Application of salt of cabozantinib in preparation of dosage form for treating cancer

Abstract

The invention relates to application of salts of cabozantinib to preparation of dosage forms for treating cancers.

Description

[0001] The present invention is a divisional application of the invention patent application with application number 201980038252.4 (PCT / US2019 / 036947, invention name: Salts of kinase inhibitors and compositions thereof, application date: June 13, 2019).

[0002] The present invention claims the rights of U.S. Provisional Patent Application No. 62 / 685,411 filed on June 15, 2018, U.S. Provisional Patent Application No. 62 / 791,356 filed on January 11, 2019, and U.S. Provisional Patent Application No. 62 / 811,368 filed on February 27, 2019. The entire contents of the above-listed documents are incorporated herein by reference as part of the disclosure of this specification. Technical Field

[0003] The present invention relates to the use of kinase inhibitors (KIs) and C8-C 16 The salts of the kinase inhibitors formed by the reaction of aliphatic sulfates. The salts of the kinase inhibitors can be combined with at least one pharmaceutically acceptable excipient and orally administered to an individual.

[0004] The present invention also relates to a kinase inhibitor comprising C8-C 16 Fatty sulfate (kinase inhibitor C8-C 16 The present invention relates to pharmaceutically acceptable compositions and dosage forms of aliphatic sulfate salts, methods for preparing the above compositions and dosage forms, and methods for treating various diseases (e.g., cancer) comprising oral administration of the compositions and dosage forms. Background Art

[0005] Kinase inhibitors are compounds that interfere with protein activation by inhibiting kinase enzymes. Kinase inhibitors are commonly used to treat cancer, but are also used to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease.

[0006] Kinase inhibitors often have pH dependent solubility and thus exhibit erratic bioavailability after oral administration.

[0007] In addition, it is known that kinase inhibitors have significant absorption fluctuations when administered after a high-fat meal or in combination with other drugs such as gastric acid secretion inhibitors [e.g., antacids, H2 antagonists, and proton pump inhibitors] compared to administration in the fasting state. For example, when some kinase inhibitor compounds are administered orally after a high-fat meal, it will cause significant increases in pharmacokinetic values such as the maximum plasma concentration (C max max

[0008] ) and the area under the plasma concentration curve (AUC) compared to administration in the fasting state. Similarly, it is known that co-administration of kinase inhibitors with gastric acid secretion inhibitors or drugs that increase the pH in the stomach reduces the absorption of kinase inhibitors. Due to numerous possible potential interferences, the timing and conditions of kinase inhibitor administration must be restricted, which is inconvenient for patients, and side effects may occur if administered incorrectly or there is a loss of efficacy. SUMMARY OF THE INVENTION

[0009] The present invention includes the above and other objects.

[0010] The present invention encompasses salts of kinase inhibitors, wherein the salts are formed by reacting a kinase inhibitor with a C8-C 16 fatty alkyl sulfate. In one embodiment, the salts of kinase inhibitors are formed by reacting a kinase inhibitor with lauryl sulfate of an alkali metal or alkaline earth metal or tetradecyl sulfate of an alkali metal or alkaline earth metal.

[0011] The present invention also encompasses compositions containing a kinase inhibitor and a C8-C 16 fatty alkyl sulfate (KI C8-C 16A composition and dosage form comprising an aliphaticsulfate salt) and at least one pharmaceutically acceptable excipient, which is preferably administered orally to an individual.

[0012] The present invention further encompasses methods for reducing or eliminating the food effect of oral kinase inhibitors. More specifically, the present invention encompasses orally administering the compositions and / or dosage forms of the present invention to an individual in a fed state or a fasted state. After orally administering the composition or dosage form of the present invention, the kinase inhibitor plasma concentration (KI plasma profile) is obtained, wherein at least one pharmacokinetic parameter differs by less than about 40% between the fed and fasted states. In different embodiments, the change in the pharmacokinetic parameter is less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5% between the fed and fasted states. Pharmacokinetic parameters that are not affected by the food effect may include, but are not limited to, the maximum plasma drug concentration (C max ), the area under the plasma drug concentration curve (AUC), the time to reach the maximum plasma drug concentration (T max ), or a combination thereof. In certain embodiments, one or more dosage forms comprising a kinase inhibitor C8-C 16 aliphatic sulfate and at least one pharmaceutically acceptable excipient are orally administered to cancer patients in a fed or fasted state with a kinase inhibitor C8-C 16 aliphatic sulfate dose, and no dose adjustment or change in the administration time is required.

[0013] The present invention further encompasses methods for reducing or eliminating drug interactions caused by orally administering a kinase inhibitor and co-administering other drugs (e.g., gastric acid secretion inhibitors or drugs that increase the pH in the stomach). More specifically, the present invention encompasses orally administering the compositions and / or dosage forms of the present invention to an individual receiving a gastric acid secretion inhibitor or a drug that increases the pH in the stomach. After orally administering the composition or dosage form of the present invention, the kinase inhibitor plasma concentration is obtained, wherein at least one pharmacokinetic parameter differs by less than about 40% with or without co-administering a gastric acid secretion inhibitor or a drug that increases the pH in the stomach. In different embodiments, when the composition or dosage form of the present invention is administered with or without a gastric acid secretion inhibitor or a drug that increases the pH in the stomach, the change in the pharmacokinetic parameter is less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5%. Pharmacokinetic parameters that are not affected by co-administering a gastric acid secretion inhibitor or a drug that increases the pH in the stomach may be the maximum plasma drug concentration (C max ), the area under the plasma drug concentration curve (AUC), the time to reach the maximum plasma drug concentration (T max ), or a combination thereof. In certain embodiments, comprising a kinase inhibitor C8-C16 One or more dosage forms of a fatty sulfate and at least one pharmaceutically acceptable excipient are orally administered to a cancer patient in combination with an inhibitor of gastric acid secretion, wherein the kinase inhibitor C8-C 16 The dose of the fatty sulfate does not require dose adjustment or change in the dosing schedule.

[0014] The present invention further encompasses a method of reducing the total daily oral dose of a kinase inhibitor. More specifically, the present invention encompasses orally administering a composition and / or dosage form prepared according to the present invention, wherein the total daily dose of the kinase inhibitor is reduced by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% compared to the currently U.S. Food and Drug Administration (U.S.FDA)-approved free base form of the kinase inhibitor or a non-C8-C 16 The total daily dose of the fatty sulfate.

[0015] In one embodiment of the present invention, the composition or dosage form for oral administration is a hard capsule, soft capsule or tablet, which contains the kinase inhibitor C8-C 16 A fatty sulfate and a pharmaceutically acceptable carrier, which is preferably in the form of an intimate mixture. In certain aspects of this embodiment, the hard or soft capsule can be a gelatin-based or non-gelatin-based capsule. In certain aspects of this embodiment, the pharmaceutically acceptable carrier is a liquid under ambient conditions (i.e., 25°C, standard atmospheric pressure); alternatively, the pharmaceutically acceptable carrier is a solid under ambient conditions, but has a melting point higher than 25°C and less than 120°C, preferably less than 100°C, and most preferably less than 80°C. If the pharmaceutically acceptable carrier is a liquid under ambient conditions, the kinase inhibitor C8-C 16 The fatty sulfate and the liquid carrier are mixed, and the resulting mixture is filled or formed into a hard or soft capsule. The liquid mixture may further contain one or more pharmaceutically acceptable excipients, such as a stabilizer, which will be described in more detail hereinafter. If the carrier is a solid at ambient temperature, the carrier can be heated to melt, and the kinase inhibitor C8-C 16 The fatty sulfate and the molten carrier are mixed, and then filled or formed into a hard or soft capsule or tablet. Alternatively, the carrier can be dissolved or dispersed in a solvent and separately combined with the kinase inhibitor C8-C 16mixed with fatty alkyl sulfates, or with kinase inhibitor C8-C 16 a combination of fatty alkyl sulfates and at least one additional pharmaceutically acceptable excipient to form a carrier and kinase inhibitor C8-C 16 a tight mixture of fatty alkyl sulfates. Once the tight mixture of kinase inhibitor C8-C 16 and the carrier is formed, it can be dried and filled or formed into hard or soft capsules; alternatively, the tight mixture can be combined with at least one or more pharmaceutically acceptable excipients, and the resulting composition can be filled or formed into hard or soft capsules or formed into tablets.

[0016] In another embodiment of the present invention, the composition and / or dosage form contains kinase inhibitor C8-C 16 fatty alkyl sulfates and a carrier with an HLB value of 10 or more, where the carrier with an HLB value of 10 or more is selected from the group consisting of: wetting agent, emulsifying agent, solubilizing agent, surfactant, or a combination thereof. In a preferred embodiment, kinase inhibitor C8-C 16 is tightly mixed with fatty alkyl sulfates and a carrier with an HLB value of 10 or more. In a further embodiment, the composition is a liquid composition that can be orally administered to an individual, or the liquid composition can be filled into hard or soft capsules for oral administration to an individual. The liquid mixture can further contain one or more pharmaceutically acceptable excipients, such as: stabilizers, which will be described in more detail later. Alternatively, the composition is a solid or semi-solid composition that can be orally administered to an individual, such as: powder or granules; or, the solid or semi-solid composition can be formed into tablets or filled into capsules for oral administration to an individual.

[0017] The present invention also encompasses methods for preparing, forming, and manufacturing compositions and dosage forms, where the compositions and dosage forms contain kinase inhibitor C8-C 16 fatty alkyl sulfates and at least one pharmaceutically acceptable excipient, and are preferably for oral administration to an individual.

[0018] The present invention further encompasses a method for treating a patient, including orally administering a composition and dosage form containing a therapeutic dose of kinase inhibitor C8-C 16 fatty alkyl sulfates and at least one pharmaceutically acceptable excipient.

[0019] The present invention also encompasses novel polymorphic forms of kinase inhibitor C8-C 16 fatty alkyl sulfates, methods for preparing novel polymorphic forms, compositions and dosage forms containing novel polymorphic forms, and methods for treating patients using novel polymorphic forms. Description of the Drawings

[0020] Figure 1 Graph of mean in vivo plasma data provided for Example 5.

[0021] Figure 2 Graph of mean in vivo plasma data provided for Example 10.

[0022] Figure 3 XRPD pattern of dasatinib monolauryl sulfate salt in Example 12.

[0023] Figure 4 XRPD pattern of dasatinib dilauryl sulfate salt in Example 13.

[0024] Figure 5 Graph of mean in vivo plasma data provided for Example 20.

[0025] Figure 6 Graph of mean in vivo plasma data provided for Example 21D.

[0026] Figure 7 Graph of mean in vivo plasma data provided for Example 24.

[0027] Figure 8 Graph of mean in vivo plasma data provided for Example 32.

[0028] Figure 9 Graph of mean in vivo plasma data provided for Example 35.

[0029] Figure 10 XRPD pattern of nilotinib dilauryl sulfate salt in Example 38.

[0030] Figure 11 Graph of mean in vivo plasma data provided for Example 40.

[0031] Figure 12 Graph of mean in vivo plasma data provided for Example 42G.

[0032] Figure 13XRPD pattern of nilotinib monolauryl sulfate salt in crystallization method A of Example 46.

[0033] Figure 14 XRPD pattern of nilotinib monolauryl sulfate salt in crystallization method C of Example 46.

[0034] Figure 15 XRPD pattern of nilotinib monolauryl sulfate salt in crystallization method D of Example 46.

[0035] Figure 16 XRPD pattern of dasatinib monolauryl sulfate salt in crystallization method A of Example 47.

[0036] Figure 17 XRPD pattern of dasatinib monolauryl sulfate salt in crystallization method B of Example 47.

[0037] Figure 18 XRPD pattern of dasatinib monolauryl sulfate salt in crystallization method C of Example 48.

[0038] Figure 19 XRPD pattern of dasatinib monolauryl sulfate salt in crystallization method D of Example 48.

[0039] Figure 20 XRPD pattern of dasatinib monolauryl sulfate salt in crystallization method E of Example 48A.

[0040] Figure 21 Graph of average in vivo plasma drug concentration data provided in Example 50.

[0041] Figures 22A - 22C Graph of average in vivo plasma drug concentration data provided in Example 51A.

[0042] Figure 23 Graph of average in vivo plasma drug concentration data provided in Example 52A.

[0043] Figure 24 Graph of average in vivo plasma drug concentration data provided in Example 53A.

[0044] Figure 25 Graph of average in vivo plasma drug concentration data provided in Example 61A.

[0045] Figure 26 Graph of average in vivo plasma drug concentration data provided in Example 61B.

[0046] Figure 27Graph showing the average in vivo plasma drug concentration data provided for Example 61C. Detailed Description

[0047] Before further describing the present invention, it is to be understood that the invention is not limited to the specific 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.

[0048] It should be noted that as used herein, the singular forms "a", "an", and "the" also include the plural referents unless the context clearly dictates otherwise.

[0049] It is to be understood that where a range of values is provided, unless the context clearly dictates otherwise, each intermediate value between the upper and lower limits of that range (taking the intermediate value at intervals of one tenth of the lower limit unit), and any other specified value or intermediate value within the specified range are encompassed within the scope of the present invention. The upper and lower limits of those smaller ranges may independently be included in the smaller ranges, subject to any specifically excluded limit in the stated range, and are also encompassed within the present invention. Where the specified range includes one or both of the limits, ranges excluding either or both of those limits are also included in the present invention.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the methods and materials described now are preferred. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials related to the cited publications.

[0051] As set forth herein, the term "normal storage conditions" means storage at room temperature (about 25 °C) and a relative humidity of about 60% for at least three months, preferably at least six months, and most preferably at least one year. The dosage forms described herein should be stored in a pharmaceutically acceptable container with or without a desiccant, such as: glass bottles, plastic bottles, metal foil bags, or blister packaging.

[0052] As used herein, the term "accelerated storage conditions" refers to storage at about 40 °C and a relative humidity of about 75% for at least two weeks or longer, one month or longer, two months or longer, three months or longer, four months or longer, five months or longer, six months or longer. The dosage forms described herein should be stored in a pharmaceutically acceptable container with or without a desiccant, such as: glass bottles, plastic bottles, metal foil bags, or blister packs.

[0053] The term "HLB" refers to the hydrophilic-lipophilic balance of a surfactant or emulsifier, which is a measure of the degree of hydrophilicity or lipophilicity and is determined by calculating values for different regions of the molecule, as described by Griffin WC in "Calculation of HLB Values of Non-Ionic Surfactants" Journal of the Society of Cosmetic Chemists, 5:259 (1954). The HLB value ranges from 0 to 20, where an HLB value of 0 corresponds to a completely lipophilic molecule and an HLB value of 20 corresponds to a completely hydrophilic molecule. HLB values are generally known and are documented in the literature, such as: the manufacturer's technical manual.

[0054] The term "C max " represents the highest drug concentration in the blood obtained during the dosing interval.

[0055] The term "T max " represents the time to reach the highest drug concentration in the blood (C max ).

[0056] The term "AUC" represents the area under the drug concentration-time curve for a specific time interval calculated using the linear trapezoidal sum. For example, AUC 0-12 refers to the area under the drug concentration-time curve from the time of dosing to 12 hours after dosing; AUC 0-24 refers to the area under the drug concentration-time curve from the time of dosing to 24 hours after dosing; AUC 0-∞ refers to the area under the drug concentration-time curve from the time of dosing to infinity; and AUC 0-t refers to the area under the drug concentration-time curve from the time of dosing to a specified time point, which can be, for example, 2 hours, 8 hours, and 18 hours after dosing, etc. In some embodiments, the specified time point is the last time point for blood sampling.

[0057] The determination of the pharmacokinetic parameters described herein is generally carried out according to methods known and understood by those skilled in the art and commonly described in publications, such as: Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products--General Considerations (March 2003) of the US Food and Drug Administration, Guidance for Industry: Statistical Approaches to Establishing Bioequivalence (January 2001) of the US Food and Drug Administration, and Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies (December 2002) of the US Food and Drug Administration. The above-mentioned documents are hereby incorporated herein by reference.

[0058] As used herein, unless otherwise defined, "individual" refers to a mammalian animal, such as: human, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, preferably human, which includes healthy mammals and mammals suffering from diseases that may be treated with kinase inhibitors. An individual suffering from a disease that may be treated with kinase inhibitors is sometimes referred to as a "patient".

[0059] As used herein, unless otherwise defined, when used in combination with a pharmaceutical composition or dosage form comprising a salt of a kinase inhibitor, the phrase "therapeutically effective amount" refers to the amount of a kinase inhibitor or its salt that is effective in treating a disease or disorder disclosed herein (e.g., cancer).

[0060] As used herein, unless otherwise defined, the terms “intimate blend”, “intimate mixture” and the like refer to a combination of a salt of a kinase inhibitor of the present invention and at least one pharmaceutically acceptable excipient, which is preferably a carrier having an HLB value of about 10 or higher, more preferably about 11 or higher, still more preferably about 12 or higher, which can be, for example: a wetting agent, an emulsifying agent, a solubilizing agent, a surfactant or a combination thereof, wherein the salt of the kinase inhibitor and at least one pharmaceutically acceptable excipient are in intimate contact or intimate combination with each other. An intimate mixture can be prepared by any method capable of blending the kinase inhibitor of the present invention and at least one pharmaceutically acceptable excipient, and at least one pharmaceutically acceptable excipient is preferably a carrier having an HLB value of about 10 or higher. Examples of suitable processes for achieving an intimate mixture include: dissolving, suspending or dispersing the salt of the kinase inhibitor in a solution or suspension containing at least one pharmaceutically acceptable excipient, which is preferably a carrier having an HLB value of about 10 or higher and optionally containing at least one other pharmaceutically acceptable excipient, such as: a pharmaceutically acceptable solvent. The pharmaceutical solvent can be removed or not removed. Another example of a suitable process for achieving an intimate mixture includes: using a liquid excipient, wherein the liquid contains at least one pharmaceutically acceptable excipient having an HLB value of about 10 or higher; or melting one or more solid excipients, wherein the melt contains at least one pharmaceutically acceptable excipient having an HLB value of about 10 or higher, to produce a molten or liquid excipient composition containing at least one excipient having an HLB value of about 10 or higher, and dissolving, suspending or dispersing the salt of the kinase inhibitor in the molten or liquid excipient composition. The liquid excipient composition contains at least one excipient having an HLB value of about 10 or higher and may also contain one or more pharmaceutically acceptable excipients, which will be described in more detail hereinafter. Other processes that can be used to achieve an intimate mixture of a salt of a kinase inhibitor and at least one pharmaceutically acceptable excipient (preferably having an HLB value of about 10 or higher) include: co-blending, co-screening, co-compacting, co-compressing or a combination thereof. Once the intimate mixture of the salt of the kinase inhibitor and at least one pharmaceutically acceptable excipient (preferably having an HLB value of about 10 or higher) is prepared, the intimate blend composition can be combined with at least one other pharmaceutical excipient or carrier. Preferably, the intimate mixture contains the salt of the kinase inhibitor and one, two or three excipients before being combined with any other excipient.

[0061] As used herein, unless otherwise defined, the term "gastric acid secretion inhibitor" refers to an excipient and / or drug that raises the pH value in the stomach or neutralizes 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 over-the-counter 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.

[0062] As used herein, unless otherwise defined, the terms "co-administer", "co-administering", and "co-dosing" refer to an individual receiving one or more non-kinase inhibitor drugs or therapeutic agents during kinase inhibitor therapy. The one or more non-kinase inhibitor drugs or therapeutic agents can be administered concurrently or sequentially with the kinase inhibitor composition or dosage form of the present invention. Concurrent administration as described herein refers to the non-kinase inhibitor drug or therapeutic agent being administered within 2 hours before or after the administration of the kinase inhibitor composition or dosage form of the present invention; more preferably within 1 hour before or after the administration of the kinase inhibitor composition or dosage; even more preferably within 30 minutes before or after the administration of the kinase inhibitor composition or dosage form of the present invention. Sequential administration as described herein refers to the non-kinase inhibitor drug or therapeutic agent being administered at any time before or after the administration of the kinase inhibitor composition or dosage form of the present invention, which can include 4, 6, 8, 12, or 14 hours before or after the administration of the kinase inhibitor composition or dosage form of the present invention.

[0063] As described herein, unless otherwise defined, the term "kinase inhibitor" refers to any one or more compounds that are pharmaceutically active and can inhibit kinases, preferably tyrosine kinase enzymes. Preferably, kinase inhibitors are small molecules that typically use the suffix "nib" in their names, and include tyrosine kinase inhibitors that typically use the suffix "tinib" in their names, angiogenesis inhibitors that typically use the suffix "anib" in their names, and rapidly accelerated fibrosarcoma kinase inhibitors that typically use the suffix "rafinib" in their names. In addition, it also includes focal adhesion kinase inhibitors (FAK).

[0064] Examples of kinase inhibitors useful in the present invention include, but are not limited to: acalabrutinib (commercially available under the name CALQUENCE), afatinib (commercially available under the name GILOTRIF), alectinib (commercially available under the name ALECENSA), apatinib, axitinib (commercially available under the name INLYTA), bafetinib, baricitinib, bosutinib (commercially available under the name BOSULIF), brigatinib (commercially available under the 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 (available from Verastem Oncology), enasidenib (commercially available under the name IDHIFA), entrectinib, erlotinib (commercially available under the name TARCEVA), filgotinib, foretinib, fostamatinib (commercially available under the name TAVALISSE), gefitinib (commercially available under the name IRESSA), glesatinib, ibrutinib (commercially available under the name IMBRUVICA), icotinib, imatinib (commercially available under the name GLEEVEC), lapatinib (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 (commercial name APOQUEL), Olmutinib, Osimertinib (commercial name TAGRISSO), Pacritinib, Pazopanib (commercial name VOTRIENT), Ponatinib (commercial name ICLUSIG), Quizartinib, Radotinib, Regorafenib (commercial name STIVARGA), Rociletinib, Ruxolitinib (commercial name JAKAFI), Saracatinib, Savolitinib, Semaxanib, Sitravtinib, Sorafenib (commercial name NEXAVAR), Sunitinib (commercial name SUTENT), Taselisib, Tesevatinib, Tivozanib, Toceranib, Tofacitinib (commercial name XELJANZ), Trametinib (commercial name MEKINIST), Upadacitinib, Vatalanib, Vandetanib (commercial name CAPRELSA), and Vemurafenib (commercial name ZELBORAF).

[0065] Some preferred kinase inhibitors 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.

[0066] Other examples of kinase inhibitors useful in the present invention include, but are not limited to:

[0067] (i) A phenyl carboxamide moiety having the following structure:

[0068]

[0069] (ii) An amino pyrimidine moiety having the following structure:

[0070]

[0071] (iii) An amino pyrimidine moiety having the following structure:

[0072]

[0073] (iv) Combinations of the groups described in (i), (ii), or (iii).

[0074] Wherein A is H, C, N, O, S, P, a halogen (F, Cl, Br, I) and / or A can be part of a larger group, for example: a straight-chain, branched-chain or cyclic group, such as: an alkyl group, an aryl group, an alkoxy group, etc. In certain embodiments, the A substituent on the nitrogen of the phenylformamide group (i) is preferably H or a C1-C4 alkyl group.

[0075] Examples of kinase inhibitors containing the phenylformamide group (i) include but are not limited to: afatinib, cabozantinib, dasatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, ponatinib, regorafenib, and trametinib.

[0076] Examples of kinase inhibitors containing one of the aminopyrimidine groups (ii) or (iii) include but are not limited to: afatinib, brigatinib, ceritinib, dabrafenib, dasatinib, defactinib, erlotinib, fortanib, gefitinib, ibrutinib, imatinib, lapatinib, nilotinib, osimertinib, pazopanib, ruxolitinib, tofacitinib, and vandetanib.

[0077] In certain preferred embodiments, the kinase inhibitors used in the present invention contain: (a) the phenylformamide group (i) and the aminopyrimidine group (ii) as described above or (b) the phenylformamide group (i) and the aminopyrimidine group (iii) as described above. Examples of kinase inhibitors containing the phenylformamide group (i) and one of the aminopyrimidine groups (ii) or (iii) include but are not limited to: afatinib, dasatinib, imatinib, nilotinib, and osimertinib.

[0078] The kinase inhibitor C8-C of the present invention 16 The fatty alkyl sulfate can be formed by reacting the kinase inhibitor molecule with C8-C 16 fatty alkyl sulfate. In one embodiment, the kinase inhibitor C8-C 16 fatty alkyl sulfate is formed by reacting the kinase inhibitor with a dodecyl sulfate or a tetradecyl sulfate of an alkali metal or an alkaline earth metal. Examples of preferred dodecyl sulfates or tetradecyl sulfates of alkali metals or alkaline earth metals include but are not limited to: sodium dodecyl sulfate, potassium dodecyl sulfate, sodium tetradecyl sulfate, or potassium tetradecyl sulfate. The most preferred anionic compound for preparing the salts of the kinase inhibitors of the present invention is sodium dodecyl sulfate or potassium dodecyl sulfate.

[0079] The kinase inhibitor C8-C of the present invention 16 The fatty alkyl sulfate can be prepared by dissolving the kinase inhibitor compound in a suitable solvent and adding C8-C 16The fatty sulfate is added to the kinase inhibitor solution, and the resulting reaction substances are mixed. The kinase inhibitor compound can be in the form of either the free base or a salt, such as: kinase inhibitor hydrochloride (KI HCl salt), kinase inhibitor citrate (KI citrate salt), kinase inhibitor phosphate (KI phosphate salt), kinase inhibitor mesylate (KI mesylate salt), kinase inhibitor maleate (KI maleate salt), or kinase inhibitor tosylate (KI tosylate salt). The solvent can be, for example: water, a C1-C6 branched or straight-chain alcohol, ether, ester, or ketone, or a mixture of organic solvents thereof, a C3-C 12 branched or straight-chain alkane or a mixture thereof as an organic solvent, or a mixture of water and an organic solvent). Alternatively, the C8-C 16 fatty sulfate can be dissolved in a suitable solvent, and the kinase inhibitor compound (which can be in the form of either the free base or a salt) is added to the C8-C 16 fatty sulfate solution, and the resulting reaction substances are mixed. The kinase inhibitor C8-C 16 fatty sulfate of the present invention can also be formed by the following method: dissolving the kinase inhibitor compound (which can be in the form of either the free base or a salt) in a suitable solvent, dissolving the C8-C 16 fatty sulfate in a suitable solvent, combining the kinase inhibitor compound solution and the C8-C 16 fatty sulfate solution and mixing the resulting reaction substances. The solvent is removed from the resulting reaction substances by conventional techniques (such as evaporation or filtration) to isolate the kinase inhibitor C8-C 16 fatty sulfate. The isolated kinase inhibitor C8-C 16 fatty sulfate of the present invention can be used in the compositions and dosage forms described herein.

[0080] In some embodiments of the present invention, the dissolved kinase inhibitor compound can react with an acid to protonate one or more nitrogen atoms, where preferably a strong acid, and most preferably an inorganic acid. Once the kinase inhibitor is protonated, it is combined with the C8-C 16 fatty sulfate to form the kinase inhibitor C8-C 16 fatty sulfate.

[0081] The molar ratio of C8-C 16 fatty sulfate to the kinase inhibitor compound in the reaction substances can be between about 0.5 moles of C8-C 16 fatty sulfate to about 6 moles of C8-C 16The aliphatic sulfate is preferably about 0.75 moles of C8-C per mole of kinase inhibitor base present in the reaction mass 16 aliphatic sulfate to about 5 moles of C8-C 16 The aliphatic sulfate is most preferably 0.85 moles of C8-C per mole of kinase inhibitor base present in the reaction mass 16 aliphatic sulfate to about 4 moles of C8-C 16 The aliphatic sulfate per mole of kinase inhibitor base present in the reaction mass. The kinase inhibitor C8-C can also be formed during the preparation of the compositions or dosage forms of the invention or as part of their manufacturing process 16 aliphatic sulfate. In some kinase inhibitor - mono C8-C 16 aliphatic sulfate salt (KI mono C8-C 16 aliphatic sulfatesalt) examples, the molar ratio of C8-C 16 aliphatic sulfate to the kinase inhibitor compound can range from about 0.8 moles of C8-C 16 aliphatic sulfate to about 1.3 moles of C8-C 16 The aliphatic sulfate per mole of kinase inhibitor base present in the reaction mass. In some kinase inhibitor - di C8-C 16 aliphatic sulfate salt (KI di C8-C 16 aliphaticsulfate salt) examples, the molar ratio of C8-C 16 aliphatic sulfate to the kinase inhibitor compound can range from about 1.6 moles of C8-C 16 aliphatic sulfate to about 2.5 moles of C8-C 16 The aliphatic sulfate of the kinase inhibitor of the invention C8-C 16 can be kinase inhibitor - mono C8-C 16 aliphatic sulfate or kinase inhibitor - multi C8-C 16 aliphatic sulfate salt (KI multi C8-C 16 aliphaticsulfate salt), for example: kinase inhibitor - di C8-C 16 aliphatic sulfate, kinase inhibitor - tri C8-C 16 aliphatic sulfate salt (KI tri C8-C 16 aliphatic sulfate salt), kinase inhibitor - tetra C8-C 16 aliphatic sulfate salt (KItetra C8-C 16aliphatic sulfate salt) or kinase inhibitor - penta C8 - C 16 Aliphatic sulfate (KI penta C8 - C 16 aliphatic sulfate salt). Unless otherwise specified, the term "kinase inhibitor C8 - C 16 aliphatic sulfate" as used herein encompasses single and multiple aliphatic sulfates, and similarly, the term "kinase inhibitor lauryl sulfate salts" encompasses single and multiple lauryl sulfates.

[0082] The present invention also encompasses compositions and dosage forms containing kinase inhibitor C8 - C 16 aliphatic sulfate and at least one pharmaceutically acceptable excipient, which are preferably orally administered to an individual. The compositions and dosage forms can be solid, semi - solid or liquid, wherein the kinase inhibitor C8 - C 16 aliphatic sulfate is combined with a pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient can be, for example: fillers, diluents, binders, stabilizing agents, lubricants, disintegrants, wetting / solubilizing / emulsifying agents or combinations thereof. Pharmaceutically acceptable excipients are well - known in the art and are described in Remington: The Science and Practice of Pharmacy, 21st Edition (2006), pages 1058 - 1092 and Handbook of Pharmaceutical Excipients, 6th Edition (2009). Representative examples of various pharmaceutically acceptable excipients for the embodiments of the present invention are provided below.

[0083] Solid and semi - solid compositions and dosage forms include: powders, granules, pellets, mini - tablets, tablets or capsules, and can be prepared by methods known in the art, such as: direct compression, wet or dry granulation and extrusion spheronization.

[0084] Liquid compositions and dosage forms include: solutions, suspensions or dispersions, which can also be prepared by methods known in the art.

[0085] In one embodiment of the invention, the composition or dosage form for oral administration is a tablet or hard or soft gelatin capsules, which contains kinase inhibitor C8-C 16 alkyl sulfates and a pharmaceutically acceptable carrier, and is preferably in the form of a intimate mixture. In certain aspects of this embodiment, the pharmaceutically acceptable carrier is liquid under ambient conditions (i.e., 25 °C and standard atmospheric pressure), or the pharmaceutically acceptable carrier is solid under ambient conditions, but has a melting point higher than 25 °C and lower than 120 °C, preferably less than 100 °C, more preferably less than 80 °C, and most preferably below 60 °C. If the pharmaceutically acceptable carrier is liquid under ambient conditions, the kinase inhibitor C8-C 16 alkyl sulfates and the liquid carrier are mixed, and the resulting mixture is filled or formed into hard or soft gelatin capsules. The liquid mixture may additionally contain one or more pharmaceutically acceptable excipients, such as stabilizers, which will be described in more detail hereinafter.

[0086] If the carrier is solid or semi-solid at ambient temperature, before forming the tablet or before filling or forming hard or soft gelatin capsules, the carrier and kinase inhibitor C8-C 16 alkyl sulfates may optionally be mixed or granulated with one or more other pharmaceutically acceptable excipients. Alternatively, if the carrier is solid or semi-solid at ambient temperature, the carrier can be melted by heating, and before forming the tablet or filling or forming hard or soft gelatin capsules, the melted carrier and kinase inhibitor C8-C 16 alkyl sulfates may optionally be mixed with one or more other pharmaceutically acceptable excipients.

[0087] In certain embodiments, kinase inhibitor C8-C 16 alkyl sulfates are dissolved in the liquid carrier or dissolved in the molten carrier. Alternatively, kinase inhibitor C8-C 16 alkyl sulfates are dispersed or suspended in the liquid carrier or dispersed or suspended in the molten carrier.

[0088] Examples of liquid carriers useful in preparing the oral dosage forms 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, or mixtures thereof. In certain embodiments, the liquid carrier should comprise 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 the foregoing values, preferably from about 15% (w / w) to about 90% (w / w) of the composition filled into the capsule, most preferably from about 20% (w / w) to about 85% (w / w).

[0089] Examples of solid carriers having a melting point between 25 °C and less than 120 °C include: aliphatic alcohols, polyethylene glycol, for example: polyethylene glycol 1000 having a melting point of 37 - 40 °C, polyethylene glycol 1500 having a melting point of 44 - 48 °C, hard fat, also known as hydrogenated vegetable glycerides, hydrogenated vegetable oil, vitamin E polyethylene glycol succinate (also known as TPGS), poloxamers [nonionic polyoxyethylene - polyoxypropylene copolymers, for example: poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407], polyoxylglycerides, polyoxyethylene stearates, and waxes, such as: carnauba wax, cetyl ester wax, microcrystalline wax, white wax, and yellow wax, and combinations of the foregoing solid carriers. In certain embodiments, the solid carrier should comprise about 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, 50%, 52.5%, 55%, 57.5%, 60%, 62.5%, 65%, 67.5%, 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 92.5%, 95% (w / w) of the composition filled into the capsule or formed into a tablet, or any range encompassed by the foregoing values, preferably from about 5% (w / w) to about 90% (w / w), most preferably from about 7.5% (w / w) to about 85% (w / w).

[0090] Other examples of solid, semi-solid and liquid carriers useful in preparing the solid, semi-solid or liquid dosage forms of the present invention (including but not limited to: hard gelatin capsules, soft gelatin capsules and tablets of the present invention) include but are not limited to: wetting agents, emulsifiers, solubilizers, surfactants or combinations thereof having an HLB value of about 10 or higher, preferably an HLB value of about 11 or higher, more preferably an HLB value of about 12 or higher, and most preferably an HLB value of 14 or higher, which will be described in more detail hereinafter.

[0091] In another embodiment of the present invention, the composition or dosage form may comprise kinase inhibitor C8-C 16 Fatty alcohol sulfates and one or more wetting agents, emulsifiers, solubilizers, surfactants or combinations thereof having an HLB value of about 10 or higher, preferably an HLB value of about 11 or higher, more preferably about 12 or higher, and most preferably about 14 or higher, and at least one other pharmaceutically acceptable excipient. Kinase inhibitor C8-C 16 The amount of fatty alcohol sulfate present in the composition may be from about 1 wt% to about 80 wt%, preferably from about 2 wt% to about 70 wt%, more preferably from about 2.5 wt% to about 60 wt%, and most preferably from about 3 wt% to about 50 wt% based on the total weight of the composition or dosage form. In certain embodiments, kinase inhibitor C8-C 16The amount of fatty alcohol sulfate present in the composition can be about 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt% or any range encompassed by the foregoing values. The amount of one or more wetting agents, emulsifiers, co-solvents, surfactants or combinations thereof having an HLB value of about 10 or higher, preferably about 11 or higher, more preferably about 12 or higher, and most preferably about 14 or higher, present in the composition can be 1 wt% or higher, preferably about 2 wt% or higher, and most preferably about 5 wt% or higher based on the total weight of the composition or dosage form. In certain embodiments, the amount of one or more wetting agents, emulsifiers, co-solvents, surfactants or combinations thereof having an HLB value of about 10 or higher, preferably about 11 or higher, more preferably about 12 or higher, and most preferably about 14 or higher, present in the composition or dosage form is about 1 wt% to about 90 wt%, preferably about 2 wt% to about 80 wt%, and most preferably about 3 wt% to about 70 wt%. In certain embodiments, the amount of one or more wetting agents, emulsifiers, co-solvents, surfactants or combinations thereof having an HLB value of about 10 or higher present in the composition can be about 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt% or any range encompassed by the foregoing values.

[0092] One or more wetting agents, emulsifiers, cosolvents, surfactants, or combinations thereof having an HLB value of about 10 or higher can be nonionic surfactants, ionic surfactants, or combinations thereof, and are preferably nonionic surfactants. Examples of nonionic surfactants that can be used include: polyethoxylated castor oil, polyoxyethylene alkyl ester, polyglycolyzed glyceride, sorbitan fatty acid ester, glycerin fatty acid ester, fatty acid polyglyceride, fatty acid alcohol polyglycol ether, acetylene glycol, acetylene alcohol, oxyalkylene block polymer, polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, polyoxyethylene styrylaryl ether, polyoxyethylene glycol alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid ester, polyoxylglycerides, polyoxyethylene stearates, or mixtures of the foregoing substances.A list of more possible nonionic surfactants can be found on pages 1243-1249 of Martindale: The Extra Pharmacopoeia, 29th Edition, which is incorporated herein by reference.

[0093] One or more wetting agents, emulsifying agents, solubilizing agents, surfactants or combinations thereof having an HLB value of about 10 or higher can be nonionic surfactants, such as: fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates alkyl polyglycosides, and mixtures thereof. Examples of these nonionic surfactants include, but are not limited to, polyoxyethylene derivatives of polyol esters, such as: polysorbate 20 (trade name 20), polysorbate 40 (trade name 40), polysorbate 60 (commercial 60) and polysorbate 80 (trade name 80).

[0094] One or more wetting agents, emulsifying agents, solubilizing agents, surfactants or combinations thereof having an HLB value of about 10 or higher can be polyoxyethylene castor oil, such as: polyoxyl castor oil or polyoxyl hydrogenated castor oil or mixtures thereof. Examples of these surfactants include, but are not limited to: polyoxyl 35 castor oil (trade name CREMAPHOR EL or KOLLIPHOR EL), polyoxyl 40 hydrogenated castor oil (trade name CREMOPHOR RH 40) and polyoxyl 60 hydrogenated castor oil.

[0095] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or higher can be polyoxyethylene alkyl ethers, such as: polyoxyl cetostearyl ether, polyoxyl cetyl ether, polyoxyl lauryl ether, polyoxyl oleyl ether, polyoxyl stearyl ether, or mixtures thereof.

[0096] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or higher can be tyloxapol, poloxamer, i.e., a nonionic polyoxyethylene-polyoxypropylene copolymer, such as: poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407, or combinations thereof.

[0097] One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or higher can be a fatty acid ester or fatty acid alcohol of a polyglyceride, such as: caprylic / capric triglyceride (commercial name MYIGLYOL).

[0098] In certain embodiments of the present invention, the composition contains kinase inhibitor C8-C 16A fatty alkyl sulfate and one or more wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of about 10 or higher, which is preferably a close mixture, and may further comprise at least one other second carrier having a low HLB value or no HLB value. The second carrier may be one or more wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of about less than 10, more preferably an HLB value of about 9 or lower, about 8 or lower, and even more preferably an HLB value of about 7 or lower. Examples of at least one other second carrier having a low HLB value include nonionic surfactants, including but not limited to: polyethoxylated castor oil, polyoxyethylene alkyl ester, polyglycolyzed glyceride, sorbitan fatty acidester, glycerin fatty acid ester, fatty acid polyglyceride, fatty acid alcohol polyglycol ether, acetylene glycol, acetylene alcohol, oxyalkylene block polymer, polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, polyoxyethylene styrylaryl ether, polyoxyethylene glycol alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid ester or mixtures of the foregoing substances.A list of more possible nonionic surfactants can be found on pages 1243 - 1249 of Martindale: The Extra Pharmacopoeia, 29th Edition, which is incorporated herein by reference.

[0099] In certain embodiments, the second carrier having an HLB value of less than about 10 is a medium - chain (i.e., about 4 to about 20 carbon atoms, preferably about 6 to about 18 carbon atoms, most preferably about 6 to 14 carbon atoms) monoglyceride or diglyceride, such as: glyceryl caprylate / caprate (commercial name CAPMUL MCM), glyceryl caprylate (commercial name CAPMUL MCM C8), glyceryl caprate (commercial name CAPMUL MCM C10), glycerylmonocaprylocaprate (commercial name CAPMUL 471) or mixtures thereof.

[0100] In certain embodiments, the second carrier having an HLB value of less than about 10 is a polyoxylglyceride, such as: caprylocaproylpolyoxylglycerides, lauroyl polyoxylglycerides, linoleoyl polyoxylglycerides, oleoylpolyoxylglycerides, stearoyl polyoxylglycerides and mixtures of the foregoing.

[0101] In certain embodiments, the second carrier having an HLB value of less than about 10 is a sorbitan ester or a sorbitan fatty acid ester, such as: sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, tyloxapol, and mixtures of the foregoing substances.

[0102] In certain embodiments, the second carrier having an HLB value of less than about 10 is a phospholipid or a lecithin.

[0103] In certain embodiments, the second carrier is an oil, a medium chain triglyceride, a hydrogenated vegetable oil, a suppository base, or a combination thereof.

[0104] In certain embodiments, the second carrier having an HLB value of less than about 10 is liquid at ambient temperature, or has a melting point of 75 °C or lower, about 70 °C or lower, about 65 °C or lower, about 60 °C or lower, about 55 °C or lower, about 50 °C or lower, about 45 °C or lower, or about 40 °C or lower.

[0105] In some embodiments using a second carrier with an HLB value of about less than 10, the amount of the second carrier with an HLB value of about less than 10 can be from 1 wt% to about 90 wt%, preferably from about 5 wt% to about 85 wt%, and most preferably from about 10 wt% to about 80 wt% based on the total weight of the composition. The above weight percentages can be based on a single second carrier or a combination of second carriers. In certain embodiments, the amount of one or more wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of about less than 10 present in the composition can be about 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt%, 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt%, 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt%, 71 wt%, 72 wt%, 73 wt%, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt%, 80 wt% or any range encompassed by the foregoing values.

[0106] The compositions and dosage forms of the present invention may also optionally contain other pharmaceutically acceptable excipients such as: stabilizers, fillers, viscosity enhancing agents, binders, disintegrants, lubricants, glidants, flavoring agents and combinations thereof.

[0107] In certain embodiments, the dosage form of the present invention is a solid or semi-solid oral dosage form, which is preferably a capsule or tablet comprising:

[0108] (i) Kinase inhibitor C8-C 16 Aliphatic sulfates, in an amount of from about 1 wt% to about 60 wt%, preferably from about 2 wt% to about 55 wt%, and most preferably from about 5 wt% to about 50 wt% based on the total weight of the solid composition or dosage form;

[0109] (ii) One or more wetting agents, emulsifying agents, solubilizing agents, surfactants or combinations thereof having an HLB value of about 10 or higher, preferably an HLB value of about 11 or higher, more preferably an HLB value of about 12 or higher, and most preferably an HLB value of about 14 or higher, in an amount of about 1 wt% to about 60 wt%, preferably about 2 wt% to about 50 wt%, and most preferably about 3 wt% to about 40 wt%; and

[0110] (iii) At least one other pharmaceutically acceptable excipient selected from stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavoring agents and combinations thereof.

[0111] In a further embodiment, for example, in a semi-solid embodiment, the oral dosage form may further comprise (iv) a thickener which is solid at ambient temperature but has 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 item (iv) thickener which is solid at ambient temperature but has a melting point below 120 °C, then item (iv) should comprise about 0.5 wt% to about 60 wt%, preferably about 1 wt% to about 55 wt%, and most preferably about 5 wt% to about 50 wt% based on the total weight of the composition of (ii).

[0112] Examples of stabilizers useful in the present invention include, but are not limited to: antioxidants, drying agents, buffers, pH adjusting agents, or combinations thereof. If a stabilizer is present in the dosage form, it 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 amount of stabilizer present in the composition can be about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, 4.0 wt%, 4.1 wt%, 4.2 wt%, 4.3 wt%, 4.4 wt%, 4.5 wt%, 4.6 wt%, 4.7 wt%, 4.8 wt%, 4,9 wt%, 50 wt%, or any range encompassed by the foregoing values.

[0113] Examples of antioxidants useful in the present invention include, but are not limited to: ascorbic acid, ascorbyl palmitate (AP), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, ethyl oleate, fumaric acid, hypophosphorous acid, malic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, tocopherols, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl benzoate, pyridoxine, ethyl vanillin, and mixtures thereof. Antioxidants preferably used according to the present invention include: BHT, BHA, AP, propyl gallate, α-tocopherol, or any mixture thereof. Generally, the amount of antioxidant present in the composition of the present invention will comprise from about 0.0001 wt% to about 5 wt%, preferably from about 0.01 wt% to about 2 wt%, most preferably from about 0.05 wt% to about 1 wt% based on the total weight of the composition.

[0114] As described herein, unless otherwise defined, the term "drying agent" refers to a pharmaceutically acceptable excipient that has the ability to bind or absorb water present in the composition. Examples of drying agents that can be used in the present invention may include, for example: magnesium oxide (MgO), aluminum oxide, attapulgite, bentonite, kaolin, pectin, saponite, colloidal silicon dioxide, and mixtures thereof. Depending on the specific dosage form, the thickening agents discussed below can also be used as drying agents. If a drying agent is present in the composition of the present invention, its content can range from about 0.05 wt% to about 10 wt% of the total weight of the composition, preferably from about 0.1 wt% to about 5 wt% of the total weight of the composition, and most preferably from about 0.5 wt% to about 2.5 wt% of the total weight of the composition.

[0115] Examples of buffers that can 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. Generally, the buffer will contain a combination of the foregoing substances to form a buffer system, for example: citric acid and sodium citrate or acetic acid and sodium acetate.

[0116] Examples of pH adjusters useful in the present invention include, but are not limited to: any pharmaceutically acceptable acid or base used to adjust the pH value of a pharmaceutical composition. General examples of compounds used to adjust the pH value of a pharmaceutical composition include: hydrochloric acid, citric acid, lactic acid, tartaric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, arginine, lysine, meglumine, triethanol amine, or combinations thereof.

[0117] If a buffer and / or pH adjuster is used in the composition of the present invention, its content can be between about 0.01 wt% and about 20 wt% of the composition, preferably about 0.1 wt% to about 10 wt% of the composition, and most preferably about 0.5 wt% to about 5 wt% of the composition.

[0118] Fillers, sometimes referred to as diluents, can also be used in the present invention, and include: water; sugars such as lactose, dextrose, sucrose, maltose, or microcrystalline cellulose; clays, and mixtures thereof. Generally, the amount of filler present in the composition of the present invention comprises from about 0 wt% to about 90 wt% based on the total weight of the composition, preferably from about 0.01 wt% to about 80 wt%, and most preferably from about 1 wt% to about 70 wt%.

[0119] Thickeners useful in the present invention include: organic materials such as natural or synthetic waxes, C 12 -C 60 alcohols, C 12 -C 60 acids, alpha-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and inorganic / organic materials such as metal ester complexes containing zinc, calcium, aluminum, or magnesium, fumed silicas, and organoclays. Other thickeners include: polyol polyesters, glyceryl esters, polyglyceryl esters, and polysiloxanes.

[0120] Waxes are also suitable for use as thickeners in the compositions of the present invention. Natural waxes may include, but are not limited to: carnauba wax, ozokerite, beeswax, candelilla, paraffin, ceresin, esparto, ouricuri, rezowax, and other known mined and mineral waxes. Synthetic waxes may include, but are not limited to, paraffin and microcrystalline waxes.

[0121] Other thickeners that can be further 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 can be used in the present invention include: swellable polymers, also known as osmopolymers or hydrogels. The swellable polymers can be uncrosslinked or lightly crosslinked. The crosslinking can be covalent or ionic bonds that enable the polymer to have the ability to swell in the presence of a fluid, and in the case of crosslinking, it will not dissolve in the fluid. The source of the polymer can be plant, animal, or synthetic. Polymer gelling agents that can be used for the purposes of the present invention include: polyhydroxyalkylcellulose with a molecular weight greater than 50,000, such as: hydroxylpropylmethylcellulose (METHOCEL K 100M, available from Dow Chemical); poly(hydroxyalkylmethacrylate) with a molecular weight of 5,000 to 5,000,000; poly(vinylpyrrolidone) with a molecular weight of 100,000 to 3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinylalcohol) having a low acetate residual; a swellable mixture of agar and carboxymethyl cellulose; a swellable composition containing methyl cellulose mixed with a small amount of crosslinked agar; polyether with a molecular weight of 10,000 to 6,000,000; a water-swellable copolymer prepared from a finely divided dispersion of a copolymer of maleic anhydride, styrene, ethylene, propylene, or isobutene; N-vinyl lactams water-swellable polymers and the like.

[0122] Other gelling agents that can be used in the present invention include: pectin with a molecular weight of 30,000 to 300,000; polysaccharides, such as: agar, acacia, karaya, tragacanth, aligns, and guar; acrylic polymers Carboxyvinyl polymer, sometimes called carboxypolymethylene; a polymer of acrylic acid cross-linked with a polyallyl ether of sucrose, as described in U.S. Patent Nos. 2,798,053 and 2,909,462 and available from 934, 940 and 941, and its salt derivatives; polyacrylamide; water-swellable indene maleic anhydride polymers; GOOD- polyacrylic acid having a molecular weight of 80,000 to 200,000; POLYOX TM polyethylene oxide polymer; starch graft copolymers; AQUA-KEEP having a water-absorbing capacity of about 400 times its original weight TM acrylate polymers; diesters of polyglucan; a mixture of cross-linked polyvinyl alcohol and poly(N-vinyl-2-pyrrolidone); polyethylene glycol having a molecular weight of 4,000 to 100,000. Representative polymers having gel properties are described in U.S. Patent Nos. 6,419,954, 4,915,949, 4,327,725, 4,207,893 and Handbook of Common Polymers (published by Scott and Roff, Cleveland Rubber Company, Cleveland, Ohio).

[0123] Generally, the amount of the thickener present in the composition of the present invention will comprise from about 0 wt% to about 30 wt%, preferably from about 0.01 wt% to about 25 wt%, most preferably from about 1 wt% to about 15 wt% based on the total weight of the composition. In the semi-solid embodiments of the present invention, as described above, the thickener is a solid at ambient temperature but has a melting point below 120 °C, preferably below 100 °C, more preferably below 80 °C, most preferably below 60 °C. And it may comprise from about 7.5 wt% to about 75 wt%, preferably from about 10 wt% to about 60 wt%, most preferably from about 12 wt% to about 50 wt% of the total weight of the composition. Examples of such thickeners include, but are not limited to, natural or synthetic waxes such as: carnauba wax, cetyl ester wax, microcrystalline wax, white wax, yellow wax, beeswax, ozokerite, paraffin wax, ceresin wax, eucalyptus wax, ouricury wax and rice bran wax, stearin (also known as hydrogenated vegetable glyceride), hydrogenated vegetable oil, C 12 -C 60 alcohols, C 12 -C 60 acids, α-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides and combinations thereof.

[0124] Examples of binders that can be used in the solid dosage forms of the present invention include: gum arabic, povidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polymethacrylates, methyl cellulose, ethyl cellulose, pregelatinized starch, gelatin, tragacanth, zein or mixtures thereof. Preferably, the binder is selected from povidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polymethacrylates, methyl cellulose, gelatin and ethyl cellulose or mixtures thereof. Particularly preferred binders include water-soluble binders such as: povidone, hypromellose, hydroxypropyl cellulose, gelatin and mixtures thereof. If the binder is a polymeric binder, it is preferred that the binder has a low molecular weight and / or when tested in an aqueous solution at a concentration of 2% (w / v) at 20 °C, its viscosity is less than 200 mPa·s, preferably less than 100 mPa·s, most preferably less than 50 mPa·s.

[0125] Generally, the amount of the binder present in the composition of the present invention will comprise from about 0 wt% to about 30 wt%, preferably from about 0.01 wt% to about 25 wt%, most preferably from about 1 wt% to about 15 wt% based on the total weight of the composition.

[0126] Examples of disintegrants that can be used in the solid dosage forms of the present invention include: croscarmellose sodium, starch, crospovidone, sodium starch glycolate, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, powdered cellulose, chitosan, guar gum, magnesium aluminum silicate, methylcellulose, sodium alginate, and mixtures thereof. Generally, the amount of disintegrant present in the compositions of the present invention will comprise from about 0 wt% to about 40 wt%, preferably from about 1 wt% to about 25 wt%, and most preferably from about 2 wt% to about 20 wt% based on the total weight of the composition.

[0127] Examples of lubricants that can be used in the solid dosage forms of the present invention include: magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, polyethylene glycol (wherein the preferred polyethylene glycol has a molecular weight of 6000 or higher), polyoxyethylene stearate, magnesium laurylsulfate, sodium oleate, and mixtures thereof. The amount of lubricant present can be from about 0.1 wt% to about 10 wt%, preferably from about 0.2 wt% to about 7 wt%, and most preferably from about 0.5 wt% to about 5 wt% based on the total weight of the dosage form.

[0128] Examples of glidants that can be used in the solid dosage forms of the present invention include: colloidal silica, cornstarch, talc, and mixtures thereof. The amount of glidant present can be from about 0.1 wt% to about 10 wt%, preferably from about 0.2 wt% to about 7 wt%, and most preferably from about 0.5 wt% to about 5 wt% based on the total weight of the dosage form.

[0129] Examples of flavoring agents that can be used in the solid dosage forms of the present invention include artificial sweeteners such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, and flavorants such as citric acid, peppermint oil, wintergreen oil, menthol, lemon, lime, orange, grape, cherry, and vanilla extract. Other flavor enhancers are described in U.S. Patent No. 6,027,746, which is incorporated herein by reference.

[0130] Example A of the present invention is an oral liquid dosage form, preferably in a hard or soft capsule, comprising:

[0131] (i) A kinase inhibitor C8-C 16 An alkyl sulfate in an amount of about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt%, wherein the preferred kinase inhibitors are selected from the group consisting of: acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fortanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably are selected from the group consisting of: afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and wherein the preferred kinase inhibitor C8-C 16 Alkyl sulfate is a kinase inhibitor dodecyl sulfate, and most preferably is a kinase inhibitor monolauryl sulfate or a kinase inhibitor dilauryl sulfate;

[0132] (ii) A liquid carrier in an amount of about 1 wt% to about 95 wt%, preferably about 5 wt% to about 90 wt%, and most preferably about 10 wt% to about 80 wt%, and which is selected from the group consisting of fatty acids, medium-chain triglycerides, fatty acid esters, fatty alcohols, vegetable oils such as corn oil, soybean oil, olive oil, sunflower oil, peanut oil, or mixtures thereof; and

[0133] (iii) Optionally includes one or more other pharmaceutically acceptable excipients selected from the group consisting of: stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavoring agents, and combinations thereof.

[0134] Example B of the present invention is an oral solid or semi-solid dosage form, which can be tablets, hard capsules or soft capsules, and includes:

[0135] (i) Kinase inhibitor C8-C 16 Alkyl sulfates, with a content of about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt%. Among them, the preferred kinase inhibitors are selected from the group consisting of: acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib. And most preferably, they are selected from the group consisting of: afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib. And among them, the preferred kinase inhibitor C8-C 16 Alkyl sulfate is kinase inhibitor dodecyl sulfate, and most preferably it is kinase inhibitor monolauryl sulfate or kinase inhibitor dilauryl sulfate;

[0136] (ii) A solid carrier with a melting point between 25°C and less than 120°C, preferably below 100°C, more preferably below 80°C, and most preferably below 60°C, with a content of about 1 wt% to about 90 wt%, preferably about 2.5 wt% to about 80 wt%, more preferably about 3 wt% to about 70 wt%, and most preferably about 5 wt% to about 60 wt%. And the preferred solid carriers are selected from the group consisting of: polyethylene glycol, hard fat, hydrogenated vegetable oil, vitamin E polyethylene glycol succinate, wax, poloxamers, and combinations of the foregoing substances; and

[0137] (iii) Optionally includes one or more other pharmaceutically acceptable excipients selected from the group consisting of: stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavoring agents, and combinations thereof.

[0138] Example C of the present invention is an oral dosage form, such as a hard capsule or a soft capsule, and includes:

[0139] (i) Kinase inhibitor C8-C 16 Alkyl sulfates, in an amount of about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt%. Preferred kinase inhibitors are selected from the group consisting of: acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib. Most preferably, they are selected from the group consisting of: afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib. And the preferred kinase inhibitor C8-C 16 The alkyl sulfate is a kinase inhibitor dodecyl sulfate, and most preferably, it is a kinase inhibitor monolauryl sulfate or a kinase inhibitor dilauryl sulfate;

[0140] (ii) At least one wetting agent, emulsifier, solubilizer, surfactant, or a combination thereof having an HLB value of about 10 or higher, preferably about 11 or higher, more preferably about 12 or higher, and most preferably about 14 or higher, in an amount of about 1 wt% to about 60 wt%, preferably about 2 wt% to about 50 wt%, and most preferably about 3 wt% to about 40 wt%, and selected from the group consisting of: fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxyalkyl polysaccharides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, tyloxapol, poloxamer, fatty acid esters of polyglycerides or fatty alcohols, or a combination thereof. Most preferably, they are selected from the group consisting of: polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride, or a combination thereof;

[0141] (iii) a second carrier having an HLB value of less than about 10, more preferably about 9 or lower, about 8 or lower, and most preferably about 7 or lower, with a content of about 5 wt% to about 90 wt%, preferably about 10 wt% to about 85 wt%, most preferably about 15 wt% to about 80 wt%, and preferably selected from the group consisting of: wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of less than about 10, more preferably selected from the group consisting of: medium chain monoglycerides, medium chain diglycerides, polyoxyethylene glycerol esters, sorbitan esters, sorbitan fatty acid esters, phospholipids and combinations thereof, and most preferably medium chain monoglycerides, medium chain diglycerides, lecithin and combinations thereof; and

[0142] (iv) optionally includes one or more other pharmaceutically acceptable excipients selected from the group consisting of: stabilizers, fillers, thickeners, binders, disintegrants, lubricants, glidants, flavoring agents and combinations thereof.

[0143] In some embodiments of the capsule dosage form, at least one wetting agent, emulsifier, cosolvent, surfactant or combination thereof having an HLB value of about 10 or higher and a second carrier having an HLB value of less than about 10 are liquid at 25 °C, and the salt of the kinase inhibitor, at least one wetting agent, emulsifier, cosolvent, surfactant or combination thereof having an HLB value of about 10 or higher and a second carrier having an HLB value of less than about 10 are a tight mixture.

[0144] Example D of the present invention is an oral solid dosage form, such as a tablet or a capsule, wherein the tablet or capsule contents include:

[0145] (i) Kinase inhibitor C8-C 16Aliphatic sulfates, with a content of about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt%. Among them, the preferred kinase inhibitors are selected from the group consisting of: acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib. And most preferably, they are selected from the group consisting of: afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib. And among them, the preferred kinase inhibitor C8-C 16 The aliphatic sulfate is a kinase inhibitor dodecyl sulfate, and most preferably, it is a kinase inhibitor monolauryl sulfate or a kinase inhibitor dilauryl sulfate;

[0146] (ii) One or more wetting agents, emulsifiers, co-solvents, surfactants or combinations thereof with an HLB value of about 10 or higher, preferably an HLB value of about 11 or higher, more preferably about 12 or higher, and most preferably about 14 or higher, with a content of about 1 wt% to about 60 wt%, preferably about 2 wt% to about 50 wt%, and most preferably about 3 wt% to about 40 wt%. Among them, one or more wetting agents, emulsifiers, co-solvents, surfactants or combinations thereof with an HLB value of about 10 or higher are selected from the group consisting of: fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxyalkyl polysaccharides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters of polyglycerol esters or fatty alcohols, or combinations thereof. And most preferably, they are selected from the group consisting of: polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride, or combinations thereof;

[0147] (iii) Disintegrants, with a content of about 0 wt% to about 40 wt%, preferably about 1 wt% to about 25 wt%, and most preferably about 2.5 wt% to about 20 wt%;

[0148] (iv) Fillers, with a content of about 5 wt% to about 90 wt%, preferably about 15 wt% to about 85 wt%, and most preferably about 20 wt% to about 80 wt%; and

[0149] (v) Optionally includes one or more other pharmaceutically acceptable excipients selected from the group consisting of: stabilizers, thickeners, binders, lubricants, glidants, flavoring agents, and combinations thereof.

[0150] In certain embodiments of Example D, kinase inhibitor C8-C 16 At least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the total amount of the fatty sulfate and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or higher is present as a tight mixture in a solid tablet or solid capsule, and is preferably formed prior to combination with elements (iii), (iv), and / or (v).

[0151] Example E of the present invention is an oral semi-solid composition comprising:

[0152] (i) Kinase inhibitor C8-C 16 A fatty sulfate in an amount of about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, most preferably about 5 wt% to about 50 wt%, wherein the preferred kinase inhibitors are selected from the group consisting of: acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, enasidenib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib, and most preferably are selected from the group consisting of: afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib, and wherein the preferred kinase inhibitor C8-C 16 Fatty sulfate is kinase inhibitor dodecyl sulfate, and most preferably is kinase inhibitor monododecyl sulfate or kinase inhibitor didodecyl sulfate;

[0153] (ii) One or more wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of about 10 or higher, preferably an HLB value of about 11 or higher, more preferably about 12 or higher, and most preferably about 14 or higher, in an amount of about 1 wt% to about 70 wt%, preferably about 2 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt%, wherein the one or more wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of about 10 or higher are selected from the group consisting of: fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxyalkyl polysaccharides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, fatty acid esters of polyglycerides or fatty acid alcohols or combinations thereof, and most preferably are selected from the group consisting of: polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride or combinations thereof;

[0154] (iii) A second carrier having an HLB value of about less than 10, more preferably an HLB value of about 9 or lower, about 8 or lower, and more preferably an HLB value of about 7 or lower, in an amount of about 1 wt% to about 70 wt%, preferably about 2 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt%, wherein the second carrier is preferably selected from the group consisting of: wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of about less than 10, more preferably is selected from the group consisting of: medium chain monoglycerides, medium chain diglycerides, polyoxyethylene glycerides, sorbitan esters, sorbitan fatty acid esters and combinations thereof, and most preferably is medium chain monoglycerides, medium chain diglycerides, lecithin and combinations thereof;

[0155] (iv) A thickener that is solid at ambient temperature but has a melting point below 120 °C, preferably below 100 °C, more preferably below 80 °C, and most preferably below 60 °C, in an amount of about 0.5 wt% to about 70 wt%, preferably about 1 wt% to about 60 wt%, and most preferably about 2.5 wt% to about 50 wt%, wherein the thickener is selected from the group consisting of: natural or synthetic waxes, such as carnauba wax, cetyl ester wax, microcrystalline wax, white wax, yellow wax, beeswax, ozokerite, paraffin wax, ceresin wax, myrica wax, microcrystalline wax of microcycas calocoma and rizzolowax, stearin (also known as hydrogenated vegetable glyceride), hydrogenated vegetable oil, C 12 -C 60 alcohols, C 12 -C 60 acids, α-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides and combinations thereof; and

[0156] (v) Optionally includes one or more other pharmaceutically acceptable excipients selected from the group consisting of: stabilizers, binders, lubricants, glidants, flavoring agents, and combinations thereof.

[0157] Wherein, kinase inhibitor C8-C 16 The fatty sulfate and one or more wetting agents, emulsifiers, solubilizers, surfactants or combinations thereof having an HLB value of about 10 or higher are present as a tight mixture.

[0158] Example F of the present invention is an oral solid dosage form, such as a tablet or a capsule, wherein the tablet or capsule contents contain a solid dispersion, including:

[0159] (i) Kinase inhibitor C8-C 16 The fatty sulfate is present in an amount of about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt%. The preferred kinase inhibitors are selected from the group consisting of: acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, foretinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib. The most preferred are selected from the group consisting of: afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib. And the preferred kinase inhibitor C8-C 16 The fatty sulfate is the kinase inhibitor dodecyl sulfate, and the most preferred is the kinase inhibitor monododecyl sulfate or the kinase inhibitor didodecyl sulfate;

[0160] (ii) One or more wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of about 10 or higher, preferably an HLB value of about 11 or higher, more preferably about 12 or higher, and most preferably about 14 or higher, in an amount of about 1 wt% to about 60 wt%, preferably about 2 wt% to about 50 wt%, and most preferably about 3 wt% to about 40 wt%, wherein the one or more wetting agents, emulsifiers, cosolvents, surfactants or combinations thereof having an HLB value of about 10 or higher are selected from the group consisting of: fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxyalkyl polysaccharides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, tyloxapol, poloxamer, fatty acid esters or fatty alcohols of polyglycerides or combinations thereof, and most preferably are selected from the group consisting of: polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride or combinations thereof; and

[0161] (iii) One or more polymer reagents, in an amount of about 1 wt% to about 60 wt%, preferably about 2 wt% to about 50 wt%, and most preferably about 3 wt% to about 45 wt% of a water-soluble polymer reagent, which has a viscosity less than 200 mPa·s, preferably less than 100 mPa·s, and most preferably less than 50 mPa·s when tested as an aqueous solution prepared at a concentration of 2% (w / v) at 20 °C, wherein the most preferred polymer reagents are selected from the group consisting of: povidone, hypromellose, hydroxypropylcellulose, gelatin and mixtures thereof.

[0162] The solid dispersion dosage form of Example F may further comprise the following either in or mixed with the solid dispersion, i.e., extra granular:

[0163] (iv) Disintegrants, in an amount of about 0 wt% to about 40 wt%, preferably about 1 wt% to about 25 wt%, and most preferably about 2.5 wt% to about 20 wt%;

[0164] (v) Fillers, in an amount of about 0 wt% to about 90 wt%, preferably about 15 wt% to about 85 wt%, and most preferably about 20 wt% to about 80 wt%; and

[0165] (vi) Optionally including one or more other pharmaceutically acceptable excipients selected from the group consisting of: stabilizers, thickeners, binders, lubricants, glidants, flavoring agents and combinations thereof.

[0166] Example G of the present invention is a sustained or controlled release oral solid dosage form, such as a tablet or a capsule, wherein the tablet or capsule contents comprise:

[0167] (i) Kinase inhibitor C8-C 16 Alkyl sulfates, in an amount of about 1 wt% to about 80 wt%, preferably about 2 wt% to about 70 wt%, more preferably about 3 wt% to about 60 wt%, and most preferably about 5 wt% to about 50 wt%. The preferred kinase inhibitors are 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, vandetanib, and vemurafenib. The most preferred are selected from the group consisting of: afatinib, dasatinib, erlotinib, imatinib, nilotinib, nintedanib, osimertinib, pazopanib, and ponatinib. And the preferred kinase inhibitor C8-C 16 The alkyl sulfate is kinase inhibitor dodecyl sulfate, and the most preferred is kinase inhibitor monolauryl sulfate or kinase inhibitor dilauryl sulfate;

[0168] (ii) One or more wetting agents, emulsifiers, co-solvents, surfactants or combinations thereof with an HLB value of about 10 or higher, preferably an HLB value of about 11 or higher, more preferably about 12 or higher, and most preferably about 14 or higher, in an amount of about 1 wt% to about 60 wt%, preferably about 2 wt% to about 50 wt%, and most preferably about 3 wt% to about 40 wt%. The one or more wetting agents, emulsifiers, co-solvents, surfactants or combinations thereof with an HLB value of about 10 or higher are selected from the group consisting of: fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxyalkyl polysaccharides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, tyloxapol, poloxamer, fatty acid esters of polyglycerides or fatty alcohols or combinations thereof. The most preferred are selected from the group consisting of: polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, caprylic / capric triglyceride or combinations thereof;

[0169] (iii) Controlled-release or sustained-release agents, in an amount of about 0.5 wt% to about 50 wt%, preferably about 1 wt% to about 40 wt%, and most preferably about 2 wt% to about 35 wt%. The controlled-release or sustained-release material is an excipient that controls or prolongs the kinase inhibitor C8-C in the dosage form 16The release time of the fatty sulfate is greater than 1 hour, greater than 2 hours, greater than 3 hours, greater than 4 hours, greater than 5 hours, or greater than 6 hours. It is preferably selected from the aforementioned thickeners, more preferably a gelling agent as described above, and may optionally be selected from the group consisting of: polyhydroxyalkyl celluloses with a molecular weight greater than 50,000, such as hydroxypropyl methylcellulose (METHOCEL K 100M, available from Dow Chemical); polyhydroxyalkyl methacrylates with a molecular weight of 5,000 to 5,000,000; polyvinylpyrrolidones with a molecular weight of 100,000 to 3,000,000; pectins with a molecular weight of 30,000 to 300,000; polysaccharides, such as agar, gum arabic, karaya gum, tragacanth gum, alginic acid, and guar gum; acrylic polymers POLYOX with a molecular weight of 100,000 to 7,000,000 TM Polyethylene oxide polymers and combinations thereof;

[0170] (iv) Optionally includes a filler, with a content of about 5 wt% to about 90 wt%, preferably about 15 wt% to about 85 wt%, and most preferably about 20 wt% to about 80 wt%; and

[0171] (v) Optionally includes one or more other pharmaceutically acceptable excipients, selected from the group consisting of: stabilizers, binders, lubricants, glidants, flavoring agents, and combinations thereof.

[0172] In certain embodiments of Example G, kinase inhibitor C8 - C 16 At least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the total amount of the fatty sulfate and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof with an HLB value of about 10 or higher is present as a tight mixture in a solid tablet or solid capsule, and is preferably formed before being combined with elements (iii), (iv), and / or (v).

[0173] In certain embodiments of Example G, when tested using the USP Type II apparatus (paddle) in an aqueous media of 900 mL, pH 6.8, and containing 0.1% sodium lauryl sulfite, at a rotation speed of 75 rpm with or without a sinker, the release of kinase inhibitor C8 - C in the sustained - release or controlled - release oral solid dosage form 16 The fatty sulfate is released as follows:

[0174] Time (hours) Preferably More preferably Most preferably 2 0-40％ 0-35％ 0-30％ 4 5％-70％ 7.5％-60％ 10％-50％ 6 10％-100％ 15％-100％ 20％-100％ 10 NLT * 45% NLT 50% NLT 55% 12 NLT 50% NLT 60% NLT 70%

[0175] *NLT = not less than

[0176] In certain embodiments of the present invention, specifically embodiments A - F, when tested using the USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at a rotational speed of 75 rpm, 37 °C, and with or without a sinker, the release of kinase inhibitor C8 - C in an oral solid dosage form is as follows: 16 The release of the fatty sulfate is as described below:

[0177] Time (minutes) Preferably More preferably Most preferably 15 0-50％ 5％-50％ 10％-50％ 30 10％-70％ 25％-70％ 35％-70％ 45 35％-100％ 45％-100％ 50％-100％ 60 NLT 80% NLT 85% NLT 90%

[0178] In certain embodiments of the present invention, specifically for liquid oral dosage forms, when tested using the USP Type II apparatus (Paddle) in 500 - 900 mL of 0.1 N HCl at a rotational speed of 75 rpm, 37 °C, and with or without a sinker, the release of kinase inhibitor C8 - C is as follows: 16 The release of the fatty sulfate is as described below:

[0179]

[0180]

[0181] In certain other embodiments of the present invention, specifically for liquid oral dosage forms, when tested using the USP Type II apparatus (Paddle) in 900 mL of 0.1 N HCl containing 0.1% Tween 80 at a rotational speed of 75 rpm, 37 °C, and with or without a sinker, the release of kinase inhibitor C8 - C is as follows: 16 The release of the fatty sulfate is as described below:

[0182] Time (minutes) Preferably More preferably Most preferably 15 5-50％ 10％-50％ 15％-50％ 30 10％-85％ 15％-80％ 20％-75％ 60 40％-95％ 45％-95％ 50％-95％ 120 NLT 70% NLT 80% NLT 85%

[0183] The compositions and dosage forms of the present invention will be stable when prepared and stored under normal and accelerated conditions, specifically referring to the compositions and dosage forms described in the aforementioned embodiments A - G. More specifically, when the dosage form is 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 a relative humidity of about 60% for at least three months, preferably at least six months, most preferably at least one year and / or at about 40 °C and a relative humidity of about 75% for one, two, or three months, the dosage form of the present invention will contain about 1.0% or less of any individual degradation product, preferably about 0.75% or less of any individual degradation product, most preferably about 0.5% or less of any individual degradation product.

[0184] When the dosage form is 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 a relative humidity of about 60% for at least three months, preferably at least six months, most preferably at least one year and / or at about 40 °C and a relative humidity of about 75% for one month, two months or three months, the compositions and dosage forms of the present invention, specifically the compositions and dosage forms described in the foregoing Examples A - G, will contain about 2.0% or less of the total amount of degradation products, preferably about 1.5% or less, most preferably about 1.0% or less.

[0185] Kinase inhibitor C8 - C 16 The fatty sulfate can be in an amorphous or crystalline form, especially referring to the dodecyl sulfate of the kinase inhibitor used in the compositions and dosage forms of the present invention and the compositions and dosage forms described in Examples A - G above. Kinase inhibitor C8 - C 16 The fatty sulfate is preferably in an amorphous form, especially referring to the dodecyl sulfate of the kinase inhibitor used in the solid dispersion dosage form of Example F.

[0186] Table 1 shows the amounts of some dodecyl sulfates of kinase inhibitors (KI lauryl sulfatesalts) present in the dosage forms of the present invention, specifically the dosage forms described in Examples A - G above:

[0187] Table 1

[0188]

[0189]

[0190]

[0191] Table 2 shows the approved indications for the preferred kinase inhibitor compounds by the US FDA, and the kinase inhibitor C8 - C 16 The fatty sulfate, specifically the dodecyl sulfate of the kinase inhibitor of the present invention, can be applied to the treatment conditions:

[0192] Table 2

[0193]

[0194]

[0195] The present invention includes a method for treating various diseases defined in Table 2 by orally administering one or more dosage forms, said dosage forms comprising kinase inhibitor C8 - C 16A fatty sulfate, which is preferably one or more dosage forms comprising a kinase inhibitor lauryl sulfate. In certain embodiments: (i) the drug can be orally administered after a meal or on an empty stomach, and this oral administration will exhibit substantially stable pharmacokinetic parameters or will not exhibit a food effect, which will be described in more detail hereinafter; (ii) compared to currently FDA-approved kinase inhibitor compositions in the United States, this oral administration will be able to reduce the total daily dose of the kinase inhibitor while maintaining similar pharmacokinetics, which will be described in more detail hereinafter; (iii) this oral administration can be co-administered with or without an inhibitor of gastric acid secretion, and this oral administration will not exhibit the effect of an inhibitor of gastric acid secretion, which will be described in more detail hereinafter; or (iv) the oral administration will exhibit a combination of (i), (ii), and / or (iii).

[0196] In certain embodiments, the present invention includes a method of treating various conditions defined in Table 2 by orally administering one or more dosage forms described in Examples A-G and comprising the kinase inhibitor lauryl sulfate set forth in Table 1. In these embodiments: (i) the drug can be orally administered after a meal or on an empty stomach, and this oral administration will exhibit substantially stable pharmacokinetic parameters or will not exhibit a food effect, which will be described in more detail hereinafter; (ii) compared to currently FDA-approved kinase inhibitor compositions in the United States, this oral administration will be able to reduce the total daily dose of the kinase inhibitor while maintaining similar pharmacokinetics, which will be described in more detail hereinafter; (iii) this oral administration can be co-administered with or without an inhibitor of gastric acid secretion, and this oral administration will not exhibit the effect of an inhibitor of gastric acid secretion, which will be described in more detail hereinafter; or (iv) the oral administration will exhibit a combination of (i), (ii), and / or (iii).

[0197] For example, a dosage form as described in Examples A-G, which contains 10-400 mg of nilotinib lauryl sulfate, preferably 15-350 mg, more preferably 25-300 mg, can be orally administered to a patient to treat chronic myeloid leukemia, wherein (i) the drug can be orally administered after a meal or on an empty stomach, and this oral administration will not exhibit a food effect; (ii) compared to currently FDA-approved kinase inhibitor compositions in the United States, this oral administration will be able to reduce the total daily dose of nilotinib free base while maintaining pharmacokinetics similar to those of taking nilotinib hydrochloride, and; (iii) this oral administration can be co-administered with or without an inhibitor of gastric acid secretion, and this oral administration will not exhibit the effect of an inhibitor of gastric acid secretion.

[0198] Similarly, the dosage forms described in Examples A - G, which contain 5 - 250 mg of dasatinib lauryl sulfate, preferably 10 - 175 mg, more preferably 15 - 150 mg, can be orally administered to a patient to treat chronic myelogenous leukemia and / or acute lymphoblastic leukemia, wherein (i) the drug can be orally administered after a meal or on an empty stomach, and this oral administration will not exhibit a food effect; and (ii) this oral administration can be co - administered with or without an inhibitor of gastric acid secretion, and this oral administration will not exhibit the effect of an inhibitor of gastric acid secretion.

[0199] The compositions and dosage forms of the present invention, including but not limited to Examples A - G, can be administered to an individual, where the individual can be in a post - meal state or a fasting state, and regardless of whether the administration is carried out in a post - meal or fasting state, the resulting pharmacokinetic parameters are substantially maintained stable or there is no food effect. Generally, the post - meal state is defined as consuming food within about 30 minutes before administering the composition or dosage form. The above - mentioned food can be a high - fat diet, a low - fat diet, a high - calorie diet or a low - calorie diet. The fasting state can be defined as not ingesting food for at least 10 hours before administering the composition or dosage form. In some embodiments, the individual can fast for at least 10 hours before administration and avoid ingesting food for about 30 minutes to 2 hours, preferably about 1 hour, after administration. In other embodiments, a fasting individual can not ingest food for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours before each dose of the composition or dosage form.

[0200] When the compositions and / or dosage forms of the present invention, including but not limited to Examples A - G, are orally administered to a patient or a healthy individual, regardless of whether the composition is administered after a meal or on an empty stomach, it will produce pharmacokinetic parameters that are substantially maintained stable, such as: the time to reach the maximum plasma drug concentration (T max ), the maximum plasma drug concentration (C max ) and the area under the plasma drug concentration curve (AUC). Substantially maintaining stable pharmacokinetic parameters means that when one or more doses of the composition or dosage form are administered to a patient or a healthy individual in a post - meal state as described in the U.S. FDA guidelines, including but not limited to Examples A - G, and the same composition is administered to a patient or a healthy individual in a fasting state as described in the U.S. FDA guidelines, the measured pharmacokinetic parameters obtained will not vary by more than 40%, preferably not more than 30%, and most preferably not more than 20%. For example, after a single - dose administration to a patient in a fasting state, if the time to reach the maximum plasma drug concentration (T max ) is 3 hours, then the T within the range of 1.8 hours to 4.2 hours maxIt can be considered to be substantially stable, that is, 3 hours ± 40%.

[0201] In certain preferred embodiments of the present invention, the compositions or dosage forms prepared according to the present invention, including but not limited to Examples A - G, will be bioequivalent or show no food effect upon single oral dose administration in the postprandial and fasting states. The terms "bioequivalent" and "no food effect" are used according to the US FDA guidelines.

[0202] In certain embodiments of the present invention, the compositions or dosage forms prepared according to the present invention, including but not limited to Examples A - G, the single oral administration thereof will result in the KI C max / KI C for fasting administration max The ratio (C max fed / C max fast ) is from about 0.60 to about 2.5, preferably from about 0.70 to about 2.0, more preferably from about 0.75 to about 1.5, and most preferably about 0.8 to about 1.25. Similarly, in certain embodiments of the present invention, the compositions or dosage forms prepared according to the present invention, including but not limited to Examples A - G, the single oral administration thereof will result in the AUC 0-∞ / AUC of the pharmaceutical composition for fasting administration 0-∞ The ratio (AUC 0-∞fed / AUC 0-∞fast ) is from about 0.60 to about 2.5, preferably from about 0.70 to about 2.0, more preferably from about 0.75 to about 1.5, and most preferably about 0.8 to about 1.25.

[0203] After oral administration of the composition or dosage form of the present invention, including but not limited to Examples A - G, the plasma concentration of the kinase inhibitor is obtained, and at least one pharmacokinetic parameter differs by less than about 40% between the postprandial and fasting states. In different embodiments, the pharmacokinetic parameter may vary by less than about 35%, 30%, 25%, 20%, 15%, 10% or 5% between the postprandial and fasting states. The pharmacokinetic parameters not affected by food effects can be, but are not limited to, C max , AUC, T max or a combination thereof.

[0204] Certain embodiments of the present invention include a method for treating cancer in a human patient, comprising the step of orally administering to the patient one or more dosage forms as described in Examples A - G, wherein administration can be carried out in the postprandial or fasting state, and wherein the kinase inhibitor C8 - C 16The dosage of the fatty sulfate, particularly the kinase inhibitor dodecyl sulfate, does not require dosage adjustment or change in the administration time.

[0205] In certain embodiments, administering the composition or dosage form prepared according to the present invention can achieve a reduction in the dosage of the kinase inhibitor free base currently approved by the US FDA and still obtain an equivalent therapeutic level. More specifically, the composition prepared according to the present invention will be able to reduce the daily dosage of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib, or vemurafenib by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%, and still provide the same therapeutic level, i.e., an equivalent plasma concentration level.

[0206] Table 3 shows the currently approved dosages of preferred kinase inhibitors by the US FDA:

[0207] Table 3

[0208]

[0209]

[0210]

[0211] In certain embodiments, orally administering the kinase inhibitor C8-C of the present invention 16 The fatty sulfate, particularly the kinase inhibitor dodecyl sulfate, will allow a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% in the total daily recommended dose of the kinase inhibitor free base recorded in Table 3 while maintaining similar pharmacokinetic parameters. For example, the currently approved daily dosage of nilotinib hydrochloride is based on 600 - 800 mg of nilotinib free base. Orally administering nilotinib dodecyl sulfate will allow a reduction in the daily dosage of at least 25%, i.e., 450 - 600 mg, while maintaining the same or substantially similar pharmacokinetic parameters, such as: C max , T max and / or AUC. Alternatively, a patient taking 800 mg of nilotinib (in hydrochloride form) will be able to take 600 mg of nilotinib (in dodecyl sulfate form) to maintain a similar nilotinib plasma concentration level.

[0212] The solubility of many kinase inhibitor drugs is pH-dependent. The solubility of many kinase inhibitors decreases as the pH increases. Patients taking kinase inhibitor drugs may also take or co-administer gastric acid secretion inhibitors, such as antacids, H2 antagonists, and proton pump inhibitors, to reduce gastric acid secretion or increase the pH in the stomach. Since gastric acid secretion inhibitors will increase the pH in the patient's stomach, the solubility of the co-administered kinase inhibitor drug in the patient's stomach will decrease, resulting in reduced absorption. To avoid this reduced absorption or gastric acid secretion inhibitor effect, patients are warned to take antacids at least two hours before and after taking kinase inhibitor drugs, or to discontinue the use of H2 antagonists or proton pump inhibitors during the kinase inhibitor drug regimen. The present invention obviates the need for staggered administration of antacids or discontinuation of the use of H2 antagonists or proton pump inhibitors during the kinase inhibitor drug regimen. The kinase inhibitor C8-C 16 alkyl sulfates, particularly the kinase inhibitor dodecyl sulfate, can be orally administered to patients or healthy individuals, and will produce similar or substantially stable pharmacokinetic parameters, such as T max , C max and AUC, whether administered with or without a gastric acid secretion inhibitor. Substantially stable pharmacokinetic parameters mean that for patients or healthy individuals who are administered one or more doses of the composition or dosage form of the present invention (including but not limited to Examples A-G) in a fasting state and taking a gastric acid secretion inhibitor, compared to patients or healthy individuals who are administered the same composition in a fasting state but not taking a gastric acid secretion inhibitor, the changes in the pharmacokinetic parameters (such as C max and / or AUC) will not exceed 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%.

[0213] In certain embodiments of the present invention, the composition or dosage form prepared according to the present invention, including but not limited to Examples A-G, a single oral administration thereof will produce a ratio of KI C max administered with a gastric acid secretion inhibitor / KI C max not administered with a gastric acid secretion inhibitor (C max w / gastric acid reducing / C max w / o gastric acid reducing) is from about 0.60 to about 2.5, preferably from about 0.70 to about 2.0, more preferably from about 0.75 to about 1.5, and most preferably from about 0.8 to about 1.25. Similarly, in certain embodiments of the present invention, for a composition or dosage form prepared according to the present invention, including but not limited to Examples A - E, a single oral administration will produce an AUC of the pharmaceutical composition administered together with an inhibitor of gastric acid secretion 0-∞ / AUC of the pharmaceutical composition not administered together with an inhibitor of gastric acid secretion 0-∞ ratio (AUC 0-∞w / gastric acid reducing / AUC 0-∞w / o gastric acid reducing ) is from about 0.60 to about 2.5, preferably from about 0.70 to about 2.0, more preferably from about 0.75 to about 1.5, and most preferably from about 0.8 to about 1.25.

[0214] Certain embodiments of the present invention will employ the dosage forms of Examples A - G and the amounts of bosutinib, dasatinib, erlotinib, gefitinib, lenatinib, nilotinib, and pazopanib listed in Table 1 to treat the conditions listed in Table 2. Whether administered orally with or without co - administration of an inhibitor of gastric acid secretion, they will produce substantially stable pharmacokinetic parameters, such as: T max 、C max and AUC.

[0215] Certain embodiments of the present invention include a method for treating a human cancer patient, the method comprising the step of orally administering to the patient one or more dosage forms as described in Examples A - G and co - administering to the patient an inhibitor of gastric acid secretion, wherein the dose of the kinase inhibitor C8 - C 16 alkyl sulfates, particularly the kinase inhibitor dodecyl sulfate, will not require dose adjustment or change in the dosing time. In this embodiment, particularly useful examples of kinase inhibitors are bosutinib, dasatinib, erlotinib, gefitinib, lenatinib, nilotinib, and pazopanib, and the specific cancers listed in Table 2 are treated with the doses listed in Table 1.

[0216] Description of Examples

[0217] The following embodiments are only for illustration and are not intended to be limiting in any way.

[0218] Example 1

[0219] Prepare nilotinib lauryl sulfate salt as follows: Dissolve 2.48 g of nilotinib hydrochloride monohydrate in 1900 mL of 0.1 N hydrochloric acid solution, and dissolve 1.16 g of sodium lauryl sulfate (SLS) in 100 mL of 0.1 N hydrochloric acid solution. Once the nilotinib hydrochloride monohydrate and sodium lauryl sulfate are dissolved, mix the two solutions uniformly and let stand for 24 hours. Remove the upper liquid and dry at 40 °C for 18 hours to collect the nilotinib lauryl sulfate precipitate.

[0220] Example 2

[0221] The lauryl sulfates of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib can be formed by a method similar to that described in Example 1 above: Dissolve acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib in a suitable solution, such as: 0.1 N hydrochloric acid solution or a mixture of 0.1 N hydrochloric acid solution and C1-C6 alcohols (such as: methanol, ethanol, isopropanol), and add lauryl sulfate or an aqueous solution of lauryl sulfate to the solution of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib.

[0222] Example 3

[0223] Mix nilotinib dodecyl sulfate (dry precipitate) prepared in Example 1 with CAPMUL (glyceryl caprylate / caprate) and EL (polyoxyl 35 castor oil), and fill the liquid mixture into No. 0 hard gelatin capsules to prepare a capsule dosage form of nilotinib dodecyl sulfate.

[0224] The composition of the capsule contents is as follows:

[0225] mg wt% Nilotinib dodecyl sulfate (dried precipitate) 75.0 12.5 Caprylic / capric glycerides 420.0 70.0 Polyoxyethylene 35 castor oil 105.0 17.5 Total 600.0 100.0

[0226] Example 4

[0227] Prepare nilotinib dodecyl sulfate capsules as follows: Dissolve 1940 mg of nilotinib dodecyl sulfate (dry precipitate) and 1040 mg of poloxamer 188 in 5 mL of ethanol. Manually mix the solution with 3100 mg of AVICEL PH 101 (microcrystalline cellulose) and 3100 mg of lactose. Dry, grind, and sieve the resulting granules through a 60-mesh sieve, and mix them with 210 mg of colloidal silicon dioxide, 1040 mg of sodium starch glycolate, and 100 mg of magnesium stearate. Fill the dry solid mixture (blend) into No. 0 hard gelatin capsules.

[0228] The composition of the capsule contents is as follows:

[0229] mg wt% Nilotinib dodecyl sulfate (dried precipitate) 75.0 18.5 Microcrystalline cellulose 119.5 29.4 Lactose 119.5 29.4 Sodium starch glycolate 40.0 9.9 Poloxamer 188 40.0 9.9 Colloidal silicon dioxide 8.0 2.0 Magnesium stearate 4.0 0.9 Total 600.0 100.0

[0230] Example 5

[0231] Adjust the capsules prepared similar to those in Examples 3 and 4 to a capsule weight containing approximately 50 mg of nilotinib free base, and administer the above capsules and the capsules obtained by dispensing commercially available TASIGNA capsules (dispense the contents of a commercially available 200-mg TASIGNA capsule into 4 capsules, each containing 50 mg of nilotinib free base equivalent) to six (6) fasted healthy adult beagle dogs for a single-center and single-dose study. Blood samples are taken before dosing and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after dosing. The average nilotinib plasma concentration values are determined as follows:

[0232]

[0233] The average plasma concentration curve is as Figure 1 shown.

[0234] The individual data obtained in the study are shown in the following list:

[0235] C max

[0236]

[0237] AUC 0-24

[0238]

[0239]

[0240] Control drug Reference (TASIGNA)

[0241]

[0242] Capsules prepared as in Example 3

[0243]

[0244]

[0245] Capsules prepared as in Example 4

[0246]

[0247] Example 6

[0248] The dodecyl sulfates of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib can be used to prepare the capsule dosage forms as described in Examples 1 and 2 according to the method described in Example 3.

[0249] The composition of the capsule contents is shown as follows:

[0250]

[0251]

[0252] Example 7

[0253] The dodecyl sulfates of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib can be used, and the capsule dosage forms described in Examples 1 and 2 are prepared according to the method described in Example 4.

[0254] The composition of the capsule contents is shown below:

[0255]

[0256] Example 8

[0257] The dodecyl sulfates of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib can be used, and the capsule dosage forms described in Examples 1 and 2 are prepared according to the method described in Example 3.

[0258] The composition of the capsule contents is shown below:

[0259]

[0260] Example 9

[0261] Prepare nilotinib dodecyl sulfate as follows: Dissolve 2.92 g of nilotinib hydrochloride monohydrate in 2900 mL of 0.1 N hydrochloric acid solution, and dissolve 1.50 g of sodium dodecyl sulfate in 100 mL of 0.1 N hydrochloric acid solution. Once the nilotinib hydrochloride monohydrate and sodium dodecyl sulfate are dissolved, the two solutions are uniformly mixed and left standing for 24 hours. The upper layer liquid is removed and dried at 40 °C for 18 hours to collect the nilotinib dodecyl sulfate precipitate.

[0262] Mix nilotinib dodecyl sulfate (dried precipitate) with CAPMUL (glyceryl caprylate / caprate) and The mixture was mixed with EL (polyoxyl 35 castor oil), and the liquid mixture was filled into a No. 00 hard gelatin capsule to prepare a nilotinib dodecyl sulfate capsule dosage form.

[0263] The composition of the capsule contents is as follows:

[0264] mg wt% Nilotinib dodecyl sulfate (dried precipitate) 100.0 16.0 Caprylic / capric glycerides 420.0 67.2 Polyoxyethylene 35 castor oil 105.0 16.8 Total 625.0 100.0

[0265] Example 10

[0266] The capsules prepared according to Example 9 were administered to nine (9) healthy subjects in fasted and fed states. The administration was randomized, open-label, single-dose, three treatments, three sequences, three periods, and crossover design, with at least a 5-day washout period between each dose. The control drug (Ref) was Nilotinib hydrochloride capsules, the dose is 200 mg (based on free base), and the test drug (Test) is a capsule prepared according to the method described in Example 9, but contains about 50 mg of nilotinib free base. Based on the results described in Example 5 herein, the dose of the selected test capsule is 100 mg (2 capsules, each capsule contains 50 mg of nilotinib free base). The 9 healthy subjects participating in this study were randomly assigned to one of the orders shown in the following table:

[0267]

[0268] During each treatment period, blood samples were drawn at 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. The AUC of each subject was determined based on non-compartmental analyses. 0-48 , AUC 0-∞ , C max 、T max and T 1 / 2 The results were normalized to the 200 mg dose and are summarized in Table 1. Log-transformed AUC 0-t , AUC 0-∞ and C maxOrder, subject (order), cycle, and treatment effect are all included in the model. The comparison of the data obtained from the test drug and the control drug is shown in Table 2. The data shows that compared with nilotinib hydrochloride approved by the US FDA, the composition of the present invention exhibits a 3.4-fold increase in C max and a 2.3-fold increase in AUC. The data also shows that the composition of the present invention does not have a food effect, that is, the composition of the present invention exhibits comparable pharmacokinetics in the fasting and postprandial states.

[0269] Table 1. Pharmacokinetic parameters of the control drug and the test prescription (normalized to a dose of 200 mg)

[0270]

[0271] Ref Fasted : Administer 200 mg (in free base form) of Tasigna capsules in the fasting state

[0272] Test Fasted : Administer 100 mg (in free base form) of the test capsule (Test) (2 capsules, 50 mg * 2) in the fasting state

[0273] Test Fed : Administer 100 mg (in free base form) of the test capsule (Test) (2 capsules, 50 mg * 2) in the postprandial state

[0274] Table 2. Comparison table of the test prescription and the control drug and Test Fed vs. Test Fasted (normalized to a dose of 200 mg)

[0275]

[0276]

[0277] The results of the individual data obtained in the study normalized to a 200 mg dose are shown in the following table:

[0278] Control drug In the fasting state (concentration (ng / mL))

[0279]

[0280] Test drug in the fasting state (concentration (ng / mL))

[0281]

[0282]

[0283] Test drug in the postprandial state (concentration (ng / mL))

[0284]

[0285] The standardized average plasma concentration curve is as Figure 2 shown.

[0286] Example 11

[0287] Prepare dasatinib lauryl sulfate salt as follows: Dissolve 253.0 mg of dasatinib monohydrate in 1000 mL of 0.1 N hydrochloric acid solution, and dissolve 432.0 mg of sodium lauryl sulfate in 100 mL of 0.1 N hydrochloric acid solution. Once the dasatinib monohydrate and sodium lauryl sulfate are dissolved, mix the two solutions evenly and let stand for 20 hours. Remove the upper liquid to collect the dasatinib lauryl sulfate precipitate, and dry the collected precipitate at 50 °C for 20 hours.

[0288] Dissolve about 10.44 mg of the precipitate in 50 mL of methanol, then sonicate for 5 minutes and stir for 5 minutes, and analyze the resulting solution by high performance liquid chromatography (HPLC). The analysis results indicate that the precipitate contains dasatinib dilauryl sulfate salt.

[0289] Example 12

[0290] Prepare dasatinib monolaurylsulfate salt via the following general procedure:

[0291] a. Mix 13 g of dasatinib·H2O and 650 mL of methanol (50 V), and stir at 50 - 55 °C;

[0292] b. Mix 7.4 g of sodium lauryl sulfate (SLS) (equivalent to 1 molar equivalent of dasatinib monohydrate) with 39 mL of methanol (3 V) and 25.7 mL of 1 N HCl (equivalent to 1 molar equivalent of SLS);

[0293] c. Maintain the temperature at 50 - 55 °C, add the composition of step (b) to the composition of step (a) and stir for 30 minutes, then cool to room temperature for about 1 hour;

[0294] d. Add 650 mL of purified water (50 V) to the reaction mass in step (c) and stir at room temperature for 30 minutes;

[0295] e. Remove the solvent from the reaction mass in step (d) and collect the residue;

[0296] f. Add 260 mL of ethyl acetate (20 V) to the residue in step (e) and wash the resulting reaction mass three times with 130 mL of purified water (10 V × 3);

[0297] g. Mix the organic extract and add 130 mL of methanol (10 V);

[0298] h. Dry the reaction mass in step (g) in vacuo at 40 °C for 6 hours to obtain crude dasatinib-1LS;

[0299] i. Mix the crude dasatinib-1LS with 130 mL of n-hexane (10 V), stir for 30 minutes, separate the solid by filtration, wash with n-hexane and dry in vacuo at 40 °C for 16 hours to obtain a white powder of dasatinib-1LS with a chromatographic purity greater than 99%.

[0300] Figure 3 The X-ray Powder Diffraction Pattern (XRPD) of the white powder of dasatinib-1LS. This XRPD pattern was obtained using a D8 Discover with GADDS (GADDS: General Area Diffraction Detection System) (Bruker AXS Gbh, Karlsruhe, Germany) under the following detection conditions:

[0301]

[0302] 40 kV 40 mA

[0303] Beam size: 1.0 mm (the analyzed surface area allowed by the collimation system is 1000 μm 2 )

[0304] Detector type: Vantec-2000 (area 14 × 14 cm 2 , pixel density 2048 × 2048)

[0305] Distance from sample to detector: 15.05 cm

[0306] 300 sec / frame (The exposure time per frame is 300 s)

[0307] Repeat the above synthesis reaction several times and summarize the results in the following table:

[0308]

[0309] Example 13

[0310] Prepare dasatinib dilaurylsulfate salt via the following general procedure:

[0311] a. Mix 10 g of dasatinib monohydrate (dasatinib·H2O) with 500 mL of methanol (50 V) and stir at 50 - 55 °C;

[0312] b. Mix 11.4 g of sodium lauryl sulfate (SLS) (equivalent to 2 molar equivalents of dasatinib monohydrate) with 30 mL of methanol (3 V) and 79 mL of 1N HCl (equivalent to 2 molar equivalents of SLS);

[0313] c. Maintain the temperature at 50 - 55 °C, add the composition of step (b) to the composition of step (a) and stir for 30 minutes, then cool to room temperature for about 1 hour;

[0314] d. Add 500 mL of purified water (50 V) to the reaction mass of step (c) and stir at room temperature for 30 minutes;

[0315] e. Remove the solvent from the reaction mass of step (d) and collect the residue;

[0316] f. Add 200 mL of ethyl acetate (20 V) to the residue of step (e) and wash the resulting reaction mass three times with 100 mL of purified water (10 V × 3);

[0317] g. Mix the organic extract and add 100 mL of methanol (10 V);

[0318] h. Dry the reaction mass of step (g) in vacuo at 40 °C for 6 hours to obtain the crude dasatinib - 2LS;

[0319] i. Mix the crude dasatinib-2LS with 100 mL of n-hexane (10V), stir for 30 minutes, separate the solid by filtration, wash with n-hexane and dry in vacuo at 40 °C for 16 hours to obtain a white powder of dasatinib-2LS with a chromatographic purity greater than 99%.

[0320] Figure 4 This is the X-ray powder diffraction pattern of the white powder of dasatinib-2LS. This XRPD pattern was obtained using a D8 Discover with GADDS (Bruker AXS Gbh, Karlsruhe, Germany) under the following detection conditions:

[0321]

[0322] 40 kV 40 mA

[0323] Beam size: 1.0 mm (the analyzed surface area allowed by the collimation system is 1000 μm 2 )

[0324] Detector type: Vantec-2000 (area 14 × 14 cm 2 , pixel density 2048 × 2048)

[0325] Distance from sample to detector: 15.05 cm

[0326] 300 sec / frame (exposure time per frame is 300 s)

[0327] Repeat the above synthesis reaction several times and summarize the results in the following table:

[0328]

[0329] Example 14

[0330] Prepare dasatinib lauryl sulfate salt as follows: Dissolve 1.012 g of dasatinib monohydrate in 1800 mL of 0.1 N hydrochloric acid solution, and dissolve 1.728 g of sodium lauryl sulfate (SLS) in 200 mL of 0.1 N hydrochloric acid solution. Once the dasatinib monohydrate and sodium lauryl sulfate are dissolved, mix the two solutions evenly and dilute with 0.1 N hydrochloric acid solution to a total volume of 5330 mL and stir for 2 hours. Remove the upper liquid and dry at 50 °C for 20 hours to collect the dasatinib lauryl sulfate precipitate.

[0331] Example 15

[0332] Mix 522.0 mg of dasatinib lauryl sulfate (dry precipitate) prepared in Example 14 with 2100.0 mg of CAPMUL (glyceryl caprylate / caprate) and 525.0 mg of EL (polyoxyl 35 castor oil), and fill the suspension mixture into size 0 hard gelatin capsules to prepare a dasatinib lauryl sulfate capsule dosage form.

[0333] The composition of the capsule contents is shown below:

[0334] mg / cap wt% Dasatinib dodecyl sulfate (dried precipitate) 104.4 16.6 Caprylic / capric glycerides 420.0 66.7 Polyoxyethylene 35 castor oil 105.0 16.7 Total 629.4 100.0

[0335] Example 16

[0336] Prepare pazopanib monolaurylsulfate salt via the following general procedure:

[0337] a. Mix 20 g of pazopanib hydrochloride (PZB·HCl), 200 mL of methanol (10V), and 400 mL of purified water (20V), and stir at 50 - 55 °C;

[0338] b. Mix 12.17 g of sodium lauryl sulfate (SLS) (equivalent to 1 molar equivalent of pazopanib hydrochloride) with 60 mL of methanol (3V) and 60 mL of purified water (3V);

[0339] c. Maintain the temperature at 50 - 55 °C, add the composition of step (b) to the composition of step (a) and stir for 30 minutes, then cool to room temperature for about 1 hour;

[0340] d. Add 400 mL of purified water (20V) to the reaction substances in step (c) and stir at room temperature for 30 minutes;

[0341] e. Collect the precipitate (white crystals) in step (d) by filtration, wash with 100 mL of purified water (5V) to obtain the crude product of pazopanib monododecyl sulfate (PZB-1LS);

[0342] f. Mix the crude product of pazopanib monododecyl sulfate with 200 mL of purified water (10V) and stir for 30 minutes, separate the solid by filtration, wash with 100 mL of purified water (5V), and dry under vacuum to obtain 28 g of white powder of pazopanib monododecyl sulfate, with a chromatographic purity of 100% and a yield of 94%.

[0343] At 37 °C, add the sample to 300 mL of the specified medium solution and shake or stir for at least 18 hours until saturation is reached to determine the solubility of the above-prepared pazopanib monododecyl sulfate and the pazopanib hydrochloride sample obtained commercially. Filter the reaction substances and determine the filtered filtrate by high performance liquid chromatography.

[0344]

[0345] Example 17

[0346] Using 17.4 g of pazopanib hydrochloride and 10.58 g of SLS as starting materials, prepare pazopanib monododecyl sulfate according to the method of Example 16. This process yields 20.5 g of pazopanib monododecyl sulfate (yield 80%), with a chromatographic purity of 99.99%.

[0347] Example 18

[0348] Mix 1009.7 mg of pazopanib monododecyl sulfate prepared according to the procedures of Examples 16 and 17, 4981.0 mg 808G (Glyceryl monocaprylate), 1.25 mg of Butylated hydroxytoluene, 281.8 mg FCC 88 (Lactic acid), and 960.1 mg ELP (polyoxyl 35 castor oil), and fill the liquid mixture into size 0 hard gelatin capsules to prepare a capsule dosage form of pazopanib dodecyl sulfate.

[0349] The composition of the capsule content is shown below:

[0350]

[0351] The above-mentioned pazopanib monolauryl sulfate capsules were determined by the following high performance liquid chromatography method:

[0352]

[0353]

[0354] Mobile phase A is water / trifluoracetic acid with a volume ratio of 100 / 0.1.

[0355] Mobile phase B is acetonitrile / trifluoracetic acid with a volume ratio of 100 / 0.1.

[0356] Prepare the test sample according to the following: Weigh about 8.0 mg of pazopanib monolauryl sulfate into a 25 mL brown volumetric flask, add about 20 mL of diluent (containing acetonitrile / water / trifluoracetic acid with a volume ratio of 50 / 50 / 0.1), ultrasonically vibrate for about 5 minutes and stir at a speed of 800 rpm for about 5 minutes until the pazopanib monolauryl sulfate is dissolved. Add additional diluent to make the test sample contain about 0.20 mg of pazopanib per milliliter.

[0357] The high performance liquid chromatography detection results are as follows:

[0358]

[0359] RRT = relative retention time

[0360] The capsules are stored in high density polyethylene (HDPE) bottles (126 c.c., containing 2 - 3 g of silica gel desiccant) with child-resistant caps and aluminum foil induction sealing films.

[0361] The above table proves that any single impurity contained in the capsules is not more than (NMT) 0.5%, preferably not more than 0.35%, most preferably not more than 0.25%, and the total impurities should not be more than 1.0%, preferably not more than 0.75%, most preferably not more than 0.60%.

[0362] When performing the in vitro test of pazopanib monolauryl sulfate capsules using the USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at a rotation speed of 75 rpm, 37 °C, with or without a sedimentation basket, the release within 45 minutes should be not less than 90%, preferably not less than 85%, most preferably not less than 80% of pazopanib.

[0363] Example 19

[0364] Prepare pazopanib dodecyl sulfate capsules as follows: Dissolve 226 mg of poloxamer 188 in 1.2 g of ethanol. Manually mix the above solution with 2421 mg of pazopanib monododecyl sulfate prepared according to the procedures of Examples 16 and 17, 1398.3 mg of lactose monohydrate, and 238.9 mg of polyvinyl pyrrolidone. Dry, grind, and sieve the resulting granules through a 60-mesh sieve, and mix them 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. Fill the dry solid mixture into No. 0 hard gelatin capsules.

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

[0366]

[0367] Detect the above pazopanib monododecyl sulfate capsules using the high-performance liquid chromatography method described in Example 18, and obtain the following results:

[0368]

[0369] The capsules are stored in high-density polyethylene (HDPE) bottles (126 c.c., containing 2 - 3 g of silica gel desiccant) with child-resistant caps and aluminum foil induction sealing films.

[0370] The above table demonstrates that any single impurity contained in the capsules is not more than 0.5%, preferably not more than 0.35%, and most preferably not more than 0.25%, while the total impurities should not be more than 1.0%, preferably not more than 0.75%, and most preferably not more than 0.60%.

[0371] Perform in vitro testing of pazopanib monododecyl sulfate capsules using the USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at a rotation speed of 75 rpm, 37 °C, with or without a sedimentation basket. The release within 45 minutes should be not less than 90%, preferably not less than 85%, and most preferably not less than 80% of pazopanib.

[0372] Example 20

[0373] The capsules prepared in Examples 18 and 19 (containing pazopanib monolauryl sulfate equivalent to 50 mg of pazopanib free base) and the capsules obtained by dispensing the commercially available VOTRIENT film-coated tablets (containing 216.7 mg of pazopanib hydrochloride) (the commercially available 200 mg VOTRIENT film-coated tablets were cut and dispensed into 4 capsules, each containing pazopanib hydrochloride equivalent to 50 mg of pazopanib free base) were administered to six (6) healthy adult beagle dogs in a fasting state, and a single-center and single-dose study was conducted. Blood samples were taken before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. The average pazopanib plasma concentration values were determined as follows:

[0374]

[0375] The average plasma concentration curve is shown in Figure 5 as follows.

[0376] The individual data obtained in the study are shown in the following table:

[0377] C max (ng / mL)

[0378]

[0379] UC 0-24 (ng·hr / mL)

[0380]

[0381] Control drug Reference (VOTRIENT)

[0382]

[0383]

[0384] The capsules prepared as in Example 18

[0385]

[0386] The capsules prepared as in Example 19

[0387]

[0388]

[0389] Example 21

[0390] Nintedanib dilaurylsulfate salt was prepared via the following general procedure:

[0391] a. Add 15 g of nintedanib esylate to a co-solvent of ethyl acetate / aqueous 10% NaHCO3 solution (450 mL / 150 mL) (30V / 10V), and stir for 1 hour at 40 °C;

[0392] b. Separate the organic phase of the reaction mixture in step (a), and wash it twice with 150 mL of purified water (10V×2);

[0393] c. Mix and concentrate the organic phase extract in step (b) to obtain yellow powder of nintedanib free base (12.3 g, yield 98.7%);

[0394] d. Add 738 mL of methanol (60V) to 12.3 g of nintedanib free base, and stir the above mixture at 50 - 55 °C;

[0395] e. Dissolve 13.1 g of sodium lauryl sulfate (SLS) (equivalent to 2 molar equivalents of nintedanib) in a co-solvent of 36.9 mL of methanol and 90 mL of 1N HCl (3V) to prepare a sodium lauryl sulfate solution;

[0396] f. Add the sodium lauryl sulfate solution in step (e) to the mixture in step (d), and stir at 50 - 55 °C for 30 minutes;

[0397] g. Add 246 mL of purified water (20V) to the reaction mixture in step (f) and stir at room temperature for 1 hour;

[0398] h. Collect the precipitate (crystal) in step (g) by filtration, and wash it with 61.5 mL of purified water (5V) to obtain crude nintedanib dilauryl sulfate;

[0399] i. Mix the crude nintedanib dilauryl sulfate with 123 mL of purified water (10V), stir for 30 minutes, separate the solid by filtration, wash it with 61.5 mL of purified water (5V) and dry it in vacuo to obtain 21.83 g of nintedanib dilauryl sulfate golden yellow powder with a chromatographic purity of 100% and a yield of 89.3%.

[0400] Example 21A

[0401] Prepare a nintedanib dilauryl sulfate tablet dosage form via the following wet granulation process:

[0402] (i) Mix 9.940 g of nintedanib dodecyl sulfate prepared by the process of Example 21 with 1.800 g of poloxamer 407 and 1.575 g of poloxamer 188;

[0403] (ii) Granulate the mixture of step (i) using a solution containing 1.500 g of ethanol (95%) and 1.500 g of purified water;

[0404] (iii) Add 6.000 g of anhydrous lactose and 8.278 g of microcrystalline cellulose sieved through a 40-mesh sieve to the granules of step (ii), and mix the resulting composition;

[0405] (iv) Dry the blend of step (iii) in an oven at 50 °C to evaporate ethanol and water, and sieve through a 40-mesh sieve after drying;

[0406] (v) Mix the dried and sieved material of step (iv) with 0.600 g of colloidal silicon dioxide and 1.500 g of polyethylene oxide (Polyox WSR303) with an average molecular weight of 7,000,000 sieved through a 40-mesh sieve;

[0407] (vi) Sieve 0.007 g of butylated hydroxytoluene (BHT) through a 40-mesh sieve and add it to the composition of step (v);

[0408] (vii) Sieve 0.300 g of magnesium stearate through a 40-mesh sieve, add it to the composition of step (vi) and mix to form the final mixture; and

[0409] (viii) Press the final mixture into tablets using a capsule-shaped punch (17.5 mm long, 7.1 mm wide), with a target hardness of about 10 kp.

[0410] The composition of the tablets is as follows:

[0411]

[0412]

[0413] Example 21B

[0414] Prepare the nintedanib dodecyl sulfate tablet dosage form according to the process described in Example 21A, and the composition of the tablets is as follows:

[0415]

[0416] Example 21C

[0417] Using the USP Type II apparatus (Paddle), in 675 mL of 0.1 N HCl containing 0.1% sodium dodecyl sulfate (the pH was changed to 6.8 after 2 hours, final volume: 900 mL), at a rotation speed of 100 rpm, 37 °C and using a sedimentation basket, the dosage forms prepared in Examples 21A and 21B (n = 2) were tested. The results of this dissolution test are shown below:

[0418]

[0419] Using the USP Type II apparatus (Paddle), in 900 mL of an aqueous solution medium with a pH of 6.8 and containing 0.1% sodium dodecyl sulfate, at a rotation speed of 100 rpm, 37 °C and using a sedimentation basket, the dosage forms prepared in Examples 21A and 21B (n = 2) were tested. The results of this dissolution test are shown below:

[0420] Time (hours) Preferably More preferably Most preferably 2 0-40% 0-35% 0-30 4 5-70% 7.5%-60% 10-50% 6 10-100% 15-100% 20-100% 10 NLT 45% NLT 50% NLT 55% 12 NLT 50% NLT 60% NLT 70% *NLT = not less than The dosage forms prepared in Examples 21A and 21B were also used to determine impurities by the following high-performance liquid chromatography method: Mobile phase A is 100% acetonitrile. Mobile phase B is 0.0075 M diammonium hydrogenphosphate (pH 6.4 ± 0.2). Prepare test samples (in triplicate) as follows: Crush the tablets and transfer the crushed material to a 100 mL brown volumetric flask, add about 80 mL of methanol, stir for about 120 minutes or longer until the material disintegrates, additionally sonicate for about 15 minutes and stir at 800 rpm for about 10 minutes. Filter the resulting composition using a 0.45 μm nylon filter and discard the first 3 mL of the filtrate.

[0421] The nintedanib dodecyl sulfate tablets prepared in Examples 21A and 21B were determined to have the impurities shown in the following table:

[0422]

[0423] The above data prove that any single impurity in the nintedanib dodecyl sulfate dosage form of the present invention is not more than (NMT) 0.5%, preferably not more than 0.35% for a single impurity, most preferably not more than 0.25% for a single impurity, and the total impurities should not be more than 1.0%, preferably not more than 0.75%, and most preferably not more than 0.60%.

[0424] Example 21D

[0425] The tablets containing nintedanib didodecyl sulfate (containing 100 mg of nintedanib free base) prepared in Example 21A (Test Formulation 1 or T1) and Example 21B (Test Formulation 2 or T2) and the commercially available tablets containing 120.4 mg of nintedanib ethanesulfonate were mixed with 1% nintedanib. Capsules (Reference) (equivalent to 100 mg nintedanib free base) were administered to six (6) healthy subjects in a single-dose, single-center study in a fasting state. This was an open-label, randomized, three-treatment, three-sequence, three-period crossover bioavailability study in healthy subjects in a fasting state. All subjects were randomly assigned to one of the sequences shown in the table below, with a washout period of at least 5 days between each cycle.

[0426]

[0427] *Rfast: Reference drug in fasting state; T1fast: Test prescription 1 in fasting state; T2fast: Test prescription 2 in fasting state

[0428] During each treatment period, blood samples were drawn at 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 48 hours after dosing. The AUC of each subject was determined based on non-compartmental analyses. 0-48 , AUC 0-∞ , C max 、T max and T 1 / 2 The results are summarized in the table below. ANOVA was used to analyze the log-transformed AUC 0-t , AUC 0-∞ and C max The sequence, subjects (sequence), period and treatment effect were included in the model. The data obtained for the test drug and the control drug are compared in the following table.

[0429] Pharmacokinetic parameters of control drug and test formulation (100 mg dose)

[0430]

[0431] Comparison table of Ex 21A(T1) vs. control drug and Ex 21B(T2) vs. control drug

[0432]

[0433] The individual data obtained in the study are shown in the following list:

[0434] Control drug in fasting state (concentration (ng / mL))

[0435]

[0436]

[0437] in fasting state (concentration (ng / mL)) of the drug of Example 21A (T1)

[0438]

[0439] in fasting state (concentration (ng / mL)) of the drug of Example 21B (T2)

[0440]

[0441]

[0442] The average plasma concentration curve of this example is as Figure 6 shown.

[0443] Example 22

[0444] Nintedanib dodecyl sulfate capsules were prepared as follows: 2386 mg of nintedanib dodecyl sulfate (powder) prepared according to the procedure of Example 21, 468 mg of croscarmellose sodium and 2122 mg of anhydrous lactose were manually mixed. The above mixture was sieved through a 40-mesh sieve. 2122 mg of microcrystalline cellulose (PH102), 390 mg of poloxamer 188 and 234 mg of hydroxypropyl cellulose (HPC-H) were sieved through a 40-mesh sieve and mixed with the above mixture. 78 mg of magnesium stearate was sieved through a 40-mesh sieve and added to the mixture. The dry solid mixture was filled into No. 1 hard gelatin capsules.

[0445] The composition of the capsule contents is as follows:

[0446]

[0447] Example 23

[0448] Prepare the nintedanib dodecyl sulfate capsule dosage form as follows: Mix 2386 mg of nintedanib dodecyl sulfate (powder, sieved through an 80-mesh sieve) prepared according to the procedure of Example 21 with 4649 mg of medium chain triglycerides (Miglyol 812N), 1920 mg of diethyleneglycol monoethyl ether (Transcutol HP), 10 mg of butylated hydroxytoluene (BHT), and 1200 mg of lecithin to obtain a homogeneous dispersion. Melt 1836 mg of hard fat (Gelucire 43 / 01) in a water bath (50 °C) and add it to the dispersion to obtain a homogeneous suspension (semi-solid). Fill the semi-solid suspension into No. 1 hard gelatin capsules.

[0449] The composition of the capsule contents is as follows:

[0450]

[0451] Example 24

[0452] Administer the capsules prepared in Examples 22 and 23 containing nintedanib dodecyl sulfate (equivalent to 30 mg of nintedanib free base) and the capsules prepared from 100 mg of capsules equivalent to 30 mg (collect the contents of 100 mg of capsules obtained commercially, which contain 120.40 mg of nintedanib ethane sulfonate, and refilled into new capsules each containing an equivalent of 30 mg of nintedanib free base) to six (6) healthy adult beagle dogs in a fasting state for a single-center and single-dose study. Blood samples are taken before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 36 hours after dosing. The average nintedanib plasma concentration values are determined as follows:

[0453]

[0454] The average plasma concentration curve is as Figure 7 shown.

[0455] The individual data obtained in the study are shown in the following table:

[0456] C max (ng / mL)

[0457]

[0458] AUC 0-t(ng·hr / mL)

[0459]

[0460] Reference of control drug

[0461] Capsules prepared in Example 22

[0462]

[0463]

[0464] Capsules prepared in Example 23

[0465]

[0466] Example 25

[0467] Nintedanib monolaurylsulfate salt was prepared via the following general procedure:

[0468] a. Add 17 g of nintedanib ethanesulfonate to a cosolvent of ethyl acetate / 10% aqueous NaHCO3 solution (510 mL / 170 mL) (30V / 10V), and stir at 40 °C for 1 hour;

[0469] b. Separate the organic phase of the reaction mixture in step (a), and wash it twice with 170 mL of purified water (10V×2);

[0470] c. Mix and concentrate the organic phase extract in step (b) to obtain yellow powder of nintedanib free base (13.4 g, yield 95%);

[0471] d. Add 1340 mL of absolute ethanol (100V) to 13.4 g of nintedanib free base, and stir the above mixture at 60 °C;

[0472] e. Prepare a sodium lauryl sulfate (SLS) solution as follows: Add 7.16 g of sodium lauryl sulfate (equivalent to 1 molar equivalent of nintedanib) to 40.2 mL of methanol (3V) and 2.3 mL of 12N HCl (equivalent to 1.1 molar equivalents), stir at room temperature for 10 minutes, then add 10 mL of 10% aqueous NaHCO3 solution, and stir at room temperature for 5 minutes.

[0473] f. Add the sodium lauryl sulfate solution in step (e) to the mixture in step (d), and stir at 60 °C for 1 hour;

[0474] g. Concentrate the reaction mass from step (f), add 268 mL of ethyl acetate (20V), and wash the resulting reaction mixture with 134 mL of purified water (10V×3);

[0475] h. Mix, concentrate, and collect the solid of the organic extract from step (g), and dry it in vacuo at 40 °C for 16 hours to obtain 16.3 g of yellow powder of nintedanib monododecyl sulfate, with a chromatographic purity of 100% and a yield of 81.5%.

[0476] Nintedanib monododecyl sulfate can be used to prepare oral dosage forms as described in Examples 22 and 23.

[0477] Example 25A

[0478] At room temperature, add the sample to 5 - 20 mL of the specified medium and shake or stir for at least 18 hours until saturation is reached to determine the solubility of nintedanib dodecyl sulfate prepared in Examples 21 and 25 and the nintedanib ethanesulfonate sample obtained commercially. Filter off the reaction mass and measure the filtered filtrate by high performance liquid chromatography. The solubility measurement results are as follows:

[0479]

[0480] Example 25B

[0481] Measure the impurities and stability of nintedanib dodecyl sulfate prepared in Examples 21 and 25 using the high performance liquid chromatography method outlined in Example 21C.

[0482] Prepare test samples as follows: Weigh approximately 29.88 mg of nintedanib monododecyl sulfate or 39.76 mg of nintedanib didodecyl sulfate (equivalent to 20 mg of nintedanib) separately and transfer them to a 20 mL brown volumetric flask. Add 16 mL of diluent (methanol), sonicate for about 5 minutes and stir at 800 rpm for about 5 minutes until completely dissolved. Add additional diluent such that the test sample is about 1.0 mg of nintedanib per milliliter.

[0483] The results obtained are as follows:

[0484]

[0485] The above data demonstrate that nintedanib didodecyl sulfate is more stable than nintedanib monododecyl sulfate, and any single impurity in the didodecyl and monododecyl sulfates of the present invention is not more than 0.5%, preferably not more than 0.35%, most preferably not more than 0.30%, and the total impurities should not be more than 1.0%, preferably not more than 0.75%, most preferably not more than 0.60%.

[0486] Example 26

[0487] Nilotinib dilaurylsulfate salt is prepared via the following general procedure:

[0488] a. Add 100 mL of methanol (10 V) to 10 g of nilotinib hydrochloride and stir at room temperature;

[0489] b. Add 1.57 mL of 12N HCl (equivalent to 1.1 molar equivalents) to the mixture of step (a) and stir at 50 - 55 °C for 2 hours;

[0490] c. Distill the mixture of step (b) under vacuum and stir the residue with 100 mL of n - hexane (10 V) for 30 minutes;

[0491] d. Filter and separate the solid of step (c), wash with n - hexane and dry in vacuum at 40 °C for 3 hours to obtain 10.8 g of nilotinib dihydrochloride salt as a golden - yellow powder (yield 98%);

[0492] e. Add 216 mL of methanol (20 V) to the 10.8 g of nilotinib dihydrochloride obtained in step (d) and stir the above - mentioned mixture at 50 - 55 °C;

[0493] f. Add 9.76 g of sodium lauryl sulfate (SLS) (2 molar equivalents) to 54 mL of methanol (5 V), and add the resulting mixture to the mixture of step (e) and stir at 50 - 55 °C for 3 hours;

[0494] g. Concentrate the reaction mixture of step (f), add 324 mL of ethyl acetate (30 V), and wash the resulting reaction mixture three times with 216 mL of purified water (20 V×3);

[0495] h. Mix, concentrate and dry the organic extract of step (g) in vacuum at 40 °C for 6 hours to obtain the crude nilotinib dilauryl sulfate;

[0496] i. Mix and stir the crude nilotinib dilauryl sulfate with 108 mL of n - hexane (10 V) for 30 minutes;

[0497] j. The solid of the reaction mixture from step (i) was separated by filtration, washed with n-hexane and dried in vacuo at 40 °C for 16 h to give 10.6 g of nilotinib dodecyl sulfate as a yellow powder, which had a chromatographic purity of 99.98% and a yield of 91%.

[0498] Example 27

[0499] Nilotinib dodecyl sulfate was prepared according to the procedure of Example 26, where 30 g of nilotinib hydrochloride and 4.71 mL of 12N HCl were used to give 32.4 g of nilotinib dihydrochloride (yield 98%), and 32.4 g of nilotinib dihydrochloride was mixed with 29.3 g of sodium dodecyl sulfate (SLS) to give 48.5 g of nilotinib dodecyl sulfate with a chromatographic purity of 99.97% (yield 90%).

[0500] Example 28

[0501] Nilotinib dodecyl sulfate was prepared via the following general procedure:

[0502] a. 768 mL of methanol (30V) was added to 25.6 g of nilotinib hydrochloride and stirred at room temperature;

[0503] b. 4.02 mL of 12N HCl (equivalent to 1.1 molar equivalents) was added to the mixture from step (a) and stirred at 50 - 55 °C for 2 h;

[0504] c. The mixture from step (b) was distilled in vacuo and the residue was stirred with 256 mL of n-hexane (10V) for 30 min;

[0505] d. The solid from step (c) was separated by filtration, washed with n-hexane and dried in vacuo at 40 °C for 3 h to give 25.7 g of nilotinib dihydrochloride as a golden yellow powder (yield 92%);

[0506] e. 514 mL of methanol (20V) was added to the 25.7 g of nilotinib dihydrochloride obtained from step (d) and the mixture was stirred at 50 - 55 °C;

[0507] f. 23.2 g of sodium dodecyl sulfate (SLS) (equivalent to 2 molar equivalents) was added to 128.5 mL of methanol (5V), and the resulting mixture was added to the mixture from step (e) and stirred at 50 - 55 °C for 3 h;

[0508] g. The reaction mixture from step (f) was concentrated and 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);

[0509] h. Mix the organic extracts, concentrate them, and dry them in vacuo at 40 °C for 6 hours to obtain the crude product of nilotinib dodecyl sulfate;

[0510] i. Mix the crude product of nilotinib dodecyl sulfate with 257 mL of n-hexane (10 V) and stir for 30 minutes;

[0511] j. Separate the solid of the reaction mixture in step (i) by filtration, wash it with n-hexane, and dry it in vacuo at 40 °C for 16 hours to obtain 36.5 g of a golden powder of nilotinib dodecyl sulfate, with a chromatographic purity of 99.93% and a yield of 85%.

[0512] Example 29

[0513] The nilotinib dodecyl sulfate prepared in Examples 26, 27, and 28 can be used to prepare the oral dosage forms as described in Examples 3, 4, 9, 15, 18, 19, 22, 23, 30, 31, 33, 34, 37, or 39.

[0514] Example 30

[0515] Prepare the nintedanib monododecyl sulfate capsule dosage form as follows: Place 1793 mg of nintedanib monododecyl sulfate prepared according to the procedure of Example 25, 600 mg of poloxamer 407, 480 mg of poloxamer 188, and 1600 mg of absolute ethanol in a container, heat to 70 °C, and mix for 10 minutes for wet granulation. Add the powder mixture of 600 mg of anhydrous lactose, 1747 mg of microcrystalline cellulose PH102 (Part I), and 300 mg of sodium starch glycolate (Part I) sieved through a 40-mesh sieve to the nintedanib monododecyl sulfate granules and mix. Evaporate the ethanol by drying the resulting mixture in an oven at 70 °C. Mix the dried mixture 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 blend. Sieve the resulting dried mixture through a 40-mesh sieve and collect it in a suitable container. Sieve 60 mg of magnesium stearate through a 40-mesh sieve and add it to the container and mix to obtain the final mixture. Fill the final dried solid mixture into No. 1 hard gelatin capsules.

[0516] The composition of the capsule contents is as follows:

[0517]

[0518]

[0519] Example 31

[0520] The nintedanib monododecyl sulfate capsule dosage form was prepared as follows: 2441 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 were mixed to obtain a homogeneous dispersion. 1200 mg of stearate (Gelucire 43 / 01) was melted in a water bath (50 °C) and added to the homogeneous dispersion to obtain a homogeneous suspension (semi-solid). 1793 mg of nintedanib monododecyl sulfate prepared according to the procedure of Example 25 was sieved through an 80-mesh sieve and added to the suspension to obtain a homogeneous suspension and / or solidify into a semi-solid. The semi-solid suspension was filled into No. 1 hard gelatin capsules.

[0521] The composition of the capsule contents is shown below:

[0522]

[0523] Example 32

[0524] The capsules prepared in Examples 30 and 31 containing nintedanib monododecyl sulfate (equivalent to 30 mg of nintedanib free base) and the capsules prepared from 100 mg of capsules equivalent to 30 mg (the contents of 100 mg of capsules obtained commercially, which contained 120.40 mg of nintedanib ethanesulfonate, were collected and refilled into new capsules each containing an equivalent of 30 mg of nintedanib free base) were administered to six (6) healthy adult beagle dogs in a fasting state in a single-center and single-dose study. Blood samples were taken before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 36 hours after dosing. The average nintedanib plasma concentration values were determined as follows:

[0525]

[0526] The average plasma concentration curve is as Figure 8 shown.

[0527] The individual data obtained in the study are shown in the following table:

[0528] C max (ng / mL)

[0529]

[0530] AUC 0-t (ng·hr / mL)

[0531]

[0532] Reference

[0533]

[0534] The capsule prepared in Example 30

[0535]

[0536] The capsule prepared in Example 31

[0537]

[0538]

[0539] Example 33

[0540] Prepare the dasatinib monododecyl sulfate capsule dosage form as follows: Place 1865 mg of dasatinib monododecyl sulfate prepared according to the process of Example 12, 750 mg of poloxamer 407, 600 mg of poloxamer 188, and 2000 mg of absolute ethanol in a container, heat to 70 °C and mix for 10 minutes for wet granulation. Add the powder mixture of 600 mg of anhydrous lactose, 1405 mg of microcrystalline cellulose PH102, and 300 mg of sodium starch glycolate (Part I) sieved through a 40-mesh sieve to the dasatinib monododecyl sulfate granules and mix. Dry the resulting mixture in an oven at 50 °C to evaporate the ethanol. Mix the dried mixture with 300 mg of sodium starch glycolate (Part II) and 120 mg of colloidal silicon dioxide sieved through a 40-mesh sieve. Sieve the resulting mixture through a 40-mesh sieve and collect it in a suitable container. Sieve 60 mg of magnesium stearate through a 40-mesh sieve and add it to the container and mix to obtain the final mixture. Fill the final dry solid mixture into No. 1 hard gelatin capsules.

[0541] The composition of the capsule contents is as follows:

[0542] mg wt% Dasatinib monododecyl sulfate 37.3 31.1 Anhydrous lactose 12.0 10.0 Microcrystalline cellulose 28.1 23.4 Sodium starch glycolate (Part I) 6.0 5.0 Poloxamer 407 15.0 12.5 Poloxamer 188 12.0 10.0 Sodium starch glycolate (Part II) 6.0 5.0 Colloidal silicon dioxide 2.4 2.0 Magnesium stearate 1.2 1.0 Total 120.0 100.0 Absolute ethanol 40.0 N / A

[0543] Example 34

[0544] Prepare dasatinib dodecyl sulfate capsule dosage form as follows: Place 2520 mg of dasatinib dodecyl sulfate prepared according to the process of Example 13, 750 mg of poloxamer 407, 600 mg of poloxamer 188, and 1000 mg of absolute ethanol in a container, heat to 70 °C and mix for 10 minutes for wet granulation. Add 300 mg of anhydrous lactose, 1050 mg of microcrystalline cellulose PH102, and 300 mg of sodium starch glycolate (Part I) powder mixture passed through a 40-mesh sieve into the dasatinib dodecyl sulfate granules and mix. Dry the resulting mixture in an oven at 50 °C to evaporate ethanol. Mix the dried mixture with 300 mg of sodium starch glycolate (Part II) and 120 mg of colloidal silicon dioxide passed through a 40-mesh sieve. Sieve the resulting mixture through a 40-mesh sieve and collect in a suitable container. Sieve 60 mg of magnesium stearate through a 40-mesh sieve and add to the container and mix to obtain the final mixture. Fill the final dry solid mixture into No. 1 hard gelatin capsules.

[0545] The composition of the capsule contents is shown below:

[0546] mg wt% Dasatinib monododecyl sulfate 50.4 42.0 Anhydrous lactose 6.0 5.0 Microcrystalline cellulose 21.0 17.5 Sodium starch glycolate (Part I) 6.0 5.0 Poloxamer 407 15.0 12.5 Poloxamer 188 12.0 10.0 Sodium starch glycolate (Part II) 6.0 5.0 Colloidal silicon dioxide 2.4 2.0 Magnesium stearate 1.2 1.0 Total 120.0 100.0 Absolute ethanol 20.0 N / A

[0547] Example 35

[0548] The capsules prepared in Examples 33 and 34 containing dasatinib dodecyl sulfate or dasatinib monododecyl sulfate and the film-coated tablets (containing 50 mg of dasatinib free base) were prepared to obtain capsules equivalent to 25 mg (the contents of the commercially available 50 mg film-coated tablets were divided into 2 capsules), and were administered to six (6) fasted healthy adult beagle dogs for a single-center and single-dose study. Blood samples were taken before dosing and at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. In this example, the test drug and the analytical dose of 25 mg were standardized to 25 mg of dasatinib monohydrate. The measured average plasma concentrations of dasatinib standardized to 25 mg are shown below: The standardized average plasma concentration curve is as

[0549]

[0550] shown. The standardized individual data obtained in the study are shown in the following table: C Figure 9 as follows. max (ng / mL)

[0551]

[0552] AUC 0-t (ng·hr / mL)

[0553]

[0554] Reference drug

[0555]

[0556]

[0557] Capsules prepared in Example 33

[0558]

[0559] Capsules prepared in Example 34

[0560]

[0561]

[0562] Example 36

[0563] Prepare nilotinib dodecyl sulfate as follows: Mix 43 g of nilotinib hydrochloride monohydrate and 1935 mL of anhydrous ethanol mixture at 50 - 55 °C. Add 21.23 g of sodium dodecyl sulfate [in 63.7 mL of ethanol (95%) and 42.5 mL of purified water] to this solution. Stir the mixture at 50 - 55 °C for 30 minutes, at room temperature for 1 hour, and at 0 - 10 °C for 30 minutes. Add 1505 mL of purified water to the mixture and stir at 0 - 10 °C for 30 minutes. Collect the resulting white crystals by filtration, wash with 215 mL of 85.5% ethanol aqueous solution to obtain crude nilotinib monolauryl sulfate - 1. Add 430 mL of purified water to the crude nilotinib monolauryl sulfate - 1 and stir for 30 minutes, collect by filtration, and wash with 430 mL of purified water to obtain crude nilotinib monolauryl sulfate - 2. Add the crude nilotinib monolauryl sulfate - 2 to 430 mL of n - hexane and stir for 30 minutes, filter and collect, and wash with 215 mL of n - hexane to obtain 48 g of nilotinib monolauryl sulfate (yield 82%) as an off - white powder with a chromatographic purity of 99.92%.

[0564] Example 37

[0565] 3.754 g of nilotinib monododecyl sulfate prepared according to the procedure of Example 36 was mixed with 12.528 g of CAPMUL (glyceryl caprylate / caprate) and 3.133 g of EL (polyoxyl 35 castor oil), and the mixture was filled into soft gelatin capsules to prepare a nilotinib monododecyl sulfate capsule dosage form.

[0566] The composition of the capsule contents is shown below:

[0567] mg wt% Nilotinib monododecyl sulfate 75.06 19.35 Caprylic / capric glycerides 250.31 64.52 Polyoxyethylene 35 castor oil 62.58 16.13 Total 387.95 100.00

[0568] Example 38

[0569] Nilotinib dodecyl sulfate was prepared as follows: 25.6 g of nilotinib hydrochloride monohydrate and 768 mL of methanol were mixed at room temperature. 4.02 mL of hydrochloric acid solution (12 N) was added to the above solution. The mixture was completely distilled in vacuo. 256 mL of n-hexane was added to the residue and stirred at room temperature for 30 minutes. The solid was separated by filtration, washed with n-hexane, and dried in vacuo at 40 °C for 3 hours to obtain a golden powder of nilotinib dihydrochloride. 25.7 g of nilotinib dihydrochloride and 514 mL of methanol were mixed at 50 - 55 °C. 23.2 g of sodium dodecyl sulfate (in 116 mL of methanol) was added to the above solution. The mixture was stirred at 50 - 55 °C for 3 hours. The mixture was concentrated and 771 mL of ethyl acetate was added, and the resulting reaction mass was washed with 514 mL of purified water. The organic extract was concentrated and dried in vacuo at 40 °C for 6 hours to obtain a crude product of nilotinib dodecyl sulfate. The crude product of nilotinib dodecyl sulfate was added to 257 mL of n-hexane and stirred for 30 minutes. The solid was separated by filtration, washed with n-hexane, and dried in vacuo at 40 °C for 16 hours to obtain 36.5 g of a golden powder of nilotinib dodecyl sulfate (yield 85%), and its chromatographic purity was 99.93%.

[0570] Figure 10 is the X-ray powder diffraction pattern of the golden powder of nilotinib dodecyl sulfate. This XRPD pattern was obtained using a D8 Discover with GADDS (Bruker AXS Gbh, Karlsruhe, Germany) under the following detection conditions:

[0571]

[0572] 40 kV 40 mA

[0573] Beam size: 1.0 mm (The allowable analysis surface area of the collimation system is 1000 μm 2 )

[0574] Detector type: Vantec-2000 (area 14 × 14 cm 2 , pixel density 2048 × 2048)

[0575] Distance from sample to detector: 15.05 cm

[0576] 300 sec / frame (exposure time per frame is 300 s).

[0577] Example 38A

[0578] At 37 °C, the sample was added to 300 mL of the specified medium and shaken or stirred for at least 18 hours to reach saturation to determine the solubility of nilotinib monododecyl sulfate prepared in Example 36 and the sample of nilotinib hydrochloride monohydrate obtained commercially. At room temperature, the sample was added to 5 - 20 mL of the specified medium and shaken or stirred for at least 18 hours to reach saturation to determine the solubility of nilotinib dodecyl sulfate prepared in Example 38. The reaction substances were filtered off and the filtered filtrate was measured by high performance liquid chromatography. The solubility measurement results are as follows:

[0579]

[0580] Example 39

[0581] 8.022 g of nilotinib dodecyl sulfate prepared according to the procedure of Example 38 was mixed with 20.042 g of CAPMUL (glyceryl caprylate / caprate), 5.010 g EL (polyoxyl 35 castor oil) and 0.667 g of sodium hydrogen carbonate, and the mixture was filled into soft gelatin capsules to prepare a nilotinib dodecyl sulfate capsule formulation.

[0582] The composition of the capsule contents is shown below:

[0583] mg wt% Nilotinib didodecyl sulfate 100.25 23.79 Caprylic / capric glycerides 250.31 59.39 Polyoxyethylene 35 castor oil 62.58 14.85 Sodium bicarbonate 8.33 1.97 Total 421.47 100.00

[0584] Example 40

[0585] The capsules prepared similar to those in Examples 37 and 39 were adjusted to a capsule weight containing approximately 50 mg of nilotinib free base. The above capsules and the capsules obtained by dispensing the commercially available TASIGNA capsules (the contents of the commercially available 200 mg TASIGNA capsules were dispensed into 4 capsules, each containing the equivalent of 50 mg of nilotinib free base) were administered to six (6) fasted healthy adult beagle dogs for a single-center and single-dose study. Blood samples were taken before dosing and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after dosing. The average nilotinib plasma concentration values were determined as follows:

[0586]

[0587] The average plasma concentration curve is as shown in Figure 11 Figure.

[0588] The individual data obtained in the study are shown in the following table:

[0589] C max

[0590]

[0591] AUC 0-24

[0592]

[0593] Reference drug (TASIGNA)

[0594]

[0595] Those below the limit of quantitation (BLQ) were set to 0.

[0596] The capsules prepared in Example 37

[0597]

[0598]

[0599] Those below the limit of quantitation (BLQ) were set to 0.

[0600] The capsules prepared in Example 39

[0601]

[0602] *Outlier, not included in the calculation.

[0603] Those below the limit of quantitation (BLQ) were set to 0.

[0604] Example 41

[0605] Cabozantinib monolauryl sulfate salt was prepared via the following general procedure:

[0606] a. 37 g of cabozantinib S-malate was added to a cosolvent of ethyl acetate / 10% aqueous NaHCO3 solution (1850 mL / 740 mL) (50V / 20V), and the mixture was stirred at 45 °C for 2 hours.

[0607] b. The organic phase of the reaction mixture from step (a) was separated and washed twice with 740 mL of purified water (20V×2).

[0608] c. The organic phase extracts from step (b) were combined and concentrated to obtain a white powder of cabozantinib free base (29.2 g, yield 100%).

[0609] d. 1022 mL of methanol (35V) was added to 29.2 g of cabozantinib free base, and the above mixture was stirred at 50 - 55 °C.

[0610] e. A solution of sodium lauryl sulfate (SLS) was prepared by dissolving 16.8 g of sodium lauryl sulfate (equivalent to 1 molar equivalent of cabozantinib) in a cosolvent of 87.6 mL of methanol (3V) / 58.26 mL of 1N HCl (1 molar equivalent).

[0611] f. The sodium lauryl sulfate solution from step (e) was added to the mixture from step (d). After stirring at 50 - 55 °C for 30 minutes, the mixture was adjusted to room temperature and stirred for 1 hour.

[0612] g. 1460 mL of purified water was added to the reaction mixture from step (f) and stirred at room temperature for 30 minutes.

[0613] h. The precipitate (crystals) from step (g) was collected by filtration and washed with 292 mL of purified water (10V) to obtain crude cabozantinib monolauryl sulfate.

[0614] i. Mix the crude cabozantinib monolauryl sulfate with 584 mL of purified water (20V), stir for 30 minutes, separate the solid by filtration, and wash it with 146 mL of purified water (5V) to obtain 41 g of white powder of cabozantinib monolauryl sulfate, with a purity of 100% and a yield of 91.7% by UPLC chromatographic analysis.

[0615] At 37 °C, add the sample to 50 mL of the specified medium and shake or stir for at least 18 hours until saturated to determine the solubility of the prepared cabozantinib monolauryl sulfate. Filter out the reaction substances and measure the filtered filtrate by high performance liquid chromatography. The solubility measurement results are as follows:

[0616]

[0617] Example 42

[0618] The cabozantinib monolauryl sulfate prepared in Example 41 can be used to prepare oral dosage forms as described in Examples 3, 4, 9, 15, 18, 19, 22, 23, 30, 31, 33, 34, 37 or 39.

[0619] Example 42A

[0620] Prepare the cabozantinib monolauryl sulfate capsule dosage form via the following wet granulation process:

[0621] (i) Dissolve 3.0595 g of cabozantinib monolauryl sulfate prepared according to the procedure of Example 41, 6.10 g of poloxamer 407, and 3.05 g of poloxamer 188 in 300 mL of 95% ethanol to prepare a granulation solution;

[0622] (ii) Sieve 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) through a 40-mesh sieve, and mix and granulate with the granulation solution in step (i);

[0623] (iii) Sieve the wet granules through a 20-mesh sieve, dry them in an oven at 55 °C to evaporate ethanol, and then sieve the dried granules through a 24-mesh sieve;

[0624] (iv) Mix the dried granules in step (iii) with 1.00 g of croscarmellose sodium (Part II) and 0.10 g of colloidal silicon dioxide (Part II);

[0625] (v) Add 0.10 g of magnesium stearate to the mixture of step (iv) and mix evenly to form the final mixture;

[0626] (vi) Fill the final dry solid mixture into No. 1 hard gelatin capsules.

[0627] The composition of the capsule contents is shown below:

[0628]

[0629] Example 42B

[0630] Prepare the cabozantinib monododecyl sulfate capsule dosage form via the following process:

[0631] (i) Dissolve 8 mg of butylated hydroxytoluene (BHT) in a mixture of 14.6856 g of CAPMUL (caprylic / capric triglyceride) and 5.2112 g EL (polyoxyl 35 castor oil);

[0632] (ii) Sieve 4.8952 g of cabozantinib monododecyl sulfate prepared according to the procedure of Example 41 through a 60-mesh sieve and add it to the solution of step (i) to obtain a homogeneous dispersion;

[0633] (iii) Melt 2.40 g of Gelucire 43 / 01 at 55 °C in a water bath and add the molten Gelucire to the dispersion of step (ii), while maintaining the temperature at 55 °C and homogenizing to obtain a homogeneous suspension; and

[0634] (iv) Fill the suspension of step (iii) into No. 3 hard gelatin capsules.

[0635] The composition of the capsule contents is shown below:

[0636]

[0637] Example 42C

[0638] Prepare the cabozantinib malate tablet dosage form via the following process:

[0639] (i) Sieve 2.0276 g of cabozantinib malate through a 60-mesh sieve and mix it with 2.4864 g of microcrystalline cellulose PH102, 1.2428 g of anhydrous lactose, and 0.192 g of croscarmellose sodium (Part I) sieved through a 40-mesh sieve;

[0640] (ii) Granulate the mixture from step (i) using a granulating solution, where the granulating solution is prepared by dissolving 0.192 g of hydroxypropyl cellulose (hydroxypropyl cellulose EXF) in 1.28 g of purified water;

[0641] (iii) Screen the wet granules through a 20-mesh sieve and dry them in an oven at 60 °C to evaporate the purified water, and then screen the dried granules through a 24-mesh

[0642] sieve;

[0643] (iv) Mix the dried and sieved granules with 0.192 g of croscarmellose sodium (Part II) and 0.0192 g of colloidal silicon dioxide;

[0644] (v) Add 0.048 g of magnesium stearate to the mixture from step (iv) and mix uniformly to form the final mixture; and

[0645] (vi) Compress the final mixture into tablets using a 6 mm round-shaped punch, with a target hardness of approximately 4 kp.

[0646] The composition of the tablet content is as follows:

[0647]

[0648]

[0649] Example 42D

[0650] Prepare the following capsule formulation according to the procedure of Example 42B. The composition of the capsule is as follows:

[0651]

[0652] Test the dosage forms prepared in Examples 42A - 42D (n = 3) using the USP Type II apparatus (Paddle) in 900 mL of 0.1 N HCl (containing 0.5% Triton X-100), at a rotation speed of 75 rpm, 37 °C, and using a sedimentation basket. The results of this dissolution test are as follows:

[0653]

[0654] * Without using a sedimentation basket

[0655] ** The capsule does not contain Gelucire 43 / 01

[0656] The in vitro dissolution data above demonstrate that the dosage forms prepared according to the present invention can: (i) release at least 40%, preferably at least 45%, most preferably at least 50% of cabozantinib after 30 minutes of testing; (ii) release at least 55%, preferably at least 60%, most preferably at least 65% of cabozantinib after 45 minutes of testing; and (iii) release at least 70%, preferably at least 75%, most preferably at least 80% of cabozantinib after 60 minutes of testing.

[0657] Example 42F

[0658] The impurities and stability of the dosage forms prepared in Examples 42A - 42D were measured using the following high performance liquid chromatography method.

[0659]

[0660] Mobile phase A is a buffer solution prepared by dissolving 2.72 g of potassium dihydrogen phosphate and 1 mL of triethylamine in 1000 mL of purified water, and adjusting the pH value to 3.20 ± 0.05 with phosphoric acid.

[0661] Mobile phase B is acetonitrile / methanol / water with a volume ratio of 60 / 30 / 10.

[0662] The test results are shown below:

[0663]

[0664]

[0665] The capsules are stored in high density polyethylene (HDPE) bottles (126 c.c., containing 2 - 3 g of silica gel desiccant) with child - resistant caps and aluminum foil induction sealing films.

[0666] Using the above HPLC method, any single impurity in the cabozantinib dodecyl sulfate dosage form is not more than 0.5%, preferably not more than 0.35%, most preferably not more than 0.25%, and the total impurities should not be more than 1.0%, preferably not more than 0.75%, most preferably not more than 0.60%.

[0667] Example 42G

[0668] The capsules containing cabozantinib monododecyl sulfate (equivalent to 20 mg of cabozantinib free base) prepared in Example 42A (Test Formulation 1 or T1) and Example 42B (Test Formulation 2 or T2), and the tablets containing equivalent to 20 mg of cabozantinib malate (equivalent to 20 mg of cabozantinib free base) prepared in Example 42C were administered to six (6) healthy adult beagle dogs in a fasting state in a single-center and single-dose study. Blood samples were taken before dosing and at 0.25, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after dosing. The average cabozantinib plasma concentration values were determined as follows:

[0669]

[0670] The average plasma concentration curve is shown in Figure 12 as follows.

[0671] The individual data obtained in the study are shown in the following table:

[0672] C max (ng / mL)

[0673]

[0674] AUC 0-t (ng·hr / mL)

[0675]

[0676] Tablets prepared in Example 42C (R)

[0677]

[0678] Tablets prepared in Example 42A (T1)

[0679]

[0680]

[0681] Tablets prepared in Example 42B (T2)

[0682]

[0683] Example 43

[0684] The single dodecyl sulfate or double dodecyl sulfate of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib prepared as in Examples 1, 11 - 14, 16 - 17, 21, 25 - 27, 33 - 34, 36, 38 and 41 can be used, and the liquid dosage form is prepared using the processes described in Examples 3, 9, 15, 18, 37 and 39.

[0685] The composition of the capsule contents is as follows:

[0686]

[0687] Example 44

[0688] The single dodecyl sulfate or double dodecyl sulfate of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib prepared as in Examples 1, 11 - 14, 16 - 17, 21, 25 - 27, 33 - 34, 36, 38 and 41 can be used, and the solid dosage form such as tablets or capsules is prepared using the processes described in Examples 4, 19, 22, 30, 33 and 34.

[0689] The composition of the solid dosage form contents is as follows:

[0690]

[0691] Example 45

[0692] The monolauryl sulfate or dilauryl sulfate of acalabrutinib, afatinib, alectinib, axitinib, bosutinib, brigatinib, cabozantinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dasatinib, defactinib, ensartinib, erlotinib, fotanib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, trametinib, vandetanib or vemurafenib prepared as in Examples 1, 11 - 14, 16 - 17, 21, 25 - 27, 33 - 34, 36, 38 and 41 can be used, and a semi - solid dosage form can be prepared using the procedure described in Example 23 or 31.

[0693] The composition of the content of the semi - solid dosage form is as follows:

[0694]

[0695] Example 46

[0696] The nilotinib monolaurylsulfate salt is prepared via the following general procedure:

[0697] a. Suspend 3 g of nilotinib free base in methanol (30V) and stir the mixture at a temperature below 60 °C, preferably at about 55 ± 5 °C for 20 minutes.

[0698] b. Mix sodium lauryl sulfate (1 molar equivalent) and 1N HBr (1 molar equivalent) dissolved in 3V methanol and 3V purified water (purified water in 1N HBr), and stir the resulting mixture at room temperature for 10 ± 5 minutes.

[0699] c. Once all the solids in step (b) are dissolved, add the nilotinib suspension from step (a) to the sodium lauryl sulfate / HBr solution from step (b) and stir the mixture at a temperature below 60 °C, preferably at about 55 ± 5 °C for 30 ± 10 minutes.

[0700] d. Once all the solids in the reaction mixture prepared in step (c) are dissolved, adjust the temperature to room temperature and stir for 60 ± 10 minutes.

[0701] e. After stirring, add purified water (30V) to the reaction mixture from step (d) and stir at room temperature for about 30 minutes.

[0702] f. The off-white crystals formed via the filtration collection step (e) were washed with purified water (5V) to yield nilotinib monododecyl sulfate (3.747 g) (yield 88.81%) (HPLC purity 99.52%).

[0703] Crystallization method A

[0704] The crude nilotinib monododecyl sulfate prepared according to steps (a)-(f) was recrystallized according to the following procedure:

[0705] 1. Methanol (MeOH) (15V) was added to the crude nilotinib monododecyl sulfate (2 g), and the mixture was stirred at a temperature below 60 °C, preferably at about 55 ± 5 °C, until the nilotinib monododecyl sulfate dissolved (about 10 ± 5 minutes).

[0706] 2. Purified water (15V) was added to the solution from step (1), and the mixture was maintained at a temperature below 60 °C, preferably about 55 ± 5 °C, for 30 ± 10 minutes to obtain a precipitate. Then, the temperature of the reaction mass was adjusted to room temperature.

[0707] 3. The precipitate formed in step (2) was collected by filtration and washed with purified water (2V × 2).

[0708] 4. The precipitate collected in step (3) was dried under high vacuum to obtain white crystals of nilotinib monododecyl sulfate (1.7846 g) (yield 89.2%) (HPLC purity 99.89%).

[0709] The XRPD of nilotinib monododecyl sulfate prepared according to the above-listed method is as Figure 13 shown. This XRPD pattern was obtained using a Rigaku D / MAX 2200 under the following detection conditions:

[0710] ·

[0711] · Power: 40 kV 30 mA

[0712] · Beam size: 1.0 mm

[0713] · Scan axis: 2Theta / theta

[0714] · Angle: 5 - 40 °

[0715] · DivH.L.Slit: 5 mm

[0716] · RecSlit: 1.0 mm

[0717] The nilotinib monododecyl sulfate crystals prepared according to crystallization method A will have 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.

[0718] Crystallization method B

[0719] The crude nilotinib monododecyl sulfate prepared according to steps (a)-(f) is recrystallized according to the following procedure:

[0720] 1. Methanol (15V) is added to the crude nilotinib monododecyl sulfate (3.747 g), and the mixture is stirred at a temperature below 60 °C, preferably at about 55 ± 5 °C, until the nilotinib monododecyl sulfate dissolves (about 10 ± 5 minutes).

[0721] 2. The solution from step (1) is filtered while hot to remove dust or other specific substances, and washed with methanol (5V).

[0722] 3. The resulting filtrate is heated to a temperature below 60 °C, preferably about 55 ± 5 °C.

[0723] 4. While maintaining the temperature at about 55 ± 5 °C, purified water (30V) is added dropwise to the reaction mixture from step (3) over a period of about 30 ± 10 minutes.

[0724] 5. Once the purified water is added, a precipitate will form. The reaction mass is cooled to room temperature and then further cooled to 0 - 5 °C to form more precipitate.

[0725] 6. The precipitate formed in step (5) is collected by filtration and washed with purified water (2 × 2V).

[0726] 7. The precipitate collected in step (6) is dried under high vacuum to obtain white crystals of nilotinib monododecyl sulfate (3.4201 g) (yield 91.3%) (HPLC purity 99.93%).

[0727] Crystallization method C

[0728] The crude nilotinib monododecyl sulfate prepared according to steps (a)-(f) is recrystallized according to the following procedure:

[0729] 1. Add ethanol (EtOH) (35V) to the crude nilotinib monododecyl sulfate product (2 g), and stir the mixture at a temperature below 60 °C, preferably at about 55 ± 5 °C, until the nilotinib monododecyl sulfate dissolves (about 10 ± 5 minutes).

[0730] 2. Add purified water (60V) to the solution of step (1), and maintain at a temperature below 60 °C, preferably at about 55 ± 5 °C for about 30 ± 10 minutes to obtain a precipitate, then adjust the temperature of the reaction mass to room temperature.

[0731] 3. Collect the precipitate formed in step (2) by filtration and wash with purified water (2 × 2V).

[0732] 4. Dry the precipitate collected in step (3) under high vacuum to obtain white crystals of nilotinib monododecyl sulfate (1.7695 g) (yield 88.5%) (HPLC purity 99.88%).

[0733] The XRPD of the white crystals of nilotinib monododecyl sulfate prepared according to crystallization method C is as Figure 14 shown, which is obtained by the method listed in crystallization method A.

[0734] The crystals of nilotinib monododecyl sulfate prepared according to crystallization method C will have 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, 24.9 ± 0.2, 25.8 ± 0.2, 26.5 ± 0.2, 27.7 ± 0.2 and / or 29.0 ± 0.2.

[0735] Crystallization method D

[0736] Recrystallize the crude nilotinib monododecyl sulfate product prepared according to steps (a)-(f) according to the following procedure:

[0737] 1. Add isopropanol (IPA) (100V) to the crude nilotinib monododecyl sulfate product (2 g), and stir the mixture at a temperature below 60 °C, preferably at about 55 ± 5 °C, until the nilotinib monododecyl sulfate dissolves (about 10 ± 5 minutes).

[0738] 2. Add purified water (265V) to the solution of step (1), and maintain at a temperature below 60 °C, preferably at about 55 ± 5 °C for about 30 ± 10 minutes to obtain a precipitate, then adjust the temperature of the reaction mass to room temperature.

[0739] 3. Collect the precipitate formed in step (2) by filtration and wash with purified water (2 × 2V).

[0740] 4. Dry the precipitate collected in step (3) under high vacuum to obtain white crystals of nilotinib monododecyl sulfate (1.6742 g) (yield 83.7%) (HPLC purity 99.88%).

[0741] The XRPD of the white crystals of nilotinib monododecyl sulfate prepared according to crystallization method D is as Figure 15 shown, which is obtained by the method listed in crystallization method A.

[0742] The crystals of nilotinib monododecyl sulfate prepared according to crystallization method D will have one or more of the following 2θ peaks: 5.6 ± 0.2, 8.5 ± 0.2, 9.1 ± 0.2, 9.6 ± 0.2, 13.1 ± 0.2, 13.9 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 17.9 ± 0.2, 18.4 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 20.9 ± 0.2, 21.3 ± 0.2, 23.0 ± 0.2, 24.1 ± 0.2, 24.7 ± 0.2, 25.8 ± 0.2, 27.7 ± 0.2, 29.0 ± 0.2, 30.0 ± 0.2, 30.7 ± 0.2, 33.8 ± 0.2, 34.6 ± 0.2 and / or 38.7 ± 0.2.

[0743] Example 47

[0744] Dasatinib monododecyl sulfate is prepared via the following general procedure:

[0745] a. Add methanol (25V) to dasatinib monohydrate (6 g) and stir at reflux temperature.

[0746] b. Mix sodium dodecyl sulfate (SLS) (1 molar equivalent) with 1N HCl (1 molar equivalent) dissolved in 3V methanol and 3V purified water (purified water in 1N HCl) and stir the resulting mixture at room temperature for 10 ± 5 minutes.

[0747] c. Once all the solids in step (b) are dissolved, add the sodium dodecyl sulfate / HCl solution from step (b) to the dasatinib mixture from step (a) and stir the resulting mixture at reflux temperature (65 - 70 °C) for about 30 ± 10 minutes, then adjust the temperature to room temperature for about 60 ± 10 minutes.

[0748] d. Concentrate the reaction mixture from step (c) (T = 45 °C) to dryness under high vacuum using a rotary evaporator.

[0749] e. Extract the concentrated reaction mass from step (d) with ethyl acetate (20V) and purified water (10V).

[0750] f. Wash the organic phase from step (e) with water (2 × 10V) separately.

[0751] g. Concentrate the washed organic phase from step (f) under high vacuum using a rotary evaporator (T = 45 °C).

[0752] h. Dry the product from step (g) under high vacuum to obtain white crystalline dasatinib monododecyl sulfate (8.7659 g) (yield 98.0%) (HPLC purity 99.61%).

[0753] i. Add isopropanol (10V) to the dasatinib monododecyl sulfate from step (h) and stir at room temperature for 30 ± 10 minutes.

[0754] j. Collect the white solid precipitate of the reaction mass from step (i) by filtration and wash with isopropanol (2 × 2V).

[0755] k. Dry the washed solid precipitate from step (j) under high vacuum to obtain white crystalline dasatinib monododecyl sulfate (7.89 g) (yield 90.0%) (HPLC purity 99.82%).

[0756] Crystallization method A

[0757] Recrystallize the crude dasatinib monododecyl sulfate prepared according to steps (a) - (k) according to the following procedure:

[0758] 1. Add methanol (5V) to the crude dasatinib monododecyl sulfate (3 g) and stir the mixture at about 60 °C for about 10 ± 5 minutes.

[0759] 2. While maintaining the temperature at about 60 °C, add isopropanol (40V) and n - hexane (40V) to the solution from step (1) until a precipitate forms, then adjust the temperature of the reaction mass to room temperature.

[0760] 3. Adjust the temperature of the reaction substances in step (2) to 0 - 5 °C for about 30 ± 10 minutes, collect the precipitate by filtration, and wash it with n - hexane (2×2V).

[0761] 4. Dry the precipitate collected in step (3) under high vacuum to obtain white crystalline dasatinib monododecyl sulfate (2.7186 g) (yield 88.8%) (HPLC purity 99.94%).

[0762] The XRPD of the dasatinib monododecyl sulfate sample prepared according to crystallization method A is as Figure 16 shown, which is obtained by the method listed in Example 46.

[0763] The dasatinib monododecyl sulfate crystals prepared according to crystallization method A will have one or more of the following 2θ peaks: 6.9 ± 0.2, 8.3 ± 0.2, 9.9 ± 0.2, 10.5 ± 0.2, 12.6 ± 0.2, 13.1 ± 0.2, 14.7 ± 0.2, 15.8 ± 0.2, 16.3 ± 0.2, 17.1 ± 0.2, 17.2 ± 0.2, 17.4 ± 0.2, 18.4 ± 0.2, 19.4 ± 0.2, 20.1 ± 0.2, 21.5 ± 0.2, 22.6 ± 0.2, 23.5 ± 0.2, 24.4 ± 0.2, 25.0 ± 0.2, 26.0 ± 0.2, 26.5 ± 0.2, 26.9 ± 0.2, 27.4 ± 0.2, 27.8 ± 0.2, 28.7 ± 0.2, 29.1 ± 0.2, 30.4 ± 0.2, 31.6 ± 0.2, 34.6 ± 0.2, 37.5 ± 0.2 and / or 39.2 ± 0.2.

[0764] Crystallization method B

[0765] Recrystallize the crude dasatinib monododecyl sulfate prepared according to steps (a) - (k) according to the following procedure:

[0766] 1. Add methanol (5V) to the crude dasatinib monododecyl sulfate (3 g), stir the mixture at about 60 °C for about 10 ± 5 minutes, and then adjust the temperature to room temperature.

[0767] 2. Add ether (60V) to the solution in step (1) while maintaining the temperature at room temperature.

[0768] 3. Adjust the temperature of the reaction substances in step (2) to 0 - 5 °C for about 30 ± 10 minutes, collect the precipitate by filtration, and wash it with ether (2×2V).

[0769] 4. Dry the precipitate collected in step (3) under high vacuum to obtain white crystals of dasatinib monododecyl sulfate (2.8910 g) (yield 94.5%) (HPLC purity 99.85%).

[0770] The XRPD of the dasatinib monododecyl sulfate sample prepared according to crystallization method B is as Figure 17 shown, which was obtained by the method listed in Example 46.

[0771] The dasatinib monododecyl sulfate crystals prepared according to crystallization method B will have one or more of the following 2θ peaks: 6.6 ± 0.2, 8.1 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 10.7 ± 0.2, 12.4 ± 0.2, 12.8 ± 0.2, 14.4 ± 0.2, 15.5 ± 0.2, 16.0 ± 0.2, 17.1 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.8 ± 0.2, 20.5 ± 0.2, 21.3 ± 0.2, 22.3 ± 0.2, 23.2 ± 0.2, 24.1 ± 0.2, 24.8 ± 0.2, 25.8 ± 0.2, 26.1 ± 0.2, 26.7 ± 0.2, 27.2 ± 0.2, 27.5 ± 0.2, 28.4 ± 0.2, 28.8 ± 0.2, 30.8 ± 0.2, 31.4 ± 0.2, 32.5 ± 0.2, 33.3 ± 0.2, 34.1 ± 0.2, 34.4 ± 0.2 and / or 39.5 ± 0.2.

[0772] Example 47A

[0773] At 37 °C, add the sample to 500 mL of the specified medium and shake or stir for at least 18 hours to reach saturation to determine the solubility of the dasatinib monododecyl sulfate crystals prepared by method A of Example 47, the amorphous dasatinib monododecyl sulfate prepared in Example 12, the amorphous dasatinib dodecyl sulfate prepared in Example 13, and the commercially available dasatinib monohydrate free base. Filter the reaction mass and measure the filtered filtrate by high performance liquid chromatography. The solubility measurement results are as follows:

[0774]

[0775] The results show that the aqueous solubility of dasatinib varies with pH.

[0776] Example 48

[0777] Dasatinib monododecyl sulfate is prepared via the following general procedure:

[0778] a. Add methanol (25V) to 3 g of dasatinib monohydrate and stir at reflux temperature.

[0779] b. Mix sodium dodecyl sulfate (SLS) (1 molar equivalent) with 1N HCl (1 molar equivalent) dissolved in 3V of methanol and 3V of purified water (purified water in 1N HCl) and stir the resulting mixture at room temperature for 10 ± 5 minutes.

[0780] c. Once all the solids in step (b) are dissolved, add the sodium dodecyl sulfate / HCl solution from step (b) to the dasatinib mixture from step (a) and stir the resulting mixture at reflux temperature (65 - 70 °C) for about 30 ± 10 minutes, then adjust the temperature to room temperature for about 60 ± 10 minutes.

[0781] d. Concentrate the reaction mixture from step (c) (T = 45 °C) to dryness under high vacuum using a rotary evaporator.

[0782] e. Extract the concentrated reaction mass from step (d) with ethyl acetate (20V) and purified water (10V).

[0783] f. Wash the organic phase from step (e) with water (2 × 10V) separately.

[0784] g. Concentrate the washed organic phase from step (f) (T = 35 °C) to dryness under high vacuum using a rotary evaporator.

[0785] h. Add methanol (10V) to the product from step (g) and heat to 60 °C until dissolved.

[0786] i. Filter the solution from step (h) while it is hot to remove dust or other specific substances and wash with methanol (5V).

[0787] j. Concentrate the filtrate from step (i) (T = 45 °C) to dryness under high vacuum using a rotary evaporator.

[0788] k. Dry the product from step (j) under high vacuum to obtain white crystalline dasatinib monododecyl sulfate (4.419 g) (yield 98.8%) (HPLC purity 99.66%).

[0789] Crystallization method C

[0790] Recrystallize the crude dasatinib monododecyl sulfate prepared according to steps (a) - (k) according to the following procedure:

[0791] 1. Methanol (5V) was added to the crude product of dasatinib monododecyl sulfate (3 g), and the mixture was stirred at about 60 °C for about 10 ± 5 minutes.

[0792] 2. Maintaining the temperature at about 60 °C, isopropanol (5V) and n-hexane (25V) were added to the solution in step (1) until a precipitate formed, and then the temperature of the reaction mixture was adjusted to room temperature.

[0793] 3. The temperature of the reaction mixture in step (2) was adjusted to 0 - 5 °C for about 30 ± 10 minutes. The precipitate was collected by filtration and washed with n-hexane (2 × 2V).

[0794] 4. The precipitate collected in step (3) was dried under high vacuum to obtain white crystals of dasatinib monododecyl sulfate (2.81 g) (yield 93.7%) (HPLC purity 99.90%).

[0795] 5. Steps (1) - (4) were repeated to obtain white crystals of dasatinib monododecyl sulfate (2.68 g) (yield 95.4%) (HPLC purity 99.96%).

[0796] The XRPD of the sample of dasatinib monododecyl sulfate prepared according to crystallization method C is as Figure 18 shown, which was obtained by the method listed in Example 46.

[0797] The crystals of dasatinib monododecyl sulfate prepared according to crystallization method C will have one or more of the following 2θ peaks: 5.9 ± 0.2, 6.5 ± 0.2, 7.9 ± 0.2, 9.5 ± 0.2, 10.2 ± 0.2, 12.3 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, 14.9 ± 0.2, 16.0 ± 0.2, 16.8 ± 0.2, 17.1 ± 0.2, 18.1 ± 0.2, 19.1 ± 0.2, 19.8 ± 0.2, 21.1 ± 0.2, 22.2 ± 0.2, 23.2 ± 0.2, 24.1 ± 0.2, 24.7 ± 0.2, 25.6 ± 0.2, 26.6 ± 0.2, 27.6 ± 0.2, 28.1 ± 0.2, 28.5 ± 0.2, 28.9 ± 0.2, 30.0 ± 0.2, 30.8 ± 0.2, 31.3 ± 0.2, 34.2 ± 0.2, 35.4 ± 0.2, 37.2 ± 0.2 and / or 38.9 ± 0.2.

[0798] Crystallization method D

[0799] Prepare the crude product of dasatinib monododecyl sulfate according to steps (a)-(k), wherein this process yields a white crystalline crude product of dasatinib monododecyl sulfate (4.4373 g) (yield 99.2%) (HPLC purity 99.58%), and recrystallize according to the following procedure:

[0800] 1. Add isopropanol (6V) to dasatinib monododecyl sulfate (3 g), and stir the mixture at room temperature for about 30 ± 10 minutes.

[0801] 2. Filter the white solid precipitate and wash with isopropanol (2V).

[0802] 3. Dry the precipitate collected in step (2) under high vacuum to obtain white crystals of dasatinib monododecyl sulfate (2.83 g) (yield 94.3%) (HPLC purity 99.75%).

[0803] 4. Repeat steps (1)-(3) to obtain white crystals of dasatinib monododecyl sulfate (2.70 g) (yield 95.4%) (HPLC purity 99.81%).

[0804] The XRPD of the dasatinib monododecyl sulfate sample prepared according to crystallization method D is as Figure 19 shown, which is obtained by the method listed in Example 46.

[0805] The crystals of dasatinib monododecyl sulfate prepared according to crystallization method D will have one or more of the following 2θ peaks: 6.6 ± 0.2, 8.0 ± 0.2, 9.5 ± 0.2, 10.2 ± 0.2, 10.6 ± 0.2, 12.3 ± 0.2, 12.8 ± 0.2, 13.2 ± 0.2, 14.4 ± 0.2, 15.5 ± 0.2, 16.0 ± 0.2, 17.1 ± 0.2, 18.1 ± 0.2, 18.9 ± 0.2, 19.7 ± 0.2, 21.2 ± 0.2, 22.2 ± 0.2, 23.1 ± 0.2, 24.0 ± 0.2, 24.7 ± 0.2, 25.7 ± 0.2, 26.6 ± 0.2, 27.1 ± 0.2, 28.4 ± 0.2, 28.7 ± 0.2, 30.9 ± 0.2, 31.3 ± 0.2, 32.4 ± 0.2, 37.2 ± 0.2 and / or 39.2 ± 0.2.

[0806] Example 48A

[0807] Prepare dasatinib monododecyl sulfate via the following general procedure:

[0808] a. Methanol (25V, 1980 g) was added to dasatinib monohydrate (1 molar equivalent, 100 g), and the mixture was stirred at the reflux temperature (60 °C ± 5 °C).

[0809] b. Sodium dodecyl sulfate (SLS) (1 molar equivalent, 57 g) was mixed with 1N HCl (1 molar equivalent, 197 ml) dissolved in methanol (3V, 237 g) and purified water (1.03V, 103 g), and the resulting mixture was stirred at room temperature for 10 ± 5 minutes.

[0810] c. Once all the solids in step (b) were dissolved, the sodium dodecyl sulfate / HCl solution from step (b) was added to the dasatinib mixture from step (a), and the resulting mixture was stirred at the reflux temperature (60 °C ± 5 °C) for about 30 ± 10 minutes, followed by adjusting the temperature to room temperature for about 60 ± 10 minutes.

[0811] d. The reaction mixture from step (c) was concentrated under high vacuum using a rotary evaporator (T = 40 °C) until dry.

[0812] e. The concentrated reaction mass from step (d) was extracted with ethyl acetate (20V, 1804 g), and the mixture was stirred at room temperature for 10 ± 5 minutes.

[0813] f. The organic phase from step (e) was washed separately with water (3 × 10V, 3 × 1000 g).

[0814] g. The washed organic phase from step (f) was concentrated under high vacuum using a rotary evaporator (T = 35 °C) until dry.

[0815] h. Methanol (5V, 589 g) was added to the product from step (g), and the mixture was heated to 60 °C until dissolved.

[0816] i. The filtrate from step (h) was concentrated under high vacuum using a rotary evaporator (T = 45 °C) until dry to obtain the crude product of dasatinib monododecyl sulfate.

[0817] Crystallization method E

[0818] The crude product of dasatinib monododecyl sulfate prepared according to steps (a)-(i) was recrystallized according to the following procedure:

[0819] 1. Methanol (3V, 353 g) was added to the crude product of dasatinib monododecyl sulfate, and the mixture was stirred at 60 °C ± 5 °C for 10 ± 5 minutes.

[0820] 2. Slowly add isopropanol (2V, 234 g) to the methanol solution of the crude product, and stir the mixture at 60 °C ± 5 °C for 10 ± 5 minutes.

[0821] 3. At 45 °C ± 5 °C, slowly add n-hexane (40V, 4000 g) to the crude product to obtain a pure product precipitate in 10 ± 5 minutes (addition process time: 30 ± 10 minutes), and then adjust the temperature to room temperature for 30 ± 5 minutes.

[0822] 4. Adjust the temperature of the reaction substance in step (3) to 0 - 5 °C for about 30 ± 10 minutes, collect the precipitate by filtration, and wash it with n-hexane (2 × 2V, 2 × 200 g).

[0823] 5. Dry the precipitate collected in step (4) under high vacuum to obtain white crystalline dasatinib monododecyl sulfate (yield 79.5%, 118.5 g) (HPLC purity is 100.00%, pH value: 4.38).

[0824] The XRPD of the dasatinib monododecyl sulfate sample prepared according to crystallization method E is as Figure 20 shown, which is obtained by the method listed in Example 46.

[0825] The dasatinib monododecyl sulfate crystal prepared according to crystallization method E will have one or more of the following 2θ peaks: 6.3 ± 0.2, 9.5 ± 0.2, 10.1 ± 0.2, 12.2 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, 15.9 ± 0.2, 16.7 ± 0.2, 17.0 ± 0.2, 18.0 ± 0.2, 19.0 ± 0.2, 21.0 ± 0.2, 22.2 ± 0.2, 23.1 ± 0.2, 23.9 ± 0.2, 24.6 ± 0.2, 25.6 ± 0.2, 27.5 ± 0.2, 28.5 ± 0.2, 28.7 ± 0.2, 31.2 ± 0.2, 34.2 ± 0.2, 37.2 ± 0.2 and / or 38.7 ± 0.2.

[0826] Example 49

[0827] Prepare a dasatinib monododecyl sulfate capsule dosage form as follows: Mix 2982 mg of dasatinib monododecyl sulfate prepared according to the procedure of Example 12 with 1500 mg of poloxamer 407 ( P407), 1200 mg of poloxamer 188 ( P188) and 3200 mg of ethanol (95%) in a suitable container and granulate by wet method for at least 2 minutes.

[0828] Screen 1800 mg of anhydrous lactose ( 21AN, anhydrous), 2958 mg of microcrystalline cellulose ( M102D+), 600 mg of sodium starch glycolate (Part I), and 120 mg of colloidal silicon dioxide (AD101) (Part I) through a 40-mesh sieve, add them to the dasatinib dodecyl sulfate granules and mix. Dry the resulting mixture in an oven at 50 °C to evaporate ethanol.

[0829] Screen 600 mg of sodium starch glycolate (Part II) and 120 mg of colloidal silicon dioxide (AD101) (Part II) through a 40-mesh sieve, add them to the dried mixture containing dasatinib dodecyl sulfate granules and mix evenly. After mixing the resulting mixture, sieve it through a 40-mesh sieve and collect it in a suitable container. Screen 120 mg of magnesium stearate through a 40-mesh sieve and add it to the container, mix it with the dasatinib dodecyl sulfate mixture to obtain the final mixture. Fill the final mixture into No. 2 hard gelatin capsules.

[0830] The composition of the capsule contents is as follows:

[0831] mg wt% Dasatinib monododecyl sulfate 29.82 24.85 Poloxamer 407 15.00 12.50 Poloxamer 188 12.00 10.00 Anhydrous lactose 18.00 15.00 Microcrystalline cellulose 29.58 24.65 Sodium starch glycolate (Part I) 6.00 5.00 Colloidal silicon dioxide (Part I) 1.20 1.00 Sodium starch glycolate (Part II) 6.00 5.00 Colloidal silicon dioxide (Part II) 1.20 1.00 Magnesium stearate 1.20 1.00 Total 120.00 100.00 Ethanol (95%) (evaporated) 32.00 N / A

[0832] Example 50

[0833] Administer the capsules containing dasatinib dodecyl sulfate prepared according to Example 49 to nine (9) healthy subject individuals in a fasting state, a postprandial state, and a fasting state with omeprazole pretreatment. Omeprazole is a commercially available proton pump inhibitor (PPI). This is a two-part trial. The first part is a bioavailability study of healthy subject individuals in a single-dose, open-label, randomized, three-treatment, three-sequence, three-cycle crossover design in the fasting and postprandial states. All subject individuals are randomly assigned to the sequences shown in the following table, and the washout period between different cycles is 7 days. The second part is a drug interaction study of healthy subject individuals in a continuous, two-treatment design. All subject individuals orally administer 40 mg of omeprazole once a day for 5 days to reach a steady state, and approximately 22 hours after the last dose of omeprazole, orally administer 20 mg of dasatinib capsules. The reference drug (Ref) is dasatinib monohydrate, with a dose of 50 mg, and the test drug (Test) is the capsule prepared according to the procedure of Example 49, containing dasatinib dodecyl sulfate with a dose equivalent to approximately 20 mg of dasatinib monohydrate. The nine (9) healthy subject individuals participating in this study are randomly assigned to one of the sequences shown in the following table.

[0834]

[0835] During each treatment period, blood samples were drawn at 0 (pre-dose), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. The AUC of each subject was determined based on non-compartmental analyses. 0-24 , AUC 0-∞ , C max 、T max and T 1 / 2 The study results were normalized to a dose of 50 mg and are summarized in the table below.

[0836] Pharmacokinetic parameters of control drugs and test formulations (normalized to a dose of 50 mg)

[0837]

[0838]

[0839] Ref Fasted : Administer 50 mg of tablet

[0840] Test Fasted : Administer 20 mg of the test drug (Dasatinib monohydrate) on an empty stomach (Test)

[0841] Test Fed : Administer 20 mg of the test drug (Dasatinib monohydrate) after a meal (Test)

[0842] Test Fasted (PPI) with 40mg omeprazole: Administer 20mg (dasatinib monohydrate) of the test drug on an empty stomach while taking 40mg omeprazole.

[0843] ANOVA analysis of log-transformed AUC 0-t , AUC 0-∞ and C max The sequence, subjects (sequence), period and treatment effect were included in the model. The data obtained for the test drug and the control drug are compared in the table below.

[0844] Test Fasted vs. Reference Fasted 、Test Fed vs.TestFasted and Test Fasted (PPI) vs. Test F Comparison table of asted (normalized to a dose of 50 mg)

[0845]

[0846] Data shows that compared with dasatinib monohydrate approved by the US FDA, the composition of the present invention exhibits a C max increase of 1.01 times and an AUC decrease of 0.88 times. The data also shows that the composition of the present invention does not have an effect of gastric acid secretion inhibitor or PPI, that is, the composition of the present invention exhibits comparable pharmacokinetics in the fasting state and in the fasting state with co - administration of omeprazole.

[0847] The individual data obtained in the study after being normalized to 50 mg are shown in the following table: Control drug In the fasting state (concentration (ng / mL))

[0848]

[0849] Test drug in the fasting state (concentration (ng / mL))

[0850]

[0851]

[0852] Test drug in the post - meal state (concentration (ng / mL))

[0853]

[0854] Test drug in the fasting state after administration of 40 mg omeprazole (concentration (ng / mL))

[0855]

[0856]

[0857] The normalized average plasma concentration curve of Example 50 is as Figure 21 shown.

[0858] Example 51

[0859] 7730 mg of dasatinib monododecyl sulfate prepared according to the process of crystallization method E of Example 48A and sieved through a 60-mesh sieve was mixed with 2500 mg of anhydrous lactose sieved through a 40-mesh sieve, 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.

[0860] The resulting mixture was wet granulated with 2500 mg of an ethanol solution, which was prepared by mixing ethanol (95%) and purified water at a weight ratio of 1:1. The resulting granules were dried in an oven at 50 °C to evaporate ethanol and water.

[0861] The dry granules were sieved through a 40-mesh sieve 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 sieve. 250 mg of magnesium stearate was sieved through a 40-mesh sieve and added to the resulting mixture and mixed to obtain a final mixture. The final mixture was filled into No. 1 hard gelatin capsules.

[0862] The composition of the capsule contents is shown below:

[0863]

[0864]

[0865] Example 51A

[0866] The capsules containing dasatinib monododecyl sulfate prepared according to Example 51 were administered to healthy subject individuals in the fasting state, postprandial state, and fasting state with pretreatment with omeprazole. Omeprazole is a commercially available proton pump inhibitor (PPI). This is a two-part trial. The first part is a bioavailability study of a single-dose, open-label, randomized, four-treatment, four-sequence, four-cycle crossover design for ten (10) healthy subject individuals in the fasting and postprandial states. All subject individuals were randomly assigned to the sequences shown in the following table, and the washout period between different cycles was 3 days or 4 days. The second part is a drug interaction study for nine (9) healthy subject individuals in a continuous, two-treatment design. All subject individuals orally administered 40 mg of omeprazole once a day for 5 days to reach a steady state, and approximately 22 hours after the last dose of omeprazole, they orally administered 50 mg of dasatinib capsules. The reference drug (Ref) is Dasatinib monohydrate, the dosage of which is 50 mg (calculated as free base), and the test drug (Test) is a capsule prepared according to the process of Example 51, containing a dosage of about 50 mg of dasatinib (calculated as free base). Ten (10) healthy subjects participating in the first part of this study or nine (9) healthy subjects participating in the second part of this study were randomly assigned to one of the sequences shown in the following table. Part I

[0867]

[0868] *Rfast: control drug (Reference) was administered in the fasting state; Rfed: control drug (Reference) was administered in the fed state;

[0869] Tfast: test drug was administered in the fasting state (Test); Tfast: test drug was administered in the postprandial state (Test).

[0870] Part 2

[0871]

[0872] *Tfast: Test drug is administered on an empty stomach

[0873] During each treatment period, blood samples were drawn at 0 (pre-dose), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. The AUC of each subject was determined based on non-compartmental analyses. 0-24 , AUC 0-∞ , C max 、T max and T 1 / 2 The results of the study are summarized in the following table.

[0874] Pharmacokinetic parameters of control drugs and test formulations

[0875]

[0876] *Ref Fasted : Administer 50 mg of tablet

[0877] *Ref Fed : Administer 50 mg of tablet

[0878] *Test Fasted : Administer 50 mg of the test drug on an empty stomach (Test)

[0879] *Test Fed :Administer 50 mg of the test drug after a meal (Test)

[0880] *Test Fasted (PPI) with 40mg omeprazole: 50mg of the test drug was administered on an empty stomach after taking 40mg of omeprazole.

[0881] ANOVA analysis of log-transformed AUC 0-t , AUC 0-∞ and C max The order, subjects (order), period and treatment effect are included in the model. The data obtained for the test drug and the control drug are compared in the table below. Fasted vs. Reference Fasted 、Test Fed vs. Reference Fed 、Test Fasted vs.Test Fed and Test Fasted (PPI) vs. Test Fasted Comparison table

[0882]

[0883]

[0884] The data show that, compared with the dasatinib monohydrate approved by the US FDA, the composition of the present invention exhibits C max The data show that compared with the dasatinib monohydrate approved by the US FDA, the composition of the present invention shows C max The data also show that the composition of the present invention has a positive effect on gastric acid secretion inhibitors or PPIs, that is, the composition of the present invention has a positive effect on gastric acid secretion inhibitors or PPIs in the fasting state when co-administered with omeprazole, compared with the fasting state C max The improvement is 1.17 times and the AUC is improved by 1.13 times.

[0885] The average plasma concentration curve of this example under fasting condition is as follows Figure 22A shown.

[0886] The average plasma concentration curve of this embodiment in the postprandial state is as follows Figure 22B shown.

[0887] The average plasma concentration curve of this example in the fasting state with co - administration of omeprazole is as Figure 22C shown.

[0888] The results of individual data obtained at a 50 mg dose in this study are shown in the following table:

[0889] Part 1: Control drug In the fasting state (concentration (ng / mL))

[0890]

[0891]

[0892] Part 1: Test drug (Example 51) in the fasting state (concentration (ng / mL))

[0893]

[0894] Part 1: Control drug In the post - meal state (concentration (ng / mL))

[0895]

[0896] Part 1: Test drug (Example 51) in the post - meal state (concentration (ng / mL))

[0897]

[0898] Part 2: Test drug (Example 51) in the fasting state (concentration (ng / mL))

[0899]

[0900] Part 2: Test drug (Example 51) in the fasting state with administration of 40 mg omeprazole (concentration (ng / mL))

[0901]

[0902]

[0903] Example 52

[0904] Mix 9276 mg of dasatinib monododecyl sulfate prepared according to the process of Example 12 and sieved through a 325 - mesh sieve, 1440 mg of cross - linked carboxymethylcellulose sodium, and 6000 mg of anhydrous lactose in a suitable container for about 1 minute. After sieving 6324 mg of microcrystalline cellulose and 720 mg of hydroxypropyl cellulose through a 40 - mesh sieve, add them to the mixture and further mix for about 2 minutes.

[0905] 240 mg of magnesium stearate was sieved through a 40-mesh screen and added to the above mixture, followed by mixing to obtain a final mixture. The final mixture was filled into a No. 1 hard gelatin capsule.

[0906] The composition of the capsule contents is as follows:

[0907] Mg wt% Dasatinib monododecyl sulfate (DSB - 1LS) 77.30 38.65 Croscarmellose sodium 12.00 6.00 Anhydrous lactose 50.00 25.00 Microcrystalline cellulose 52.70 26.35 Hydroxypropyl cellulose (HPC - H) 6.00 3.00 Magnesium stearate 2.00 1.00 Total 200.00 100.00

[0908] Example 52A

[0909] The capsules containing dasatinib monododecyl sulfate prepared according to Example 52 were administered to six (6) healthy subjects in a fasting state. This administration was a single-dose, open-label, randomized, two-course, two-order, two-period crossover design bioavailability study in healthy subjects in a fasting state. All subjects were randomly assigned to the order shown in the following table, and the washout period between different cycles was 3 days. The control drug (Ref) was The dosage of dasatinib monohydrate is 50 mg (calculated as free base), and the test drug (Test) is a capsule prepared according to the process of Example 52, containing a dosage approximately equivalent to 50 mg of dasatinib (calculated as free base).

[0910] Six (6) healthy subjects who participated in this study were randomly assigned to one of the sequences shown in the table below.

[0911]

[0912] During each treatment period, blood samples were drawn at 0 (pre-dose), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. The AUC of each subject was determined based on non-compartmental analyses. 0-24 , AUC 0-∞ , C max , T max and T 1 / 2 The results of the study are summarized in the following table.

[0913] Pharmacokinetic parameters of control drugs and test formulations

[0914]

[0915] *Ref Fasted : Administer 50 mg of tablet

[0916] *Test Fasted : Administer 50 mg of the test drug on an empty stomach (Test)

[0917] Analyze the logarithmically transformed AUC by ANOVA 0-t 、AUC 0-∞ and C max . Order, subject (order), period, and treatment effect are all included in the model. The comparison of data obtained from the test drug and the control drug is shown in the table below.

[0918] Test Fasted vs.Reference Fasted Comparison table

[0919]

[0920] Data shows that compared with the dasatinib monohydrate approved by the US FDA, the composition of the present invention shows that C max is reduced to 0.46 times and AUC is reduced to 0.79 times.

[0921] The average plasma concentration curve of this example is as Figure 23 shown.

[0922] The results of individual data obtained at a dose of 50 mg in this study are shown in the table below:

[0923] Control drug in the fasting state (concentration (ng / mL))

[0924]

[0925]

[0926] Test drug in the fasting state (concentration (ng / mL))

[0927]

[0928] Example 53

[0929] Prepare dasatinib monododecyl sulfate capsules as follows:

[0930] (i) Dissolve 6 mg of butylated hydroxytoluene (BHT) in 9756 mg of medium-chain triglyceride;

[0931] (ii) Melt 3600 mg of lauroyl polyoxyl glycerides (Gelucire 44 / 14) using a water bath (60 °C);

[0932] (iii) Add the molten material from step (ii) to the solution from step (i) to obtain a homogeneous solution;

[0933] (iv) 4638 mg of dasatinib monododecyl sulfate prepared according to the procedure of Example 48A (Crystallization Method E) was sieved through a 60-mesh sieve and added to the solution of step (iii) to obtain a homogeneous semi-solid suspension. The semi-solid suspension was filled into No. 1 hard gelatin capsules.

[0934] The composition of the capsule contents is shown below:

[0935] mg wt% Dasatinib Monododecyl Sulfate 30.92 25.77 Medium Chain Triglycerides 65.04 54.20 Glyceryl Laurate Polyoxyl 40 Hydrogenated Castor Oil (Gelucire 44 / 14) 24.00 20.00 Butylated Hydroxytoluene (BHT) 0.04 0.03 Total 120.00 100.00

[0936] Example 53A

[0937] The capsules containing dasatinib monododecyl sulfate prepared according to Example 53 were administered to four (4) healthy subject individuals in the fasting state. This administration was a bioavailability study with a single-dose, open-label, randomized, two-treatment, two-sequence, two-period crossover design for healthy subject individuals in the fasting state. All subject individuals were randomly assigned to the sequences shown in the following table, and the washout period between different periods was 3 days. The reference drug (Ref) was dasatinib monohydrate, with a dose of 50 mg (calculated as the free base), and the test drug (Test) was the capsule prepared according to the procedure of Example 53, but containing a dose equivalent to approximately 20 mg of dasatinib (calculated as the free base). The four (4) healthy subject individuals participating in this study were randomly assigned to one of the sequences shown in the following table.

[0938]

[0939] During each treatment period, blood samples were taken at 0 (before dosing), 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. The AUC 0-24 、AUC 0-∞ 、C max 、T max and T 1 / 2 of each subject individual were determined according to non-compartmental analyses. The study results are summarized in the following table.

[0940] Pharmacokinetic parameters of the reference drug and the test formulation (normalized to a dose of 50 mg)

[0941]

[0942] *Ref Fasted : Administered 50 mg of tablet

[0943] *Test Fasted: Administer 50 mg of the test drug on an empty stomach (Test)

[0944] ANOVA analysis of log-transformed AUC 0-t , AUC 0-∞ and C max The sequence, subjects (sequence), period and treatment effect were included in the model. The data obtained for the test drug and the control drug are compared in the table below.

[0945] Test Fasted vs. Reference Fasted Comparison table (standardized to 50 mg dose)

[0946]

[0947] The data show that, compared with the dasatinib monohydrate approved by the US FDA, the composition of the present invention exhibits C max The accuracy was reduced to 0.99 times and the AUC was reduced to 0.98 times.

[0948] The mean plasma concentration curve of this example is as follows Figure 24 shown.

[0949] The results of the individual data obtained from the 50 mg dose in this study are shown in the following table:

[0950] Comparator drugs In fasting state (concentration (ng / mL))

[0951]

[0952] Test drug (Example 53) in fasting state (concentration (ng / mL)) (normalized to a dose of 50 mg)

[0953]

[0954]

[0955] Embodiment 54

[0956] The dasatinib monododecyl sulfate prepared according to Example 12 and Example 47 was determined to contain the following impurities.

[0957]

[0958]

[0959] *NMT: Not greater than the above relative retention time values are measured based on the following HPLC parameters:

[0960]

[0961] The mobile phase A is an aqueous solution of 0.05 M ammonium acetate (pH 5.25) / acetonitrile / methanol with a volume ratio of 90 / 5 / 5.

[0962] The mobile phase B is an aqueous solution of 0.05 M ammonium acetate (pH 5.25) / acetonitrile / methanol with a volume ratio of 10 / 85 / 5.

[0963] The impurities and stability of the dosage forms prepared in Examples 49, 51 - 52 and dasatinib dodecyl sulfate prepared in Examples 12 - 13 were measured using the above high performance liquid chromatography method.

[0964] Prepare test samples as follows: Weigh approximately 30.92 mg of dasatinib monododecyl sulfate or 41.84 mg of dasatinib didodecyl sulfate (equivalent to 20 mg of dasatinib) into a 100 mL brown volumetric flask, add approximately 80 mL of methanol, sonicate for about 5 minutes and stir at 800 rpm for about 5 minutes until completely dissolved. Add additional methanol to make the test sample approximately 0.2 mg of dasatinib per milliliter.

[0965] The test results are as follows:

[0966]

[0967]

[0968] Any single impurity (impurities 1, 2, 3, 4 and 5) in dasatinib monododecyl sulfate was determined to be not more than 0.5%, preferably not more than 0.35%, most preferably not more than 0.25%, and the total impurities should be not more than 1.0%, preferably not more than 0.75%, most preferably not more than 0.60%.

[0969] In vitro testing of dasatinib monododecyl sulfate capsules was carried out using a USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at 75 rpm, 37 °C and with or without a sinker. The release within 45 minutes should be not less than 90%, preferably not less than 85%, most preferably not less than 80% of dasatinib.

[0970] Example 55

[0971] Dasatinib monododecyl sulfate prepared according to the procedure of Example 48A (crystallization method E) was mixed with the specified excipients and filled into hard gelatin capsules in the specified amounts to prepare a dosage form of dasatinib monododecyl sulfate capsules.

[0972]

[0973] Example 55E

[0974] Dasatinib monododecyl sulfate prepared according to the procedure of Example 48A (Crystallization Method E) was added to molten polyoxyl stearate Type I (Gelucire 48 / 16) to prepare a capsule dosage form of dasatinib monododecyl sulfate. The composition was cooled and mixed with microcrystalline cellulose, hydrogenated vegetable oil (LUBRITAB), and colloidal silicon dioxide, and then filled into No. 2 hard gelatin capsules. The capsule contents had the following composition:

[0975]

[0976]

[0977] Example 55F

[0978] A capsule dosage form of dasatinib monododecyl sulfate was prepared according to the procedure of Example 55, but polyoxyl stearate Type I (Gelucire 48 / 16) was used in place of polyoxylglycerol laurate. The composition of the capsules was as follows:

[0979]

[0980] Example 56

[0981] The dosage forms prepared in Examples 49, 51, 52, 53, and 55 were tested using the USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at 75 rpm, 37 °C, and using a sinker basket. The results of this dissolution test are shown below:

[0982]

[0983] Example 57

[0984] The following table lists the contents of dasatinib monododecyl sulfate capsules, which were prepared as follows: Dasatinib monododecyl sulfate (prepared according to the procedure of Example 48A - Crystallization Method E) was dissolved in the specified excipients and solvents; the solvent was evaporated to form granules, and the granules were mixed with extra granular excipients to form a mixture, which was then filled into hard gelatin capsules:

[0985]

[0986] The dosage form prepared in Example 57 was tested using a USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at 75 rpm, 37 °C, and with a sinker. The results of this dissolution test are shown below:

[0987]

[0988]

[0989] Example 58

[0990] The following table describes the contents of dasatinib monododecyl sulfate capsules, which were prepared according to a wet granulation procedure similar to that described in Examples 33, 49, and 55: Dasatinib monododecyl sulfate (prepared according to the procedure of Example 48A - crystallization method E) was dissolved in the specified excipients and solvents; the solvent was evaporated to form granules, and the granules were mixed with the external - mixing excipients to form a mixture, which was then filled into hard gelatin capsules:

[0991]

[0992]

[0993] *Dissolved in granulating fluid

[0994] The dosage form prepared in Example 58 was tested using a USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at 75 rpm, 37 °C, and with a sinker. The results of this dissolution test are shown below:

[0995]

[0996] Example 59A

[0997] Prepare dasatinib monododecyl sulfate in capsule form as follows. Grind and mix 2319 mg of dasatinib monododecyl sulfate prepared according to the procedure of Example 48A - Crystallization Method E, 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 about 15 seconds. Add 600 mg of purified water to the mixer and granulate for 15 seconds. Evaporate the water in an oven at 50 °C to dry the mixture, grind it into a powder, and sieve it through a 40 - mesh screen. Sieve 750 mg of microcrystalline cellulose, 375 mg of sodium starch glycolate (Part II), and 150 mg of colloidal silicon dioxide through a 40 - mesh screen and mix them uniformly with the mixture. Sieve 75 mg of sodium stearyl fumarate through a 40 - mesh screen and add it to the container, mix it with the powder to obtain the final mixture. Fill the dry solid mixture into No. 1 hard gelatin capsules.

[0998] The composition of the capsule contents is as follows:

[0999]

[1000]

[1001] Example 59B

[1002] Prepare a dasatinib monododecyl sulfate capsule form with the following composition according to a procedure similar to that described in Example 59A.

[1003] The composition of the capsule contents is as follows:

[1004] mg wt% Dasatinib Monododecyl Sulfate 77.30 38.65 Type I Polyoxyl Stearate (Gelucire 48 / 16) 48.00 24.00 Poloxamer 407 10.00 5.00 Microcrystalline Cellulose 34.00 17.00 Sodium Starch Glycolate (I) 4.00 2.00 Microcrystalline Cellulose 18.70 9.35 Sodium Starch Glycolate (II) 5.00 2.50 Colloidal Silicon Dioxide 2.00 1.00 Sodium Stearyl Fumarate 1.00 0.50 Total 200.00 100.00 Purified Water 15.00 N / A

[1005] Example 59C

[1006] Prepare a dasatinib monododecyl sulfate capsule form with the following composition according to a procedure similar to that described in Example 59A.

[1007] The composition of the capsule contents is as follows:

[1008]

[1009]

[1010] Test the dosage forms prepared in Examples 59A - 59C using the USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at 75 rpm, 37 °C, and using a sedimentation basket. The results of this dissolution test are as follows:

[1011]

[1012] Example 60

[1013] Prepare nilotinib monododecyl sulfate capsules having the following composition according to the procedure outlined in Example 36:

[1014]

[1015] Test the dosage forms prepared in Examples 60A - 60I using the USP Type II apparatus (Paddle) in 675 mL of 0.1 N HCl at 75 rpm, 37 °C and using a sedimentation basket, or using the USP Type II apparatus (Paddle) in 900 mL of 0.1 N HCl containing 0.1% Tween 80 at 75 rpm, 37 °C and using a sedimentation basket. The results of this dissolution test are shown below:

[1016] Test average value obtained at 75 rpm in 675 mL of 0.1 N HCl

[1017]

[1018] Test average value obtained in 900 mL of 0.1 N HCl containing 0.1% Tween 80

[1019]

[1020] Example 61A

[1021] Administer the capsules containing nilotinib monododecyl sulfate prepared according to Example 60A to nine (9) healthy subject individuals in the fasting and post - prandial states. This study is a randomized, open - label, single - dose, three - treatment, three - sequence, three - cycle and crossover design, and there is a washout period of at least 5 days between doses. The reference drug (Ref) is nilotinib hydrochloride capsules at a dose of 200 mg (as free base), and the test drug (Test) is the capsule prepared according to the method described in Example 60A but containing approximately 80 mg of nilotinib free base. The 9 healthy subject individuals participating in this study are randomly assigned to one of the sequences shown in the following table:

[1022]

[1023] During each treatment period, blood samples were drawn at 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. The AUC of each subject was determined based on non-compartmental analyses. 0-48 , AUC 0-∞ , C max , T max and T 1 / 2 The study results were normalized to the 200 mg dose and are summarized in the table below.

[1024] Pharmacokinetic parameters of control drugs and test formulations (normalized to a dose of 200 mg)

[1025]

[1026] Ref Fasted : Administer 200 mg (based on free base) of Tasigna capsules on an empty stomach

[1027] Test Fasted : Administer 80 mg (based on free base) of test capsules on an empty stomach

[1028] Test Fed : Administer 80 mg (based on free base) of test capsules after meals.

[1029] ANOVA analysis of log-transformed AUC 0-t , AUC 0-∞ and C max The sequence, subjects (sequence), period and treatment effect were included in the model. The data obtained for the test drug and the control drug are compared in the table below.

[1030] Test prescription vs. control drug and Test Fed vs.Test Fasted Comparison table

[1031] (Standardized to a 200mg dose)

[1032]

[1033] The data show that compared with nilotinib hydrochloride approved by the US FDA, the composition of the present invention exhibits C max The increase was 2.5 times and the AUC was 2.0 times. The data also showed that the composition of the present invention had no food effect, that is, the composition of the present invention exhibited comparable pharmacokinetics in the fasting and postprandial states.

[1034] The individual data obtained in this study (normalized to a dose of 200 mg) are shown below: control drug In the fasting state (concentration (ng / mL))

[1035]

[1036] Test drug (Example 60A) in the fasting state (concentration (ng / mL))

[1037]

[1038]

[1039] Test drug (Example 60A) in the postprandial state (concentration (ng / mL))

[1040]

[1041] The standardized mean plasma concentration curve obtained from Example 61A is as Figure 25 shown.

[1042] Example 61B

[1043] Capsules containing nilotinib monododecyl sulfate prepared according to Example 60F were administered to nine (9) healthy subject individuals in the fasting and postprandial states. This study was a bioavailability study with a single-dose, open-label, randomized, three-treatment, three-sequence, three-period crossover design for healthy subject individuals in the fasting and postprandial states. All subject individuals were randomly assigned to the sequences shown in the following table, and the washout period between different periods was at least 5 days. The control drug (Ref) was nilotinib hydrochloride capsules at a dose of 200 mg (in terms of free base), and the test drug (Test) was a capsule prepared according to the method described in Example 60F but containing approximately 80 mg of nilotinib free base. The nine healthy subject individuals participating in this study were randomly assigned to one of the sequences shown in the following table:

[1044]

[1045] *Ref: Administer control drug (Reference) in the fasting state; Tfast: Administer test drug (Test) in the fasting state; Tpost: Administer test drug (Test) in the postprandial state

[1046] During each treatment period, blood samples were taken at 0 (before dosing), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. The AUC of each subject individual was determined according to non-compartmental analyses0-48 、AUC 0-∞ 、C max 、T max and T 1 / 2 。The research results are summarized in the following table.

[1047] Pharmacokinetic parameters of the control drug and the test formulation (normalized to a dose of 200 mg)

[1048]

[1049] Ref Fasted : Administer 200 mg (as the free base) of Tasigna capsules in the fasting state

[1050] Test Fasted : Administer 80 mg (as the free base) of the test capsule (Test) in the fasting state

[1051] Test Fed : Administer 80 mg (as the free base) of the test capsule (Test) in the postprandial state

[1052] Analyze the log-transformed AUC 0-t 、AUC 0-∞ and C max 。Sequence, subject (sequence), cycle, and treatment effect are all included in the model. The comparison of the data obtained from the test drug and the control drug is shown in the following table. Test formulation vs. control drug and Test Fed vs.Test Fasted Comparison table (normalized to a dose of 200 mg)

[1053]

[1054]

[1055] The individual data obtained from this study (normalized to a dose of 200 mg) are as follows: control drug In the fasting state (concentration (ng / mL))

[1056]

[1057] Test drug (Example 60F) in the fasting state (concentration (ng / mL))

[1058]

[1059]

[1060] Test drug (Example 60F) in the postprandial state (concentration (ng / mL))

[1061]

[1062] The average plasma concentration curve obtained in Example 61B is as shown in Figure 26 shown below

[1063] Example 61C

[1064] Capsules containing nilotinib monododecyl sulfate prepared according to Example 60G were administered to nine (9) healthy subject individuals in the fasting and postprandial states. This study was a bioavailability study with a single-dose, open-label, randomized, three-treatment, three-sequence, three-period crossover design in healthy subject individuals in the fasting and postprandial states. All subject individuals were randomly assigned to the sequences shown in the following table, and the washout period between different periods was at least 5 days. The reference drug (Ref) was nilotinib hydrochloride capsules at a dose of 200 mg (in terms of free base), and the test drug (Test) was the capsule prepared according to the method described in Example 60G but containing approximately 80 mg of nilotinib free base. The nine healthy subject individuals participating in this study were randomly assigned to one of the sequences shown in the following table:

[1065]

[1066] *Ref: Administer the reference drug (Reference) in the fasting state; Tfast: Administer the test drug (Test) in the fasting state; Tpost: Administer the test drug (Test) in the postprandial state

[1067] During each treatment period, blood samples were taken at 0 (before dosing), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, and 48 hours after dosing. The AUC 0-48 AUC 0-∞ C max T max and T 1 / 2 of each subject individual were determined according to non-compartmental analyses. The study results are summarized in the following table.

[1068] Pharmacokinetic parameters of the reference drug and the test formulation (normalized to a dose of 200 mg)

[1069]

[1070] Ref Fasted : Administer 200 mg (in terms of free base) of Tasigna capsules in the fasting state

[1071] TestFasted : Administer 80 mg (based on free base) of test capsules on an empty stomach

[1072] Test Fed : Administer 80 mg (based on free base) of test capsules after meals.

[1073] ANOVA analysis of log-transformed AUC 0-t , AUC 0-∞ and C max The order, subjects (order), period and treatment effect are included in the model. The data obtained for the test drug and the control drug are compared in the table below. Fed vs.Test Fasted Comparison table (standardized to 200 mg dose)

[1074]

[1075] The individual data obtained in this study (normalized to a dose of 200 mg) are as follows:

[1076] Comparator drugs In fasting state (concentration (ng / mL))

[1077]

[1078] Test drug (Example 60G) in fasting state (concentration (ng / mL))

[1079]

[1080]

[1081] Test drug (Example 60G) in the postprandial state (concentration (ng / mL))

[1082]

[1083]

[1084] The standardized mean plasma concentration curve obtained in Example 61C is as follows Figure 27 shown.

[1085] Embodiment 62

[1086] The nilotinib dodecyl sulfate and nilotinib dodecyl sulfate dosage forms prepared according to the embodiments of the present invention were determined to contain the following impurities:

[1087]

[1088] The relative retention time values, impurities and stability of nilotinib monododecyl sulfate and the dosage forms prepared according to Examples 60F and 60G were determined using the following high performance liquid chromatography parameters:

[1089]

[1090]

[1091] Mobile phase A was 0.25% Formic Acid / acetonitrile in a volume ratio of 90 / 10.

[1092] Mobile phase B was 0.10% Formic Acid / acetonitrile in a volume ratio of 10 / 90.

[1093] A test sample of nilotinib monododecyl sulfate prepared according to Preparation Example 46 (Crystallization Method B) below: Weigh approximately 7.5 mg of nilotinib monododecyl sulfate (equivalent to 5 mg of nilotinib) and add it to a 50 mL brown volumetric flask. Add approximately 40 mL of diluent (ethanol), sonicate for approximately 5 minutes and stir at a speed of 800 rpm for approximately 5 minutes until the nilotinib monododecyl sulfate is dissolved. Add additional diluent to make the test sample contain approximately 0.10 mg of nilotinib per milliliter.

[1094] A test sample of the dosage form prepared according to Preparation Examples 60F and 60G below:

[1095] 1. Cut the top of the capsule with scissors and squeeze the contents into a 100 mL volumetric flask through the opening. Cut the capsule in half and add it to the volumetric flask. Add ethanol to 80%, sonicate for approximately 10 minutes and stir at a speed of 800 rpm for approximately 30 minutes to completely dissolve the contents.

[1096] 2. Add sufficient ethanol and invert the volumetric flask at least 10 times to mix evenly.

[1097] 3. Take 3 ml of the sample and add it to a 25 mL brown volumetric flask. Add sufficient ethanol and invert the volumetric flask at least 10 times to mix evenly. This test sample contains approximately 0.096 mg of nilotinib per milliliter.

[1098] The impurities and stability of nilotinib didodecyl sulfate prepared according to Example 26 were determined using the following high performance liquid chromatography parameters:

[1099]

[1100]

[1101] Test sample of nilotinib dodecyl sulfate prepared according to Preparation Example 26 below: Weigh approximately 10 mg of nilotinib dodecyl sulfate (equivalent to 5 mg of nilotinib) and add it to a 25 mL brown volumetric flask. Add approximately 20 mL of diluent (ethanol), ultrasonically vibrate for about 5 minutes and stir at a speed of 800 rpm for about 5 minutes until the nilotinib dodecyl sulfate dissolves. Add additional diluent to make the test sample contain approximately 0.20 mg of nilotinib per milliliter.

[1102] Detect the test sample using the above procedure and obtain the following results:

[1103]

[1104] The above sample is stored in a high-density polyethylene (HDPE) bottle (126 c.c., containing 2 - 3 g of silica gel desiccant) with a child-resistant cap and an aluminum foil induction sealing film.

[1105] The above data confirm that nilotinib monododecyl sulfate is more stable than nilotinib dodecyl sulfate, and any single impurity contained in the monododecyl sulfate and dodecyl sulfate of the present invention is not more than 0.5%, preferably not more than 0.35%, most preferably not more than 0.30%, and the total impurities should not be more than 1.0%, preferably not more than 0.75%, most preferably not more than 0.60%.

[1106]

[1107]

[1108] The above capsules are stored in a high-density polyethylene (HDPE) bottle (126 c.c., containing 2 - 3 g of silica gel desiccant) with a child-resistant cap and an aluminum foil induction sealing film.

[1109] Using the above HPLC method, any single impurity contained in the nilotinib dodecyl sulfate dosage form is not more than 0.5%, preferably not more than 0.35%, most preferably not more than 0.25%, and the total impurities should not be more than 1.0%, preferably not more than 0.75%, most preferably not more than 0.60%.

[1110] Example 63A

[1111] Prepare dasatinib monododecyl sulfate tablet dosage forms as follows. Grind and mix 7730 mg of dasatinib monododecyl sulfate prepared according to the procedure of Example 48A - Crystallization Method E and 4800 mg of type I polyoxyethylene stearate in a small mixer for about 15 seconds. Add 1000 mg of purified water to the mixer and granulate for 15 seconds. Evaporate the water in an oven at 50 °C to dry the granules. Grind the dried granules into a powder and sieve through a 30 - mesh sieve. Mix 16695 mg of microcrystalline cellulose sieved through a 40 - mesh sieve, 1400 mg of sodium starch glycolate, 3500 mg of croscarmellose sodium, and 700 mg of colloidal silicon dioxide with the dried, ground, and sieved granules to obtain a premix. Add 175 mg of sodium fumarate stearate sieved through a 40 - mesh sieve to the premix and mix to obtain the final mixture. Press the final mixture into tablets using a 9.5 - mm round punch, with a target hardness of about 5 kp.

[1112] The composition of the tablet content is shown below:

[1113]

[1114] Example 63B

[1115] Prepare dasatinib monododecyl sulfate tablet dosage forms as follows. Grind and mix 2319 mg of dasatinib monododecyl sulfate prepared according to the procedure of Example 48A - Crystallization Method E, 1800 mg of type I polyoxyethylene stearate, and 1800 mg of microcrystalline cellulose (Part I) in a small mixer for about 15 seconds. Add 450 mg of purified water to the mixer and granulate for 15 seconds. Evaporate the water in an oven at 50 °C to dry the granules. Grind the dried granules into a powder and sieve through a 40 - mesh sieve. Mix 2638.5 mg of microcrystalline cellulose (Part II) sieved through a 40 - mesh sieve, 420 mg of sodium starch glycolate, 1260 mg of croscarmellose sodium, and 210 mg of colloidal silicon dioxide with the dried, ground, and sieved granules to obtain a premix. Add 52.5 mg of sodium fumarate stearate sieved through a 40 - mesh sieve to the premix and mix to obtain the final mixture. Press the final mixture into tablets using a 9.5 - mm round punch, with a target hardness of about 5 kp.

[1116] The composition of the tablet content is shown below:

[1117]

[1118] Example 63C

[1119] Tablets prepared in Examples 63A and 63B were tested using a USP Type II apparatus (Paddle) in 500 mL of 0.1 N HCl at 75 rpm and 37 °C using a sinker. The results of this dissolution test are shown below:

[1120]

[1121] The inventions described herein by way of example can be suitably practiced and realized without one or more components, limitations that are not explicitly disclosed herein. Thus, for example, in each instance herein, any one of the terms "comprising", "consisting essentially of", and "consisting of" can be replaced by any of the other two terms. The terms and expressions used are illustrative terms and not restrictive, and it is not intended to use these terms and expressions to exclude any equivalents or portions thereof of any features shown or described herein, and it should be recognized that various modifications can be made within the scope of the invention claimed herein. Accordingly, it is to be understood that although the invention has been specifically disclosed by preferred embodiments and optional features, those skilled in the art can adopt modifications and variations of the concepts described herein, and such modifications and variations should be considered to be within the scope of the invention as defined by the appended claims for invention.

Claims

1. Use of cabozantinib dodecyl sulfate in the preparation of a dosage form for treating thyroid cancer, renal cell carcinoma or hepatocellular carcinoma, wherein, The dosage form is orally administered to a patient in need thereof, and the dosage form comprises a therapeutically effective dose of cabozantinib dodecyl sulfate and at least one pharmaceutically acceptable excipient, wherein the therapeutically effective dose of cabozantinib dodecyl sulfate is equivalent to about 5 mg to about 200 mg of cabozantinib in free base form.

2. The use according to claim 1, wherein The dosage form comprises the cabozantinib dodecyl sulfate in an amount of about 5 wt% to about 50 wt%.

3. The use according to claim 1, wherein, The dosage form is a capsule.

4. The use according to claim 1, wherein, The pharmaceutically acceptable excipient includes one or more excipients having an HLB value of 10 or higher.

5. Use according to claim 4, wherein The one or more excipients having an HLB value of 10 or higher are selected from the group consisting of fatty alcohol acids or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxyalkyl polysaccharides, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, tyloxapol, polyglyceryl fatty acid esters, and polyglyceryl fatty acid alcohols or combinations thereof.

6. The use according to claim 4, wherein The one or more excipients having an HLB value of 10 or higher are selected from the group consisting of polyethoxylated castor oil, polyoxyethylene alkyl esters, polyethylene glycolated glycerol esters, sorbitan fatty acid esters, glycerol fatty acid esters, polyglyceryl fatty acid esters, fatty alcohol polyethylene glycol ethers, acetylene diols, acetylene alcohols, alkylene oxide block polymers, polyoxyethylene alkyl ethers, polyoxyethylene alkyl aryl ethers, polyoxyethylene styryl aryl ethers, polyoxyethylene ethylene glycol alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerol fatty acid esters, polyoxyethylene hydrogenated castoroil, polyoxypropylene fatty acid esters, polyoxyethylene glycerol esters, polyoxyethylene stearates, or mixtures of the foregoing.

7. The use according to claim 1, wherein, The dissolution rate of the dosage form is about 35% to about 100% after 45 minutes of testing under the test conditions of a paddle-type USP Type II apparatus, 0.1 N hydrochloric acid solvent, 37 °C, and a rotation speed of 75 rpm.

8. The use according to claim 1, wherein, The dissolution rate of the dosage form is at least 40% after 30 minutes of testing and at least 70% after 60 minutes of testing under the test conditions of a paddle-type USP Type II apparatus, 0.1 N hydrochloric acid solvent, 37 °C, and a rotation speed of 75 rpm.

9. The use according to claim 1, wherein, The dosage form is administered to the patient in a postprandial state or a fasting state and does not produce a food effect.

10. The use according to claim 1, wherein, Compared to when the dosage form is administered to the patient in a fasting state, cabozantinib C when the dosage form is administered to the patient in a postprandial state max , cabozantinib AUC 0-∞ or cabozantinib AUC 0-24 does not change by more than 40%.

11. The use according to claim 1, wherein, The dosage form has a C maxfed / C maxfast ratio of from about 0.60 to about 2.5, where C maxfed is the highest plasma cabozantinib concentration achieved by administering a single dose of the cabozantinib dodecyl sulfate dosage form to a group of human patients or healthy human individuals in a postprandial state, and C maxfast is the highest plasma cabozantinib concentration achieved by administering a single dose of the cabozantinib dodecyl sulfate dosage form to the patients or the individuals in a fasting state.

12. The use according to claim 1, wherein, The dosage form has an AUC 0-∞fed / AUC 0-∞fast ratio of from about 0.60 to about 2.5, where AUC 0-∞fed is the AUC of cabozantinib from zero to infinity obtained by administering a single dose of the cabozantinib dodecyl sulfate dosage form to a group of human patients or healthy human individuals in a postprandial state, and AUC 0-∞fast is the AUC of cabozantinib from zero to infinity obtained by administering a single dose of the cabozantinib dodecyl sulfate dosage form to the patient or the individual in a fasting state.

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