WO2022040446A1 - Amorphous pazopanib particles and pharmaceutical compositions thereof - Google Patents

Abstract

Amorphous solid dispersions and pharmaceutical compositions comprising the protein kinase inhibitor pazopanib. In some embodiments, the pharmaceutical compositions may be administered without regard to food consumption. In other embodiments, the pharmaceutical compositions are in the form of a tablet that may be crushed prior to administration. In other embodiments, the pharmaceutical compositions can be administered at a significantly lower dose as compared to a commercially available immediate-release pazopanib formulation, while providing a comparable therapeutic effect. The pharmaceutical compositions may be used in methods of treating a proliferative disorder such as cancer.

Description

TITLE

AMORPHOUS ΡΑΖΟΡΑΝIΒ PARTICLES AND PHARMACEUTICAL COMPOSITIONS

THEREOF

REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of U.S. Provisional App. No. 63/067,572 (filed August 19, 2020) and the benefit of U.S. Provisional App. No. 63/132,914 (filed December 31, 2020), the entire disclosures of which are hereby incorporated by reference.

BACKGROUND

[0002] Protein kinase inhibitors (PKIs) have been studied for their potential use in treating various disorders of cellular proliferation, including cancer. The potential for PKIs as a treatment is based on the role that protein kinases are known to play in regulating many cellular pathways, including those involved in signal transduction. Dysregulation of protein kinases has been implicated in the development and progression of many cancers, which suggests that PKIs may be useful as a treatment for disorders or diseases such as cancer that are caused by uncontrolled overexpression or upregulation of protein kinases.

[0003] One such PKI is pazopanib. Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR) VEGFR-1, VEGFR-2, and VEGFR-3, platelet- derived growth factor receptors (PDGFR) PDGFR-α and PDGFR-β, fibroblast growth factor receptors (FGFR) FGFR-1 and FGFR-3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms).

[0004] Pazopanib is currently marketed as an immediate-release tablet formulation for oral administration under the brand name VOTRIENT. VOTRIENT is indicated for (a) treatment of patients with advanced renal cell carcinoma (RCC), and (b) treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. [0005] However, VOTRIENT suffers from numerous limitations that make it a less-than-optimal formulation for providing pazopanib therapy to a patient. For example, oral administration of VOTRIENT is accompanied by a large, positive food effect. The current prescribing information for VOTRIENT instructs the patient to dose VOTRIENT once daily without food. The patient is further advised to take the dose “[O]n an empty stomach, at least 1 hour before or 2 hours after food.” According to the prescribing information, “Systemic exposure to pazopanib is increased when [VOTRIENT is] administered with food. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and C_max. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal[.]” [0006] Excessive exposure (expressed as area-under-the-curve, or AUC) and/or maximum plasma concentration (C_max ) due to an increase in absorption of pazopanib that can occur when VOTRIENT is taken with food can lead to undesirable side effects. The prescribing information for VOTRIENT references overdosage studies, which demonstrated grade 3 fatigue and grade 3 hypertension as common effects of overdosage. Increased serum levels may also exacerbate or increase the prevalence of more common side effects such as diarrhea, hypertension, nausea, vomiting, fatigue, headache, blood test abnormalities, and the like. [0007] The requirement to take VOTRIENT without food (for a three-hour period for each dose) is a considerable burden to patients. The restriction on food intake may be especially acute with VOTRIENT, because the recommended dosage is 4 tablets, providing a large dose of 800 mg pazopanib at one time. In addition, administration of VOTRIENT is commonly (10-30% of patients or more) accompanied by gastrointestinal side effects such as diarrhea, nausea, vomiting, poor appetite, and abdominal pain. These side effects may be worsened or more prevalent because of the restrictions on food intake. [0008] As a further limitation of VOTRIENT, patients are explicitly instructed to not crush VOTRIENT tablets prior to administration: “Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure.” Crushing tablets is a known alternative method for dosing patients who have a difficulty or inability to swallow. [0009] Certain patients sometimes have difficulty swallowing an intact solid oral dosage form (such as a tablet). This can be especially challenging for elderly or geriatric patients and pediatric patients, for example. Patients suffering from dysphagia for any reason also experience difficulty swallowing an intact solid oral dosage form. For such patients suffering from a proliferative disorder, an alternative method of dosing pazopanib may be highly beneficial. One approach for such patients is to alleviate the swallowing problem by oral administration of a medicament in powder form, such as a powder obtained by crushing a tablet or tablets.

[0010] Dosing VOTRIENT as crushed tablet(s) is not an option permitted by the current prescribing information. With respect to the rate and extent of absorption of crushed VOTRIENT tablets, the prescribing information states: “Administration of a single pazopanib 400-mg crushed tablet increased AUC_0-72h by 46% and C_max by approximately 2-fold and decreased T by approximately 2 hours compared with administration of the whole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorption are increased after administration of the crushed tablet relative to administration of the whole tablet. Therefore, due to this potential for increased exposure, tablets of VOTRIENT should not be crushed.”

[0011] As stated above, one approach to alleviate the swallowing problem is by oral administration of a powder obtained by crushing a tablet or tablets. Alternatively, a crushed tablet(s) could be dispersed in a soft food (such as a fruit preparation), and administered along with the soft food. However, neither of these approaches is an option for VOTRIENT tablets, which cannot be crushed prior to administration, and which cannot be taken with food.

[0012] As can be seen, poor adherence to the dosing recommendations can be very detrimental to patients. Relatedly, a patient may forgo taking regular doses of VOTRIENT due to the dosing recommendations around food effect and/or other dosing restrictions, and poor compliance could result, with the patient being deprived the benefit of therapy.

[0013] Patient compliance with a prescribed dosing regimen may be especially critical for pazopanib. Retrospective analysis of clinical studies has demonstrated a strong relationship between pazopanib steady-state plasma “trough” levels and the outcomes of tumor shrinkage and progression-free survival (“PFS”). In particular a threshold minimum plasma concentration (Cmin) of at least 20.5 mg/L was significantly related to tumor shrinkage and PFS. (See Verheijen, et al., “Clinical Pharmacokinetics and Pharmacodynamics of Pazopanib: Towards Optimized Dosing.” Clinical Pharmacokinetics vol. 56,9 (2017): 987-997. doi : 10.1007/s40262-017-0510-z.)

[0014] When a patient deviates from the prescribed pazopanib regimen for any reason, the chances of plasma concentration falling below the important Cmin threshold is greatly increased, and by extension, the likelihood of less-than-optimal outcomes is enhanced. Therefore, any formulation limitation that contributes to deviations from the prescribed regimen (such as a food effect or limitations on dosing as a powder or dispersion, for example) is undesirable.

[0015] As yet another shortcoming of the currently available pazopanib therapies, it is known that there is considerable inter- and intra-patient variability in pharmacokinetic parameters with VOTRIENT. The high variability may be due to several factors, including differences in absorption, metabolism, elimination, or other variables. (See de Wit, et al., “Therapeutic Drug Monitoring to Individualize the Dosing of Pazopanib.” Therapeutic Drug Monitoring: 37, 3 (2015): 331-338. doi: 10.1097/FTD.0000000000000141. See also Verheijen, etal., cited above.) However, in some cases it is possible to reduce the variability of drug products by improving the formulation by which they are administered. In addition, a less variable formulation would be desirable in order to minimize the chances of deviating below the important C_min threshold, as described above.

[0016] As a further limitation, VOTRIENT is administered at a relatively large dose of 800 mg pazopanib, once per day. However, a large fraction of the administered pazopanib is not absorbed into the plasma in vivo. (In other words, pazopanib is dosed in excess.) This increases the chance that changing conditions can result in overexposure to the patient, due to a change in absorption of the excess pazopanib that is administered.

[0017] Thus, there remains a need in the art for a means for a wide variety of patients to receive the full benefits of pazopanib therapy, while minimizing the risk of experiencing adverse side effects, especially those that are associated with VOTRIENT’ s food effect. There remains a need also for a pazopanib treatment that can be dosed in a manner other than as intact tablet(s). There remains a need in the art for a formulation for the administration of pazopanib that exhibits reduced in vivo variability. And there further remains a need in the art for a pazopanib formulation that provides the optimal likelihood of patient compliance with a prescribed regimen.

SUMMARY OF DISCLOSURE

[0018] The present disclosure relates to the field of amorphous solid dispersions and pharmaceutical compositions of the protein kinase inhibitor pazopanib. The present disclosure also relates to methods of treatment involving the administration of amorphous solid dispersions and pharmaceutical compositions of pazopanib.

[0019] An aspect of the disclosure relates to a pharmaceutical composition comprising an amorphous solid dispersion (“ASD”) of pazopanib. The ASD comprises pazopanib and one or more polymers. In another aspect, the present disclosure provides a pharmaceutical composition in the form of a tablet comprising the ASD. The pharmaceutical composition comprises an ASD of pazopanib and one or more pharmaceutically acceptable excipients.

[0020] Yet another aspect of the disclosure relates to a method of treating a disease which responds to an inhibition of protein kinase activity, such as a proliferative disorder. The method comprises administration of a pharmaceutical composition of the present disclosure.

[0021] Other aspects of the disclosure relate to methods of treating a proliferative disorder in a patient, without a food effect, by administering a pharmaceutical composition of the disclosure. In other aspects, the disclosure relates to methods of treating a proliferative disorder in a patient without regard to whether the patient is in a fasted state or fed state.

[0022] In another aspect, the pharmaceutical compositions of the present disclosure overcome the challenges faced by patients who have difficulty swallowing an intact solid oral dosage form, by providing a tablet that can be crushed prior to administration. This pharmaceutical formulation may be particularly beneficial for geriatric or pediatric patients, or patients suffering from dysphagia for any reason. [0023] In yet another aspect, the present disclosure provides a pharmaceutical composition that may achieve a pharmacokinetic profile that is comparable to the pharmacokinetic profile obtained by orally administering an immediate-release crystalline pazopanib formulation, but administered at a fraction of the dosage.

[0024] In still another aspect, the present disclosure provides a pharmaceutical composition that may achieve a reduced inter-subject variability, as compared to the inter-subject variability observed for VOTRIENT.

[0025] Further aspects of the disclosure relate to kits comprising a pharmaceutical composition of the disclosure, and a package insert. The package insert informs the user of the proper use of the pharmaceutical composition, in accord with other aspects of the present disclosure.

BRIEF DESCRIPTION OF THE FIGURES

[0026] Figure 1 shows the pharmacokinetic profiles obtained upon administration of intact and crushed tablets according to the disclosure, as described in Example 10.

DETAILED DESCRIPTION

[0027] The present disclosure relates to pharmaceutical compositions comprising pazopanib ASDs, and methods of treatment comprising administration of the pharmaceutical compositions.

[0028] The ASDs and pharmaceutical compositions of the present disclosure may provide particular advantages over immediate-release crystalline pazopanib formulations, such as VOTRIENT. As one such advantage, certain pharmaceutical compositions of the present disclosure provide an enhanced bioavailability and/or enhanced pharmacokinetic performance. For instance, certain pharmaceutical compositions of the present disclosure can be administered without regard to food consumption. As another advantage, pharmaceutical compositions of the disclosure may achieve a reduced inter-subject variability, as compared to the inter-subject variability observed for VOTRIENT.

[0029] Moreover, certain pharmaceutical compositions of the present disclosure unexpectedly provide a pharmacokinetic profile similar to that of VOTRIENT, even when the dose of pazopanib administered in the pharmaceutical compositions is a fraction of the dose of pazopanib normally administered when using VOTRIENT.

[0030] As yet another advantage, pharmaceutical compositions of the present disclosure can be crushed and dosed as a powder, providing an alternative method of dosing to patients for which such dosing is beneficial.

[0031] Thus, the ASDs and the pharmaceutical compositions of the present disclosure may offer a safer but equally effective presentation of pazopanib as compared to the currently available commercial product.

Pazopanib

[0032] Pazopanib is a kinase inhibitor having the following structure:

[0033] The chemical name for pazopanib is 5-((4-((2,3-dimethyl-2H-indazol-6- yl)(methyl)amino)pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide. The molecular formula is C21H23N7O2S, which corresponds to a molecular weight of 437.5 g/mol (pazopanib base, anhydrous). Pazopanib is described in WO 2002/059110 and U.S. Patent 7,105,530 to Boloor, et al., and pazopanib monohydrochloride is described in U.S. Patent 8,114,885 to Boloor, et al.

[0034] Pazopanib is marketed under the tradename VOTRIENT, as an immediate-release tablet formulation containing pazopanib monohydrochloride (474.0 g/mol). Currently available VOTRIENT tablets (marketed in the United States under New Drug Application 22-465) are labeled as containing 200 mg pazopanib base (equivalent to 216.7 mg pazopanib monohydrochloride.) As used herein, “VOTRIENT IR Tablet” refers to commercially available VOTRIENT immediate-release tablets marketed in the United States under New Drug Application 22-465.

[0035] Pazopanib monohydrochloride in crystalline form is characterized as a Class II compound (low/moderate aqueous solubility and high permeability) according to the Biopharmaceutical Classification System (“BCS”). The solubility of pazopanib hydrochloride in aqueous media varies significantly with pH. At pH 1.1 the reported solubility is 0.65 mg/mL. Peak observed solubility is near pH 3 (approximately 1.2 mg/mL), and the observed solubility drops significantly with increasing pH. Per the VOTRIENT prescribing information, pazopanib hydrochloride is practically insoluble above pH 4 in aqueous media.

[0036] A preparation of pazopanib in a form that is intended to enhance its solubility could increase its bioavailability. One approach for enhancing solubility is to produce an amorphous solid dispersion.

Amorphous Solid Dispersions of Pazopanib

[0037] One aspect of the present disclosure relates to amorphous solid dispersions (“ASDs”) comprising pazopanib and one or more polymers. A pharmaceutically suitable amorphous solid dispersion generally comprises a pharmaceutically active ingredient, such as pazopanib, dispersed in a pharmacologically inert carrier, such as a polymer. One aim of a pharmaceutically suitable amorphous solid dispersion is to improve the bioavailability of the pharmaceutically active ingredient. This improvement can occur, for example, because of enhanced surface area, improved wettability or dispersibility, increased dissolution rate, or other factors.

[0038] In general, it is favorable if the pharmaceutically active ingredient is dispersed in the polymer to form what has been termed in the art as a “glass solution.” However, other forms of dispersion, such as those termed as “solid solution” or “glass suspension,” may also be suitable. The precise characterization of the solid dispersion is not important, provided that the amorphous solid dispersion is capable of providing desired characteristics and performance. [0039] In the ASDs of the disclosure, the pazopanib may be as a free base or as a salt such as a hydrochloride. In some embodiments, the pazopanib is as an anhydrous monohydrochloride salt. Such forms of pazopanib and processes of preparing pazopanib are disclosed, for example, in WO 2002/059110. In the description of the amorphous solid dispersions and pharmaceutical compositions below, and in the claims, any reference to “pazopanib” refers broadly to pazopanib free base, salts of pazopanib, anhydrous pazopanib (or salts thereof), hydrates or solvates of pazopanib, and hydrates or solvates of pazopanib salts as suitable alternatives, unless specified.

[0040] The one or more polymers, which should be pharmacologically inert, should be suitable to provide structure and stability to the ASD. By “pharmacologically inert,” it is meant that the material does not initiate a pharmacological response or an adverse reaction when introduced to a relevant biological system (such as the gastrointestinal tract).

[0041] In some embodiments, the ASD comprises pazopanib and one or more polymers. In certain embodiments, the ASD consists of pazopanib and the one or more polymers. In certain other embodiments, the ASD consists essentially of pazopanib and the one or more polymers.

[0042] Polymers that can be used in the ASDs of the present disclosure may include, but are not limited to, those described below. The term “polymer" includes, but is not limited to, organic homopolymers, copolymers (such as for example, block, graft, random, and terpolymers, etc.), and blends and modifications thereof. The term “copolymer” refers to polymers containing two or more different monomeric units or segments, and includes terpolymers, tetrapolymers, etc. Information regarding suitable polymers, and commercial sources therefor, can be found in Sheskey PJ (ed.) Handbook of Pharmaceutical Excipients, 9^th Ed.. London: Pharmaceutical Press; 2020 (ISBN 0857113755); alternatively, the most up-to-date edition of the same title may be consulted.

[0043] Polymers that can be used in the ASDs of the present disclosure may include ionizable or non-ionizable polymers, or a combination thereof.

[0044] In some embodiments, the one or more polymers may be non-ionizable polymers. In certain embodiments, the ASD consists of pazopanib and one or more non-ionizable polymers. In certain other embodiments, the ASD consists essentially of pazopanib and one or more non- ionizable polymers.

[0045] In some embodiments, the one or more polymers may be ionizable polymers. In certain embodiments, the ASD consists of pazopanib and one or more ionizable polymers. In certain other embodiments, the ASD consists essentially of pazopanib and one or more ionizable polymers.

[0046] In yet other embodiments, a combination of ionizable and non-ionizable polymers may be used. In certain embodiments, the ASD consists of pazopanib and a combination of one or more non-ionizable polymers and one or more ionizable polymers. In certain other embodiments, the ASD consists essentially of pazopanib and a combination of one or more non-ionizable polymers and one or more ionizable polymers.

[0047] Polymers that can be used in the ASDs of the present disclosure may include polymers that exhibit pH-dependent solubility, or polymers that are generally insensitive to pH, or a combination thereof.

[0048] In some embodiments, the one or more polymers may exhibit pH-dependent solubility. In certain embodiments, the ASD consists of pazopanib and one or more polymers that exhibits pH- dependent solubility. In certain other embodiments, the ASD consists essentially of pazopanib and one or more polymers that exhibits pH-dependent solubility.

[0049] In other embodiments, the one or more polymers may be generally insensitive to pH. In certain embodiments, the ASD consists of pazopanib and one or more polymers generally insensitive to pH. In certain other embodiments, the ASD consists essentially of pazopanib and one or more polymers generally insensitive to pH.

[0050] In yet other embodiments, a combination of polymers may include one or more polymers exhibiting pH-dependent solubility and one or more polymers generally insensitive to pH. In certain embodiments, the ASD consists of pazopanib and a combination of one or more polymers exhibiting pH-dependent solubility and one or more polymers generally insensitive to pH. In certain other embodiments, the ASD consists essentially of pazopanib and a combination of one or more polymers exhibiting pH-dependent solubility and one or more polymers generally insensitive to pH.

[0051] Non-ionizable polymers. Suitable non-ionizable polymers may include: polysaccharides and polysaccharide derivatives (including cellulose ethers and non-ionizable cellulose esters); polymers or copolymers of N-vinylpyrrolidone and/or vinyl acetate; polymers of ethylene oxide; homopolymers or copolymers of lactic acid and/or glycolic acid; maleic anhydride copolymers; polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and poloxamers.

[0052] Suitable non-ionizable polysaccharides and polysaccharide derivatives may include cellulose ethers and non-ionizable cellulose esters. Examples of suitable cellulose ethers include methylcellulose (“MC”; e.g., METHOCEL A15 LV, METHOCEL A4M), ethylcellulose (“EC”; e.g., ETHOCEL), hypromellose or hydroxypropyl methylcellulose (“HPMC”; e.g., METHOCEL E3, METHOCEL E5, METHOCEL E6, METHOCEL El 5, AFFINISOL HPMC HME), hydroxyethyl cellulose (“HEC”; e.g., NATROSOL 250 Pharm), and hydroxypropyl cellulose (“HPC”; e.g., HPC EF, HPC LF, HPC JF, HPC L, KLUCEL).

[0053] Examples of non-ionizable cellulose esters that may be suitable include cellulose acetate, cellulose propionate, cellulose butyrate, and cellulose acetate butyrate.

[0054] Examples of suitable polymers or copolymers of N-vinylpyrrolidone and/or vinyl acetate include polyvinylpyrrolidone (“PVP”; e.g., PVP K25, PVP K90, VIVAPHARM PVP), crospovidone or crosslinked polyvinylpyrrolidone (e.g., KOLLIDON CL, VIVAPHARM PVPP), copovidone or vinylpyrrolidone/vinyl acetate copolymer (“PVP/VA”; e.g., KOLLIDON VA 64, VIVAPHARM PVP/VA 64), and polyvinyl alcohol (“PVA”; e.g., VIVAPHARM PVA).

[0055] Examples of suitable polymers of ethylene oxide include polyethylene glycol (“PEG”; e.g., KOLLISOLV PEG 8000) and polyethylene oxide) (“PEG”; e.g., POLYOX).

[0056] Examples of suitable homopolymers or copolymers of lactic acid and/or glycolic acid include polylactide or poly(lactic acid) (“PLA”), polyglycolide or poly(glycolic acid) (“PGA”), and poly(lactic-co-glycolic acid) (“PLGA”). [0057] Non-ionizable maleic anhydride copolymers such as poly(methyl vinyl ether/maleic anhydride) (“PVM/MA”) may also be suitable. Non-ionizable poloxamers (e.g., PLURONIC, KOLLIPHOR) may also be suitable. Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene.

[0058] A polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., SOLUPLUS) may also be a suitable non-ionizable polymer.

[0059] Ionizable polymers. Suitable ionizable polymers may be considered “anionic” or “cationic” polymers. Anionic and cationic polymers often exhibit pH-dependent solubility.

[0060] Anionic polymers often include carboxylate (such as acetate), phthalate, succinate, or acrylate functionalities. Anionic polymers are generally insoluble at low pH and more soluble at higher pH. Suitable anionic polymers may include anionic polysaccharides and polysaccharide derivatives (such as ionizable cellulose esters), copolymers of methacrylic acid and/or alkyl acrylate, and derivatized vinyl acetate polymers, for example.

[0061] An example of an ionizable polysaccharide that may be suitable is xanthan gum. Examples of suitable ionizable cellulose esters may include carboxymethylcellulose (“CMC”; carboxymethylcellulose sodium), hypromellose acetate succinate, or hydroxypropyl methylcellulose acetate succinate (“HPMC-AS”; e.g., AFFINISOL HPMC-AS, AQUASOLVE, AQOAT), hydroxypropyl methylcellulose phthalate (“HPMC-P”; e.g., HP-50, HP-55), and cellulose acetate phthalate (“CAP”; e.g., EASTMAN C-A-P).

[0062] Suitable copolymers of methacrylic acid and/or alkyl methacrylate may include methacrylic acid/methyl methacrylate copolymer (e.g., EUDRAGIT L100) and methacrylic acid/ethyl acrylate copolymer (e.g., EUDRAGIT L100-55, KOLLICOAT MAE).

[0063] An example of a derivatized vinyl acetate polymer that may be suitable is polyvinyl acetate phthalate (PVA-P; PHTHALAVIN).

[0064] Cationic polymers often include amine functionalities. Cationic polymers are generally soluble at low pH and less soluble at higher pH Suitable cationic polymers may include cationic polysaccharides and polysaccharide derivatives, and amine-functionalized copolymers of methacrylic acid and/or alkyl acrylate, for example.

[0065] An example of a cationic polysaccharide that may be suitable is chitosan.

[0066] Suitable amine-functionalized copolymers of methacrylic acid and/or alkyl acrylate include, for example, dimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylate copolymer (e.g., EUDRAGIT El 00) and aminoalkyl methacryyate copolymer such as poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride (e.g., EUDRAGIT RLIOO, EUDRAGIT RL PO, EUDRAGIT RS PO).

[0067] Amorphous solid dispersions. The pharmaceutical compositions of the present disclosure comprise ASDs of pazopanib, which comprise pazopanib and one or more polymers. In some embodiments, the one or more polymers includes one or more polymers from those identified above.

[0068] In certain embodiments, the ASD comprises pazopanib and one or more non-ionizable polymers. In certain embodiments, the ASD consists of pazopanib and one or more non- ionizable polymers. In certain other embodiments, the ASD consists essentially of pazopanib and one or more non-ionizable polymers. In particular embodiments, the non-ionizable polymers can be a cellulose ether or a polymer or copolymer of N-vinylpyrrolidone and/or vinyl acetate.

[0069] In certain embodiments, the ASD comprises pazopanib and one or more non-ionizable cellulose ethers. In certain embodiments, the ASD consists of pazopanib and one or more non- ionizable cellulose ethers. In certain other embodiments, the ASD consists essentially of pazopanib and one or more non-ionizable cellulose ethers. In any of the foregoing, the non- ionizable cellulose ether can be methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose, for example. In certain embodiments, hydroxypropyl methylcellulose or hydroxypropyl cellulose may be particularly suitable.

[0070] In some embodiments, the one or more polymers comprises a hydroxypropyl methylcellulose (also known as “hypromellose” or “HPMC”), such as METHOCEL E3, METHOCEL E5, METHOCEL E6, or METHOCEL El 5, for example. These METHOCEL grades are non-ionic water-soluble cellulose ethers, characterized by a methoxyl substitution of 28 to 30%, and a hydroxypropoxyl substitution of 7 to 12%. These grades are characterized by a low solution viscosity (as determined at 20°C for a 2% solution in water, according to manufacturer’s specifications), where the grade number indicates the midpoint of the viscosity range (e.g., METHOCEL E3 is characterized a viscosity of 2.4-3.6 mPa.s; METHOCEL E5 is characterized a viscosity of 4.0-6.0 mPa^.s). These grades are considered low molecular-weight HPMC products, having a number average molecular weight (Mn) of about 20kDa or lower.

[0071] In some embodiments, the one or more polymers comprise a hydroxypropyl methylcellulose (such as METHOCEL E3, METHOCEL E5, METHOCEL E6, or METHOCEL El 5, for example). In certain embodiments, the one or more polymers consists of a hydroxypropyl methylcellulose. In certain embodiments, the one or more polymers consists essentially of a hydroxypropyl methylcellulose. While all these grades are suitable for use in the ASDs of the disclosure, METHOCEL E5 has been demonstrated to be particularly suitable. A combination or mixture of grades of hydroxypropyl methylcellulose may also be employed.

[0072] In some embodiments, the one or more polymers comprise a low molecular-weight hydroxypropyl methylcellulose. In certain embodiments, the one or more polymers consists of a low molecular-weight hydroxypropyl methylcellulose. In certain embodiments, the one or more polymers consists essentially of a low molecular-weight hydroxypropyl methylcellulose.

[0073] In some embodiments, the one or more polymers comprise a low molecular-weight hydroxypropyl methylcellulose characterized by a solution viscosity of 4.0-6.0 mPa^.s. In certain embodiments, the one or more polymers consists of a low molecular-weight hydroxypropyl methylcellulose characterized by a solution viscosity of 4.0-6.0 mPa^.s. In certain embodiments, the one or more polymers consists essentially of a low molecular-weight hydroxypropyl methylcellulose characterized by a solution viscosity of 4.0-6.0 mPa.s.

[0074] In certain embodiments, the ASD comprises pazopanib and one or more hydroxypropyl methylcellulose polymers. In certain embodiments, the ASD consists of pazopanib and one or more hydroxypropyl methylcellulose polymers. In certain other embodiments, the ASD consists essentially of pazopanib and one or more hydroxypropyl methylcellulose polymers. In certain embodiments, the ASD comprises pazopanib hydrochloride and HPMC. In certain embodiments, the ASD consists of pazopanib hydrochloride and HPMC. In certain embodiments, the ASD consists essentially of pazopanib hydrochloride and HPMC. In any of the foregoing, a low molecular-weight hydroxypropyl methylcellulose characterized by a solution viscosity of 4.0-6.0 mPa^.s may be suitable. In any of the foregoing, METHOCEL E5 may be particularly suitable.

[0075] In some embodiments, the ASD comprises pazopanib and one or more polymers or copolymers ofN-vinylpyrrolidone and/or vinyl acetate. In certain embodiments, the ASD consists of pazopanib and one or more polymers or copolymers ofN-vinylpyrrolidone and/or vinyl acetate. In certain other embodiments, the ASD consists essentially of pazopanib and one or more polymers or copolymers ofN-vinylpyrrolidone and/or vinyl acetate. In any of the foregoing, vinylpyrrolidone/vinyl acetate copolymer may be particularly suitable as a copolymer ofN-vinylpyrrolidone and vinyl acetate.

[0076] In some embodiments, the one or more polymers comprise a vinylpyrrolidone/vinyl acetate copolymer (also known as “copovidone” or “copolyvidone”), such as KOLLIDON VA 64, for example. Copoly vidones are non-ionic copolymers ofN-vinylpyrrolidone and vinyl acetate monomers. Copolyvidones are generally soluble in hydrophilic solvents including alcoholic solvents (such as methanol, ethanol, and isopropanol), methylene chloride, glycerol, propylene glycol, and in water and other aqueous media. In aqueous media, the solubility of copolyvidone is largely pH-independent over a wide range of pH.

[0077] KOLLIDON VA 64 is a commercially available copolyvidone (BASF) derived from approximately 60% N-vinylpyrrolidone monomers and 40% vinyl acetate monomers. KOLLIDON VA 64 is characterized by a typical weight-average molecular weight in the range of 45kDa-70kDa (as determined by solution light scattering), and exhibits a glass transition temperature of about 101°C (per technical literature published by BASF).

[0078] In some embodiments, the one or more polymers comprise a vinylpyrrolidone/vinyl acetate copolymer. In certain embodiments, the polymer consists of a vinylpyrrolidone/vinyl acetate copolymer. In certain embodiments, the polymer consists essentially of a vinylpyrrolidone/vinyl acetate copolymer. In the foregoing embodiments, KOLLIDON VA 64 or a similar grade of copolyvidone may suitably be employed.

[0079] In some embodiments, the ASD comprises pazopanib and a vinylpyrrolidone/vinyl acetate copolymer. In certain embodiments, the ASD consists of pazopanib and a vinylpyrrolidone/vinyl acetate copolymer. In certain other embodiments, the ASD consists essentially of pazopanib and a vinylpyrrolidone/vinyl acetate copolymer. In some embodiments, the ASD comprises pazopanib hydrochloride and a vinylpyrrolidone/vinyl acetate copolymer. In certain embodiments, the ASD consists of pazopanib hydrochloride and a vinylpyrrolidone/vinyl acetate copolymer. In certain other embodiments, the ASD consists essentially of pazopanib hydrochloride and a vinylpyrrolidone/vinyl acetate copolymer. In the foregoing embodiments, KOLLIDON VA 64 or a similar grade of copolyvidone may suitably be employed.

[0080] In certain embodiments, the ASD comprises pazopanib and one or more ionizable polymers. In certain embodiments, the ASD consists of pazopanib and one or more ionizable polymers. In certain other embodiments, the ASD consists essentially of pazopanib and one or more ionizable polymers. In particular embodiments, the ionizable polymer can be an ionizable cellulose ester.

[0081] In certain embodiments, the ASD comprises pazopanib and one or more ionizable cellulose ester. In certain embodiments, the ASD consists of pazopanib and one or more ionizable cellulose ester. In certain other embodiments, the ASD consists essentially of pazopanib and one or more ionizable cellulose ester. In any of the foregoing, the ionizable cellulose ester can be carboxymethylcellulose, hydroxypropyl methylcellulose acetate succinate (“HPMC-AS”), hydroxypropyl methylcellulose phthalate, or cellulose acetate phthalate, for example.

[0082] In some embodiments, the one or more polymers comprise polymers that are characterized by pH-dependent solubility. In some embodiments, the one or more polymers comprise an anionic polymer characterized by pH-dependent solubility. In some embodiments, the one or more polymers consist essentially of one or more anionic polymers characterized by pH-dependent solubility. In some embodiments the one or more polymers consist of one or more anionic polymers characterized by pH-dependent solubility. HPMC-AS is an example of a suitable anionic polymer that demonstrates pH-dependent solubility, but other polymers that demonstrate pH-dependent solubility may also be employed.

[0083] In certain embodiments, HPMC-AS may be a particularly suitable polymer. In certain embodiments, the one or more polymers comprise HPMC-AS. In certain embodiments, the polymer consists of HPMC-AS. In certain embodiments, the polymer consists essentially of HPMC-AS.

[0084] HPMC-AS is available in a variety of grades, which each demonstrate pH-dependent aqueous solubility. Generally speaking, HPMC-AS is largely insoluble in an aqueous medium at pH of 4 or lower, with increased solubility in an aqueous medium at pH 7 or greater. It is insoluble in normal gastric fluid, but swells and partially dissolves in the higher pH environment of the upper small intestine. Available grades of HPMC-AS are differentiated by the relative proportion of acetyl/succinyl substituents. Low-grade HPMC-AS comprises 5-9% acetyl substituents and 14-18% succinyl substituents; mid-grade HPMC-AS comprises 7-11% acetyl substituents and 10-14% succinyl substituents; high-grade HPMC-AS comprises 10-14% acetyl substituents and 4-8% succinyl substituents.

[0085] In the practice of the disclosure, any grade of HPMC-AS may be suitable, or a mixture of two or more grades may be suitable. In certain embodiments, mid-grade HPMC-AS is particularly suitable. AFFINISOL HPMC-AS 912G (Dow Pharma Solutions/Colorcon) is a commercially available mid-grade HPMC-AS that is suitable for use in the practice of the disclosure. Other grades of AFFINISOL HPMC-AS are also commercially available and suitable for use in the practice of the disclosure.

[0086] In certain embodiments, the ASD comprises pazopanib and HPMC-AS. In certain embodiments, the ASD consists of pazopanib and HPMC-AS. In certain embodiments, the ASD consists essentially of pazopanib and HPMC-AS. In certain embodiments, the ASD comprises pazopanib hydrochloride and HPMC-AS. In certain embodiments, the ASD consists of pazopanib hydrochloride and HPMC-AS. In certain embodiments, the ASD consists essentially of pazopanib hydrochloride and HPMC-AS. In any of the foregoing, mid-grade HPMC-AS may be particularly suitable.

[0087] In any of the foregoing ASD embodiments, the pazopanib may be present as a hydrochloride salt, such as the monohydrochloride salt. (References herein to “pazopanib hydrochloride” are to the monohydrochloride salt.) In any of the foregoing ASD embodiments, the pazopanib may be present as an anhydrous hydrochloride salt, such as anhydrous pazopanib hydrochloride.

[0088] In certain embodiments, the ASD comprises pazopanib hydrochloride and one or more polymers. In certain embodiments, the ASD consists of pazopanib hydrochloride and one or more polymers. In certain other embodiments, the ASD consists essentially of pazopanib hydrochloride and one or more polymers.

[0089] In certain embodiments, the ASD comprises anhydrous pazopanib hydrochloride and one or more polymers. In certain embodiments, the ASD consists of anhydrous pazopanib hydrochloride and one or more polymers. In certain other embodiments, the ASD consists essentially of anhydrous pazopanib hydrochloride and one or more polymers.

[0090] In some embodiments of the ASD, the one or more polymers does not comprise a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (e.g., SOLUPLUS). In some embodiments, the ASD is substantially free from a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer. In some embodiments, the ASD is essentially free from a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer. In some embodiments, the ASD is free from a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer. In yet other embodiments, the ASD comprises pazopanib and one or more polymers, with the proviso that the one or more polymer is not a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer.

[0091] In some embodiments of the ASD, the one or more polymers does not comprise a poloxamer. In some embodiments, the ASD is substantially free from a poloxamer. In some embodiments, the ASD is essentially free from a poloxamer. In some embodiments, the ASD is free from a poloxamer. In yet other embodiments, the ASD comprises pazopanib and one or more polymers, with the proviso that the one or more polymer is not a poloxamer.

[0092] As used herein, the phrase “substantially free from” means that the stated component represents not more than 5% of the ASD, based on weight. The phrase “essentially free from” means that the stated component represents not more than 1% of the ASD, based on weight. The term “free from” means that the stated component represents not more than 0.1% of the ASD, based on weight.

[0093] In the ASDs described in the disclosure, the amount of pazopanib as compared to the amount of the one or more polymers may vary. For example, pazopanib and the one or more polymers may be present in a w/w ratio (pazopanib :polymer) of 20:80 to 80:20, or 25:75 to 75:25, or 30:70 to 70:30, or 35:65 to 65:35, or 40:60 to 60:40. In particular embodiments, pazopanib and the one or more polymers may be present in a ratio of 20:80, or 25:75, or 30:70, or 35:65, or 40:60, or 45:55, or 50:50, or 55:45, or 60:40, or 65:35, or 70:30, or 75:25, or 80:20.

[0094] In some embodiments, the ASD consists of pazopanib and one or more polymers. In some embodiments, the ASD consists essentially of pazopanib and one or more polymers. In other embodiments, the ASDs may additionally comprise one or more other pharmaceutically acceptable functional components, such as one or more antioxidants, wetting agents, or solubilizers.

[0095] As used herein, the phrase “pharmaceutically acceptable” means that the component does not initiate a pharmacological response or an adverse reaction when introduced to a relevant biological system. By way of non-limiting example only, a substance found in the U.S. Food & Drug Administration’s “Generally Recognized as Safe” (“GRAS”) list, or a substance used in accordance with guidelines in its Inactive Ingredient Database, would be considered pharmaceutically acceptable. Similarly, a substance in a corresponding database or list maintained by a parallel regulatory body, such as the European Medicines Agency, would be considered pharmaceutically acceptable. In general, in the pharmaceutical compositions of the disclosure, it is desirable to employ only components that do not cause an unacceptable level of physical or chemical instability in the resulting composition [0096] Examples of antioxidants that that may be used in the ASDs of the present disclosure include, but are not limited to, acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT’), monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, ethylenediaminetetraacetic acid (“EDTA”) (e.g., disodium edetate), diethylenetriaminepentaacetic acid (“DTP A”), bismuth sodium triglycollamate, or a combination thereof. Antioxidants may also comprise amino acids such as methionine, histidine, cysteine and those carrying a charged side chain, such as arginine, lysine, aspartic acid, and glutamic acid. Any stereoisomer (e.g., 1-, d-, or a combination thereof) of any particular amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and combinations thereof) or combinations of these stereoisomers, may be present so long as the amino acid is present either in its free base form or its salt form.

[0097] In some embodiments, the one or more antioxidants comprise BHT. In some embodiments, the one or more antioxidants consists of BHT. In some embodiments, the one or more antioxidants comprise propyl gallate. In some embodiments, the one or more antioxidants consists of propyl gallate.

[0098] The one or more antioxidants may be present in the ASD in an amount of 0.001% to 2%, or 0.01% to 1.5%, or 0.05% to 1%, or 0.1% to 0.5%, or 0.3% to 0.4%, by weight. Examples of the amount of the one or more antioxidants in the ASD include 0.001%, or 0.003%, or 0.005%, or 0.008%, or 0.01%, or 0.015%, or 0.02%, or 0.025%, or 0.03%, or 0.035%, or 0.04%, or 0.05%, or 0.075%, or 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%, or 0.75%, or 1%, or 1.5%, or 2%, by weight.

[0099] A variety of pharmaceutically acceptable wetting agents may be included. As a nonlimiting example of a wetting agent, poloxamers, such as poloxamer 407 (e.g., PLURONIC F- 127) or poloxamer 188 (e.g., PLURONIC F-68), may be suitable. Other known pharmaceutically acceptable wetting agents may be suitably employed. A wetting agent may be included in the ASD in an amount of 0.5% to 10%, or 1% to 8%, or 2% to 6%, by weight. [0100] A variety of pharmaceutically acceptable solubilizers may be included. Non-limiting examples of suitable solubilizers include vitamin E TPGS (D-a-tocopherol polyethylene glycol succinate), SLS (sodium lauryl sulfate), and docusate sodium. A polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft copolymer (e.g., SOLUPLUS) may also be a suitable solubilizer. Other known pharmaceutically acceptable solubilizers may be suitably employed. A solubilizer may be included in the ASD in an amount of 0.1% to 10%, or 0.25% to 5%, or 0.5 to 1%, by weight.

[0101] In some embodiments, the one or more solubilizers comprises vitamin E TPGS. In some embodiments, the one or more solubilizers consists of vitamin E TPGS. In some embodiments, the one or more solubilizers consists essentially of vitamin E TPGS. In some embodiments, the ASD is free from vitamin E TPGS.

[0102] In some embodiments, the one or more solubilizers comprise polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the one or more solubilizers consists of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the one or more solubilizers consists essentially of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the ASD is free from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0103] The drug load of pazopanib in the ASDs of the present disclosure may suitably range from 20% to 80%, or 25% to 75%, or 30% to 70%, or 35% to 65%, or 40% to 60%, or 45% to 55%. As used herein, the phrase “drug load” refers to the ratio (by weight %) of pazopanib in an ASD to the total solids weight of the ASD. By way of example, for an ASD consisting of pazopanib and a polymer, a 1 : 1 w/w ratio of pazopanib :polymer would represent a 50% drug load; a 1:2 w/w ratio of pazopanib: polymer would represent a 33.3% drug load, etc. Examples of the drug load of pazopanib in specific embodiments of the ASDs include 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%.

[0104] The pazopanib ASDs may be in the form of particles. In some embodiments, the particles do not comprise a surfactant. In other embodiments, the particles do not comprise a wetting agent. In other embodiments, the particles do not comprise a solubilizer. In other embodiments, the particles comprise neither a surfactant nor a solubilizer. In yet other embodiments, the particles are free from surfactants, wetting agents, and solubilizers. In other embodiments, the particles consist of polymer and pazopanib, and no additional functional components.

[0105] Particles of the ASDs of the disclosure may generally comprise the shapes of spheroids. As measured by conventional light scattering or laser diffraction techniques, the diameter of the particles may generally range from 0.05 μm to 100 μm. The median diameter (D50 or DvO.5) of the particle distribution may be in the range from 0.2 μm to 60 μm, or 0.5 μm to 50 μm, or 0.5 μm to 40 μm.

[0106] In some embodiments, the median diameter of the particle distribution may be from 1 μm to 40 μm, or from 2 μm to 25 μm, or from 3 μm to 20 μm, or from 4 μm to 15 μm, or from 5 μm to 10 μm. By way of example only, such particle size distributions can be achieved by known methods of spray diying.

[0107] In some embodiments, the median diameter of the particle distribution may be from 0.1 μm to 10 μm, or from 0.2 μm to 5 μm, or from 0.5 μm to 2 μm. By way of example only, such particle size distributions can be achieved by methods involving electrospraying, discussed further below.

Physical and Chemical Stability of ASDs

[0108] The pazopanib ASDs of the present disclosure may demonstrate a desirable level of physical and/or chemical stability, which can be assessed by different measures. Stability is generally assessed using conventional analytical techniques commonly known in pharmaceutical sciences.

[0109] Physical and chemical stability is generally assessed after storage under controlled, elevated environmental conditions (“accelerated conditions”) over a specified period of time.

The storage conditions may be one or more of 25°C/60% relative humidity (“RH”), or 25°C/protected, or 30°C/65% RH, or 40°C/75% RH, or 40°C/protected, or 50°C/80% RH. (As used herein in this context, “protected” means samples were sealed in foil pouches and placed in a controlled chamber for the storage period. For example “40°C/protected” would indicate that a sample was sealed in a foil pouch, and held in a chamber controlled at 40°C/75% RH.) The period of time may be one or more of 1 week, or 2 weeks, or 4 weeks or 1 month, or 2 months, or 3 months, or 4 months, or 6 months, or 9 months, or 12 months, or 15 months, or 18 months, or 21 months, or 24 months, or any period of time therebetween.

[0110] The pazopanib ASDs may demonstrate stability by having a particular assay value or a particular level of total related substances (e.g., impurities, degradation products, and the like), as measured by high performance liquid chromatography (“HPLC”), after preparation or after storage under accelerated conditions over a specified period of time. The assay value is generally presented as a percentage of the quantity of analyte (e.g., pazopanib) detected relative to the quantity expected, where 100% is a favorable result and large deviations from 100% are unfavorable. The total related substances is generally presented as a percentage relative to the total quantity of substances detected (i.e., analyte plus the sum of all individual related substances), where near 0% is favorable and large deviations from 0% are unfavorable.

[0111] In some embodiments, the pazopanib ASDs may have an assay as measured by HPLC of at least 90%, or at least 93%, or at least 95%, or at least 97%, or at least 98%, or at least 99%. In some embodiments, the assay is assessed promptly after the particles are prepared. Generally, a reported assay value should be corrected to deduct the water content (discussed below).

[0112] In some embodiments, the pazopanib ASDs may have a level of total related substances as measured by HPLC of no more than 3%, no more than 2.5%, no more than 2%, or no more than 1.5%, or no more than 1%, or no more than 0.9%, or no more than 0.8%, or no more than 0.7%, or no more than 0.6%, or no more than 0.5%. In some embodiments, the total related substances is assessed promptly after the particles are prepared.

[0113] In some embodiments, the pazopanib ASDs may have an assay as measured by HPLC of at least 90%, or at least 93%, or at least 95%, or at least 97%, or at least 98%, after storage at 25°C/60% RH for 1 month, or 2 months, or 3 months, or 6 months, or 9 months, or 12 months; or after storage at 40°C/75% RH for 1 month, or 2 months, or 3 months, or 6 months. [0114] In some embodiments, the pazopanib ASDs may have a level of total related substances as measured by HPLC of no more than 2%, or no more than 1.5%, or no more than 1%, or no more than 0.9%, or no more than 0.8%, or no more than 0.7%, or no more than 0.6%, or no more than 0.5%, after storage at 25°C/60% RH for 1 month, or 2 months, or 3 months, or 6 months, or 9 months, or 12 months; or after storage at 40°C/75% RH for 1 month, or 2 months, or 3 months, or 6 months.

[0115] Stability may also be assessed by evaluating changes in glass transition temperature of the pazopanib ASDs under different storage conditions over time. Glass transition temperature can be evaluated by modulated DSC (“mDSC”) using conventional techniques. In some embodiments, the ASD is characterized by a single glass transition, the transition observed in the range from 25°C to 200°C, or more suitably from 40°C to 150°C, by DSC or mDSC. In other embodiments, the ASD is characterized by more than one transition, the transitions observed in the range from 25°C to 200°C, or more suitably from 40°C to 150°C, by DSC or mDSC.

[0116] In some embodiments, the glass transition temperature as measured by mDSC does not change by more than 10°C, or more than 8°C, or more than 6°C, or more than 4°C, or more than 3°C, or more than 2°C, after storage at 25°C/60% RH for 1 month, or 2 months, or 3 months, or 6 months, or 9 months, or 12 months.

[0117] In some embodiments, the glass transition temperature as measured by mDSC does not change by more than 10°C, or more than 8°C, or more than 6°C, or more than 4°C, or more than 3°C, or more than 2°C, after storage at 40°C/75% RH for 1 month, or 2 months, or 3 months, or 6 months.

[0118] In some embodiments, the glass transition temperature as measured by mDSC does not change by more than 10°C, or more than 8°C, or more than 6°C, or more than 4°C, or more than 3°C, or more than 2°C, after storage at 40°C/protected for 1 month, or 2 months, or 3 months, or 6 months.

[0119] Stability may also be assessed by evaluating changes in crystallinity of the pazopanib ASDs under different storage conditions over time, such as by suitable conventional x-ray diffraction (“XRD”) techniques (also known in the art as powder XRD or PXRD). In the practice of the present disclosure, it is preferred (but not required) that the pazopanib ASDs remain amorphous or essentially amorphous. In some embodiments, “amorphous” may be defined as having no detectable crystallinity as determined using methods known in the art, for instance, by using XRD. An example of using XRD to determine amorphicity is provided in Example 1.

[0120] In some embodiments, “amorphous” may be defined as having a percent crystallinity no more than 5%, or no more than 4%, or no more than 3%, or no more than 2%, or no more than 1%, as determined by XRD. In some embodiments, “essentially amorphous” may be defined as having a percent crystallinity of no more than 8%, or no more than 7%, or no more than 6%, as measured by XRD.

[0121] The ASDs of the disclosure may be amorphous or essentially amorphous when analyzed promptly after preparation, i.e., at t=0. As used herein, the phrase “promptly after preparation” means that the ASD is analyzed within a few days after preparation, and stored under protected conditions at ambient temperature and humidity after preparation and before analysis.

[0122] The ASDs may be amorphous or essentially amorphous after storage under various storage conditions (e.g., 25°C/60% RH, 25°C/protected, 40°C/75% RH, 40°C/protected, 50°C/80% RH, etc.) for a period of at least 1 week, or a period of at least 2 weeks, or a period of at least 3 weeks, or a period of at least 4 weeks or 1 month, or a period of at least 2 months, or a period of at least 3 months, or a period of at least 4 months, or a period of at least 5 months, or a period of at least 6 months, or a period of at least 9 months, or a period of at least 12 months or 1 year. In some embodiments, the ASDs of the disclosure may be amorphous or essentially amorphous under conditions of high temperature and humidity (e.g., 40°C/75% RH) for a period of at least 1 month, or a period of at least 2 months, or a period of at least 3 months, or a period of at least 6 months.

[0123] The pazopanib ASDs of the present disclosure can be characterized for water content, such as by using standard Karl Fischer coulometric titration methods. In some embodiments, the pazopanib ASDs may comprise a water content as assessed by Karl Fischer coulometric titration method of no more than 5%, or no more than 4%, or no more than 3%, or no more than 2.5%, or no more than 2%, or no more than 1.5%, or no more than 1%.

[0124] In some embodiments, the pazopanib ASDs may comprise a water content as assessed by Karl Fischer coulometric titration method of no more than 10%, or no more than 7.5%, or no more than 5%, or no more than 4%, or no more than 3%, after storage at 25°C/60% RH for 1 month, or 2 months, or 3 months, or 6 months, or 9 months, or 12 months.

[0125] In some embodiments, the pazopanib ASDs may comprise a water content as assessed by Karl Fischer coulometric titration method of no more than 10%, or no more than 7.5%, or no more than 5%, or no more than 4%, or no more than 3%, after storage at 40°C/75% RH for 1 month, or 2 months, or 3 months, or 6 months, or 9 months, or 12 months.

[0126] In some embodiments, the pazopanib ASDs may comprise a water content as assessed by Karl Fischer coulometric titration method of no more than 10%, or no more than 7.5%, or no more than 5%, or no more than 4%, or no more than 3%, after storage at 40°C/protected for 1 month, or 2 months, or 3 months, or 6 months, or 9 months, or 12 months.

Methods of Making Amorphous Solid Dispersions

[0127] The pazopanib ASDs of the present disclosure may be prepared by a variety of methods known in the art. Suitable methods generally include mixing, dissolving, or compounding the pazopanib and the one or more polymers and, if present, one or more other functional components (such as antioxidants, wetting agents, or solubilizers) to integrate the various components. In the practice of the various methods, the pazopanib may be introduced as pazopanib free base, or as a salt of pazopanib (such as pazopanib hydrochloride), or as a solvate or hydrate of pazopanib.

[0128] Suitable methods are generally known in the art, and include kneading, co-grinding, melting, melt extrusion, melt agglomeration, dropping, and the like. After the integration step, the material can be further processed by drying, grinding or crushing, sieving, etc. [0129] In the practice of certain methods, pazopanib and the one or more polymers (and other functional components, if present) may be mixed or dissolved with one or more solvents to provide a liquid feedstock. Suitable solvents may include, but are not limited to, water; an alcohol, such as ethanol, methanol, propanol or isopropanol; an ether, such as ethyl ether or methyl tert-butyl ether; acetonitrile; tetrahydrofuran or methyl tetrahydrofuran; an acetate, such as methyl acetate or ethyl acetate; a ketone, such as acetone or 2-butanone (methyl ethyl ketone, or “MEK”); toluene; ethyl formate; 1,4-dioxane; dimethylsulfoxide; N-methyl 2-pyrrolidone; volatile halogenated solvents such as chloroform or dichloromethane; and combinations thereof. The mixing or dissolving of these contents may be by methods known in the art. For example, the contents may be mixed by manually mixing, or may be mixed with a mixing device continuously, periodically, or a combination thereof. Examples of mixing devices may include, but are not limited to, a magnetic stirrer, shaker, a paddle mixer, homogenizer, and any combination thereof.

[0130] After the pazopanib and the one or more polymers (and other functional components, if present) are mixed, the liquid feedstock may be formed into an amorphous solid dispersion, such as through solvent evaporation, lyophilization, precipitation or co-precipitation, spray diying, electrospraying, supercritical fluid extraction, etc. These methods are known and commonly understood in the art.

[0131] In certain embodiments of the disclosure, the liquid feedstock may be formed into an ASD through electrospraying. Electrospraying, which has also been referred to as electrohydrodynamic atomization, has been used to produce ASD particles on a micron or submicron scale from suitable liquid feedstocks.

[0132] In one suitable electrospraying technique, the liquid feedstock is emitted through one or more nozzles toward a substrate in the presence of an electric potential applied between the nozzles and the substrate. The liquid feedstock experiences electrical shear stress due to the applied potential. When the shear stress overcomes the surface tension of the liquid feedstock, droplets are emitted from the tips of the nozzles. [0133] Conditions are controlled such that a cone jet of droplets is emitted at the tip of the nozzles. The droplets take on an electric charge and repel one another, which prevents their coagulation and promotes self-dispersion. The charged droplets accelerate toward the substrate as a result of the applied electric field.

[0134] During the short flight path, the solvent “flashes off” from the charged droplets. This fast evaporation creates a situation in which the charged droplets shrink in size but increase in charge density. At a critical limit, the droplets will break up into yet smaller droplets. An essentially monodisperse population of fine droplets is ultimately produced. The size of the droplets can range from sub-micron to several microns.

[0135] The essentially complete evaporation of solvent from the charged droplets results in the formation of relatively uniform particles of the non-volatile components from the liquid feedstock. The evaporation process occurs at a time-scale that does not permit crystallization of the non-volatile components. Additionally, evaporative cooling associated with the extremely rapid solvent evaporation contributes a quenching effect to preserve the particles in an amorphous state. Furthermore, electrospray conditions can be selected and the system can be configured such that the amorphous particles contain little residual solvent.

[0136] In some embodiments of the disclosure, the liquid feedstock may be formed into an ASD using electrospray techniques and/or devices. Suitable methods and equipment are described, for example, in U.S. Patent No. 6,746,869, U.S. Patent No. 6,764,720, U.S. Patent No. 7,279,322, U.S. Patent No. 7,498,063, U.S. Patent No. 7,951,428, U.S. Patent No. 7,972,661, U.S. Patent No. 8,992,603, U.S. Patent No. 9,040,816, U.S. Patent No. 9,050,611, U.S. Patent No. 9,108,217, U.S. Patent No. 9,642,694, U.S. Patent No. 10,562,048, U.S. Patent Publication No. 2014- 0158787, U.S. Patent Publication No. 2015-0190253, U.S. Patent Publication No. 2016- 0038968, U.S. Patent Publication No. 2016-0175881, U.S. Patent Publication No. 2016- 0235677, U.S. Patent Publication No. 2019-0193109, and U.S. Patent Publication No. 2020- 0179963.

[0137] As noted above, by using an electrospray technique, the median diameter of the pazopanib ASD particle distribution may be from 0 1 μm to 10 μm, or from 0.2 μm to 5 μm, or from 0.5 μm to 2 μm. It should further be noted that the pazopanib in the amorphous particles is generally not considered to be solvated. Even where the liquid feedstock may have been prepared using a solvate or hydrate form of pazopanib, the solvate or hydrate is understood to flash off with the other solvents, and the electrosprayed amorphous particles comprise non- solvated pazopanib (such as anhydrous pazopanib).

[0138] In some embodiments, the electrospray technique may be performed at room temperature. In certain embodiments, no heated air is used. In other embodiments, the liquid feedstock is held at an elevated temperature during the electrospray process.

[0139] In some embodiments, the electrospray technique may be performed using one or more capillary nozzles. In certain embodiments, the electrospray technique does not use pneumatic nozzles such as nozzles that rely on kinetic energy; pressure nozzles; rotary nozzles; or nozzles that rely on centrifugal energy; or ultrasonic nozzles such as nozzles that rely on acoustic energy. In some embodiments, the electrospray technique generates a yield of over 85%, or over 90%, or over 95%, or over 98%.

[0140] In other embodiments, the liquid feedstock may be formed into an ASD through spray drying. Generally speaking, spray drying involves the atomization of a liquid feedstock into very small droplets within a hot drying gas. The feedstock is pumped or otherwise propelled through a nozzle or other atomizing apparatus to form droplets within a drying chamber. Within the diying chamber, the droplets are exposed to an environment of the heated diying gas (usually flowing air or nitrogen), leading to flash drying of the droplets (by evaporative removal of solvent) and resultant production of solid particles. The dried particles are collected, generally at an output port in the drying chamber.

[0141] Various apparatus and methods of spray drying may be employed to form an ASD of the disclosure. In the practice of the present disclosure, the median diameter of the ASD particle distribution achieved by spray diying may be from 1 μm to 40 μm, or from 2 μm to 25 μm, or from 3 μm to 20 μm, or from 4 μm to 15 μm, or from 5 μm to 10 μm. [0142] In some embodiments, the process for forming an ASD does not require a secondary drying step, i.e., a drying step that occurs after the particles are produced. In other embodiments, a secondary drying step is employed to further remove most or all of the residual solvents. The secondary drying step can be done under suitable conditions (such as elevated temperature) that allow for the removal of solvent but do not result in the recrystallization of the pazopanib. For example, a secondary drying step can be done below a glass transition temperature. A secondary drying step can also be done at reduced pressure. A combination of elevated temperature and reduced pressure can also be used for a secondary drying step.

Pharmaceutical Compositions

[0143] An aspect of the present disclosure relates to pharmaceutical compositions comprising pazopanib ASD. The pharmaceutical compositions generally comprise pazopanib ASD and one or more pharmaceutically acceptable excipients. The pharmaceutical compositions of the present disclosure may be in a dosage form suitable for oral administration. In particular, in one aspect the present disclosure provides a pharmaceutical composition in the form of a tablet.

[0144] Information regarding suitable excipients, and commercial sources therefor, can be found in Sheskey PJ (ed.) Handbook of Pharmaceutical Excipients, 9^th Ed.. London: Pharmaceutical Press; 2020 (ISBN 0857113755); alternatively, the most up-to-date edition of the same title may be consulted.

[0145] In some embodiments, the pharmaceutical composition may be in the form of an aqueous or nonaqueous suspension or solution. In some embodiments, the pharmaceutical compositions may be in a solid dosage form for oral administration, such as a capsule, tablet, sprinkle, or pellet. In particular, in one aspect the present disclosure provides a pharmaceutical composition in the form of a tablet. In some embodiments, the pharmaceutical compositions may be in the form of granules, or may be prepared as granules as an intermediate step to forming another oral dosage form, such as tablets, sprinkles, or pellets.

[0146] Suspension/Solution A pharmaceutical composition may be in the form of an aqueous or nonaqueous suspension or solution. Such compositions may be prepared using known excipients and known preparation methods. Such compositions may comprise a pazopanib ASD of the present disclosure and one or more suitable pharmaceutically acceptable carriers, along with optional excipients, such as one or more solubilizers, one or more buffering agent(s), one or more pH-adjusting agents, one or more surfactants, and/or one or more antioxidants.

[0147] Carriers that that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, water, salt solutions (e.g., Ringer’s solution and the like), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidine, and mixtures or solutions including any of the foregoing. The carrier may be used in combination with a buffering agent.

[0148] In some embodiments, the composition of the present disclosure may comprise a carrier at a pH from 5 to 9, or from 6 to 8. In certain embodiments, the composition may comprise a carrier having a neutral pH. In certain embodiments, the pH of the carrier may be at or near physiological pH.

[0149] Solubilizers that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (SOLUPLUS), d-a-tocopherol acid polyethylene glycol (PEG) 1000 succinate (TPGS), PEG-40 hydrogenated castor oil (CREMOPHOR RH40), PEG-35 castor oil (CREMOPHOR EL), PEG-40 stearate (MYRJ 540), hard fat (such as GELUCIRE 33/01), polyoxylglycerides (such as GELUCIRE 44/14), stearoyl polyoxylglycerides (such as GELUCIRE 50/13), PEG-8 caprylic/capric glycerides (such as LABRASOL) and poloxamers (such as PLURONIC, KOLLIPHOR).

[0150] Buffering agents that that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, triethylamine, meglumine, diethanolamine, ammonium acetate, arginine, lysine, histidine, a phosphate buffer (e.g., sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, or o-phosphoric acid), sodium bicarbonate, a Britton-Robinson buffer, a Tris buffer (containing Tris(hydroxymethyl)-aminomethane), a HEPES buffer (containing N-(2-hydroxyethyl)piperazine-N^,-(2-ethanesulfonic acid), acetate, a citrate buffer (e.g., citric acid, citric acid anhydrous, citrate monobasic, citrate dibasic, citrate tribasic, citrate salt), ascorbate, glycine, glutamate, lactate, malate, formate, sulfate, and mixtures thereof.

[0151] Further, pH-adjusting agents that that may be used in the pharmaceutical compositions of the present disclosure include pharmaceutically acceptable acids or bases. For example, acids may include, but are not limited to, one or more inorganic mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, and the like; or one or more organic acids such as acetic, succinic, tartaric, ascorbic, citric, glutamic, benzoic, methanesulfonic, ethanesulfonic, trifluoroacetic, and the like. The bases may be one or more inorganic bases or organic bases, including, but not limited to, alkaline carbonate, alkaline bicarbonate, alkaline earth metal carbonate, alkaline hydroxide, alkaline earth metal hydroxide, or amine. For example, the inorganic or organic base may be an alkaline hydroxide such as lithium hydroxide, potassium hydroxide, cesium hydroxide, sodium hydroxide, or the like; an alkaline carbonate such as calcium carbonate, sodium carbonate, or the like; or an alkaline bicarbonate such as sodium bicarbonate, or the like; the organic base may also be sodium acetate.

[0152] Surfactants that that may be used in the pharmaceutical compositions of the present disclosure may include, but are not limited to, sodium lauryl sulfate, docusate sodium, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, benzalkonium chloride, benzethonium chloride, lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 10, 50, or 60), glycerol monostearate, polysorbate (e.g., polysorbate 40, 60, 65, or 80), sucrose fatty acid ester, methyl cellulose, polyalcohols and ethoxylated polyalcohols, thiols (e.g., mercaptans) and derivatives, poloxamers, polyethylene glycol-fatty acid esters (e.g., KOLLIPHORRH40, KOLLIPHOREL), lecithins, and mixtures thereof.

[0153] Antioxidants that that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, acetylcysteine, ascorbyl palmitate, BHA, BHT, monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabi sulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, EDTA (e.g., disodium edetate), DTP A, bismuth sodium triglycollamate, or a combination thereof. Antioxidants may also comprise amino acids such as methionine, histidine, cysteine and those carrying a charged side chain, such as arginine, lysine, aspartic acid, and glutamic acid. Any stereoisomer (e.g., 1-, d-, or a combination thereof) of any particular amino acid (e.g., methionine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine and combinations thereof) or combinations of these stereoisomers, may be present so long as the amino acid is present either in its free base form or its salt form.

[0154] In some embodiments, the pharmaceutical compositions of the present disclosure may include other suitable pharmaceutical additives such tonicity-adjusting agents, preservatives, emulsifiers, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.

[0155] A suspension or solution according to the present disclosure may be prepared using methods known in the art. For example, the pazopanib ASD and the one or more pharmaceutically acceptable excipients may be mixed by simple mixing, or may be mixed with a mixing device continuously, periodically, or a combination thereof. Examples of mixing devices may include, but are not limited to, a magnetic stirrer, shaker, a paddle mixer, homogenizer, and any combination thereof.

[0156] Solid dosage forms. In some embodiments, the pharmaceutical compositions may be in a solid dosage form for oral administration, such as a capsule, tablet, sprinkle, or pellet. In particular, in one aspect the present disclosure provides a pharmaceutical composition in the form of a tablet. In some embodiments, the pharmaceutical compositions may be in the form of granules, or may be prepared as granules as an intermediate step to forming another oral dosage form, such as tablets, sprinkles, or pellets.

[0157] The solid oral dosage form pharmaceutical compositions comprise a pazopanib ASD and one or more pharmaceutically acceptable excipients, such as one or more fillers, one or more disintegrants, and/or other optional excipients such as one or more binders, one or more lubricants, one or more wetting agents, one or more solubilizers, one or more surfactants, one or more antioxidants, and/or one or more glidants, for example.

[0158] Suitable fillers include acacia, calcium carbonate, calcium sulfate, calcium sulfate dihydrate, compressible sugar, dibasic calcium phosphate anhydrous (e.g., FUJICALIN, EMCOMPRESS), dibasic calcium phosphate dihydrate, tribasic calcium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, lactose monohydrate, lactose anhydrous, magnesium oxide, magnesium carbonate, silicon dioxide, magnesium aluminum silicate, maltodextrin, mannitol, methyl cellulose, microcrystalline cellulose (e.g., AVICEL PH-101, AVICEL PH-102, AVICEL PH-105), powdered cellulose, starches, sorbitol, dextrose, dextrates, dextrin, sucrose, xylitol and mixtures thereof. In some embodiments, microciystalline cellulose, alone or in combination with other fillers, may be particularly suitable.

[0159] One or more disintegrants may be included. Suitable disintegrants in the practice of the disclosure include natural, modified or pre-gelatinized starch, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpolypyrrolidone, and mixtures thereof. In some embodiments, crospovidone, alone or in combination with other disintegrants, may be particularly suitable.

[0160] Suitable binders include various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose (e.g., AVICEL PH-101, AVICEL PH-102, AVICEL PH-105), or silicified microcrystalline cellulose (e.g., PROSOLV SMCC), for example.

[0161] One or more lubricants may be included to reduce friction with and adherence to processing equipment during processing and tableting. Examples of lubricants known in the art include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, steaiyl alcohol, glyceryl monostearate, sodium stearyl fumarate, talc, glyceryl behenate, sodium benzoate, sodium lauryl sulfate, and the like.

[0162] In certain embodiments, the one or more lubricants comprises magnesium stearate. In certain embodiments, the lubricant is magnesium stearate. [0163] In excipient compatibility studies, it was found that the presence of sodium stearyl fumarate tended to destabilize the pazopanib ASD. Accordingly, in other embodiments, the one or more lubricants does not comprise sodium stearyl fumarate. In other embodiments, the composition does not comprise sodium stearyl fumarate. In other embodiments, the compositions are essentially free of sodium stearyl fumarate. In other embodiments, the compositions are free of sodium stearyl fumarate.

[0164] Solubilizers that may be optionally included in the pharmaceutical compositions of the present disclosure include, but are not limited to, polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol copolymer (SOLUPLUS), d-a-tocopherol acid polyethylene glycol (PEG) 1000 succinate (TPGS), PEG-40 hydrogenated castor oil (CREMOPHOR RH40), PEG-35 castor oil (CREMOPHOR EL), PEG-40 stearate (MYRJ 540), hard fat (such as GELUCIRE 33/01), polyoxylglycerides (such as GELUCIRE 44/14), stearoyl polyoxylglycerides (such as GELUCIRE 50/13), PEG-8 caprylic/capric glycerides (such as LABRASOL) and poloxamers (such as PLURONIC, KOLLIPHOR). In some embodiments, a poloxamer, alone or in combination with other solubilizers, may be particularly suitable.

[0165] In some embodiments, the pharmaceutical compositions may comprise a pazopanib ASD and one or more pharmaceutically acceptable excipients, with the proviso that the pharmaceutically acceptable excipients do not comprise polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (e.g., SOLUPLUS).

[0166] Surfactants that may be optionally included in the pharmaceutical compositions of the present disclosure may include, but are not limited to, sodium lauiyl sulfate, docusate sodium, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, benzalkonium chloride, benzethonium chloride, lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene hydrogenated castor oil 10, 50, or 60), glycerol monostearate, polysorbate (e.g., polysorbate 40, 60, 65 or 80), sucrose fatty acid ester, methyl cellulose, polyalcohols and ethoxylated polyalcohols, thiols (e.g., mercaptans) and derivatives, poloxamers, polyethylene glycol-fatty acid esters (e.g., KOLLIPHOR RH40, KOLLIPHOR EL), lecithins, and mixtures thereof. [0167] A variety of pharmaceutically acceptable wetting agents may be included. As a nonlimiting example of a wetting agent, poloxamers, such as poloxamer 407 (e.g., PLURONIC F- 127) or poloxamer 188 (e.g., PLURONIC F-68), may be suitable. Other known pharmaceutically acceptable wetting agents may be suitably employed. A wetting agent may be included in the ASD in an amount of 0.5% to 10%, or 1% to 8%, or 2% to 6%, by weight.

[0168] Antioxidants that may be optionally included in the pharmaceutical compositions of the present disclosure include, but are not limited to, acetylcysteine, ascorbyl palmitate, BHA, BHT, monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, EDTA (e.g., disodium edetate), DTP A, bismuth sodium triglycollamate, or a combination thereof.

[0169] Glidants are employed to improve flow properties of a powder or granule mixture prior to prior to further processing (such as tablet compression, for example). Suitable glidants that may be employed in the present disclosure include, but are not limited to, colloidal silica (e.g., hydrophobic colloidal silica, such as AEROSIL), silica gel, precipitated silica, and the like.

[0170] In some cases, a single excipient may provide more than one function. For example, microciystalline cellulose (when present) can function as both a filler and a binder. Alternatively, such multi-functional excipients can be used in combination with other excipients. (For example, microcrystalline cellulose may be used with other fillers and/or other binders.)

[0171] Also suitable are a variety of marketed co-processed excipients that have found application in pharmaceutical formulations. A co-processed excipient is any combination of two or more excipients pre-processed by physical co-processing that does not generally lead to the formation of covalent bonds. Co-processed excipients can possess superior properties as compared to individual excipients. Co-processed excipients been developed primarily to improve flowability, compressibility, and disintegration performance.

[0172] By way of example, co-processed excipients comprising microcrystalline cellulose may be suitably employed in some embodiments. Co-processed excipients comprising microcrystalline cellulose include (as non-limiting examples): co-processed microcrystalline cellulose and mannitol (e.g., AVICEL HFE); co-processed microcrystalline cellulose and colloidal silica (e.g., PROSOLV SMCC, AVICEL SMCC); co-processed microcrystalline cellulose and dibasic calcium phosphate (e.g., AVICEL DG); co-processed microcrystalline cellulose and lactose (e.g., MICROLELA).

[0173] Co-processed excipients comprising sugars or sugar alcohols may be suitably employed in some embodiments. Co-processed excipients comprising sugars or sugar alcohols include (as non-limiting examples): co-processed lactose and povidone (e.g., LUDIPRESS); co-processed lactose and cellulose (e g., CELLACTOSE); co-processed mannitol and starch (e.g., PEARLITOL FLASH); co-processed mannitol, crospovidone and silicon dioxide (e.g., PHARMABURST).

[0174] Granules. In some embodiments, the pharmaceutical compositions may be in the form of granules. In other embodiments, granules may be prepared as an intermediate step to forming another oral dosage form, such as a tablet or pellet, or as a fill for a capsule. Granules typically have improved flow, handling, blending, and compression properties relative to ungranulated materials.

[0175] The granules may be prepared using the ASD particles by processes known in the art, including wet granulation and dry granulation. In some embodiments, a granule blend is formed by dry-blending granule components, and then the granule blend is densified using a roller compactor which typically forms ribbons of material. The ribbons are then reduced in size by milling to form granules.

[0176] Wet granulation techniques may also be employed to form granules, provided the solvents and process selected do not alter the properties of the ASD. Improved wetting, disintegrating, dispersing and dissolution properties may be obtained by the inclusion of suitable excipients, as described above.

[0177] In some embodiments, the granule blend (and accordingly the resulting granules) can include some or all of the components of a desired tablet formulation. After granulation, the granules can be incorporated into a tableting blend and compressed into tablets, as described below.

[0178] Accordingly, in another aspect, the present disclosure provides a pharmaceutical composition in the form of granules comprising ASD particles. In another aspect, the present disclosure provides a pharmaceutical composition comprising granules that include ASD particles.

[0179] In certain embodiments, the granules may comprise the ASD in an amount of 30% to 80%, more suitably 40% to 70% by weight of the granule; one or more granulation fillers in an amount of 15% to 70%, more suitably 20% to 50% by weight of the granule; one or more granulation disintegrants in an amount of 2% to 20%, more suitably 5% to 15% by weight of the granule; and optionally one or more solubilizers in an amount of 2% to 20% by weight of the granule; and optionally one or more lubricants in an amount of 0.2% to 5% by weight of the granule; and optionally one or more glidants in an amount of 0.2% to 5% by weight of the granule. In particular embodiments, the granule may comprise the components as set forth in Table 1.

[0180] In some embodiments, a solubilizer may be included in the granules. A variety of pharmaceutically acceptable solubilizers may be included. As a non-limiting example of a suitable solubilizer, poloxamers, such as poloxamer 407 (e.g., PLURONIC F-127) or poloxamer 188 (e.g., PLURONIC F-68), may be included. Other known pharmaceutically acceptable solubilizers may be suitably employed. A solubilizer may be included in the granules in an amount of 0.5% to 10%, or 1% to 10%, or 3% to 8%, or 5%, by weight of the granules.

[0181] Tablets In another aspect, the present disclosure provides a pharmaceutical composition in the form of a tablet. The tablet of the disclosure comprises a pazopanib ASD and one or more pharmaceutically acceptable excipients, such as one or more fillers, one or more disintegrants, and/or other optional excipients such as one or more binders, one or more lubricants, one or more wetting agents, one or more solubilizers, one or more surfactants, one or more antioxidants, and/or one or more glidants, for example.

[0182] The tablet may comprise 10% to 75% of the pazopanib ASD, based on the weight of the tablet. In some embodiments, the tablet comprises 15% to 60% of the pazopanib ASD. In other embodiments, the tablet comprises 20% to 50% of the pazopanib ASD. In other embodiments, the tablet comprises 25% to 40% of the pazopanib ASD. In yet other embodiments, the tablet comprises 30% of the pazopanib ASD.

[0183] Generally, the tablet will comprise from 10% to 80% of the one or more fillers, by weight of the tablet. Suitable fillers are described above. In some embodiments, the tablet comprises 20% to 75% of the one or more fillers. In other embodiments, the tablet comprises 30% to 70% of the one or more fillers. In yet other embodiments, the tablet comprises 40% to 65% of the one or more fillers. In yet other embodiments, the tablet comprises 50% to 60% of the one or more fillers. In some embodiments, the tablet comprises 55% of the one or more fillers.

[0184] Generally, the tablet will comprise from 2% to 20% of the one or more disintegrants, by weight of the tablet. Suitable disintegrants are described above. In some embodiments, the tablet will comprise from 5% to 15% of the one or more disintegrants. In other embodiments, the tablet will comprise from 5% to 10% of the one or more disintegrants.

[0185] One or more lubricants can optionally be included in the tablet. Suitable lubricants are described above. When included, the one or more lubricant is generally present in the range of 0.1% to 5%, by weight of the tablet. In some embodiments, the one or more lubricant is generally present in the range of 0.25% to 2%, by weight of the tablet. In certain embodiments, the lubricant is magnesium stearate.

[0186] In excipient compatibility studies, it was found that the presence of sodium stearyl fumarate in tablet formulations tended to destabilize the ASD present in the tablet. Accordingly, in other embodiments, the tablet comprises one or more lubricants, with the proviso that the lubricant does not comprise sodium stearyl fumarate. In other embodiments, the tablet does not comprise sodium stearyl fumarate. In other embodiments, the tablets are essentially free of sodium stearyl fumarate. In other embodiments, the tablets are free of sodium stearyl fumarate.

[0187] When included, the one or more antioxidant is generally present in the range of 0.05% to 2%, by weight of the tablet. In some embodiments, the one or more antioxidant is generally present in the range of 0.1% to 0.5%, by weight of the tablet.

[0188] One or more glidants can optionally be included in the tablet. Suitable glidants are described above. When included, the one or more glidant is generally present in the range of 0.1% to 5%, by weight of the tablet. In some embodiments, the one or more glidant is generally present in the range of 0.25% to 2%, by weight of the tablet. In certain embodiments, the glidant is hydrophobic colloidal silica.

[0189] In certain embodiments, the tablet may comprise the ASD in an amount of 20% to 40% by weight of the tablet; one or more fillers (such as microcrystalline cellulose) in an amount of 40% to 70% by weight of the tablet; one or more disintegrants (such as crospovidone) in an amount of 5% to 15% by weight of the tablet; one or more lubricants and/or glidants (such as hydrophobic colloidal silica and/or magnesium stearate) in an amount of 0.5% to 5% by weight of the tablet.

[0190] As described above, in some embodiments, it may be desirable to form granules as an intermediate step to forming a tableting blend. In another aspect, the present disclosure provides a pharmaceutical composition in the form of tablets which comprise granules that include ASD particles. [0191] In some embodiments, the tablets of the disclosure include granules as described above, along with additional excipients external to the granules (“extra-granular excipients”). In one embodiment, the tablet comprises from 20% to 80% of the granules, by weight of the tablet; and 20% to 80% of the extra-granular excipients, by weight of the tablet. In certain embodiments, the tablet comprises from 30% to 70% of the granules, by weight of the tablet; and 30% to 70% of the extra-granular excipients, by weight of the tablet. In yet other embodiments, the tablet comprises from 40% to 60% of the granules, by weight of the tablet; and 40% to 60% of the extra-granular excipients, by weight of the tablet.

[0192] By way of example, the extra-granular excipients could include one or more tablet fillers and/or one or more tablet disintegrants. Suitable fillers and disintegrants are described above. In some embodiments, the one or more tablet fillers comprises microcrystalline cellulose. In some embodiments, the one or more tablet disintegrants comprises crospovidone.

[0193] In addition, the extra-granular excipients could include one or more solubilizers, one or more lubricants and/or one or more glidants. Suitable solubilizers, lubricants and glidants are described above.

[0194] In particular embodiments, the tablets of the disclosure may comprise the components as set forth in Table 2.

[0195] Pharmaceutical compositions of the disclosure in the form of a tablet may be prepared using methods known in the art. For example, the pazopanib ASD and the one or more pharmaceutically acceptable excipients may be blended to provide a tableting blend by hand or bag blending, or using a suitable device. Examples of suitable blending devices may include, but are not limited to, a tumble blender, v-blender, acoustic blender, paddle mixer, screw mixer, and the like.

[0196] Suitable tableting blends may then be compressed into tablets weighing from 100 to 1000 mg using, for example, a manual tablet press or a conventional mechanical tablet press. In the case of tablets, compression force must be carefully selected to achieve desired mechanical properties of the tablet without compromising performance. If too high a compression force is used, the porosity of the tablet decreases, which can slow the rate of water wicking into the tablet, and can undesirably result in degraded dissolution performance.

[0197] The pharmaceutical compositions of the present disclosure may demonstrate a desirable level of physical and/or chemical stability over some suitable period of time, and optionally under accelerated conditions. The stability of the pharmaceutical compositions can be assessed by different measures. For instance, the pharmaceutical compositions may demonstrate chemical stability by having a particular assay value or a particular level of total related substances (e.g., impurities, degradation products, and the like), measured after storage under accelerated conditions over a specified period of time. In some embodiments, the pharmaceutical compositions may be amorphous as assessed using XRD (i.e., no crystalline character detected) after storage under the specified conditions.

[0198] In some embodiments, the pharmaceutical compositions may be substantially amorphous as assessed using XRD, after storage under the specified conditions. The storage conditions may be one or more of 25°C/60% RH, or 30°C/65% RH, or 40°C/75% RH. The period of time may be one or more of 1 week, or 2 weeks, or 1 month, or 2 months, or 3 months, or 4 months, or 6 months, or 9 months, or 12 months, or 15 months, or 18 months, or 21 months, or 24 months, or any period of time therebetween.

[0199] In some embodiments, pharmaceutical compositions of the present disclosure are “food- insensitive compositions,” as further described below. In some embodiments, pharmaceutical compositions of the present disclosure are “improved variability compositions,” as further described below. Characterization by In Vitro Dissolution Testing

[0200] In vitro dissolution testing is routinely performed both for quality control and as a surrogate for in vivo drug release to ensure proper exposure for the patient or subject in use. Apparatus and testing procedures for dissolution testing are fully described in USP <711> Dissolution For pazopanib hydrochloride immediate-release tablets, FDA’s published recommendations for dissolution testing specify Apparatus 2 (paddles; 75 rpm) using 900 mL of 50 mM sodium acetate buffer (pH 4.5) containing 0.75% sodium dodecyl sulfate as a dissolution medium, with sampling at 10 min, 15 min, 30 min, 45 min, and 60 min.

[0201] In one embodiment, the present disclosure provides a pharmaceutical composition in the form of an orally administrable tablet characterized in that, when subjected to dissolution testing according to USP <711> Dissolution using Apparatus 2 (paddles; 75 rpm) using 900 mL of 50 mM sodium acetate buffer at pH 4.5 and containing 0.75% sodium dodecyl sulfate as a dissolution medium, at least 55% of the pazopanib is released into the dissolution medium within 15 minutes. In other embodiments, at least 60% of the pazopanib is released into the dissolution medium within 15 minutes. In other embodiments, at least 65% of the pazopanib is released into the dissolution medium within 15 minutes. In other embodiments, at least 70% of the pazopanib is released into the dissolution medium within 15 minutes. In other embodiments, at least 75% of the pazopanib is released into the dissolution medium within 15 minutes.

[0202] In one embodiment, the present disclosure provides a pharmaceutical composition in the form of an orally administrable tablet characterized in that, when subjected to dissolution testing according to USP <711> Dissolution using Apparatus 2 (paddles; 75 rpm) using 900 mL of 50 mM sodium acetate buffer at pH 4.5 and containing 0.75% sodium dodecyl sulfate as a dissolution medium, at least 75% of the pazopanib is released into the dissolution medium within 30 minutes. In other embodiments, at least 80% of the pazopanib is released into the dissolution medium within 30 minutes. In other embodiments, at least 85% of the pazopanib is released into the dissolution medium within 30 minutes. In other embodiments, at least 90% of the pazopanib is released into the dissolution medium within 30 minutes. [0203] In another embodiment, the present disclosure provides a pharmaceutical composition in the form of an orally administrable tablet characterized in that, when subjected to dissolution testing according to USP <711> Dissolution using Apparatus 2 (paddles; 75 rpm) using 900 mL of 50 mM sodium acetate buffer at pH 4.5 and containing 0.75% sodium dodecyl sulfate as a dissolution medium, at least 90% of the pazopanib is released into the dissolution medium within 60 minutes. In other embodiments, at least 95% of the pazopanib is released into the dissolution medium within 60 minutes.

Treatment of Proliferative Disorders

[0204] Aspects of the present disclosure relate to uses of the pharmaceutical compositions of the present disclosure. In the practice of embodiments of the present disclosure, the pharmaceutical compositions may be suitably administered to subjects or to patients (i.e., persons being treated for a disease or condition).

[0205] In some embodiments, the pharmaceutical composition is administered to a subject. The subject in the methods of the present disclosure may be a mammal, which includes, but is not limited to, a human, monkey, cow, hog, sheep, horse, dog, cat, rabbit, rat, and mouse. In certain embodiments, the subject is a human. In other embodiments, the pharmaceutical composition is administered to a human patient. The human patient may be adult or of a pediatric age, e.g., younger than 17 years old. In certain embodiments, the human patient is 1 year of age or older.

[0206] An aspect of the present disclosure relates to the use of the pharmaceutical compositions of the present disclosure to treat a proliferative disorder. Some embodiments relate to a method of treating a proliferative disorder, the method comprising administering a pharmaceutical composition of the present disclosure to a patient in need thereof. Some embodiments relate to a use of a pharmaceutical composition of the present disclosure for treating a proliferative disorder in a patient in need thereof, the use comprising administering the pharmaceutical composition to the patient. Some embodiments relate to a pharmaceutical composition of the present disclosure for use in treating a proliferative disorder in a patient in need thereof, the use comprising administering the pharmaceutical composition to the patient. [0207] In one aspect, the present disclosure relates to a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient.

[0208] In some embodiments, the proliferative disorder is cancer. Examples of such cancers may include, but are not limited to: carcinomas such as renal cell carcinoma, basal cell carcinoma, and squamous cell carcinoma; osteosarcoma; soft tissue sarcomas such as angiosarcoma and gastrointestinal stromal tumor; gliomas such as glioblastomas; leukemias such as acute lymphocytic leukemia (or acute lymphoblastic leukemia), acute myeloid leukemia (or acute myelogenous leukemia), chronic lymphocytic leukemia (or chronic lymphoblastic leukemia), chronic myeloid leukemia (or chronic myelogenous leukemia); ovarian cancer; lung cancer; breast cancer; pancreatic cancer; prostate cancer; bladder cancer; colon cancer; neuroendocrine tumor.

[0209] In certain embodiments, the proliferative disorder may be renal cell carcinoma (RCC) in advanced phase. In certain embodiments, the proliferative disorder may be soft tissue sarcoma (STS) in advanced phase. In certain embodiments, the patient may have received prior chemotherapy.

[0210] In other embodiments, the proliferative disorder is a non-cancerous proliferative disorder. Examples of non-cancerous proliferative disorders include, but are not limited to, age-related macular degeneration, proliferative diabetic retinopathy, and inflammatory diseases such as rheumatoid arthritis.

[0211] In the methods and uses of the present disclosure, a therapeutically effective amount of the pharmaceutical composition of the present disclosure will be based on, among other factors, the route of administration, the age and size of the patient, and the proliferative disorder being treated. As used herein, the term “therapeutically effective amount” means that amount that is expected to elicit the biological or medical response that is being sought by a clinician.

[0212] In some embodiments, a therapeutically effective amount may be based on body surface area, and may range from 50 mg/m² to 800 mg/m² of pazopanib, or from 100 mg/m² to 400 mg/m² of pazopanib. In other embodiments, a therapeutically effective amount may be fixed dose. For instance, the fixed dose may be 200 mg to 1600 mg, or 300 mg to 1200 mg, or 400 mg to 800 mg, per day of pazopanib. In certain embodiments, the fixed dose may be 200 mg, or 250 mg, or 300 mg, or 350 mg, or 400 mg, or 450 mg, or 500 mg, or 550 mg, or 600 mg, or 650 mg, or 700 mg, or 750 mg, or 800 mg of pazopanib.

[0213] Depending on the treatment regimen, the quantity of pazopanib dosed per day may be dosed all at once (once-daily dosing), or may be dosed more frequently than once per day based on labeling guidelines or physician’s recommendation. In some embodiments, dosing is once daily.

Methods of Administering with Food

[0214] An aspect of the present disclosure relates to a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient without a food effect.

[0215] In another aspect, the present disclosure relates to a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient without regard to consumption of food.

[0216] In another aspect, the present disclosure relates to a method of treating a proliferative disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient without regard to whether the patient is in a fasted state or in a fed state.

[0217] In yet another aspect, the present disclosure relates to a method of safely delivering pazopanib to a patient in need thereof, comprising step (a), administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient; and step (b), administering a meal to the patient. In some embodiments, step (b) occurs before step (a). In other embodiments, step (a) occurs before step (b) In some embodiments, steps (a) and (b) occur within less than two hours of each other. In some embodiments, steps (a) and (b) occur within 90 minutes of each other. In some embodiments, steps (a) and (b) occur within one hour of each other. In some embodiments, steps (a) and (b) occur within thirty minutes of each other. In some embodiments, steps (a) and (b) occur within fifteen minutes of each other.

[0218] In some embodiments, step (b) occurs less than one hour after step (a). In some embodiments, step (b) occurs less than 30 minutes after step (a). In some embodiments, step (b) occurs less than 15 minutes after step (a).

[0219] In some embodiments, step (a) occurs less than two hours after step (b). In some embodiments, step (a) occurs less than 90 minutes after step (b). In some embodiments, step (a) occurs less than one hour after step (b). In some embodiments, step (a) occurs less than 30 minutes after step (b). In some embodiments, step (a) occurs less than 15 minutes after step (b).

[0220] In some embodiments, the “meal” is any solid food that is consumed that provides at least 200 calories to the patient or subject. In other embodiments, the meal is any solid food that is consumed that provides at least 400 calories to the patient or subject. In yet other embodiments, the meal is any solid food that is consumed that provides at least 600 calories to the patient or subject. In other embodiments, the meal is a high-fat test meal as described below. In other embodiments, the meal is a low-fat test meal as described below.

[0221] In another aspect, the present disclosure relates to a method of delivering a therapeutically effective amount of pazopanib to a patient without regard to a food effect, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient.

[0222] In a further aspect, the present disclosure relates to a method of delivering a therapeutically effective amount of pazopanib to a patient without regard to consumption of food, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient.

[0223] In another aspect, the present disclosure relates to a method of delivering a therapeutically effective amount of pazopanib to a patient without regard to whether the patient is in a fed state or in a fasted state, comprising administering a therapeutically effective amount of a pharmaceutical composition of the present disclosure to the patient.

[0224] As generally interpreted, “food effect” broadly refers to all aspects of interactions of food on drug dissolution, absorption, distribution, metabolism and elimination. The implications of food effect include changes in bioavailability, rate of on-set, duration of therapeutic effect and incidence and seriousness of side effects. The magnitude of a food effect is generally greatest when the drug product is administered shortly after a meal is ingested. An example of a drug product that exhibits a significant food effect is VOTRIENT, which as described above can produce an approximately 2-fold increase in AUC and C_max when taken with either a high-fat or low-fat meal as compared to levels obtained under fasting conditions.

[0225] In practice, a food effect is generally assessed by measuring standard pharmacokinetic parameters observed upon administration of a drug to a subject in a fasted state, versus the same measurements observed upon administration to the same subject in a fed state. Typically, data for a number of test subjects is pooled for analysis. For further information about food effect studies, refer to “Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies” (Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), December 2002), which is hereby incorporated by reference in its entirety. Reference is also made to “Guidance for Industry: Assessing the Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology Considerations (Draft Guidance)” (CDER, FDA, February 2019), which is hereby incorporated by reference in its entirety.

[0226] As used in relation to the methods of the present disclosure, the phrase “food effect” refers to a relative difference in one or more of AUC (area under the plasma concentration vs. time curve for a specified time interval), C_max (maximum plasma concentration), and/or T max (time to maximum plasma concentration) for an active substance, when said substance or a formulation thereof (such as a solid dispersion or pharmaceutical composition) is administered orally to a human subject, concomitantly with food or in a fed state, as compared to the measured value for the same parameter when the same formulation is administered to the same subject in a fasted state. The food effect F is calculated as F — (Y_fed Y_fasted) / Y_fasted wherein Y_fed and Y_fasted are the measured values of AUC, C_max or T_max in the fed and fasted state, respectively.

[0227] The phrase “positive food effect” refers to a food effect where the AUC and/or C_max is higher when the drug is administered orally in a fed state than when it is administered in a fasted state. The phrase “negative food effect” refers to a food effect where the AUC and/or C_max is lower when the drug is administered orally in the fed state than when it is administered in the fasted state.

[0228] In assessing food effect, data obtained from fasted and fed studies is processed using conventional pharmacokinetic statistical analyses and methods. Fasted and fed studies may be single-dose studies or steady-state studies, as appropriate. Using pooled data from a suitable number of subjects, an absence of food effect is indicated when the 90 percent confidence interval (“Cl”) for the ratio of population geometric means between fed and fasted administrations, based on log-transformed data, is contained in the equivalence limits of 80% to 125% for AUC_0-inf (AUC_0-t when appropriate) and C_max. On the other hand, an absence of food effect is not established if the 90 percent Cl for the ratio of population geometric means between fed and fasted administrations, based on log-transformed data, is not contained in the equivalence limits of 80% to 125% for either AUC_0-inf (AUC_0-t when appropriate) or C_max.

[0229] In the methods of the present disclosure, “without a food effect” means that the relative difference is not substantially large, e.g., less than 20%, or less than 15%, or less than 10%, for AUC (which can be, for example, AUC_0-24h, AUC_0-iast or AUC_0-inf) and/or C_max, for pazopanib when the ASD or pharmaceutical composition of the present disclosure is administered orally, concomitantly with food or in a fed state, as compared to the measured value for the same parameter when the same ASD or pharmaceutical composition is administered in a fasted state. (As used herein, for a relative difference stated as a percentage, each stated range is with respect to the absolute value of that relative difference; i.e., “less than 20%” means that the relative difference F falls in the range -20% < F < +20%.) [0230] In the methods of the present disclosure, “without regard to consumption of food” means that no consideration has to be made whether the ASD or pharmaceutical composition of the present disclosure is being administered to the subject or patient concomitantly with food, or whether the patient or subject is in a fed state or fasted state. The administration will be expected to provide a therapeutically relevant exposure, and will not be expected to cause an unsafe overexposure, regardless of whether the patient or subject is in a fed state or fasted state.

[0231] “Therapeutically relevant exposure” as used herein means an exposure that provides AUC_0-t (such as AUC_0-24h for example) and/or C_max, in the subject’s plasma that would be expected to produce the desired therapeutic effect. One way to determine a similar therapeutic effect is if the AUC_0-t or C_max is within the 80% to 125% bioequivalence criteria compared to administration of an appropriate strength (determined with reference to the product’s labeling) of the conventional commercially available immediate-release composition to the same healthy subject (or set of healthy subjects, as appropriate), dosed according to its labeled instructions.

[0232] The phrase “concomitantly with food,” as used herein, refers to administration to the subject from 30 minutes after the subject ingests food to 1 hour after the subject ingests food. Administration in a “fed state” or under “fed conditions,” as used herein, refers to administration to the subject from 30 minutes after the subject starts ingesting a meal to 1 hour after complete ingestion of a meal.

[0233] Similarly, “fed state” or “fed conditions” refers to the condition of a subject 30 minutes after the subject starts ingesting a meal to 1 hour after complete ingestion of a meal.

[0234] In some embodiments, the meal is a “high-fat test meal,” which in accordance with FDA’s Guidance for Industry (December 2002) referenced above, is a high-fat and high-calorie (approximately 800 to 1000 calories) meal comprising approximately 150 calories from protein, 250 calories from carbohydrate, and 500-600 calories from fat. In other embodiments, the meal is a “low-fat test meal,” which in accordance with FDA’s Draft Guidance for Industry (February 2019) referenced above, is a lower-calorie (approximately 400 to 500 calories) meal comprising approximately 11-14 grams of fat and approximately 25% calories from fat (with the balance from protein and carbohydrate). [0235] The phrase “administration in the fasted state” (or equivalently “fasting state”) as used herein refers to administration to the subject at least 2 hours, more suitably at least 4 hours, or more suitably at least 8 hours after the subject’s previous meal. Preferably, administration in the fasted state or under fasting conditions follows an overnight fast of at least 10 hours. Similarly, “fasted state” or “fasting conditions,” as used herein, refers to the condition in which the subject has not eaten for at least two hours, more suitably at least 4 hours, or more suitably at least 8 hours; or the condition of the subject following an overnight fast of at least 10 hours. Moreover, administration in the fasted state or under fasting conditions may also require continued fasting for at least 1 hour, more suitably at least 2 hours, or more suitably at least 4 hours following the administration.

[0236] In certain embodiments, the ASD or pharmaceutical composition is administered without regard to whether the subject is in a fasted state. In certain embodiments, the ASD or pharmaceutical composition is administered without regard to whether the subject is in a fed state. In certain embodiments, the ASD or pharmaceutical composition is administered without regard to whether the subject is in a fasted state or in a fed state. In certain embodiments, the ASD or pharmaceutical composition is administered without regard to a food effect. In certain embodiments, the ASD or pharmaceutical composition is administered concomitantly with food.

[0237] Some embodiments relate to a method of delivering pazopanib to a subject without regard to whether the subject is in a fasted state, the method comprising administering to the subject an ASD or pharmaceutical composition according to the disclosure.

[0238] Some embodiments relate to a method of delivering pazopanib to a subject without regard to whether the subject is in a fed state, the method comprising administering to the subject an ASD or pharmaceutical composition according to the disclosure.

[0239] Some embodiments relate to a method of delivering pazopanib to a subject without regard to whether the subject is in a fasted state or a fed state, the method comprising administering to the subject an ASD or pharmaceutical composition according to the disclosure. [0240] Administration of the ASD or pharmaceutical composition of the present disclosure can be characterized by the pharmacokinetic profile (i.e., plasma concentrations of pazopanib over time), or by, for example, calculated pharmacokinetic parameters (such as C_max and/or AUC_0-t, which can be, for example, AUC_0-12h, AUC_0-24h, AUC_0-72h, AUC_0-last or AUC_0-inf) resulting from the administration of the ASD or pharmaceutical composition at certain dosages to a subject in a fasted state or a fed state.

[0241] Administration of the ASD or pharmaceutical composition of the present disclosure can also be characterized by how the pharmacokinetic profile resulting from administration of the ASD or pharmaceutical composition to a subject in a fed state compares to the pharmacokinetic profile resulting from administration of the ASD or pharmaceutical composition to a subject in a fasted state. As an example, for some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state and in a fasted state may result in a relative difference in the plasma exposure of pazopanib between the fed state and the fasted state of less than 40%, or less than 35%, or less than 30%, or less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%. Exposure may be expressed as AUC_0-12h. AUC_0-24h, AUC_0-72h. AUC_0-last, or AUC_0-inf, for example. Exposure can be demonstrated for an individual subject, or alternatively for a suitable number of subjects (n>l). When comparing a number of subjects for which data is pooled, the exposure may be expressed as a population geometric mean, in accordance with conventional pharmacokinetic statistical analyses and methods.

[0242] In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state may result in plasma AUC_0-24h of pazopanib that is within 40%, or within 35%, or within 30%, or within 25%, or within 20% of the plasma AUC_0-24h of pazopanib that may result from administration of the pharmaceutical composition to the subject in a fasted state. Plasma AUC_0-24h can be for an individual subject, or a geometric mean from a number of subjects.

[0243] In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state may result in plasma AUC_0-last of pazopanib that is within 40%, or within 35%, or within 30%, or within 25%, or within 20% of the plasma AUCo- last of pazopanib that may result from administration of the pharmaceutical composition to the subject in a fasted state. Plasma AUC_0-last can be for an individual subject, or a geometric mean from a number of subjects.

[0244] In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state may result in plasma AUC_0-inf of pazopanib that is within 40%, or within 35%, or within 30%, or within 25%, or within 20% of the plasma AUC_0-inf of pazopanib that may result from administration of the pharmaceutical composition to the subject in a fasted state. Plasma AUCo-inf can be for an individual subject, or a geometric mean from a number of subjects.

[0245] For some embodiments, administration of an ASD or pharmaceutical composition of the present disclosure to a subject in a fed state and in a fasted state may result in a relative difference in the plasma C_max of pazopanib between the fed state and the fasted state of less than 30%, or less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%. C_max can be demonstrated for an individual subject, or alternatively for a suitable number of subjects (n>l). When comparing a number of subjects for which data is pooled, the C_max may be expressed as a population geometric mean, in accordance with conventional pharmacokinetic statistical analyses and methods.

[0246] In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fed state may result in plasma C_max of pazopanib that is within 30%, or within 25%, of the plasma C_max of pazopanib that may result from administration of the pharmaceutical composition to the subject in a fasted state. Plasma C_max can be for an individual subject, or a geometric mean from a number of subjects.

[0247] In yet other embodiments, administration of the ASD or pharmaceutical composition to a subject in a fed state provides an exposure of pazopanib that is similar to the exposure resulting from administration of the pharmaceutical composition to the subject in a fasted state. Exposure may be expressed as AUC_0-12. AUC_0-24h, AUC_0-72h, AUC_0-last, or AUC_0-inf, for example; exposure can be for an individual subject, or a geometric mean from a number of subjects. [0248] In some embodiments, administration of the ASD or pharmaceutical composition to a subject in a fed state provides a plasma C_max of pazopanib that is similar to the plasma C_max of pazopanib resulting from administration of the ASD or pharmaceutical composition to the subject in a fasted state. Plasma C_max can be for an individual subject, or a geometric mean from a number of subjects.

[0249] As used herein in this context, “similar” exposure means a relative difference in the plasma exposure of pazopanib between the fed state and the fasted state of less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%; and “similar” C max likewise means a relative difference in the plasma C_max of pazopanib between the fed state and the fasted state of less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5% (each stated percentage is understood to be an absolute value; i.e., “less than 20%” means that the relative difference F falls in the range -20% < F < +20%).

[0250] As used herein, the phrase “food-insensitive composition” indicates a pharmaceutical composition of the present disclosure that can be administered without regard to the patient’s or subject’s fed or fasted state. A food-insensitive composition provides a therapeutically relevant exposure to the patient or subject regardless of whether the patient or subject has recently ingested a meal, or whether the patient or subject ingests a meal shortly after administration of the pharmaceutical composition, or whether the patient or subject was in a fasted state at the time of administration and remains in the fasted state for some time following administration. In some embodiments, the food-insensitive composition is a crushable tablet as described herein.

Methods of Administering at Reduced Dosage

[0251] In addition, administration of the ASD or pharmaceutical composition of the present disclosure can be characterized by how the pharmacokinetic profile resulting from administration of the ASD or pharmaceutical composition compares to the pharmacokinetic profile resulting from administration of an immediate-release crystalline pazopanib formulation, such as the standard commercially-available pazopanib product, VOTRIENT, which contains pazopanib monohydrochloride. For instance, in some embodiments, administration of an ASD or pharmaceutical composition of the present disclosure may result in a pharmacokinetic profile that is comparable to the pharmacokinetic profile obtained by orally administering an immediate- release crystalline pazopanib formulation, but administered at a fraction of the dosage. For this comparison, administration must be done in a fasted state, since VOTRIENT should only be administered in a fasted state.

[0252] By “comparable,” it is meant that the administration of the ASD or the pharmaceutical composition of the disclosure to the subject may provide a relevant AUG_0-t (such as AUC_0-72h or AUCo-in_f) and/or C_max in the subject’s plasma that are within the 80% to 125% bioequivalence criteria compared to administration of the immediate-release crystalline pazopanib formulation to the same subject, dosed according to its labeled instructions.

[0253] As used herein, “fraction of the dosage” may mean that the dose of pazopanib in the ASD or pharmaceutical composition of the present disclosure may be 70% less, or 65% less, or 60% less, or 55% less, or 50% less, or 45% less, or 40% less, or 35% less, or 30% less, or 25% less, or 20% less, as compared to the labeled dosage of the immediate-release crystalline pazopanib formulation.

[0254] By way of hypothetical example only, a pharmaceutical composition containing approximately 400 mg pazopanib hydrochloride (provided, for example, as a single 400 mg dosage unit, or as 2 x 200 mg dosage units) may provide a pharmacokinetic profile that is comparable to the pharmacokinetic profile obtained by orally administering a dose of immediate- release crystalline pazopanib formulation labeled to contain 800 mg of pazopanib (such as 4 x 200 mg VOTRIENT IR Tablet). In this hypothetical example, the dose of pazopanib in the pharmaceutical composition is 50% less than the dosage of the immediate-release crystalline pazopanib formulation.

[0255] In some embodiments, the dose of pazopanib in the ASD or pharmaceutical composition of the present disclosure is 70% less, or 65% less, or 60% less, or 55% less, or 50% less, or 45% less, or 40% less, or 35% less, or 30% less, or 25% less, as compared to the labeled dosage of the immediate-release crystalline pazopanib formulation. In particular embodiments, the dose of pazopanib in the ASD or pharmaceutical composition of the present disclosure may be 60% less, or 55% less, or 50% less, or 45% less, as compared to the labeled dosage of the immediate- release crystalline pazopanib formulation. In one particular embodiment, the dose of pazopanib in the ASD or pharmaceutical composition of the present disclosure may be 55% less, as compared to the labeled dosage of the immediate-release crystalline pazopanib formulation.

[0256] For some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma exposure of pazopanib that is within 20%, or within 15%, or within 10%, of the plasma exposure of pazopanib that may result from administration to a subject in a fasted state of an immediate-release crystalline pazopanib formulation, where the ASD or pharmaceutical composition is administered at a fraction of the dosage. In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma exposure of pazopanib that is greater than the plasma exposure of pazopanib that may result from administration to a subject in a fasted state of an immediate-release crystalline pazopanib formulation, where the ASD or pharmaceutical composition is administered at a fraction of the dosage. Exposure may be expressed as AUC_0-12, AUC_0-24h, AUC_0-72h, AUC_0-last, or AUC_0-inf, for example. Exposure can be for an individual subject, or a geometric mean from a number of subjects.

[0257] For some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma C_max of pazopanib that is within 20%, or within 15%, or within 10%, of the plasma C_max of pazopanib that may result from administration to a subject in a fasted state of an immediate-release crystalline pazopanib formulation, where the ASD or pharmaceutical composition is administered at a fraction of the dosage. In certain embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma C_max of pazopanib that is greater than the plasma C_max of pazopanib that may result from administration to a subject in a fasted state of an immediate-release crystalline pazopanib formulation, where the ASD or pharmaceutical composition is administered at a fraction of the dosage. C_max can be for an individual subject, or a geometric mean from a number of subjects. [0258] In the practice of some embodiments, the dosage of immediate-release crystalline pazopanib formulation is a multiple of the dose of the pazopanib contained in the pharmaceutical composition according to the disclosure. In some embodiments, the immediate-release crystalline pazopanib formulation may comprise at least two times the amount of pazopanib as the pharmaceutical composition according to the disclosure. In some embodiments, the immediate- release crystalline pazopanib formulation may comprise 2 to 2.5 times the amount of pazopanib as the pharmaceutical composition according to the disclosure.

[0259] In some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma AUC_0-12h of pazopanib that is greater than the plasma AUC_0-12h of pazopanib that may result from the administration of an immediate-release crystalline pazopanib formulation that has twice the amount of pazopanib as the ASD or pharmaceutical composition. Plasma AUC_0-12h can be for an individual subject, or a geometric mean from a number of subjects.

[0260] In some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma AUC_0-12h of pazopanib that is within 20%, or within 15%, of the plasma AUC_0-12h of pazopanib that may result from the administration of an immediate-release crystalline pazopanib formulation that has twice the amount of pazopanib as the ASD or pharmaceutical composition. Plasma AUC_0-12h can be for an individual subject, or a geometric mean from a number of subjects.

[0261] In some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma AUC_0-24h of pazopanib that is greater than the plasma AUC_0-24h of pazopanib that may result from the administration of an immediate-release crystalline pazopanib formulation that has twice, the amount of pazopanib as the ASD or pharmaceutical composition. Plasma AUC_0-24h can be for an individual subject, or a geometric mean from a number of subjects.

[0262] In some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma AUC_0-24h of pazopanib that is within 20%, or within 15%, of the plasma AUC_0-24h of pazopanib that may result from the administration of an immediate-release crystalline pazopanib formulation that has twice the amount of pazopanib as the ASD or pharmaceutical composition. Plasma AUCo-24_h can be for an individual subject, or a geometric mean from a number of subjects.

[0263] In some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma AUC_0-last of pazopanib that is within 20%, or within 15%, of the plasma AUC_0-last of pazopanib that may result from the administration of an immediate-release crystalline pazopanib formulation that has twice the amount of pazopanib as the ASD or pharmaceutical composition. Plasma AUC_0-last can be for an individual subject, or a geometric mean from a number of subjects.

[0264] In some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma AUC_0-inf of pazopanib that is within 25%, or within 20%, of the plasma AUC_0-inf of pazopanib that may result from the administration of an immediate-release crystalline pazopanib formulation that has twice the amount of pazopanib as the ASD or pharmaceutical composition. Plasma AUC_0-last can be for an individual subject, or a geometric mean from a number of subjects.

[0265] In some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma C_max of pazopanib that is greater than the plasma C_max of pazopanib that may result from the administration of an immediate-release crystalline pazopanib formulation that has twice the amount of pazopanib as the ASD or pharmaceutical composition. Plasma C_max can be for an individual subject, or a geometric mean from a number of subjects.

[0266] In some embodiments, administration of the ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state may result in plasma C_max of pazopanib that is within 25%, or within 20%, of the plasma C_max of pazopanib that may result from the administration of an immediate-release crystalline pazopanib formulation that has twice the amount of pazopanib as the ASD or pharmaceutical composition. Plasma C_max can be for an individual subject, or a geometric mean from a number of subjects. [0267] In yet other embodiments, administration of an ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state provides an exposure of pazopanib that is similar to the exposure resulting from administration of an immediate-release crystalline pazopanib formulation, but administered at a fraction of the dosage. Exposure may be expressed as AUC_0-12h, AUC_0-24h, AUC_0-72h, AUC_0-last, or AUC_0-inf, for example; exposure can be for an individual subject, or a geometric mean from a number of subjects.

[0268] In yet other embodiments, administration of an ASD or pharmaceutical composition of the present disclosure to a subject in a fasted state provides plasma C_max of pazopanib that is similar to the plasma C_max of pazopanib resulting from administration of an immediate-release crystalline pazopanib formulation, but administered at a fraction of the dosage. Plasma C_max can be for an individual subject, or a geometric mean from a number of subjects.

[0269] In yet other embodiments, administration of an ASD or pharmaceutical composition of the present disclosure to a subject in a fed state provides an exposure of pazopanib that is similar to the exposure resulting from administration of an immediate-release crystalline pazopanib formulation to the subject in a fasted state, but administered at a fraction of the dosage. Exposure may be expressed as AUC_0-12h, AUC_0-24h, AUC_0-72h. AUC_0-last, or AUC_0-inf, for example; exposure can be for an individual subject, or a geometric mean from a number of subjects.

[0270] In yet other embodiments, administration of an ASD or pharmaceutical composition of the present disclosure to a subject in a fed state provides plasma C_max of pazopanib that is similar to the plasma C_max of pazopanib resulting from administration of an immediate-release crystalline pazopanib formulation to the subject in a fasted state, but administered at a fraction of the dosage. Plasma C_max can be for an individual subject, or a geometric mean from a number of subjects.

[0271] As used herein in this context, “similar” exposure means a relative difference in the plasma exposure of pazopanib between administration of the pharmaceutical composition and administration of the immediate-release crystalline pazopanib formulation, of less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%; and “similar C_max ” means a relative difference in the plasma C_max of pazopanib between administration of the pharmaceutical composition and administration of the immediate-release crystalline pazopanib formulation, of less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5% (each stated percentage is understood to be an absolute value; i.e., “less than 20%” means that the relative difference F falls in the range -20% < F < +20%).

Effective Bioequivalence to Reference Composition

[0272] In another aspect, the disclosure provides pharmaceutical compositions that are effectively bioequivalent to a suitable reference composition when administered to healthy human subjects or suitable patients in a fasted state, but at a lower molar dose of the active ingredient as compared to the reference composition. In some embodiments, the reference composition is a conventional immediate-release pazopanib composition comprising pazopanib monohydrochloride. In some embodiments, the reference composition is VOTRIENT IR Tablet containing 200 mg pazopanib base (equivalent to 216.7 mg pazopanib monohydrochloride).

[0273] Pertaining to bioequivalence studies, FDA has published “Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (Draft Guidance)” (CDER, FDA, December 2013), which is hereby incorporated by reference in its entirety. Pertaining to statistical methods for determining bioequivalence, FDA has published “Guidance for Industry: Statistical Approaches to Establishing Bioequivalence” (CDER, FDA, January 2001), which is hereby incorporated by reference in its entirety.

[0274] Per FDA guidelines, a drug product (a “test composition”) is bioequivalent to a reference drug product (the “reference composition”) when the rate and extent of absorption of the drug substance (i.e., the active ingredient) from the test composition do not show a significant difference from the rate and extent of absorption of the drug substance when administered using the reference composition, under similar experimental conditions. For many drug substances that are orally bioavailable, including pazopanib, the preferred method for assessing bioequivalence is by assessing the pharmacokinetic profile attained upon oral administration of the test and reference compositions. [0275] The bioequivalence assessment frequently relies on pharmacokinetic endpoints such as C_max and AUC that are reflective of rate and extent of absorption, respectively. Generally speaking, using pooled data from a suitable number of subjects, bioequivalence between the test composition and reference composition is established when the 90% confidence interval (“CI) for the ratio of population geometric means between test composition and reference composition administrations, based on log-transformed data, is contained in the equivalence limits of 80% to 125% for both AUCo-inr(or AUCo-t when appropriate) and C_max. On the other hand, bioequivalence is not established if the 90% confidence interval for the ratio of population geometric means between test composition and reference composition administrations, based on log-transformed data, is not contained in the equivalence limits of 80% to 125% for either AUCo- inf(or AUC_0-t when appropriate) or C max.

[0276] As discussed above, a pharmacokinetic profile is assessed by monitoring the subject’s or patient’s blood plasma over time for the presence of the active ingredient (or in some cases a suitable surrogate, such as a metabolite) after administration of the pharmaceutical composition of interest. Per the FDA draft guidance for pazopanib hydrochloride compositions, the plasma analyte of interest is pazopanib. Pazopanib is also the relevant plasma analyte for the pharmaceutical compositions of the present disclosure.

[0277] Depending on the nature of the drug substance and the reference and test compositions, the required showing may require single-dose or multiple-dose studies. The most recent FDA guidance document (draft guidance, March 2021) on bioequivalence studies pertaining to pazopanib hydrochloride oral tablets (200 mg) recommends a steady-state study (multiple-dose, two-period, two-treatment crossover study) under fasting conditions. The guidance further recommends that the study should be done in “[A]dvanced renal cell carcinoma adult patients for whom pazopanib is indicated, who are already receiving pazopanib hydrochloride tablets in standard therapy, and who are tolerating a stable dosing regimen of EQ 800 mg Base per day.”

[0278] Per FDA guidelines, a test composition can only be bioequivalent when dosed at the same molar dose of the active ingredient as the reference composition. As discussed above, however, administration of an ASD or pharmaceutical composition of the present disclosure may result in a pharmacokinetic profile that is comparable to the pharmacokinetic profile obtained by orally administering a conventional immediate-release pazopanib formulation, but administered at a fraction of the dosage. For such embodiments, a more appropriate comparison is to assess the relative bioavailability when the test composition is dosed at a fraction of the corresponding molar dose of the chosen reference composition. As used herein, the phrases “effectively bioequivalent” and “effective bioequivalence” are used to refer to the situation where a test composition and reference composition meet stated bioequivalence criteria, but at different molar doses.

[0279] In one embodiment, the disclosure provides a pharmaceutical composition comprising pazopanib in an oral dosage form; wherein a single administration of the composition comprises a suitable number of dosage units comprising a total of 320 to 400 mg pazopanib; and wherein, when the dosage units are administered to patients in a fasted state, achieves a steady-state AUC_0-inf and C_max within the 80% to 125% bioequivalence criteria as compared to steady-state AUC_0-inf and C_max achieved upon administration of a reference composition, wherein the reference composition is a conventional immediate-release pazopanib composition comprising 800 mg pazopanib. In some embodiments, the pharmaceutical composition and reference composition are administered to suitable patients.

[0280] In another embodiment, the disclosure provides a pharmaceutical composition comprising 80 to 100 mg pazopanib in an oral dosage form; wherein the pharmaceutical composition is effectively bioequivalent under fasting conditions to a reference composition which is a conventional immediate-release pazopanib composition comprising 200 mg pazopanib; where effective bioequivalence is established under steady state by: (a) a 90% confidence interval for AUC which is between 80% and 125%; and (b) a 90% confidence interval for C_max, which is between 80% and 125%. In some embodiments, the pharmaceutical composition and reference composition are administered to suitable patients.

[0281] In another aspect, the disclosure provides pharmaceutical compositions that meet one or more bioequivalence criteria when administered to healthy human subjects or suitable patients in either a fasted or fed state, as compared to a suitable reference composition when administered to healthy human subjects or suitable patients in a fasted state, but at a lower molar dose of the active ingredient as compared to the reference composition. In any of the foregoing embodiments, the AUC can be AUC_0-24h, AUC_0-last, or AUC_0-inf, for example, as appropriate.

[0282] In some embodiments, the reference composition is a conventional immediate-release pazopanib composition comprising pazopanib monohydrochloride. In some embodiments, the reference composition comprises crystalline pazopanib monohydrochloride. In some embodiments, the reference composition is in tablet form. In some embodiments, the reference composition is VOTRIENT IR Tablet.

Methods of Treating a Patient Using Crushed Tablets

[0283] Crushing tablets is a known alternative method for dosing patients who have a difficulty or inability to swallow. Certain patients sometimes have difficulty swallowing an intact solid oral dosage form (such as a tablet). Swallowing an intact tablet can be especially challenging for elderly or geriatric patients, pediatric patients, and patients with conditions related to impaired swallowing (known as “dysphagia”), for example.

[0284] For such patients suffering from a proliferative disorder, an alternative method of dosing pazopanib may be highly beneficial. One approach for such patients is to alleviate the swallowing problem by oral administration of a medicament in powder form, such as a powder obtained by crushing a tablet or tablets. A crushable formulation is intended to address potential issues of patient compliance for such patient populations.

[0285] As stated above, one approach to alleviate the swallowing problem is by oral administration of a powder obtained by crushing a tablet or tablets. Tablets can be crushed using known methods, such as by using a commercially available pill crusher according to its instructions, or by using a mortar and pestle, for example.

[0286] A powder obtained from the crushing of tablet(s) can be dosed directly, generally with water or other fluid to aid in ingestion. Alternatively, a crushed tablet(s) could be dispersed in a small quantity of water or another fluid (such as fruit juice or milk) to be ingested. Alternatively, a crushed tablet(s) could be dispersed in a soft food and administered along with the soft food. For these purposes, commonly employed soft foods include such foods as yogurt, mashed potatoes, mashed vegetables, and fruit preparations (such as applesauce or jam), for example.

[0287] In one embodiment, the disclosure provides a method of safely delivering a therapeutically effective dose of pazopanib to a patient in need thereof, comprising the steps of (a) providing a pharmaceutical composition in the form of one or more tablets, such that the one or more tablets would provide a therapeutically effective amount of pazopanib if administered intact; (b) crushing the one or more tablets to provide a powder; and (c) administering the powder to the patient to provide the therapeutically effective dose.

[0288] In another embodiment, the disclosure provides method of delivering pazopanib to a patient in need thereof, comprising the steps of : (a) providing a pharmaceutical composition in the form of one or more tablets; (b) crushing the one or more tablets to provide a powder; and (c) administering the powder to the patient; wherein the pharmaceutical composition comprises an amorphous solid dispersion, the amorphous solid dispersion comprising pazopanib and one or more polymers.

[0289] In the practice of some embodiments of the methods, the one or more tablets comprise 320 to 400 mg pazopanib. In other embodiments, the one or more tablets comprise 360 mg pazopanib.

Pharmaceutical Composition Having Improved Variability

[0290] The pharmaceutical compositions of the present disclosure may, in some embodiments, provide a less variable in vivo pharmacokinetic performance.

[0291] As used herein, the phrase “improved variability composition” refers to a composition of the present disclosure that exhibits a lower coefficient of variation with respect to one or more pharmacokinetic parameters when administered to healthy human subjects, as compared to the coefficient of variation observed for the standard commercial, immediate-release composition of pazopanib (e.g., VOTRIENT) when administered under similar conditions. In some embodiments, the improved variability composition provides a coefficient of variation with respect to at least one pharmacokinetic parameter that is 20% lower, 15% lower, or 10% lower than the coefficient of variation observed for the standard commercial, immediate-release composition of pazopanib (e.g., VOTRIENT IR Tablet) when administered under similar conditions. The pharmacokinetic parameter can be any of C_max, AUC_0-last and AUC_0-inf. In some embodiments, the improved variability composition provides an improvement with respect to C_max and at least one of AUC_0-last and AUC_0-inf. In other embodiments, the improved variability composition provides an improvement with respect to all of C_max, AUC_0-last and AUC_0-inf.

Kits Comprising a Pharmaceutical Composition and a Package Insert

[0292] In some embodiments, the disclosure provides a kit containing a pharmaceutical composition according to any of the above-described aspects of the disclosure, as well as a package insert. As used herein, a “kit” is a commercial unit of sale, which may comprise a fixed number of doses of the pharmaceutical composition. By way of example only, a kit may provide a 30-day supply of dosage units of one or more fixed strengths, the kit comprising 30 dosage units, 60 dosage units, 90 dosage units, 120 dosage units, or other appropriate number according to a physician’s instruction. As another example, a kit may provide a 90-day supply of dosage units.

[0293] As used herein, “package insert” means a document which provides information on the use of the pharmaceutical composition, safety information, and other information required by a regulatory agency. A package insert can be a physical printed document in some embodiments. Alternatively, a package insert can be made available electronically to the user, such as via the Daily Med service of the National Library of Medicines of the National Institute of Health, which provides up-to-date prescribing information (see https://dailymed.nlm.nih.gov/dailymed/ index.cfm).

[0294] In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition can be administered with food. In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition can be administered with or without food. In some embodiments, the package insert does not include a warning that the pharmaceutical composition should be administered without food. In some embodiments, the package insert does not include a warning that the pharmaceutical composition should be administered at least 1 hour before or 2 hours after a meal. In some embodiments, the package insert does not include a warning that the pharmaceutical composition should be administered at least 1 hour before or 2 hours after food.

[0295] In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition can be crushed prior to administration. In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition can be crushed and dispersed in water prior to administration. In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition can be crushed and dispersed in water or juice prior to administration. In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition can be crushed and dispersed in a soft food prior to administration. In some embodiments, the package insert informs a user of the kit that the pharmaceutical composition can be crushed and dispersed in a fruit preparation prior to administration. In some embodiments, the package insert does not include a warning that the pharmaceutical composition cannot be crushed prior to administration.

[0296] In other embodiments, the package insert informs a user of the kit of a recommended dosage, wherein the recommended dosage is in the range from 320 to 400 mg administered orally, once daily. In other embodiments, the package insert informs a user of the kit of a recommended dosage, wherein the recommended dosage is 360 mg administered orally, once daily.

Embodiments of the Disclosure Include:

[0297] Embodiment ASD1 is an amorphous solid dispersion comprising pazopanib and one or more polymers; wherein pazopanib and the one or more polymers are present in the amorphous solid dispersion in a ratio (pazopanib :polymer) of 20:80 to 80:20 (w/w).

[0298] Embodiment ASD2 is the amorphous solid dispersion according to Embodiment ASD1, wherein the one or more polymers comprises a polymer or copolymer of N-vinylpyrrolidone and/or vinyl acetate. [0299] Embodiment ASD3 is the amorphous solid dispersion according to Embodiment ASD1 or ASD2, wherein the one or more polymers comprises a vinylpyrrolidone/vinyl acetate copolymer.

[0300] Embodiment ASD4 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD3, wherein the one or more polymers is a vinylpyrrolidone/vinyl acetate copolymer.

[0301] Embodiment ASD5 is the amorphous solid dispersion according to Embodiment ASD1, wherein the one or more polymers comprises a polymer that exhibits pH-dependent solubility.

[0302] Embodiment ASD6 is the amorphous solid dispersion according to Embodiment ASD5, wherein the polymer that exhibits pH-dependent solubility comprises an ionizable cellulose ester.

[0303] Embodiment ASD7 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD6, wherein the one or more polymers comprises a hydroxypropyl methylcellulose acetate succinate.

[0304] Embodiment ASD8 is the amorphous solid dispersion according to Embodiment ASD1, wherein the one or more polymers is a hydroxypropyl methylcellulose acetate succinate.

[0305] Embodiment ASD9 is the amorphous solid dispersion according to Embodiment ASD7 or ASD8, wherein the hydroxypropyl methylcellulose acetate succinate is characterized by an acetyl substitution of 7 to 11% and a succinyl substitution of 10 to 14%.

[0306] Embodiment ASDIO is the amorphous solid dispersion according to Embodiment ASD1, wherein the one or more polymers comprises a cellulose ether or non-ionizable cellulose ester.

[0307] Embodiment ASD11 is the amoiphous solid dispersion according to Embodiment ASD1, wherein the one or more polymers comprises a cellulose ether.

[0308] Embodiment ASD12 is the amorphous solid dispersion according to Embodiment ASD1, wherein the one or more polymers comprises a hydroxypropyl methylcellulose. Embodiment ASD13 is the amorphous solid dispersion according to Embodiment ASD1, wherein the one or more polymers is a hydroxypropyl methylcellulose. Embodiment ASD14 is the amorphous solid dispersion according to Embodiment ASD12 or ASD13, wherein the hydroxypropyl methylcellulose is characterized by a methoxyl substitution of 28 to 30% and a hydroxypropoxyl substitution of 7 to 12%. Embodiment ASD15 is the amorphous solid dispersion according to Embodiment ASD12 or ASD13, wherein the hydroxypropyl methylcellulose is characterized by a viscosity of 2 to 18 mPa^.s, as determined at 20°C for a 2% solution in water. Embodiment ASD16 is the amorphous solid dispersion according to Embodiment ASD12 or ASD13, wherein the hydroxypropyl methylcellulose is characterized by a number average molecular weight (Mn) of 20kDa or lower.

[0309] Embodiment ASD17 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD16, wherein the one or more polymers are present in an amount of 20% to 80% by weight of the amorphous solid dispersion. Embodiment ASD18 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD16, wherein the one or more polymers are present in an amount of 50% by weight of the amorphous solid dispersion.

[0310] Embodiment ASD19 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD16, wherein pazopanib and the one or more polymers are present in the amorphous solid dispersion in a ratio (pazopanib :polymer) of 50:50 (w/w).

[0311] Embodiment ASD20 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD16, wherein the drug load is 20% to 80%. Embodiment ASD21 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD16, wherein the drug load is 50%.

[0312] Embodiment ASD22 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD21, wherein the amorphous solid dispersion consists essentially of nilotinib and the one or more polymers.

[0313] Embodiment ASD23 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD21, wherein the amorphous solid dispersion comprises one or more additional pharmaceutically acceptable components. [0314] Embodiment ASD24 is the amorphous solid dispersion according to Embodiment ASD23, wherein the amorphous solid dispersion comprises one or more surfactants. Embodiment ASD25 is the amorphous solid dispersion according to Embodiment ASD23, wherein the amorphous solid dispersion comprises one or more surfactants including tocopheryl polyethylene glycol succinate. Embodiment ASD26 is the amorphous solid dispersion according to Embodiment ASD24 or ASD25, wherein the one or more surfactants are present in an amount of 0.01% to 20% by weight of the amorphous solid dispersion.

[0315] Embodiment ASD27 is the amoiphous solid dispersion according to Embodiment ASD23, wherein the amorphous solid dispersion comprises one or more antioxidants. Embodiment ASD28 is the amorphous solid dispersion according to Embodiment ASD27, wherein the one or more antioxidants are present in an amount of 0.001% to 2% by weight of the amorphous solid dispersion. Embodiment ASD29 is the amorphous solid dispersion according to Embodiment ASD27, wherein the one or more antioxidants are present in an amount of 0.05% to 0.5% by weight of the amorphous solid dispersion. Embodiment ASD30 is the amorphous solid dispersion according to any of Embodiments ASD27 to ASD29, wherein the one or more antioxidants includes propyl gallate.

[0316] Embodiment ASD31 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD30, wherein the amorphous solid dispersion is prepared by a process comprising electrospraying. Embodiment ASD32 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD30, wherein the amorphous solid dispersion is an electrosprayed amorphous solid dispersion. Embodiment ASD33 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD30, wherein the amorphous solid dispersion is prepared by a process comprising spray drying. Embodiment ASD34 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD30, wherein the amorphous solid dispersion is a spray-dried amorphous solid dispersion.

[0317] Embodiment ASD35 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD34, wherein the amorphous solid dispersion remains amorphous or essentially amorphous as determined by X-ray diffraction (XRD) after storage at 40°C/75% relative humidity for 3 months. Embodiment ASD36 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD34, wherein the amorphous solid dispersion is characterized by an assay level of at least 95% as measured by high performance liquid chromatography (HPLC) after storage at 40°C/75% relative humidity for 3 months. Embodiment ASD37 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD34, wherein the assay level of the amorphous solid dispersion is at least 97% after storage at 40°C/75% relative humidity for 6 months. Embodiment ASD38 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD34, wherein a glass transition temperature of the amorphous solid dispersion, as determined by differential scanning calorimetry (DSC), does not change by more than 10°C after storage at 40°C/75% relative humidity for 6 months. Embodiment ASD39 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD34, wherein a glass transition temperature of the amorphous solid dispersion, as determined by differential scanning calorimetry (DSC), does not change by more than 5°C after storage at 25°C/60% relative humidity for 6 months. Embodiment ASD40 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD34, wherein the amorphous solid dispersion comprises a water content as measured by coulometric Karl Fischer titration of less than 10% after storage at 25°C/60% relative humidity for 9 months. Embodiment ASD41 is the amorphous solid dispersion according to any of Embodiments ASD1 to ASD34, wherein the amorphous solid dispersion comprises a total related substances as measured by HPLC of less than 1% after storage at 25°C/60% relative humidity for 9 months.

[0318] Embodiment PCI is a pharmaceutical composition comprising the amorphous solid dispersion according to any of Embodiments ASD1 to ASD41.

[0319] Embodiment PC2 is a pharmaceutical composition comprising the amorphous solid dispersion according to any of Embodiments ASD1 to ASD41, and one or more pharmaceutically acceptable additives.

[0320] Embodiment PC3 is the pharmaceutical composition according to Embodiment PC2, wherein the one or more pharmaceutically acceptable additives comprises one or more solubilizers, one or more buffering agent, one or more pH-adjusting agents, one or more surfactants, one or more antioxidants, one or more carriers, or a combination thereof.

[0321] Embodiment PC4 is the pharmaceutical composition according to Embodiment PC2, wherein the one or more pharmaceutically acceptable additives comprises one or more filling agents, one or more binding agents, one or more lubricants, one or more disintegrants, one or more glidants, or a combination thereof.

[0322] Embodiment PCS is the pharmaceutical composition according to any of Embodiments PCI to PC4, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration.

[0323] Embodiment PC6 is the pharmaceutical composition according to any of Embodiments PCI to PC4, wherein the pharmaceutical composition is presented as a solid dosage form suitable for oral administration, and comprising 80 to 100 mg pazopanib. Embodiment PC7 is the pharmaceutical composition according to any of Embodiments PCI to PC4, wherein the pharmaceutical composition is presented as a solid dosage form suitable for oral administration, and comprising 90 mg pazopanib.

[0324] Embodiment PCS is the pharmaceutical composition according to any of Embodiments PCI to PC7, wherein the pharmaceutical composition is a food-insensitive composition. Embodiment PC9 is the pharmaceutical composition according to any of Embodiments PCI to PCS, wherein the pharmaceutical composition is an improved variability composition. Embodiment PC 10 is the pharmaceutical composition according to any of Embodiments PCI to PC9, wherein the pharmaceutical composition is a crushable composition.

[0325] Embodiment PCI 1 is the pharmaceutical composition according to any of Embodiments PCI to PC 10, wherein administration of the pharmaceutical composition to healthy human subjects in a fed state results in plasma C_max that is within 25% of the plasma C_max resulting from administration of the pharmaceutical composition to the subjects in a fasted state.

[0326] Embodiment PC12 is the pharmaceutical composition according to any of Embodiments PCI to PCI 1, wherein administration of the pharmaceutical composition to healthy human subjects in a fed state results in plasma AUC that is within 40% of a comparable plasma AUC resulting from administration of the pharmaceutical composition to the subjects in a fasted state. Embodiment PC 13 is the pharmaceutical composition according to Embodiment PC12, wherein the AUC is AUCo-24_h. Embodiment PC 14 is the pharmaceutical composition according to Embodiment PC 12, wherein the AUC is AUC_0-last. Embodiment PC 15 is the pharmaceutical composition according to Embodiment PC 12, wherein the AUC is AUC_0-inf.

[0327] Embodiment PC16 is the pharmaceutical composition according to any of Embodiments PCI to PC 10, wherein administration of the pharmaceutical composition to healthy human subjects in a fasted state results in plasma C_max of pazopanib that is within 25% of the plasma C_max of pazopanib resulting from administration of a reference composition to the subjects in a fasted state; wherein the reference composition is an immediate-release crystalline pazopanib formulation that has 2 to 2.5 times the amount of pazopanib as the pharmaceutical composition. Embodiment PC 17 is the pharmaceutical composition according to Embodiment PC16, wherein administration of the pharmaceutical composition results in plasma C_max of pazopanib that is within 20% of the plasma C_max of pazopanib resulting from administration of the reference composition.

[0328] Embodiment PC 18 is the pharmaceutical composition according to Embodiment PC 16 or PC17, wherein the coefficient of variation in plasma C_max observed for the pharmaceutical composition is less than the coefficient of variation in plasma C_max observed upon administration of the reference composition.

[0329] Embodiment PC19 is the pharmaceutical composition according to any of Embodiments PC1 to PC 10, wherein administration of the pharmaceutical composition to healthy human subjects in a fasted state results in plasma AUC of pazopanib that is within 25% of a comparable plasma AUC of pazopanib resulting from administration of a reference composition to the subjects in a fasted state; wherein the reference composition is an immediate-release crystalline pazopanib formulation that has 2 to 2.5 times the amount of pazopanib as the pharmaceutical composition. Embodiment PC20 is the pharmaceutical composition according to Embodiment PC 19, wherein administration of the pharmaceutical composition results in plasma AUC of pazopanib that is within 20% of the comparable plasma AUC of pazopanib resulting from administration of the reference composition. Embodiment PC21 is the pharmaceutical composition according to Embodiment PC 19, wherein administration of the pharmaceutical composition results in plasma AUC of pazopanib that is within 15% of the comparable plasma AUC of pazopanib resulting from administration of the reference composition. Embodiment PC22 is the pharmaceutical composition according to Embodiment PC 19, wherein administration of the pharmaceutical composition results in plasma AUC of pazopanib that is within 10% of the comparable plasma AUC of pazopanib resulting from administration of the reference composition. Embodiment PC23 is the pharmaceutical composition according to Embodiment PC 19, wherein administration of the pharmaceutical composition results in plasma AUC of pazopanib that is within 5% of the comparable plasma AUC of pazopanib resulting from administration of the reference composition.

[0330] Embodiment PC24 is the pharmaceutical composition according to any of Embodiments PC19 to PC23, wherein the coefficient of variation in plasma AUC observed for the pharmaceutical composition is less than the coefficient of variation in plasma AUC observed upon administration of the reference composition.

[0331] Embodiment PC25 is the pharmaceutical composition according to any of Embodiments PC19 to PC24, wherein the AUC is AUC_0-24h. Embodiment PC26 is the pharmaceutical composition according to any of Embodiments PC 19 to PC24, wherein the AUC is AUC_0-last. Embodiment PC27 is the pharmaceutical composition according to any of Embodiments PC19 to PC24, wherein the AUC is AUC_0-inf.

[0332] Embodiment PC28 is the pharmaceutical composition according to any of Embodiments PC1 to PC27, wherein, when the pharmaceutical composition is administered to healthy human subjects in a fasted state, provides plasma C_max that is similar to the plasma C_max observed upon administration of a reference composition to the subjects in a fasted state; wherein the reference composition is a conventional immediate-release pazopanib composition providing 400 mg pazopanib; and wherein the pharmaceutical composition comprises 50% to 60% less pazopanib than the reference composition. [0333] Embodiment PC29 is the pharmaceutical composition according to Embodiment PC28, wherein the coefficient of variation in plasma C_max observed for the pharmaceutical composition is less than the coefficient of variation in plasma C_max observed upon administration of the reference composition.

[0334] Embodiment PC30 is the pharmaceutical composition according to any of Embodiments PC1 to PC29, wherein, when the pharmaceutical composition is administered to healthy human subjects in a fasted state, provides plasma AUC that is similar to a comparable plasma AUC observed upon administration of a reference composition to the subjects in a fasted state; wherein the reference composition is a conventional immediate-release pazopanib composition providing 400 mg pazopanib; and wherein the pharmaceutical composition comprises 50% to 60% less pazopanib than the reference composition.

[0335] Embodiment PC31 is the pharmaceutical composition according to Embodiment PC30, wherein the coefficient of variation in plasma AUC observed for the pharmaceutical composition is less than the coefficient of variation in plasma AUC observed upon administration of the reference composition.

[0336] Embodiment PC32 is the pharmaceutical composition according to Embodiment PC30 or PC31, wherein the AUC is AUC_0-24h. Embodiment PC33 is the pharmaceutical composition according to Embodiment PC30 or PC31, wherein the AUC is AUC_0-iast. Embodiment PC34 is the pharmaceutical composition according to Embodiment PC30 or PC31, wherein the AUC is AUCo-inf.

[0337] Embodiment PC35 is the pharmaceutical composition according to any of Embodiments PC30 to PC34, wherein the pharmaceutical composition comprises 55% less pazopanib than the reference composition.

[0338] Embodiment TAB1 is a pharmaceutical composition according to any of Embodiments PC1 to PC35, in the form of a tablet suitable for oral administration.

[0339] Embodiment TAB2 is the tablet according to Embodiment TAB1, wherein the one or more pharmaceutically acceptable additives comprises one or more filling agents, one or more binding agents, one or more lubricants, one or more disintegrants, one or more glidants, or a combination thereof.

[0340] Embodiment TABS is the tablet according to Embodiment TAB1 or TAB2, wherein the tablet comprises 80 to 100 mg pazopanib. Embodiment TAB4 is the tablet according to Embodiment TAB1 or TAB2, wherein the tablet comprises 90 mg pazopanib.

[0341] Embodiment TAB8 is the tablet according to any of Embodiments TAB1 to TAB4, wherein the tablet is a food-insensitive composition. Embodiment TAB6 is the tablet according to any of Embodiments TAB 1 to TAB4, wherein the tablet is an improved variability composition.

[0342] Embodiment TAB7 is the tablet according to any of Embodiments TAB1 to TAB4, wherein the tablet is a crushable tablet. Embodiment TAB8 is the tablet according to any of Embodiments TAB1 to TAB4, wherein the tablet is suitable for administration as an intact tablet, as a split tablet, and as a powder obtained by crushing the tablet.

[0343] Embodiment TAB9 is the tablet according to any of Embodiments TAB1 to TAB8, the tablet comprising granules and extra-granular excipients, wherein: the granules comprise, by weight of the granules: (a) 30% to 80% of the amorphous solid dispersion consisting essentially of pazopanib and polymer in a w/w ratio (pazopanib :polymer) of 20:80 to 80:20; (b) 15% to 70% of one or more granulation fillers; and (c) 2% to 20% of one or more granulation disintegrants; the extra-granular excipients comprise, by weight of the tablet: (a) 20% to 80% of one or more tablet fillers; and (b) 2% to 20% of one or more tablet disintegrants; wherein the tablet comprises 20% to 80% granules, by weight of the tablet.

[0344] Embodiment TAB10 is the tablet according to any of Embodiments TAB1 to TAB8, the tablet comprising granules and extra-granular excipients, wherein: the granules comprise, by weight of the granules: (a) 30% to 80% of the amorphous solid dispersion consisting essentially of pazopanib and polymer in a w/w ratio (pazopanib :polymer) of 50:50; (b) 15% to 70% of one or more granulation fillers including microcrystalline cellulose; and (c) 2% to 20% of one or more granulation disintegrants including crospovidone; the extra-granular excipients comprise, by weight of the tablet: (a) 20% to 80% of one or more tablet fillers including microcrystalline cellulose; and (b) 2% to 20% of one or more tablet disintegrants including crospovidone; wherein the tablet comprises 20% to 80% granules, by weight of the tablet.

[0345] Embodiment TAB11 is the tablet of Embodiment TAB9 or TAB 10, wherein the granules further comprise 1 to 10% of a solubilizer, by weight of the granules. Embodiment TAB12 is the tablet of Embodiment TAB9 or TAB10, wherein the granules further comprise 5% of a solubilizer, by weight of the granules. Embodiment TAB13 is the tablet of Embodiment TAB9 or TAB 10, wherein the extra-granular excipients further comprise 1 to 10% of a solubilizer, by weight of the tablet. Embodiment TAB14 is the tablet of Embodiment TAB9 or TAB 10, wherein the extra-granular excipients further comprise 5% of a solubilizer, by weight of the tablet. Embodiment TAB15 is the tablet according to any of Embodiments TAB11 to TAB 14, wherein the solubilizer is a poloxamer.

[0346] Embodiment TAB16 is the tablet according to any of Embodiments TAB1 to TAB15, wherein, when a number of crushable tablets are orally administered intact to healthy human subjects in a fasted state, the administration provides plasma C_max that is similar to plasma C_max observed upon oral administration of a powder to the subjects in a fasted state; wherein, the number of crushable tablets is selected to provide a total dose of 320 mg to 400 mg pazopanib; and wherein the powder is obtained by crushing the same number of the crushable tablets prior to administration.

[0347] Embodiment TAB17 is the tablet according to any of Embodiments TAB1 to TAB 16, wherein, when a number of crushable tablets are orally administered intact to healthy human subjects in a fasted state, the administration provides plasma AUC that is similar to plasma AUC observed upon oral administration of a powder to the subjects in a fasted state; wherein, the number of crushable tablets is selected to provide a total dose of 320 mg to 400 mg pazopanib; and wherein the powder is obtained by crushing the same number of the crushable tablets prior to administration.

[0348] Embodiment TAB18 is the tablet of Embodiment TAB17, wherein the AUC is AUC_0-24h, AUC_0-last, Οr AUCo-inf. [0349] Embodiment MOT1 is a method of treating a proliferative disorder in a patient in need thereof, comprising administering a pharmaceutical composition to the patient without regard to consumption of food; wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15.

[0350] Embodiment MOT2 is a method of treating a proliferative disorder in a patient in need thereof, comprising administering a pharmaceutical composition to the patient without regard to whether the patient is in a fasted state or a fed state; wherein the pharmaceutical composition is a composition according to any of Embodiments PC1 to PC35 or a tablet according to any of Embodiments TAB1 to TAB15.

[0351] Embodiment MOT3 is a method of treating a proliferative disorder in a patient in need thereof, comprising administering a pharmaceutical composition to the patient without a food effect; wherein the pharmaceutical composition is a composition according to any of Embodiments PC1 to PC35 or a tablet according to any of Embodiments TAB1 to TAB15.

[0352] Embodiment MOT4 is a method of treating a proliferative disorder in a patient in need thereof, comprising administering a pharmaceutical composition to the patient without a food effect with respect to plasma C_max ; wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15.

[0353] Embodiment MOT5 is a method of treating a proliferative disorder in a patient in need thereof, comprising administering a pharmaceutical composition to the patient; wherein the pharmaceutical composition is a composition according to any of Embodiments PC1 to PC35 or a tablet according to any of Embodiments TAB1 to TAB15; and wherein 320 to 400 mg of pazopanib is administered orally, once daily.

[0354] Embodiment MOT6 is the method according to any of Embodiments MOT1 to MOT5, wherein the proliferative disorder is cancer. Embodiment MOT7 is the method according to any of Embodiments MOT1 to MOT5, wherein the proliferative disorder is renal cell carcinoma. Embodiment MOTS is the method according to any of Embodiments MOT1 to MOTS, wherein the proliferative disorder is soft tissue sarcoma.

[0355] Embodiment MODI is a method of safely delivering pazopanib to a patient, comprising:

(a) administering a therapeutically effective amount of pharmaceutical composition to the patient, wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15; and

(b) administering a meal to the patient; wherein steps (a) and (b) occur within less than two hours of each other. Embodiment MOD2 is the method according to Embodiment MODI, wherein steps (a) and (b) occur within less than one hour of each other. Embodiment MODS is the method according to Embodiment MODI, wherein steps (a) and (b) occur within less than thirty minutes of each other.

[0356] Embodiment MOD4 is a method of delivering a therapeutically effective amount of pazopanib to a patient without regard to consumption of food, comprising administering a pharmaceutical composition to the patient; wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15. Embodiment MODS is a method of delivering a therapeutically effective amount of pazopanib to a patient without regard to whether the patient is in a fasted state or a fed state, comprising administering a pharmaceutical composition to the patient; wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15.

[0357] Embodiment MOD6 is a method of delivering a therapeutically effective dose of pazopanib to a patient in need thereof, comprising administering a pharmaceutical composition to the patient; wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15; and wherein 320 to 400 mg of pazopanib is administered orally, once daily, to provide the therapeutically effective dose. Embodiment MOD7 is a method according to Embodiment MOD6, wherein 360 mg pazopanib is administered orally, once daily. Embodiment MODS is a method according to Embodiment MOD6 or MOD7, wherein the pharmaceutical composition is administered without regard to consumption of food. Embodiment MOD9 is a method according to Embodiment MOD6 or MOD7, wherein the pharmaceutical composition is administered without regard to whether the patient is in a fasted or a fed state. Embodiment MOD10 is a method according to any of Embodiments MOD4 to MOD 7, wherein the pharmaceutical composition is administered when the patient is in a fed state.

[0358] Embodiment MODI 1 is a method according to any of Embodiments MODI to MOD 10, wherein the patient suffers from a proliferative disorder. Embodiment MOD12 is a method according to Embodiment MODI 1, wherein the proliferative disorder is cancer. Embodiment MOD13 is a method according to Embodiment MODI 1, wherein the proliferative disorder is renal cell carcinoma. Embodiment MOD14 is a method according to Embodiment MODI 1, wherein the proliferative disorder is soft tissue sarcoma.

[0359] Embodiment MOC1 is a method of safely delivering a therapeutically effective dose of pazopanib to a patient in need thereof, comprising: (a) providing a pharmaceutical composition in the form of one or more tablets, such that the one or more tablets would provide a therapeutically effective amount of pazopanib if administered intact; (b) crushing the one or more tablets to provide a powder; and (c) administering the powder to the patient to provide the therapeutically effective dose. Embodiment MOC2 is the method of Embodiment MOC1, wherein the pharmaceutical composition is a tablet according to any of Embodiments TAB1 to TAB15. Embodiment MOC3 is the method according to Embodiment MOC1 or MOC2, wherein the one or more tablets comprise 320 to 400 mg pazopanib. Embodiment MOC4 is the method according to Embodiment MOC1 or MOC2, wherein the one or more tablets comprise 360 mg pazopanib.

[0360] Embodiment MOC5 is a method of delivering pazopanib to a patient in need thereof, comprising: (a) providing a pharmaceutical composition in the form of one or more tablets; (b) crushing the one or more tablets to provide a powder; and (c) administering the powder to the patient; wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15. [0361] Embodiment MOC6 is a method according to any of Embodiments MOC1 to MOC5, further comprising the step of dispersing the powder in a soft food prior to administration to the patient. Embodiment MOC7 is a method according to any of Embodiments MOC1 to MOC5, further comprising the step of dispersing the powder in a fruit preparation prior to administration to the patient. Embodiment MOC8 is a method according to any of Embodiments MOC1 to MOC7, wherein the patient is a pediatric patient. Embodiment MOC9 is a method according to any of Embodiments MOC1 to MOC7, wherein the patient is a geriatric patient. Embodiment MOCIO is a method according to any of Embodiments MOC1 to MOC9, wherein the patient suffers from dysphagia.

[0362] Embodiment MOC11 is a method according to any of Embodiments MOC1 to MOCIO, wherein the patient suffers from a proliferative disorder. Embodiment MOC12 is a method according to Embodiment MOC11, wherein the proliferative disorder is cancer. Embodiment MOC13 is a method according to Embodiment MOC11, wherein the proliferative disorder is renal cell carcinoma. Embodiment MOC14 is a method according to Embodiment MOC11, wherein the proliferative disorder is soft tissue sarcoma.

[0363] Embodiment KITFl is a kit comprising: (a) a pharmaceutical composition comprising pazopanib; and (b) a package insert that informs a user of the kit that the pharmaceutical composition can be administered with food.

[0364] Embodiment ΚΠΈ2 is a kit comprising: (a) a pharmaceutical composition comprising pazopanib; and (b) a package insert that informs a user of the kit that the pharmaceutical composition can be administered with or without food.

[0365] Embodiment ΚΠΤ3 is a kit comprising: (a) a pharmaceutical composition comprising pazopanib; and (b) a package insert that does not include a warning that the pharmaceutical composition should not be administered with food.

[0366] Embodiment ΚΠΤ4 is the kit according to any of Embodiments KITFl to ΚΠΤ3, wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15. [0367] Embodiment KITCl is a kit comprising: (a) a pharmaceutical composition in the form of an orally administrable crushable tablet comprising pazopanib; and (b) a package insert that informs a user of the kit that the crushable tablet can optionally be crushed to provide a powder for oral administration. Embodiment KITC2 is the kit of Embodiment KITCl, wherein the package insert further informs the user of the kit that the powder can be dispersed in a soft food for administration. Embodiment KITC3 is the kit of Embodiment KITCl or KITC2, wherein the package insert further informs the user of the kit that the powder can be dispersed in a fruit preparation for administration. Embodiment KITC4 is a kit comprising: (a) a pharmaceutical composition in the form of an orally administrable crushable tablet and comprising pazopanib; and (b) a package insert that does not inform a user of the kit that the tablet cannot be crushed prior to administration. Embodiment KITC5 is the kit according to any of KITCl to KITC4, wherein each crushable tablet comprises 80 to 100 mg pazopanib. Embodiment KITC6 is the kit according to any of Embodiments KITCl to KITC5, wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15.

[0368] Embodiment KITD1 is a kit comprising: (a) a pharmaceutical composition in the form of an orally administrable tablet comprising pazopanib; and (b) a package insert that informs a user of the kit of a recommended dosage, wherein the recommended dosage is in the range from 320 to 400 mg administered orally, once daily. Embodiment KITD2 is a kit comprising: (a) a pharmaceutical composition in the form of an orally administrable tablet comprising pazopanib; and (b) a package insert that informs a user of the kit of a recommended dosage, wherein the recommended dosage is 360 mg administered orally, once daily. Embodiment KITD3 is a kit according to Embodiment KITD1 or KITD2, wherein the pharmaceutical composition is a composition according to any of Embodiments PCI to PC35 or a tablet according to any of Embodiments TAB1 to TAB15.

[0369] The present disclosure will be further illustrated and/or demonstrated in the following Examples, which are given for illustration/demonstration purposes only and are not intended to limit the disclosure in any way. EXAMPLES

Example 1. Preparation and characterization of Pazopanib ASDs with various polymers

[0370] Pazopanib ASDs were prepared according to embodiments of the present disclosure, and the ASDs were subjected to certain characterization tests. Several different ASDs comprising pazopanib HC1 were prepared, using AFFINISOL HPMC-AS 912G (denoted “HPMC-AS” in the Examples), KOLLIDON VA 64 (“PVP/VA”), METHOCEL E5 (“HPMC-E5”), or SOLUPLUS as the polymer. For this study, the drug: polymer ratios (w/w) were 60:40, 50:50, and 30:70.

[0371] To prepare the ASDs, appropriate quantities of pazopanib HC1 and polymer were dissolved in a solvent mixture to provide a liquid feedstock having a total solids concentration of 25 mg/mL. The solvent mixture was a 90:10 (v/v) mixture of methanol and water.

[0372] The ASDs were formed by spray drying the liquid feedstock using a Buchi B-290 spray dryer equipped with a two-fluid nozzle and a Buchi B-295 inert loop. For each spray run, the spray process parameters, such as inlet temperature, pump rate, outlet temperature, etc. were adjusted to achieve an acceptable outcome. Inlet temperature was set at 145-155°C, pump rate was set at 20%, and outlet temperature was 80-90°C. The resulting ASD powder was collected using a cyclone separator. After spray drying, each ASD powder was dried at 50-60°C under vacuum for at least about 18 hours to remove residual solvents.

[0373] The ASD powders were evaluated for amorphicity (i.e., the lack of crystallinity), water content (Karl Fisher), glass transition temperature (mDSC), and total related substances (HPLC) using suitable analytical methods, as described below.

Amorphicity

[0374] Amorphicity was assessed by XRD promptly after preparation. Diffraction patterns were obtained using a Rigaku MiniFlex 600. The X-ray source was a long anode Cu Ka. Samples were prepared by placing a small amount of ASD powder on a Rigaku zero-background sample holder with a 0.1 mm indent. A glass slide was then used to firmly pack the powder and ensure the surface of the sample was level with the edge of the sample holder. Instrument details and measurement conditions are specified in Table 3.

[0375] Each of the ASD powders was amorphous as determined by XRD.

Water Content

[0376] Water content was determined by Karl Fischer coulometric titration method, using a Mettler Toledo C30S Karl Fischer with Stromboli Oven Sampler. Approximately 40-50 mg of ASD powder was weighed into a glass Stromboli sample vial and the vial was immediately sealed with a foil coated vial cover, and a rubber vial cap cover was placed on top of the sample vial. The vial was then placed onto instrument and analysis was conducted using nitrogen carrier gas. Instrument details and measurement conditions are specified in Table 4.

[0377] Results of the Karl Fischer analysis are provided in Table 8. Glass Transition Temperature

[0378] Modulated differential scanning calorimetry (mDSC) analysis was run on a TA Instruments Model Q200, equipped with a RCS90 refrigerated cooling system, to assess glass transition temperatures (Tg) of the ASDs. In general, about 5-10 mg of ASD powder was loaded in a TA Tzero low-mass aluminum pan and sealed with a Tzero lid. Instrument details and measurement conditions are provided in Table 5. The results of the mDSC analysis are provided in Table 8.

Total Related Substances

[0379] Total related substances was determined by HPLC using either an Agilent 1200 or a Waters Alliance 2695 instrument utilizing a Waters Atlantis T3 3.0 x 150 mm x 3 μm column. The instrument and measurement conditions are specified in Table 6, while the gradient profile is listed in Table 7. Sample solutions of each ASD were prepared by accurately weighing ASD powder into a volumetric flask, and diluted in 80:20 methanol: water. The final concentration of the analyte (pazopanib) in the sample was approximately 0.1 mg/ml.

[0380] Individual related substances were calculated as peak area percent. Total related substances is calculated as the sum of all detected individual related substances. Total related substances results are given in Table 8.

Example 2. Preparation and characterization of Pazopanib ASDs at various drug loads

[0381] Pazopanib ASDs were prepared according to embodiments of the present disclosure, and certain characterization tests were run on the ASDs. ASDs comprising pazopanib HC1 were prepared using AFFINISOL HPMC-AS 912G (“HPMC-AS”) and KOLLIDON VA 64 (“PVP/VA”) as the polymer. For this study, the drug:polymer ratios (w/w) were 70:30, 60:40, and 50:50.

[0382] To prepare the ASDs, appropriate quantities of pazopanib HC1 and polymer were dissolved in a solvent mixture to provide a liquid feedstock having a total solids concentration of about 50-75 mg/mL. The solvent mixture was a 47.5:47.5:5 (v/v/v) mixture of methanol, dichloromethane, and water.

[0383] The ASDs were formed by spray drying the liquid feedstock using a Buchi B-290 spray dryer equipped with a two-fluid nozzle and a Buchi B-295 inert loop. For each spray run, the spray process parameters, such as inlet temperature, pump rate, outlet temperature, etc. were adjusted to achieve an acceptable outcome. Inlet temperature was set at 130-145°C, pump rate was set at 20%, and outlet temperature was 75-85°C. The resulting ASD was collected using a cyclone separator. After spray drying, each ASD was dried at 50-60°C under vacuum for at least about 18 hours to remove residual solvents.

[0384] Amorphicity (i.e., the lack of crystallinity) for the ASDs was assessed by XRD promptly after preparation, using the method provided in Example 1. Each of the ASD powders was amorphous as determined by XRD.

[0385] The ASD powders were also evaluated for water content (Karl Fisher), glass transition temperature (mDSC), and total related substances (HPLC) using suitable analytical methods as described in Example 1. Results are provided in Table 9.

Example 3. Stability of Pazopanib ASDs under harsh accelerated conditions

[0386] Several of the ASDs prepared according to Example 1 were placed on stability under harsh accelerated conditions at 40°C/75% RH (open dish). (Additional samples were held at 40°C/protected, with selected data reported as indicated in the tables below.) The ASDs were assessed at t=0, 2 weeks, 1 month, 2 months, and 6 months for amorphicity (XRD), water content (Karl Fisher), glass transition temperature (mDSC), and assay/related substances (HPLC) using suitable analytical methods.

Amorphicity

[0387] Amorphicity (i.e., the lack of crystallinity) for the ASDs was assessed by XRD as described in Example 1. Results are provided in Table 10. Samples were deemed “Amorphous” if no crystalline character was detected, and “Crystalline” if characteristic peaks indicating crystalline character were observed.

[0388] As shown in Table 10, each ASD was amorphous after preparation. The Pazopanib: PVP/VA, Pazopanib :HPMC- AS, and Pazopanib :HPMC ASDs continued to show amorphous character throughout this study.

[0389] After two weeks on stability at 40°C/75% RH, the Pazopanib 60:40 SOLUPLUS ASD began to show signs of crystallization in the XRD scans; after 4 weeks, the Pazopanib 30:70 SOLUPLUS ASD also began to show signs of crystallization in the XRD scans. Although not shown in the table, samples of Pazopanib 60:40 SOLUPLUS ASD and Pazopanib 30:70 SOLUPLUS ASD were also held under 40°C/protected conditions; these samples remained amorphous throughout the 6-month study period. Despite the fact that crystallinity was observed after some time for some of the Pazopanib: SOLUPLUS ASDs under certain storage conditions, this result was considered not disqualifying because of the harsh accelerated storage conditions (which are not reflective of real-world storage conditions). Water Content

[0390] Water content was determined by a Karl Fischer coulometric titration method as described in Example 1. Results are provided in Table 11.

[0391] The initial moisture levels were under 3% for all ASDs, as shown in Table 11. All ASDs demonstrated a significant increase in water content after exposure for two weeks to high humidity (75% RH).

[0392] For the Pazopanib : P VP/V A ASDs, additional samples were held at 40°C/protected conditions; data for 1 to 6 months is reported in Table 11. These samples remained under 5% water content throughout the study.

[0393] For the Pazopanib :HPMC -AS ASDs, the moisture content did not increase significantly after the initial rise, and remained under 8% throughout the study.

[0394] For the Pazopanib :HPMC ASDs, the moisture content increased somewhat after the initial rise, and remained under 11% throughout the study. [0395] For the Pazopanib : SOLUPLUS ASDs, additional samples were held at 40°C/protected conditions; data for 1 to 6 months is reported in Table 11. These samples remained under 5% water content throughout the study.

Glass Transition Temperature

[0396] Glass transition characteristics were observed by a suitable mDSC method as described in Example 1. Results are provided in Table 12.

[0397] For the Pazopanib :PVP/V A ASDs, samples held at 40°C/75% RH (t=0 to 1 month) and additional samples held at 40°C/protected conditions (1, 2 and 6 months) exhibited glass transition temperatures consistently in the range of about 147-150°C, for the 60:40 ASD and in the range of about 128-131°C for the 30:70 ASD.

[0398] For the Pazopanib :HPMC- AS ASDs, samples exhibited glass transition temperatures consistently in the range of about 143-148°C for the 60:40 ASD, and in the range of about 120- 128°C for the 30:70 ASD. [0399] For the Pazopanib :HPMC ASDs, samples exhibited glass transition temperatures in the range of about 151-163°C for the 60:40 ASD, and in the range of about 143-148°C for the 30:70 ASD.

[0400] The Pazopanib : SOLUPLUS 60:40 ASD exhibited two transitions at t=0 and a single transition after being held at 40°C/75% RH for two weeks; subsequent testing of samples held at 40°C/75% RH exhibited no distinct transition temperature. Samples held at 40°C/protected were tested after 1 and 2 months, and exhibited a single transition; after 6 months, no discernible transition was observed. The observed changes in glass transition for these ASDs suggested that some type of physical change may have occurred with the ASDs held under accelerated conditions during stability testing.

[0401] The Pazopanib: SOLUPLUS 30:70 ASD exhibited a single transition at t=0 and two transitions after being held at 40°C/75% RH for two weeks; subsequent testing of samples held at 40°C/75% RH exhibited no distinct transition temperature. Samples held at 40°C/protected were tested after 1 and 2 months, and exhibited a single transition; after 6 months, no discernible transition was observed. The observed changes in glass transition for these ASDs suggested that some type of physical change may have occurred with the ASDs held under accelerated conditions during stability testing.

Assay/Related Substances

[0402] Assay values and total related substances were determined for the ASDs post-spray (t=0) and at the designated stability timepoints using an appropriate HPLC method as provided in Example 1. Measured assay values for the ASDs are listed in Table 13. The reported assay values have been corrected for water content. Measured total related substances values for the ASDs are listed in Table 14.

[0403] As demonstrated in Tables 13 and 14, the ASDs exhibited suitably high assay values (exceeding 97% in all cases; generally exceeding 98%) and suitably low related substances values (less than 1% in all cases) that did not change unexpectedly over time, indicating that the ASDs were chemically stable under the harsh accelerated storage conditions.

Example 4. Stability of Pazopanib ASDs under 25°C/60% RH accelerated conditions

[0404] Pazopanib :PVP/VA 50:50 and Pazopanib :HPMC- AS 50:50 ASDs were prepared using a process similar to prior Examples. The ASDs were placed on stability under accelerated conditions at 25°C/60% RH (open dish). The ASDs were assessed at t=0, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, and 18 months for amorphicity (XRD), water content (Karl Fisher), glass transition temperature (mDSC), and related substances (HPLC) using suitable analytical methods as in Example 1.

Amorphicity

[0405] Amorphicity for the ASDs was assessed by XRD as in Example 1. Samples were deemed “Amorphous” if no crystalline character was detected, and “Crystalline” if characteristic peaks indicating crystalline character were observed. All samples remained amorphous throughout this stability study.

Water Content

[0406] Water content was determined by a Karl Fischer coulometric titration method as in Example 1. Results are provided in Table 15. Water content results for this study were consistent with the results for the study reported in Example 3.

Glass Transition Temperature

[0407] Glass transition characteristics were observed by a suitable mDSC method as in Example

1.

[0408] For the Pazopanib 50:50 PVP/VA ASD, observed glass transition temperatures were consistently in the range of about 136-144°C, which is in line with the results for the study reported in Example 3.

[0409] For the Pazopanib 50:50 HPMC-AS ASD, observed glass transition temperatures were consistently in the range of about 135-140°C, which is in line with the results for the study reported in Example 3.

Related Substances

[0410] Total related substances were determined for the ASDs post-spray (t=0) and at the designated stability timepoints using an appropriate HPLC method. For t=0 and for 1 month, 2 months, and 3 months, the HPLC method described in Example 1 was employed. For data at 6 months, 12 months, and 18 months, a refined HPLC method described in Example 7 (below) was employed. Measured total related substances values for the ASDs at all time points was <0.05%.

Example 5. Preparation of Pazopanib ASD Granules

[0411] Granulated products comprising Pazopanib ASDs were fabricated. The fabrication process required several steps including: 1) preparing desired Pazopanib ASDs; 2) preparing a granule blend comprising the desired Pazopanib ASD; 3) roller-compacting the granule blend to provide the desired Pazopanib ASD Granules. [0412] Two ASDs comprising pazopanib HC1 were prepared. For the first, PVP/VA (KOLLIDON VA 64) was the sole polymer, and the dmg:polymer ratio was 50:50. For the second, HPMC-AS (AFFINISOL HPMC-AS 912G) was the sole polymer, and the drug:polymer ratio was 50:50.

[0413] To prepare the ASDs, appropriate quantities of pazopanib HC1 and polymer were dissolved in a solvent mixture to provide a liquid feedstock having a total solids concentration of about 50-75 mg/mL. The solvent mixture was a 47.5:47.5:5 (v/v/v) mixture of methanol, dichloromethane, and water. For the spray processing, a commercially available MOBILE MINOR spray dryer was employed. The inlet temperature was held at 140-160°C and the outlet temperature was held at 75-95°C. Atomization air pressure was about 1.5 bar and atomization air flow was set at 40%. The resulting ASD powders were collected and dried at 60°C in an oven for at least about 24 hours to remove residual solvents.

[0414] Granule blends comprising the two Pazopanib ASDs were prepared using the components given in Tables 16 and 17. KOLLIPHOR P188 (when used) was pre-ground using a mortar and pestle, then sieved through a 20-mesh screen. To prepare the respective granule blends, the granule blend components (except magnesium stearate) were first bag-blended for 1 minute, then sieved through a 20-mesh screen and chaiged into a v-blender shell. That mixture was then blended using a P-K V-Blender for 30 minutes at approximately 20-25 RPM. A portion of that blended mixture was then bag-blended with the magnesium stearate for 1 minute; this mixture was then sieved through a 20-mesh screen and added to the contents of the v-blender shell. The resulting mixtures were blended using the PK V-Blender for an additional 5 minutes to provide the final granule blends.

[0415] The granule blends were next roller-compacted and granulated. Roller compaction and granulation was done using a Gerteis M1NI-POLYGRAN System equipped with knurled rollers and 0.8 mm screen. For roller compaction of the granule blend, the press force was set in the range of 3-6 kN/cm, the gap was set at 1.1-1.5 mm, the roller speed was set in the range of 1.5- 2.5 rpm, and the granulator speed was set in the range of 20-40 rpm. Resulting ribbons of compacted material were milled through an oscillating granulator fitted with the 0.8 mm screen. Granular material passing through was collected to provide Pazopanib 50:50 PVP/VA ASD Granules and Pazopanib 50:50 HPMC-AS ASD Granules from the respective granule blends.

Example 6. Preparation of Pazopanib ASD Tablets

[0416] Tablets comprising the Pazopanib ASD Granules were fabricated. The fabrication process steps included: 1) preparing a tableting blend comprising the granules; and 2) mechanically pressing the tableting blend to provide Pazopanib ASD Tablets.

[0417] Tableting blends were prepared using the Pazopanib ASD Granules and other blend components given in Tables 18 and 19. KOLLIPHOR P188 (when used) was pre-ground using a mortar and pestle, then sieved through a 20-mesh screen. To prepare the respective tableting blends, the tableting blend components (except magnesium stearate) were first bag-blended for 1 minute, then sieved through a 20-mesh screen and charged into a v-blender shell. That mixture was then blended using a P-K V-Blender for 30 minutes at approximately 20-25 RPM. A portion of that blended mixture was then bag-blended with the magnesium stearate for 1 minute; this mixture was then sieved through a 20-mesh screen and added to the contents of the v-blender shell. The resulting mixtures were blended using the PK V-Blender for an additional 5 minutes to provide the final tableting blends.

[0418] Each tableting blend was then used to prepare tablets having nominally 50 mg pazopanib. Tablets were mechanically pressed using a Piccola Tablet Press, operating at a turret speed of 20 rpm. For the tableting blend comprising Pazopanib :PVP/V A ASD Granules, the press was equipped with 10 mm modified round tooling, and the average main compression force was set to achieve an average tablet hardness of about 6 kP. For the tableting blend comprising Pazopanib :HPMC- AS ASD Granules, the press was equipped with 11 mm modified round tooling, and the average main compression force was set to achieve an average tablet hardness of 9-15 kP. [0419] The resulting tablets comprising Pazopanib 50:50 PVP/VA ASD Granules are denoted “Pazopanib ASD Tablet FI” in the following Examples. The tablets comprising Pazopanib 50:50 HPMC-AS ASD Granules are denoted “Pazopanib ASD Tablet F2” in the following Examples.

Example 7. In vitro dissolution and stability of Pazopanib ASD Tablets

[0420] Pazopanib ASD Tablets FI and Pazopanib ASD F2 Tablets were characterized by in vitro dissolution testing promptly after preparation. Apparatus and testing procedures for dissolution testing are fully described in USP <711> Dissolution. For pazopanib hydrochloride immediate- release tablets, FDA’s published recommendations for dissolution testing specify Apparatus 2 (paddles; 75 rpm) using 900 mL of 50 mM sodium acetate buffer (pH 4.5) containing 0.75% sodium dodecyl sulfate as a dissolution medium, with sampling at 10 min, 15 min, 30 min, 45 min, and 60 min.

[0421] Pazopanib ASD Tablets FI and Pazopanib ASD F2 Tablets were characterized according to this test procedure, using a single 50-mg tablet per dissolution vessel. Results are provided in Table 20. Data obtained for a reference composition (VOTRIENT IR Tablet, 200 mg) is also included in Table 20.

[0422] Pazopanib ASD Tablets were held under accelerated conditions in sealed pouches at 40°C/75% RH (i.e., 40°C/protected). Tablets held under these conditions were subjected to in vitro dissolution testing at 1 month, 3 months, 5 months, and 6 months. [0423] For Pazopanib ASD Tablets FI held under these conditions, it was observed that the average release was at least 51% by 10 minutes, and at least 64% by 15 minutes, but with some increase in standard deviation at these dissolution time points. However, at 30 minutes and later dissolution time points, the average release was at least 91% with a small relative deviation at these dissolution time points.

[0424] For Pazopanib ASD Tablets F2 held under these conditions, it was observed that the average release was at least 52% by 10 minutes, at least 63% by 15 minutes, at least 82% by 30 minutes, at least 90% by 45 minutes, and at least 94% by 60 minutes. A small relative deviation was also observed at each of these dissolution time points.

[0425] Separately, additional Pazopanib ASD Tablets were held under accelerated conditions in sealed pouches at 25°C/60% RH. Tablets held under these conditions were subjected to in vitro dissolution testing at 1 month, 3 months, 5 months, 6 months, 9 months, and 12 months.

[0426] For Pazopanib ASD Tablets FI held under these conditions, it was observed that the average release was at least 55% by 10 minutes, and the average release was at least 70% by 15 minutes, but with some increase in standard deviation at these time points. However, at 30 minutes and later time points, the average release was at least 92% with a small relative deviation at these dissolution time points.

[0427] For Pazopanib ASD Tablets F2 held under these conditions, it was observed that the average release was at least 48% by 10 minutes, at least 60% by 15 minutes, at least 79% by 30 minutes, at least 86% by 45 minutes, and at least 9% by 60 minutes. A small relative deviation was also observed at each of these time points.

[0428] These in vitro dissolution results indicate that the Pazopanib ASD Tablets provide stable dissolution performance after storage under accelerated conditions.

[0429] Pazopanib ASD Tablets held under accelerated conditions were also evaluated for amorphicity, water content, and total related substances using suitable analytical methods. Tablets held at 40°C/75% RH were subjected to analysis at 1 month, 3 months, 5 months, and 6 months. Tablets held at 25°C/60% RH were subjected to analysis at 1 month, 3 months, 5 months, 6 months, 9 months, and 12 months. For these analyses, a composite of 20 tablets was manually crushed into powder using mortar and pestle. The resulting powder was then subjected to the appropriate analytical test. Amorphicity and water content (Karl Fisher) were assessed using suitable methods as described in prior Examples. Total related substances was assessed using an HPLC method described below.

Amorphicity

[0430] All samples from all stability time points for each Pazopanib ASD Tablet were amorphous as determined by XRD.

Water Content

[0431] The measured water content for all samples from all stability time points for each Pazopanib ASD Tablet was less than 4%, with no significant increase observed over time.

Total Related Substances

[0432] Total related substances was determined by HPLC using either an Agilent 1200 or a Waters Alliance 2695 instrument utilizing an Agilent Poroshell HPH-83.0 x 150 mm x 2.7 μm column. The instrument and measurement conditions are specified in Table 21, while the gradient profile is listed in Table 22.

[0433] Sample solutions of each powder were prepared by accurately weighing powder comprising about 10 mg pazopanib, and quantitatively transferring the powder into an amber volumetric flask (100 mL) using 20 mL acetonitrile. The resulting solution was sonicated for 20 minutes to dissolve the powder, allowed to equilibrate to room temperature, and then diluted to volume using 0.1% phosphoric acid. The final concentration of the analyte (pazopanib) in each sample was approximately 0.1 mg/ml.

[0434] Individual related substances were calculated as peak area percent. Total related substances is calculated as the sum of all detected individual related substances. The measured total related substances for all samples from all stability time points for each Pazopanib ASD Tablet was less than 0.1%, with no significant increase observed over time.

Example 8. Human In Vivo Pharmacokinetic and Relative Bioavailability Studies under Fasted Conditions

[0435] A study was performed in human subjects to assess the pharmacokinetics observed upon administration of Pazopanib ASD Tablet compositions under fasted conditions, as compared to pharmacokinetics observed upon administration of commercially available conventional immediate-release pazopanib tablets under fasted conditions.

[0436] Healthy subjects were orally administered either VOTRIENT IR Tablets (400 mg pazopanib; administered as 2x200 mg tablets) or Pazopanib ASD Tablet (either 100 mg or 200 mg pazopanib; administered as 2x50 mg tablets or 4x50 mg tablets) in accordance with the regimens described in Table 23. The study employed a crossover study design, in which each subject participated in each regimen for each period of the study

[0437] Subjects were screened for inclusion in the study up to 28 days before dosing. The enrollment target was for at least 26 healthy adult subjects. Each study period followed the same design. Subjects were admitted to the clinical unit on the morning of the day prior to administration of the study product (Day -1) where eligibility was reviewed and confirmed. After an overnight fast of a minimum of 10 hours, subjects were dosed on the morning of Day 1 of each period, and subjects continued to fast for approximately 4 hours post-dose. Subjects remained on site for the first 72 hours post-dose and returned to the clinical unit for a pharmacokinetic blood sample and safety assessments at both 120 and 168 hours post-dose.

There was a minimum washout of 10 days between each study period.

[0438] A subject was considered evaluable for the pharmacokinetic assessment if the subject received the reference product (VOTRIENT IR Tablet) and at least one of the test products (Pazopanib ASD Tablet FI or F2) in the fasted state, and if pharmacokinetic and safety data up to 168 hours post-dose were obtained. An initial set of 26 subjects was dosed according to Regimen A; however, due to study withdrawals and other factors, the number of evaluable subjects for Regimen B was 25, and for Regimen C and Regimen D was 23. All subjects are included in PK evaluation for each regimen, with exceptions noted in the table.

[0439] Following oral administration, blood samples were taken at the following time points to assess the plasma concentration of pazopanib: 0 (prior to administration), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 72, 120, and 168 hours. Plasma concentration of pazopanib was determined using a validated analytical method by an independent laboratoiy.

[0440] Key pharmacokinetic parameters were calculated for each regimen using pooled data for evaluable subjects. Statistical analysis was performed using natural log-transformed C_max and AUC values. Table 24 provides the geometric means and coefficients of variation (CV%) for key pharmacokinetic parameters determined for the dosing regimens. Table 25 provides geometric means and coefficients of variation (CV%) of non-dose adjusted relative bioavailabilities (F_rei) in subjects following administration of each regimen.

[0441] Under fasted conditions, Regimens B and C exhibited AUC and C_max values that are somewhat lower than the AUC and C_max attained by Regimen A (VOTRIENT IR Tablet). Each of the relevant non-dose adjusted relative bioavailabilities (F_rei) were in the range from about 55 to about 65. (See Table 25.) However, Regimens B and C were dosed at a nominal dose of 100 mg pazopanib, as compared to the 400 mg nominal pazopanib dose for Regimen A.

[0442] For Regimen D (200 mg nominal dose of pazopanib), AUC and C max values were observed that are somewhat higher than the AUC and C_max attained by Regimen A (VOTRIENT IR Tablet), even though Regimen A is dosed at a 400 mg nominal dose of pazopanib. Each of the relevant non-dose adjusted relative bioavailabilities (F_rel) were above 100. (See Table 25.)

[0443] Thus, it can be seen that the Pazopanib ASD Tablet formulations of the present disclosure are able to achieve the desired pharmacokinetic parameters that would be expected to confer a therapeutic benefit to a patient, but at a significantly reduced dose as compared to the commercially available conventional immediate-release pazopanib tablets.

[0444] As a further observation, it can be seen that the Pazopanib ASD Tablet formulations of the present disclosure are also able to achieve an improvement in variability, designated by the coefficient of variation (CV, expressed in percent), relative to VOTRIENT IR Tablet. (See Table 24.) For each of the pharmacokinetic parameters C_max, AUC_0-12h, AUC_0-24h, AUC_0-last and AUC_0-inf, a CV of 50% or greater was observed for VOTRIENT IR Tablet. On the other hand, for each of the Pazopanib ASD Tablet regimens, the relevant CV was under 50%, and in most cases, was under 40%. Particular improvement is noted with Regimen D, where the CV for C max was observed to be 33%, and the CV for each of the AUC parameters was observed to be under 30%.

Example 9. Human In Vivo Pharmacokinetic and Relative Bioavailability Study under Fasted vs. Fed Conditions

[0445] A study was performed in human subjects to assess the pharmacokinetics observed upon administration of a Pazopanib ASD Tablet composition according to the disclosure under fed conditions. Comparison was made to pharmacokinetics observed upon administration of the same formulation dosed under fasted conditions (Regimen D from Example 8). Table 26 indicates the relevant regimens involved in this study.

[0446] Regimen D was conducted as described in Example 8. Regimen E was conducted using the same set of healthy subjects using a crossover study design. Regimen E was conducted similarly to the regimens described in Example 8, except that following the overnight fast, subjects were fed a high-fat breakfast 30 minutes prior to dosing. Subjects were instructed to eat the meal within a maximum period of 20 minutes, and were required to consume at least 95% of the provided meal. After dosing, a lunch meal was then provided approximately 4 hours postdose, an evening meal was provided approximately 10 hours post-dose, and an evening snack was provided approximately 14 hours post-dose.

[0447] A subject was considered evaluable for the pharmacokinetic/effective bioequivalence assessment if the subject received the study product in both the fasted state and in the fed state, and if pharmacokinetic and safety data up to 168 hours post-dose were obtained. The number of evaluable subjects for Regimen E was 22. Key pharmacokinetic parameters were calculated for each regimen using pooled data for evaluable subjects. Statistical analysis was performed using natural log-transformed C_max and AUC values.

[0448] Table 27 provides the geometric means and coefficients of variation (CV%) for key pharmacokinetic parameters determined for the relevant dosing regimens. Table 28 provides geometric means and coefficients of variation (CV%) of relative bioavailabilities (F_rei) in subjects for fed Regimen E, as compared to fasted Regimen D.

[0449] With respect to maximum blood concentrations, Regimen E (fed) exhibited a geometric mean C_max value that was somewhat higher than the geometric mean C_max value observed for Regimen D (fasted), with F_rel of 112 (C V 31.1%). (See Tables 27 and 28.) These data indicate that compositions according to the disclosure may be capable of providing therapeutic concentrations under fed conditions, and did not exhibit a significant food effect with respect to C_max·

[0450] With respect to exposure, Regimen E (fed) exhibited somewhat higher AUC values than Regimen D, with AUC_0-24), AUC_0-last) and AUC_0-inf) all increased by 29-34% relative to Regimen D (Table 28). Although an increase in exposure was observed indicating a slight positive food effect with respect to exposure for the Pazopanib ASD Tablet composition, these data indicate that compositions according to the disclosure could be expected to provide therapeutic concentrations under fed conditions.

[0451] The results given in Tables 27 and 28 indicate the slight positive food effect with respect to exposure for the Pazopanib ASD Tablet composition, and an insignificant food effect with respect to C_max. These results were a substantial improvement as compared to the significant food effect reported for VOTRIENT. As stated above, reported results for VOTRIENT indicate that an approximately 2-fold increase in AUC and C_max was observe when administered with a high- fat or low-fat meal, as compared to levels obtained under fasting conditions.

[0452] It can also be seen that for each of the pharmacokinetic parameters C_max, AUC_0-12h, AUC_0-24h, AUC_0-last and AUC_0-inf, administration under fed conditions resulted in a somewhat higher CV than for administration under fasted conditions. (See Table 27.) However, in each case, the CV was under 50%. (Reference is made to Regimen A of Example 8, in which VOTRIENT IR Tablet was dosed under fasted conditions; for each of the pharmacokinetic parameters C_max, AUC_0-12h, AUC_0-24h, AUC_0-last and AUC_0-inf, a CV of 50% or greater was observed.) [0453] The data therefore establish that the Pazopanib ASD Tablet composition performs much better than the commercially available conventional immediate-release pazopanib tablets with respect to food effect. The improvement in food effect was an unexpected and highly advantageous result obtained by the compositions of the present disclosure. In providing a dosage form that can be taken with food, without food, or without regard to consumption of food, the present disclosure provides a significant advance over formulations currently available for the administration of pazopanib.

Example 10. Human In Vivo Pharmacokinetic and Relative Bioavailability Study Using Intact and Crushed Pazopanib ASD Tablets

[0454] A study was performed in human subjects to assess the pharmacokinetics observed upon administration of a Pazopanib ASD Tablet composition according to the disclosure as a crushed tablet under fasted conditions. Comparison was made to pharmacokinetics observed upon administration of the same formulation dosed as an intact tablet (Regimen D from Example 8). Table 29 indicates the relevant regimens involved in this study.

[0455] Regimen D was conducted as described in Example 8. Regimen F was conducted using the same set of healthy subjects using a crossover study design. Regimen F was conducted similarly to the regimens described in Example 8, except that the study product was administered in the form of a powder derived from manual crushing (by mortar and pestle) of four Pazopanib ASD Tablet FI (each nominally 50 mg pazopanib). The obtained powder was transferred to a dosing cup, and the powder was orally administered in dry form to the subject. Subjects were provided with 240 mL of water to ingest with the powder, of which an approximately 10-20 mL portion was used to rinse the dosing cup prior to ingestion. The number of evaluable subjects for Regimen F was 22.

[0456] Table 30 provides the geometric means and coefficients of variation (CV%) for key pharmacokinetic parameters determined for the relevant dosing regimens. Table 31 provides geometric means and coefficients of variation (CV%) of relative bioavailabilities (F_rel) in subjects for Regimen F (crushed tablets), as compared to Regimen D (intact tablets).

[0457] The pharmacokinetic data (presented as non-transformed arithmetic-averaged data from evaluable subjects for each time point) is graphically represented in Figure 1. It can be seen that the pharmacokinetic profiles for crushed and intact administration are nearly identical. Regimen F (crushed) exhibited a slightly higher C_max at approximately the same T_max, which is consistent with the statistical analysis. Regimen F exhibited very slightly lower average plasma levels at later time points as compared to Regimen D (intact).

[0458] From the statistical analysis (Table 31), the median T_max for Regimen F was 1 hour as compared to 2 hours for Regimen D; however, Regimen F exhibited a noticeably tighter spread (1 to 3 hours) in T_max as compared to Regimen D (1 to 12 hours). The relative bioavailabilities (Frel) for various parameters demonstrated that Regimen F provided similar peak and overall exposure, with no statistically significant difference.

[0459] The study therefore establishes that the Pazopanib ASD Tablet composition performs much better than the commercially available conventional immediate-release pazopanib tablets with respect to administration as a crushed tablet. As stated above, administering VOTRIENT as a crushed tablet (400 mg nominal dose) increased AUC_0-72hby 46% and C_max by approximately 2-fold and decreased T_max by approximately 2 hours compared with administration of the intact tablet. The improvement in crushability provided by the present disclosure was an unexpected and highly advantageous result, since VOTRIENT cannot be administered as a crushed tablet.

[0460] In providing a dosage form that can be taken in the form of a powder obtained from crushing a tablet, the present disclosure provides a significant advance over formulations currently available for the administration of pazopanib. The disclosure further meets an unmet need, providing an alternative to patients who may have difficulty swallowing an intact solid oral dosage form (such as a tablet), such as elderly or geriatric patients, pediatric patients, or patients suffering from dysphagia for any reason.

* * * * *

[0461] The foregoing description is given for clearness of understanding only, and no unnecessary limitations should be understood therefrom. Various modifications and alterations to this disclosure will become apparent to those skilled in the art without departing from the scope and spirit of this disclosure. It should be understood that this disclosure is not intended to be unduly limited by the illustrative embodiments and examples set forth herein, and such examples and embodiments are presented by way of example only.

[0462] Reference throughout this specification to “one embodiment,” “ an embodiment,” “certain embodiments,” or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0463] Throughout the specification, where compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise. Likewise, where methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise.

[0464] The practice of a method disclosed herein, and individual steps thereof, can be performed manually and/or with the aid of or automation provided by electronic equipment. Although processes have been described with reference to particular embodiments, a person of ordinaiy skill in the art will readily appreciate that other ways of performing the acts associated with the methods may be used. For example, the order of various steps may be changed without departing from the scope or spirit of the method, unless described otherwise. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0465] The term “comprises” and variations such as “comprises” and “comprising” do not have a limiting meaning where these terms appear in the description and claims. Such terms will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.

[0466] By “consists of’ (or similarly “consisting of’) is meant including, and limited to, whatever follows the phrase “consists of.” Thus, the phrase “consists of’ in dictates that the listed elements are required or mandatory, and that no other elements may be present. By “consists essentially of’ (or similarly “consisting essentially of’) is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consists essentially of’ indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they materially affect the activity or action of the listed elements.

[0467] The words “preferred” and “preferably” refer to embodiments of the disclosure that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the disclosure.

[0468] In this application, terms such as “a,” “ an,” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terms “a,” “ an,” and “the” are used interchangeably with the term “at least one.” The phrases “at least one of’ and “comprises at least one of’ followed by a list refer to any one of the items in the list and any combination of two or more items in the list.

[0469] As used herein, the term “or” is generally employed in its usual sense including “and/or” unless the content clearly dictates otherwise. The term “and/or” means one or all of the listed elements or a combination of any two or more of the listed elements (e.g., preventing and/or treating an affliction means preventing, treating, or both treating and preventing further afflictions).

[0470] Also herein, all numbers are assumed to be modified by the term “about” and preferably by the term “exactly.” As used herein in connection with a measured quantity, the term “about” refers to that variation in the measured quantity as would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment used. Herein, “up to” a number (e g., up to 50) includes the number (e.g., 50). Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range as well as the endpoints (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.) and any sub-ranges (e.g., 1 to 5 includes 1 to 4, 1 to 3, 2 to 4, etc.).

[0471] The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. To the extent that there is any conflict or discrepancy between the present disclosure and the disclosure in any document that is incorporated by reference, this disclosure as written will control.

Claims

WHAT IS CLAIMED IS:

1. A method of safely delivering a therapeutically effective dose of pazopanib to a patient in need thereof, comprising:

(a) providing a pharmaceutical composition in the form of one or more crushable tablets, such that the one or more crushable tablets would provide a therapeutically effective amount of pazopanib if administered intact;

(b) crushing the one or more crushable tablets to provide a powder; and

(c) orally administering the powder to the patient to provide the therapeutically effective dose.

2. The method of claim 1, further comprising the step of dispersing the powder in a soft food or a fruit preparation prior to administration to the patient.

3. The method of claim 1, wherein the patient is a pediatric patient, a geriatric patient, or a patient that suffers from dysphagia.

4. The method of claim 1, wherein the one or more crushable tablets comprise a total of 320 to 400 mg pazopanib.

5. A method of delivering pazopanib to a patient in need thereof, comprising:

(a) providing a pharmaceutical composition in the form of one or more crushable tablets;

(b) crushing the one or more crushable tablets to provide a powder; and

(c) orally administering the powder to the patient; wherein the crushable tablets comprise an amorphous solid dispersion, the amorphous solid dispersion comprising pazopanib and one or more polymers in a w/w ratio (pazopanib:polymer) of 20:80 to 80:20.

6. The method of claim 5, further comprising the step of dispersing the powder in a soft food or a fruit preparation prior to administration to the patient.

7. The method of claim 5, wherein the patient is a pediatric patient, a geriatric patient, or a patient that suffers from dysphagia.

8. The method of claim 5, wherein the one or more polymers is a vinylpyrrolidone/vinyl acetate copolymer.

9. The method of claim 5, wherein the one or more polymers is a hydroxypropyl methylcellulose acetate succinate.

10. The method of claim 5, wherein the amorphous solid dispersion consists essentially of pazopanib and the one or more polymers in a w/w ratio (pazopanib:polymer) of 50:50.

11. The method of claim 5, wherein the one or more crushable tablets comprise a total of 320 to 400 mg pazopanib.

12. A kit comprising:

(a) a pharmaceutical composition in the form of an orally administrable crushable tablet comprising pazopanib; and

(b) a package insert that informs a user of the kit that the crushable tablet can optionally be crushed to provide a powder for oral administration.

13. The kit of claim 12, wherein the package insert further informs the user of the kit that the powder can be dispersed in a soft food for administration.

14. The kit of claim 12, wherein the package insert further informs the user of the kit that the powder can be dispersed in a fruit preparation for administration.

15. The kit of claim 12, wherein each crushable tablet comprises 80 to 100 mg pazopanib.

16. A crushable tablet suitable for oral administration and comprising granules and extra- granular excipients, wherein: the granules comprise, by weight of the granules: (a) 30% to 80% of an amorphous solid dispersion consisting essentially of pazopanib and one or more polymers in a w/w ratio (pazopanib:polymer) of 20: 80 to 80:20;

(b) 15% to 70% of one or more granulation fillers; and

(c) 2% to 20% of one or more granulation disintegrants; the extra-granular excipients comprise, by weight of the tablet:

(a) 20% to 80% of one or more tablet fillers; and

(b) 2% to 20% of one or more tablet disintegrants; wherein the tablet comprises 20% to 80% granules, by weight of the tablet.

17. The crushable tablet of claim 16, wherein the one or more polymers comprises a polymer or copolymer of N-vinylpyrrolidone and/or vinyl acetate.

18. The crushable tablet of claim 16, wherein the one or more polymers is a vinylpyrrolidone/vinyl acetate copolymer.

19. The crushable tablet of claim 16, wherein the one or more polymers comprises an ionizable cellulose ester.

20. The crushable tablet of claim 16, wherein the one or more polymers is a hydroxypropyl methylcellulose acetate succinate.

21. The crushable tablet of claim 16, wherein the amorphous solid dispersion consists essentially of pazopanib and the one or more polymers in a w/w ratio (pazopanib: polymer) of 50:50.

22. The crushable tablet of claim 16, wherein the tablet comprises 1 to 10% of a solubilizer, by weight of the tablet.

23. The crushable tablet of claim 22, wherein the solubilizer is a poloxamer.

24. The crushable tablet of claim 16, wherein the crushable tablet comprises 80 to 100 mg pazopanib.

25. The crushable tablet of claim 16, wherein the crushable tablet comprises 90 mg pazopanib.

26. The crushable tablet of claim 16, wherein the tablet is suitable for administration as an intact tablet, as a split tablet, and as a powder obtained by crushing the tablet.

27. The crushable tablet of claim 16, wherein: the granules comprise, by weight of the granules:

(a) 30% to 80% of amorphous solid dispersion consisting essentially of pazopanib and polymer in a w/w ratio (pazopanib: polymer) of 50:50;

(b) 15% to 70% of granulation fillers including microcrystalline cellulose; and

(c) 2% to 20% of granulation disintegrants including crospovidone; the extra-granular excipients comprise, by weight of the tablet:

(a) 20% to 80% of tablet fillers including microcrystalline cellulose; and

(b) 2% to 20% of tablet disintegrants including crospovidone.

28. The crushable tablet of claim 16, wherein, when a number of crushable tablets are orally administered intact to healthy human subjects in a fasted state, the administration provides plasma C_max that is similar to plasma C_max observed upon oral administration of a powder to the subjects in a fasted state; wherein, the number of crushable tablets is selected to provide a total dose of 320 mg to 400 mg pazopanib; and wherein the powder is obtained by crushing the same number of the crushable tablets prior to administration.

29. The crushable tablet of claim 16, wherein, when a number of cmshable tablets are orally administered intact to healthy human subjects in a fasted state, the administration provides plasma AUC that is similar to plasma AUC observed upon oral administration of a powder to the subjects in a fasted state; wherein, the number of cmshable tablets is selected to provide a total dose of 320 mg to 400 mg pazopanib; and wherein the powder is obtained by cmshing the same number of the cmshable tablets prior to administration.

30. The crushable tablet of claim 29, wherein the AUC is AUC_0-24h, AUC_0-last, or AUC_0-inf.