Improved Cabozantinib Compositions and Methods of Use

Abstract

The present invention relates to oral compositions comprising a cabozantinib salt and at least one pharmaceutically acceptable excipient, and methods of using the oral compositions to improve the oral bioavailability of cabozantinib and reduce adverse events associated with oral administration of cabozantinib. The present invention also relates to methods for preparing cabozantinib lauryl sulfate.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 482,334, filed January 31, 2023, and U.S. Provisional Patent Application No. 63 / 467,388, filed May 18, 2023, all of which are incorporated herein by reference in their entireties.

[0002] (Technical field) The present invention relates to cabozantinib compositions and methods of use thereof. The cabozantinib compositions may be orally administered to a subject in combination with one or more pharmaceutically acceptable excipients. In certain embodiments, the present invention relates to oral dosage forms comprising the mono- or dilauryl sulfate salt of cabozantinib and one or more pharmaceutically acceptable excipients, and methods of treating various conditions, including cancer, including oral administration of these dosage forms.

[0003] The present invention further relates to methods for preparing cabozantinib lauryl sulfate and its polymorphs. [Background technology]

[0004] Cabozantinib lauryl sulfate is described in International Patent Application No. PCT / US2019 / 036947, filed June 13, 2019, published as WO2019 / 241504. It is also described in U.S. Patent Application No. 18 / 096,598, filed January 13, 2023. These patent applications also disclose pharmaceutical formulations containing cabozantinib lauryl sulfate and methods for treating various diseases by oral administration of cabozantinib lauryl sulfate. The contents of WO2019 / 241504 and U.S. Patent Application No. 18 / 096,598, filed January 13, 2023, are incorporated herein by reference.

[0005] Cabozantinib and various pharmaceutically acceptable salts other than lauryl sulfate are described in numerous publications, including U.S. Patent Nos. 7,579,473 and 8,877,776. Formulations containing cabozantinib and cabozantinib malate are also described, for example, in U.S. Patent Nos. 9,724,342, 10,034,873, and 11,091,439.

[0006] Cabozantinib, in capsule and tablet form containing cabozantinib (S)-malate, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of various cancers, including renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid carcinoma. More specifically, cabozantinib is currently marketed as CABOMETYX® film-coated tablets and COMETRIQ® capsules.

[0007] CABOMETYX tablets contain 20 mg, 40 mg, or 60 mg of cabozantinib free base (i.e., 25 mg, 51 mg, or 76 mg of cabozantinib (S)-malate) and contain microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, triacetin, and yellow iron oxide. According to the U.S. Food and Drug Administration (FDA)-approved prescribing information (package insert or labeling), CABOMETYX tablets are indicated for the treatment of patients with advanced renal cell carcinoma (RCC), patients receiving advanced renal cell carcinoma in combination with nivolumab as first-line treatment, and patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. According to the U.S. FDA prescribing information, the recommended dose is 60 mg or 40 mg once daily in combination with nivolumab 240 mg every two weeks or 480 mg every four weeks. According to the U.S. FDA prescribing information, CABOMETYX should be taken at least one hour before or at least two hours after a meal. This is because the C of cabozantinib may be increased when taken with a high-fat meal compared to when taken on an empty stomach. maxThis is because a study in which a single oral dose of cabozantinib (S)-malate capsule formulation was administered to healthy subjects demonstrated a 41% increase in maximum blood concentration (maximum blood concentration) and a 57% increase in AUC (area under the blood concentration-time curve).

[0008] COMETRIQ capsules are hard gelatin capsules containing 20 mg or 80 mg of cabozantinib free base in the form of cabozantinib (S)-malate. Other ingredients include silicified microcrystalline cellulose, croscarmellose sodium, sodium starch saccharide, fumed silica, and stearic acid. According to the U.S. FDA-approved prescribing information, the recommended dose of COMETRIQ capsules is 140 mg once daily. It should be taken at least 1 hour before or at least 2 hours after a meal. This is because cabozantinib C-values ​​may be increased when taken with a high-fat meal compared to when taken on an empty stomach. max This is because a study in which a single oral dose of 140 mg of COMETRIQ was administered to healthy subjects confirmed that the maximum blood concentration (maximum blood concentration) increased by 41% and the area under the blood concentration-time curve (AUC) increased by 57%. Summary of the Invention [Means for solving the problem]

[0009] The present invention relates to pharmaceutical compositions comprising cabozantinib and / or a pharmaceutically acceptable salt thereof, e.g., cabozantinib lauryl sulfate, for oral administration, and methods of using the oral compositions in the treatment of cancer that meet one or more of the following needs and desires:

[0010] The present invention further relates to oral pharmaceutical compositions containing a therapeutic amount of cabozantinib (preferably cabozantinib lauryl sulfate) and one or more pharmaceutically acceptable excipients, wherein the oral compositions are characterized by improved bioavailability or absorption under fasting conditions compared to an equivalent dose of commercially available CABOMETYX tablets and / or COMETRIQ capsules. In one aspect of the invention, the compositions do not exhibit a food effect. In yet another aspect, the present invention provides compositions that exhibit improved bioavailability or absorption under fasting conditions when administered under fed and fasting conditions. max and / or AUC are similar or equivalent, indicating overall similar or equivalent bioavailability.

[0011] The present invention also relates to oral pharmaceutical compositions containing a therapeutic amount of cabozantinib (preferably cabozantinib lauryl sulfate) and one or more pharmaceutically acceptable excipients, wherein the oral compositions are characterized by a reduced incidence or severity of adverse events compared to commercially available CABOMETYX tablets and / or COMETRIQ capsules. In some embodiments of the present invention, the compositions contain C-terminal fragments equivalent to or similar to CABOMETYX tablets and / or COMETRIQ capsules. max and / or AUC, i.e., "equivalent bioavailability" or "similar bioavailability," results in a reduction in the frequency or severity of adverse events, which may include gastrointestinal irritation, diarrhea, decreased appetite, weight loss, or a combination thereof.

[0012] The present invention further relates to an oral formulation containing a therapeutic amount of cabozantinib (preferably cabozantinib lauryl sulfate) and one or more pharmaceutically acceptable excipients, which, when orally administered to humans, exhibits a decrease in at least one pharmacokinetic parameter (i.e., C) compared to commercially available CABOMETYX tablets and / or COMETRIQ capsules. max , AUC0-t , AUC 0-infinity ) is characterized by low inter-subject variability.

[0013] In one aspect, the present invention provides low-dose oral pharmaceutical compositions comprising cabozantinib, preferably cabozantinib lauryl sulfate, and one or more pharmaceutically acceptable excipients, which, when orally administered, provide comparable efficacy to commercially available CABOMETYX tablets and / or COMETRIQ capsules, despite a lower cabozantinib dose, where the dose of cabozantinib free base, preferably provided in the form of cabozantinib lauryl sulfate, is at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% lower than the dose of cabozantinib free base provided in the form of cabozantinib (S)-malate.

[0014] The oral compositions of the present invention may be in the form of tablets, capsules, granules, beads, pellets, or powder. In one embodiment, the oral composition is a capsule, and the capsule contents comprise a therapeutic amount of cabozantinib, preferably cabozantinib lauryl sulfate, and at least one pharmaceutically acceptable excipient. In one embodiment, the capsule contents comprise 2.5 mg to 250 mg of cabozantinib lauryl sulfate, which is amorphous, crystalline, or a combination of amorphous and crystalline. In another embodiment, the capsule contents comprise one or more excipients with an HLB value of 10 or greater, which are solid at room temperature but have a melting point of 100°C, 95°C, 90°C, 85°C, 80°C, 75°C, 70°C, 65°C, 60°C, 55°C, 50°C, 45°C, or 40°C or less.

[0015] The present invention further relates to methods for administering to a patient in need thereof, particularly a human patient in need thereof, disorders treatable with multiple receptor tyrosine kinase inhibitors. Examples of disorders treatable with the oral compositions of the present invention comprising cabozantinib lauryl sulfate include, but are not limited to, renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid carcinoma.

[0016] The present invention also relates to methods for preparing cabozantinib lauryl sulfate and its polymorphs. In certain embodiments, the methods for preparing cabozantinib lauryl sulfate produce stable crystalline forms with low impurity levels. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is a graph of the mean in vivo plasma data presented in Example 17. [Figure 2] 1 is a graph of the mean in vivo plasma data presented in Example 18. [Figure 3] 1 is a graph of the mean in vivo plasma data presented in Example 19. [Figure 4] 2 is a graph of the mean in vivo plasma data presented in Example 20. [Figure 5] 2 is a graph of the mean in vivo plasma data presented in Example 21. [Figure 6] 1 is a graph of the mean weight change data presented in Example 22. [Figure 7] 1 is a graph of the mean diarrhea data presented in Example 22. [Figure 8] 1 is a graph of the mean appetite data presented in Example 22. [Figure 9] 1 is a graph of the mean survival data presented in Example 22. [Figure 10] FIG. 2 is an XRPD pattern of non-micronized cabozantinib monolauryl sulfate as described in Example 23. [Figure 11A] 1 is an XRPD pattern of cabozantinib monolauryl sulfate described in Examples 25A, 25B, and 25C. [Figure 11B] 1 is an XRPD pattern of cabozantinib monolauryl sulfate described in Examples 25A, 25B, and 25C. [Figure 11C] 1 is an XRPD pattern of cabozantinib monolauryl sulfate described in Examples 25A, 25B, and 25C. [Figure 12A] 1 is a graph of the mean diarrhea scores and rates in the study described in Example 28. [Figure 12B] 1 is a graph of the mean diarrhea scores and rates in the study described in Example 28. DETAILED DESCRIPTION OF THE INVENTION

[0018] The U.S. FDA package inserts for CABOMETYX tablets and COMETRIQ capsules state that the recommended dose may be reduced for patients with moderate hepatic impairment and warn of a very high incidence of gastrointestinal adverse effects, specifically diarrhea, which was experienced in approximately 63% of patients receiving COMETRIQ capsules and approximately 62% of patients receiving CABOMETYX tablets. Diarrhea is believed to be due to large amounts of unabsorbed cabozantinib present in the patient's intestinal tract. This belief is based on data provided in the U.S. FDA-approved package inserts for CABOMETYX tablets and COMETRIQ capsules. According to these documents, radiolabeled cabozantinib was administered to healthy subjects. 14 In a single-dose study of C-cabozantinib, approximately 81% of the total administered radioactivity was recovered within the 48-day collection period, with approximately 54% in the feces and 27% in the urine. The US FDA package insert recommends dose reduction, temporary interruption, or discontinuation of treatment depending on the severity of adverse events.

[0019] The U.S. FDA package inserts for CABOMETYX tablets and COMETRIQ capsules report high inter-subject variability for Cmax and AUC values ​​after administration [CV%C max : 51% for tablet form and 61% for capsule form; CV%AUC 0―last or AUC0-infinity : 40-43% for tablet form, 43% for capsule form]. The reported geometric mean C max was approximately 49% higher than that observed for the capsule dosage form. The geometric mean AUC reported for the tablet formulation 0-last and AUC 0-infinity values ​​were higher than those observed with the capsule formulation (15% and 19%, respectively).

[0020] Given the following points, there is a need to develop pharmaceutical compositions that can enhance the bioavailability or absorption of cabozantinib, which could allow for a reduction in the currently approved daily dose of cabozantinib while maintaining therapeutic efficacy and reducing adverse events.

[0021] Additionally, the food effect exhibited by the commercially available CABOMETYX tablets and COMETRIQ capsules should be reduced, allowing cabozantinib to be administered at any time, regardless of whether a subject has eaten or not. This reduction in food effect should maintain equivalent bioavailability when subjects take cabozantinib in both fed and fasted states. This reduction in food effect would allow patients to take their medication at a time convenient for them, improving medication adherence. It would also prevent unwanted peaks and troughs in cabozantinib plasma concentrations, maintaining optimal therapeutic cabozantinib concentrations in patients and reducing adverse events.

[0022] Oral dosage forms may provide cabozantinib to patient populations with reduced variability in bioavailability, thereby providing consistent PK parameters (e.g., C max and a narrower observed range of AUC values).

[0023] U.S. Patent Application Publication No. 2022 / 0387418 and International Patent Application Publication No. WO2022 / 115464 propose pharmaceutical compositions that may fulfill some of the aforementioned needs and desires. However, the compositions described in these publications are very complicated to prepare, and neither of these publications discloses compositions using cabozantinib lauryl sulfate.

[0024] Before the present invention is further described, it is to be understood that this invention is not limited to the particular embodiments described herein, and that the terminology used herein is for the purpose of describing particular embodiments, and is not intended to be limiting. It should be noted that as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0025] Where ranges are provided, it is understood that each intervening value between the upper and lower limits, and other values ​​stated within that range, is included to one-tenth of the unit of the lower limit, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed in the invention, subject to any specifically excluded limit in the stated range. When the stated range includes one or both limits, ranges excluding those included limits are also encompassed in the invention.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. All publications cited herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0027] As used herein, the term "normal storage conditions" refers to storage at room temperature of 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. Dosage forms according to the present invention should be stored in a pharmaceutically acceptable container such as a glass bottle, a plastic bottle, a metal foil bag, or a blister pack with or without a desiccant.

[0028] As used herein, the term "accelerated storage conditions" refers to storage at about 40°C and about 75% relative humidity for at least 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. Dosage forms according to the invention should be stored in a pharmaceutically acceptable container such as a glass bottle, plastic bottle, metal foil pouch, or blister pack with or without a desiccant.

[0029] The term "HLB" refers to the "hydrophilic-lipophilic balance" of a surfactant or emulsifier and is a measure of its degree of hydrophilicity or lipophilicity. It is determined by calculating values ​​for different regions of the molecule. This is described by Griffin, WC, in "Calculation of the HLB Value of Nonionic Surfactants" [Journal of the Society of Cosmetic Chemists, 5:259 (1954)]. HLB values ​​range from 0 to 20, with an HLB value of 0 corresponding to a completely lipophilic molecule and an HLB value of 20 corresponding to a completely hydrophilic molecule. HLB values ​​are commonly known and reported in the literature and manufacturer's technical catalogs.

[0030] "C max The term "maximum blood concentration achieved during the dosing interval" refers to the maximum blood concentration achieved during the dosing interval.

[0031] "T max The term "maximum blood concentration (C max ) is the time it takes to reach

[0032] The term "AUC" refers to the area under the concentration-time curve of a drug over a specific time interval and is calculated using the linear trapezoidal rule. For example, AUC 0-12 refers to the area under the drug concentration-time curve from immediately before administration to 12 hours after administration, and AUC 0-24 refers to the area under the drug concentration-time curve from immediately before administration to 24 hours after administration, and AUC 0-infinity or AUC 0-inf refers to the area under the drug concentration-time curve from just before administration to infinity, and AUC 0-t refers to the area under the drug concentration time curve from immediately before administration to a specified time point after administration, such as 2 hours, 8 hours, 18 hours, etc. In some embodiments, the specified time point is the last time point of the blood sample.

[0033] The pharmacokinetic parameters described herein are measured according to methods generally known and understood by those skilled in the art and are generally described in documents such as the United States Food and Drug Administration's (USFDA) "Guidance on Bioavailability and Bioequivalence Testing of Orally Administered Pharmaceuticals (March 2003)," "Guidance on Statistical Approaches for Establishing Bioequivalence (January 2001)," and "Guidance on Bioavailability and Fed Bioequivalence Testing for the Effect of Food (December 2002)," all of which are incorporated herein by reference.

[0034] "Bioequivalence" and "equivalent" pharmacokinetic values ​​(C max , T max , AUC, etc.) means that there is no significant difference in bioavailability or a specified pharmacokinetic value between two pharmaceuticals (e.g., a test composition and a reference composition) over a given period of time, at the same dose, and / or under the same conditions. For example, the mean ratio of AUC(24 hours) and C maxThe average ratio of is within 80% to 125% between two drug products (e.g., test and reference compositions) over a period of time. Whether a test composition is bioequivalent to a reference composition can be determined by conducting a study called a bioequivalence study or comparative bioavailability study in a group of subjects under controlled conditions.

[0035] The term "bioavailability" refers to the extent to which a drug or other substance is utilized by a target tissue after administration. For example, "bioavailability" may refer to the proportion of a drug that is absorbed after administration to a subject or patient under fed or fasting conditions. Bioavailability includes the C max The pharmacokinetic parameters may include one or more pharmacokinetic values ​​such as , AUC, and combinations thereof.

[0036] Throughout this specification, reference is made to administration of pharmaceutical compositions under fed or fasted conditions. It is understood in the art that the pharmacokinetic behavior of some drugs and pharmaceutical compositions is affected by the presence or absence of food in the gastrointestinal tract. Thus, these references to fed and fasted conditions refer to "fed" or "fasted" administration conditions as generally recognized in the art.

[0037] As used herein, the term "fasted conditions" generally means that a human or other mammal has not ingested 500 calories or more for at least 1 hour before and at least 2 hours after ingestion of a dosage form containing a drug.

[0038] As used herein, the term "fed state" refers to a person who ingested a U.S. Food and Drug Administration (FDA) high-fat breakfast (or another meal containing a comparable amount of fat and calories) during the period described above, which is high in both fat (approximately 50% of the total calorie content of the meal) and calories (approximately 800-1000 calories).

[0039] As used herein, the term "food effect" refers to the interaction between food and a drug that reduces or increases the amount of drug absorption. In other words, the bioavailability of a drug changes when administered under fasting conditions compared to when administered under fed conditions. This refers to the AUC of a drug when the drug or its formulation is orally administered to humans with food or in the fed state. 0-infinity , AUC 0-t and / or C max may refer to the difference between one or more of the above and the same value when the same formulation is administered under fasting conditions or without food.

[0040] In one aspect, the effect of food is to determine the C of the test drug in fed and fasted conditions. max and / or AUC values ​​of the test drug in the fed and fasted states. max Measuring the AUC and / or AUC values ​​is a standard method in the art.

[0041] In certain embodiments, the pharmaceutical compositions described herein reduce or eliminate the food effect. As used herein, "reducing the food effect" refers to a decrease in the bioavailability, e.g., AUC, of ​​a drug administered in fasted conditions versus a drug administered in a fed state. 0―infinity , AUC 0―t , AUC 0―12 , AUC 0-24 and / or C max This refers to reducing the difference between the pharmacokinetic parameters of a mammal and the food-dependent pharmacokinetic parameters of a human. In some embodiments, the food effect is eliminated. Thus, when the pharmaceutical compositions described herein are orally administered to a mammal in need thereof, no significant food effect is observed. In other words, the difference in pharmacokinetic parameters measured after oral administration to a mammal with and without food is less than 40%, for example, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%, respectively. Preferably, the composition or pharmaceutical composition of the present invention reduces the food effect by at least 15%, preferably 20%, preferably 25%, preferably 30%, preferably 40%.

[0042] As used herein, "no food effect" means that the dosage form can be administered with or without food. Furthermore, when administered under fed or fasted conditions, C max There is no significant effect on the value. max The average fed / fasted ratio of AUC values ​​preferably ranges from about 0.8 to about 1.25. Furthermore, when administered under fed or fasted conditions, 0-t value, e.g., AUC 0-72 There is no significant effect on the AUC 0-t The average fed / fasted ratio of values ​​preferably ranges from about 0.8 to about 1.25.

[0043] The difference in AUC for the compositions of the invention when administered under fed and fasted conditions is preferably less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.

[0044] C when the compositions of the present invention are administered under fed and fasted conditions max The difference (in maximum blood concentration) is preferably less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%.

[0045] In certain embodiments, the pharmaceutical composition, when administered to a subject under fed and / or fasted conditions, exhibits an AUC 0-t , T max , C max and / or AUC 0-infinityThe coefficient of variation in is less than about 60% (e.g., less than about 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, and 15%). In certain embodiments, the coefficient of variation in these parameters is in the range of about 20% to about 60% (e.g., 20% to 30%, 20% to 35%, 20% to 40%, 20% to 45%, 20% to 50%, 20% to 55%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 30% to 55%, 30% to 60%, 35% to 40%, 35% to 45%, 35% to 50%, 35% to 55%, 35% to 60%, 40% to 45%, 40% to 50%, 40% to 55%, 40% to 60%, 45% to 50%, 45% to 55%, 45% to 60%, 50% to 55%, 50% to 60%, and 55% to 60%, etc.).

[0046] Oral administration of the pharmaceutical composition of the present invention improves the bioavailability of cabozantinib, allowing for the use of lower doses of cabozantinib (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 , 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, or 125 mg / day) to achieve therapeutic efficacy equivalent to or substantially equivalent to commercially approved doses (e.g., CABOMETYX Tablets 20 mg, 40 mg, 60 mg or COMETRIQ Capsules 140 mg / day).

[0047] On the other hand, the pharmaceutical compositions of the present invention may be administered in smaller doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, or 125 mg / day) while maintaining the therapeutic effect of cabozantinib. As a result, unwanted side effects associated with conventional doses, such as bleeding, gastrointestinal perforation and fistula, thrombotic events, hypertension and hypertensive crisis, diarrhea, vomiting, nausea, palmar-plantar erythematous pain syndrome, proteinuria, anorexia, and weight loss, can be reduced.

[0048] In certain embodiments, the pharmaceutical compositions of the present invention allow for a reduced dosage of cabozantinib, preferably in the form of cabozantinib lauryl sulfate, while achieving similar or substantially equivalent therapeutic efficacy compared to the commercially approved CABOMETYX tablets and / or COMETRIQ capsules.

[0049] [Table 1]

[0050] In one aspect of this embodiment, the invention includes a method of administering cabozantinib to a patient at a reduced dose, comprising the steps of: (i) determining a therapeutic dose of cabozantinib free base in a subject in need thereof by orally administering cabozantinib (S)-malate in the form of solid immediate-release tablets (i.e., CABOMETYX tablets) and / or immediate-release capsules (i.e., COMETRIQ capsules); and (ii) orally administering to the subject a formulation according to the invention having a reduced dose of cabozantinib or a pharmaceutically acceptable salt thereof, as set forth in the Reduced Dosage Table.

[0051] For example, if a subject is therapeutically benefiting from a once-daily administration of 60 mg CABOMETYX tablets, the subject would be administered a dosage form according to the present invention containing 20-50 mg, 25-45 mg, or 30-40 mg of cabozantinib or a pharmaceutically acceptable salt thereof. Similarly, if a subject is therapeutically benefiting from a once-daily administration of 80 mg COMETRIQ capsules, the subject would be administered a dosage form according to the present invention containing 24-65 mg, 30-60 mg, or 40-55 mg of cabozantinib or a pharmaceutically acceptable salt thereof.

[0052] In another aspect of this embodiment, the present invention provides a method for administering a low dose of cabozantinib to a patient, the method comprising the steps of: (i) determining the amount of cabozantinib free base that functions or is functioning as a therapeutically effective dose of cabozantinib by orally administering cabozantinib (S)-malate in the form of an immediate-release solid tablet (e.g., CABOMETYX tablet) or immediate-release capsule (e.g., COMETRIQ capsule); and (ii) orally administering to the subject a dosage form of the present invention comprising a low dose of cabozantinib or a pharmaceutically acceptable salt thereof that corresponds to 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the amount of cabozantinib determined in step (i).

[0053] Oral administration of the pharmaceutical compositions of the invention reduces one or more undesirable adverse events, particularly decreased appetite, weight loss, and gastrointestinal adverse reactions such as diarrhea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, or any combination thereof, compared to commercially available CABOMETYX tablets and / or COMETRIQ capsules.

[0054] In certain embodiments, administration of a composition according to the present invention to a human subject may reduce the incidence of one or more adverse reactions compared to commercially available CABOMETYX tablets and / or COMETRIQ capsules, as follows:

[0055] [Table 2]

[0056] In certain embodiments, administration of a composition of the present invention to a human subject may result in a reduced incidence of one or more serious adverse reactions (Grade 2-4 AEs) compared to commercially available CABOMETYX tablets and / or COMETRIQ capsules.

[0057] [Table 3]

[0058] In certain embodiments, administration of a composition according to the present invention to a human subject may reduce the incidence of dose interruptions and / or dose reductions due to adverse reactions compared to commercially available CABOMETYX tablets and / or COMETRIQ capsules, as follows:

[0059] [Table 4]

[0060] For example, 63% of patients receiving commercially available CABOMETYX tablets reportedly experienced diarrhea. Human subjects receiving the compositions of the present invention are expected to experience diarrhea in 56% or less, representing at least a 10% reduction in incidence.

[0061] In one embodiment, a reduction in adverse events is measured by administering a composition of the invention and commercially available CABOMETYX tablets or COMETRIQ capsules, wherein the composition of the invention and the commercially available CABOMETYX tablets or COMETRIQ capsules contain the same or equivalent amount of cabozantinib free base. Alternatively, a reduction in adverse events is measured by administering a composition of the invention and commercially available CABOMETYX tablets or COMETRIQ capsules, wherein the composition of the invention contains a reduced or lower amount of cabozantinib free base as described herein compared to the amount of cabozantinib administered in commercially available CABOMETYX tablets or COMETRIQ capsules. In this alternative embodiment, the reduced or lower amount of cabozantinib free base administered in the composition of the invention results in the same or equivalent C as that achieved by administering commercially available CABOMETYX tablets or COMETRIQ capsules. max and / or AUC values ​​should be obtained.

[0062] In certain embodiments, administering a composition according to the present invention to a human subject can reduce the incidence of one or more adverse reactions as follows:

[0063] [Table 5]

[0064] In certain embodiments, the incidence of one or more serious side effects (grade 2-4 adverse events) may be reduced by administering to a human subject a composition according to the invention as follows.

[0065] [Table 6]

[0066] In certain embodiments, the incidence of dose interruptions and / or dose reductions due to side effects may be reduced by administering a composition according to the present invention as follows.

[0067] [Table 7]

[0068] In certain embodiments, after administration of a pharmaceutical composition of the invention to a subject (e.g., under fed or fasted conditions), the average bioavailability is greater than about 10% (e.g., greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, or greater than 99%), or between about 10% and about 90% (e.g., between 10% and 20%, 10% and 30%, 10% and 40%, 10% and 50%, 10% and 60%, 10% and 70%, 10% and 80%, 10% and 90%, 15% and 20%), compared to commercially available CABOMETYX tablets and / or COMETRIQ capsules. , 15%~30%, 15%~40%, 15%~50%, 15%~60%, 15%~70%, 15%~80%, 15%~90%, 20%~30%, 20%~40%, 20%~50%, 20%~60%, 20%~70%, 20%~80%, 20%~90%, 30%~40%, 30%~50%, 30%~60%, 30%~70% , 30%~80%, 30%~90%, 40%~50%, 40%~60%, 40%~70%, 40%~80%, 40%~90%, 50%~60%, 50%~70%, 50%~80%, 50%~90%, 60%~70%, 60%~80%, 60%~90%, 70%~80%, 70%~90%, and 80%~90%) improvement.

[0069] As used herein, unless otherwise defined, the term "subject" refers to mammals such as humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, and guinea pigs, and is preferably a human, and includes healthy mammals and mammals suffering from a disease treatable with cabozantinib. A subject suffering from a disease treatable with cabozantinib may also be referred to as a "patient."

[0070] As used herein, unless otherwise defined, the phrase "therapeutically effective amount" when used in connection with a composition or dosage form containing cabozantinib lauryl sulfate means an amount of cabozantinib lauryl sulfate effective to treat a disease or disorder disclosed herein, such as cancer, including but not limited to renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid carcinoma.

[0071] Unless otherwise defined, the terms "homogenously mixed" and "homogenous mixture" used herein refer to a combination of cabozantinib lauryl sulfate and at least one pharmaceutically acceptable excipient (preferably a carrier with an HLB value of approximately 10 or greater, 11 or greater, 12 or greater, 13 or greater, or 14 or greater, such as a wetting agent, emulsifier, solubilizer, surfactant, or a combination thereof). This means that cabozantinib lauryl sulfate and at least one pharmaceutically acceptable excipient are in homogeneous contact or close proximity with each other. A homogeneous mixture can be prepared by any method capable of thoroughly mixing cabozantinib lauryl sulfate and at least one pharmaceutically acceptable excipient (preferably a carrier with an HLB value of approximately 10 or greater). An example of a suitable method for obtaining a homogeneous mixture is to dissolve, suspend, or disperse cabozantinib sulfate in a solution or suspension containing at least one pharmaceutically acceptable excipient (preferably a carrier having an HLB value of approximately 10 or greater), and optionally at least one additional pharmaceutically acceptable excipient, such as a pharmaceutically acceptable solvent. The pharmaceutically acceptable solvent may or may not be removed. Another example of a suitable method for obtaining a homogeneous mixture is to use a liquid excipient containing at least one pharmaceutically acceptable excipient having an HLB value of approximately 10 or greater, or to melt one or more solid excipients to obtain a melt containing at least one pharmaceutically acceptable excipient having an HLB value of approximately 10 or greater, thereby producing a molten or liquid excipient composition containing at least one excipient having an HLB value of approximately 10 or greater, in which cabozantinib (preferably cabozantinib lauryl sulfate) can be dissolved, suspended, or dispersed. A liquid excipient composition comprising at least one excipient having an HLB value of approximately 10 or greater can further comprise one or more pharmaceutically acceptable excipients, as described below.Other methods that can be used to obtain a homogenous mixture of cabozantinib (preferably cabozantinib lauryl sulfate) and at least one pharmaceutically acceptable excipient, preferably having an HLB value of approximately 10 or greater, include co-blending, co-sieving, co-compression, co-compression molding, or combinations thereof. After a homogenous mixture of cabozantinib (preferably cabozantinib lauryl sulfate) and at least one pharmaceutically acceptable excipient (preferably having an HLB value of approximately 10 or greater) is prepared, the homogenous mixture can be combined with at least one additional pharmaceutical excipient or carrier. Preferably, the homogenous mixture comprises cabozantinib (preferably cabozantinib lauryl sulfate) and one, two, or three excipients before combining with the additional excipient.

[0072] The cabozantinib used in the present invention may be cabozantinib free base, one or more pharmaceutically acceptable salts of cabozantinib, or a combination thereof. Pharmaceutically acceptable salts include acid addition salts such as acetate (formed with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfite, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, bisulfate, heptanoate, and hexahydroxybenzoate. Examples of salts include acetate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., with sulfuric acid), sulfonate (such as those described herein), tartrate, thiocyanate, toluenesulfonate, and undecanoate. Cabozantinib lauryl sulfate is preferably used in the present invention.

[0073] Cabozantinib lauryl sulfate can be formed by reacting cabozantinib molecules with an alkali metal or alkaline earth metal lauryl sulfate. Preferred alkali metal or alkaline earth metal lauryl sulfates include, but are not limited to, sodium lauryl sulfate or potassium lauryl sulfate. An example of a method for preparing cabozantinib lauryl sulfate is described in Example 41 of International Patent Application Publication No. WO 2019 / 241504, which is incorporated herein by reference.

[0074] The present invention also encompasses compositions and dosage forms for oral administration to a subject, comprising cabozantinib, preferably cabozantinib lauryl sulfate, and at least one pharmaceutically acceptable excipient. These compositions and dosage forms can be solid, semi-solid, or liquid, in which cabozantinib, preferably cabozantinib lauryl sulfate, is combined with a pharmaceutically acceptable excipient, such as a filler, diluent, binder, stabilizer, lubricant, disintegrant, wetting agent / solubilizer / emulsifier, or mixtures thereof. Pharmaceutically acceptable excipients are well known in the art and are described in Remington, "The Science and Practice of Pharmacy," 21st Edition, 2006, pp. 1058-1092, and "Handbook of Pharmaceutical Excipients," 6th Edition, 2009. Representative examples of various pharmaceutically acceptable excipients that may be used in embodiments of the present invention are provided below.

[0075] Solid and semi-solid compositions and dosage forms include powders, granules, pellets, beads, minitablets, tablets, or capsules and can be prepared by methods known in the art such as direct compression, wet or dry granulation, and extrusion-spheronization.

[0076] Liquid compositions and dosage forms include solutions, suspensions, or dispersions, which may also be prepared by methods known in the art.

[0077] In one embodiment of the present invention, the composition or dosage form for oral administration is a tablet, or a hard capsule such as a gelatin capsule or an HPMC capsule, or a soft capsule comprising cabozantinib, preferably cabozantinib lauryl sulfate, and one or more pharmaceutically acceptable excipients, preferably in a homogeneous mixture. In some aspects of this embodiment, the pharmaceutically acceptable carrier is solid at ambient temperature, i.e., 25°C, and standard atmospheric pressure, and has a melting point greater than 25°C but less than 100°C, 95°C, 90°C, 85°C, 80°C, 75°C, 70°C, 65°C, 60°C, 55°C, 50°C, 45°C, 40°C, 35°C, or any range of temperatures aforesaid.

[0078] If the carrier is solid or semi-solid at ambient temperature, it may be mixed or granulated with cabozantinib (preferably cabozantinib lauryl sulfate) and, optionally, one or more pharmaceutically acceptable excipients, and then formed into a tablet or filled into or molded into a hard or soft capsule. Alternatively, if the carrier is solid or semi-solid at ambient temperature, it may be heated to melt the carrier and mixed with cabozantinib (preferably cabozantinib lauryl sulfate) and, optionally, one or more pharmaceutically acceptable excipients, and then formed into a tablet or filled into or molded into a hard or soft capsule.

[0079] In one embodiment, cabozantinib, preferably cabozantinib lauryl sulfate, is dispersed or suspended in a liquid carrier or in a molten solid or semi-solid carrier.

[0080] Examples of liquid carriers that can be used 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, and peanut oil, or mixtures thereof. In one embodiment, the liquid carrier comprises about 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, and 95% (w / w) of the composition or any range subsumed therein, preferably about 15% (w / w) to about 90% (w / w) of the composition filled into the capsule, and most preferably about 20% (w / w) to about 85% (w / w) of the composition.

[0081] Examples of solid carriers having a melting point of 25°C to 100°C, preferably 30°C to 90°C, more preferably 35°C to 80°C, and most preferably 40°C to 75°C include aliphatic alcohols, polyethylene glycols such as polyethylene glycol 1000 having a melting point of 37 to 40°C and polyethylene glycol 1500 having a melting point of 44 to 48°C, hard fats (also known as hydrogenated vegetable glycerides), hydrogenated vegetable oils, vitamin E polyethylene glycol succinate (also known as TPGS), poloxamers (nonionic polyoxyethylene-polyoxypropylene copolymers, such as poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), polyoxyglycerides, polyoxyethylene stearate, polyoxyl stearate, and waxes such as carnauba wax, cetyl ester wax, microcrystalline wax, white wax, and yellow wax, as well as combinations of the aforementioned solid carriers. In certain embodiments, the solid support comprises about 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, 50%, 52.5%, 55%, 57.5%, 60%, 62.5%, 65%, 67.5%, 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 92.5%, 95% (w / w) or any range thereof. Preferably, it is about 5% (w / w) to about 90% (w / w) of the composition filled into a capsule or formed into a tablet, and most preferably about 7.5% (w / w) to about 85% (w / w).

[0082] Additional examples of solid, semi-solid, and liquid carriers that may be used in preparing the solid, semi-solid, or liquid dosage forms of the present invention include, but are not limited to, hard HPMC capsules, hard gelatin capsules, soft gelatin capsules, and tablets of the present invention, wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, which exhibit an HLB value of about 10 or greater, an HLB value of about 11 or greater, an HLB value of about 12 or greater, an HLB value of about 13 or greater, or an HLB value of about 14 or greater, as described in detail below.

[0083] In another embodiment of the present invention, the composition or dosage form can comprise cabozantinib, preferably cabozantinib lauryl sulfate, and one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, having an HLB value of about 10 or greater, about 11 or greater, about 12 or greater, about 13 or greater, or about 14 or greater, and optionally at least one additional pharmaceutically acceptable excipient. Cabozantinib, preferably cabozantinib lauryl sulfate, can be present in the composition in an amount of about 1% to about 80% by weight, preferably about 2% to about 70% by weight, more preferably about 2.5% to about 60% by weight, and most preferably about 3% to about 50% by weight, based on the total weight of the composition or dosage form. In some embodiments, cabozantinib, preferably cabozantinib lauryl sulfate, is present in the composition at about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119 It can be present in an amount of 1%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% by weight, or any range subsumed within the aforementioned values. One or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, exhibiting an HLB value of about 10 or greater, about 11 or greater, about 12 or greater, about 13 or greater, or about 14 or greater, should be present in the composition or dosage form in an amount of 1% by weight or greater based on the total weight of the composition or dosage form, preferably in an amount of about 2% by weight or greater based on the total weight of the composition or dosage form, and most preferably in an amount of about 5% by weight or greater based on the total weight of the composition or dosage form.In some embodiments, the one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof exhibiting an HLB value of about 10 or greater, about 11 or greater, about 12 or greater, about 13 or greater, or about 14 or greater are present in the composition or dosage form in an amount of about 10% to about 90% by weight, preferably about 20% to about 80% by weight, and most preferably about 30% to about 70% by weight. In some embodiments, the one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof exhibiting an HLB value of about 10 or greater, about 11 or greater, about 12 or greater, about 13 or greater, or about 14 or greater are present in the composition or dosage form in an amount of about 40% to about 90% by weight, preferably about 45% to about 85% by weight, and most preferably about 50% to about 80% by weight. In some embodiments, one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or greater may be present in the composition in an amount of about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% by weight. Weight%, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 46% by weight, 47% by weight, 48% by weight, 49% by weight, 50% by weight, 51% by weight, 52% by weight, 53% by weight, 54% by weight , 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, 61% by weight, 62% by weight, 63% by weight, 64% by weight, 65% by weight, 66% by weight, 67% by weight, 68 %, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% by weight, or any range subsumed within the foregoing values.

[0084] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of approximately 10 or greater may be non-ionic surfactants, ionic surfactants, or combinations thereof, preferably non-ionic surfactants. Examples of usable nonionic surfactants include polyethoxylated castor oil, polyoxyethylene alkyl esters, polyglycolized glycerides, sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty alcohol polyglycol ethers, acetylenic diols, acetylenic alcohols, oxyalkylene block polymers, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyoxyethylene styrylaryl ethers, polyoxyethylene glycol alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid esters, polyoxylglycerides, polyoxyethylene stearates, polyoxylstearates, vitamin E polyethylene glycol succinate (also known as TPGS), or mixtures thereof. Further lists of usable nonionic surfactants are listed in "Martindale, The Extra Pharmacopoeia," 29th Edition, pages 1243-1249, which is incorporated herein by reference.

[0085] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, each having an HLB value of about 10 or greater, may be nonionic surfactants such as fatty alcohol acid 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 (commercially available under the trade name TWEEN® 20), polysorbate 40 (commercially available under the trade name TWEEN 40), polysorbate 60 (commercially available under the trade name TWEEN 60), and polysorbate 80 (commercially available under the trade name TWEEN 80).

[0086] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of about 10 or greater may be polyoxyethylene castor oils, such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, or mixtures thereof. Examples of these surfactants include, but are not limited to, polyoxyl 35 castor oil (commercially available under the tradenames CREMAPHOR EL or KOLLIPHOREL), polyoxyl 40 hydrogenated castor oil (commercially available under the tradename CREMOPHOR RH40), and polyoxyl 60 hydrogenated castor oil.

[0087] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, each having an HLB value of approximately 10 or greater, may be tyloxapol, poloxamers, i.e., nonionic polyoxyethylene-polyoxypropylene copolymers such as poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407, or combinations thereof. Polyoxyethylene stearate is a nonionic surfactant produced by polyethoxylation of stearic acid. Many commercially available grades are available, differing by the approximate polymer length or molecular weight of the oxyethylene units. Polyoxyethylene stearate may be monostearate, distearate, or a combination of monostearate and distearate. Preferred polyoxyethylene stearates include monostearates such as PEG-150 stearate, PEG-100 stearate, PEG-50 stearate, PEG-40 stearate, PEG-32 stearate, PEG-20 stearate, and PEG-12 stearate.

[0088] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, exhibiting an HLB value of about 10 or greater, may be polyoxyethylene alkyl ethers such as polyoxylcetostearyl ether, polyoxylcetyl ether, polyoxyllauryl ether, polyoxyloleyl ether, polyoxylstearyl ether, or mixtures thereof.

[0089] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, exhibiting an HLB value of about 10 or greater, may be tyloxapol, poloxamers, i.e., non-ionic polyoxyethylene-polyoxypropylene copolymers such as poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, or combinations thereof.

[0090] The one or more humectants, emulsifiers, solubilizers, surfactants, or combinations thereof, having an HLB value of about 10 or greater, may be fatty acid esters of polyglycerides or fatty acid alcohols, such as caprylic / capric triglyceride (commercially available under the trade name MYIGLYOL).

[0091] The one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, having an HLB value of about 10 or greater, may be a vitamin E derivative, such as vitamin E polyethylene glycol succinate (also known as TPGS).

[0092] In one embodiment of the present invention, a composition comprises cabozantinib, preferably cabozantinib lauryl sulfate, and, preferably in the form of a homogeneous mixture, one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, each having an HLB value of about 10 or greater, and optionally further comprising at least one additional secondary carrier having a low or no HLB value. The secondary carrier may be one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof, each having an HLB value of less than about 10, more preferably an HLB value of about 9 or less, about 8 or less, and most preferably an HLB value of about 7 or less. Examples of the at least one additional secondary carrier having a low HLB value include nonionic surfactants. These include, but are not limited to, polyethoxylated castor oil, polyoxyethylene alkyl esters, polyglycolized glycerides, sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty acid alcohol polyglycol ethers, acetylene glycol, acetylene alcohol, oxyalkylene block polymers, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyoxyethylene styrylaryl ethers, polyoxyethylene glycol alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid esters, or mixtures thereof. A further list of nonionic surfactants that may have low HLB values ​​is provided in Martindale, "The Extra Pharmacopoeia," 29th Edition, pp. 1243-1249, which is incorporated herein by reference.

[0093] In one embodiment, the secondary carrier having an HLB value of less than about 10 is a medium chain (i.e., from about 4 to about 20 carbon atoms, preferably from about 6 to about 18 carbon atoms, and most preferably from about 6 to about 14 carbon atoms) mono- or diglyceride, such as glyceryl caprylate / caprate (commercially available under the trade name CAPMUL MCM), glyceryl caprylate (commercially available under the trade name CAPMUL MCM C8), glyceryl caprate (commercially available under the trade name CAPMUL MCM C10), glyceryl monocaprylocaprate (commercially available under the trade name CAPMUL 471), or a mixture thereof.

[0094] In one embodiment, the secondary carrier having an HLB value of less than about 10 is a polyoxylglyceride such as caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, stearoyl polyoxylglyceride, and mixtures thereof.

[0095] In one embodiment, the secondary carrier having an HLB value of less than about 10 is a sorbitan ester or sorbitan fatty acid ester, such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, tyloxapol, and mixtures thereof.

[0096] In certain embodiments, the secondary carrier having an HLB value of less than about 10 is a phospholipid or lecithin.

[0097] In certain embodiments, the secondary carrier is an oil, a medium chain triglyceride, a hydrogenated vegetable oil, a suppository base, or a combination thereof.

[0098] In certain embodiments, a secondary carrier having an HLB of less than about 10 is liquid at ambient temperature or exhibits a melting point of about 75°C or less, about 70°C or less, about 65°C or less, about 60°C or less, about 55°C or less, about 50°C or less, about 45°C or less, or about 40°C or less.

[0099] In embodiments using a secondary carrier having an HLB value of less than about 10, the amount of secondary carrier having an HLB value of less than about 10 may be from about 1% to about 90% by weight, preferably from about 5% to about 85% by weight, and most preferably from about 10% to about 80% by weight, based on the total weight of the composition. In certain embodiments using a secondary carrier having an HLB value of less than about 10, the amount of secondary carrier having an HLB value of less than about 10 may be from about 1% to about 50% by weight, preferably from about 5% to about 45% by weight, and most preferably from about 10% to about 40% by weight, based on the total weight of the composition. The above weight percentages may be based on a single secondary carrier or a combination of multiple secondary carriers. In some embodiments, one or more wetting agents, emulsifiers, solubilizers, surfactants, or combinations thereof having an HLB value of less than about 10 are present in the composition at about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 1 It may be present in an amount of 0%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80% by weight, or any range encompassed by the foregoing values.

[0100] The compositions and dosage forms of the present invention may optionally include additional pharmaceutically acceptable excipients such as stabilizers, fillers, thickeners, binders, disintegrants, glidants, glidants, flavoring agents, and combinations thereof.

[0101] In one embodiment, the dosage form of the present invention is a solid or semi-solid oral dosage form, preferably a capsule or tablet, comprising the following components:

[0102] (i) about 1% to about 60% by weight, preferably about 2% to about 55% by weight, and most preferably about 5% to about 50% by weight of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the solid composition or dosage form; (ii) from about 1% to about 95% by weight, preferably from about 5% to about 90% by weight, and most preferably from about 10% to about 85% by weight of one or more wetting agents, solubilizers, emulsifiers, surfactants, or combinations thereof, having an HLB value of about 10 or greater, an HLB value of about 11 or greater, an HLB value of about 12 or greater, an HLB value of about 13 or greater, or an HLB value of about 14 or greater; and (iii) optionally, at least one additional pharmaceutically acceptable excipient selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, glidants, glidants, flavoring agents, and combinations thereof.

[0103] In one embodiment, the composition of the present invention is a capsule, preferably a hard capsule, and the contents of the capsule comprise: (i) about 1% to about 60% by weight, preferably about 2% to about 55% by weight, and most preferably about 5% to about 50% by weight of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the solid composition or dosage form; (ii) from about 10% to about 95%, preferably from about 15% to about 90%, and more preferably from about 20% to about 85%, by weight of one or more wetting agents, solubilizers, emulsifiers, surfactants, or combinations thereof, having an HLB value of about 10 or greater, about 11 or greater, about 12 or greater, about 13 or greater, or about 14 or greater; (iii) optionally, at least one additional pharmaceutically acceptable excipient selected from stabilizers, fillers, glidants, glidants, and combinations thereof.

[0104] In one embodiment, the composition of the present invention is a capsule, preferably a hard capsule, the contents of which comprise: (i) about 1% to about 60% by weight, preferably about 2% to about 55% by weight, and most preferably about 5% to about 50% by weight of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the solid composition or dosage form; (ii) from about 10% to about 95% by weight, preferably from about 15% to about 90% by weight, and most preferably from about 20% to about 85% by weight of one or more wetting agents, solubilizers, emulsifiers, surfactants, or combinations thereof, having an HLB value of about 10 or greater, an HLB value of about 11 or greater, an HLB value of about 12 or greater, an HLB value of about 13 or greater, or an HLB value of about 14 or greater; (iii) about 1% to about 50% by weight, preferably about 2% to about 45% by weight, and most preferably about 3% to about 40% by weight of a secondary carrier having an HLB value of less than about 10, an HLB value of about 9 or less, an HLB value of about 8 or less, or an HLB value of about 7 or less, the secondary carrier being selected from the group consisting of a wetting agent, a solubilizing agent, an emulsifying agent, a surfactant, or a combination thereof; (iv) optionally, at least one additional pharmaceutically acceptable excipient selected from the group consisting of stabilizers, fillers, glidants, lubricants, and combinations thereof.

[0105] In certain aspects of preferred capsule embodiments, the one or more humectants, solubilizers, emulsifiers, surfactants, or combinations thereof having an HLB value of about 10 or greater are selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene stearate, polyoxyethylene hydrogenated castor oil, poloxamers, tyloxapol, fatty acid esters of polyglycerides or fatty alcohols, vitamin E derivatives such as vitamin E polyethylene glycol succinate, or combinations thereof. Most preferably, they are selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate, poloxamers, caprylic / capric triglyceride, vitamin E polyethylene glycol succinate, or combinations thereof.

[0106] In certain aspects of preferred capsule embodiments, the capsule contents are free or substantially free of polymers, such as binding polymers, viscosity enhancing polymers, disintegration polymers, etc., that have a melting point above 100° C. As used in this context, “free” means 0% by weight or below the detectable limit, and “substantially free” means less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1.5% by weight, less than 1.0% by weight, less than 0.75% by weight, less than 0.5% by weight, less than 0.25% by weight, or less than 0.1% by weight based on the total weight of the capsule contents.

[0107] In one embodiment, the composition of the present invention is a hard capsule, and the contents of the capsule comprise: (i) about 1% to about 60% by weight, preferably about 2% to about 55% by weight, and most preferably about 5% to about 50% by weight of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the capsule contents; (ii) about 10% to about 95% by weight, preferably about 15% to about 90% by weight, and most preferably about 20% to about 85% by weight of one or more humectants, solubilizers, emulsifiers, surfactants, or combinations thereof, each having an HLB value of about 12 to about 16, selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene stearate, polyoxyethylene hydrogenated castor oil, poloxamers, tyloxapol, fatty acid esters of polyglycerides or fatty acid alcohols, vitamin E derivatives such as vitamin E polyethylene glycol succinate, or combinations thereof, preferably selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate, and poloxamers; caprylic / capric triglyceride, vitamin E polyethylene glycol succinate, or combinations thereof; and (iii) optionally, at least one stabilizer, filler, glidant, glidant, and combinations thereof, wherein the cabozantinib, preferably cabozantinib lauryl sulfate, is crystalline, micronized, or non-micronized.

[0108] In one embodiment, the composition of the present invention is a capsule, preferably a hard capsule, and the contents of the capsule comprise: (i) about 5% to about 50% by weight, preferably about 10% to about 45% by weight, and most preferably about 15% to about 40% by weight of a pharmaceutically acceptable salt of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the capsule contents; (ii) about 50% to about 95% by weight, preferably about 55% to about 90% by weight, and most preferably about 60% to about 85% by weight of one or more polyoxyethylene stearates exhibiting an HLB value of about 12 or greater; and (iii) optionally, at least one additional pharmaceutically acceptable excipient selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, glidants, glidants, flavoring agents, and combinations thereof;

[0109] In one embodiment, the composition of the present invention is a capsule, preferably a hard capsule, and the contents of the capsule comprise: (i) about 5% to about 50% by weight, preferably about 10% to about 45% by weight, and most preferably about 15% to about 40% by weight of a pharmaceutically acceptable salt of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the capsule contents; (ii) about 50% to about 95% by weight, preferably about 55% to about 90% by weight, and most preferably about 60% to about 85% by weight, of one or more polyoxyethylene alkyl ethers exhibiting an HLB value of about 12 or greater; and (iii) optionally, at least one additional pharmaceutically acceptable excipient selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, glidants, glidants, flavoring agents, and combinations thereof.

[0110] In one embodiment, the composition of the present invention is a capsule, preferably a hard capsule, and the contents of the capsule comprise: (i) about 5% to about 50% by weight, preferably about 10% to about 45% by weight, and most preferably about 15% to about 40% by weight of a pharmaceutically acceptable salt of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the capsule contents; (ii) about 50% to about 95% by weight, preferably about 55% to about 90% by weight, and most preferably about 60% to about 85% by weight, of one or more polyoxyethylene-polyoxypropylene copolymers exhibiting an HLB value of about 12 or greater; and (iii) optionally, at least one additional pharmaceutically acceptable excipient selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, glidants, glidants, flavoring agents, and combinations thereof.

[0111] In one embodiment, the composition of the present invention is a capsule, preferably a hard capsule, and the contents of the capsule comprise:

[0112] (i) about 5% to about 50% by weight, preferably about 10% to about 45% by weight, and most preferably about 15% to about 40% by weight of a pharmaceutically acceptable salt of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the capsule contents; (ii) about 50% to about 95% by weight, preferably about 55% to about 90% by weight, and most preferably about 60% to about 85% by weight, of one or more polyglyceride fatty acid esters exhibiting an HLB value of about 12 or greater; and (iii) optionally, at least one additional pharmaceutically acceptable excipient selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, glidants, glidants, flavoring agents, and combinations thereof.

[0113] In one embodiment, the composition of the present invention is a capsule, preferably a hard capsule, and the contents of the capsule comprise: (i) about 5% to about 50% by weight, preferably about 10% to about 45% by weight, and most preferably about 15% to about 40% by weight of a pharmaceutically acceptable salt of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the capsule contents; (ii) about 50% to about 95% by weight, preferably about 55% to about 90% by weight, and most preferably about 60% to about 85% by weight, of one or more polyglyceride fatty acid alcohols exhibiting an HLB value of about 12 or greater; and (iii) optionally, at least one additional pharmaceutically acceptable excipient selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, glidants, glidants, flavoring agents, and combinations thereof.

[0114] In one embodiment, the composition of the present invention is a capsule, preferably a hard capsule, and the contents of the capsule comprise: (i) about 5% to about 50% by weight, preferably about 10% to about 45% by weight, and most preferably about 15% to about 40% by weight of a pharmaceutically acceptable salt of cabozantinib, preferably cabozantinib lauryl sulfate, based on the total weight of the capsule contents; (ii) about 50% to about 95% by weight, preferably about 55% to about 90% by weight, and most preferably about 60% to about 85% by weight, of one or more vitamin E derivatives exhibiting an HLB value of about 12 or greater; and (iii) optionally, at least one additional pharmaceutically acceptable excipient selected from the group consisting of stabilizers, fillers, thickeners, binders, disintegrants, glidants, glidants, flavoring agents, and combinations thereof.

[0115] Examples of stabilizers that can be used in the present invention include, but are not limited to, antioxidants, desiccants, buffers, pH adjusters, or combinations thereof. When stabilizers are present in the dosage form, the stabilizer should be less than about 20% of the total weight of the composition, preferably less than about 15% of the total weight of the composition, and most preferably less than about 10% of the total weight of the composition. In some embodiments, the stabilizer is present in the composition in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, or 3.2% by weight. %, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, 4.0 wt%, 4.1 wt%, 4.2 wt%, 4.3 wt%, 4.4 wt%, 4.5 wt%, 4.6 wt%, 4.7 wt%, 4.8 wt%, 4.9 wt%, 5.0 wt%, or any range subsumed by the foregoing values.

[0116] Examples of antioxidants that can be used in the present invention include, but are not limited to, ascorbic acid, ascorbyl palmitate (AP), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, ethyl oleate, fumaric acid, hypophosphorous acid, malic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, tocopherol, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl benzoate, pyridoxine, ethyl vanillin, and mixtures thereof. Preferred antioxidants for use in the present invention include BHT, BHA, AP, propyl gallate, α-tocopherol, or mixtures thereof. Generally, the amount of antioxidant, if present, in the compositions of the present invention is from about 0.0001% to about 5% by weight, preferably from about 0.01% to about 2% by weight, and most preferably from about 0.05% to about 1% by weight, based on the total weight of the composition.

[0117] Unless otherwise defined, the term "desiccant" as used herein refers to a pharmaceutically acceptable excipient capable of binding or absorbing moisture present in a composition. Examples of desiccants useful in the present invention include magnesium oxide (MgO), aluminum oxide, attapulgite, bentonite, kaolin, pectin, saponite, colloidal silicon dioxide, and mixtures thereof. Depending on the specific formulation, thickeners, as described below, can also be used as desiccants. When present in a composition of the present invention, the amount of desiccant may range from about 0.05% to about 10% by weight of the total composition, preferably from about 0.1% to about 5% by weight of the total composition, and most preferably from about 0.5% to about 2.5% by weight of the total composition.

[0118] 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. Typically, buffers include combinations of the foregoing to form buffer systems, such as citric acid and sodium citrate, or acetic acid and sodium acetate.

[0119] The example of pH adjusting agent that can be used in the present invention includes, but is not limited to, the pharmaceutically acceptable acid or base that is used to adjust the pH of pharmaceutical compositions.The example of the compound that is typically used to adjust the pH of pharmaceutical compositions includes hydrochloric acid, citric acid, lactic acid, tartaric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, arginine, lysine, meglumine, triethanolamine, or combinations thereof.

[0120] Buffers and / or pH adjusters, when used, may comprise from about 0.01% to about 20% by weight of the composition, preferably from about 0.1% to about 10% by weight of the composition, and most preferably from about 0.5% to about 5% by weight of the composition.

[0121] Fillers, sometimes referred to as diluents, may 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 compositions of the present invention is from about 0% to about 90% by weight, preferably from about 0.01% to about 80% by weight, and most preferably from about 1% to about 70% by weight, based on the total weight of the composition.

[0122] Thickeners that can be used in the present invention include organic materials such as natural or synthetic waxes, C 12 -C 60 Alcohol, C 12 -C 60These include inorganic and organic materials such as acids, α-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and metal ester complexes containing zinc, calcium, aluminum, or magnesium, fumed silica, and organoclays. Other thickening agents include polyol polyesters, glyceryl esters, polyglyceryl esters, and polysiloxanes.

[0123] 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, ozokerite, beeswax, candelilla, paraffin, ceresin, esparto, ouricle, rezowax, and other known mined and mineral waxes. Synthetic waxes may include, but are not limited to, paraffin wax and microcrystalline wax.

[0124] A thickening agent that can be further included in the composition of the present invention is a gelling agent. A gelling agent is a substance that has the property of expanding or swelling upon contact with water. Examples of gelling agents that can be used in the present invention include swellable polymers, also known as osmopolymers or hydrogels (hydrophilic gels). Swellable polymers may be uncrosslinked or lightly crosslinked. The crosslinks are covalent or ionic bonds, and the polymer has the ability to swell in liquid, but when crosslinked, it does not dissolve in liquid. The polymer may be of plant, animal, or synthetic origin. Examples of polymeric gelling agents useful in the present invention include polyhydroxyalkylcelluloses having a molecular weight greater than 50,000 (e.g., hydroxypropylmethylcellulose available commercially as METHOCEL K 100M from Dow Chemical), poly(hydroxyalkyl methacrylates) having a molecular weight of 5,000 to 5,000,000, poly(vinylpyrrolidone) having a molecular weight of 100,000 to 3,000,000, anionic and cationic hydrogels, poly(electrolyte) complexes, poly(vinyl alcohol) having low residual acetate, swellable mixtures of agar and carboxymethylcellulose, swellable mixtures of lightly crosslinked agar and methylcellulose, polyethers having a molecular weight of 10,000 to 6,000,000, water-swellable copolymers prepared from finely dispersed copolymers of maleic anhydride and styrene, ethylene, propylene, or isobutylene, and water-swellable polymers of N-vinyl lactams.

[0125] Other gelling agents useful in the present invention include pectin having a molecular weight of 30,000 to 300,000; polysaccharides such as agar, acacia, karaya, tragacanth, alginates, and guar; the acrylic acid polymer CARBOPOL® (carboxyvinyl polymer, often called carboxpolymethylene), i.e., a polymer of acrylic acid crosslinked with a polyallyl ether of sucrose, as described in U.S. Pat. Nos. 2,798,053 and 2,909,462 and commercially available as CARBOPOL 934, 940, 941, and salt derivatives thereof; polyacrylamide; water-swellable indene-maleic anhydride copolymers; Glycerides having a molecular weight of 80,000 to 200,000; Examples of suitable gelling agents include OOD-RITE (registered trademark: polyacrylic acid; POLYOX® polyethylene oxide polymers having a molecular weight of 100,000 to 7,000,000; starch graft copolymers; AQUA-KEEP®, which has a water absorption capacity of approximately 400 times its original weight; acrylate polymers; diesters of polyglucan; mixtures of cross-linked polyvinyl alcohol and poly(N-vinyl-2-pyrrolidone); and polyethylene glycols having a molecular weight of 4,000 to 100,000. Representative polymers having gelling properties are described in U.S. Pat. Nos. 6,419,954, 4,915,949, 4,327,725, and 4,207,893, and in Scott and Roff, "Handbook of Common Polymers," Cleveland Rubber Company, Cleveland, Ohio.

[0126] Generally, the amount of thickener contained in the composition of the present invention is about 0% to about 30% by weight, preferably about 0.01% to about 25% by weight, and most preferably about 1% to about 15% by weight, based on the weight of the total composition. In certain embodiments, the content of thickener is about 5% to about 60% by weight, preferably about 10% to about 55% by weight, and most preferably about 15% to about 50% by weight, based on the weight of the total composition. The semi-solid formulation of the present invention may contain a thickener that is solid at room temperature but has a melting point of less than 120°C, preferably less than 100°C, more preferably less than 80°C, and most preferably less than 60°C. These thickeners account for about 7.5% to about 75% by weight, preferably about 10% to about 60% by weight, and most preferably about 12% to about 50% by weight, based on the weight of the total composition. Examples of these thickeners include natural or synthetic waxes (carnauba wax, cetyl ester wax, microcrystalline wax, white wax, yellow wax, beeswax, ozokerite, paraffin, ceresin, esparto, ouricle wax, rezowax, etc.), hard fats (also known as hydrogenated vegetable glycerides), hydrogenated vegetable oils, C 12 -C 60 Alcohol, C 12 -C 60 These include, but are not limited to, fatty acids, alpha-hydroxy fatty acids, polyhydroxy fatty acid esters, polyhydroxy fatty acid amides, and combinations thereof.

[0127] Examples of binders used in the solid formulations of the present invention include acacia, povidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polymethacrylate, methylcellulose, ethylcellulose, pretreated starch, gelatin, tragacanth, zein, or mixtures thereof. Preferably, the binder is selected from povidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polymethacrylate, methylcellulose, gelatin, ethylcellulose, or mixtures thereof. Particularly preferred binders include water-soluble binders such as povidone, hypromellose, hydroxypropyl cellulose, gelatin, and mixtures thereof. When the binder is a polymeric binder, it is desirable to use one with a low molecular weight or one that exhibits a viscosity of less than 200 mPa·s, preferably less than 100 mPa·s, and most preferably less than 50 mPa·s, when measured as a 2% (w / v) aqueous solution at 20°C.

[0128] Generally, the amount of binder contained in the composition of the present invention is about 0% to about 30% by weight, preferably about 0.01% to about 25% by weight, and most preferably about 1% to about 15% by weight, based on the weight of the total composition.

[0129] Examples of disintegrants that can be used in the solid formulations of the present invention include croscarmellose sodium, starch, crospovidone, sodium carboxymethyl starch, 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 contained in the dosage form of the present invention accounts for about 0% to about 40% by weight, preferably about 1% to about 25% by weight, and most preferably about 2% to about 20% by weight, based on the weight of the total composition.

[0130] Examples of lubricants that can be used in the oral solid formulation of the present invention include magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, polyethylene glycol (preferably polyethylene glycol with a molecular weight of 6000 or more), polyoxyethylene stearate, magnesium lauryl sulfate, sodium oleate, and mixtures thereof. The lubricant can be contained in an amount ranging from about 0.1% to about 10% by weight, preferably from about 0.2% to about 7% by weight, and more preferably from about 0.5% to about 5% by weight, based on the weight of the entire formulation.

[0131] Examples of lubricants that can be used in the solid dosage form of the present invention include colloidal silicon dioxide, cornstarch, talc, and mixtures thereof. The amount of lubricant to be added ranges from about 0.1% to about 10% by weight, preferably from about 0.2% to about 7% by weight, and more preferably from about 0.5% to about 5% by weight, based on the total weight of the dosage form.

[0132] 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, as well as citric acid, peppermint oil, wintergreen oil, menthol, lemon, lime, orange, grape, cherry, and vanilla extract, etc. Additional taste enhancers are described in U.S. Patent No. 6,027,746, which is incorporated herein by reference.

[0133] In one embodiment of the present invention, the dissolution rate of the oral dosage form is as follows when tested using a USP Type II apparatus (paddle) in 500 mL to 900 mL of 0.01 N hydrochloric acid at a stirring speed of 50 to 75 rpm, with or without a sinker, with or without a surfactant, at 37°C:

[0134] [Table 8]

[0135] In one embodiment of the present invention, the dissolution rate of the oral dosage form is as follows when tested using a USP Type II apparatus (paddle) in 500 ml to 900 ml of 0.01 N hydrochloric acid containing 0.02% to 0.5% surfactant, using a sinker, at 50 to 75 rpm, and at 37°C:

[0136] [Table 9]

[0137] In one embodiment of the present invention, the dissolution rate of the oral dosage form is as follows when tested using a USP Type II apparatus (paddles) with 500 ml to 900 ml of 0.01 N hydrochloric acid containing 0.02% to 0.5% surfactant, a stationary basket, at 50 to 75 rpm, and at 37°C:

[0138] [Table 10]

[0139] In one embodiment of the invention, the dissolution rate of the oral dosage form, when tested using a USP Type II apparatus (paddles) at 500 ml to 900 ml of pH 4.5 acetate buffer at 50-75 rpm, with or without a sinker, with or without a surfactant, at 37°C, is as follows:

[0140] [Table 11]

[0141] In one embodiment of the present invention, the dissolution rate of the oral dosage form is as follows when tested using a USP Type II apparatus (paddle) in 500 ml to 900 ml of acetate buffer at pH 4.5 containing 0.02% to 0.5% surfactant, with a sinker at 50 to 75 rpm and at 37°C:

[0142] [Table 12]

[0143] In one embodiment of the present invention, the dissolution rate of the oral dosage form, when tested using a USP Type II apparatus (paddles) with 500 ml to 900 ml of pH 4.5 acetate buffer containing 0.2% to 0.5% surfactant, with a stationary basket at a rotation speed of 50-75 rpm and at 37°C, is as follows:

[0144] [Table 13]

[0145] The compositions and dosage forms of the present invention are stable when prepared and stored under normal and accelerated conditions. More specifically, the dosage forms of the present invention are characterized by having an individual degradant content of about 1.0% or less, preferably about 0.75% or less, and most preferably about 0.5% or less. This is confirmed when the dosage form is stored in a sealed container (preferably a sealed plastic container such as a high-density polyethylene bottle, with or without a desiccant) under the following conditions: at about 25°C and about 60% relative humidity for at least 3 months (preferably at least 6 months, most preferably at least 1 year), and / or at about 40°C and about 75% relative humidity for 1 month, 2 months, or 3 months.

[0146] The compositions and dosage forms of the present invention desirably contain less than about 2.0%, preferably less than about 1.5%, and most preferably less than about 1.0% total degradants, which is achieved when the dosage form is stored in a sealed container (preferably a sealed plastic container such as a high-density polyethylene bottle, with or without a desiccant) under the following storage conditions: at about 25° C. and about 60% relative humidity for at least 3 months (preferably at least 6 months, most preferably at least 1 year), and / or at about 40° C. and about 75% relative humidity for 1 month, 2 months, or 3 months.

[0147] The cabozantinib (preferably cabozantinib lauryl sulfate) used in the compositions and dosage forms of the present invention can exist in amorphous, crystalline, or a mixture of amorphous and crystalline forms. In some embodiments, the cabozantinib (preferably cabozantinib lauryl sulfate) is substantially crystalline, i.e., greater than 50%, 60%, 70%, 80%, 90%, or 100%. The cabozantinib (preferably cabozantinib lauryl sulfate) incorporated into the compositions and dosage forms of the present invention may or may not be micronized. In some embodiments, the cabozantinib (preferably cabozantinib lauryl sulfate) may have a particle size D90 of less than 100 μm, preferably less than 90 μm, and more preferably less than 85 μm. In yet another embodiment, the particle size D50 may be less than 75 μm, preferably less than 65 μm, more preferably less than 55 μm, and / or the particle size D10 may be less than 40 μm, preferably less than 35 μm, more preferably less than 25 μm.

[0148] In one embodiment, the crystalline cabozantinib lauryl sulfate used in the present invention is crystalline cabozantinib monolauryl sulfate, which exhibits any one or more (two, three, four, or more) of the following 2θ peaks in X-ray powder diffraction (XRPD) analysis: 5.0±0.2, 11.3±0.2, 12.1±0.2, 13.5±0.2, 16.8±0.2, 17.5±0.2, 18.6±0.2, 20.2±0.2, 20.6±0.2, 21.3±0.2, 21.9±0.2, 22.4±0.2, 22.7±0.2, 23.2±0.2, 24.2±0.2, 26.6±0.2, and / or 27.7±0.2.

[0149] The amount of cabozantinib, preferably cabozantinib lauryl sulfate, present in the dosage form of the present invention is about 5 mg to about 120 mg, about 5 mg to about 100 mg, about 5 mg to about 80 mg, about 7.5 mg to about 100 mg, about 7.5 mg to about 80 mg, about 7.5 mg to about 70 mg, about 10 mg to about 50 mg, about 10 mg to about 60 mg, about 10 mg to about 80 mg, about 12 mg to about 60 mg, about 12 mg to about 50 mg, about 12 mg to about 50 mg, or about 12 mg to about 45 mg. Cabozantinib is present in the form of a cabozantinib base, preferably in the form of a cabozantinib salt, more preferably in the form of cabozantinib lauryl sulfate.

[0150] The present invention includes methods of treating various cancers, including, but not limited to, renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid carcinoma. In one embodiment: (i) Oral administration can be given with or without food, and oral administration exhibits substantially similar, equivalent, or constant pharmacokinetic values ​​or no food effect as detailed below. (ii) oral administration may allow for a reduced total daily dose of cabozantinib compared to the currently U.S. FDA-approved CABOMETYX tablets and / or COMETRIQ capsules while maintaining similar pharmacokinetics as described in detail below. (iii) Also, by oral administration, it has a C similar or equivalent to that of the oral cabozantinib composition of the present invention. max and AUC, a reduction in the occurrence or severity of one or more of the adverse events listed in the table below when compared to marketed CABOMETYX tablets and / or COMETRIQ capsules with an amount of cabozantinib (S)-malate that provides similar or equivalent overall bioavailability.

[0151] [Table 14]

[0152] (iv) demonstrate a significant improvement in at least one pharmacokinetic parameter (C) compared to the marketed CABOMETYX tablets and / or COMETRIQ capsules upon oral administration to human subjects; max , AUC 0-t , and AU C0-infinity ) indicates low inter-subject variability. (v) Oral administration refers to a combination of (i), (ii), (iii), and / or (iv).

[0153] In certain embodiments, the present invention includes methods for treating the above-identified cancers, comprising orally administering one or more dosage forms described herein containing about 5 mg to about 100 mg, preferably about 7.5 mg to about 80 mg, and more preferably about 10 mg to about 50 mg of cabozantinib base in the form of cabozantinib sulfate. In these embodiments: (i) Oral administration can be given with or without food, and oral administration exhibits substantially similar, equivalent, or consistent pharmacokinetic values ​​or no food effect as detailed below. (ii) oral administration may allow for a lower total daily dose of cabozantinib compared to the currently U.S. FDA-approved CABOMETYX tablets and / or COMETRIQ capsules while maintaining similar pharmacokinetics, as described in more detail below. (iii) reduce the incidence and / or severity of diarrhea compared to currently U.S. FDA-approved CABOMETYX tablets and / or COMETRIQ capsules when administered orally; or (iv) Oral administration refers to a combination of (i), (ii), and / or (iii).

[0154] The compositions and dosage forms of the present invention can be administered to subjects in either a fed or fasted state, with administration under either condition resulting in substantially similar, comparable, or consistent pharmacokinetic values ​​or characterized by the absence of a food effect. A fed state is generally defined as a state in which food is consumed within about 30 minutes of administration of the composition or dosage form. This food may be a high-fat, low-fat, high-calorie, or low-calorie meal. A fasted state may be defined as a state in which no food is consumed for up to 10 hours before administration of the composition or dosage form. In certain embodiments, subjects are required to fast for at least 10 hours prior to administration and to abstain from food for about 30 minutes to 2 hours (preferably about 1 hour) after administration. In other embodiments, fasting subjects include those who have abstained from food for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours prior to each administration.

[0155] The method of orally administering the compositions and / or dosage forms of the present invention to a patient or healthy subject is one in which the administration of the composition provides substantially similar, equivalent, or constant T max , C max and AUC. Substantially similar, equivalent, or constant pharmacokinetic values ​​mean that the pharmacokinetic values ​​measured after administration of a single dose or multiple doses of a composition or dosage form to a patient or healthy subject under fasted conditions as defined in U.S. FDA (U.S. Food and Drug Administration) guidance documents vary by no more than 40%, preferably no more than 30%, and most preferably no more than 20% from the values ​​when the same composition is administered to the same patient or healthy subject under fed conditions as defined in U.S. FDA guidance documents. For example, a patient may be administered a single dose under fasted conditions and the T max was 3 hours, T ranged from 1.8 hours to 4.2 hours. max is considered to be substantially constant, i.e., ±40% over 3 hours.

[0156] In a preferred embodiment of the present invention, a single oral dose of a composition or dosage form prepared according to the present invention is bioequivalent with or without food, or is confirmed to be unaffected by food. The terms "bioequivalence" and "unaffected by food" are used in accordance with U.S. FDA guidance documents. In one embodiment of the present invention, a single oral dose of a composition or dosage form prepared according to the present invention is bioequivalent to the C of cabozantinib administered with food. max and C of cabozantinib administered in the fasting state. max The ratio (C max摂取 / C max絶食 ) is about 0.60 to about 2.5, preferably about 0.70 to about 2.0, more preferably about 0.75 to about 1.5, and most preferably about 0.8 to about 1.25. In one embodiment of the present invention, a single oral administration of a composition or dosage form prepared according to the present invention reduces the cabozantinib AUC of the pharmaceutical composition administered with food. 0ーt Cabozantinib AUC of the pharmaceutical composition administered with and without food 0-t Ratio of feeding AUC 0-t / Fasting AUC 0-t ) is about 0.60 to about 2.5, preferably about 0.70 to about 2.0, more preferably about 0.75 to about 1.5, and most preferably about 0.8 to about 1.25. Similarly, in certain embodiments of the present invention, a single oral administration of a composition or dosage form prepared according to the present invention reduces the cabozantinib AUC of the pharmaceutical composition administered with food. 0-infinity and cabozantinib AUC of the pharmaceutical composition administered without food 0ーinfinity Ratio of (AUC 0-infinity摂食 / AUC 0-infinity絶食 ) is about 0.60 to about 2.5, preferably about 0.70 to about 2.0, more preferably about 0.75 to about 1.5, and most preferably about 0.8 to about 1.25.

[0157] Oral administration of the compositions or dosage forms of the present invention results in a cabozantinib plasma profile in which at least one pharmacokinetic parameter changes by less than about 40% under fed and fasted conditions. In various embodiments, the difference in pharmacokinetic parameters may be less than about 35%, 30%, 25%, 20%, 15%, 10%, or 5% under fed and fasted conditions. Pharmacokinetic parameters that are independent of food include C max ,AUC,T max or combinations thereof.

[0158] Certain embodiments of the invention include methods of treating cancer in a human patient, comprising orally administering to the patient one or more of the dosage forms described herein, wherein the administration is with or without food, and the dose of cabozantinib lauryl sulfate does not require a dose adjustment or alteration of the administration time.

[0159] In certain embodiments, administration of a composition or dosage form prepared in accordance with the present invention can achieve therapeutically equivalent blood levels of cabozantinib at reduced doses of cabozantinib base currently approved by the U.S. FDA for CABOMETYX tablets and / or COMETRIQ capsules. More specifically, the compositions of the present invention can maintain therapeutically equivalent blood levels (therapeutic range) at a daily dose of cabozantinib free base that is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

[0160] In certain embodiments of the invention, the dose reduction is a C of at least about 7.0 ng / mL / mg, at least about 7.5 ng / mL / mg, at least about 8.0 ng / mL / mg, at least about 8.5 ng / mL / mg, at least about 9.0 ng / mL / mg, at least about 9.5 ng / mL / mg, at least about 10.0 ng / mL / mg, at least about 10.5 ng / mL / mg, at least about 11 ng / mL / mg, at least about 11.5 ng / mL / mg, or at least about 12 ng / mL / mg of administered cabozantinib free base.max In one embodiment, C max may range from at least about 7.0 ng / mL / mg to about 25 ng / mL / mg of administered cabozantinib free base, preferably from at least about 7.5 ng / mL / mg to about 20 ng / mL / mg, and more preferably from at least about 8.0 ng / mL / mg to about 15 ng / mL / mg. These values ​​are based on a single dose administered to healthy adult humans and adult cancer patients under fasting conditions.

[0161] In one embodiment of the invention, the dose reduction is determined by the AUC 0-infinity or about 550 ng hr / mL / mg, about 575 ng hr / mL / mg, about 600 ng hr / mL / mg, about 625 ng hr / mL / mg, about 650 ng hr / mL / mg, or about 675 ng hr / mL / mg. In certain embodiments, the AUCO-infinity is in the range of at least about 550 ng hr / mL / mg to about 1200 ng hr / mL / mg, preferably at least about 575 ng hr / mL / mg to about 1000 ng hr / mL / mg, and more preferably at least about 600 ng hr / mL / mg to about 800 ng hr / mL / mg, based on the administered cabozantinib free base. The above values ​​are based on single-dose administration to adult healthy humans or adult cancer patients under fasting conditions.

[0162] The present invention also includes a method for preparing cabozantinib that can be used in the formulations of the present invention, the method comprising the steps of:

[0163] (a) reacting 4-halo-6,7-dimethoxyquinoline with p-aminophenol to produce 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline; (b) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with 1,1-cyclopropanedicarboxylic acid to produce 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid; and (c) reacting 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid with 4-fluoroaniline to produce crude cabozantinib free base.

[0164] The present invention also includes a method for preparing cabozantinib lauryl sulfate that can be used in the dosage forms of the present invention, the method comprising the steps of:

[0165] (a) reacting 4-halo-6,7-dimethoxyquinoline with p-aminophenol to produce 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline; (b) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with 1,1-cyclopropanedicarboxylic acid to produce 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid; (c) reacting 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid with 4-fluoroaniline to produce crude cabozantinib free base; and (d) reacting the crude cabozantinib free base with lauryl sulfate to form cabozantinib lauryl sulfate.

[0166] The above process can be carried out using a variety of solvents familiar to those skilled in the art and are illustrated in the examples below.

[0167] The resulting cabozantinib lauryl sulfate is preferably crystalline, pure, and stable. As used herein, "pure" means that cabozantinib lauryl sulfate has less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of each individual impurity, including but not limited to, the individual impurities identified in Example 25 herein, on a basis of less than 2%, less than 1.5%, or less than 1% of total impurities. As used herein, "stable" means that cabozantinib lauryl sulfate exhibits the aforementioned purity after storage in a sealed plastic container at room temperature with or without a desiccant for at least 6 months, 12 months, 18 months, or 24 months or more, or after storage at 40°C and 75% relative humidity with or without a desiccant for at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more.

[0168] In one embodiment, cabozantinib or a salt thereof, preferably cabozantinib lauryl sulfate, is stable and contains the following amounts of compounds:

[0169] (a) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N,N'-bis(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide); (b) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide); (c) Less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of N-(4-fluorophenyl)-N-(4-((6-hydroxy-7-methoxyquinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide. (d) Less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarboxamide). (e) Any combination of the above ingredients.

[0170] In one embodiment, cabozantinib or a salt thereof, preferably cabozantinib lauryl sulfate, is stable and contains the following amounts of compounds:

[0171] (a) Less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm of (4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline); (b) Less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm of (6,7-dimethoxy-4-(4-nitrophenoxy)quinolone) (c) Less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm (3,4-dimethoxyaniline) (d) (4-aminophenol) less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm (e) Less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm (4-fluoroaniline) (f) Any combination of the above ingredients.

[0172] (Example) The following are presented as examples only and are in no way limiting.

[0173] (Comparative Example 1) Cabozantinib (S)-malate tablets were prepared as follows: (i) 2.028 g of cabozantinib (S)-malate was passed through a 60-mesh sieve and mixed with 2.486 g of microcrystalline cellulose PH102, 1.243 g of anhydrous lactose, and 0.192 g of croscarmellose sodium (Part I) that had been passed through a 40-mesh sieve. (ii) The mixture from step (i) and a granulation solution prepared by dissolving 0.192 g of hydroxypropyl cellulose EXF in 1.28 g of purified water were used to wet granulate the mixture. (iii) The wet granules were passed through a 20-mesh sieve and dried in an oven at 60°C to evaporate the purified water, and the dried granules were passed through a 24-mesh sieve. (iv) The dried and sieved granules were mixed with 0.192 g of croscarmellose sodium (Part II) and 0.019 g of colloidal silicon dioxide. (v) 0.048 g of magnesium stearate was added to the mixture of step (iv) and mixed well to obtain the final mixture. (vi) The final mixture was compressed into tablets using 6 mm diameter round punches with a target hardness of approximately 4 Kp.

[0174] The composition of the tablets is as follows:

[0175] [Table 15]

[0176] Cabozantinib (S)-malate tablets were tested using a USP Type II (paddle) apparatus under the following conditions:

[0177] Conditions: 0.01 N HCl containing 0.5% TRITON® X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0178] Avg.: Average RSD: relative standard deviation N / A: Not measured

[0179] [Table 16]

[0180] TRITON X-100 is a commercially available nonionic surfactant, also known as 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol; octylphenol ethoxylate; t-octylphenoxypolyethoxyethanol; polyethylene glycol tert-octylphenyl ether.

[0181] Conditions: Acetate buffer (ABS) pH 4.5 containing 0.025% TRITON X-100, 90 mL, paddle with sinker, 75 rpm, 37°C

[0182] [Table 17]

[0183] Conditions: ABS containing 0.2% TRITON X-100, pH 4.5, 900 mL, paddle with sinker, 75 rpm, 37°C

[0184] [Table 18]

[0185] Conditions: pH 6.8 phosphate buffer solution (PBS), 900 mL, paddle with sinker, 75 rpm, 37°C

[0186] [Table 19]

[0187] Conditions: 900 mL PBS, pH 6.8, containing 0.025% TRITON X-100, paddle with sinker, 75 rpm, 37°C

[0188] [Table 20]

[0189] Conditions: 900 mL of PBS containing 0.2% TRITON X-100, pH 6.8, paddle with sinker, 75 rpm, 37°C

[0190] [Table 21]

[0191] Example 1 Butylated hydroxytoluene (BHT) was dissolved in glyceryl monocaprylate (CAPMUL® MCM C8) and polyoxyl 40 stearate (SP MYRJ S40 MBAL-PA-(SG)) was added to obtain a homogeneous solution using a hot water bath at 55 ± 5°C. Cabozantinib monolauryl sulfate (unmicronized) was added to this solution to obtain a homogeneous dispersion or solidify into a semisolid. Cabozantinib capsules were prepared by filling size 3 hypromellose capsules (HPMC capsules, Vcaps Plus) with the semisolid suspension containing 20 mg of cabozantinib free base.

[0192] The capsules have the following composition:

[0193] [Table 22]

[0194] The HLB value of glyceryl monocaprylate (CAPMUL® MCM C8) is reported to be between 3.7 and 5.8.

[0195] The HLB value of polyoxyl 40 stearate (SP MYRJ S40 MBAL-PA-(SG)) has been reported to be 16.5-17.5.

[0196] Cabozantinib capsules were tested using a USP Type II (paddle) testing apparatus under the following conditions:

[0197] Conditions: 0.5% TRITON X-100, 0.01 N HCl, 900 mL, paddle with sinker, 75 rpm, 37°C

[0198] [Table 23]

[0199] Conditions: ABS containing 0.025% TRITON X-100, pH 4.5, 900 mL, paddle with sinker, 75 rpm, 37°C

[0200] [Table 24]

[0201] Conditions: ABS containing 0.2% TRITON X-100, pH 4.5, 900 mL, paddle with sinker, 75 rpm, 37°C

[0202] [Table 25]

[0203] Conditions: PBS pH 6.8, 900 mL, paddle with sinker, 75 rpm, 37°C

[0204] [Table 26]

[0205] Conditions: 900 mL of PBS containing 0.025% TRITON X-100, pH 6.8, paddle with sinker, 75 rpm, 37°C

[0206] [Table 27]

[0207] Conditions: 900 mL of PBS containing 0.2% TRITON X-100, pH 6.8, paddle with sinker, 75 rpm, 37°C

[0208] [Table 28]

[0209] Example 2 Butylated hydroxytoluene (BHT) was dissolved in glyceryl monocaprylate (CAPMUL® MCM C8) and polyoxyl 40 stearate (SP MYRJ S40 MBAL-PA-(SG)) was added to obtain a homogeneous solution using a hot water bath at 55 ± 5°C. Cabozantinib free base (non-micronized) was added to this solution to obtain a homogeneous dispersion or solidify into a semisolid. Cabozantinib capsules were prepared by filling size 3 HPMC capsules with the semisolid suspension containing 20 mg of cabozantinib free base.

[0210] The capsule contents are as follows:

[0211] [Table 29]

[0212] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0213] Conditions: 0.01 N HCl containing 0.5% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0214] [Table 30]

[0215] Conditions: ABS, pH 4.5, containing 0.025% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0216] [Table 31]

[0217] Conditions: ABS containing 0.2% TRITO X-100, pH 4.5, 900 mL, paddle with sinker, 75 rpm, 37°C

[0218] [Table 32]

[0219] Conditions: pH 6.8 BS, 900 mL, paddle with sinker, 75 rpm, 37°C

[0220] [Table 33]

[0221] Conditions: 900 mL PBS, pH 6.8, containing 0.025% TRITON X-100, paddle with sinker, 75 rpm, 37°C

[0222] [Table 34]

[0223] Conditions: 900 mL of PBS containing 0.2% TRITON X-100, pH 6.8, paddle with sinker, 75 rpm, 37°C

[0224] [Table 35]

[0225] Example 3 Butylated hydroxytoluene (BHT) was dissolved in glyceryl monocaprylate (CAPMUL® MCM C8) and polyethylene glycol monostearate was added to obtain a homogeneous solution using a hot water bath at 55 ± 5°C. To this solution, micronized cabozantinib monolauryl sulfate was added to obtain a homogeneous dispersion or allowed to solidify into a semisolid. Cabozantinib capsules were prepared by filling size 3 HPMC capsules with the semisolid suspension containing 20 mg of cabozantinib free base.

[0226] The composition of the capsule contents is as follows:

[0227] [Table 36]

[0228] Polyethylene glycol monostearate is sold under the trade name GELUCIRE® 48 / 16 and has a reported HLB value of 12.

[0229] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0230] Conditions: 0.01 N HCl containing 0.5% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0231] [Table 37]

[0232] Conditions: ABS containing 0.2% TRITON X-100, pH 4.5, 900 mL, paddle with sinker, 75 rpm, 37°C

[0233] [Table 38]

[0234] Example 4 Butylated hydroxytoluene (BHT) was dissolved in caprylocaproyl polyoxylglyceride, stearoyl polyoxylglyceride was added, and a homogeneous solution was obtained using a hot water bath at 55 ± 5°C. Micronized cabozantinib monolauryl sulfate was added to this solution to obtain a homogeneous dispersion or solidify into a semisolid. Cabozantinib capsules were prepared by filling size 3 HPMC capsules with the semisolid suspension containing 20 mg of cabozantinib free base.

[0235] The composition of the capsule contents is as follows:

[0236] [Table 39]

[0237] Caprylocaproyl polyoxylglyceride is sold under the trade name LABRASOL® and has a reported HLB value of 12.

[0238] Stearoyl polyoxylglyceride is sold under the trade name GELUCIRE® 50 / 13 and has a reported HLB value of 11.

[0239] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0240] Conditions: 0.01 N HCl containing 0.5% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0241] [Table 40]

[0242] Conditions: ABS, pH 4.5, containing 0.025% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0243] [Table 41]

[0244] Conditions: ABS containing 0.2% TRITON X-100, pH 4.5, 900 mL, paddle with sinker, 75 rpm, 37°C

[0245] [Table 42]

[0246] Example 5 Polyethylene glycol monostearate (GELUCIRE® 48 / 16) was melted in a 55±5°C water bath to obtain a solution. Micronized cabozantinib monolauryl sulfate was added to the solution to obtain a uniform dispersion or solidify into a semisolid. Cabozantinib capsules were prepared by filling size 1 hard gelatin capsules with a semisolid suspension containing 40 mg of cabozantinib free base, and size 9 hard gelatin capsules with semisolid suspensions containing 2 mg and 8 mg of cabozantinib free base.

[0247] The composition of the capsule contents is as follows:

[0248] [Table 43]

[0249] The 40 mg cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0250] Conditions: 0.01 N HCl containing 0.375% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0251] [Table 44]

[0252] Example 6 Vitamin E polyethylene glycol succinate (Vitamin E TPGS) was melted in a 55±5°C water bath to obtain a solution. Micronized cabozantinib monolauryl sulfate was added to the solution to obtain a uniform dispersion or allowed to solidify into a semi-solid. Cabozantinib capsules were prepared by filling a semi-solid suspension containing 40 mg of cabozantinib free base into size 1 hard gelatin capsules, and a semi-solid suspension containing 2 mg of cabozantinib free base into size 9 hard gelatin capsules.

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

[0254] [Table 45]

[0255] The HLB value of Vitamin E TPGS is reported to be approximately 13.2. The 40 mg cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0256] Conditions: 0.01N HCl containing 0.375% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0257] [Table 46]

[0258] Example 7 Vitamin E polyethylene glycol succinate was dissolved in a 55±5°C water bath to obtain a solution. Cabozantinib (S)-malate (non-micronized) was added to the solution and either homogenized or solidified into a semi-solid. The semi-solid suspension containing 20 mg of cabozantinib free base was then filled into size 3 hard gelatin capsules to prepare cabozantinib capsules.

[0259] The composition of the capsule contents is as follows:

[0260] [Table 47]

[0261] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0262] Conditions: 0.01 N HCl containing 0.375% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0263] [Table 48]

[0264] Example 8 Polyethylene glycol monostearate was added to polyethylene glycol 400 (PEG 400) and melted in a hot water bath at 55 ± 5°C to obtain a homogeneous solution. Micronized cabozantinib monolauryl sulfate was added to obtain a homogeneous dispersion or solidified into a semisolid. Cabozantinib capsules were prepared by filling 20 mg of the semisolid suspension containing cabozantinib free base into size 3 hard gelatin capsules and 40 mg of the semisolid suspension containing cabozantinib free base into size 1 hard gelatin capsules.

[0265] The composition of the capsule contents is as follows:

[0266] [Table 49]

[0267] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0268] Conditions: 0.01 N HCl containing 0.375% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0269] [Table 50]

[0270] Example 9 Polyethylene glycol 1500 (PEG 1500) and polyethylene glycol monostearate were dissolved in a warm water bath at 55 ± 5°C to obtain a homogeneous solution. To this solution, micronized cabozantinib monolauryl sulfate was added to obtain a homogeneous dispersion or solidified into a semisolid. Cabozantinib capsules were prepared by filling size 3 hard gelatin capsules with the semisolid suspension containing 20 mg of cabozantinib free base.

[0271] The composition of the capsule contents is as follows:

[0272] [Table 51]

[0273] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0274] Conditions: 0.01 N HCl containing 0.375% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0275] [Table 52]

[0276] Conditions: ABS containing 0.2% TRITON X-100, pH 4.5, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0277] [Table 53]

[0278] Example 10 Poloxamer 188 was dissolved in a 55±5°C water bath to obtain a solution, to which micronized cabozantinib monolauryl sulfate was added to obtain a uniform dispersion or solidify into a semi-solid. Cabozantinib capsules were prepared by filling size 3 hard gelatin capsules with the semi-solid suspension containing 20 mg of cabozantinib free base.

[0279] The composition of the capsule contents is as follows:

[0280] [Table 54]

[0281] Poloxamer 188 is reported to have an HLB value of approximately 29. Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0282] Conditions: 0.01 N HCl containing 0.375% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0283] [Table 55]

[0284] Example 11 Polyoxyl 40 hydrogenated castor oil was dissolved in a 55±5°C water bath to obtain a solution. Micronized cabozantinib monolauryl sulfate was added to the solution to obtain a uniform dispersion or solidify into a semi-solid. Cabozantinib capsules were prepared by filling size 3 hard gelatin capsules with the semi-solid suspension containing 20 mg of cabozantinib free base.

[0285] The composition of the capsule contents is as follows:

[0286] [Table 56]

[0287] The HLB value of polyoxyl 40 hydrogenated castor oil (KOLLIPHOR RH 40) is reported to be 14-16.

[0288] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0289] Conditions: 0.01 N HCl containing 0.375% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0290] [Table 57]

[0291] Example 12 Polyethylene glycol monostearate was dissolved in a 55±5°C warm water bath to obtain a solution. Micronized cabozantinib monolauryl sulfate was added to obtain a uniform dispersion or allowed to solidify to obtain a semisolid suspension. Cabozantinib capsules were prepared by filling size 3 hard gelatin capsules with the semisolid suspension containing 14 mg of cabozantinib free base.

[0292] The composition of the capsule contents is as follows:

[0293] [Table 58]

[0294] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0295] Conditions: 0.01 N HCl containing 0.375% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0296] [Table 59]

[0297] Conditions: 0.01 N HCl containing 0.5% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0298] [Table 60]

[0299] Conditions: 0.01 N HCl containing 0.5% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0300] [Table 61]

[0301] Conditions: 900 mL of ABS containing 0.2% TRITON X-100, pH 4.5, paddle with sinker, 75 rpm, 37°C

[0302] [Table 62]

[0303] Conditions: 25 mM ABS pH 4.5 containing 0.5% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0304] [Table 63]

[0305] Conditions: 900 mL of 25 mM ABS, pH 4.5, containing 0.2% TRITON X-100, paddle with stationary basket, 75 rpm, 37°C

[0306] [Table 64]

[0307] Conditions: 25 mM pH 4.5 ABS containing 0.5% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0308] [Table 65]

[0309] Conditions: 50 mM ABS pH 4.5 containing 0.2% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0310] [Table 66]

[0311] Conditions: 50 mM pH 4.5 ABS containing 0.5% TRITON X-100, 900 mL, paddle with stationary basket, 75 rpm, 37°C

[0312] [Table 67]

[0313] Conditions: 50 mM pH 4.5 ABS containing 0.2% TRITON X-100, 900 mL, paddle with stationary basket, 50 rpm, 37°C

[0314] [Table 68]

[0315] Example 13 Polyethylene glycol monostearate was dissolved in a 55±5°C water bath to obtain a solution. Micronized cabozantinib monolaurate was added to the solution to obtain a uniform dispersion or agglomerated to a semisolid. The semisolid was cooled and pulverized, and cabozantinib capsules were prepared by filling a size 3 hard gelatin capsule with the semisolid containing 14 mg of cabozantinib free base.

[0316] The composition of the capsule contents is as follows:

[0317] [Table 69]

[0318] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0319] Conditions: 0.01 N HCl containing 0.5% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0320] [Table 70]

[0321] Conditions: ABS containing 0.2% TRITON X-100, pH 4.5, 900 mL, paddle with sinker, 75 rpm, 37°C

[0322] [Table 71]

[0323] Example 14 Polyethylene glycol monostearate was dissolved in a warm water bath at 55±5°C to obtain a solution. Micronized cabozantinib monolauryl sulfate was added to obtain a uniform dispersion or solidified into a semisolid. The semisolid was cooled, pulverized, screened through a 30-mesh screen, and then blended with the supergranular excipients. Cabozantinib capsules were prepared by filling the resulting mixture (containing 14 mg of cabozantinib free base) into size 3 hard gelatin capsules.

[0324] The composition of the capsule contents is as follows:

[0325] [Table 72]

[0326] Cabozantinib capsules were tested using a USP Type II (paddle) apparatus under the following conditions:

[0327] Conditions: 0.01 N HCl containing 0.5% TRITON X-100, 900 mL, paddle with sinker, 75 rpm, 37°C

[0328] [Table 73]

[0329] Conditions: ABS containing 0.2% TRITON X-100, pH 4.5, 900 mL, paddle with sinker, 75 rpm, 37°C

[0330] [Table 74]

[0331] Example 15 Polyethylene glycol monostearate was dissolved in a 55±5°C warm water bath to obtain a solution. Micronized cabozantinib monolauryl sulfate was added to obtain a uniform dispersion or solidified into a semi-solid. Cabozantinib capsules were prepared by filling size 9 hard gelatin capsules with the semi-solid suspension containing 0.6 mg, 1.2 mg, 1.6 mg, 2.4 mg, and 4.8 mg of cabozantinib free base.

[0332] The composition of the capsule contents is as follows:

[0333] [Table 75]

[0334] Example 16 Vitamin E polyethylene glycol succinate was dissolved in a 55±5°C hot water bath to obtain a solution. Micronized cabozantinib monolauryl sulfate was added to obtain a uniform dispersion or solidified into a semi-solid. Cabozantinib capsules were prepared by filling size 9 hard gelatin capsules with the semi-solid suspension containing 0.6 mg, 1.2 mg, 2.4 mg, and 4.8 mg of cabozantinib free base.

[0335] The composition of the capsule contents is as follows:

[0336] [Table 76]

[0337] Example 17 Capsules containing cabozantinib monolauryl sulfate (equivalent to 20 mg of cabozantinib free base) prepared in Example 1 (Study 1) and capsules containing cabozantinib free base prepared in Example 2 (Study 2) were administered together with 20 mg equivalent cabozantinib malate tablets prepared in Comparative Example 1 (reference) to six healthy adult beagle dogs in a single-center, single-dose study under fasted conditions. A seven-day washout period was included between treatment periods. Blood samples were collected pre-dose and at 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose. The six healthy adult beagle dogs enrolled in this study were randomly assigned to one of the treatment sequences shown in the table below.

[0338] [Table 77]

[0339] The results are summarized in the table below.

[0340] [Table 78]

[0341] Ln-transformed AUC 0-t , AUC 0-infinity , and C max were analyzed using the FDA-approved pharmacokinetic program Phoenix WinNonlin 7.0 (Pharsight, USA). A comparison of the data obtained from the test and reference doses is shown in the table below.

[0342] [Table 79]

[0343] Individual subject data obtained from this study are as follows:

[0344] [Table 80]

[0345] [Table 81]

[0346] [Table 82]

[0347] A graph of the mean plasma profile in the study is shown in Figure 1.

[0348] Example 18 In a single-center, single-dose study, capsules containing cabozantinib monolauryl sulfate (equivalent to 20 mg of cabozantinib free base) prepared in Example 3 (Test 1) and Example 4 (Test 2) were administered together with 20 mg tablets of cabozantinib malate prepared in Comparative Example 1 (Ref) to six healthy adult beagle dogs in a fasted state. A seven-day washout period was included between the administration periods. Blood samples were collected pre-dose and at 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose. The six healthy adult beagle dogs participating in this study were randomly assigned to one of the sequences shown in the following table.

[0349] [Table 83]

[0350] The results are summarized in the table below.

[0351] [Table 84]

[0352] Ln-transformed AUC 0-t , AUC 0-infinity , and C maxwere analyzed using the FDA-approved pharmacokinetic program Phoenix WinNonlin 7.0 (Pharsight, USA). A comparison of the data obtained from the test and reference doses is shown in the table below.

[0353] [Table 85]

[0354] Individual subject data obtained from this study are as follows:

[0355] [Table 86]

[0356] [Table 87]

[0357] [Table 88]

[0358] A graph of the mean plasma profile in this study is shown in Figure 2.

[0359] Example 19 Capsules containing cabozantinib monolauryl sulfate (equivalent to 2 mg of cabozantinib free base) prepared in Example 5 (Study 1) and Example 6 (Study 2) were administered to 18 fasted Wistar rats in a single-center, single-dose study, along with equivalent 2 mg capsules prepared from cabozantinib tablets (60 mg tablets containing 76.05 mg of commercially available cabozantinib (S)-malate were crushed and refilled into new capsules each containing 2 mg of cabozantinib free base) (reference). Blood samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, and 24 hours post-dose. The 18 Wistar rats used in this study were randomly assigned to one of the sequences shown in the following table.

[0360] [Table 89]

[0361] The results are summarized in the table below.

[0362] [Table 90]

[0363] Ln-transformed AUC was calculated using an FDA-approved pharmacokinetic program (Phoenix WinNonlin 7.0 (Pharsight, USA)). 0-t , AUC 0-infinity and C max A comparison of the data obtained from the test and reference doses is shown in the table below:

[0364] [Table 91]

[0365] Individual subject (subject) data obtained from the study is as follows:

[0366] [Table 92]

[0367] [Table 93]

[0368] [Table 94]

[0369] A graph of the mean plasma concentration profile in this study is shown in Figure 3.

[0370] Example 20 Cabozantinib monolauryl sulfate (containing 40 mg of cabozantinib free base equivalent) prepared in Example 6 (Test 1) and Example 6 (Test 2) was administered to 24 healthy human subjects under fasting conditions. This was a single-dose, open-label, randomized, three-treatment, three-sequence, one-period comparative bioavailability study between cabozantinib lauryl sulfate capsules (containing 40 mg of cabozantinib free base equivalent) and CABOMETYX tablets (Ref) containing 60 mg of cabozantinib in the form of cabozantinib (S)-malate. All subjects were randomized to the sequence shown in the following table.

[0371] [Table 95]

[0372] During each treatment period, blood samples were collected at 0 hours before administration and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, and 72 hours after administration. 0-72 , AUC 0-infinity , C max , T max , T 1 / 2 The results are summarized in the table below.

[0373] [Table 96]

[0374] *reference 絶食 : 60 mg CABOMETYX tablets under fasting conditions. *Test 1 絶食 : Test drug 1 (Test 1) 40 mg (equivalent to 40 mg of free base) under fasting conditions. *Test 2 絶食 : Test drug 2 (Test 2) 40 mg (equivalent to 40 mg of free base) under fasting conditions.

[0375] Ln-transformed AUC 0-t , AUC 0-infinity and C max The data were analyzed using the FDA-approved pharmacokinetic program Phoenix WinNonlin 7.0 (Pharsight, USA). The model included sequence, subject (sequence), duration, and treatment effects. A comparison of the data obtained from the test and reference doses is shown in the table below.

[0376] [Table 97]

[0377] Individual subject data from the study are as follows:

[0378] [Table 98]

[0379] [Table 99]

[0380] [Table 100]

[0381] [Table 101]

[0382] [Table 102]

[0383] [Table 103]

[0384] A graph of the mean plasma profile from this study is shown in Figure 4.

[0385] Example 21 Capsules containing cabozantinib monolauryl sulfate (equivalent to 40 mg of cabozantinib free base) prepared in Example 5 were administered to 45 healthy adult subjects under fasted and fed conditions to evaluate relative bioavailability and the effect of food conditions. This study was a single-dose, open-label, randomized, three-treatment, three-sequence, one-period comparative bioavailability study. The reference drug (reference) was CABOMETYX tablets (cabozantinib (S)-malate, 60 mg of free base), and the test drug (test) was capsules prepared according to the procedure in Example 5, containing 40 mg of cabozantinib free base. The 45 healthy subjects enrolled in this study were randomly assigned to one of the sequences shown in the table below.

[0386] [Table 104]

[0387] During each treatment period, blood samples were collected pre-dose (0 h), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, 72, 120, and 168 h later. AUC 0-168 , AUC 0-infinity, C max , T max and T 1 / 2 was determined for each subject based on non-compartmental analysis.

[0388] Ln-transformed AUC 0-t , AUC 0-infinity and C max was analyzed by ANOVA. The model included sequence, subject (administration sequence), period, and treatment effects.

[0389] The results of this test were as follows:

[0390] [Table 105]

[0391] *reference 絶食 60 mg CABOMETYX tablets under fasting conditions *test 絶食 : 40 mg of test drug (test) under fasting conditions (equivalent to 40 mg of free base) *test 摂食 : Test drug (test) 40 mg (equivalent to 40 mg of free base) under fed conditions

[0392] [Table 106]

[0393] Individual subject data from the study are as follows:

[0394] [Table 107]

[0395] [Table 108]

[0396] [Table 109]

[0397] [Table 110]

[0398] [Table 111]

[0399] [Table 112]

[0400] A graph of the mean plasma concentration profile in this study is shown in FIG.

[0401] Example 22 Capsules containing the composition comprising cabozantinib monolauryl sulfate described in Example 5 were administered to 30 Wistar rats under fasting conditions. This study was a single-dose, open-label, randomized, three-treatment, three-sequence, one-period bioavailability study. All rats were randomly assigned to the dosing sequence shown in the table below. The reference drug (reference) was prepared by crushing CABOMETYX tablets (commercially available 60 mg tablets) and filling new capsules with an amount equivalent to 2.4 mg of cabozantinib free base from each tablet containing 76.05 mg of cabozantinib (S)-malate. The test drug (test) was capsules prepared according to the procedure in Example 5, containing 1.6 mg of cabozantinib free base. Thirty Wistar rats participated in this study and were randomly assigned to one of the dosing sequences shown in the table below.

[0402] [Table 113]

[0403] Test drug or placebo was administered by oral gavage. One capsule was administered daily for at least 28 days. Animals were fasted 3 hours before dosing and again 1 hour after each daily dose. Water was available throughout the day. Changes in diarrhea, body weight, food intake, and mortality (survival rate) were observed and recorded.

[0404] The results are summarized in the table below.

[0405] [Table 114]

[0406] *Only one rat survived, resulting in a large variation in average weight. A graph showing the changes in body weight is shown in Figure 6.

[0407] [Table 115]

[0408] [Table 116]

[0409] [Table 117]

[0410] [Table 118]

[0411] The diarrhea scores were recorded twice daily. standard: 0 - no diarrhea; 1 - mild diarrhea, anal soiling; 2 - Moderate diarrhea, stains on the legs and lower abdomen; 3 - Severe diarrhea, soiling on the legs and upper abdomen, often accompanied by persistent anal leakage. A graph showing the mean diarrhea scores is shown in FIG.

[0412] [Table 119]

[0413] A graph showing the mean food intake scores is shown in FIG.

[0414] A graph showing the survival curve for rats in this study is shown in Figure 9. The data demonstrate that compositions according to the present invention reduced the incidence and / or severity of adverse events, including but not limited to diarrhea, loss of appetite, and weight loss.

[0415] Example 23 The cabozantinib lauryl sulfate used in the preceding examples can be prepared as outlined in Example 41 of International Patent Application No. PCT / US2019 / 036947, filed June 13, 2019, and published as WO2019 / 241504. X-ray powder diffraction (XRPD) data for the cabozantinib lauryl sulfate used in Examples 12 and 14 was obtained using an Empyrean (Malvern Panalytical) with the following test conditions:

[0416] [Table 120]

[0417] The XPRD graph is shown in Figure 10, with peak values ​​as follows:

[0418] [Table 121]

[0419] In certain embodiments, crystalline cabozantinib monolauryl sulfate may exhibit two, three, four, five, six, seven, eight, nine, ten or more of the following 2θ peaks: 5.0±0.2; 6.6±0.2; 8.4±0.2; 10.0±0.2; 11.3±0.2; 12.1±0.2; 12.6±0.2; 13.1±0.2; 13.5±0.2; 14.4±0.2; 15.6±0.2; 16.8±0.2; 17.5±0.2; 18.0±0.2; 18. 6±0.2; 20.2±0.2; 20.6±0.2; 21.3±0.2; 21.9±0.2; 22.4±0.2; 22.7±0.2; 23.2±0.2; 23.7±0.2; 24.2±0.2; 25.1±0.2; 26.6±0.2; 27.1±0.2; 27.7±0.2; 28.4±0.2; 30.4±0.2; 31.5±0.2; 32.4±0.2; 33.4±0.2; 34.6±0.2; 38.4±0.2; 43.7±0.2; and / or 47.7±0.2. In certain aspects of the invention, crystalline cabozantinib monolauryl sulfate may exhibit one, two, three, four or more of the following 2θ peaks: 5.0±0.2; 11.3±0.2; 12.1±0.2; 13.5±0.2; 16.8±0.2; 17.5±0.2; 18.6±0.2; 20.2±0.2; 20.6±0.2; 21.3±0.2; 21.9±0.2; 22.4±0.2; 22.7±0.2; 23.2±0.2; 24.2±0.2; 26.6±0.2; and / or 27.7±0.2.In certain aspects of the invention, crystalline cabozantinib monolauryl sulfate exhibits at least the following 2θ peaks: 5.0±0.2; 12.1±0.2; 16.8±0.2; 21.3±0.2; 21.9±0.2 and 23.2±0.2, and optionally 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the following 2θ peaks: 6.6±0.2; 8.4±0.2; 10.0±0.2; 11.3±0.2; 12.6±0.2; 13.1±0.2; 13.5±0.2; 14.4±0.2 0.2; 15.6±0.2; 17.5±0.2; 18.0±0.2; 18.6±0.2; 20.2±0.2; 20.6±0.2; 22.4±0.2; 22.7±0.2; 23.7±0.2; 24.2±0.2; 25.1±0.2; 26.6±0.2; 27.1±0.2; 27.7±0.2; 28.4±0.2; 30.4±0.2; 31.5±0.2; 32.4±0.2; 33.4±0.2; 34.6±0.2; 38.4±0.2; 43.7±0.2 and / or 47.7±0.2.

[0420] Cabozantinib lauryl sulfate was micronized in an SJM-50 spiral jet mill (Kunshan Unique) at a milling rate of approximately 0.5 g / min using the following parameters: Grinding pressure: 0.6±0.05Mpa Supply pressure: 0.65±0.05Mpa Voltage: 40-60V

[0421] The particle size of cabozantinib lauryl sulfate in some of the examples above was measured using a Malvern Mastersize 3000 in wet mode with the following parameters:

[0422] [Table 122]

[0423] (Test Method) (1) Preparation of dispersion medium (water containing 0.05% Tween 80): Add 1000 mL of water to a volumetric flask and add 0.5 mL of Tween 80. Stir the solution to mix thoroughly.

[0424] (2) Sample preparation: Weigh 0.0628 g of sample into a 25 mL beaker and add 10 mL of dispersion medium. Disperse the sample with ultrasound for 60 seconds to form a uniform suspension.

[0425] (3) Operation procedure: Fill the measurement cell with the dispersion medium, add the sample solution, and analyze according to the measurement procedure.

[0426] The particle size data obtained is as follows:

[0427] [Table 123]

[0428] Example 24 Cabozantinib lauryl sulfate salts that may be used in the present invention (including the examples described herein) can be prepared according to the following reaction scheme:

[0429] Step 1 - Synthesis of Intermediate 1 (4-((6,7-dimethoxyquinulin-4-yl)oxy)aniline)

[0430] [ka]

[0431] 60.91 g of dimethylacetamide (DMAc) is added to the reactor. While stirring, 6.50 g of 4-chloro-6,7-dimethoxyquinoline (compound SM1) and 3.91 g of sodium tert-butoxide are added sequentially and stirred at room temperature for approximately 0.5 hours. Then, 4.45 g of p-aminophenol (compound SM2) is added. After the addition of p-aminophenol, the reaction mixture continues to stir at room temperature for approximately 0.5 hours. The temperature of the reaction mixture is raised to approximately 95-110°C and the reaction is allowed to proceed for approximately 15 hours under a nitrogen atmosphere.

[0432] Step 2 - Synthesis of Intermediate 2 (1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid)

[0433] [ka]

[0434] To the first reactor, 66.75 g of tetrahydrofuran was added, followed by 0.23 g of dimethylformamide (DMF) catalyst. While stirring, 4.94 g of 1,1-cyclopropanedicarboxylic acid (compound SM3) was added to the reactor. The reactor was purged with nitrogen, and the reaction mixture was cooled to approximately 0-10°C. Once cooled, thionyl chloride was added to the reaction mixture and stirred at approximately 0-10°C for approximately 2 hours. Next, 99.38 g of dichloromethane was added to a separate reactor, and while stirring, 75.00 g of Intermediate 1 and 8.98 g of trimethylamine were added sequentially. The second reactor was purged with nitrogen and cooled to approximately 0-10°C. After cooling, 71.92 g of the acyl chloride solution from the first reactor was added to the third reactor, maintaining the temperature of the reaction mixture at approximately 0-15°C, and the reaction was continued for approximately 3 hours.

[0435] Step 3 - Synthesis of Intermediate 3 (Crude Cabozantinib Free Base)

[0436] [ka]

[0437] Add 119.25 g of dichloromethane to a reactor and, while stirring, add 9.00 g of Intermediate 2. After adding Intermediate 2, purge the reactor with nitrogen and cool to about 0 to 10°C. After cooling, add 3.93 g of thionyl chloride dropwise while maintaining the temperature at about 0 to 15°C. After adding the thionyl chloride, react the reaction mixture at about 5 to 15°C for about 3 hours. While maintaining the temperature of the reaction mixture below 10°C, add 4.46 g of triethylamine to the reaction mixture. After adding the trimethylamine, add 3.67 g of 4-fluoroaniline while maintaining the temperature of the reaction mixture below 15°C. After adding the 4-fluoroaniline, increase the temperature of the reaction mixture to about 30 to 40°C and react for about 2 hours.

[0438] Step 4 - Synthesis of Cabozatinib Lauryl Sulfate

[0439] [ka]

[0440] Add 4.86 g of sodium lauryl sulfate, 15.42 g of methanol, and 1 mol / L hydrochloric acid solution to the transfer barrel and stir until completely dissolved. Next, add 128.54 g of methanol to the reactor. While stirring, add 6.50 g of Intermediate 3 to the reactor and heat the reaction mixture to about 45°C to about 55°C. Add the sodium lauryl sulfate / methanol / hydrochloric acid solution to the reaction mixture with stirring until the reactants are completely dissolved, and then maintain that temperature for about 0.5 hours. The resulting mixture is filtered hot and transferred to a new, clean reactor. The filtrate is stirred at about 45°C to about 55°C for about 0.5 hours, then cooled to about 20°C to about 30°C and reacted for about 1 hour.

[0441] Step 5 - Crystallization of Cabozatinib Lauryl Sulfate

[0442] (a) Remove some of the methanol from the reaction mixture in Step 4 by vacuum concentration, and add 97.50 g of purified water dropwise at a temperature between about 20°C and about 30°C. This process continues for about 2 to 2.5 hours, with the temperature of the reaction mixture being below 35°C during the water addition. After the water addition, stir the reaction mixture for about 1 hour to promote crystallization. The resulting crystals are collected as a wet cake by centrifugation.

[0443] (b) 130.00 g of purified water is added to the reactor and the wet cake from step (a) is slurried at about 20° C. to about 30° C. for about 1 hour, followed by centrifugation to collect the wet cake.

[0444] (c) 61.70 g of methanol is added to the reactor, followed by the wet cake from step (b), and the reaction mixture is heated to about 55°C to about 70°C and stirred until completely dissolved. The solution is maintained at this temperature for about 0.5 hours, then cooled to about 20°C to about 30°C. After cooling, 117.00 g of purified water is added dropwise over about 1 to 2 hours, maintaining the temperature below 35°C during the water addition process. Once the water is added, cabozantinib lauryl sulfate crystallizes while maintaining the temperature for about 1 hour.

[0445] (d) The reaction mixture from step (c) is centrifuged and the resulting wet cake is washed with purified water before each discharge. Centrifugation is continued until no liquid is observed to flow through the sight glass before each discharge.

[0446] (e) The wet purified cabozantinib lauryl sulfate crystals obtained in step (d) are collected and vacuum dried at approximately 45-55°C for approximately 20 hours, resulting in a yield of 70-95%. This is then jet-milled to obtain the final product (milling yield: 90-100%).

[0447] Example 25 Three lots of crystalline cabozantinib lauryl sulfate were prepared according to the procedure outlined in Example 24, and the XRPD of each lot was measured according to the procedure in Example 23. The XPRD graphs for Lots 25A, 25B, and 25C are shown in Figures 11A, 11B, and 11C, respectively, with the following peak values:

[0448] [Table 124]

[0449] In certain embodiments, crystalline cabozantinib monolauryl sulfate may exhibit two, three, four, five, six, seven, eight, nine, ten or more of the following 2θ peaks: 5.0±0.2; 6.7±0.2; 8.4±0.2; 10.1±0.2; 11.4±0.2; 12.1±0.2; 12.6±0.2; 13.2±0.2; 13.5±0.2; 14.4±0.2; 15.6±0.2; 16.6±0.2; 16.9±0.2; 17.5±0.2; 18.1±0.2; 18.7±0.2; 19.1±0.2; 20.3±0.2; 20.6±0.2; 21.4±0.2; 22.0±0.2; 22.5±0.2; 22.8±0.2; 23.3±0.2; 23.8±0.2; 24.2±0.2; 24.5±0.2; 25.1±0.2; 26.7±0.2; 27.8±0.2; 28.5±0.2; 28.9±0.2; 29.5±0.2; 30.4±0.2; 31.6±0.2; 32.5±0.2; 33.4±0.2; 34.7±0.2; 36.5±0.2; 38.6±0.2; 43.6±0.2 and / or 46.6±0.2. In certain aspects of the invention, the crystalline cabozantinib monolauryl sulfate exhibits one, two, three, four or more of the following 2θ peaks: 5.0±0.2; 10.1±0.2; 12.1±0.2; 16.6±0.2; 16.9±0.2; 18.7±0.2; 20.3±0.2; 20.6±0.2; 21.4±0.2; 22.0±0.2; 22.5±0.2; 22.8±0.2; 23.3±0.2; 26.7±0.2; and / or 27.8±0.2.

[0450] In certain aspects of the invention, crystalline cabozantinib monolauryl sulfate exhibits at least the following 2-theta peaks: 5.0±0.2; 12.1±0.2; 16.9±0.2; 21.4±0.2; 22.0±0.2, and 23.3±0.2, and optionally two, three, four, five, six, seven, eight, nine, ten, or more of the following 2-theta peaks: 6.7±0.2; 8.4±0.2; 10.1±0.2; 11.4±0.2; 12.6±0.2; 13.2±0.2; 13.5±0.2; 14.4±0.2; 15.6±0.2; 16.6±0.2. 2;17.5±0.2;18.1±0.2;18.7±0.2;19.1±0.2;20.3±0.2;20.6±0.2;22.5±0.2;22.8±0.2;23.8±0.2;24.2±0.2;24.5±0.2;25.1±0.2;26.7±0.2;27.8±0.2;28.5±0.2;28.9±0.2;29.5±0.2;30.4±0.2;31.6±0.2;32.5±0.2;33.4±0.2;34.7±0.2;36.5±0.2;38.6±0.2;43.6±0.2 and / or 46.6±0.2.

[0451] [Table 125]

[0452] In certain embodiments of the present invention, crystalline cabozantinib monolauryl sulfate may exhibit 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the following 2θ peaks: 5.0±0.2; 6.7±0.2; 8.4±0.2; 9.8±0.2; 10.1±0.2; 11.3±0.2; 12.1±0.2; 12.7±0.2; 13.2±0.2; 13.5±0.2; 13.7±0.2; 14.4±0.2; 15.6±0.2; 15.9±0.2; 16.6±0.2; 16.9±0.2; 17.5±0.2; 18.0±0.2; 18.6±0.2; 19. 2±0.2;20.2±0.2;20.7±0.2;21.3±0.2;21.5±0.2;21.9±0.2;22.5±0.2;22.8±0.2;23.2±0.2;23.7±0.2;24.2±0.2;24.4±0.2;25.1±0.2;25.9±0.2;26.3 ±0.2; 26.6±0.2; 27.7±0.2; 28.5±0.2; 29.5±0.2; 30.5±0.2; 31.6±0.2; 32.2±0.2; 33.4±0.2; 34.7±0.2; 38.6±0.2; 42.1±0.2; 43.7±0.2 and / or 46.6±0.2. In certain aspects of the invention, crystalline cabozantinib monolauryl sulfate may exhibit one, two, three, four or more of the following 2θ peaks: 5.0±0.2; 8.4±0.2, 9.79±0.2, 11.3±0.2; 12.1±0.2; 12.7±0.2, 13.2±0.2; 13.5±0.2, 16. 6±0.2, 16.9±0.2; 17.5±0.2; 18.0±0.2, 18.6±0.2; 20.2±0.2; 20.7±0.2; 21.3±0.2; 21.5±0.2, 21.9±0.2; 22.5±0.2; 22.8±0.2; 23.2±0.2, 24.2±0.2; 24.4±0.2, 25.1±0.2, 26.6±0.2; and / or 27.7±0.2.

[0453] In certain embodiments of the present invention, the crystalline cabozantinib monolauryl sulfate exhibits 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the following 2θ peaks: 5.0±0.2; 6.7±0.2; 8.4±0.2; 9.8±0.2; 10.1±0.2; 11.3±0.2; 12.1±0.2; 12.7±0.2; 13.2±0.2; 13.5±0.2; 13.7±0.2; 14.4±0.2; 15.6±0.2; 15.9±0.2; 16.6±0.2; 16.9±0.2; 17.5±0.2; 18.0±0.2; 18.6±0.2; 19.2±0.2. 2;20.2±0.2;20.7±0.2;21.3±0.2;21.5±0.2;21.9±0.2;22.5±0.2;22.8±0.2;23.2±0.2;23.7±0.2;24.2±0.2;24.4±0.2;25.1±0.2;25.9±0.2;26.3±0 .2; 26.6±0.2; 27.7±0.2; 28.5±0.2; 29.5±0.2; 30.5±0.2; 31.6±0.2; 32.2±0.2; 33.4±0.2; 34.7±0.2; 38.6±0.2; 42.1±0.2; 43.7±0.2 and / or 46.6±0.2.

[0454] [Table 126]

[0455] In certain embodiments, crystalline cabozantinib monolaurate may exhibit two, three, four, five, six, seven, eight, nine, ten or more of the following 2θ peaks: 4.9±0.2; 8.3±0.2; 9.7±0.2; 9.9±0.2; 11.2±0.2; 12.0±0.2; 12.5±0.2; 13.0±0.2; 13.4±0.2; 14.3±0.2; 14.6±0.2; 15.5±0.2; 15.8±0.2; 16.4±0.2; 16.7±0.2; 17.4±0.2; 1 7.9±0.2; 18.5±0.2; 20.1±0.2; 20.5±0.2; 21.2±0.2; 21.4±0.2; 21.8±0.2; 22.3±0.2; 22.7±0.2; 23.1±0.2, 23.6±0.2; 24.1±0.2; 25.0±0.2; 25.7±0.2; 26.5±0.2; 27.6±0.2; 28.3±0.2; 29.3±0.2; 30.4±0.2; 31.4±0.2; 33.3±0.2; 34.6±0.2; 35.7±0.2 and / or 43.7±0.2. In certain embodiments of the invention, the crystalline cabozantinib monolauryl sulfate exhibits one, two, three, four or more of the following 2θ peaks: 4.9±0.2, 9.7±0.2, 11.2±0.2, 12.0±0.2, 12.5±0.2, 13.0±0.2, 13.4±0.2, 16.4±0.2, 16.7±0.2, 17.4±0.2, 18.5±0.2, 20.1±0.2, 20.5±0.2, 21.2±0.2, 21.4±0.2, 21.8±0.2, 22.3±0.2, 22.7±0.2, 23.1±0.2, 25.0±0.2, 26.5±0.2, and / or 27.6±0.2.

[0456] In certain aspects of the invention, crystalline cabozantinib monolauryl sulfate exhibits at least the following 2-theta peaks: 4.9±0.2; 12.0±0.2; 16.7±0.2; 21.2±0.2; 22.7±0.2; 23.1±0.2, and optionally two, three, four, five, six, seven, eight, nine, ten or more of the following 2-theta peaks. 8.3±0.2;9.7±0.2;9.9±0.2;11.2±0.2;12.5±0.2;13.0±0.2;13.4±0.2;14.3±0.2;14.6±0.2;15.5±0.2;15.8±0.2;16.4±0.2;17.4±0.2;17.9±0.2;18.5±0.2;20.1±0.2;20.5±0.2;21.4±0.2;21.8±0.2;22.3±0.2;23.6 ±0.2; 24.1±0.2; 25.0±0.2; 25.7±0.2; 26.5±0.2; 27.6±0.2; 28.3±0.2; 29.3±0.2; 30.4±0.2; 31.4±0.2; 33.3±0.2; 34.6±0.2; 35.7±0.2 and / or 43.7±0.2.

[0457] Cabozantinib lauryl sulfate in Examples 25B and 25C was packaged in a low-density polyethylene bag double-lined with aluminum foil and stored at 40°C and 75% relative humidity. The impurity profile was determined as follows: 1. Related Substances 1 1.1 Chromatography conditions

[0458] [Table 127]

[0459] 1.2 Solution preparation *Blank solution: 90% methanol. Take 900 mL of methanol, add 100 mL of water and mix well. *Reference standard solution: Accurately weigh approximately 18 mg of cabozantinib lauryl sulfate reference material, transfer to a 20 mL volumetric flask, and dissolve with diluent to the specified volume. Mix thoroughly. Transfer 1.0 mL of this solution to a 50 mL volumetric flask, dilute to the specified volume with diluent, and mix thoroughly. Transfer 1.0 mL of this solution to a 20 mL volumetric flask, and dilute to the specified volume with diluent. Mix thoroughly.

[0460] *Sample solution: Accurately weigh approximately 18 mg of API, transfer to a 20 mL volumetric flask, dissolve in diluent to the specified volume, and mix well.

[0461] 2. Related Substances 2 (GTIs, mutagenic impurities) 2.1 Chromatography conditions

[0462] [Table 128]

[0463] 2.2 Preparation of solutions *Blank solution: DMSO-MeOH 80:20 Take 800 mL of DMSO, add 200 mL of methanol, and mix well.

[0464] *Reference standard solution: Accurately weigh approximately 9 mg of SM1-Imp4 standard, 9 mg of SM2 standard, 9 mg of SM4 standard, 9 mg of Int1 standard, and 9 mg of Int1-Imp1 standard into the same 100 mL volumetric flask, dissolve, dilute to the specified volume with diluent, and mix well. Transfer 1.0 mL of the above solution to a 100 mL volumetric flask, dilute to the required volume with diluent, and mix well.

[0465] *Sample solution: Accurately weigh approximately 760 mg of API, transfer to a 10 mL volumetric flask, add diluent until the volume is approximately 80%, sonicate with shaking for 1 minute, dilute to the specified volume with diluent, and mix well.

[0466] The identified impurities are set forth below, and each of the identified impurities is present in cabozantinib lauryl sulfate in amounts of less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05%.

[0467] [Table 129]

[0468] Int=Intermediate Imp = Impurity The stability results are as follows:

[0469] [Table 130]

[0470] [Table 131]

[0471] Example 26 An oral capsule formulation according to the present invention was prepared according to the method described in Example 5. The capsule contents contain:

[0472] [Table 132]

[0473] The capsules were placed in 60 mL Huanuno HDPE bottles with 1 gram of desiccant and sealed. The sealed bottles were stored at 40°C and 75% relative humidity and periodically tested for impurities and solubility. Impurities were determined using the following chromatographic conditions:

[0474] 1.1 Chromatography conditions

[0475] [Table 133]

[0476] 1.2 Preparation of solutions *Blank solution: 90% methanol. Take 900 mL of methanol, add 100 mL of water and mix well.

[0477] *Standard stock solution: Accurately weigh approximately 18.4 mg of cabozantinib lauryl sulfate standard (equivalent to 12.0 mg of cabozantinib) and transfer to a 50 mL beaker. Add diluent to 80% volume, sonicate for 5 minutes to dissolve, cool, then dilute to volume with diluent and mix well. Transfer 5.0 mL of the above solution to a 20 mL beaker, dilute to volume with diluent and mix well.

[0478] *Reference standard solution: Transfer 2.0 mL of the standard stock solution to a 25 mL beaker, dilute to volume with diluent and mix well.

[0479] Transfer 5.0 mL of the above solution to a 50 mL beaker, dilute to volume with diluent, and mix well.

[0480] *Sample solution: Take 10 capsules, carefully open them, and transfer the contents and capsule shells to a 200 mL (for 10 mg or 20 mg formulations) or 250 mL (for 30 mg formulations) volumetric flask. Add diluent until the container is 80% full, sonicate for 20 minutes, then stir for 15 minutes. After cooling, dilute to the mark with diluent and mix well. Quantitatively dilute with diluent based on the formulation volume shown in the table below and filter through a 0.45 μm nylon filter.

[0481] For 10 mg: Take 5.0 mL of the above solution and transfer it to a 10 mL volumetric flask. Dilute to the mark with diluent, mix well, and filter through a 0.45 μm nylon filter.

[0482] For 20 mg: Take 5.0 mL of the above solution and transfer it to a 20 mL volumetric flask. Dilute to the mark with diluent, mix well, and filter through a 0.45 μm nylon filter.

[0483] For 30 mg: Take 5.0 mL of the above solution and transfer it to a 25 mL volumetric flask. Dilute to the mark with diluent, mix well, and filter through a 0.45 μm nylon filter.

[0484] The dissolution test was carried out using USP (United States Pharmacopeia) Method II (a paddle-mounted fixed basket apparatus) at 75 rpm and 37°C using 900 mL of a medium containing 0.01 N hydrochloric acid and 0.375% TRITON X-100 as the solvent.

[0485] The results of the stability test are as follows:

[0486] [Table 134]

[0487] Example 27 An oral capsule dosage form according to the present invention was prepared by the method described in Example 5. The components of the capsule contents were as follows:

[0488] [Table 135]

[0489] The capsules of Examples 27A, 27B, and 27C were placed in 60 mL Huanuno HDPE bottles with 1 gram of desiccant and sealed. The sealed bottles were stored at 40°C and 75% humidity and periodically tested for impurities and solubility. The impurities in Examples 27A, 27B, and 27C were determined using the following chromatographic conditions:

[0490] 1.1 Chromatography conditions

[0491] [Table 136]

[0492] 1.2 Preparation of solutions *Blank solution: 90% methanol. Take 900 mL of methanol, add 100 mL of water and mix well.

[0493] *Int1 / Int1-Imp1 / SM2 / SM4 Impurity Stock Solution: Accurately measure approximately 15 mg of Int1 / Int1-Imp1 / SM2 / SM4 Impurity Standard and transfer to a 100 mL volumetric flask. Add diluent to 80% volume, sonicate for 5 minutes to dissolve, cool, then dilute to the required volume with diluent and mix well.

[0494] *Reference standard solutions: Transfer 1.0 mL each of Int1 impurity stock solution, Int1-Imp1 impurity stock solution, SM2 impurity stock solution, and SM4 impurity stock solution into the same 100 mL volumetric flask, dilute to the specified volume with diluent, and mix well.

[0495] Transfer 2.0 mL of the above solution to a 10 mL volumetric flask, dilute to the required volume with diluent, and mix well.

[0496] *Sample solution: Take 12 capsules (10 mg content), 6 capsules (20 mg content), or 4 capsules (30 mg content), carefully open them, weigh out approximately 984 mg of the contents (equivalent to approximately 120 mg of cabozantinib), and transfer them to a 10 mL volumetric flask. Add 80% diluent, sonicate for 20 minutes to dissolve, cool, adjust volume with diluent, mix well, and filter through a 0.45 μm nylon 66 filter.

[0497] The stability results for Example 27A are as follows: Dissolution was measured in a USP Type II (paddle with stationary basket) apparatus using 900 mL of 0.01 N HCl containing 0.25% TRITON X-100 medium and was performed at 75 rpm and 37°C.

[0498] [Table 137]

[0499] The stability results for Example 27B are as follows:

[0500] Solubility was measured using 0.01 N HCl containing 0.25% TRITON X-100 in 900 mL of media at 75 rpm and 37°C using a USP Type II (paddle with stationary basket) apparatus.

[0501] [Table 138]

[0502] The stability results for Example 27C are as follows: Dissolution volumes were measured using a USP Type II (paddle with stationary basket) apparatus in 900 mL of media at 75 rpm and 37°C using 0.01 N HCl containing 0.375% TRITON X-100.

[0503] [Table 139]

[0504] Example 28 Capsules according to the invention were prepared according to the procedure outlined in Example 5 and administered to Wistar rats in a multiple dose adverse event study. The composition of the test capsules according to the invention was as follows:

[0505] [Table 140]

[0506] Wistar rats received one of two reference compositions, which were prepared by removing the outer coating from commercially available CABOMETYX tablets, crushing the uncoated tablets, and filling 20 μl small animal capsules.

[0507] The reference capsule contained 1.5 mg of cabozantinib free base in the form of cabozantinib (S)-malate, hereafter referred to as RLD-1.5. It also contains 2.0 mg of cabozantinib free base in the form of cabozantinib (S)-malate, hereafter referred to as RLD-2.

[0508] In addition to cabozantinib (S)-malate, the reference capsule contains microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, sodium carboxymethylcellulose, colloidal silica, and magnesium stearate, as described in the CABOMETYX tablet package insert.

[0509] The Wistar rats used in the study were female, specific pathogen-free (SPF), and weighed approximately 190 g at the time of the first dose. Prior to dosing, the rats were acclimated for 25 days to animal room conditions of 20-25°C, 40-70% relative humidity, and a 12-hour light / 12-hour dark cycle. SPF mouse growth and breeding chow was provided ad libitum throughout the in vivo portion of the study. Reverse osmosis water was also available ad libitum. After the acclimation period, 30 rats were weighed and randomly divided into three groups of 10 rats each, as follows:

[0510] [Table 141]

[0511] According to the table above, the test and reference capsules were administered orally once daily for 35 days. The animals were fasted 4 hours before dosing and again 2 hours after dosing. Water was available throughout the day. The rats' weights were recorded daily. Food intake was monitored and recorded twice daily. Blood pressure was measured every 3 days. Diarrhea scores were recorded twice daily. The number of deaths and diarrhea in each group were monitored, and the date and time of death were recorded. At the end of the study, all animals were euthanized by excessive CO2 inhalation, and the entire stomach tissue, small intestine, and large intestine from the cecum to the anus were removed.

[0512] The stomach was dissected along the greater curvature, and the intestine was dissected along the mesentery. The length and weight of the stomach, intestine, and colon were measured before and after saline elevating. An ulcer scoring system was used to evaluate erosions at necropsy in the stomach, intestine, and colon. Gastrointestinal tissues were fixed in lesional sections and subjected to histopathological examination using 10% formalin.

[0513] Diarrhea was scored using the following criteria: Score 0 = hard stool Score 1 = soft feces with no soiling of anal fur Score 2 = Wet feces with soiling around the anus Score 3 = Very wet feces, soiling spreads to legs and / or adheres to abdomen.

[0514] To clarify the relationship between treatment regimens and safety parameters, this study performed rigorous data analysis, with statistical significance considered to be a P value of less than 0.05. Statistical analysis was performed using IBM SPSS Statistics 23 and R software (R Foundation for Statistical Computing).

[0515] Over the 35 days of administration, the RLD-2 group experienced a total of 28 episodes of diarrhea, with 19 recorded as a score of 1 and 9 recorded as a score of 2. The RLD-1.5 group experienced a total of 25 episodes of diarrhea, with 10 recorded as a score of 1, 14 recorded as a score of 2, and 1 recorded as a score of 3. The test group experienced a total of 10 episodes of diarrhea, with 7 recorded as a score of 1 and 3 recorded as a score of 2. The onset of diarrhea was observed on day 4 in the RLD-2 group, day 7 in the RLD-1.5 group, and day 4 in the test group.

[0516] When evaluating the diarrhea data between groups, several analytical methods were used to determine whether there were significant differences in the occurrence, frequency, and severity of diarrhea between treatment groups. Time-to-event (TTE) analysis, which considers both the occurrence and severity of diarrhea, was the primary method used for this evaluation. TTE analysis was performed in R using the survival package. Because diarrhea was monitored twice daily, "day" was used as the time variable, incremented in half-day increments. Because diarrhea was assessed at three levels, events were identified in three ways: (1) diarrhea score ≥ 1; (2) diarrhea score ≥ 2; and (3) diarrhea score ≥ 3. Kaplan-Meier curves were created for diarrhea scores. Significant differences were confirmed by P values ​​from the log-rank test. The analysis revealed statistically significant differences between the study group and the RLD-2 and RLD-1.5 groups for diarrhea scores ≥ 1. Additionally, in the group with diarrhea scores of 2 or more, statistically significant differences were observed between the test group and the RLD-2 and RLD-1.5 groups.

[0517] Diarrhea scores and diarrhea rates were calculated throughout the study period and are shown in Figures 12A and 12B. The table below shows the diarrhea rate (%) on day 34 and the overall average rate per day.

[0518] [Table 142]

[0519] An ulcer is an injury to the mucous membrane, such as the lining of the stomach or duodenum, that is accompanied by inflammation, pus, and tissue loss. The ulcer score and ulcer area indicate the severity and extent of the injury, as summarized in the table below.

[0520] [Table 143]

[0521] *P<0.05 compared with the control group **P<0.01 compared with the control group

[0522] [Table 144]

[0523] *Significant difference compared to the test group (P<0.01)

[0524] As shown in the table above, there were significant differences in duodenal (intestinal) ulcer scores and ulcer areas between the test group and the RLD-2 and RLD-1.5 groups. There were no significant differences in stomach and colon ulcer scores and ulcer areas between all groups, but the test group had lower stomach ulcer scores and smaller ulcer areas.

[0525] No mortality was observed in the test groups throughout the study period. In the RLD-2 group, mortality began on day 23, reached 50% on day 26, and increased to 80% on day 35, with only two animals surviving to the end of the experiment. In the RLD-1.5 group, mortality began on day 22, with 20% mortality from days 24 to 28 and 70% mortality on day 35. Statistical analysis revealed that the mortality rate in the test group was significantly lower (P<0.001) compared with both the RLD-2 and RLD-1.5 groups.

[0526] In all groups, body weight decreased on days 1 and 2, but then began to increase from day 2 onward. This increase ended on day 13 in the RLD-2 group, day 11 in the RLD-1.5 group, and day 24 in the Test group. Body weight in the Test group was significantly higher than that in the RLD-2 group from day 17 to the end of the study (P<0.01). Body weight in the Test group was also significantly higher than that in the RLD-1.5 group from day 14 to the end of the study (P<0.001). Furthermore, body weight in the RLD-1.5 group was significantly higher than that in the RLD-2 group from day 27 to day 34 (P<0.001).

[0527] The mean food intake of the test group was statistically significantly higher than that of the RLD-2 group (P<0.001) and the RLD-1.5 group (P<0.005), but there was no statistically significant difference in food intake between the RLD-2 group and the RLD-1.5 group.

[0528] Before lavage, the weights of the stomach, intestine, and colon of animals in the RLD-1.5 group were lower than those of the RLD-2 group and the test group, and the weight of the colon was statistically significantly lower than that of the test group (P<0.05).There were no statistically significant differences in the weights of the stomach, intestine, and colon of rats before lavage between the RLD-2 group and the test group, and between the RLD-1.5 group and the test group. After lavage, the stomach and colon weights of the test group were statistically significantly heavier than those of the RLD-1.5 group (P<0.05).There were no statistically significant differences in the stomach, intestine, and colon weights of animals between the RLD-2 group and the test group, and there were no statistically significant differences between the RLD-2 group and the RLD-1.5 group after lavage.

[0529] No significant differences were observed in bowel and colon lengths between the RLD-2, RLD-1.5, and test groups.

[0530] Systolic blood pressure (SBP) in all three groups increased from days 1 to 4 and then decreased overall from day 4 to the end of the study. Specifically, SBP in the RLD-1.5 group was statistically significantly lower than that of the RLD-2 group on day 22, and was also statistically significantly lower than that of the test group on days 16, 22, 25, and 28. Furthermore, SBP in the RLD-2 group was statistically significantly lower than that of the test group on day 34. Diastolic blood pressure (DBP) in the RLD-1.5 and test groups increased from days 1 to 4, whereas DBP in the RLD-2 group increased from days 1 to 7. However, in all three groups, the trend from peak DBP to the end of the study consistently decreased and did not reflect the trend in SBP. Specifically, DBP in the RLD-1.5 group was statistically significantly higher than that of the RLD-2 group on day 4, but was statistically significantly lower than that of the RLD-2 group on day 22. In particular, DBP in the test group was found to be statistically significantly higher than that in the RLD-2 group on days 4 and 28, and statistically significantly higher than that in the RLD-1.5 group on days 22 and 28.

[0531] The test capsules demonstrated approximately 50% higher bioavailability compared to commercially available CABOMETYX tablets and bioequivalence to RLD-1.5 capsules. The above data demonstrate the superior performance of the inventive dosage form compared to the commercially available cabozantinib (S)-malate oral composition, demonstrating significant benefits in reducing diarrhea incidence, ulcer severity, and mortality. Therefore, the inventive dosage form offers improved safety compared to the commercially available cabozantinib (S)-malate oral composition.

[0532] The dosage forms of the present invention are believed to improve bioavailability and thereby reduce unnecessary exposure of subjects to cabozantinib, thereby reducing the incidence and severity of adverse events, including, but not limited to, gastrointestinal perforation and / or fistula, diarrhea, abdominal pain, dyspepsia, decreased appetite, hypertension, and weight loss.

[0533] Example 29 A low-dose cabozantinib capsule dosage form with at least approximately 30% dose reduction, i.e., 70% reduction in cabozantinib free base, compared to commercially available CABOMETYX tablets, was prepared by melting the carrier (melting point 30°C-60°C) in a water bath (below 60°C) to obtain a solution. Cabozantinib 7-lauryl sulfate was added to this solution and obtained a homogeneous mixture either as a homogeneous dispersion or by solidifying into a semisolid. This semisolid suspension was filled into hard gelatin capsules.

[0534] The composition of the capsule contents is as follows:

[0535] [Table 145]

[0536] The capsule contents of a low-dose cabozantinib capsule dosage form equivalent to a 20 mg CABOMETYX tablet contain the following composition:

[0537] [Table 146]

[0538] The capsule contents of a low-dose cabozantinib capsule dosage form equivalent to a 40 mg CABOMETYX tablet contain the following composition:

[0539] [Table 147]

[0540] The capsule contents of a low-dose cabozantinib capsule dosage form equivalent to a 60 mg CABOMETYX tablet are as follows:

[0541] [Table 148]

[0542] Low-dose cabozantinib capsule dosage forms are indicated for either: (a) Oral administration of the low-dose cabozantinib capsule dosage form may reduce the total daily cabozantinib dose by at least approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the currently U.S. FDA-approved CABOMETYX tablets. (b) Oral administration of the low-dose cabozantinib capsule dosage form can be with or without food. (c) When comparing postprandial administration with fasting administration, C max and / or the difference in AUC is less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%. (d) When the low-dose cabozantinib capsule dosage form is orally administered to subjects in the fed and / or fasted state, the coefficient of variation of AUC is less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, and / or C max The coefficient of variation of is less than about 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, or less than 10%. (e) the oral administration of a low-dose cabozantinib capsule dosage form results in at least a 20%, 25%, 30%, 35%, or 40% increase in bioavailability compared to the currently U.S. FDA-approved CABOMETYX tablets; (f) Oral administration of the low-dose cabozantinib capsule dosage form reduces the occurrence of one or more side effects compared to marketed CABOMETYX tablets. (g) Oral administration of low-dose cabozantinib capsule formulation reduces the incidence of one or more grade 2-4 adverse reactions. (h) Oral administration of the low-dose cabozantinib capsule dosage form reduces the incidence of dose interruptions and / or dose reductions due to adverse effects. (i) Oral administration of low-dose cabozantinib capsule formulation produces the combined effects described above.

[0543] The present invention illustratively described herein can be suitably practiced in the absence of any element or limitation not specifically disclosed herein. Thus, for example, in each example herein, any of the terms "comprising," "consisting essentially of," and "consisting of" can be replaced with either of the other two terms. The terms and expressions used are descriptive and not limiting. Furthermore, the use of these terms and expressions is not intended to exclude equivalents of the illustrated and described features or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as defined in the claims. Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and that such modifications and variations are deemed to be within the scope of the invention as defined by the appended claims.

[0544] (Appendix 1) A method for reducing the incidence or severity of appetite loss, weight loss, and / or gastrointestinal adverse events associated with oral cabozantinib therapy, comprising orally administering to a patient in need of such therapy a cabozantinib dosage form comprising a therapeutic amount of cabozantinib and at least one pharmaceutically acceptable excipient.

[0545] (Appendix 2) 2. The method of claim 1, wherein the gastrointestinal adverse event is diarrhea.

[0546] (Appendix 3) 2. The method of claim 1, wherein the cabozantinib dosage form is a capsule and comprises a therapeutic amount of cabozantinib lauryl sulfate and 50% to 95% by weight of one or more pharmaceutically acceptable excipients having an HLB value of 10 or greater.

[0547] (Appendix 4) 4. The method of claim 3, wherein the one or more pharmaceutically acceptable excipients having an HLB value of 10 or greater are selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene stearates, polyoxyethylene hydrogenated castor oils, poloxamers, tyloxapol, fatty acid esters of polyglycerides or fatty alcohols, vitamin E derivatives, or combinations thereof.

[0548] (Appendix 5) 4. The method of claim 3, wherein the one or more pharmaceutically acceptable excipients having an HLB value of 10 or greater are selected from the group consisting of polyoxyethylene stearate, polyoxyethylene alkyl ether, polyoxyethylene-polyoxypropylene copolymer, polyglyceride fatty acid ester, polyglyceride fatty acid alcohol, vitamin E derivative, or a combination thereof.

[0549] (Appendix 6) 4. The method of claim 3, wherein the one or more pharmaceutically acceptable excipients having an HLB value of 10 or greater are one or more polyoxyethylene stearates.

[0550] (Appendix 7) (a) reacting a 4-halo-6,7-dimethoxyquinoline with p-aminophenol to produce 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline; (b) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with 1,1-cyclopropanedicarboxylic acid to form 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid; and (c) reacting 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid with 4-fluoroaniline to produce crude cabozantinib free base; A method for producing cabozantinib, comprising:

[0551] (Appendix 8) (a) reacting a 4-halo-6,7-dimethoxyquinoline with p-aminophenol to produce 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline; (b) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with 1,1-cyclopropanedicarboxylic acid to produce 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid; (c) reacting 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid with 4-fluoroaniline to produce crude cabozantinib free base; and (d) reacting the crude cabozantinib free base with lauryl sulfate to form cabozantinib lauryl sulfate; 1. A method for producing cabozantinib lauryl sulfate, comprising:

[0552] (Appendix 9) (a) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N,N'-bis(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide); (b) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide); (c) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of N-(4-fluorophenyl)-N-(4-((6-hydroxy-7-methoxyquinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide; (d) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarboxamide, or (e) any combination of the above ingredients; Cabozantinib or a salt thereof comprising:

[0553] (Appendix 10) (a) 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline at less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm; (b) 6,7-dimethoxy-4-(4-nitrophenoxy)quinolone at less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm; (c) 3,4-dimethoxyaniline at less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm; (d) 4-aminophenol at less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm; (e) 4-fluoroaniline at less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm; or (f) any combination of the above; Cabozantinib or a salt thereof comprising:

[0554] (Appendix 11) Cabozantinib lauryl sulfate exhibiting an X-ray powder diffraction (XRPD) pattern having four or more 2θ peaks selected from the group consisting of 5.0±0.2, 11.3±0.2, 12.1±0.2, 13.5±0.2, 16.8±0.2, 17.5±0.2, 18.6±0.2, 20.2±0.2, 20.6±0.2, 21.3±0.2, 21.9±0.2, 22.4±0.2, 22.7±0.2, 23.2±0.2, 24.2±0.2, 26.6±0.2, and / or 27.7±0.2.

[0555] (Appendix 12) 1. A method of treating a human subject in need of cabozantinib treatment, comprising: (i) determining the amount of cabozantinib free base that will provide or is currently providing a therapeutic dose of cabozantinib to said subject in need of cabozantinib treatment by oral administration of cabozantinib (S)-malate in the form of a solid immediate-release tablet and / or immediate-release capsule; and (ii) orally administering to said subject one or more capsules; Including, the capsule contents comprising a therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate and 50% to 90% by weight of one or more pharmaceutically acceptable excipients, wherein the therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate is 90% or less of the amount of cabozantinib determined in step (i); method.

[0556] (Appendix 13) 13. The method of claim 12, wherein the therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate is 85% or less of the amount of cabozantinib determined in step (i).

[0557] (Appendix 14) 13. The method of claim 12, wherein the therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate is 80% or less of the amount of cabozantinib determined in step (i).

[0558] (Appendix 15) 13. The method of claim 12, wherein the therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate is 75% or less of the amount of cabozantinib determined in step (i).

[0559] (Appendix 16) 16. The method of any of claims 12 to 15, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oils, polyoxyethylene stearates, polyoxyethylene hydrogenated castor oils, poloxamers, tyloxapol, fatty acid esters of polyglycerides or fatty alcohols, vitamin E derivatives, or combinations thereof.

Claims

1. A method for reducing the incidence or severity of appetite loss, weight loss, and / or gastrointestinal adverse events associated with oral cabozantinib therapy, comprising orally administering to a patient in need of such therapy a cabozantinib dosage form comprising a therapeutic amount of cabozantinib and at least one pharmaceutically acceptable excipient.

2. 10. The method of claim 1, wherein the gastrointestinal adverse event is diarrhea.

3. 10. The method of claim 1, wherein the cabozantinib dosage form is a capsule and comprises a therapeutic amount of cabozantinib lauryl sulfate and 50% to 95% by weight of one or more pharmaceutically acceptable excipients having an HLB value of 10 or greater.

4. 4. The method of claim 3, wherein the one or more pharmaceutically acceptable excipients having an HLB value of 10 or greater are selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene stearates, polyoxyethylene hydrogenated castor oils, poloxamers, tyloxapol, fatty acid esters of polyglycerides or fatty acid alcohols, vitamin E derivatives, or combinations thereof.

5. 4. The method of claim 3, wherein the one or more pharmaceutically acceptable excipients having an HLB value of 10 or greater are selected from the group consisting of polyoxyethylene stearate, polyoxyethylene alkyl ether, polyoxyethylene-polyoxypropylene copolymer, polyglyceride fatty acid ester, polyglyceride fatty acid alcohol, vitamin E derivative, or combinations thereof.

6. 4. The method of claim 3, wherein the one or more pharmaceutically acceptable excipients having an HLB value of 10 or greater are one or more polyoxyethylene stearates.

7. (a) reacting a 4-halo-6,7-dimethoxyquinoline with p-aminophenol to produce 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline; (b) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with 1,1-cyclopropanedicarboxylic acid to produce 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid; and (c) reacting 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid with 4-fluoroaniline to produce crude cabozantinib free base; A method for producing cabozantinib, comprising:

8. (a) reacting a 4-halo-6,7-dimethoxyquinoline with p-aminophenol to produce 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline; (b) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with 1,1-cyclopropanedicarboxylic acid to produce 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid; (c) reacting 1-((4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)carbamoyl)cyclopropane-1-carboxylic acid with 4-fluoroaniline to produce crude cabozantinib free base; and (d) reacting the crude cabozantinib free base with lauryl sulfate to form cabozantinib lauryl sulfate; A method for producing cabozantinib lauryl sulfate, comprising:

9. (a) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N,N'-bis(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide); (b) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide); (c) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of N-(4-fluorophenyl)-N-(4-((6-hydroxy-7-methoxyquinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide; (d) less than 0.2%, less than 0.15%, less than 0.1%, or less than 0.05% of (N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarboxamide, or (e) any combination of the above ingredients; Cabozantinib or a salt thereof comprising:

10. (a) less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm of 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline; (b) 6,7-dimethoxy-4-(4-nitrophenoxy)quinolone at less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm; (c) less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm of 3,4-dimethoxyaniline; (d) less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm of 4-aminophenol; (e) less than 250 ppm, less than 125 ppm, less than 37.5 ppm, less than 25 ppm, less than 15 ppm, less than 10 ppm, or less than 7.5 ppm of 4-fluoroaniline, or (f) any combination of the above; Cabozantinib or a salt thereof comprising:

11. Cabozantinib lauryl sulfate, exhibiting an X-ray powder diffraction (XRPD) pattern with four or more 2-theta peaks selected from the group consisting of 5.0±0.2, 11.3±0.2, 12.1±0.2, 13.5±0.2, 16.8±0.2, 17.5±0.2, 18.6±0.2, 20.2±0.2, 20.6±0.2, 21.3±0.2, 21.9±0.2, 22.4±0.2, 22.7±0.2, 23.2±0.2, 24.2±0.2, 26.6±0.2, and / or 27.7±0.

2.

12. 1. A method of treating a human subject in need of cabozantinib treatment, comprising: (i) determining the amount of cabozantinib free base that will provide or is currently providing a therapeutic dose of cabozantinib to said subject in need of cabozantinib treatment by oral administration of cabozantinib (S)-malate in the form of a solid immediate-release tablet and / or immediate-release capsule; and (ii) orally administering one or more capsules to said subject; Including, the capsule contents comprising a therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate and 50% to 90% by weight of one or more pharmaceutically acceptable excipients, wherein the therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate is 90% or less of the amount of cabozantinib determined in step (i); method.

13. 13. The method of claim 12, wherein the therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate is no more than 85% of the amount of cabozantinib determined in step (i).

14. 13. The method of claim 12, wherein the therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate is no more than 80% of the amount of cabozantinib determined in step (i).

15. 13. The method of claim 12, wherein the therapeutic amount of cabozantinib in the form of cabozantinib lauryl sulfate is no more than 75% of the amount of cabozantinib determined in step (i).

16. 16. The method of any of claims 12-15, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, polyoxyethylene castor oil, polyoxyethylene stearates, polyoxyethylene hydrogenated castor oil, poloxamers, tyloxapol, fatty acid esters of polyglycerides or fatty alcohols, vitamin E derivatives, or combinations thereof.

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