MRTX1133 capsule pharmaceutical compositions

Abstract

Capsule pharmaceutical compositions of MRTX1133 (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1Hpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol) in suspension; methods for preparing these compositions, and methods of their use for the treatment of 5 various diseases and disorders.

Description

[0001] MRTX1133 CAPSULE PHARMACEUTICAL COMPOSITIONS

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 706,267, filed October 11, 2024, the entire content of which is hereby incorporated herein by reference.

[0004] FIELD OF THE INVENTION

[0005] The present invention generally relates to capsule pharmaceutical compositions of MRTX1133 (4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-lHpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol); methods for preparing these compositions, and methods of their use for the treatment of various diseases and disorders.

[0006] BACKGROUND OF THE INVENTION

[0007] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch cycling between inactive (GDP -bound) and active (GTP -bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors regulating a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0008] The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 -30% of lung adenocarcinomas, (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038 / nrd428). Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma. KRAS G12D mutation is present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal carcinoma patients, 10.1% of all rectal carcinoma patients, 4.1% of all non-small cell lung carcinoma patients and 1.7% of all small cell lung carcinoma patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8): 818-831. Dataset Version 4). The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy.

[0009] Compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi: 10.1002 / anie201201358) as well recent advances in the covalent targeting of an allosteric pocket of KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9: 1230-1234). Clearly, there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants, especially KRas G12D.

[0010] A noncovalent inhibitor of KRas G12D is MRTX1133 (4-(4-((lR,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-lHpyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol). An amorphous form of this compound was described in International Patent Application PCT / US2020 / 048194 filed August 27, 2020 and published as WIPO publication WO202 1 / 041671 on March 4, 2021 at Example 252. The compound is also described in Qinheng Zheng et al, Identification ofMRTX1133, a Noncovalent, Potent, and Selective KRAS°12DInhibitor, J. Med. Chem, 2022, 65,4,3123-3133.

[0011] A need therefore exists for a pharmaceutical composition of MRTX1133 which displays suitable bioavailability and shelf-life chemical stability, and which has fewer side effects compared with prior art capsule formulations.

[0012] SUMMARY OF THE INVENTION

[0013] In one embodiment, the present invention provides a capsule pharmaceutical composition, suitable for oral administration to a subject, including but not limited to a human subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing AUC o^ / (the area under the curve of a plot of plasma drug concentration versus time) for MRTX1133 of at least, or about, 6900 ng*hr / mL.

[0014] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC o^iast for MRTX1133 of at least, or about, 6700 ng*hr / mL. In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC 24^48 for MRTX1133 of at least, or about, 3900 ng*hr / mL.

[0015] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC 0^36 for MRTX1133 of at least, or about, 4700 ng*hr / mL.

[0016] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC 0^24 for MRTX1133 of at least, or about, 2800 ng*hr / mL.

[0017] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC 0^12 for MRTX1133 of at least, or about, 700 ng*hr / mL.

[0018] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing Cmax for MRTX1133 of at least, or about, 710 ng / mL.

[0019] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing: a) AUC 0^ / for MRTX1133 of at least, or about, 6900 ng*hr / mL; b) AUC oblast for MRTX1133 of at least, or about, 6700 ng*hr / mL; c) AUC 24^48 for MRTX1133 of at least, or about, 3900 ng*hr / mL; d) AUC < 36 for MRTX1133 of at least, or about, 4700 ng*hr / mL; e) AUC 0^24 for MRTX1133 of at least, or about, 2800 ng*hr / mL; f) AUC 0^12 for MRTX1133 of at least, or about, 700 ng*hr / mL; and g) Cmax for MRTX1133 of at least, or about, 710 ng / mL.

[0020] In any of the embodiments, it is not required that the recited pharmacokinetic (PK) values, such as AUC 0^ / , AUC o->iast, AUC 24^48, AUC < 36, AUC 0^24, AUC 0^12 and Cmax, are achieved by administering a single pharmaceutical composition. The invention contemplates, and explicitly includes, embodiments where these PK values are achieved following administration of several capsule pharmaceutical compositions as a single dose (e.g., if a capsule pharmaceutical composition comprises 150 mg MRTX1133, the single dose may include, for example, three of such pharmaceutical compositions, for the total administered amount of 450 mg MRTX1133).

[0021] In another embodiment, MRTX1133 is present as a salt thereof. In another embodiment, the capsule pharmaceutical composition comprises at least one additional anticancer compound in addition to MRTX1133.

[0022] In one embodiment, the pharmaceutical composition of the invention comprises MRTX1133 and sucrose acetate isobutyrate (“SAIB”).

[0023] In one embodiment, the pharmaceutical composition of the invention comprises medium-chain triglycerides (“MCT”).

[0024] In one embodiment, the capsule pharmaceutical composition of the invention comprises MRTX1133, SAIB, an emulsifier, and a surfactant.

[0025] In a preferred embodiment, the surfactant is a non-ionic surfactant. In a more preferred embodiment, the surfactant comprises mixtures containing mono-, di- / triglycerides and mono- / di-fatty acid esters of polyethylene glycol (PEG). In another preferred embodiment, the surfactant comprises caprylocaproyl Polyoxyl-8 glycerides (Labrasol®). In another embodiment, the surfactant comprises one or more poloxamers.

[0026] In a preferred embodiment, the emulsifier comprises one or more of D-u-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) and propylene glycol diesters of saturated fatty acids (Captex® 200P).

[0027] In a preferred embodiment, the capsule pharmaceutical composition is free of a solvent.

[0028] In a preferred embodiment, the capsule is an hydroxypropyl methylcellulose (HPMC) capsule.

[0029] In another embodiment, the capsule pharmaceutical composition is provided as a unit dosage form.

[0030] In one embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 25 mg.

[0031] In one embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 50 mg.

[0032] In one embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 100 mg.

[0033] In one embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 150 mg. In another embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 200 mg.

[0034] In another embodiment, the amount of MRTX1133in the capsule pharmaceutical composition is at least, or about, 300 mg.

[0035] In another embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 400 mg.

[0036] In another embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 600 mg.

[0037] In another embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 800 mg.

[0038] In one embodiment, the amount of MRTX1133 in the composition is between 5-50%; preferably between 10-45%; more preferably between 15-40%, and most preferably between 20-40% by weight of the composition.

[0039] In another embodiment, the composition comprises:

[0040] (1) MRTX1133 constituting about 10-40% of the composition;

[0041] (2) SAIB constituting about 25-60%, preferably about 35-60% of the composition;

[0042] (3) an emulsifier constituting about 10-35%, preferably about 15-35% of the composition; and

[0043] (4) a surfactant constituting up to about 5-30%, preferably about 10-30% of the composition; wherein all percentages are percentages by weight and wherein the total weight is 100%, and wherein the composition is in the form of a capsule, and wherein the MRTX1133, the SAIB, the emulsifier, and the surfactant are mixed in a suspension.

[0044] In a preferred embodiment, MRTX1133 constitutes between about 10% and about 30% of the composition.

[0045] In another preferred embodiment, MRTX1133 constitutes about 10% of the composition.

[0046] In another preferred embodiment, MRTX1133 constitutes about 15% of the composition. In another preferred embodiment, MRTX1133 constitutes about 20% of the composition.

[0047] In another preferred embodiment, MRTX1133 constitutes about 35% of the composition.

[0048] In another embodiment, the composition comprises:

[0049] (1) MRTX1133 at about 20% of the composition;

[0050] (2) a mixture of SAIB and MCT at about 37% of the composition;

[0051] (3) propylene glycol diesters of saturated fatty acids (Captex® 200P) at about 20% of the composition;

[0052] (4) Vitamin E TPGS at about 11% of the composition; and

[0053] (5) Caprylocaproyl Polyoxyl-8 glycerides (Labrasol®) at about 11% of the composition; wherein all percentages are percentages by weight and wherein the total weight is 100%, and wherein the composition is in the form of a capsule comprising a suspension.

[0054] In another embodiment, the composition comprises:

[0055] (1) MRTX1133 at about 20% of the composition;

[0056] (2) SAIB at about 35% of the composition;

[0057] (3) Caprylocaproyl Polyoxyl-8 glycerides (Labrasol ®)at about 15% of the composition;

[0058] (4) Vitamin E TPGS at about 15% of the composition; and

[0059] (5) pol oxamer 407 at about 15% of the composition, wherein all percentages are percentages by weight and wherein the total weight is 100% and wherein the composition is in the form of a capsule comprising a suspension.

[0060] In one embodiment, the capsule pharmaceutical composition may comprise additional excipients selected from the group consisting of fillers, super-disintegrants, binders, glidants, lubricants, and combinations thereof.

[0061] In another embodiment, the invention is directed to a method of treating cancer in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of the capsule pharmaceutical composition of the present invention. In one embodiment, the therapeutically effective amount is at least, or about, 25 mg of MRTX1133. In another embodiment, the therapeutically effective amount is at least, or about, 50 mg of MRTX1 133. In another embodiment, the therapeutically effective amount is at least, or about, 100 mg of MRTX1133. In one embodiment, the therapeutically effective amount is at least, or about, 150 mg of MRTX1133. In one embodiment, the cancer is a KRas G12D- associated cancer. In one embodiment, the KRas G12D-associated cancer is lung cancer.

[0062] Also provided herein are methods for treating cancer in a subject in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer) (e.g., as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of the capsule pharmaceutical composition of the present invention.

[0063] BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 is a graph of plasma concentration of MRTX1133 after MRTA301 dosing.

[0065] Figure 2 is a graph of plasma concentration of MRTX1133 after MRTA304 dosing.

[0066] DETAILED DESCRIPTION OF THE INVENTION

[0067] Definitions

[0068] The term “MRTX1133” as used herein refers to a compound with the following formula: as well as pharmaceutically acceptable salts of this compound. The compound has the following chemical name: (4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-lHpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol). The invention encompasses amorphous and crystalline forms of MRTX1133. An amorphous form of this compound was described in International Patent Application PCT / US2020 / 048194 filed August 27, 2020 and published as WIPO publication W02021 / 041671 on March 4, 2021 at Example 252. The compound is also described in Qinheng Zheng et al, Identification ofMRTX1133, a Noncovalent, Potent, and Selective KRASG12DInhibitor, J. Med. Chem, 2022, 65,4,3123-3133. The contents of this patent application and of the literature reference are hereby incorporated by reference in their entirety.

[0069] As used herein, “KRas G12D” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Glyl2Asp.

[0070] The term “composition” as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0071] The term “capsule composition” as used herein is intended to encompass capsules, including but not limited to HPMC capsules, gelatinous capsules, and other capsules containing a suspension.

[0072] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0073] The term “crystalline” and related terms used herein, when used to describe a substance, component or product, means that the substance, component or product is crystalline as determined by X-ray diffraction. See, for example, Remington ’s Pharmaceutical Sciences, 18thed., Mack Publishing, Easton PA, p. 173 (1990); The United States Pharmacopeia, 23rded., pp. 1843-1844 (1995); the contents of which are hereby incorporated by reference in their entireties. The term “crystalline forms” and related terms herein refers to the various crystalline modifications of a given substance, including, but not limited to, polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof.

[0074] The term “pharmaceutically acceptable salts” is meant to include salts of active compounds which are prepared with relatively nontoxic acids. Acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic; propionic; isobutyric; maleic; malonic; benzoic; succinic; suberic; fumaric; mandelic; phthalic; benzenesulfonic; toluenesulfonic, including -toluenesulfonic, m-toluenesulfonic, and o-toluenesulfonic; citric; tartaric; methanesulfonic; and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like see, for example, Berge et al. J. Pharm. Sci. 66: 1-19 (1977)).

[0075] The term, “amorphous form,” as used herein, refers to a noncrystalline form of a substance.

[0076] The terms, “polymorphs” and “polymorphic forms” and related terms herein refer to crystal forms of a molecule. Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and / or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in bioavailability). Polymorphs of a molecule can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation. Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, e.g., IR and Raman spectroscopy, solid state NMR, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies.

[0077] The term, “solvate,” as used herein, refers to a crystal form of a substance which contains solvent. The term “hydrate” refers to a solvate wherein the solvent is water.

[0078] The term, “desolvated solvate,” as used herein, refers to a crystal form of a substance which can only be made by removing the solvent from a solvate.

[0079] The term “excipient” refers to an inactive ingredient of the pharmaceutical compositions of the invention. It includes, but is not limited to, solvents, wetting agents, diluents, superdisintegrants, binders, glidants, and lubricants.

[0080] The terms “treat”, “treating” or “treatment”, as used herein, refer to the reduction or amelioration of the progression, severity, and / or duration of a disorder or the eradication, reduction or amelioration of symptoms of a disorder, or the delay of the recurrence or onset of a disorder or one or more symptoms thereof in a subject that results from the administration of one or more compound.

[0081] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0082] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.

[0083] As used herein, the term “subject,” "individual," or "patient," used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRas G12D mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a KRas G12D mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a KRas G12D mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a KRas G12D mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12D gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRas G12D mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0084] The term “pediatric patient” as used herein refers to a patient under the age of 16 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0085] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the patient has KRas G12D mutation using a sample (e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12D-associated cancer, a patient having one or more symptoms of a KRas G12D-associated cancer, and / or a patient that has an increased risk of developing a KRas G12D-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping or ddPCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof. The term “regulatory agency” is a country’s agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0086] As used herein, a "therapeutically effective amount" is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12D. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0087] As used herein, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0088] The term, “AUC,” as used herein, refers to the area under the curve of a plot of plasma drug concentration versus time.

[0089] The term, “Tmax,” as used herein, refers to the time after administration of a drug when the maximum plasma concentration is reached.

[0090] A "KRas G12D-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12D mutation. A non-limiting example of a KRas G12D-associated disease or disorder is a KRas G12D-associated cancer.

[0091] DETAILED DESCRIPTION OF COMPOSITIONS AND METHODS

[0092] The present invention is based on a surprising discovery that capsule pharmaceutical compositions comprising MRTX1133 and that also include SAIB (sucrose acetate isobutyrate) that are suspended in the lipids without a solvent result in chemically stable formulations.

[0093] In one embodiment, the present invention provides a capsule pharmaceutical composition, suitable for oral administration to a subject, including but not limited to a human subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof, in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing AUC o^ / (the area under the curve of a plot of plasma drug concentration versus time) for MRTX1133 of at least, or about, 6900 ng*hr / mL.

[0094] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC o^iast for MRTX1133 of at least, or about, 6700 ng*hr / mL.

[0095] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC 24^48 for MRTX1133 of at least, or about, 3900 ng*hr / mL.

[0096] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC 0^36 for MRTX1133 of at least, or about, 4700 ng*hr / mL.

[0097] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC 0^24 for MRTX1133 of at least, or about, 2800 ng*hr / mL.

[0098] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing AUC 0^12 for MRTX1133 of at least, or about, 700 ng*hr / mL.

[0099] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing Cmax for MRTX1133 of at least, or about, 710 ng / mL.

[0100] In another embodiment, the capsule pharmaceutical composition, after administration to a subject, is capable of providing: a) AUC 0^ / for MRTX1133 of at least, or about, 6900 ng*hr / mL; b) AUC oblast for MRTX1133 of at least, or about, 6700 ng*hr / mL; c) AUC 24^48 for MRTX1133 of at least, or about, 3900 ng*hr / mL; d) AUC < 36 for MRTX1133 of at least, or about, 4700 ng*hr / mL; e) AUC 0^24 for MRTX1133 of at least, or about, 2800 ng*hr / mL; f) AUC 0^12 for MRTX1133 of at least, or about, 700 ng*hr / mL; and g) Cmax for MRTX1133 of at least, or about, 710 ng / mL.

[0101] In any of the embodiments, it is not required that the recited pharmacokinetic (PK) values, such as AUC 0^ / , AUC o->iast, AUC 24^48, AUC < 36, AUC 0^24, AUC 0^12 and Cmax, are achieved by administering a single pharmaceutical composition. The invention contemplates, and explicitly includes, embodiments where these PK values are achieved following administration of several capsule pharmaceutical compositions as a single dose (e.g., if a capsule pharmaceutical composition comprises 150 mg MRTX1133, the single dose may include, for example, three of such pharmaceutical compositions, for the total administered amount of 450 mg MRTX1133).

[0102] In another embodiment, MRTX1133 is present as a salt thereof.

[0103] In another embodiment, the capsule pharmaceutical composition comprises at least one additional anticancer compound in addition to MRTX1133.

[0104] In one embodiment, the pharmaceutical composition of the invention comprises MRTX1133 and sucrose acetate isobutyrate (“SAIB”).

[0105] In one embodiment, the pharmaceutical composition of the invention comprises medium-chain triglycerides (“MCT”).

[0106] In one embodiment, the capsule pharmaceutical composition of the invention comprises MRTX1133, SAIB, an emulsifier, and a surfactant.

[0107] In a preferred embodiment, the surfactant is a non-ionic surfactant. In a more preferred embodiment, the surfactant comprises mixtures containing mono-, di- / triglycerides and mono- / di-fatty acid esters of polyethylene glycol (PEG). In another preferred embodiment, the surfactant comprises caprylocaproyl Polyoxyl-8 glycerides (Labrasol®). In another embodiment, the surfactant comprises one or more poloxamers.

[0108] In a preferred embodiment, the emulsifier comprises one or more of D-u-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) and propylene glycol diesters of saturated fatty acids (Captex® 200P).

[0109] In a preferred embodiment, the capsule pharmaceutical composition is free of a solvent.

[0110] In a preferred embodiment, the capsule is an hydroxypropyl methylcellulose (HPMC) capsule.

[0111] In another embodiment, the capsule pharmaceutical composition is provided as a unit dosage form.

[0112] In one embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 25 mg.

[0113] In one embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 50 mg. In one embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 100 mg.

[0114] In one embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 150 mg.

[0115] In another embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 200 mg.

[0116] In another embodiment, the amount of MRTX1133in the capsule pharmaceutical composition is at least, or about, 300 mg.

[0117] In another embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 400 mg.

[0118] In another embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 600 mg.

[0119] In another embodiment, the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 800 mg.

[0120] In one embodiment, the amount of MRTX1133 in the composition is between 5-50%; preferably between 10-45%; more preferably between 15-40%, and most preferably between 20-40% by weight of the composition.

[0121] In another embodiment, the composition comprises:

[0122] (1) MRTX1133 constituting about 10-40% of the composition;

[0123] (2) SAIB constituting about 35-60% of the composition;

[0124] (3) an emulsifier constituting about 15-35% of the composition; and

[0125] (4) a surfactant constituting up to about 10-30% of the composition; wherein all percentages are percentages by weight and wherein the total weight is 100%, and wherein the composition is in the form of a capsule, and wherein the MRTX1133, the SAIB, the emulsifier, and the surfactant are in a suspension.

[0126] In a preferred embodiment, MRTX1133 constitutes between about 10% and about 30% of the composition.

[0127] In another preferred embodiment, MRTX1133 constitutes about 10% of the composition. In another preferred embodiment, MRTX1133 constitutes about 15% of the composition.

[0128] In another preferred embodiment, MRTX1133 constitutes about 20% of the composition.

[0129] In another preferred embodiment, MRTX1133 constitutes about 35% of the composition.

[0130] In another embodiment, the composition comprises:

[0131] (1) MRTX1133 at about 20% of the composition;

[0132] (2) a mixture of SAIB and MCT at about 37% of the composition;

[0133] (3) propylene glycol diesters of saturated fatty acids (Captex® 200P) at about 20% of the composition;

[0134] (4) Vitamin E TPGS at about 11% of the composition; and

[0135] (5) Caprylocaproyl Polyoxyl-8 glycerides (Labrasol®) at about 11% of the composition; wherein all percentages are percentages by weight and wherein the total weight is 100%, and wherein the composition is in the form of a capsule comprising a suspension.

[0136] In another embodiment, the composition comprises:

[0137] (1) MRTX1133 at about 20% of the composition;

[0138] (2) SAIB at about 35% of the composition;

[0139] (3) Caprylocaproyl Polyoxyl-8 glycerides (Labrasol®) at about 15% of the composition;

[0140] (4) Vitamin E TPGS at about 15% of the composition; and

[0141] (5) pol oxamer 407 at about 15% of the composition, wherein all percentages are percentages by weight and wherein the total weight is 100% and wherein the composition is in the form of a capsule comprising a suspension.

[0142] In one embodiment, the capsule pharmaceutical composition may comprise additional excipients selected from the group consisting of fillers, super-disintegrants, binders, glidants, lubricants, and combinations thereof. Also provided herein are methods for treating cancer in a subject in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation (e.g., a KRas G12D-associated cancer) (e.g., as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of the capsule pharmaceutical composition of the present invention.

[0143] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including, for example, the activity of the specific polymorph employed, the metabolic stability and length of action of that polymorph, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, and the severity of the patient’s condition.

[0144] The pharmaceutical compositions provided herein can be combined with other compounds having related utilities to treat or prevent cancer. In many instances, administration of the subject pharmaceutical compositions in conjunction with these alternative agents enhances the efficacy of such agents. Accordingly, in some instances, the present pharmaceutical compositions, when combined or administered in combination with, e.g., anti-cancer agents, can be used in dosages which are less than the expected amounts when used alone, or less than the calculated amounts for combination therapy.

[0145] EXAMPLES OF THE INVENTION

[0146] The following Examples illustrate the invention.

[0147] EXAMPLE 1 : MRTX1133 formulations

[0148] This example illustrates MRTX1133 capsule pharmaceutical compositions.

[0149] Materials and Methods:

[0150] Vitamin E TPGS was purchased from Antares Pharma; Labrasol® ALF (Caprylocaproyl Polyoxyl-8 glycerides) were provided by Gattefosse; Sucrose Acetate Isobutyrate (SAIB), BioSustane SAIB NF, was purchased from Eastman Chemicals; MRTX1 133 (96%) was provided by Mirati Therapeutics Process Chemistry Group.

[0151] Instruments: Agilent 1260 HPLC equipped with a reverse phase HPLC column and method and Agilent Gas Chromatograph model. Reduced pressure evaporation equipment: Heidolph model Hei-VAP Core. Table 1 illustrates the MRTA301 composition and Table 2 illustrates the MRTA304 composition.

[0152] TABLE 1

[0153] MRTA301 composition Formulation composition of oral lipid suspension lot no. MRTA301 filled in a vegan clear HPMC capsule, size 00 (Capsuline)

[0154] TABLE 2

[0155] MRTA304 composition Formulation composition of oral lipid suspension lot no. MRTA304 filled in a vegan clear HPMC capsule, size 00 (Capsuline)

[0156] Preparation of MRTA-301

[0157] Captex 200P, Labrasol ALF, TPGS, and a mixture of SAIB / MCT were weighed into an 8 oz wide mouth jar. The jar was placed into 70°C oven until all solid materials were melted and formed into a single-phase solution. The solution was swirled well to enable mixing. The solution was set on a magnetic stir plate at 60°C for at least 5 minutes prior to adding API. Under stirring, MRTX1133 was incrementally added. The mixture was mixed for approximately 60 minutes. The jar was then placed in a 60°C oven for 15-30 minutes and vortexed intermittently to complete a solution resembling a viscous paste. The 750 mg suspension formulation was filled into size 00 HPMC capsules.

[0158] Preparation of MRTA-304

[0159] SAIB was heated in an oven to 70°C to reduce its viscosity and enable dispensing. The SAIB was weighed into an 8 oz wide mouth jar. Labrasol ALF was weighed into the jar using a pipette for fine addition. The jar was heated in a 60°C water bath. Then, the overhead mixer started rotating. The other excipients were weighed individually and added to the jar to melt and were mixed thoroughly. API was weighed on weigh paper and added to the jar and was mixed thoroughly. The 500 mg suspension formulation was filled into size 00 HPMC capsules.

[0160] EXAMPLE 2: pharmacokinetics IN DOGS

[0161] Test System and Study Design:

[0162] Three, non-naive, fasted and pentagastrin-pretreated (IM injection, 6 pg / kg, 30 mins prior to each administration), male beagle dogs (> 8kg and >6 months old) were administered 3 (three) 150 mg MRTX1133 (00 size) capsules, administered twice a day (BID) for two days.

[0163] Blood samples were collected on:

[0164] T=0, 0.25, 0.5, 1,2, 4, 8, 12, 13, 14, 15, 18, 24, 25, 26, 27, 30, 36, 37, 38, 39, 42 and 48 h. Blood was collected into commercially available tubes (Jiangsu Kangjian Medical Supplies co., LTD) containing Potassium (K2) EDTA (0.85-1.15 mg) gently inverted several times to ensure mixing and placed on wet ice until processed for plasma. Samples were centrifuged (3,200 x g for 10 minutes at 2 to 8°C) within 30 minutes from collection. The plasma sample (2*100pL, one for analysis, one for backup) were transferred into labeled polypropylene micro-centrifuge tubes and stored frozen in a <-60°C freezer until analyzed.

[0165] Test articles concentrations (ng / mL) in plasma were quantified by LC-MS / MS with internal standard.

[0166] Results

[0167] The pharmacokinetic profile of MRTA301 formulation is shown in Figure 1. The X- axis is time (hours) and the Y-axis is blood concentration (ng / mL). The main measure of success of each formulation is the ability to deliver MRTX1133 in blood at levels above 100 ng / mL during the 12 hours post-administration time interval. Based on the data illustrated in Figure 1, formulations MRTA301 was able to deliver 100 ng / mL MRTX1133 for the majority of time post dosage administration.

[0168] The pharmacokinetic profile of MRTA304 formulation is shown in Figure 2.

[0169] EXAMPLE 3: CHEMICAL STABILITY

[0170] MRTX1 133 Lipid Suspension Capsules prototype batches of the 100 mg and 150 dose strengths were packaged in 60 cc high density polyethylene (HDPE) bottles and polypropylene (PP), child resistant (CR) closures with heat induction seals. The packaged products were stored at long term storage condition of -20°C and the elevated temperature of 2-8°C.

[0171] Available stability data indicates that there are no significant changes observed at -20°C over 7 months. At 2-8°C, assay strength remains remarkably strong, with very little if any, change, but there is a slight increase in the amount of impurities. At 25°C, there is a trend of assay strength decrease and impurities increase. Representative stability sets are shown in Tables 3 and 4 below. TABLE 3

[0172] Chemical Stability of Oral Lipid Suspension Lot No. MRTA301

[0173] TABLE 4

[0174] Chemical Stability of Oral Lipid Suspension Lot No. MRTA304

[0175] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of the specification that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A capsule pharmaceutical composition, suitable for oral administration to a subject, which comprises MRTX1133 ((4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-lHpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol) or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing AUC o^ / (the area under the curve of a plot of plasma drug concentration versus time) for MRTX1133 of at least, or about, 6900 ng*hr / mL.

2. A capsule pharmaceutical composition, suitable for oral administration to a subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing AUC oblast for MRTX1133 of at least, or about, 6700 ng*hr / mL.

3. A capsule pharmaceutical composition, suitable for oral administration to a subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing AUC 24^48 for MRTX1133 of at least, or about, 3900 ng*hr / mL.

4. A capsule pharmaceutical composition, suitable for oral administration to a subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing AUC 0^36 for MRTX1133 of at least, or about, 4700 ng*hr / mL.

5. A capsule pharmaceutical composition, suitable for oral administration to a subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing AUC 0^24 for MRTX1133 of at least, or about, 2800 ng*hr / mL.

6. A capsule pharmaceutical composition, suitable for oral administration to a subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing AUC 0^12 for MRTX1133 of at least, or about, 700 ng*hr / mL.

7. A capsule pharmaceutical composition, suitable for oral administration to a subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing Cmax for MRTX1133 of at least, or about, 710 ng / mL.

8. A capsule pharmaceutical composition, suitable for oral administration to a subject, which comprises MRTX1133 or a pharmaceutically acceptable salt thereof in a suspension, wherein the capsule pharmaceutical composition, after administration to the subject, is capable of providing: a)for MRTX1133 of at least, or about, 6900 ng*hr / mL; b) AUC oblast for MRTX1133 of at least, or about, 6700 ng*hr / mL; c) AUC 24^48 for MRTX1 133 of at least, or about, 3900 ng*hr / mL; d) AUC < 36 for MRTX1133 of at least, or about, 4700 ng*hr / mL; e) AUC 0^24 for MRTX1133 of at least, or about, 2800 ng*hr / mL; f) AUC 0^12 for MRTX1133 of at least, or about, 700 ng*hr / mL; and g) Cmax for MRTX1133 of at least, or about, 710 ng / mL.

9. The capsule pharmaceutical composition of any one of claims 1-8 wherein the capsule pharmaceutical composition is free of solvents.

10. The capsule pharmaceutical composition of claim 9, wherein MRTX1133 constitutes 5-50% by the weight of the composition.

11. The capsule pharmaceutical composition of claim 9, wherein MRTX1133 constitutes 10-45% by the weight of the composition.

12. The capsule pharmaceutical composition of claim 9, wherein MRTX1133 constitutes 15-40% by the weight of the composition.

13. The s capsule pharmaceutical composition of claim 9, wherein MRTX1133 constitutes 20-40% by the weight of the composition.

14. The capsule pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises:(1) MRTX1133 constituting about 10-40% of the composition;(2) SAIB constituting about 35-60% of the composition;(3) an emulsifier constituting about 15-35% of the composition; and(4) a surfactant constituting up to about 10-30% of the composition; wherein all percentages are percentages by weight and wherein the total weight is 100%, and wherein the composition is in the form of a capsule, and wherein the MRTX1133, the SAIB, the emulsifier, and the surfactant are in a suspension.

15. The capsule pharmaceutical composition of claim 14, wherein MRTX1133 constitutes between about 10% and about 20% percent of the composition.

16. The capsule pharmaceutical composition of claim 14, wherein MRTX1133 constitutes about 15% of the composition.

17. The capsule pharmaceutical composition of claim 14, wherein MRTX1133 constitutes about 20% of the composition.

18. The capsule pharmaceutical composition of claim 14, wherein MRTX1133 constitutes about 35% of the composition.

19. The capsule pharmaceutical composition of any one of claims 1-18, wherein MRTX1 133 is present as a salt thereof.

20. The capsule pharmaceutical composition of any one of claims 1-19, wherein the capsule pharmaceutical composition comprises at least one additional anticancer compound in addition to MRTX1133.

21. The capsule pharmaceutical composition of any one of claims 1-20, wherein the capsule pharmaceutical composition is provided as a unit dosage form.

22. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 25 mg.

23. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 50 mg.

24. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 100 mg.

25. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 150 mg.

26. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 200 mg.

27. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 300 mg.

28. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 400 mg.

29. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 600 mg.

30. The capsule pharmaceutical composition of any one of claims 1-21, wherein the amount of MRTX1133 in the capsule pharmaceutical composition is at least, or about, 800 mg.

31. The capsule pharmaceutical composition of claim 9, comprising(1) MRTX1133 at about 20% of the composition;(2) a mixture of SAIB and MCT at about 37% of the composition;(3) propylene glycol diesters of saturated fatty acids (Captex® 200P) at about 20% of the composition;(4) Vitamin E TPGS at about 11% of the composition; and(5) Caprylocaproyl Polyoxyl-8 glycerides (Labrasol®) at about 11% of the composition; wherein all percentages are percentages by weight and wherein the total weight is 100%, and wherein the composition is in the form of a capsule comprising a suspension.

32. The capsule pharmaceutical composition of claim 9, comprising(1) MRTX1133 at about 20% of the composition;(2) SAIB at about 35% of the composition;(3) Caprylocaproyl Polyoxyl-8 glycerides (Labrasol®) at about 15% of the composition;(4) Vitamin E TPGS at about 15% of the composition; and(5) pol oxamer 407 at about 15% of the composition, wherein all percentages are percentages by weight and wherein the total weight is 100% and wherein the composition is in the form of a capsule comprising a suspension.

33. The capsule pharmaceutical composition of claim 14, wherein the emulsifier comprises one or more of D-u-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) and propylene glycol diesters of saturated fatty acids (Captex® 200P).

34. The capsule pharmaceutical composition of claim 14, wherein the surfactant comprises one or more of Capryl ocaproyl Polyoxyl-8 glycerides (Labrasol®) and a poloxamer.

35. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the capsule pharmaceutical composition of any one of claims 1-34.

36. The method of claim 35, wherein the therapeutically effective amount is at least, or about, 25 mg ofMRTX1133.

37. The method of claim 35, wherein the cancer is a KRas G12D-associated cancer.

38. The method of claim 35, wherein the cancer is lung cancer.

39. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation; and (b) administering to the subject a therapeutically effective amount of the capsule pharmaceutical composition of any one of claims 1-34.

40. A pharmaceutical composition comprising MRTX1133, SAIB and one or more propylene glycol diesters of saturated fatty acids.

41. The pharmaceutical composition of claim 40, wherein said composition is a suspension.

42. The pharmaceutical composition of claim 41, wherein said suspension is encapsulated in a capsule.

43. The pharmaceutical composition of any of claims 40-42, further comprising Vitamin E TPGS.

44. The pharmaceutical composition of any of claims 40-43, further comprising one or more Capryl ocaproyl Polyoxyl-8 glycerides.

45. The pharmaceutical composition of any of claims 42-44, wherein said composition comprises about 10-40% of MRTX1133, wherein all percentages are percentages by weight and wherein the total weight is 100% and wherein the composition is in the form of a capsule comprising a suspension.

46. The pharmaceutical composition of any of claims 42-45, wherein said composition comprises about 25-60% of SAIB, wherein all percentages are percentages by weight andwherein the total weight is 100% and wherein the composition is in the form of a capsule comprising a suspension.

47. The pharmaceutical composition of any of claims 42-46, wherein said composition comprises about 10-35% of Caprylocaproyl Polyoxyl-8 glycerides, wherein all percentages are percentages by weight and wherein the total weight is 100% and wherein the composition is in the form of a capsule comprising a suspension.

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