WO2022061120A1

WO2022061120A1 - Solid dispersions containing amorphous nintedanib, their synthesis and use thereof

Info

Publication number: WO2022061120A1
Application number: PCT/US2021/050883
Authority: WO
Inventors: Daniel J. ELLENBERGER; Dave A. Miller
Original assignee: Dispersol Technologies, Llc
Priority date: 2020-09-18
Filing date: 2021-09-17
Publication date: 2022-03-24

Abstract

The invention relates to solid dispersions containing amorphous nintedanib and methods making such solid dispersions. The invention also relates to pharmaceutical compositions containing such solid dispersions. The invention further relates to methods of making and administering such pharmaceutical compositions. The pharmaceutical compositions of the invention are useful in the treatment of oncological diseases, immunologic: diseases, or pathological conditions involving an immunologic component, or fibrotic diseases.

Description

SOLID DISPERSIONS CONTAINING AMORPHOUS NINTEDANIB, THEIR SYNTHESIS, AND USE THEREOF

Cross Reference to Related Applications

[001] This application claims priority to U.S. Provisional Application No. 63/080,134 filed on September 18, 2020, the disclosure of which is incorporated by reference.

Technical Field

[002] This invention relates to solid dispersions containing nintedanib prepared by use of an advanced amorphous solid dispersion strategy. The invention also relates to pharmaceutical compositions containing such solid dispersions, methods of making and administering such pharmaceutical compositions, and methods of treatment using such pharmaceutical compositions.

Background of the Invention

[003] Interstitial lung diseases (ILD) include a large and diverse group of more than 200 lung diseases and respiratory conditions characterized by inflammation and fibrosis of the interstitium, the tissue between the air sacs of the lung. See, e.g., du Bois, Nat. Rev. Drug Discov. 9:129-140 (2010).

[004] One of the most common types of ILD is idiopathic pulmonary fibrosis (IPF). Other ILDs with similar pathological fibrotic alterations in the lung interstitium and a progressive fibrosis include connective tissue disease-associated ILD (CTD-ILD) which is mainly systemic sclerosis-ILD (SSc-ILD) and rheumatoid arthritis-ILD (RA-ILD), idiopathic non-specific interstitial pneumonia (i SIP), chronic hypersensitivity pneumonitis (CHP), unclassifiable idiopathic interstitial pneumonia (IIP), interstitial pneumonia with autoimmune features (IPAF) and environmental/occupational fibrosing lung diseases like asbestosis and silicosis.

[005] IPF is a rare disease of unknown etiology and poor prognosis that is characterized by progressive fibrosis of the interstitium of the lung, leading to decreasing lung volume and progressive pulmonary insufficiency. The lung function in patients with lung fibrosis is determined as forced vital capacity (FVC). [006] Nintedanib, methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-l-yl)acetyl]amino}phenyl)amino]- (phenyl)methylidene}-2-oxo-2,3-dihydro-IH-indole-6-carboxylate, is an innovative substance having valuable pharmacological properties, especially for the treatment of oncological diseases, immunologic diseases, or pathological conditions involving an immunologic component, or fibrotic diseases.

[007] The chemical structure of nintedanib is depicted below as Formula (I):

[008] This substance is described as base in WO 01/27081, as monoethanesulfonate salt form in WO 2004/013099, for its use in the treatment of immunologic diseases or pathological conditions involving an immunologic component in WO 2004/017948, for its use in the treatment of oncological diseases in WO 2004/096224, for its use in the treatment of fibrotic diseases in WO 2006/067165,

[009] WO 2007/141283 discloses salts of nintedanib prepared with hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, methanesulfonic acid, ethanedisulfuric acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphtalene-l,5-disulfonic acid, citric acid, D- and L-tartaric acid, fumaric acid, maleic acid, L-lactic acid, glycolic acid, glycine, L- and D-malic acid, malonic acid, oxalic acid, succinic acid, gentisic acid, camphoric acid, benzoic acid, mandelic acid, saccharic acid, salicylic acid, L- aspartic acid, ascorbic acid and xinafoic acid. And WO 2012/068441 discloses salts of nintedanib prepared with formic acid, adipic acid, acetic acid, ethanesulfonic acid, and orotic acid. US 7119093 discloses prodrugs of nintedanib.

[010] WO 2009/147212 and in WO 2009/147220 disclose pharmaceutical dosage forms comprising nintedanib. Also, Vartiainen et al., poster presentation at the International Colloquium of Lung and Airway Fibrosis in Dublin (2016), discloses a dry powder formulation for inhalation.

[Oil] Nintedanib is a highly potent, orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs). It binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks intracellular signalling. In addition, nintedanib inhibits Fms-like tyrosine-protein kinase 3 (Fit 3), lymphocyte- specific tyrosine-protein kinase (Lek), tyrosine-protein kinase lyn (Lyn) and proto- oncogene tyrosine-protein kinase sre (Src). See Hilberg et al., Cancer Res. 68:4774- 4782 (2008). [012] Nintedanib was shown to be able to inhibit or attenuate cellular proliferation, contributing to angiogenesis (see Hilberg et al., Cancer Res. 68:4774-4782 (2008)), as well as lung fibroblast proliferation, migration (see Hostettler et al., Respir Res. 15:157 (2014)) and transformation to myofibroblasts (see Wollin et al., Eur. Respir J 45:1434-1445 (2015)) contributing to lung fibrosis (e.g., IPF), SSc-ILD, and RA- ILD. Furthermore, it revealed anti-fibrotic and anti- inflammatory activity in lung fibrosis models (see Wollin et al., Eur. Respir J 45:1434-1445 (2015); Wollin et al., J. Pharmacol. Exp. Then 394:209-220(2014)). Nintedanib demonstrated the ability to inhibit fibroblast migration, proliferation, and transformation to myofibroblasts in SSc cellular models, to attenuate skin and lung fibrosis in SSc animal models (see Huang et al., Ann. Rheum. Dis. 74:883-890 (2016)) and to reduce lung fibrosis in RA-ILD animal models (see Redente et al., Am J Respir Crit Care Med 193:A4170 (2016)).

[013] Positive results, in terms of rate reduction of decline in FVC, were obtained for the use of nintedanib in the treatment of patients with IPF in clinical trials. See Richeldi et al., N. Engl. J. Med. 370:2071-2082 (2014); Richeldi et al., N. Engl. J. Med. 365:1079-1087 (2011).

[014] Recently, nintedanib esylate, sold under the brand names OFEV® and Vargatef®, was approved for the treatment of IPF. In March 2020, the U.S. Food and Drug Administration (FDA) approved nintedanib for use in the United States to treat chronic fibrosing (scarring) ILD with a progressive phenotype (trait). It is the first treatment for this group of fibrosing lung diseases that worsen over time that was approved by the FDA. It was also approved in the European Union and other parts of the world for combination therapy of some types of non-small-cell lung cancer.

[015] Nintedanib is being tested in several phase I to III clinical trials for cancer, including lung, ovarian, metastatic bowel, liver, and brain cancer.

[016] Current phase II trials are investigating the effect of nintedanib in patients with bladder cancer, metastatic bowel cancer, liver cancer and the brain tumor glioblastoma multiforme.

[017] Phase III trials are investigating the use of nintedanib in combination with carboplatin and paclitaxel as a first line treatment for patients with ovarian cancer.

[018] Only a small percentage of orally taken nintedanib is absorbed in the gut, partially due to transport proteins (such as P-glycoprotein) moving the substance back into the lumen. Combined with a high first-pass effect, this results in an oral bioavailability of about 4.7% with a 100 mg dose. The drug reaches peak plasma levels in 2 to 4 hours after oral intake in the form of a soft gelatin capsule. Adverse reactions leading to permanent dose reductions and/or discontinuation in OFEV®-treated patients was gastrointestinal disorders, such as diarrhea, nausea, and decreased appetite. [019] The aim of the present invention is to obtain for nintedanib a pharmaceutical dosage form which meets adequate bioavailability requirements for the desired target dosage range. For example, a pharmaceutical dosage form may have an immediate release profile range providing an appropriate plasma concentration-time profile of nintedanib, may bypass first-pass metabolism, may have the same or an improved pharmacokinetic profile compared to OFEV®, and/or may reduce gastrointestinal disorders relative to OFEV®. Such specific characteristics are not known from the prior art for nintedanib.

Summary of the Invention

[020] The invention relates to a solid dispersion comprising, consisting essentially of, or consisting of nintedanib, dispersed in a pharmaceutically acceptable polymer matrix, wherein the nintedanib is substantially amorphous.

[021] The invention also relates to a process for preparing the solid dispersion of the invention, comprising, consisting essentially of, or consisting of thermokinetic compounding nintedanib and at least one pharmaceutical carrier in a thermokinetic mixer at a temperature less than or equal to 200°C for less than 300 seconds to form an amorphous solid dispersion of nintedanib and at least one pharmaceutical carrier.

[022] The invention further relates to a pharmaceutical composition comprising, consisting essentially of, or consisting of the solid dispersion of the invention, and at least one pharmaceutically acceptable excipient.

[023] The invention also relates to the use of the pharmaceutical composition of the invention for the treatment of oncological diseases, immunologic diseases, or pathological conditions involving an immunologic component, or fibrotic diseases. For example, the pharmaceutical composition of the invention may be used to treat interstitial lung diseases (ILD), such as idiopathic pulmonary fibrosis (I PF), systemic sclerosis ILD, and rheumatoid arthritis ILD; muscular dystrophy; and cancers, such as breast, lung (including non-small-cell and small-cell), ovarian, fallopian tube, metastatic colon, bowel, liver, bladder, pancreas, thyroid, prostate, leukemia, mesothelioma, and brain cancer.

[024] The invention also relates to a method for the treatment of oncological diseases, immunologic diseases, or pathological conditions involving an immunologic component, or fibrotic diseases, comprising, consisting essentially of, or consisting of the administration of a therapeutically effective amount of the pharmaceutical composition of the invention to a subject in need thereof. For example, the invention relates to the treatment of interstitial lung diseases, such as idiopathic pulmonary fibrosis, systemic sclerosis ILD, and rheumatoid arthritis ILD; muscular dystrophy; and cancers, such as breast, lung (including non-small-cell and small-cell), ovarian, fallopian tube, metastatic colon, bowel, liver, bladder, pancreas, thyroid, prostate, leukemia, mesothelioma, and brain cancer, comprising, consisting essentially of, or consisting of the administration of a therapeutically effective amount of the pharmaceutical composition of the invention to a subject in need thereof.

[025] The invention further relates to a method of administering nintedanib to a subject in the oral mucosa thereof, comprising: a) providing a therapeutically effective amount of the pharmaceutical composition of the invention; and b) administrating the pharmaceutical composition to the subject via, for example, a buccal route, a sublingual route, or a gingival route.

Brief Description of the Drawings

[026] FIG. 1 shows the XRD analysis of KinetiSol® dispersed (KSD) processed materials overlayed with nintedanib active pharmaceutical ingredient (free base).

[027] FIG. 2 shows the HPLC analysis from the μFLUX dissolution donor compartment of the formulations from Table 2.

[028] FIG. 3 shows the μFLUX dissolution acceptor compartment of certain formulations from Table 2. [029] FIG. 4 shows the HPLC analysis from the μFLUX dissolution donor compartment of certain formulations from Table 2.

[030] FIG. 5 shows the μFLUX dissolution acceptor compartment of certain formulations from Table 2.

[031] FIG. 6 shows the data (plasma concentration over 8 hours) for the dog pharmacokinetic study.

[032] FIG. 7 shows the HPLC analysis from the μFLUX dissolution donor compartment externally adding 5 mg/mL of cyclodextrin (CD) to HPMCAS-LMP samples.

[033] FIG. 8 shows the HPLC analysis from the μFLUX dissolution donor compartment externally adding 5 mg/mL of cyclodextrin to HPMC E3 samples.

[034] FIG. 9 shows the HPLC analysis from the μFLUX dissolution donor compartment externally adding 5 mg/mL of cyclodextrin to nintedanib esylate.

[035] FIG. 10 shows the μFLUX dissolution acceptor compartment of certain formulations from Table

9.

[036] FIG. 11 shows the μFLUX dissolution acceptor compartment of certain formulations from Table

10.

[037] FIG. 12 shows the μFLUX dissolution acceptor compartment of certain formulations from Table

11. [038] FIG. 13 shows the HPLC analysis from the μFLUX dissolution donor compartment externally adding cyclodextrin complexes to HPMCAS-LMP samples.

[039] FIG. 14 shows the HPLC analysis from the μFLUX dissolution donor compartment externally adding cyclodextrin complexes to HPMC E3 samples.

Description of the Invention

[040] The invention relates to an advanced amorphous solid dispersion strategy which is used for providing a new immediate-release formulation of nintedanib that can effectively and quickly release nintedanib in oral fluid.

[041] As used herein, "nintedanib" means methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-l- yl)acetyl]amino}phenyl)amino]-(phenyl)methylidene}-2-oxo-2,3-dihydro-IH-indole-6-carboxylate free base.

[042] The invention thus relates to a solid dispersion comprising, consisting essentially of, or consisting of amorphous nintedanib dispersed in a pharmaceutically acceptable polymer matrix.

[043] The total amount of nintedanib may constitute about 5-60% (w/w), such as about 10-50% (w/w), such as about 15-40% (w/w), such as about 20-30% (w/w), such as about 18-22% (w/w), such as about 20% (w/w) of the solid dispersion.

[044] The pharmaceutically acceptable polymer matrix comprises, consists essentially of, or consists of at least one pharmaceutical carrier, such as at least one polymer. The at least one polymer may be selected from the group consisting of hypromellose, hypromellose acetate succinate, vinylpyrrolidonevinyl acetate copolymer, ethylcellulose, hydroxypropylcellulose, cellulose acetate butyrate, poly(vinylpyrrolidone), polyethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethyl-cellulose, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, cellulose acetate phthalate, cellulose acetate trimelletate, poly(vinyl acetate) phthalate, hydroxypropylmethylcellulose phthalate, poly(methacrylate ethylacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:2) copolymer, hydroxypropylmethylcellulose acetate succinate, polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer (e.g., Soluplus®), and mixtures thereof. Preferably, the at least one polymer is a hypromellose polymer, in particular, Hypromellose E3, Hypromellose E5, Hypromellose E50, Hypromellose E15, Hypromellose K3, and mixtures thereof, preferably Hypromellose E3. The hypromellose acetate succinate polymer may be substituted by 2-16% acetyl groups, 4-28% succinyl groups, or mixtures thereof. The vinylpyrrolidone-vinyl acetate copolymer may be Kollidon VA 64 or Copovidone 64. The polyvinylpyrrolidone may be selected from the group consisting of Kollidon 12, Kollidon 17, Kollidon 25, Kollidon 30, Kollidon 90, and mixtures thereof. The at least one pharmaceutical carrier may constitute about 40-95% (w/w), such as about 50-90% (w/w), such as about 60-85% (w/w), such as about 70-80% (w/w), such as about 78-82% (w/w), such as about 80% (w/w) of the solid dispersion. [045] The solid dispersions of the invention may also comprise, consist essentially of, or consist of at least one antioxidant. The antioxidant may be butylated hydroxytoluene (BHT), sodium citrate, propyl gallate, methionine, a-tocopherol, butylated hydroxyanisole (BHA), citric acid, arginine, piperine, sodium bicarbonate, ascorbic acid, fumaric acid, tartaric acid, sodium acetate, sodium carbonate, sodium thiosulfate, sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA), salts thereof, esters thereof, and mixtures thereof. For example, the antioxidant may be sodium ascorbate, sodium ascorbyl phosphate, calcium ascorbate, magnesium ascorbate, magnesium ascorbyl phosphate, potassium ascorbate, ascorbyl palmitate, ascorbyl stearate, and mixtures thereof. Preferably, the antioxidant is sodium ascorbate and/or calcium ascorbate. The at least one antioxidant may constitute about 1-10% (w/w), such as about 2-8% (w/w), such as about 3-6% (w/w), such as about 5% (w/w) of the solid dispersion. The solid dispersion may also not contain an antioxidant.

[046] The solid dispersions of the invention may also contain at least one lubricant, such as those described in US 2019/0142756, which is incorporated herein by reference. The lubricant may be, for example, a non-polymeric lubricant, such as an alcohol, a stearate, a carboxylic acid, a glyceryl, sodium stearyl fumarate, ascorbyl palmitate, and mixtures thereof. The alcohol may be selected from the group consisting of myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and fatty alcohol. The stearate may be selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, aluminum monostearate, aluminum distearate, and aluminum tristearate. The carboxylic acid may be selected from the group consisting of myristic acid, palmitic acid, and stearic acid. The glyceryl may be selected from the group consisting of glyceryl monostearate, glyceryl behenate, and glyceryl palmitostearate. The at least one lubricant may be present in an amount of about 20% or less (w/w), such as about 10% or less (w/w), such as about 5% or less (w/w), such as about 2% or less (w/w), or such as about 1% or less (w/w) of the solid dispersion.

[047] The solid dispersions of the invention may provide a pharmacokinetic profile in vivo which is about the same or improved in comparison to the pharmacokinetic profile in vivo obtained by OFEV®. [048] Methods of Formulating the Solid Dispersion

[049] A solid dispersion of the invention may be prepared using thermokinetic compounding, which is a method of compounding components until they are melt-blended. A solid dispersion prepared by this method is also known as a KinetiSol® dispersed (KSD). For example, a solid dispersion of the invention may be processed using a TC-254B KinetiSol compounder designed by DisperSol Technologies (see, e.g., PCT/US18/51914; WO 2015/175505; US 8,486,423; DiNunzio et al., J.Pharm. Sci. 99(3):1239-1253 (2010); Brough and Williams, int. J. Pharm. 453:157-166 (2013), each of which are incorporated herein by reference). Thermokinetic compounding may be particularly useful for compounding heat-sensitive or thermolabile components. Thermokinetic compounding may provide brief processing times, low processing temperatures, high shear rates, and the ability to compound thermally incompatible materials. [050] Thermokinetic compounding may be carried out in a thermokinetic chamber using one or multiple speeds during a single, compounding operation on a batch of components to form a pharmaceutical formulation of the present disclosure.

[051] A thermokinetic chamber includes a chamber having an inside surface and a shaft extending into or through the chamber. Extensions extend from the shaft into the chamber and may extend to near the inside surface of the chamber. The extensions are often rectangular in cross-section, such as in the shape of blades, and have facial portions. During thermokinetic compounding, the shaft is rotated causing the components being compounded, such as particles of the components being compounded, to impinge upon the inside surface of the chamber and upon facial portions of the extensions. The shear of this impingement causes comminution, frictional heating, or both of the components and translates the rotational shaft energy into heating energy. Any heating energy generated during thermokinetic compounding is evolved from the mechanical energy input. Thermokinetic compounding is carried out without an external heat source. The thermokinetic chamber and components to be compounded are not pre-heated prior to commencement of thermokinetic compounding.

[052] The thermokinetic chamber may include a temperature sensor to measure the temperature of the components or otherwise within the thermokinetic chamber.

[053] During thermokinetic compounding, the average temperature of the thermokinetic chamber may increase to a pre-defined final temperature over the duration of the thermokinetic compounding to achieve thermokinetic compounding of nintedanib and the pharmaceutical carrier, and any other components of a solid dispersion of the invention, such as an antioxidant, lubricant, and additional therapeutic agents. The pre-defined final temperature may be such that degradation of nintedanib, the pharmaceutical carrier, or other components is avoided or minimized. Similarly, the one or multiple speeds of use during thermokinetic compounding may be such that degradation of nintedanib, the pharmaceutical carrier, or other components is avoided or minimized. As a result, nintedanib, the pharmaceutical carrier, or other components of the solid amorphous dispersion may lack substantial impurities.

[054] The average maximum temperature in the thermokinetic chamber during thermokinetic compounding may be less than the glass transition temperature, melting point, or molten transition point, of nintedanib or any other therapeutic agents present, the pharmaceutical carrier, or one or all other components of the amorphous solid dispersion, or any combinations or sub-combinations of components. [055] Pressure, duration of thermokinetic compounding, and other environmental conditions such as pH, moisture, buffers, ionic strength of the components being mixed, and exposure to gasses, such as oxygen, may also be such that degradation of nintedanib or any other therapeutic agents present, the pharmaceutical carrier, or one or all other components is avoided or minimized.

[056] Thermokinetic compounding may be performed in batches or in a semi-continuous fashion, depending on the product volume. When performed in a batch, semi-continuous, or continuous manufacturing process, each thermokinetic compounding step may occur for less than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 100, 120, 240, or 300 seconds.

[057] Variations of thermokinetic compounding may be used depending on the amorphous solid dispersion and its components. For example, the thermokinetic chamber may be operated at a first speed to achieve a first process parameter, then operated at a second speed in the same thermokinetic compounding process to achieve a final process parameter. In other examples, the thermokinetic chamber may be operated at more than two speeds, or at only two speeds, but in more than two time internals, such as at a first speed, then at a second speed, then again at the first speed.

[058] The nintedanib component may be in a crystalline or semi-crystalline form prior to thermokinetic compounding.

[059] In another variation, nintedanib or other therapeutic agent particle size is reduced prior to thermokinetic compounding. This may be accomplished by milling, for example dry milling the nintedanib or other therapeutic agent to a small particle size prior to thermokinetic compounding, wet milling the nintedanib or other therapeutic agent with a pharmaceutically acceptable solvent to reduce the particle size prior to thermokinetic compounding, or melt milling the nintedanib or other therapeutic agent with the pharmaceutical carrier having limited miscibility with the nintedanib or other therapeutic agent to reduce the particle size prior to thermokinetic compounding. [060] Another variation includes milling the nintedanib or other therapeutic agent in the presence of the pharmaceutical carrier to create an ordered mixture where nintedanib or other therapeutic agent particles adhere to the surface of the pharmaceutical carrier particles, the pharmaceutical carrier particles adhere to the surface of nintedanib or other therapeutic agent, or both.

[061] The thermokinetically compounded amorphous solid dispersion may exhibit substantially complete amorphicity (e.g., > 90%, preferably > 95%, more preferably > 98%, even more preferably > 99%, most preferably > 99.9% amorphous). For example, the solid dispersion may be characterized by an x-ray diffraction pattern having a substantially amorphous pattern (e.g., an amorphous halo pattern). Preferably, the amorphous nintedanib in the solid dispersion includes less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.1% crystalline or semi-crystalline nintedanib, while the solid dispersion still exhibits substantially complete amorphicity.

[062] Thus, the invention relates to a process for preparing a solid dispersion of the invention comprising, consisting essentially of, or consisting of thermokinetic compounding nintedanib and at least one pharmaceutical carrier in a thermokinetic mixer at a temperature less than or equal to 200°C for less than 300 seconds to form an amorphous solid dispersion of nintedanib and at least one pharmaceutical carrier. Preferably, the thermokinetic compounding in the thermokinetic mixer does not cause substantial degradation of nintedanib, the pharmaceutical carrier, or any other component in the solid dispersion (e.g., < 2.0%, preferably < 1.5%, more preferably < 1.0%, even more preferably < 0.5%, most preferably < 0.1% total impurities).

[063] Pharmaceutical Compositions and Methods of Treatment

[064] The invention also relates to pharmaceutical compositions comprising, consisting essentially of, or consisting of a solid dispersion of the invention, and at least one pharmaceutically acceptable excipient. [065] The solid dispersion may constitute about 1-98% (w/w), such as 10-90% (w/w), such as 15-80% (w/w), such as 20-70% (w/w), such as 25-60% (w/w) of the pharmaceutical composition. The at least one pharmaceutically acceptable excipient may constitute about 2-99% (w/w), such as 10-90% (w/w), such as 20-85% (w/w), such as 30-80% (w/w), such as 40-75% (w/w) of the pharmaceutical composition.

[066] The at least one pharmaceutically acceptable excipient may be, for example, a pH adjusting substance, a surfactant, a processing aid (e.g., plasticizers), a permeation enhancer, a pharmaceutical polymer, a disintegrant, a filler, a lubricant (e.g., the non-polymeric lubricants mentioned above), a preservative (e.g., parabens), a glidant, a binder, an antioxidant, a thickener, a sweetener, a flavorant, a coloring component, and mixtures thereof. Like the solid dispersion, the pharmaceutical compositions of the invention may also not contain an antioxidant. [067] Examples of the pH adjusting substance include acidifying agents, alkalizing agents, and buffering agents. The acidifying agents may be, for example, adipic acid, ammonium chloride, citric acid monohydrate, lactic acid, and tartaric acid. The alkalizing agents may be, for example, calcium hydroxide, magnesium carbonate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium borate, sodium citrate dihydrate, and sodium hydroxide. And the buffering agents may be, for example, adipic acid, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate tribasic, citric acid monohydrate, dibasic sodium phosphate, glycine, maleic acid, malic acid, methionine, monobasic sodium phosphate, monosodium glutamate, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, and sodium lactate.

[068] Examples of the surfactant include sodium dodecyl sulfate, dioctyl sodium sulphosuccinate, polyoxyethylene (20) sorbitan monooleate, glycerol polyethylene glycol oxystearate-fatty acid glycerol polyglycol esters-polyethylene glycols-glycerol ethoxylate, glycerol-polyethylene glycol ricinoleate-fatty acid esters of polyethyleneglycol-polyethylene glycols-ethoxylated glycerol, vitamin E TPGS, and sorbitan laurate.

[069] Examples of the permeation enhancer include bile salts, fatty acids and derivatives, glycerides, chelators, and salicylates.

[070] Examples of the pharmaceutical polymer include water-soluble, ionic, or non-ionic polymers. For example, suitable pharmaceutical polymers include without limitation a cellulose-based polymer, a polyvinyl-based polymer, or an acrylate-based polymer. These polymers may have varying degrees of polymerization or functional groups. These pharmaceutical polymers can also be used in the solid dispersion.

[071] Suitable cellulose-based polymers include an alkylcellulose, such as a methyl cellulose, a hydroxyalkylcellulose, or a hydroxyalkyl alkylcellulose. Suitable cellulose-based polymers more particularly include hydroxymethylcellulose, hydroxy ethyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, such as METHOCEL™ E3 and METHOCEL™ E5 (Dow Chemical, Michigan, US); ethylcellulose, such as ETHOCEL® (Dow Chemical), cellulose acetate butyrate, hydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, such as AFFINISOL® HPMCAS 126 G (Dow Chemical), cellulose acetate, cellulose acetate phthalate, such as AQUATERIC™ (FMC, Pennsylvania, US), carboxymethylcellulose, such as sodium carboxymethycellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, crystalline cellulose, and any combinations thereof.

[072] Suitable polyvinyl-based polymers include polyvinyl alcohol, such as polyvinyl alcohol 4-88, such as EMPROVE® (Millipore Sigma, Massachusetts, US) polyvinyl pyrrolidone, such as LUVITEK® (BASF, Germany) and KOLLIDON® 30 (BASF), polyvinylpyrrolidone-covinylacetate, poly(vinyl acetate)-co- poly(vinylpyrrolidone) copolymer, such as KOLLIDON ® SR (BASF), poly(vinyl acetate) phthalate, such as COATERIC® (Berwind Pharmaceutical Services, Pennsylvania, US) or PHTHALAVIN® (Berwind Pharmaceutical Services), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, such as SOLUPLUS® (BASF), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, such as SOLUPLUS® (BASF), hard polyvinylchloride, and any combinations thereof.

[073] Suitable acrylate-based polymers include acrylate and methacrylate copolymer, type A copolymer of ethylacrylate, methyl methacrylate and a methacrylic acid ester with quaternary ammonium groups in a ratio of l:2:0.1, such as EUDRAGIT® RS PO (Evonik, Germany), poly(meth)acrylate with a carboxylic acid functional group, such as EUDRAGIT® S100 (Evonik), dimethylaminoethyl methacrylate- methacrylic acid ester copolymer, ethylacrylatemethylmethacrylate copolymer, poly(methacrylate ethylacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1 :2) copolymer, poly(methacrylic acid-co-ethyl acrylate) (1:1), such as EUDRAGIT® L-30-D (Evonik), poly(methacylic acid-co-ethyl acrylate) (1:1), such as EUDRAGIT® LI00-55 (Evonik), poly(butyl methacylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate (1:2:1), such as EUDRAGIT® EPO (Evonik), methacrylic acid-ethacrylate copolymer, such as KOLLICOAT MAE 100-55 (BASF), polyacrylate, polymethacrylate, and any combinations thereof.

[074] Suitable non-ionic polymers include hydroxy propyl methyl cellulose, such as METHOCEL™ E15 (Dow Chemical, Michigan, US) or METHOCEL™ E50 (Dow Chemical), and polyvinylpyrrolidone, such as KOLLIDON® 90 (BASF, Germany). Suitable ionic polymers include hydroxy propyl methyl cellulose acetate succinate, such as AFFINISOL® HPMCAS 716 G (Dow Chemical), AFFINISOL® HPMCAS 912 G (Dow Chemical), and AFFINISOL® HPMCAS 126 G (Dow Chemical), polyvinyl acetate phthalate, such as PHTHALAVIN® (Berwind Pharmaceutical Services), methacrylic acid based copolymer, such as methacrylic acid-ethacrylate copolymer, such as EUDRAGIT® L100-55 (Evonik, Germany), and any combinations thereof.

[075] Examples of the disintegrant include sodium starch glycolate, crospovidone, magnesium aluminum silicate, microcrystalline cellulose, croscarmelose sodium, and cross-linked hydroxypropyl cellulose. [076] Examples of the filler include mannitol, dextrose, lactose, sucrose, calcium carbonate, sorbitol, xylitol, and glucose.

[077] The at least one pharmaceutically acceptable excipient may also be at least one cyclodextrin. Cyclodextrin (CD) can be used as an excipient in the external phase of the pharmaceutical composition. Here, "external phase" means that the pharmaceutically acceptable excipient, for example, the CD, is not processed into the amorphous solid dispersion (i.e., the CD forms a physical mixture with the amorphous solid dispersion in the pharmaceutical composition, rather than an inclusion complex with nintedanib in the pharmaceutical composition). Examples of CD that may be used include, but are not limited to, commercially available CDs, such as, for example, α-cyclodextrin (ACD), β-cyclodextrin (BCD), 2- hydroxypropyl-β-cyclodextrin (HPBCD), 2-hydroxylpropyl-γ-cyclodextrin (HPGCD), y-cyclodextrin (GCD), methyl-β-cyclodextrin (MBCD), sulfobutylether-β-cyclodextrin (SBECD), and mixtures thereof. The at least one cyclodextrin may be present in the external phase of the pharmaceutical composition in an amount ranging from about 0.5 wt.% to about 50 wt.% (e.g., 1 wt.% to 45 wt.%, 5 wt.% to 40 wt.%, 10 wt.% to 35 wt.%, 15 wt.% to 30 wt.%, 20 wt.% to 25 wt.%). The use of CD in the external phase can enhance various aspects of the pharmaceutical compositions, such as, for example, by increasing the solubility of the nintedanib. Furthermore, pharmaceutical compositions containing externally added cyclodextrin may exhibit a higher release concentration (i.e., C_max, C|_ast, and/or AUDC) and/or a higher absorption rate (i.e., higher AUC and/or FLUX value) than unprocessed nintedanib material at comparable intraoral concentrations and media. Therefore, the solubility, C_max, C_last, AUDC, AUC, and/or FLUX value of the nintedanib in a pharmaceutical composition containing the at least one CD may be greater than it would be in an equivalent pharmaceutical composition that does not contain the at least one CD.

[078] In some cases, one or more of the pharmaceutically acceptable excipients, other than the at least one cyclodextrin, may be present in the internal phase of the amorphous solid dispersion (i.e., not the external phase of the pharmaceutical composition).

[079] The pharmaceutical compositions of the invention will generally be presented in unit dosage form and, as such, will typically contain an amount of nintedanib sufficient to provide a desired level of biological activity. The nintedanib will be administered to a subject (patient) in need thereof (e.g., a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

[080] The total amount of nintedanib in the pharmaceutical compositions of the invention may range from about 0.0001-200 mg, about 0.0001-150 mg, about 0.001-100 mg, about 0.01-50 mg, about 0.1-25 mg, about 1-20 mg, about 2-10 mg, about 5-10 mg, or about 7-10 mg. For example, the pharmaceutical compositions of the invention may contain 1 mg, 2 mg, 5 mg, 7 mg, 8 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg of nintedanib. The actual amount required for treatment of any particular patient may depend upon a variety of factors including, for example, the disease being treated and its severity; the specific pharmaceutical composition employed; the age, body weight, general health, sex, and diet of the patient; the mode of administration; the time of administration; the route of administration; and the rate of excretion; the duration of the treatment; any drugs used in combination or coincidental with the specific compound employed; and other such factors well known in the medical arts. These factors are discussed in Goodman and Gilman's "The Pharmacological Basis of Therapeutics," Tenth Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173 (2001), which is incorporated herein by reference.

[081] The pharmaceutical compositions of the invention may contain nintedanib as the sole therapeutic agent, or they may contain at least one other therapeutic agent in addition to nintedanib. For example, the pharmaceutical compositions of the invention may further comprise at least one therapeutic agent that treats interstitial lung diseases or cancers. The therapeutic agents that treat interstitial lung diseases include, but are not limited to, pirfenidone, sildenafil, sarllumab, N-acetylcysteine, and pamrevlumab. The therapeutic agents that treat cancers include chemotherapeutic agents, such as, but not limited to, carboplatin, paclitaxel, docetaxel, sorafenib, cytarabine, nivolumab, ipilimumab, and capecitabine.

[082] The pharmaceutical compositions of the invention can be in any form suitable for oral administration, in particular, sublingual administration. For example, the pharmaceutical compositions may be an oral unit dosage form, such as a tablet, a sublingual tablet, a film, a buccal tablet, a buccal patch, a buccal pouch, a sublingual powder, a sublingual sachet, or a polymer strip. Preferably, the oral unit dosage form is a sublingual tablet. The oral unit dosage form may further include at least one bioadhesive, such as, for example, an alginate, a lectin, a carageenan, a pectin, a cellulosic material, or mixtures thereof, wherein the bioadhesive increases the contact time between the dosage form and the oral mucosa.

[083] The oral unit dosage form may disintegrate in oral fluid (e.g., saliva) and may be substantially absorbed in the oral mucosa. The oral dosage form may substantially disintegrate in the oral fluid within 10 minutes, such as within 5 minutes, such as within 2 minutes, such as within 1 minute from contacting the oral fluid.

[084] The pharmaceutical compositions of the invention can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA. [085] The invention also relates to the use of the pharmaceutical composition of the invention for the treatment of oncological diseases, immunologic diseases, or pathological conditions involving an immunologic component, or fibrotic diseases. For example, the pharmaceutical composition of the invention may be used to treat interstitial lung diseases (ILD), such as idiopathic pulmonary fibrosis (I PF), systemic sclerosis ILD, and rheumatoid arthritis ILD; muscular dystrophy; and cancers, such as breast, lung (including non-small-cell and small-cell), ovarian, fallopian tube, metastatic colon, bowel, liver, bladder, pancreas, thyroid, prostate, leukemia, mesothelioma, and brain cancer.

[086] The invention also relates to a method for the treatment of oncological diseases, immunologic diseases, or pathological conditions involving an immunologic component, or fibrotic diseases, comprising, consisting essentially of, or consisting of the administration of a therapeutically effective amount of the pharmaceutical composition of the invention to a subject in need thereof. For example, the invention relates to the treatment of interstitial lung diseases, such as idiopathic pulmonary fibrosis, systemic sclerosis ILD, and rheumatoid arthritis ILD; muscular dystrophy; and cancers, such as breast, lung (including non-small-cell and small-cell), ovarian, fallopian tube, metastatic colon, bowel, liver, bladder, pancreas, thyroid, prostate, leukemia, mesothelioma, and brain cancer, comprising, consisting essentially of, or consisting of the administration of a therapeutically effective amount of the pharmaceutical composition of the invention to a subject in need thereof.

[087] The invention also provides for a method of administering nintedanib to a subject in the oral mucosa thereof, comprising: a) providing a therapeutically effective amount of the pharmaceutical composition of the invention; and b) administrating the pharmaceutical composition to the subject via, for example, a buccal route, a sublingual route, or a gingival route, preferably a sublingual route.

[088] EXPERIMENTAL

[089] Materials and Characterization:

[090] The nintedanib was purchased from Shenzhen Nexconn Pharmatechs Ltd. Hypromellose acetate succinate (I. Grade) (HPMCAS-LMP) was manufactured by Shin-Etsu Chemical Co., Copovidone VA64 and Soluplus were manufactured by BASF, hypromellose (E3 Grade) (HPMC E3) was manufactured by Dow Chemical Co., and magnesium stearate were manufactured by Peter Greven GmbH & Co. KG. a- Cyclodextrin (ACD), P-cyclodextrin (BCD), 2-hydroxypropyl-P-cyclodextrin (HPBCD), and 2-hydroxylpropyl- y-cyclodextrin (HPGCD), were obtained from Ashland, y-cyclodextrin (GCD) and methyl-β-cyclodextrin (MBCD) were purchased from Davos and manufactured by Cyclolab. Sulfobutylether-β-cyclodextrin (SBECD) was purchased from/manufactured by Nexconn Pharmatechs Ltd. [091] X-Ray Diffraction (XRD): Apparatus: Rigaku MiniFlex 600. Standard XRD pan. XRD Conditions: Range: 2.5-40 deg; Speed: 5 deg/min; Step: 0.02 deg; Voltage: 40 kV; Current: 15 mA; Detector: D/teX high speed detector. Data: 2.5-5° excluded due to direct beam exposure; 30-40° excluded due to residual sodium chloride in hypromellose samples at ~31° and metal diffraction from the sample holder at ~37°; Figures formatted for patent are translated along the y-axis for clarity; Intensity count values not displayed as a result.

[092] μFLUX Dissolution Methodology: Pion's proprietary apparatus: Lipid infused membrane separating donor and receiver compartments; Fiber optic UV probe used to monitor sample concentrations. Donor: 16 mL of pH 6.8 phosphate buffer with NaCI added; 150 rpm stirring. Receiver: 16 mL of sink buffer (Pion proprietary media); 150 rpm stirring. FLUX Calculation = Slope x (V/A), where Slope = concentration vs. time plot in the acceptor compartment; V = media volume in acceptor compartment; and A = surface area of membrane separating donor and receiver compartments. The lipid is a Pion proprietary lipid (see, e.g., Tsinman et al., Pharm. Res. 35(8):161 (2018)).

[093] Donor analyzed by 0.5 mL sample withdrawal at 2 and 4 hours. Centrifuged at 13,000 rpm for 5 minutes. Supernatant diluted 1:9 with 50/50 acetonitrile/water. HPLC conditions: Column: C18, 2.6 um, 150x4.6mm column; 65/35 0.1 M acetate buffer; pH 5/acetonitrile; Flow rate: 1.0 mL/min; Run time: 12 min, Column Temperature: 40°C; Wavelength: 290 nm.

[094] Synthesis:

[095] Example 1: Initial Formulations of Nintedanib

[096] Table 1 shows the formulation information for the nintedanib formulations.

[097] Table 1. Formulation Information

[098] Samples blended by hand in a suitable container.

[099] All examples generated on KBC20 (KinetiSol formulator; research scale unit).

[0100] Procedure: Feed batch at listed size into chamber via powder feed port. If using nitrogen purge, feed medical grade nitrogen into the chamber for a period of at least 10 minutes. Initiate process at listed conditions. A stage is completed when it either reaches the input set time or temperature. If the stage is the last stage in the process, sample is ejected from the process. Process can be manually advanced to the next stage or ejected by the operator. Ejected sample is immediately quenched between metal plates by the operator to compress sample into a thin disk and rapidly cool.

[0101] Processing Information:

[0102] Table 2 shows the thermokinetic compounding parameters for nintedanib.

[0103] Table 2. Thermokinetic Compounding Parameters

[0104] Post-Processing After Thermokinetic Compounding: Process in IKA Tube Mill 100 at 25,000 rpm for 30 seconds to reduce particle size. Pass material through #60 Mesh (250 pm).

[0105] Each of these formulations were rendered amorphous by thermokinetic compounding. See FIG. 1.

[0106] Example 2: μFLUX Dissolutions

[0107] FIG. 2 shows the HPLC analysis from the μFLUX dissolution donor compartment of certain formulations from Table 2.

[0108] FIG. 3 shows the μFLUX dissolution acceptor compartment of certain formulations from Table 2. [0109] Table 3 provide the calculated summary values (Average Donor Concentration, Amount Fluxxed at 4 hours, and FLUX) for the tested processed and unprocessed samples containing varying concentration of different pharmaceutical carriers.

[0110] Table 3. Calculated Summary Values - 1.0 mg/mL Nintedanib Concentration

[0111] FLUX was calculated from 60-120 minutes.

[0112] Example 3: μFLUX Dissolution Donor Compartment (HPLC Analysis)

[0113] FIG. 4 shows the HPLC analysis from the μFLUX dissolution donor compartment of certain formulations from Table 2.

[0114] FIG. 5 shows the μFLUX dissolution acceptor compartment of certain formulations from Table 2. [0115] Table 4 provide the calculated summary values (Average Donor Concentration, Amount Fluxxed at 4 hours, and FLUX) for the tested processed and unprocessed samples containing varying concentration of different pharmaceutical carriers.

[0116] Table 4. Calculated Summary Values - 1.0 mg/mL Nintedanib Concentration

[0117] FLUX was calculated from 60-120 minutes.

[0118] Example 4: In-Vivo Study in Dogs

[0119] Animal model: Male beagle dogs; Fasted for 12 hours prior to study; n=4 per arm; anesthesia induced in dogs before dosing with Zoletil with maintenance by respiratory anesthesia with isoflurane. [0120] Dose: 10 mg (For powder samples, ~200 mg of powder dosed); Powder blend.

[0121] Arms: Two sublingual and one intravenous; powder equivalent to 10 mg of nintedanib dosed to sublingual cavity; sublingual cavity wiped out 15 minutes after administration; intravenous arm dosed at 0.5 mg/kg

[0122] Sampling Time Points: Pre-dose, 0.083, 0.25, 0.33, 0.5, 1, 2, 4, 6, 8 hours post-dose; 1 mL blood sampled per time point; anticoagulant: sodium heparin; spun down to obtain plasma for bioanalysis.

[0123] Table 5 shows the formulation information for the additional samples for the in-vivo study in dogs.

[0124] Table 5. Additional Samples Formulation Information

[0125] Table 6 shows the data (AUCi_ast, C_max, T_max, and F) for the dog pharmacokinetic study, and FIG. 6 shows the data (plasma concentration over 8 hours) for the dog pharmacokinetic study.

[0126] Table 6. Dog Pharmacokinetic Study Data

[0127] Example 5: Nintedanib Initial Formulations Summary

[0128] The performance enhancing properties of cyclodextrin (CD) as an excipient in the external phase (outside the amorphous solid dispersion) were evaluated.

[0129] The physical mixtures are found in Table 7. The samples were blended by hand in a suitable container.

[0130] Table 7. Physical Mixtures

[0131] The thermokinetic compounding parameters are found in Table 8. After thermokinetic compounding, the mixtures were post-processed in a IKA Tube Mill 100 at 25,000 rpm for 30 seconds to reduce particle size and were then passed through #60 mesh (250 pm).

[0132] Table 8. Thermokinetic Compounding Parameters

[0133] XRD was performed on the mixtures according to the methodology and conditions described above. The XRD analysis of KinetiSol® dispersed (KSD) processed materials was overlayed with nintedanib API (free base). The XRD spectrum was comparable to that in FIG. 1.

[0134] Example 6: μFLUX Dissolutions Summary

[0135] The maximum concentration and absorption rate between thermokinetic compounded and unprocessed nintedanib materials with external cyclodextrin across a range of grades and cyclodextrin concentrations were compared.

[0136] μFLUX dissolution was performed in the apparatus described above. Here, the donor compartment contained 16 mL of pH 6.8 phosphate buffer with NaCI added. There was 500 rpm stirring and 1 mg/mL API content. Cyclodextrin was added as a powder at a specified concentration prior to the media addition. The receiver compartment contained 16 mL of acceptor sink buffer (Pion proprietary media) with 150 rpm stirring. The run time was 4 hours. A FLUX calculation was made using the formula described above.

[0137] High-performance liquid chromatography (HPLC) was performed on the donor compartment. The donor was analyzed by a 0.5 mL sample withdrawal at 2 and 4 hours. It was centrifuged at 13,000 rpm for 5 minutes. The supernatant was diluted 1:9 with 50/50 acetonitrile/water. The HPLC conditioners were as follows: 65/35 0.1 M acetate buffer, pH 5/acetonitrile; flow rate: 1.0 mL/min; run time: 12 minutes; and other parameters as previously described.

[0138] The HPLC analysis of the μFLUX dissolution donor compartment externally adding 5 mg/mL of cyclodextrin to HPMCAS-LMP samples, HPMC E3 samples, and esylate salt + CD (as a control) samples are shown in FIGs. 7, 8, and 9, respectively. All samples were run at 5 mg/mL of cyclodextrin. Regarding the HPMCAS-LMP and HPMC E3 samples, most cyclodextrin materials boosted the donor compartment solubility of nintedanib substantially over just the KSD material alone. Regarding the esylate salt + CD (as a control) samples, while most cyclodextrin materials boosted the donor compartment solubility of nintedanib substantially over just the KSD material alone, the gains are less than the KSD +CD material. This suggests that there is synergy in performance between the KSD and the external CD.

[0139] The μFLUX dissolution acceptor compartment externally adding 5 mg/mL of cyclodextrin to HPMCAS-LMP samples, HPMC E3 samples, and esylate salt + CD (as a control) samples are shown in FIGs. 10, 11, and 12, respectively. All samples were run at 5 mg/mL of cyclodextrin. Regarding the HPMCAS- LMP and HPMC E3 samples, most cyclodextrin materials boosted the FLUX of nintedanib substantially over just the KSD material alone as seen in Tables 9 and 10, respectively. Regarding the esylate salt + CD (as a control) samples, while most cyclodextrin materials boosted the FLUX of nintedanib substantially over just the esylate salt alone, the gains are less than the KSD + CD material as seen in Table 11. This is suggestive that there is synergy in performance between the KSD and the external CD.

[0140] Table 9. FLUX Values for HPMCAS-LMP Samples

[0141] Table 10. FLUX Values for HPMC E3 Samples

[0142] Table 11. FLUX Values for Esylate Salt + CD Samples

[0143] The HPLC analysis of the μFLUX dissolution donor compartment externally adding cyclodextrin complexes to HPMCAS-LMP samples and HPMC E3 samples is shown in FIGs. 13 and 14, respectively. The cyclodextrins were selected based on previous performance. The samples were run at 2.5, 5, and 10 mg/mL of cyclodextrin. For both the HPMCAS-LMP and HPMC E3 samples, the solubility increased with increasing cyclodextrin concentration.

Claims

What is claimed is:

1. A solid dispersion comprising nintedanib, dispersed in a pharmaceutically acceptable polymer matrix, wherein the solid dispersion is substantially amorphous.

2. The solid dispersion of claim 1, wherein the total amount of nintedanib constitutes about 5-60% (w/w) of the solid dispersion.

3. The solid dispersion of claim 1 or claim 2, wherein the pharmaceutically acceptable polymer matrix comprises at least one pharmaceutical carrier.

4. The solid dispersion of claim 3, wherein the pharmaceutical carrier is at least one polymer.

5. The solid dispersion of claim 4, wherein the at least one polymer is selected from the group consisting of hypromellose, hypromellose acetate succinate, vinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and mixtures thereof.

6. The solid dispersion of claim 4 or claim 5, wherein the polymer is hypromellose selected from the group consisting of Hypromellose E3, Hypromellose E5, Hypromellose E50, Hypromellose E15, Hypromellose K3, and mixtures thereof.

7. The solid dispersion of claim 5, wherein the polymer is hypromellose acetate succinate polymer is substituted by 2-16% acetyl groups, 4-28% succinyl groups, or mixtures thereof.

8. The solid dispersion of claim 5, wherein the polymer is vinylpyrrolidone-vinyl acetate copolymer polymer is Kollidon® VA 64.

9. The solid dispersion of claim 5, wherein the polymer is a polyvinylpyrrolidone polymer selected from the group consisting of Kollidon® 12, Kollidon® 17, Kollidon® 25, Kollidon® 30, Kollidon® 90, and mixtures thereof.

10. The solid dispersion of any of claims 3-9, wherein the at least one pharmaceutical carrier constitutes about 40-95% (w/w) of the solid dispersion.

11. The solid dispersion of any of claims 1-10, further comprising at least one lubricant.

12. The solid dispersion of claim 11, wherein the lubricant is a non-polymeric lubricant selected from the group consisting of an alcohol, a stearate, a carboxylic acid, a glyceryl, sodium stearyl fumarate, ascorbyl palmitate, and mixtures thereof.

13. The solid dispersion of claim 11 or claim 12, wherein the at least one lubricant is present in an amount of about 20% or less (w/w) of the solid dispersion.

14. The solid dispersion of any of claims 1-13, wherein the solid dispersion provides a pharmacokinetic profile in vivo which is about the same or improved in comparison to the pharmacokinetic profile in vivo obtained by OFEV®.

15. The solid dispersion of any of claims 1-14, wherein the solid dispersion is > 90% amorphous.

16. The solid dispersion of any of claims 1-15, wherein the solid dispersion is characterized by an x- ray diffraction pattern having a substantially amorphous pattern.

17. A pharmaceutical composition comprising the solid dispersion of any of claims 1-16, and at least one pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17, wherein the solid dispersion constitutes about 1- 98% (w/w) of the pharmaceutical composition.

19. The pharmaceutical composition of claim 17 or claim 18, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of a pH adjusting substance, a surfactant, a processing aid, a permeation enhancer, a pharmaceutical polymer, a disintegrant, a filler, a lubricant, a preservative, a glidant, a binder, an antioxidant, a thickener, a sweetener, a flavorant, a coloring component, and mixtures thereof.

20. The pharmaceutical composition of any of claims 17-19, wherein the at least one pharmaceutically acceptable excipient is present in the internal phase of the solid dispersion.

21. The pharmaceutical composition of any of claims 17-19, wherein the at least one pharmaceutically acceptable excipient is at least one cyclodextrin present in the external phase of the pharmaceutical composition.

22. The pharmaceutical composition of claim 21, where the at least one cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxylpropyl- y-cyclodextrin, y-cyclodextrin, methyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and mixtures thereof.

23. The pharmaceutical composition of claim 21 or claim 22, wherein the solubility of the nintedanib is greater than it would be in an equivalent pharmaceutical composition that does not contain the at least one cyclodextrin.

24. The pharmaceutical composition of any of claims 21-23, wherein the C_max, Ci_ast, and/or AUDC of the nintedanib is greater than it would be in an equivalent pharmaceutical composition that does not contain the at least one cyclodextrin.

25. The pharmaceutical composition of any of claims 21-24, wherein the AUC and/or FLUX value of the nintedanib is greater than it would be in an equivalent pharmaceutical composition that does not contain the at least one cyclodextrin.

26. The pharmaceutical composition of any of claims 21-25, wherein the at least one cyclodextrin is present in the pharmaceutical composition in an amount ranging from about 0.5 wt.% to about 50 wt.%.

27. The pharmaceutical composition of any of claims 17-26, wherein the total amount of nintedanib is in the range of about 0.0001-25 mg.

28. The pharmaceutical composition of any of claims 17-27, wherein the nintedanib is the sole therapeutic agent comprised in the composition.

29. The pharmaceutical composition of any of claims 17-27, further comprising at least one additional therapeutic agent.

30. The pharmaceutical composition of claim 29, wherein the at least one additional therapeutic agent is selected from the group consisting of pirfenidone, sildenafil, sarilumab, N-acetylcysteine, pamrevlumab, carboplatin, paclitaxel, docetaxel, sorafenib, cytarabine, nivolumab, ipilimumab, capecitabine, and mixtures thereof.

31. The pharmaceutical composition of any of claims 17-30, wherein the pharmaceutical composition is an oral unit dosage form.

32. The pharmaceutical composition of claim 31, wherein the oral unit dosage form is a tablet, a sublingual tablet, a film, a buccal tablet, a buccal patch, a buccal pouch, a sublingual powder, a sublingual sachet, or a polymer strip.

33. The pharmaceutical composition of claim 32, wherein the oral unit dosage form is a sublingual tablet.

34. The pharmaceutical composition of any of claims 31-33, wherein the oral unit dosage form further includes at least one bioadhesive, wherein the bioadhesive increases the contact time between the dosage form and the oral mucosa.

35. The pharmaceutical composition of claim 34, wherein the at least one bioadhesive is selected from the group consisting of an alginate, a lectin, a carageenan, a pectin, a cellulosic material, and mixtures thereof.

36. The pharmaceutical composition of any of claims 17-35, wherein the oral unit dosage form disintegrates in oral fluid and is substantially absorbed in the oral mucosa.

37. The pharmaceutical composition of any of claims 17-36, wherein the oral unit dosage form substantially disintegrates in the oral fluid within 10 minutes from contacting the oral fluid.

38. The pharmaceutical composition of any of claims 17-37 for use in the treatment of interstitial lung disease (ILD).

39. The pharmaceutical composition of claim 38, wherein the ILD is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), systemic sclerosis ILD, and rheumatoid arthritis ILD.

40. The pharmaceutical composition of any of claims 17-37 for use in the treatment of muscular dystrophy.

41. The pharmaceutical composition of any of claims 17-37 for use in the treatment of cancer.

42. The pharmaceutical composition of claim 41, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, fallopian tube cancer, metastatic colon cancer, bowel cancer, liver cancer, bladder cancer, pancreas cancer, thyroid cancer, prostate cancer, leukemia, mesothelioma, and brain cancer.

43. A method for the treatment of interstitial lung disease (ILD), comprising the administration of a therapeutically effective amount of the pharmaceutical composition of any of claims 17-37 to a subject in need thereof.

44. The method of claim 43, wherein the ILD is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), systemic sclerosis ILD, and rheumatoid arthritis ILD.

45. A method for the treatment of muscular dystrophy, comprising the administration of a therapeutically effective amount of the pharmaceutical composition of any of claims 17-37 to a subject in need thereof.

46. A method for the treatment of cancer, comprising the administration of a therapeutically effective amount of the pharmaceutical composition of any of claims 17-37 to a subject in need thereof.

47. The method of claim 46, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, fallopian tube cancer, metastatic colon cancer, bowel cancer, liver cancer, bladder cancer, pancreas cancer, thyroid cancer, prostate cancer, leukemia, mesothelioma, and brain cancer.

48. A method of administering nintedanib to a subject in the oral mucosa thereof, comprising: a) providing a therapeutically effective amount of the pharmaceutical composition of any of claims 17-36; and b) administrating the pharmaceutical composition to the subject.

49. The method of claim 48, wherein the pharmaceutical composition is administered to the subject via a buccal route, a sublingual route, or a gingival route.