight, 33% by weight, 34% by weight, 35% by weight, 36% by weight, 37% by weight, 38% by weight, 39% by weight, 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, 50% by weight, 51% by weight, 52% by weight, 53% by weight, 54% by weight, 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, 61% by weight, 62% by weight, 63% by weight, 64% by weight, 65% by weight, 66% by weight, 67% by weight, 68% by weight, 69% by weight, 70% by weight, 71% by weight, 72% by weight, 73% by weight, 74 The composition may be present in an amount of 9%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% by weight, or any range of weights contained therein. One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof exhibiting an HLB value of about 10 or more, preferably an HLB value of about 11 or more, more preferably an HLB value of about 12 or more, and most preferably an HLB value of about 14 or more, should be present in the composition or dosage form in an amount of 1% or more by weight based on the total weight of the composition or dosage form, and preferably about 2% or more by weight, and most preferably about 5% or more by weight based on the total weight of the composition or dosage form. In one embodiment, one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, having an HLB value of about 10 or greater, preferably about 11 or greater, more preferably about 12 or greater, and most preferably about 14 or greater, should be present in the composition or dosage form in an amount ranging from about 1% to about 90% by weight, preferably from about 2% to about 80% by weight, and most preferably from about 3% to about 70% by weight.In some embodiments, the one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof exhibiting an HLB value of about 10 or greater is about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 102%, 104%, 106%, 108%, 109%, 110%, 111%, 120%, 122%, 130%, 140%, 150%, 160%, 170%, 182%, %, 30% by weight, 31% by weight, 32% by weight, 33% by weight, 34% by weight, 35% by weight, 36% by weight, 37% by weight, 38% by weight, 39% by weight, 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, 50% by weight, 51% by weight, 52% by weight, 53% by weight, 54% by weight, 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, or all ranges subsumed within these values.

[0057] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof that show an HLB value of about 10 or more can be non-ionic surfactants, ionic surfactants, or combinations thereof, and are preferably non-ionic surfactants.Examples of usable non-ionic surfactants include polyethoxylated castor oil, polyoxyethylene alkyl esters, polyglycolized glycerides, sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty acid alcohol polyglycol ethers, acetylene glycols, acetylene 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 oils, polyoxypropylene fatty acid esters, polyoxylglycerides, polyoxyethylene stearate, or mixtures thereof. A further list of possible non-ionic surfactants is provided in Martindale, The Extra Pharmacopoeia, 29th ed., pages 1243-1249, incorporated herein by reference.

[0058] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, exhibiting an HLB value of about 10 or more, may be non-ionic surfactants, such as fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates alkyl polyglycosides, and mixtures thereof. Examples of non-ionic 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] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, exhibiting an HLB value of about 10 or more, may be polyoxyl castor oils, such as polyoxyl castor oils or polyoxyethylene hydrogenated castor oils, or combinations thereof. Examples of these surfactants include, but are not limited to, polyoxyl 35 castor oil (commercially available under the tradename CREMAPHOR EL or KOLLIPHOR EL), polyoxyl 40 hydrogenated castor oil (commercially available under the tradename CREMOPHOR RH40), and polyoxyl 60 hydrogenated castor oil.

[0060] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, exhibiting an HLB value of about 10 or greater, 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] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, exhibiting an HLB value of about 10 or greater, may be tyloxapol, poloxamers, i.e., non-ionic polyoxyethylene-polyoxypropylene copolymers such as poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, and the like, or combinations thereof.

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

[0063] In some embodiments of the present invention, the composition comprises a C8-C 16The composition may further comprise at least one additional second carrier, preferably thoroughly mixed, having a low or no HLB value, comprising an aliphatic sulfate and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, each of which exhibits an HLB value of about 10 or greater. The second carrier may be a wetting agent, emulsifier, solubilizer, surfactant, or combination of these, each of which exhibits 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 with low HLB value include non-ionic surfactants, including but not limited to polyethoxylated castor oil, polyoxyethylene alkyl esters, polyglycolized glycerides, sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty acid alcohol polyglycol ethers, acetylene glycols, acetylene 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, or mixtures thereof.A further list of possible non-ionic surfactants with low HLB value is listed in Martindale, The Extra Pharmacopoeia, 29th ed., pages 1243-1249, which is incorporated herein by reference.

[0064] In one embodiment, the second carrier having an HLB value of less than about 10 is a medium chain (i.e., from about 4 to about 20 carbon atoms, preferably from about 6 to about 18 carbon atoms, and most preferably from about 6 to about 14 carbon atoms) mono- or diglyceride, such as glyceryl caprylate / caprate (commercially available under the tradename CAPMUL MCM), glyceryl caprylate (commercially available under the tradename CAPMUL MCM C8), glyceryl caprate (commercially available under the tradename CAPMUL MCM C10), glyceryl monocaprylate caprate (commercially available under the tradename CAPMUL 471), or mixtures thereof.

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

[0066] In one embodiment, 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, a medium chain triglyceride, hydrogenated vegetable oils, a suppository base, or a combination 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 embodiments 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 from about 1% to about 90% by weight, preferably from about 5% to about 85% by weight, and most preferably from about 10% to about 80% by weight, based on the total weight of the composition. The foregoing weight percentages may be based on one second carrier or a combination of second carriers. In some embodiments, the one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of less than about 10 is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1090%, 1091%, 1092%, 1093%, 1094%, 1095%, 1096 %, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, 50% by weight, 51% by weight, 52% by weight, 53% by weight, 54% by weight, 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, 61% by weight, 62% by weight, 63% by weight, 64% by weight, 65% by weight, 66% by weight, 67% by weight, 68% by weight, 69% by weight, 70% by weight, 71% by weight, 72% by weight, 73% by weight, 74% by weight, 75% by weight, 76% by weight, 77% by weight, 78% by weight, 79% by weight, 80% by weight, or any range of weights subsumed between these values.

[0071] The compositions and dosage forms of the present invention may also optionally comprise additional pharma- ceutically acceptable excipients, such as stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof.

[0072] In one embodiment, the dosage form of the present invention comprises: (i) about 1% by weight to about 60% by weight, preferably about 2% by weight to about 55% by weight, and most preferably about 5% by weight to about 50% by weight of C8-C KI based on the total weight of the solid composition or dosage form; 16 Aliphatic sulfate ester salts, (ii) from about 1% by weight to about 60% by weight, preferably from about 2% by weight to about 50% by weight, and most preferably from about 3% by weight to about 40% by weight of one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, each having an HLB value of about 10 or more, preferably an HLB value of about 11 or more, more preferably an HLB value of about 12 or more, and most preferably an HLB value of about 14 or more; and (iii) at least one additional pharma- ceutically acceptable excipient selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof; is a solid or semi-solid oral dosage form, preferably a capsule or tablet, comprising:

[0073] In further embodiments, such as semi-solid embodiments, the oral dosage form may further comprise (iv) a thickening agent that is solid at ambient temperature but exhibits a melting point below 120° C., preferably below 100° C., more preferably below 80° C., and most preferably below 60° C. If the dosage form comprises (iv) a thickening agent that is solid at ambient temperature but exhibits a melting point below 120° C., agent (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, and 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 the 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 about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.0 ... %, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9% 4.0% 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0% by weight, or any range of weight values ​​subsumed therein.

[0075] Examples of antioxidants that may be 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 pyrosulfite, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, tocopherol, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl benzoate, pyridoxine, ethylvanillin, and mixtures thereof. Preferred antioxidants for use in the present invention include BHT, BHA, AP, propyl gallate, alpha tocopherol, or any mixtures thereof. In general, the amount of antioxidant present in the compositions of the present invention is from about 0.0001% to about 5% by weight, preferably from about 0.01% to about 2% by weight, and most preferably from about 0.05% to about 1% by weight, based on the total weight of the composition.

[0076] As used herein, unless otherwise defined, the term "desiccant" refers to a pharma- ceutically 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, thickeners, as described below, may also be used as desiccants. When present, the amount of desiccant in the composition of the present invention may range from about 0.05% to about 10% by weight of the total weight of the composition, preferably from about 0.1% to about 5% by weight of the total weight of the composition, and most preferably from about 0.5% to about 2.5% by weight of the total weight of the composition.

[0077] Examples of buffers that may be 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, buffers include combinations of the above to create buffer systems such as citric acid and sodium citrate or acetic acid and sodium acetate.

[0078] Examples of pH adjusting agents used in the present invention include, but are not limited to, any pharma- ceutically acceptable acid or base that is used to adjust the pH of pharmaceutical compositions.Examples of typical compounds that are used to adjust the pH of pharmaceutical compositions 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, buffers and / or pH adjusters may comprise from about 0.01% to about 20% by weight of the composition, preferably from about 0.1% to about 10% by weight, and most preferably from 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, carbohydrates such as lactose, glucose, sucrose, maltose, or microcrystalline cellulose, clays, and mixtures thereof. Generally, the amount of filler present in the compositions of the present invention is 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 may be used in the present invention include natural or synthetic waxes, C 12 -C 60 Alcohol, C. 12 -C 60These include organic materials such as acids, alpha-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, etc., and inorganic / organic materials such as metal ester complexes containing zinc, calcium, aluminum, or magnesium, fumed silica, and organoclays, etc. Further thickening agents 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, ouricle, rezowax, and other known mined and mineral waxes.Synthetic waxes include, but are not limited to, paraffin wax and microcrystalline wax.

[0083] Further thickening agents that may be included in the compositions of the present invention are gelling agents. Gelling agents are materials that swell or expand when in contact with water. Examples of gelling agents that may be used in the present invention include swellable polymers, also known as osmopolymers or hydrogels. Swellable polymers may be non-crosslinked or lightly crosslinked. Crosslinks may be covalent or ionic bonds with the polymer having the ability to swell in the presence of fluid, and when crosslinked, it does not dissolve in the fluid. The polymer may be of plant, animal, or synthetic origin. Polymeric gelling agents useful for this purpose include polyhydroxyalkylcelluloses having a molecular weight greater than 50,000, such as hydroxypropyl dimethylcellulose (METHOCEL K100M available from Dow Chemical); poly(hydroxyalkyl methacrylates) having a molecular weight of 5,000 to 5,000,000; poly(vinylpyrrolidones) having a molecular weight of 100,000 to 3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinyl alcohols) having low acetate residuals; swellable mixtures of agar and carboxymethylcellulose; swellable compositions comprising methylcellulose mixed with loosely crosslinked agar; polyethers having a molecular weight of 10,000 to 6,000,000; water-swellable copolymers made by dispersion of finely divided copolymers of maleic anhydride with styrene, ethylene, propylene or isobutylene; water-swellable polymers of N-vinyl lactams, and the like.

[0084] Other gelling agents useful in the present invention include pectins having a molecular weight of 30,000 to 300,000; polysaccharides such as agar, acacia, karaya, tragacanth, algin, and guar; polymers of acrylic acid crosslinked with polyallyl ethers of sucrose as described in U.S. Pat. Nos. 2,798,053 and 2,909,462, acrylic acid polymers, carboxyvinyl polymers, also known as carboxypolymethylenes, available as CARBOPOL® 934, 940, and 941, and salts thereof; polyacrylamides; water-swellable indene maleic anhydride polymers; GOOD-RITE®, a polyacrylic acid having a molecular weight of 80,000 to 200,000; POLYOX®, a polyethylene oxide polymer having a molecular weight of 100,000 to 7,000,000. TM ; Starch graft copolymer; AQUA-KEEP, an acrylate polymer that can absorb approximately 400 times its own weight in water. TM diesters of polyglucans; mixtures of crosslinked polyvinyl alcohol and poly(N-vinyl-2-pyrrolidone); and poly(ethylene glycol) having a molecular weight of 4,000 to 100,000. Representative polymers having gelling properties are described in U.S. Patent Nos. 6,419,954, 4,915,949, 4,327,725, and 4,207,893, and in Handbook of Common Polymers by Scott and Roff, published by the Cleveland Rubber Company, Cleveland, Ohio.

[0085] In general, the amount of thickener present in the composition of the present invention is about 0% to about 30% by weight, preferably about 0.01% to about 25% by weight, and most preferably about 1% to about 15% by weight, based on the total weight of the composition. In the semi-solid embodiment of the present invention, the thickener, which 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, and most preferably less than 60°C, as described above, may be present in an amount of about 7.5% to about 75% by weight, preferably about 10% to about 60% by weight, and most preferably about 12% to about 50% by weight, based on 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, ouricuri, rezowax, etc., hydrogenated oils (also known as hydrogenated vegetable glycerides), hydrogenated vegetable oils, C 12 -C 60 Alcohol, C. 12 -C 60 These include, but are not limited to, acids, alpha hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and combinations of the foregoing.

[0086] Examples of binders that may be used in the solid dosage forms of the present invention include acacia, povidone, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, polyethylene oxide, polymethacrylates, methylcellulose, ethylcellulose, pregelatinized starch, gelatin, tragacanth, zein, or mixtures thereof. Preferably, the binder is selected from povidone, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, polymethacrylates, methylcellulose, gelatin, and ethylcellulose, or combinations thereof. Particularly preferred binders include povidone, hypromellose, hydroxypropylcellulose, gelatin, and mixtures thereof. When the binder is a polymeric binder, it is preferred that the binder 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 compositions of the present invention is from about 0% to about 30% by weight, preferably from about 0.01% to about 25% by weight, and most preferably from about 1% to about 15% by weight, based on the total weight of the composition.

[0088] Examples of disintegrants that may 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 comprised between about 0% and about 40% by weight, preferably between about 1% and about 25% by weight, and most preferably between about 2% and about 20% by weight, based on the total weight of the composition.

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

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

[0091] Flavorings that may be used in the solid dosage forms of the present invention include artificial sweeteners such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, flavors such as citric acid, peppermint oil, wintergreen oil, menthol, lemon, lime, orange, grape, cherry, vanilla extract, etc. Additional 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) About 1% by weight to about 80% by weight, preferably about 2% by weight to about 70% by weight, more preferably about 3% by weight to about 60% by weight, and most preferably about 5% by weight to about 50% by weight of C8-C 16The KI is an aliphatic sulfate salt, and preferably the KI is acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilot ... and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and preferably selected from the group consisting of C8-C of KI. 16 The aliphatic sulfate is a lauryl sulfate of KI, most preferably a mono- or di-lauryl sulfate of KI; (ii) about 1% to about 95% by weight, preferably about 5% to about 90% by weight, and most preferably about 10% to about 80% by weight of a liquid carrier selected from the group consisting of fatty acids, medium chain triglycerides, fatty acid esters, fatty acid alcohols, vegetable oils such as corn oil, soybean oil, olive oil, sunflower oil, peanut oil, and the like, or mixtures thereof; and (iii) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof; The liquid dosage form is preferably filled into a hard or soft capsule.

[0093] Embodiment B of the present invention is (i) About 1% by weight to about 80% by weight, preferably about 2% by weight to about 70% by weight, more preferably about 3% by weight to about 60% by weight, and most preferably about 5% by weight to about 50% by weight of C8-C 16The KI is an aliphatic sulfate salt, and preferably the KI is acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilot ... and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and preferably selected from the group consisting of C8-C of KI. 16 The aliphatic sulfate is a lauryl sulfate of KI, most preferably a mono- or di-lauryl sulfate of KI; (ii) about 1% by weight to about 90% by weight, preferably about 2.5% by weight to about 80% by weight, more preferably about 3% by weight to about 70% by weight, most preferably about 5% by weight to about 60% by weight of 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, and most preferably less than 60°C, the solid carrier being preferably a carrier 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 pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof; The present invention is a solid or semi-solid oral dosage form which may be a tablet, or a soft or hard capsule comprising:

[0094] Embodiment C of the present invention is (i) About 1% by weight to about 80% by weight, preferably about 2% by weight to about 70% by weight, more preferably about 3% by weight to about 60% by weight, and most preferably about 5% by weight to about 50% by weight of C8-C 16 The KI is an aliphatic sulfate salt, and preferably the KI is acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilot ... and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and preferably selected from the group consisting of C8-C of KI. 16 The aliphatic sulfate is a lauryl sulfate of KI, most preferably a mono- or di-lauryl sulfate of KI; (ii) about 1% to about 60% by weight, preferably about 2% to about 50% by weight, most preferably 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 acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylate alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters of polyglycerides or fatty acid alcohols, 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 5% by weight to about 90% by weight, preferably about 10% by weight to about 85% by weight, and most preferably about 15% by weight 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, and most preferably 7 or less, the second carrier being selected from the group consisting of a humectant, an emulsifier, a solubilizer, a surfactant, or a combination thereof, each having an HLB value of less than about 10, more preferably a medium-chain monoglyceride, a medium-chain diglyceride, a polyoxylglyceride, a sorbitan ester, a sorbitan fatty acid ester, a phospholipid, and a combination thereof, most preferably a medium-chain monoglyceride, a medium-chain diglyceride, a lecithin, and a combination thereof; and (iv) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof; The present invention relates to a solid or semi-solid oral dosage form, such as a soft or hard capsule, comprising:

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

[0096] Embodiment D of the present invention is a solid oral dosage form such as a tablet or capsule, the contents of the tablet or capsule comprising: (i) About 1% by weight to about 80% by weight, preferably about 2% by weight to about 70% by weight, more preferably about 3% by weight to about 60% by weight, and most preferably about 5% by weight to about 50% by weight of C8-C 16The KI is an aliphatic sulfate salt, and preferably the KI is acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilot ... and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and preferably selected from the group consisting of C8-C of KI. 16 The aliphatic sulfate is a lauryl sulfate of KI, most preferably a mono- or di-lauryl sulfate of KI; (ii) about 1% to about 60% by weight, preferably about 2% to about 50% by weight, most preferably about 3% to about 40% by weight of one or more wetting agents, solubilizers, emulsifiers, 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, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or more are preferably selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylate alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters of polyglycerides or fatty acid alcohols, 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) about 0% to about 40% by weight, preferably about 1% to about 25% by weight, and most preferably 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, and most preferably from about 20% to about 80% by weight, of a filler; and (v) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, thickeners, binders, lubricants, glidants, flavorings, and combinations thereof; Includes.

[0097] In some embodiments of embodiment D, the C8-C 16 The aliphatic sulfate salt and at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% by weight of one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or greater are present in the solid tablet or solid capsule in an intimate admixture, preferably formed prior to combining with components (iii), (iv) and / or (v).

[0098] Embodiment E of the present invention is (i) About 1% by weight to about 80% by weight, preferably about 2% by weight to about 70% by weight, more preferably about 3% by weight to about 60% by weight, and most preferably about 5% by weight to about 50% by weight of C8-C 16 The KI is an aliphatic sulfate salt, and preferably the KI is acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilot ... and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and preferably selected from the group consisting of C8-C of KI. 16The aliphatic sulfate is a lauryl sulfate of KI, most preferably a mono- or di-lauryl sulfate of KI; (ii) about 1% to about 70% by weight, preferably about 2% to about 60% by weight, most preferably about 5% to about 50% by weight of one or more wetting agents, solubilizers, emulsifiers, 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, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or more are selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylate alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters of polyglycerides or fatty acid alcohols, or combinations thereof, most preferably polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride, or combinations thereof; (iii) about 1% by weight to about 70% by weight, preferably about 2% by weight to about 60% by weight, most preferably about 5% by weight 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, most preferably 7 or less, wherein the second carrier is selected from the group consisting of a humectant, an emulsifier, a solubilizer, a surfactant, or a combination thereof, each having an HLB value of less than about 10, more preferably a medium-chain monoglyceride, a medium-chain diglyceride, a polyoxylglyceride, a sorbitan ester, a sorbitan fatty acid ester, a phospholipid, and a combination thereof, most preferably a medium-chain monoglyceride, a medium-chain diglyceride, a lecithin, and a combination thereof; (iv) about 0.5% by weight to about 70% by weight, preferably about 1% by weight to about 60% by weight, and most preferably about 2.5% by weight to about 50% by weight of a thickening agent 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., and most preferably less than 60° C., said thickening agent being a natural or synthetic wax such as carnauba wax, cetyl ester wax, microcrystalline wax, white wax, yellow wax, beeswax, ozokerite, paraffin, ceresin, esparto, ouricle, rezowax, etc., hydrogenated oils (also known as hydrogenated vegetable glycerides), hydrogenated vegetable oils, C 12 -C 60 Alcohol, C. 12 -C 60 a thickening agent selected from the group consisting of acids, alpha-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and combinations thereof; and (v) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, binders, lubricants, glidants, flavorings, and combinations thereof; A semi-solid oral composition comprising: KI's C8-C 16 The aliphatic sulfate salt and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, having an HLB value of 10 or greater, are present in an intimate mixture.

[0099] Embodiment F of the invention is a solid oral dosage form, such as a tablet or capsule, the contents of the tablet or capsule comprising: (i) About 1% by weight to about 80% by weight, preferably about 2% by weight to about 70% by weight, more preferably about 3% by weight to about 60% by weight, and most preferably about 5% by weight to about 50% by weight of C8-C 16The KI is an aliphatic sulfate salt, and preferably the KI is acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilot ... and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and preferably selected from the group consisting of C8-C of KI. 16 The aliphatic sulfate is a lauryl sulfate of KI, most preferably a mono- or di-lauryl sulfate of KI; (ii) about 1% by weight to about 60% by weight, preferably about 2% by weight to about 50% by weight, and most preferably about 3% by weight to about 40% by weight of one or more wetting agents, solubilizers, emulsifiers, surfactants, or combinations thereof, each 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, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or more are fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, an agent or combination thereof selected from the group consisting of sorbitan ester ethoxylate alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters of polyglycerides or fatty acid alcohols, 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) from about 1% to about 60% by weight, preferably from about 2% to about 50% by weight, and most preferably from about 3% to about 45% by weight of one or more polymeric agents, preferably a water-soluble polymeric agent having 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., most preferably a polymeric agent selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, gelatin, and mixtures thereof; The solid dispersion comprises:

[0100] The solid dispersion dosage form of embodiment F may further comprise additional granules within or mixed with the solid dispersion, i.e.: (iv) about 0% to about 40% by weight, preferably about 1% to about 25% by weight, and most preferably about 2.5% to about 25% by weight, of a disintegrant; (v) from about 0% to about 90% by weight, preferably from about 15% to about 85% by weight, and most preferably from about 20% to about 80% by weight, of a filler; and (vi) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, thickeners, binders, lubricants, glidants, flavorings, and combinations thereof.

[0101] Embodiment G of the present invention is a sustained or extended release solid oral dosage form, such as a tablet or capsule, the contents of which are: (i) About 1% by weight to about 80% by weight, preferably about 2% by weight to about 70% by weight, more preferably about 3% by weight to about 60% by weight, and most preferably about 5% by weight to about 50% by weight of C8-C 16The KI is an aliphatic sulfate salt, and preferably the KI is acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilot ... and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably selected from the group consisting of afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and preferably selected from the group consisting of C8-C of KI. 16 The aliphatic sulfate is a lauryl sulfate of KI, and most preferably a mono- or di-lauryl sulfate of KI. 16 Aliphatic sulfate ester salts, (ii) about 1% to about 60% by weight, preferably about 2% to about 50% by weight, most preferably about 3% to about 40% by weight of one or more wetting agents, solubilizers, emulsifiers, 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, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or more are preferably selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylate alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters of polyglycerides or fatty acid alcohols, 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) about 0.5% to about 50% by weight, preferably about 1% to about 40% by weight, and most preferably about 2% to about 35% by weight, of a sustained release or extended release agent, the sustained release or extended release agent being capable of releasing the C8-C KI from the dosage form for more than 1 hour, more than 2 hours, more than 3 hours, more than 4 hours, more than 5 hours, or more than 6 hours. 16 The additive for slow or sustained release of the aliphatic sulfate ester salt is preferably selected from the thickeners described above, more preferably the gelling agent described above, and is selected from the thickeners described above, and is preferably a polyhydroxyalkylcellulose having a molecular weight of more than 50,000, such as hydroxypropyl methylcellulose (METHOCEL K100M available from Dow Chemical Co.), 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 having a molecular weight of 100,000 to 7,000,000 (POLYOX®), and the like. TM ), and combinations thereof; (iv) optionally, from about 5% to about 90%, preferably from about 15% to about 85%, and most preferably from about 20% to about 80% by weight of a filler; and (v) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, binders, lubricants, glidants, flavorings, and combinations thereof; Includes.

[0102] In some embodiments of embodiment G, the C8-C 16The 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 the solid tablet or solid capsule in an intimate admixture, preferably formed prior to combining with components (iii), (iv) and / or (v).

[0103] In an embodiment of embodiment G, the sustained or extended release solid oral dosage form has a C8-C KI when tested using a USP Type II Apparatus (Paddle) (900 ml of aqueous medium at pH 6.8 and 0.1% sodium lauryl sulfite, 75 rpm, with or without a sinker). 16 The aliphatic sulfate salts are released as follows: [Table 1]

[0104] In certain embodiments of the present invention, particularly embodiments A-F, the solid oral dosage form has a C8-C KI when tested using a USP Type II Apparatus (Paddle) (500 ml of 0.1 N HCl, 75 rpm, with or without sinker, 37° C.). 16 The aliphatic sulfate salts are released as follows: [Table 2]

[0105] Certain embodiments of the present invention, particularly liquid oral dosage forms, exhibit a C8-C KI when tested using a USP Type II Apparatus (Paddle) (500-900 ml of 0.1 N HCl, 75 rpm, with or without sinker, 37° C.). 16 The aliphatic sulfate salts are released as follows: [Table 3]

[0106] Alternatively, certain embodiments of the present invention, particularly liquid oral dosage forms, may exhibit a C8-C KI when tested using a USP Type II Apparatus (Paddle) (900 ml of 0.1 N HCl and 0.1% Tween® 80, 75 rpm, with or without sinker, 37° C.). 16 The aliphatic sulfate salts are released as follows: [Table 4]

[0107] The compositions and dosage forms of the invention, particularly those described in embodiments A-G above, are stable when prepared and stored under normal and accelerated conditions. More specifically, the dosage forms of the invention contain less than about 1% of individual degradants, preferably less than about 0.75% of individual degradants, most preferably less than about 0.5% of individual degradants when stored 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. and about 60% relative humidity for at least 3 months, preferably 6 months, most preferably 1 year, and / or at about 40° C. and about 75% relative humidity for 1 month, 2 months, or 3 months.

[0108] The compositions and dosage forms of the invention, particularly those described in embodiments A-G above, should also contain less than about 2% total degradants, preferably less than about 1.5%, and most preferably less than about 1.0%, when stored 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. and about 60% relative humidity for at least 3 months, preferably 6 months, most preferably 1 year, and / or at about 40° C. and about 75% relative humidity for 1 month, 2 months, or 3 months.

[0109] KI's C8-C 16The aliphatic sulfates, particularly the lauryl sulfates 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. 16 The aliphatic sulfates, particularly the lauryl sulfates of KI used in the solid dispersion dosage form of embodiment F, are preferably amorphous.

[0110] Table 1 shows the amount of lauryl sulfate salt of KI present in the dosage forms of the present invention, particularly those described in embodiments A through G above. [Table 5]

[0111] Table 2 shows the C8-C 16 US FDA approved indications are provided for preferred KI compounds and conditions for which the aliphatic sulfate salts, particularly the lauryl sulfate salts of the KI of the present invention, may be used to treat. [Table 6]

[0112] The present invention relates to the C8-C 16 The present invention includes a method of treating various conditions identified in Table 2 by oral administration of one or more dosage forms comprising an aliphatic sulfate salt, preferably one or more dosage forms comprising a lauryl sulfate salt of KI. In certain embodiments, (i) oral administration may be with or without food, where oral administration exhibits substantially constant pharmacokinetic values ​​or no food effect, as described in more detail below, (ii) oral administration allows for a reduction in the total daily dose of KI compound while maintaining similar pharmacokinetics compared to currently U.S. FDA approved KI compositions, as described in more detail below, (iii) oral administration may be with or without co-administration of a gastric acid suppressant, where oral administration exhibits no gastric acid suppressant effect, as described in more detail below, or (iv) oral administration exhibits a combination of (i), (ii) and / or (iii).

[0113] In certain embodiments, the invention includes methods of treating a condition identified in Table 2 by oral administration of one or more dosage forms described in embodiments A-G and comprising a lauryl sulfate salt of KI in the amounts listed in Figure 1. In these embodiments, (i) oral administration may be with or without food, and oral administration exhibits substantially constant pharmacokinetic values ​​or no food effect, as described in more detail below, (ii) oral administration allows for a reduction in the total daily dose of KI compound while maintaining similar pharmacokinetics compared to currently U.S. FDA approved KI compositions, as described in more detail below, (iii) oral administration may be with or without co-administration of a gastric acid suppressant, and oral administration exhibits no gastric acid suppressant effect, as described in more detail below, or (iv) oral administration exhibits a combination of (i), (ii) and / or (iii).

[0114] For example, a dosage form comprising 10-400 mg, preferably 15-350 mg, more preferably 25-300 mg of nilotinib sulfate as described in embodiments A-G can be orally administered to a patient to treat chronic myeloid leukemia, where (i) oral administration can be with or without food, and oral administration shows no food effect, (ii) oral administration allows for a reduction in the total daily amount of nilotinib free base compared to currently approved doses of nilotinib hydrochloride while maintaining similar pharmacokinetics to oral administration of nilotinib hydrochloride, and (iii) oral administration can be with or without co-administration of a gastric acid suppressant, and oral administration shows no gastric acid suppressant effect.

[0115] Similarly, the dosage forms described in embodiments A-G and comprising 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 myeloid leukemia and / or acute lymphoblastic leukemia, where (i) oral administration may be with or without food, and oral administration does not exhibit a food effect, and (ii) oral administration may be with or without co-administration of a gastric acid suppressant, and oral administration does not exhibit a gastric acid suppressant effect.

[0116] The compositions and dosage forms of the present invention, including but not limited to embodiments A-G, can be administered to a subject, which may be in either a fed or fasted state, and which have substantially constant pharmacokinetic values ​​or no food effect when administered under either fed or fasted conditions. Generally, a fed state is defined as a state in which food is consumed within about 30 minutes prior to administration of the composition or dosage form. The meal may be a high-fat meal, a low-fat meal, a high-calorie meal, or a low-calorie meal. A fasted state can be defined as a state in which no food is consumed 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 refrains from consuming food for about 30 minutes to 2 hours, preferably about 1 hour, after administration. In another embodiment, a fasted subject should not consume 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] Methods of orally administering compositions and / or dosage forms of the invention to a patient or healthy subject, including but not limited to embodiments A-G, can be administered with or without food, regardless of whether the composition is administered with or without food. max , C max Pharmacokinetic values ​​such as AUC, T, and AUC are substantially constant. A substantially constant pharmacokinetic value means that the measured pharmacokinetic values ​​obtained after single or multiple administration of compositions and dosage forms, including but not limited to embodiments A-G, to a patient or healthy subject under fasted conditions as described in US FDA guidance documents do not vary by more than 40%, preferably by more than 30%, and most preferably by more than 20% when the same compositions are administered to the same patient or healthy subject under fed conditions as described in US FDA guidance documents. For example, the T at 3 hours after a single administration to a patient under fed conditions is not significantly different from the T at 3 hours. max If obtained, T in the range of 1.8 hours to 4.2 hours max is considered to be 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 bioequivalent or shows no food effect when administered under fed and fasted conditions. The terms "bioequivalent" and "no food effect" are used in accordance with US FDA guidance documents.

[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, provides a C of KI administered with a meal. max and C of KI administered without food. max is about 0.60 to about 2.5, preferably about 0.70 to about 2.0, more preferably about 0.75 to about 1.5, and most preferably 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 to G, reduces the AUC 0-∞ and the AUC of the KI of the pharmaceutical composition administered without food. 0-∞ Ratio of (AUC 0-∞ fed / AUC 0-∞ fast ) is about 0.60 to about 2.5, preferably about 0.70 to about 2.0, more preferably about 0.75 to about 1.5, and most preferably about 0.8 to about 1.25.

[0120] Oral administration of compositions or dosage forms of the invention, including but not limited to embodiments A-G, results in a plasma profile in which at least one pharmacokinetic parameter differs by less than 40% under fed and fasted conditions. In various embodiments, the pharmacokinetic parameter may vary by less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5% under fed and fasted conditions. Food-independent pharmacokinetic parameters include, but are not limited to, C max ,A.U.C.,T. max , or a combination thereof.

[0121] In one embodiment of the invention, the method comprises orally administering to a patient one or more of the dosage forms described in embodiments A-G, which may be administered with or without food, and wherein the C8-C 16 Dosing of the aliphatic sulfate salts, and particularly the lauryl sulfate salt of KI, comprises a method of treating cancer in a human patient that does not require adjustment of the dosage or alteration of the time of administration.

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

[0123] Table 3 shows the current US FDA approved doses of some suitable KIs. [Table 7]

[0124] In one embodiment, the C8-C 16Aliphatic sulfates, particularly lauryl sulfate of KI, can reduce the recommended total daily dose of KI free base 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 of nilotinib free base. Oral administration of nilotinib lauryl sulfate can reduce the daily dose by at least 25%, i.e., to 450-600 mg, while C max , T max and / or pharmacokinetics such as AUC, etc. remain similar or substantially similar. Alternatively, a patient receiving 800 mg of nilotinib (as the hydrochloride salt) can be administered 600 mg of nilotinib (as the lauryl sulfate salt) while maintaining similar plasma concentrations of nilotinib.

[0125] The solubility of many KI drugs is pH dependent. The solubility of many KI drugs decreases as the pH increases. Patients taking KI drugs may also be administered or co-administered with gastric acid suppressants, such as antacids, H2 antagonists, and proton pump inhibitors, to reduce gastric acid secretion or increase gastric pH. Gastric acid suppressants increase the pH of the patient's stomach, thereby decreasing the solubility of the co-administered KI drug in the patient's stomach, which results in decreased absorption. To avoid decreased absorption or the effects of gastric acid suppressants, patients are advised to take an antacid at least 2 hours before or after taking the KI drug, or to discontinue use of H2 antagonists or proton pump inhibitors during treatment with the KI drug. According to the present invention, there is no need to stagger administration of antacids or discontinue use of H2 antagonists or proton pump inhibitors during treatment with the KI drug. The C8-C of the KI of the present invention 16 Aliphatic sulfates, particularly the lauryl sulfate of KI, can be administered orally to patients or healthy subjects and, with or without a gastric acid suppressant, have been shown to be effective in reducing C max , T maxPharmacokinetic values ​​such as AUC and AUC are similar or substantially constant. Substantially constant pharmacokinetic values ​​mean that the measured pharmacokinetic values ​​obtained after administration of the compositions and dosage forms of the invention, including but not limited to embodiments A-G, one or more times to a patient or healthy subject under fasted conditions with a gastric acid suppressant do not change by more than 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% when the same compositions are administered to the same patient or healthy subject under fasted conditions without a gastric acid suppressant.

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

[0127] In one embodiment of the invention, the dosage forms of embodiments A-G are employed in the amounts of bosutinib, dasatinib, erlotinib, gefitinib, neratinib, nilotinib, and pazopanib set forth in Table 1 for treating the conditions set forth in Table 2, and administration is oral, with or without co-administration of a gastric acid suppressant, and ... max , T max Pharmacokinetic values ​​such as AUC and IL-10 will remain substantially constant.

[0128] One embodiment of the invention comprises orally administering to a patient one or more of the dosage forms described in embodiments A-G and co-administering to the patient a gastric acid suppressant, 16 Dosage of the aliphatic sulfate salt, particularly the lauryl sulfate salt of KI, includes a method of treating cancer in a human patient that does not require dosage preparation or modification of administration time. Examples of KIs that are particularly useful in this embodiment are bosutinib, dasatinib, erlotinib, gefitinib, neratinib, nilotinib, and pazopanib, in the amounts set forth in Table 1, to treat the specific cancers set forth in Table 2.

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

[0130] Example 1 Nilotinib hydrochloride monohydrate (2.48 g) was dissolved in 1900 mL of 0.1N hydrochloric acid solution, and 1.16 g of sodium lauryl sulfate was dissolved in 100 mL of 0.1N 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 precipitated nilotinib hydrochloride was collected by removing the supernatant and dried at 40°C for 18 hours.

[0131] Example 2 Calabrutinib, 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, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib lauryl sulfate Tertib salts are 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, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib in 0.1N HCl or 0.1N Dissolve sodium lauryl sulfate in a suitable solvent, such as a combination of HCl and C1-C6 alcohols, such as methanol, ethanol, and isopropanol, and use sodium lauryl sulfate or sodium lauryl sulfate aqueous solution to treat acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, and other conditions. , enasidenib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib solutions in a manner similar to that described in Example 1.

[0132] Example 3 A capsule dosage form of nilotinivulauril sulfate was prepared by mixing the nilotinivulauril 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 Nilotiniblauric sulfate capsules were prepared by dissolving 1940 mg of Nilotiniblauric sulfate (dried precipitate) and 1040 mg of Poloxamer 188 in 5 mL of ethanol. The solution was mixed manually with AVICEL PH 101 (microcrystalline cellulose) and 3100 mg of lactose. The resulting granules were dried, sieved through a 60 mesh screen, powdered, and blended with 210 mg of colloidal silicon dioxide, 1040 mg of sodium starch glycolate, 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 Capsules similar to those prepared in Examples 3 and 4, but adjusted to contain a weight resulting in approximately 50 mg of nilotinib free base, along with capsules obtained by dividing a commercially available TASIGNA 200 mg capsule into four capsules, each containing the equivalent of 50 mg of nilotinib free base, were administered in the fasted state to six healthy adult beagle dogs (6) in a single-center, single-dose study. Plasma samples were collected pre-dose and 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post-dose. The mean plasma concentration of nilotinib was calculated as follows: [Table 10]

[0137] A graph of the mean plasma profiles is shown in FIG.

[0138] Individual data from this study are shown in the table below. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5]

[0139] Example 6 Capsule dosage forms 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, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib 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 Capsule dosage forms 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, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib 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 Capsule dosage forms 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, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib prepared in Examples 1 and 2 using the procedures described in Example 3.

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

[0145] Example 9 Nilotinib hydrochloride monohydrate (2.92 g) was dissolved in 2900 mL of 0.1 N hydrochloric acid solution, and 1.50 g of sodium lauryl sulfate was dissolved 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] Nilotinivulauril sulfate capsule dosage form was prepared by blending Nilotinivulauril sulfate (dry precipitate) with CAPMUL® MCM (caprylic / capric glyceryl) and KOLLIPHOR® EL (Polyoxyl 35 Castor Oil) and filling the liquid blend into size 00 hard gelatin capsules.

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

[0148] Example 10 Capsules prepared according to Example 9 were administered to nine healthy subjects under fed and fed conditions. Treatment was a randomized, open-label, single-dose, three-treatment, three-arm, three-period crossover design with at least a five-day washout period between treatments. The reference drug (Ref) was a TASIGNA capsule containing 200 mg (free base) of nilotinib HCl. The test drug (Test) was a capsule prepared according to the procedure of Example 9 and containing approximately 50 mg of nilotinib free base. Based on the results described in Example 5 herein, the amount of test capsules was 100 mg (two capsules each containing 50 mg of nilotinib free base). The nine healthy subjects participating in this study were randomly assigned to one of the groups as shown in the table below.

[0149] [Table 16]

[0150] During each treatment period, blood samples were collected at 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. 0-48 , AUC 0-∞ , C max , T max , and T 1 / 2 was determined based on noncompartmental analysis. The study results were normalized to the 200 mg dose and are summarized in Table 1. AUC 0-t , AUC 0-∞ , C max The analysis was performed by ANOVA. The model included group, subject (group), period, and treatment effect. A comparison of the data obtained from administration of the test drug and the reference drug is shown in Table 2. The data shows that the composition of the present invention had a 3.4-fold higher C maxThe data show that the compositions of the present invention exhibit no food effect, i.e., they exhibit comparable pharmacokinetics under fasted and fed conditions.

[0151] [Table 17]

[0152] [Table 18]

[0153] Individual subject data obtained in this study, normalized to the 200 mg dose, are as follows: [Table 19-1] [Table 19-2] [Table 19-3]

[0154] A graph of the normalized mean plasma profile is shown in FIG.

[0155] Example 11 Dasatinib monohydrate was prepared by dissolving 253.0 mg of dasatinib monohydrate in 1000 mL of 0.1 N hydrochloric acid solution and 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 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, then sonicated for 5 minutes and stirred for 5 minutes, and the precipitate was analyzed by high pressure liquid chromatography (HPLC). Analysis showed that the precipitate contained dasatinib dilauryl sulfate.

[0157] Example 12 Dasatinib monolauryl sulfate was prepared by the following general procedure. a. 13 g of dasatinib monohydrate (dasatinib·HO) 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 to dasatinib·HO) was combined with 39 mL of methanol (3V) and 25.7 mL of 1 N HCl (1 molar equivalent to SLS). c. The composition of step (b) is added to the composition of step (a) and stirred for 30 minutes while maintaining the temperature at 50-55° C., then cooled to room temperature for about 1 hour. d. 650 mL of purified water (50V) was added to the reaction from step (c) and stirred at room temperature for 30 minutes. e. The solvent was removed from the reaction of step (d) and the residue was collected. f. 260 mL of ethyl acetate (20V) was added to the residue of step (e), and the resulting reaction mass 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 reaction mixture from step (g) was dried under vacuum at 40° C. for 6 hours to obtain crude product of dasatinib monolauryl sulfate (dasatinib-1LS). i. The crude dasatinib-1LS was combined with 130 mL of hexanes (10V), stirred for 30 min, and the solid was isolated by filtration, washed with hexanes, and dried in vacuum at 40° C. for 16 h to give dasatinib-1LS as a white powder exhibiting a chromatographic purity of >99%.

[0158] The powder X-ray diffraction pattern ("XRPD") of dasatinib monolauryl sulfate white powder is shown in Figure 3. The XRPD was obtained using a D8 Discover with GADDS (Bruker AXS GmbH, Karlsruhe, Germany) (GADDS: General Area Diffraction Detection System) using the following test conditions: Cukα 1+2 =1.54184Å 40kV, 40mA Beam size: 1.0 mm (1000 μm by collimator system) 2 (surface area can be analyzed) Detector type: Vantec-2000 (area 14 x 14 cm2, pixel density 2048 x 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 are summarized in the table below. [Table 20]

[0160] (Example 13) Dasatinib dilauryl sulfate was prepared by the following general procedure. a. 10 g of dasatinib·H2O and 500 mL of methanol (50V) were combined and stirred at 50–55 °C. b. 11.4 g of SLS (2 molar equivalents relative to dasatinib·HO) was combined with 30 mL of methanol (3V) and 79 mL of 1 N HCl (2 molar equivalents relative to SLS). c. The composition of step (b) is added to the composition of step (a) and stirred for 30 minutes while maintaining the temperature at 50-55° C., then cooled to room temperature for about 1 hour. d. 500 mL of purified water (50V) was added to the reaction of step (c) and stirred at room temperature for 30 minutes. e. The solvent was removed from the reaction of step (d) and the residue was collected. f. 200 mL of ethyl acetate (20V) was added to the residue of step (e), and the resulting reaction mass was washed three times with 100 mL of purified water (10V×3). g. The organic extracts were combined and 100 mL of methanol (10V) was added. h. The reaction mixture from step (g) was dried under vacuum at 40° C. for 6 hours to obtain crude dasatinib dilauryl sulfate (dasatinib-2LS). i. The dasatinib-2LS crude product was combined with 100 mL of hexanes (10V), stirred for 30 minutes, and the solids were isolated by filtration, washed with hexanes, and dried in vacuum at 40° C. for 16 hours to give dasatinib dilauryl sulfate as a white powder exhibiting chromatographic purity of >99%.

[0161] The XRPD of the dasatinib dilauryl sulfate white powder is shown in Figure 4. The XRPD was obtained using a D8 Discover with GADDS (Bruker AXS GmbH, Karlsruhe, Germany) (GADDS: General Area Diffraction Detection System) using the following test conditions: Cukα 1+2 =1.54184Å 40kV, 40mA Beam size: 1.0 mm (1000 μm by collimator system) 2 (surface area can be analyzed) Detector type: Vantec-2000 (area 14 x 14 cm2, pixel density 2048 x 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 are summarized in the table below. [Table 21]

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

[0164] Example 15 A capsule dosage form of dasatiniblaueril sulfate was prepared by mixing 522.0 g of dasatiniblaueril sulfate (dried 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 (10 V), and 400 mL of purified water (20 V) 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) is added to the composition of step (a) and stirred for 30 minutes while maintaining the temperature at 50-55° C., then cooled to room temperature for about 1 hour. d. 400 mL of purified water (20V) was added to the cooled reaction of step (c) and stirred at room temperature for 1 hour. e. The precipitate (white crystals) from step (d) was collected by filtration and washed with 100 mL of purified water (5V) to obtain the 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 min, and the solid was collected by filtration, washed with 100 mL of purified water (5 V), and dried in vacuum to give 28 g of PZB-1LS as a white powder with chromatographic purity of 100% and yield of 94%.

[0167] The solubility of the above prepared pazopanib monolauryl sulfate and commercial pazopanib hydrochloride was determined by adding the samples to 300 mL of the indicated solvent at 37°C and shaking or stirring for at least 18 hours until saturated. The reactions were filtered and the filtrates were analyzed by HPLC.

[0168] [Table 23]

[0169] (Example 17) PZB-1LS salt was prepared using 17.4 g of PZB·HCl and 10.58 g of SLS as starting materials by the procedure of Example 16. This method afforded 20.5 g of PZB-1LS (80% yield) with a chromatographic purity of 99.99%.

[0170] (Example 18) A capsule dosage form of pazopanivlauril 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 mg 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 pazopanib monolauryl sulfate capsules were tested using the following high performance liquid chromatography (HPLC) method. [Table 25]

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

[0174] Test samples were prepared by weighing approximately 8.0 mg of pazopanib monolauryl sulfate into a 25 mL amber volumetric flask, adding 20 mL of diluent containing 50 / 50 / 0.1 acetonitrile / water / trifluoroacetic acid by volume, sonicating for approximately 5 minutes, and stirring at approximately 800 rpm for approximately 5 minutes until the pazopanib monolauryl sulfate was dissolved. Additional diluent was added to provide approximately 0.20 mg of pazopanib per mL of test sample.

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

[0176] Capsules were stored in child-resistant, closed, foil-induction-sealed, high-density polyethylene (HDPE) bottles (126 c.c., containing 2–3 g of silica gel).

[0177] The above table indicates that the capsules should contain no more than 0.5% individual impurities ("or less"), preferably no more than 0.35% individual impurities, and most preferably no more than 0.25% individual impurities, with the total amount of impurities being no more than 1.0%, preferably no more than 0.75%, and most preferably no more than 0.60%.

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

[0179] (Example 19) A capsule dosage form of pazopaniblauric sulfate was prepared by dissolving 226 mg of poloxamer 188 in 1.2 g of ethanol. The solution was mixed manually with 2421 mg of PZB-1LS prepared by the procedures of Examples 16 and 17, 1398.3 mg of lactose monohydrate, and 238.9 mg of polyvinylpyrrolidone. The resulting granules were dried, sieved through a 60 mesh screen, powdered, 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 pazopanib monolauryl sulfate capsules were tested using the HPLC method described in Example 18 with the following results: [Table 28]

[0182] Capsules were stored in child-resistant, closed, foil-induction-sealed, high-density polyethylene (HDPE) bottles (126 c.c., containing 2–3 g of silica gel).

[0183] The above table indicates that the capsules should contain no more than 0.5% individual impurities, preferably no more than 0.35% individual impurities, and most preferably no more than 0.25% individual impurities, and the total amount of impurities should be no more than 1.0%, preferably no more than 0.75%, and most preferably no more than 0.60%.

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

[0185] (Example 20) Capsules prepared in Examples 18 and 19 containing PZB-1LS equivalent to 50 mg of pazopanib free base, together with capsules obtained by dividing a commercially available 200 mg VOTRIENT FILM COATED tablet (containing 216.7 mg of pazopanib HCl) into four capsules (each capsule containing pazopanib hydrochloride equivalent to 50 mg of pazopanib free base), were administered to six (6) healthy adult beagle dogs in the fasted state in a single-center, single-dose study. Blood was collected pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose. The mean plasma concentration of pazopanib was calculated as follows: [Table 29]

[0186] A graph of the mean plasma profiles is shown in FIG.

[0187] The individual data from this study are shown in the table below. [Table 30-1] [Table 30-2] [Table 30-3] [Table 30-4] [Table 30-5]

[0188] Example 21 Nintedanib dilauryl sulfate was prepared by the following general procedure. a. 15 g of Nintedanib esylate was added to a co-solvent of ethyl acetate / 10% NaHCO3 aqueous solution (450 ml / 150 ml) (30V / 10V) and stirred at 40° C. for 1 hour. b. The organic layer of the reaction mixture of step (a) was separated and washed twice with 150 mL of purified water (10V x 2). c. The organic extracts from step (b) were combined and concentrated to give nintedanib free base as a yellow powder (12.3 g, 98.7% yield). 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. An SLS solution was prepared by dissolving 13.1 g of SLS (2 molar equivalents relative to nintedanib) in 36.9 mL of methanol / 90 mL of 1 N HCl co-solvent (3V). f. The SLS solution of step (e) was added to the mixture of step (d) and stirred at 50-55 °C for 30 min. g. 246 mL of purified water was added to the reaction mixture of step (f) and stirred at room temperature for 1 hour. h. The precipitate (crystals) from step (g) was collected by filtration and washed with 61.5 mL of purified water (5 V) to obtain a crude product of nintedanib dilauryl sulfate. i. The crude product of nintedanib dilauryl sulfate was combined with 123 mL of purified water (10 V), stirred for 30 minutes, and the solid was collected by filtration, washed with 61.5 mL of purified water (5 V), and dried under vacuum to give nintedanib dilauryl sulfate as a golden yellow powder with chromatographic purity of 100% and yield of 89.3%.

[0189] Example 21A A tablet dosage form of nintedanib dilauryl sulfate was prepared by the following wet granulation process. (i) 9.940 g of nintedanib dilauryl sulfate prepared by the procedure of Example 21 was mixed with 1.800 g of poloxamer 407 and 1.575 g of poloxamer 188. (ii) The mixture of step (i) was granulated with a solution containing 1.500 g of alcohol (95%) and 1.500 g of purified water. (iii) 6.000 g of anhydrous lactose and 8.278 g of microcrystalline cellulose were sifted through a No. 40 mesh sieve and added to the granules of step (ii) and the resulting composition was blended. (iv) The blend of step (iii) was dried in an oven at 50°C to evaporate the alcohol and water and after drying was sieved through a 40 mesh sieve. (v) The dried and sieved material of step (iv) was mixed with 0.600 g colloidal silicon dioxide sieved through a 40 mesh sieve and 1.500 g polyethylene oxide of average molecular weight 7,000,000 (Polyox WSR303). (vi) 0.007 g of butylated hydroxytoluene (BHT) was sieved through a 40 mesh sieve and added to the composition of step (v) and mixed. (vii) 0.300 g of magnesium stearate was sieved through a 40 mesh sieve and added to the composition of step (vi) and blended to obtain the final blend. (viii) The final blend was compressed into tablets using capsule-shaped punches (17.5 mm length, 7.1 mm width) to a target hardness of approximately 10 kp.

[0190] The composition of the tablets is as follows: [Table 31]

[0191] Example 21B A tablet formulation of nintedanib dilauryl sulfate was prepared according to the procedure described in Example 21A, and the tablet composition was as follows: [Table 32]

[0192] Example 21C Dosage forms (n=2) prepared in Examples 21A and 21B were tested using a USP Type II Apparatus (Paddle) with 675 ml of 0.1N HCl for 2 hours, followed by pH change to 6.8 (final volume: 900 ml) with 0.1% sodium lauryl sulfate at 100 rpm and a sinker at 37° C. The results of this dissolution test are as follows: [Table 33]

[0193] The dosage forms (n=2) prepared in Examples 21A and 21B were also tested using a USP Type II Apparatus (Paddle) (900 mL of aqueous medium 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 above in vitro dissolution data indicates that the dosage forms prepared according to the present invention can exhibit sustained release that allows for once or twice daily administration. For example, the sustained release dosage form releases Nintedanib Lauril sulfate as follows when tested using a USP Type II Apparatus (Paddle) (900 mL of pH 6.8 aqueous medium and 0.1% sodium lauryl sulfate, 75 rpm): [Table 35]

[0195] The dosage forms prepared in Examples 21A and 21B were also tested for impurities using an HPLC method as follows. [Table 36]

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

[0197] Test samples were prepared in triplicate by crushing the tablets, transferring the crushed material to a 100 mL amber volumetric flask, adding 80 mL of methanol, stirring for about 120 minutes or more until the material was 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] Tablet dosage forms of nintedanib dilauryl sulfate prepared in Examples 21A and 21B were found to have the following impurity profile: [Table 37]

[0199] The above data indicate that nintedanib dilauryl sulfate dosage forms of the present invention should have no more than 0.5% individual impurities, preferably no more than 0.35% individual impurities, and most preferably no more than 0.25% individual impurities, and the total amount of impurities should be no more than 1.0%, preferably no more than 0.75%, and most preferably no more than 0.60%.

[0200] (Example 21D) Tablets prepared according to 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 in the fasted state together with commercially available OFEV® capsules (reference) containing 120.4 mg of nintedanib esylate (equivalent to 100 mg of nintedanib free base) in a single-center, single-dose study to six (6) healthy subjects in a fasted state. This was an open-label, randomized, three-treatment, three-arm, three-period crossover bioavailability study conducted in healthy subjects under fasting conditions. All subjects were randomly assigned to the groups shown in the table below, with a seven-day washout period between each period. [Table 38]

[0201] During each treatment period, blood samples were taken at 0 (pre-dose), 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 was determined for each subject based on non-compartmental analysis. The study results are summarized in the table below. Ln-transformed AUC 0-t , AUC 0-∞ , C max was analyzed by ANOVA. The model included group, subject (group), period and treatment effects. Comparison of data obtained from administration of test and reference drugs is shown in the table below. [Table 39-1] [Table 39-2]

[0202] The individual subject data obtained in this study are as follows: [Table 40-1] [Table 40-2] [Table 40-3]

[0203] A graph of the mean plasma profiles obtained in this example is shown in FIG.

[0204] Example 22 Nintedanib dilauryl sulfate capsules were prepared by manually blending 2386 mg of nintedanib dilauryl 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) A capsule dosage form of nintedanib dilauryl sulfate was prepared by mixing 2386 mg of nintedanib dilauryl sulfate (powder passed through an 80 mesh screen) prepared by 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 size 1 hard gelatin capsules.

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

[0208] (Example 24) Capsules containing nintedanib dilauryl sulfate (equivalent to 30 mg of nintedanib free base) prepared in Examples 22 and 23, together with 30 mg equivalent capsules prepared from 100 mg OFEV capsules (obtained by withdrawing the contents from a commercially available 100 mg OFEV capsule containing 120.40 mg of nintedanib esylate and refilling into new capsules, each with contents equivalent to 30 mg of nintedanib free base), were administered to six (6) healthy adult beagle dogs in the fasted state in a single-center, single-dose study. Blood samples were taken pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 36 hours post-dose. The mean plasma concentrations of nintedanib were calculated as follows: [Table 43]

[0209] A graph of the mean plasma profiles is shown in FIG.

[0210] The individual data from this study are shown in the table below. [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 esylate was added to a co-solvent of ethyl acetate / 10% NaHCO3 aqueous solution (210 mL / 170 mL) (30 V / 10 V) and stirred at 40° C. for 1 hour. b. The organic layer of the reaction product of step (a) was separated and washed twice with 170 mL of purified water (10V x 2). c. The organic extracts from step (b) were combined and concentrated to give nintedanib free base as a yellow powder (13.4 g, 95% yield). 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. An SLS solution was prepared by adding 7.16 g of SLS (1 molar equivalent relative to nintedanib) to 40.2 mL of methanol (3V) and 2.3 mL of 12 N HCl (1.1 molar equivalents), stirring for 10 min at room temperature, adding 10 mL of 10% aqueous NaHCO3, and stirring for 5 min at room temperature. f. The SLS solution of step (e) was added to the mixture of step (d) and stirred at 60° C. for 1 hour. g. The reaction mixture of step (f) was concentrated, 268 mL of ethyl acetate (20V) was added, and the resulting reaction mixture was washed with 134 mL of purified water (10V x 3). h. The organic extracts from step (g) were combined and concentrated to recover the solids and dried under vacuum at 40° C. for 16 hours to give 16.3 g of nintedanib monolauryl sulfate as a yellow powder with chromatographic purity of 100% and 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 The solubility of samples of Nintedanib lauril sulfate prepared in Examples 21 and 25, and commercially available Nintedanib esilate, was measured by adding the sample to 5-20 mL of the specified solvent at room temperature and shaking or stirring for at least 18 hours to saturation. The reaction was filtered and the filtrate was measured by HPLC. The solubility results are as follows: [Table 45]

[0214] Example 25B The HPLC method outlined in Example 21C was used to determine impurities and stability of the Nintedaniblaurill sulfate salts prepared in Examples 21 and 25.

[0215] Test samples were each prepared by weighing 29.88 mg of nintedanib monolauryl sulfate or 39.76 mg of nintedanib dilauryl sulfate (equivalent to 20 mg of nintedanib) into a 20 mL amber volumetric flask, adding 16 mL of diluent (methanol), sonicating for approximately 5 minutes, and stirring at 800 rpm for approximately 5 minutes until completely dissolved. Additional diluent was added to provide approximately 1.0 mg of nintedanib per mL of test sample.

[0216] The following results were obtained: [Table 46]

[0217] The above data indicates that nintedanib dilauryl sulfate is more stable than monolauryl sulfate and both the monolauryl and dilauryl sulfate ester salts of the present invention should contain no more than 0.5% individual impurities, preferably no more than 0.35% individual impurities, and most preferably no more than 0.30% individual impurities, and the total amount of impurities should be no more than 1.0%, preferably no more than 0.75%, and most preferably no more than 0.60%.

[0218] (Example 26) Nilotinib dilauryl sulfate was prepared by the following general procedure. a. 10 g of Nilotinib HCl was added to 100 mL of methanol (10V) and stirred at room temperature. b. 1.57 mL of 12 N HCl (1.1 molar equivalents) was added to the mixture of step (a) and stirred at 50-55 °C for 2 h. 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 from step (c) was isolated 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 yellow powder (yield 98%). e. To 10.8 g of nilotinib dihydrochloride from step (d) was added 216 mL of methanol (20 V) 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 (5 V), and the resulting mixture was added to the mixture from step (e) and stirred at 50-55 °C for 3 h. g. The reaction mixture of step (f) was concentrated, 324 mL of ethyl acetate (30V) was added, and the resulting reaction mixture was washed three times with 216 mL of purified water (20V x 3). h. The organic extracts from step (g) were combined, concentrated and dried under vacuum at 40° C. for 6 hours to obtain crude nilotinib dilauryl sulfate. i. The crude nilotinib dilauryl sulfate was combined with 108 mL of hexane (10V) and stirred for 30 minutes. j. The solids of the reaction mixture of step (i) were separated by filtration, washed with hexane, and dried under reduced pressure at 40° C. for 16 hours to give 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 Nilotinib dilauryl sulfate was prepared by the procedure of Example 26 using 30 g of nilotinib HCl and 4.71 mL of 12N NCl to give 32.4 g of nilotinib dihydrochloride (98% yield), which was combined with 29.3 g of SLS to give 48.5 g of nilotinib dilauryl sulfate with chromatographic purity of 99.97% (90% yield).

[0220] (Example 28) Nilotinib dilauryl sulfate was prepared by the following general procedure. a. 25.6 g of Nilotinib HCl was added to 768 mL methanol (30V) and stirred at room temperature. b. 4.02 mL of 12 N HCl (1.1 molar equivalents) was added to the mixture of step (a) and stirred at 50-55 °C for 2 h. c. The mixture from step (b) was distilled under vacuum and the residue was stirred with 256 mL of hexane (10 V) for 30 min. d. The solid from step (c) was separated by filtration, washed with hexane and dried under vacuum at 40° C. for 3 hours to obtain 25.7 g of nilotinib dihydrochloride as a golden yellow powder (yield 92%). e. To 25.7 g of nilotinib dihydrochloride from step (d) was added 514 mL of methanol (20 V) and the mixture was stirred at 50-55 °C. f. 23.2 g of SLS (2 molar equivalents) was added to 128.5 mL of methanol (5 V), and the resulting mixture was added to the mixture from step (e) and stirred at 50-55 °C for 3 h. g. The reaction mixture of step (f) was concentrated, 771 mL of ethyl acetate (30V) was added, and the resulting reaction mixture was washed three times with 514 mL of purified water (20V×3). h. The combined organic extracts were concentrated and dried under vacuum at 40° C. for 6 hours to give crude nilotinib dilauryl sulfate. i. The crude nilotinib dilauryl sulfate was combined with 257 mL of hexane (10 V) and stirred for 30 minutes. j. The solids of the reaction mixture of step (i) were separated by filtration, washed with hexane and dried under reduced pressure at 40° C. for 16 hours to give 36.5 g of nilotinib dilauryl sulfate as a golden yellow powder resulting in a chromatographic purity of 99.93% and a yield of 85%.

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

[0222] (Example 30) A capsule dosage form of nintedanib monolauryl sulfate was prepared by wet granulating 1,793 mg of nintedanib monolauryl sulfate prepared by the procedure of Example 25 with 600 mg of poloxamer 407, 480 mg of poloxamer 188, and 1,600 mg of anhydrous alcohol in a vessel, 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 and 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 blend 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 blended. The resulting dry blend 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 and 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.

[0223] The composition of the capsule contents is as follows: [Table 47]

[0224] (Example 31) A capsule dosage form of nintedanib monolauryl sulfate was prepared by mixing 2,441 mg of medium chain triglyceride (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 uniform dispersion. 1200 mg of hard fat (Gelucire 43 / 01) was melted in a water bath (50°C) and added to the uniform dispersion to obtain a uniform suspension (semi-solid). 1.793 mg of nintedanib monolauryl sulfate prepared by the procedure of Example 25 was sieved through an 80 mesh sieve and added to the suspension to obtain a uniform suspension and / or solidify 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, together with 30 mg equivalent capsules prepared from 100 mg OFEV capsules (obtained by withdrawing the contents from a commercially available 100 mg OFEV capsule containing 120.40 mg of nintedanib esylate and refilling into new capsules, each with a content equivalent to 30 mg of nintedanib free base), were administered to six (6) healthy adult beagle dogs in the fasted state in a single-center, single-dose study. Blood samples were taken pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 36 hours post-dose. The mean plasma concentrations of nintedanib were calculated as follows: [Table 49]

[0227] A graph of the mean plasma profiles is shown in FIG.

[0228] The individual data from this study are shown in the table below. [Table 50-1] [Table 50-2] [Table 50-3] [Table 50-4] [Table 50-5]

[0229] (Example 33) A capsule dosage form of dasatinib monolauryl sulfate was prepared by wet granulating 1,865 mg of dasatinib monolauryl sulfate prepared by the procedure of Example 12 with 750 mg of poloxamer 407, 600 mg of poloxamer 188, and 2,000 mg of absolute alcohol in a suitable container, 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 and 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 passed through a 40 mesh sieve and collected in a suitable container. 60 mg of magnesium stearate was passed through a 40 mesh sieve and 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) A capsule dosage form of dasatinib dilauryl sulfate was prepared by wet granulating 2,520 mg of dasatinib dilauryl sulfate prepared by the procedure of Example 13 with 750 mg of poloxamer 407, 600 mg of poloxamer 188, and 1000 mg of absolute alcohol in a suitable container. 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 and added to the dasatinib dilauryl 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), 120 mg of colloidal silicon dioxide, sieved through a 40 mesh sieve, 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 screen and added to the vessel 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 Capsules prepared in Examples 33 and 34 containing dasatinib monolauryl sulfate or dasatinib dilauryl sulfate, 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 dasatinib) into two capsules, were administered to six (6) healthy adult beagle dogs in the fasted state in a single-center, single-dose study. Blood samples were collected pre-dose and 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose. In this example, the doses in the analysis were standardized to 25 mg dasatinib monohydrate for the test drug and 25 mg dasatinib for Sprycel®. The mean plasma dasatinib concentrations normalized to 25 mg were as follows: [Table 53]

[0234] A graph of the mean normalized plasma profiles is shown in FIG.

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

[0236] (Example 36) Nilotinib monolauryl sulfate 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 min, at room temperature for 1 h, and at 0-10 °C for 30 min. 1,505 mL of purified water was added to the mixture and stirred at 0-10 °C for 30 min. The white crystals obtained by filtration were collected and washed with 215 mL of 85.5% aqueous ethanol 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 min, collected by filtration, and washed with 430 mL of purified water to obtain crude product 2 of nilotinib monolauryl sulfate. The crude nilotinib monolauryl sulfate product 2 was added to 430 mL of hexane, stirred for 30 minutes, collected by filtration, and washed with 215 mL of hexane to give 48 g of nilotinib monolauryl sulfate (82% yield) as an off-white powder with a chromatographic purity of 99.92%.

[0237] (Example 37) A capsule dosage form of nilotinib monolauryl sulfate was prepared by mixing 3.754 g of nilotinib monolauryl sulfate prepared by the procedure of Example 36, 12.528 g of CAPMUL® MCM (caprylic / capric glyceryl), 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, 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 stirred at room temperature for 30 min. The solid was separated by filtration, washed with hexane and dried in vacuum at 40 °C for 3 h to obtain nilotinib dihydrochloride as a golden yellow 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 h. The mixture was concentrated, 771 mL of ethyl acetate was added and the resulting reaction was washed with 514 mL of purified water. The organic extract was concentrated and dried under vacuum at 40°C for 6 hours to give crude nilotinib dilauryl sulfate. 257 mL of hexane was added to the crude nilotinib dilauryl sulfate and stirred for 30 minutes. The solid was separated by filtration, washed with hexane, and dried under vacuum at 40°C for 16 hours to give 36.5 g of nilotinib dilauryl sulfate as a golden powder with a chromatographic purity of 99.93% (85% yield).

[0240] The XRPD of the nilotinib dilauryl sulfate 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) using the following test conditions: Cukα 1+2 =1.54184Å 40kV, 40mA Beam size: 1.0 mm (1000 μm by collimator system) 2 (surface area can be analyzed) Detector type: Vantec-2000 (area 14 x 14 cm2, pixel density 2048 x 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 a commercial sample of nilotinib hydrochloride monohydrate 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 saturate. The solubility of nilotinib dilauryl sulfate prepared in Example 38 was measured by adding the sample to 5-20 mL of the specified solvent at room temperature and shaking or stirring for at least 18 hours to saturate. The reaction was filtered and the filtrate was measured by HPLC. The solubility measurement results are as follows: [Table 56]

[0242] (Example 39) A capsule dosage form of nilotinib dilauryl sulfate was prepared by mixing 8.022 g of nilotinib dilauryl sulfate prepared by the procedure of Example 38 with 20.042 g of CAPMUL® MCM (caprylic / capric glyceryl), 5.010 g of KOLLIPHOR® EL (polyoxyl 35 castor oil), and 0.667 g of sodium bicarbonate and filling the mixture into a soft gelatin capsule.

[0243] The composition of the capsule contents is as follows: [Table 57]

[0244] (Example 40) Capsules similar to those prepared in Examples 37 and 39, but adjusted to contain the approximate weight equivalent of about 50 mg of nilotinib free base, along with commercially available TASIGNA 200 mg capsules divided into four capsules (each containing the equivalent of 50 mg of nilotinib free base), were administered in the fasted state to six healthy adult beagle dogs (6) in a single-center, single-dose study. Blood was collected pre-dose and 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post-dose. The mean plasma concentration of nilotinib was calculated as follows: [Table 58]

[0245] A graph of the mean plasma profiles is shown in FIG.

[0246] The individual data from this study are shown in the table below. [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 ethyl acetate / 10% NaHCO3 aqueous solution (50V / 20V) and stirred at 45° C. for 2 hours. b. The organic layer of the reaction mixture of 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 give cabozantinib free base as a white powder (29.2 g, 100% yield). d. 1022 mL of methanol (35 V) was added to 29.2 g of cabozantinib free base and the mixture was stirred at 50-55 °C. e. An SLS solution was prepared by dissolving 16.8 g of SLS (1 molar equivalent relative to cabozantinib) in a co-solvent of 87.6 mL of methanol (3V) / 58.26 mL of 1 N HCl (1 molar equivalent). f. The SLS solution of step (e) was added to the mixture of step (d) and stirred at 50-55 °C for 30 min, and then allowed to adjust to room temperature for 1 h. g. 1460 mL of purified water (50V) was added to the reaction mixture of step (f) and stirred at room temperature for 30 minutes. h. The precipitate (crystals) from step (g) was collected by filtration and washed with 292 mL of purified water (10 V) 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 (20 V), stirred for 30 minutes, and the solid was collected by filtration and washed with 146 mL of purified water (5 V) to give 41 g of cabozantinib monolauryl sulfate as a white powder resulting in a UPLC chromatographic 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 indicated solvent at 37°C and shaking or stirring for at least 1 hour to reach saturation. The reaction was filtered and the filtrate was analyzed by HPLC. The solubility results are as follows: [Table 60]

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

[0250] Example 42A A capsule dosage form of cabozantinib monolauryl sulfate was prepared by a wet granulation process as follows. (i) 3.0595 g of cabozantinib monolauryl sulfate prepared by the procedure of Example 41, 6.10 g of poloxamer 407, and 3.05 g of poloxamer 188 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 sifted 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 dry 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 the final blend. (vi) The final blend, which is a dry solid, is filled into size 1 hard gelatin capsules.

[0251] The composition of the capsule contents is as follows: [Table 61]

[0252] Example 42B A capsule dosage form of cabozantinib monolauryl sulfate was prepared by the following steps: (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 by 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 hydrogenated oil (Gelucire 43 / 01) was melted using a water bath at 55°C and the melted hydrogenated 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) A tablet dosage form 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, previously sieved through a 40 mesh sieve, 1.2428 g of anhydrous lactose, and 0.192 g of croscarmellose sodium (Part I). (ii) A granulation solution prepared by dissolving the mixture of step (i) in 0.192 g of hydroxypropylcellulose EXF in 1.28 g of purified water. The mixture was wet granulated. (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 dry granules were sieved through a 24 mesh sieve. (iv) The dried and sieved granules were mixed with 0.192 g of croscarmellose sodium (Part 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 into tablets using 6 mm circular punches to a target hardness of approximately 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 capsule composition is as follows: [Table 64]

[0257] Example 42E The dosage forms (n=3) prepared in Examples 42A to 42D were tested using a USP Type II Apparatus (Paddle) (900 mL of 0.1 N HCl (with 0.5% TritonX-100), 75 rpm, using a sinker, 37°C). The results of this dissolution test are as follows: [Table 65]

[0258] The above in vitro dissolution data demonstrate that dosage forms prepared according to the present invention release (i) at least 40%, preferably at least 45%, and most preferably 50% of cabozantinib after 30 minutes of testing, (ii) at least 55%, preferably at least 60%, and most preferably 65% ​​of cabozantinib after 45 minutes of testing, and (III) at least 70%, preferably at least 75%, and most preferably 80% of cabozantinib after 60 minutes of testing.

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

[0260] Mobile phase A was 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 was acetonitrile / methanol / water in a volume ratio of 60 / 30 / 10.

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

[0262] Capsules were stored in child-resistant, closed, foil-induction-sealed, high-density polyethylene (HDPE) bottles (126 c.c., containing 2–3 g of silica gel).

[0263] Using the above HPLC method, cabozantinib monolauryl sulfate dosage forms were found to contain no more than 0.5% of any individual impurity, preferably no more than 0.35% of any individual impurity, and most preferably no more than 0.25% of any individual impurity, and the total amount of impurities should be no more than 1.0%, preferably no more than 0.75%, and most preferably no more than 0.60%.

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

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

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

[0267] (Example 43) The liquid dosage forms are acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, ibromidine ... The mono- or dilauryl sulfate ester salts of lutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib may be used and prepared using the procedures described in Examples 3, 9, 15, 18, 37, and 39.

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

[0269] (Example 44) Solid dosage forms such as tablets or capsules can be prepared using acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, geffenib, and the like prepared in Examples 1, 11 to 14, 16 to 17, 21, 25 to 27, 33 to 34, 36, 38, and 41. The mono- or dilauryl sulfate ester salts of ritinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib may be used and prepared 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 forms are acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fostamatinib, gefitinib, and cefotiib, prepared in Examples 1, 11 to 14, 16 to 17, 21, 25 to 27, 33 to 34, 36, 38, and 41. The mono- or dilauryl sulfate ester salts of nib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib may be used and prepared using the procedures described in Examples 23 or 31.

[0272] The composition of the semi-solid dosage form includes the following: [Table 72]

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

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

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

[0276] 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)-(f) was recrystallized according to the following procedure. 1. MeOH (15V) was added to the crude product of nilotinib monolauryl sulfate (3.747 g) and the mixture was stirred at a temperature below 60° C., preferably at about 55±5° C., until the nilotinib monolauryl sulfate was dissolved (approximately 10±5 minutes). 2. The solution from step (1) was filtered hot to remove dust or other particulate matter and washed with MeOH (5V). 3. The resulting filtrate was heated to a temperature of less than 60°C, preferably about 55±5°C. 4. Purified water (30V) was added dropwise to the solution from step (3) over a period of about 30±10 minutes while maintaining a temperature of about 55±5° C. 5. Purified water was added to form a precipitate, and the reaction was cooled to room temperature and then further cooled to 0-5°C to allow further precipitation. 6. The precipitate formed in step (5) was collected by filtration and washed with purified water (2 x 2V). 7. The precipitate collected in step (6) was dried under high vacuum to give 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)-(f) was recrystallized according to the following procedure. 1. EtOH (35V) was added to the crude product of nilotinib monolauryl sulfate (2 g) and the mixture was stirred at a temperature below 60° C., preferably at about 55±5° C., until the nilotinib monolauryl sulfate was dissolved (approximately 10±5 minutes). 2. Purified water (60V) was added to the solution of step (1) and 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 was adjusted to room temperature. 3. The precipitate formed in step (2) was collected by filtration and washed with purified water (2 x 2V). 4. The precipitate collected in step (3) was dried under high vacuum to give white crystalline nilotinib monolauryl sulfate (1.7695 g) (yield: 88.5%) (HPLC purity: 99.88%).

[0279] The XRPD pattern of white crystalline nilotinib monolauryl sulfate prepared by Crystallization Method C, obtained by the procedure outlined for Crystallization Method A, is shown in FIG.

[0280] Crystalline nilotinib monolauryl sulfate prepared by crystallization method C exhibits 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)-(f) was recrystallized according to the following procedure. 1. IPA (100V) was added to the crude product of nilotinib monolauryl sulfate (2 g) and the mixture was stirred at a temperature below 60° C., preferably at about 55±5° C., until the nilotinib monolauryl sulfate was dissolved (approximately 10±5 minutes). 2. Purified water (265V) was added to the solution of step (1) and 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 was adjusted to room temperature. 3. The precipitate formed in step (2) was collected by filtration and washed with purified water (2 x 2V). 4. The precipitate collected in step (3) was dried under high vacuum to give white crystalline nilotinib monolauryl sulfate (1.6742 g) (yield: 83.7%) (HPLC purity: 99.88%).

[0282] The XRPD pattern of white crystalline nilotinib monolauryl sulfate prepared by Crystallization Method D, obtained by the procedure outlined for Crystallization Method A, is shown in FIG.

[0283] Crystalline nilotinib monolauryl sulfate prepared by crystallization method D has 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. Dasatinib monohydrate (6 g) was added with MeOH (25 V) and the mixture was stirred at reflux temperature. b. Sodium lauryl sulfate (1 eq.) and 1N 1N HCl (1 eq.) in 3V MeOH and 3V purified water (1N HCl in purified water) were combined and the resulting mixture was stirred at room temperature for 10±5 minutes. c. Step (b) Once all solids have dissolved, the sodium lauryl sulfate / HCl solution from step (b) is added to the dasatinib mixture from step (a) and the resulting mixture is stirred at reflux temperature (65-70 °C) for approximately 30 ± 10 minutes, after which the temperature is adjusted to room temperature for 60 ± 10 minutes. d. The reaction mixture of step (c) was concentrated to dryness in vacuum on a rotary evaporator (T=45° C.). e. The concentrated reaction 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 of step (f) was concentrated in vacuo using a rotary evaporator (T=45° C.). h. The product of step (g) was dried under high vacuum to give white crystalline dasatinib monolauryl sulfate (8.7659 g) (yield: 98.0%) (HPLC purity: 99.61%). i. IPA (10 V) was added to the dasatinib monolauryl sulfate from step (h) and stirred at room temperature for 30±10 minutes. j. The white solid precipitate in the reaction of step (i) was collected by filtration and washed with IPA (2×2V). k. The washed solid precipitate of 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. To the crude product of dasatinib monolauryl sulfate (3 g) was added MeOH (5 V) and the mixture was stirred at about 60° C. for approximately 10±5 minutes. 2. Isopropyl alcohol (IPA) (40V) and hexane (40V) were added to the solution from step (1) and the temperature was maintained at about 60° C. until a precipitate formed, after which the temperature of the reaction was adjusted to room temperature. 3. The temperature of the reaction mass in step (2) was adjusted to 0-5°C for 30±10 min, and the precipitate was collected by filtration and washed with hexane (2x2V). 4. The precipitate collected in step (3) was dried under high vacuum to give white crystalline dasatinib monolauryl sulfate (2.7196 g) (yield: 88.8%) (HPLC purity: 99.94%).

[0286] The XRPD pattern of a sample of dasatinib monolauryl sulfate prepared by Crystallization Method A, obtained according to the procedures outlined in Example 46, is shown in FIG.

[0287] Crystalline dasatinib monolauryl sulfate prepared by crystallization method A has 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. 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. MeOH (5V) was added to the crude product of dasatinib monolauryl sulfate (3 g) and the mixture was stirred at about 60° C. for approximately 10±5 minutes, after which the temperature was adjusted to room temperature. 2. Ether (60V) was added to the solution from step (1) while maintaining the temperature at about 60°C. 3. The temperature of the reaction mass in step (2) was adjusted to 0-5°C for 30±10 min, and the precipitate was collected by filtration and washed with ether (2x2V). 4. The precipitate collected in step (3) was dried under high vacuum to give white crystalline dasatinib monolauryl sulfate (2.8910 g) (yield: 94.5%) (HPLC purity: 99.85%).

[0289] The XRPD pattern of a sample of dasatinib monolauryl sulfate prepared by crystallization method B, obtained according to the procedure outlined in Example 46, is shown in FIG.

[0290] Crystalline dasatinib monolauryl sulfate prepared by crystallization method B has 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 Example 47 Method A, amorphous dasatinib monolauryl sulfate prepared by Example 12, amorphous dasatinib dilauryl sulfate prepared by Example 13, and a commercial sample of dasatinib monohydrate free base was determined by adding the sample to 500 mL of the indicated solvent at 37° C. and shaking or stirring for at least 18 hours to saturation. The reactions were filtered and the filtrate was measured by HPLC. The results of the solubility measurements are as follows: [Table 73]

[0292] Solubility studies showed that the aqueous solubility of dasatinib varies with pH.

[0293] (Example 48) Dasatinib monolauryl sulfate was prepared by the following general procedure. a. Dasatinib monohydrate (3 g) was added with MeOH (25 V) and the mixture was stirred at reflux temperature. b. Sodium lauryl sulfate (1 eq.) and 1N 1N HCl (1 eq.) in 3V MeOH and 3V purified water (1N HCl in purified water) were combined and the resulting mixture was stirred at room temperature for 10±5 minutes. c. Once the solids from step (b) have dissolved, the sodium lauryl sulfate / HCl solution from step (b) is added to the dasatinib mixture from step (a) and the resulting mixture is stirred at reflux temperature (65-70 °C) for 30 ± 10 minutes, after which the temperature is adjusted to room temperature for 60 ± 10 minutes. d. The reaction mixture of step (c) was concentrated in vacuo to dryness by rotary evaporator (T=45° C.). e. The concentrated reaction from step (d) was extracted with ethyl acetate (20V) and water (10V). f. The organic layer from step (e) was washed separately with water (2×10V). g. The washed organic layer of step (f) was concentrated in vacuo using a rotary evaporator (T=35° C.). h. The product of step (g) was added to MeOH (10V) and heated to 60° C. until dissolved. i. The solution from step (h) was filtered hot to remove dust or other particulate matter and washed with MeOH (5V). j. The filtrate of step (i) was concentrated in vacuum to dryness using a rotary evaporator (T=45° C.). k. The product of step (j) was dried under high vacuum to give 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)-(k) was recrystallized according to the following procedure. 1. To the crude product of dasatinib monolauryl sulfate (3 g) was added MeOH (5 V) and the mixture was stirred at about 60° C. for approximately 10±5 minutes. 2. IPA (5V) and hexanes (25V) were added to the solution from step (1) and the temperature was maintained at about 60° C. until a precipitate formed, after which the temperature of the reaction was adjusted to room temperature. 3. The temperature of the reaction mass in step (2) was adjusted to 0-5°C for 30±10 min, and the precipitate was collected by filtration and washed with hexane (2x2V). 4. The precipitate collected in step (3) was dried under high vacuum to give white crystalline dasatinib monolauryl sulfate (2.81 g) (yield: 93.7%) (HPLC purity: 99.90%). 5. Steps 1 to 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 a dasatinivlauric sulfate sample prepared by Crystallization Method C, obtained by the procedure outlined in Example 46, is shown in FIG.

[0296] Crystalline dasatinib monolauryl sulfate prepared by crystallization method C has 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, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0±0.2, 54.0±0 0.1±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±0.2and / or 38.9±0.2.

[0297] (Crystallization method D) The crude product of dasatinib monolauryl sulfate was prepared by steps (a)-(k), which produced white crystalline dasatinib monolauryl sulfate (4.4373 g) (yield: 99.2%) (HPLC purity: 99.58%), which 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 collected in step (2) was dried under high vacuum to give white crystalline dasatinib monolauryl sulfate (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 (2.70 g) (yield: 95.4 g) (HPLC purity: 99.81%).

[0298] The XRPD pattern of a dasatinivlauric sulfate sample prepared by Crystallization Method D, obtained by the procedure outlined in Example 46, is shown in FIG.

[0299] Crystalline dasatinib monolauryl sulfate prepared by crystallization method D has 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. 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) Dasatinib monolauryl sulfate was prepared by the following general procedure. a. MeOH (25V, 1980 g) was added to dasatinib monohydrate (1 eq, 100 g) and the mixture was stirred at reflux temperature (60° C.±5° C.). b. Sodium lauryl sulfate (1 eq, 57 g) and 1N HCl (1 eq, 197 ml) in MeOH (3 V, 327 g) and purified water (1.03 V, 103 g) were combined and the resulting mixture was stirred at room temperature for 10±5 min. c. Once the solids from step (b) have dissolved, the sodium lauryl sulfate / HCl solution from step (b) is added to the dasatinib mixture from step (a) and the resulting mixture is stirred at reflux temperature (60° C.±5° C.) for about 30±10 minutes, after which the temperature is adjusted to room temperature for 60±10 minutes. d. The reaction mixture from step (c) was concentrated in vacuo to dryness using a rotary evaporator (T=40° C.). e. The concentrated reaction of 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 of step (f) was concentrated in vacuum to dryness using a rotary evaporator (T=35° C.). h. MeOH (5V, 589 g) was added to the product of step (g) and heated to 60° C. until dissolved. i. The filtrate of step (h) was concentrated in vacuum to dryness using a rotary evaporator (T=45° C.) to obtain crude product of dasatinib monolauryl sulfate.

[0301] (Crystallization method E) The crude product of dasatinib monolauryl sulfate prepared by steps (a)-(i) was recrystallized according to the following procedure. 1. MeOH (3V, 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 (2V, 234 g) was slowly added to the methanolic solution of the crude product and the mixture was stirred at 60° C.±5° C. for 10±5 minutes. 3. Hexane (40V, 4000 g) was slowly added to the crude product at 45°C ± 5°C for 10 ± 5 min (addition time: 30 ± 10 min) to obtain precipitation of pure product, which was then allowed to adjust to room temperature for 30 ± 5 min. 4. The temperature of the reaction mass 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 x 2V, 2 x 200 g). 5. The precipitate collected in step (4) was dried under high vacuum to obtain white crystalline dasatinib monolauryl sulfate (yield: 79.5%, 118.5 g) (HPLC purity: 100.00%, pH value: 4.38).

[0302] The XRPD pattern of a dasatinivlauric sulfate sample prepared by Crystallization Method E, obtained by the procedure outlined in Example 46, is shown in FIG.

[0303] Crystalline dasatinib monolauryl sulfate prepared by crystallization method E had 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, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0±0.2, 54.0±0.2, 55.0±0.2, 56.0±0.2, 57.0 .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) A capsule dosage form of dasatinib monolauryl sulfate was prepared by wet granulating 2,982 mg of dasatinib monolauryl sulfate prepared by 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 mixed into the dasatinib monolauryl sulfate granules. The resulting blend was dried in an oven at 50° C. to evaporate the alcohol.

[0306] 600 mg of sodium starch glycolate (Part II) and 120 mg of colloidal silicon dioxide (AD101) (Part II) were passed through a 40 mesh screen and added to the dry blend containing the dasatinib monolauryl sulfate granules 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 and added to a 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 omeprazole pre-medicated fasting conditions. Omeprazole is a commercially available proton pump inhibitor (PPI). This is a two-part study. Part 1 is a single-dose, open-label, randomized, three-treatment, three-arm, three-period crossover bioavailability study in healthy subjects under fasting and fed conditions. All subjects were randomized into groups as shown in the table below, with a seven-day washout period between periods. Part 2 is a sequential two-treatment drug-drug interaction study in healthy subjects. All subjects were dosed with omeprazole 40 mg QD orally for five days to reach a stable condition, and then 20 mg dasatinib capsules were administered orally approximately 22 hours after the last omeprazole dose. The reference drug (Ref) was a 50 mg dose of dasatinib monohydrate, Sprycel®, and the test drug (Test) was a capsule prepared according to the procedure of Example 49, containing an amount of dasatinib monolauryl sulfate equivalent to approximately 20 mg of dasatinib monohydrate. Nine healthy subjects enrolled in this study were randomly assigned to one of the groups as shown in the table below.

[0309] [Table 75]

[0310] During each treatment period, blood samples were collected at 0 (pre-dose), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. 0-24 , AUC 0-∞ , C max , T max , and T 1 / 2 was determined based on non-compartmental analysis. The study results were normalized to a 50 mg dose and are summarized in the table below. [Table 76]

[0311] Ln-transformed AUC 0-t , AUC 0-∞ , and C max The analyses were carried out by ANOVA. The model included group, subject (group), period and treatment effects. Comparison of the data obtained from the administration of test and reference drugs is shown in the table below. [Table 77]

[0312] The data show that the compositions of the present invention have a C max The data show that the composition of the present invention increases AUC by 1.01-fold and decreases AUC by 0.88-fold. The data also show that the composition of the present invention does not exhibit the effects of gastric acid suppressants or PPIs, i.e., the composition of the present invention exhibits comparable pharmacokinetics under fasting conditions and under fasting conditions with omeprazole co-administration.

[0313] Individual study data for subjects standardized at the 50 mg dose are as follows: [Table 78-1] [Table 78-2] [Table 78-3] [Table 78-4]

[0314] A graph of the mean normalized plasma profiles provided in Example 50 is shown in FIG.

[0315] (Example 51) A capsule dosage form of dasatinib monolauryl sulfate was prepared by mixing 7730 mg of dasatinib monolauryl sulfate, sieved through a 60 mesh screen, prepared according to the procedure of Crystallization Method E in Example 48A, 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 hydroxypropyl cellulose (HPC-H), 500 mg of sodium starch glycolate (Part I), and 250 mg of colloidal silicon dioxide (Part I) for 2 minutes.

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

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

[0318] The composition of the capsules is as follows: [Table 79]

[0319] (Example 51A) Capsules prepared in Example 51 containing dasatinib monolauryl sulfate were administered to healthy subjects under fasted, fed, and omeprazole premedicated fasted conditions. Omeprazole is a commercially available proton pump inhibitor (PPI). This is a two-part study. Part 1 is a single-dose, open-label, randomized, four-treatment, four-arm, four-period crossover bioavailability study under fasted and fed conditions in ten (10) healthy subjects. All subjects were randomized into groups as shown in the table below, with a three- or four-day washout period between periods. Part 2 is a sequential two-treatment drug-drug interaction study in nine (9) healthy subjects. All subjects were dosed with omeprazole 40 mg QD orally for five days to reach a stable state, and then administered a 50 mg dasatinib capsule orally approximately 22 hours after the last omeprazole dose. The reference drug (Ref) was dasatinib monohydrate Sprycel® in a strength of 50 mg (free base) and the test drug (Test) was a capsule prepared by the procedure of Example 51 containing approximately 50 mg of dasatinib (free base). Ten (10) healthy subjects in Part 1 or nine (9) healthy subjects in Part 2 were randomly assigned to one of the groups as shown in the table below.

[0320] [Table 80-1] [Table 80-2]

[0321] During each treatment period, blood samples were collected at 0 (pre-dose), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. 0-24 , AUC0-∞ , C max , T max , and T 1 / 2 was determined based on non-compartmental analysis. The study results are summarized in the table below. [Table 81]

[0322] Ln-transformed AUC 0-t , AUC 0-∞ , and C max The analyses were carried out by ANOVA. The model included group, subject (group), period and treatment effects. Comparison of the data obtained from the administration of test and reference drugs is shown in the table below. [Table 82]

[0323] The data show that the compositions of the present invention have a C max The data show that the compositions of the present invention reduce C to 0.79-fold and AUC to 0.84-fold compared to U.S. FDA approved dasatinib monohydrate under fed conditions. max The data also show that the compositions of the present invention reduce the positive effects of gastric acid suppressants or PPIs, i.e., the compositions of the present invention reduce C under fasted conditions with omeprazole co-administration compared to fasted conditions. max These results show that it increases the AUC by 1.17-fold and the AUC by 1.13-fold.

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

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

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

[0327] Individual subject data from the study at the 50 mg dose are presented below. [Table 83-1] [Table 83-2] [Table 83-3] [Table 83-4] [Table 83-5] [Table 83-6]

[0328] (Example 52) A capsule dosage form of dasatinib monolauryl sulfate was prepared by blending 9276 mg of dasatinib monolauryl sulfate, sieved through a 325 mesh screen, prepared according to the procedure of Example 12, with 1440 mg of croscarmellose sodium and 6000 mg of anhydrous lactose in a suitable container for approximately 1 minute. 6342 mg of microcrystalline cellulose, sieved through a 40 mesh screen, 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, sieved through a 40 mesh sieve, was added to the blend and further blended to obtain the final blend. The final blend was filled into size 1 hard gelatin capsules.

[0330] The composition of the capsules 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 was a single-dose, open-label, randomized, two-treatment, two-arm, two-period crossover bioavailability study in healthy subjects under fasting conditions. All subjects were randomized into the groups shown in the table below, with a 3-day washout period between periods. The reference drug (Ref) was Sprycel®, a dasatinib monohydrate with a strength of 50 mg (free base), and the test drug (Test) was the capsules prepared in Example 52, containing approximately 50 mg of dasatinib (free base). The 6 healthy subjects participating in this study were randomized into one of the groups shown in the table below.

[0332] [Table 85]

[0333] During each treatment period, blood samples were taken at 0 (pre-dose), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. 0-24 , AUC 0-∞ , C max , T max , and T 1 / 2 was determined based on non-compartmental analysis. The study results are summarized in the table below. [Table 86]

[0334] Ln-transformed AUC 0-t , AUC 0-∞ , and C max The analyses were carried out by ANOVA. The model included group, subject (group), period and treatment effects. Comparison of the data obtained from the administration of test and reference drugs is shown in the table below. [Table 87]

[0335] The data show that the compositions of the present invention have a C max These results show that it reduces the AUC by 0.46-fold and the AUC by 0.79-fold.

[0336] A graph of the mean plasma profiles in this example is shown in FIG.

[0337] Individual subject data from the study at the 50 mg dose are presented below. [Table 88-1] [Table 88-2]

[0338] (Example 53) A capsule dosage form of dasatinib monolauryl sulfate was prepared as follows: (i) 6 mg of butylated hydroxytoluene (BHT) is dissolved in 9756 mg of medium chain triglycerides. (ii) 3600 mg of lauroyl polyoxylglyceride (Gelucire 44 / 14) was melted using a water bath (60° C.). (iii) The molten material of step (ii) was added to the solution of step (i) to obtain a homogenous solution. (iv) 4638 mg of dasatinib monolauryl sulfate prepared by the procedure of Example 48A (Crystallization Method E) sieved through a 60 mesh screen was added to the solution of step (iii) to obtain a homogenous 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) Capsules containing dasatinib monolauryl sulfate prepared in Example 53 were administered to 4 healthy subjects under fasting conditions. This was a single-dose, open-label, randomized, two-treatment, two-arm, two-period crossover bioavailability study in healthy subjects under fasting conditions. All subjects were randomized into the groups shown in the table below, with a 3-day washout period between periods. The reference drug (Ref) was Sprycel®, a dasatinib monohydrate with a strength of 50 mg (free base), and the test drug (Test) was a capsule prepared according to the procedure of Example 53, containing approximately 20 mg of dasatinib (free base). The 4 healthy subjects participating in this study were randomized into the groups shown in the table below.

[0341] [Table 90]

[0342] During each treatment period, blood samples were taken at 0 (pre-dose), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. 0-24 , AUC 0-∞ , C max , T max , and T 1 / 2 was determined based on non-compartmental analysis. The study results are summarized in the table below. [Table 91]

[0343] Ln-transformed AUC 0-t , AUC 0-∞ , and C max The analyses were carried out by ANOVA. The model included group, subject (group), period and treatment effects. Comparison of the data obtained from the administration of test and reference drugs is shown in the table below. [Table 92]

[0344] The data show that the compositions of the present invention have a C max This shows that it reduces the AUC by 0.99-fold and the AUC by 0.98-fold.

[0345] A graph of the mean plasma profiles in this example is shown in FIG.

[0346] Individual subject data from the study at the 50 mg dose are presented below. [Table 93-1] [Table 93-2]

[0347] (Example 54) The following impurities were found to be present in the dasatinib monolauryl sulfate salts 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 was a 90 / 5 / 5 volume ratio of 0.05 M ammonium acetate aqueous solution (pH 5.25) / acetonitrile / methanol. Mobile phase B was 0.05 M aqueous ammonium acetate (pH 5.25) / acetonitrile / methanol in a volume ratio of 10 / 85 / 5.

[0351] The dosage forms prepared in Examples 49, 51-52 and the dasatiniblauric sulfate salts prepared in Examples 12-13 were tested for impurities and stability using the HPLC methods described above.

[0352] Test samples were prepared by weighing approximately 30.92 mg of dasatinib monolauryl sulfate or 41.84 mg of dasatinib dino lauryl sulfate (equivalent to 20 mg of dasatinib) into a 100 mL amber volumetric flask, adding approximately 80 mL of methanol, sonicating for approximately 5 minutes, and stirring at 800 rpm for 5 minutes until completely dissolved. Additional methanol was added to provide approximately 0.2 mg of dasatinib per mL of test sample.

[0353] The test results are as follows: [Table 96-1] [Table 96-2]

[0354] Dasatiniblauril sulfate capsules should contain no more than 0.5% of any individual impurity 1, 2, 3, 4, or 5, preferably no more than 0.35% of any individual impurity, and most preferably no more than 0.25% of any individual impurity, and the total amount of impurities should be no more than 1.0%, preferably no more than 0.75%, and most preferably no more than 0.60%.

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

[0356] (Example 55) A capsule dosage form of dasatinib monolauryl sulfate was prepared by blending dasatinib monolauryl sulfate prepared by the procedure of Example 48A (Crystallization Method E) with certain excipients and filling hard gelatin capsules in the following amounts: [Table 97]

[0357] (Example 55E) A 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 fill having the following composition: [Table 98]

[0358] (Example 55F) A capsule dosage form of dasatinib monolauryl sulfate was prepared according to the procedure of Example 55, except that lauroyl polyoxylglyceride was replaced with Type I polyoxyl stearate (Gelucire 48 / 16). The capsule composition was as follows: [Table 99]

[0359] (Example 56) A USP Type II Apparatus (Paddle) (500 mL of 0.1 N HCl, 75 rpm, with sinker, 37° C.) was used to test the dosage forms prepared in Examples 49, 51, 52, 53, and 55. The results of this dissolution test are as follows: [Table 100]

[0360] (Example 57) The contents of capsules of dasatinib monolauryl sulfate prepared by dissolving dasatinib monolauryl sulfate (by the procedure of Example 48A (Crystallization Method E)) in specified excipients and solvents, evaporating the solvent to form granules, and blending the granules with additional granular excipients to form a blend that is filled into hard gelatin capsules are set forth in the table below. [Table 101]

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

[0362] (Example 58) Similar to the procedures described in Examples 33, 49 and 55, the contents of capsules of dasatinib monolauryl sulfate are listed in the table below, prepared by dissolving dasatinib monolauryl sulfate (by the procedure of Example 48A, Crystallization Method E) in certain excipients and solvents, wet granulating, evaporating the solvent to form granules, and blending the granules with additional particulate excipients to form a blend that is filled into hard gelatin capsules. [Table 103-1] [Table 103-2]

[0363] A USP Type II Apparatus (Paddle) (500 mL of 0.1 N HCl, 75 rpm, with sinker, 37° C.) was used to test the dosage form prepared in Example 58. The results of this dissolution test are as follows: [Table 104]

[0364] (Example 59A) A capsule dosage form of dasatinib monolauryl sulfate was prepared by grinding 2319 mg of dasatinib monolauryl sulfate prepared according to the procedure of Example 48, Crystallization Method E, and mixing with 1500 mg of type I polyoxyl stearate (Gelucire 48 / 16), 375 mg of poloxamer 407, 1806 mg of microcrystalline cellulose, and 150 mg of sodium starch glycolate (Part I) in a small mixer for 15 seconds. 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 the water, ground into powder, and sieved through a 40 mesh sieve. 750 mg of microcrystalline cellulose, 375 mg of sodium starch glycolate (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 sifted through a 40 mesh sieve into a container and blended with the powder to obtain the 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 of the following composition was prepared by a procedure similar to that described in Example 59A. The composition of the capsule contents is as follows: [Table 106]

[0367] (Example 59C) A capsule dosage form of dasatinib monolauryl sulfate of the following composition was prepared by a procedure similar to that 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 a USP Type II Apparatus (Paddle) (500 mL of 0.1 N HCl, 75 rpm, with sinker, 37° C.) The results of this dissolution test are as follows: [Table 108]

[0369] (Example 60) Capsules of nilotinib monolauryl sulfate were prepared according to the procedure outlined in Example 36 with the following composition: [Table 109]

[0370] The dosage forms prepared in Examples 60A-60I were tested using a USP Type II Apparatus (Paddle) (675 mL of 0.1 N HCl, 75 rpm, with sinker, 37° C.) or a USP Type II Apparatus (Paddle) (900 mL of 0.1 N HCl and 0.1% Tween® 80, 75 rpm, with sinker, 37° C.). The results of this dissolution test are as follows: [Table 110-1] [Table 110-2]

[0371] (Example 61A) Capsules containing nilotinib monolauryl sulfate prepared in Example 60A were administered to nine healthy subjects under fed and fed conditions. The study was a randomized, open-label, single-dose, three-treatment, three-arm, three-period crossover design with at least a five-day washout period between doses. The reference drug (Ref) was TASIGNA® capsules of nilotinib HCl at a strength of 200 mg (free base). The test drug (Test) was a capsule prepared according to the procedure in Example 60A containing approximately 80 mg of nilotinib free base. The nine healthy subjects participating in this study were randomized into one of the groups as shown in the table below. [Table 111]

[0372] During each treatment period, blood samples were taken at 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. 0-48 , AUC 0-∞ , C max , T max , and T 1 / 2 was determined based on non-compartmental analysis. The study results were normalized to the 200 mg dose and are summarized in the table below. [Table 112]

[0373] Ln-transformed AUC 0-t , AUC 0-∞ , and C max The analyses were carried out by ANOVA. The model included group, subject (group), period and treatment effects. Comparison of the data obtained from the administration of test and reference drugs is shown in the table below. [Table 113]

[0374] The data show that the compositions of the present invention have a C max The data show that the compositions of the present invention exhibit a 2.5-fold increase in β-blockers and a 2.0-fold increase in AUC. The data also show that the compositions of the present invention do not exhibit a food effect, i.e., the compositions of the present invention exhibit comparable pharmacokinetics under fasted and fed conditions.

[0375] Individual subject data from the study (normalized to the 200 mg dose) are presented below. [Table 114-1] [Table 114-2] [Table 114-3]

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

[0377] (Example 61B) Capsules containing nilotinib monolauryl sulfate prepared in Example 60F were administered to nine healthy subjects under fed and fed conditions. The study was a single-dose, open-label, randomized, three-treatment, three-arm, three-period crossover bioavailability study in healthy subjects under fasted and fed conditions. All subjects were randomized to the groups shown in the table below, with at least a five-day washout period between periods. The reference drug (Ref) was TASIGNA® capsules of 200 mg (free base) strength nilotinib HCl, and the test drug (Test) was capsules prepared according to the procedure of Example 60F, containing approximately 80 mg of nilotinib free base. The nine healthy subjects participating in the study were randomized to one of the groups as shown in the table below.

[0378] [Table 115]

[0379] During each treatment period, blood samples were taken at 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. 0-48 , AUC 0-∞ , C max , T max , and T 1 / 2 was determined based on non-compartmental analysis. The study results are summarized in the table below. [Table 116]

[0380] Ln-transformed AUC 0-t , AUC 0-∞ , and C max The analyses were carried out by ANOVA. The model included group, subject (group), period and treatment effects. Comparison of the data obtained from the administration of test and reference drugs is shown in the table below. [Table 117]

[0381] Individual subject data from this study (normalized to a 200 mg dose) are as follows: [Table 118-1] [Table 118-2] [Table 118-3]

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

[0383] (Example 61C) Capsules containing nilotinib monolauryl sulfate prepared in Example 60G were administered to nine healthy subjects under fasting and fed conditions. This was a single-dose, open-label, randomized, three-treatment, three-arm, three-period crossover bioavailability study in healthy subjects under fasting and fed conditions. All subjects were randomized into the groups shown in the table below, with at least a five-day washout period between periods. The reference drug (Ref) was TASIGNA® capsules of nilotinib HCl at a strength of 200 mg (free base), and the test drug (Test) was capsules prepared according to the procedure of Example 60G, containing approximately 80 mg of nilotinib free base. The nine healthy subjects participating in this study were randomized into one of the groups as shown in the table below.

[0384] [Table 119]

[0385] During each treatment period, blood samples were taken at 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. 0-48 , AUC 0-∞ , C max , T max , and T 1 / 2 was determined based on non-compartmental analysis. The study results are summarized in the table below. [Table 120]

[0386] Ln-transformed AUC 0-t , AUC 0-∞ , and C max The analyses were carried out by ANOVA. The model included group, subject (group), period and treatment effects. Comparison of the data obtained from the administration of test and reference drugs is shown in the table below. [Table 121]

[0387] Individual subject data from this study (normalized to a 200 mg dose) are as follows: [Table 122-1] [Table 122-2] [Table 122-3]

[0388] A graph of the mean plasma profile for Example 61C is shown in FIG.

[0389] (Example 62) The following impurities were found to be present in the formulations of nilotinivulauril sulfate and nilotinivulauril sulfate prepared according to the present invention: [Table 123]

[0390] The above RRT, nilotinivlauric sulfate salts 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 was 0.25% formic acid / acetonitrile in a volume ratio of 90 / 10. Mobile phase B was 0.1% formic acid / acetonitrile in a volume ratio of 10 / 90.

[0392] A test sample of nilotinib monolauryl sulfate prepared in Example 46 (Crystallization Method B) was prepared by weighing out 7.5 mg of nilotinib monolauryl sulfate (equivalent to 5 mg of nilotinib), transferring to a 50 mL amber volumetric flask, adding 40 mL of diluent (ethanol), sonicating for 5 minutes, and stirring at 800 rpm for approximately 5 minutes until the nilotinib monolauryl sulfate was dissolved. Additional diluent was added to provide approximately 0.10 mg of nilotinib per mL of test sample.

[0393] Test samples of the dosage forms prepared in Examples 60F and 60G were prepared according to the following procedure. 1. Cut the tip of the capsule with scissors and squeeze the contents out of the hole into a 100mL volumetric flask. Cut the capsule in two and add to the flask. Add 80% ethanol, sonicate for 10 minutes, and stir at 800 rpm for 30 minutes to completely dissolve the contents. 2. Dilute to volume with ethanol and mix well by inverting the flask at least 10 times. 3. Pipette 3 mL into a 25 mL amber volumetric flask, add ethanol, and mix well by inverting the flask at least 10 times. The test sample is approximately 0.096 mg of nilotinib per 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] A test sample of nilotinib dilauryl sulfate prepared in Example 26 was prepared by weighing 10 mg of nilotinib dilauryl sulfate (equivalent to 5 mg of nilotinib) into a 25 mL amber volumetric flask, adding 20 mL of diluent (ethanol), sonicating for approximately 5 minutes, and stirring at 800 rpm for approximately 5 minutes until the nilotinib dilauryl sulfate was dissolved. Additional diluent was added so that the test sample had approximately 0.20 mg of nilotinib per mL.

[0396] The test samples were tested as described above with the following results: [Table 126-1] [Table 126-2]

[0397] Capsules were stored in child-resistant, closed, foil-induction-sealed, high-density polyethylene (HDPE) bottles (126 c.c., containing 2–3 g of silica gel).

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

[0399] [Table 127]

[0400] Capsules were stored in child-resistant, closed, foil-induction-sealed, high-density polyethylene (HDPE) bottles (126 c.c., containing 2–3 g of silica gel).

[0401] Using the above HPLC method, nilotinib monolauryl sulfate dosage forms were found to contain no more than 0.5% of any individual impurity, preferably no more than 0.35% of any individual impurity, and most preferably no more than 0.25% of any individual impurity, and the total amount of impurities should be no more than 1.0%, preferably no more than 0.75%, and most preferably no more than 0.60%.

[0402] Example 63A Dasatinib monolauryl sulfate tablets were prepared by milling 7730 mg of dasatinib monolauryl sulfate prepared according to the procedure of Example 48A, Crystallization Method E, and mixing 4800 mg of type I polyoxyl stearate in a small mixer for 15 seconds. 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 milled to powder and sieved through a 30 mesh sieve. 16695 mg of microcrystalline cellulose, 1400 mg of sodium starch glycolate, 3500 mg of sodium croscarmellose, and 700 mg of colloidal silicon dioxide, previously sieved through a 40 mesh sieve, were mixed with the dried, milled, and sieved granules to obtain a preblend. 175 mg of sodium stearyl fumarate, previously sieved through a 40 mesh sieve, was added to the preblend and blended to obtain the final blend. The final blend was compressed into tablets using 9.5 mm round punches with a target hardness of approximately 5 kp.

[0403] The composition of the tablet contents is as follows: [Table 128]

[0404] Example 63B Dasatinib monolauryl sulfate tablets were prepared by milling 2319 mg of dasatinib monolauryl sulfate prepared according to the procedure of Example 48A, Crystallization Method E, and mixing with 1800 mg of type I polyoxyl stearate and 1800 mg of microcrystalline cellulose (Part I) in a small mixer for 15 seconds. 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 milled to powder and sieved through a 40 mesh sieve. 2638.5 mg of microcrystalline cellulose (Part II), 420 mg of sodium starch glycolate, 1260 mg of croscarmellose sodium, and 210 mg of colloidal silicon dioxide, previously sieved through a 40 mesh sieve, were mixed with the dried, milled, and sieved granules to obtain a preblend. 52.5 mg of sodium stearyl fumarate, previously sieved through a 40 mesh screen, was added to the pre-blend and blended to obtain the final blend. The final blend was compressed into tablets using 9.5 mm round punches with a target hardness of approximately 5 kp.

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

[0406] Example 63C The 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, with sinker, 37° C.) The results of this dissolution test are as follows: [Table 130]

[0407] The present invention illustratively described herein can be practiced without one or more elements or one or more limitations not specifically disclosed herein. Thus, for example, in each example of the present specification, any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with any of the other two terms. The terms and expressions employed are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to exclude the features shown and described or equivalents thereof, but recognizes that various modifications are possible within the scope of the invention as claimed. Thus, the present invention has been specifically described by preferred embodiments and optional features, and it should be understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and such modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

[0408] (Additional Note) (Appendix 1) (i) C8-C of kinase inhibitors (KI) 16 Aliphatic sulfate ester salts, and (ii) at least one pharma- ceutically acceptable excipient; 23. A pharmaceutical composition for oral administration comprising:

[0409] (Appendix 2) 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a hard or soft gel capsule, and the at least one pharma- ceutically acceptable excipient is a liquid carrier, a solid carrier having a melting point between 25° C. and less than 120° C., or a combination thereof.

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

[0411] (Appendix 4) The pharmaceutical composition of claim 2, wherein the carrier is a solid carrier having a melting point between 25° C. and less than 120° C. 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.

[0412] (Appendix 5) (i) C8-C of KI 16 Aliphatic sulfate ester salts, (ii) a carrier having an HLB value of about 10 or more; and (iii) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof; 2. The pharmaceutical composition of claim 1, comprising:

[0413] (Appendix 6) (i) C8-C of KI 16 Aliphatic sulfate ester salts, (ii) a carrier having an HLB value of less than about 10; and (iii) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof; 2. The pharmaceutical composition of claim 1, comprising:

[0414] (Appendix 7) (i) C8-C of KI 16 Aliphatic sulfate ester salts, (ii) a carrier having an HLB value of about 10 or more; (iii) a carrier having an HLB value of less than about 10; and (iv) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof; 2. The pharmaceutical composition of claim 1, comprising:

[0415] (Appendix 8) A pharmaceutical composition which is a tablet or capsule, the contents of said tablet or said capsule comprising: (i) C8-C of KI 16 Aliphatic sulfate ester salts, (ii) a carrier having an HLB value of about 10 or more; (iii) a filler, and (iv) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of disintegrants, stabilizers, thickeners, binders, lubricants, glidants, flavorings, and combinations thereof; 2. The pharmaceutical composition of claim 1, comprising:

[0416] (Appendix 9) C8-C of the KI 16 2. The pharmaceutical composition of claim 1, wherein the aliphatic sulfate is a lauryl sulfate of KI.

[0417] (Appendix 10) The pharmaceutical composition of claim 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, ruxolitinib, sorafenib, sunitinib, trametinib, and vandetanib.

[0418] (Appendix 11) 6. The pharmaceutical composition of claim 5, wherein the carrier having an HLB value of about 10 or greater is selected from the group consisting of a wetting agent, an emulsifier, a solubilizer, a surfactant, or a combination thereof.

[0419] (Appendix 12) 7. The pharmaceutical composition of claim 6, wherein the carrier having an HLB value of less than about 10 is selected from the group consisting of a wetting agent, an emulsifying agent, a solubilizing agent, a surfactant, or a combination thereof.

[0420] (Appendix 13) 8. The pharmaceutical composition of claim 7, wherein the carrier having an HLB value of about 10 or greater 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] (Appendix 14) 9. The pharmaceutical composition of claim 8, wherein the carrier having an HLB value of about 10 or greater is selected from the group consisting of a wetting agent, an emulsifying agent, a solubilizing agent, a surfactant, or a combination thereof.

[0422] (Appendix 15) (i) About 1% by weight to about 80% by weight of KI C8-C 16 Aliphatic sulfate ester salts, (ii) about 1% by weight to about 90% by weight of a carrier having an HLB value of about 10 or more; (iii) about 1% by weight to about 90% by weight of a carrier having an HLB value of less than about 10; and (iv) optionally, one or more additional pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavorings, and combinations thereof; 2. The pharmaceutical composition of claim 1, comprising:

[0423] (Appendix 16) A pharmaceutical composition which is a tablet or capsule, the contents of said tablet or said capsule comprising: (i) About 1% by weight to about 80% by weight of KI C8-C16 Aliphatic sulfate ester salts, (ii) about 1% by weight 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 pharma- ceutically acceptable excipients selected from the group consisting of disintegrants, stabilizers, thickeners, binders, lubricants, glidants, flavorings, and combinations thereof; 2. The pharmaceutical composition of claim 1, comprising:

[0424] (Appendix 17) 6. The pharmaceutical composition of claim 5, further comprising about 0.1% to about 60% by weight of a thickening agent that is solid at ambient temperature but has a melting point below 120° C.

[0425] (Appendix 18) 7. The pharmaceutical composition of claim 6, further comprising about 1% to about 60% by weight of the carrier that is solid at ambient temperature but has a melting point below 120° C.

[0426] (Appendix 19) 8. The pharmaceutical composition of claim 7, further comprising about 0.1% to about 60% by weight of a thickening agent that is solid at ambient temperature but has a melting point below 120° C.

[0427] (Appendix 20) 9. The pharmaceutical composition of claim 8, further comprising about 1% to about 60% by weight of the carrier that is solid at ambient temperature but has a melting point below 120° C.

[0428] (Appendix 21) The KI is, for example, acalabrutinib, afatinib, alectinib, apatinib, axitinib, bafetinib, baricitinib, bosutinib, brigatinib, cabozantinib, canertinib, cediranib, ceritinib, cobimetinib, crenolanib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, entrectinib, erlotinib, filgotinib, foretinib, fostamatinib, gefitinib, glesatinib, ibrutinib, icotinib, imatinib, lapatinib, lestaurtinib, lenvatinib, linifanib, or rucitinib. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of tanib, momelotinib, motesanib, mubritinib, neratinib, nilotinib, nintedanib, oclacitinib, olmutinib, osimertinib, pacritinib, pazopanib, ponatinib, quizartinib, radotinib, regorafenib, rociletinib, ruxolitinib, saracatinib, savolitinib, semaxanib, sitravatinib, sorafenib, sunitinib, taselisib, tecevatinib, tivozanib, toceranib, trametinib, upadacitinib, vatalanib, vandetanib, and vemurafenib.

[0429] (Appendix 22) The KI is (i) a phenylcarboxamide moiety having the structure [ka] (ii) an aminopyrimidine moiety having the structure [ka] (iii) an aminopyrimidine moiety having the structure [ka] or (iv) a combination of the moieties described in (i), (ii) or (iii). Including, A is selected from the group consisting of H, C, N, O, S, P, halogen, or combinations thereof, or A is selected from the group consisting of H, C, N, O, S, P, halogen, or combinations thereof and is part of a straight chain, branched chain, or cyclic moiety; 2. The pharmaceutical composition of claim 1.

Claims

1. A composition for oral administration comprising nilotiniblauric sulfate and one or more pharma- ceutically acceptable excipients.

2. The nilotiniblauric sulfate salt is (a) amorphous, (b) crystalline, or (c) a combination of amorphous and crystalline; The composition of claim 1.

3. (i) 5% to 50% by weight of nilotiniblauric sulfate, and (ii) from about 5% to about 90% by weight of one or more additives selected from the group consisting of wetting agents, emulsifiers, solubilizing agents, surfactants, and combinations thereof; The composition of claim 1 or 2, comprising:

4. 4. The composition of claim 3, further comprising one or more pharma- ceutically acceptable excipients selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavoring agents, and combinations thereof.

5. The crystalline nilotiniblauric sulfate salt is (i) characterized by an X-ray powder diffraction (XRPD) pattern including 2θ peaks at 5.6±0.2, 8.5±0.2, and one or more 2θ peaks selected from the group consisting of 9.4±0.2, 19.1±0.2, 21.5±0.2, and 24.9±0.2; (ii) is characterized by an XRPD pattern including 2θ peaks at 5.6±0.2, 8.5±0.2, and one or more 2θ peaks selected from the group consisting of 17.1±0.2, 20.2±0.2, 22.0±0.2, 22.8±0.2, 25.8±0.2, 26.1±0.2, and 26.6±0.2; or (iii) is characterized by an XRPD pattern including 2θ peaks at 5.6±0.2, 8.5±0.2, and one or more 2θ peaks selected from the group consisting of 9.1±0.2, 16.7±0.2, 17.9±0.2, 18.4±0.2, 19.6±0.2, 20.9±0.2, 23.0±0.2, 24.1±0.2, 25.8±0.2, 27.7±0.2, and 29.0±0.2; The composition according to any one of claims 1 to 4.

6. The crystalline nilotiniblauric sulfate salt is (i) is characterized by an XRPD pattern including 2θ peaks at 5.6±0.2, 8.5±0.2, 9.4±0.2, 19.1±0.2, 21.5±0.2, and 24.9±0.2, and including one or more 2θ peaks selected from the group consisting of 13.1±0.2, 20.2±0.2, 26.5±0.2, 27.7±0.2, and 29.0±0.2; (ii) is characterized by an XRPD pattern including 2θ peaks at 5.6±0.2, 8.5±0.2, 26.6±0.2, and one or more 2θ peaks selected from the group consisting of 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, 24.8±0.2, 25.8±0.2, and 26.1±0.2; or (iii) is characterized by an XRPD pattern including: (a) 2θ peaks at 5.6±0.2, 8.5±0.2; (b) one or more 2θ peaks selected from the group consisting of 9.1±0.2, 16.7±0.2, 17.9±0.2, 18.4±0.2, 19.6±0.2, 20.9±0.2, 23.0±0.2, 24.1±0.2, 25.8±0.2, 27.7±0.2, and 29.0±0.2; and (c) one or more 2θ peaks selected from the group consisting of 9.6±0.2, 13.1±0.2, 13.9±0.2, 17.2±0.2, 19.1±0.2, 21.3±0.2, and 24.7±0.

2. The composition of claim 5.

7. (i) is characterized by an XRPD pattern comprising 2θ peaks at 5.6±0.2, 8.5±0.2, 9.4±0.2, 13.1±0.2, 13.7±0.2, 17.1±0.2, 19.1±0.2, 20.2±0.2, 21.5±0.2, 24.9±0.2, 26.5±0.2 and 27.7±0.2; (ii) is characterized by an XRPD pattern comprising 2θ peaks at 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, 22.8±0.2, 24.8±0.2, and 26.6±0.2; or (iii) is characterized by an XRPD pattern comprising 2θ peaks at 5.6±0.2, 8.5±0.2, 9.6±0.2, 13.1±0.2, 13.9±0.2, 17.2±0.2, 19.1±0.2, 21.3±0.2, 23.0±0.2, 24.7±0.2, 27.7±0.2, and 29.0±0.2; The composition of claim 5.

8. 8. The composition of claim 3, wherein the one or more additives selected from the group consisting of wetting agents, emulsifiers, solubilizers, surfactants, and combinations thereof exhibit a hydrophilic lipophilic balance (HLB) value of less than 10.

9. 9. The composition of claim 8, wherein the one or more additives having an HLB value of less than 10 include medium chain monoglycerides, medium chain diglycerides, medium chain triglycerides, vegetable oils, hydrogenated vegetable oils, fatty acid esters, fatty acid alcohols, polyoxylglycerides, sorbitan esters, sorbitan fatty acid esters, phospholipids, or combinations thereof.

10. 10. The composition of claim 9, wherein the one or more additives having an HLB value of less than 10 include medium chain monoglycerides, medium chain diglycerides, medium chain triglycerides, or combinations thereof.

11. 11. The composition of any one of claims 1 to 10, further comprising 1% to 60% by weight of one or more additives selected from the group consisting of wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, and having an HLB value of 10 or greater.

12. 12. The composition of claim 11, wherein the one or more additives having an HLB value of 10 or greater include polyoxyethylene stearates, fatty acid alcohols, fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oils, polyoxyethylene hydrogenated castor oils, poloxamers, tyloxapols, fatty acid esters of polyglycerides or fatty acid alcohols, and combinations thereof.

13. 13. The composition of claim 12, wherein the one or more additives having an HLB value of 10 or greater include polyoxyethylene stearate or polyoxyethylene castor oil.

14. 14. The composition according to any one of claims 1 to 13, which exhibits a dissolution rate of about 10% to about 85% after 30 minutes of testing, or about 40% to about 95% after 60 minutes of testing, when using a USP Type II Apparatus (Paddle) at 37°C with 0.1 N HCl and 0.1% Tween 80, at 75 rpm, with or without a sinker.

15. The composition according to any one of claims 1 to 14, wherein the composition is a capsule.

16. 16. The composition of claim 15, wherein the capsule comprises from about 10 mg to about 400 mg of nilotiniblauric sulfate.

17. The composition of any one of claims 1 to 16, used in an effective amount for the treatment of chronic myelogenous leukemia and / or lymphoblastic leukemia in a subject.

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