Danikopan formulation and method of use

Abstract

The present disclosure features solid dispersion and liquid gelatin capsule formulations of danikopan that can improve the oral bioavailability and / or storage stability of danikopan. The present disclosure also features methods for treating complement factor D-mediated disorders, including paroxysmal nocturnal hemoglobinuria (PNH), e.g., PNH with clinically evident extravascular hemolysis (EVH), and geographic atrophy (GA) secondary to age-related macular degeneration (AMD), using the formulations.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 451,894, filed March 13, 2023, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present disclosure features formulations for improving the oral bioavailability and / or storage stability of Danikopan, as well as methods for using the formulations to treat complement factor D-mediated disorders, including paroxysmal nocturnal hemoglobinuria (PNH), e.g., PNH with clinically evident extravascular hemolysis (EVH), and geographic atrophy (GA) secondary to age-related macular degeneration (AMD). [Background technology]

[0003] The complement system is a part of the innate immune system that does not adapt to changes throughout the host's life but is recruited and used by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytes to eliminate pathogens. This elaborate regulatory pathway allows for a rapid response to pathogenic organisms while protecting host cells from destruction. More than 30 proteins and protein fragments comprise the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cytolysis (disrupting the membranes of foreign cells), and agglutination (clustering and binding pathogens together).

[0004] The complement system has three pathways: the classical pathway, the alternative pathway, and the lectin pathway. Complement factor D plays an early, central role in activation of the alternative pathway of the complement cascade. Activation of the alternative pathway is initiated by spontaneous hydrolysis of a thioester bond within the C3 protein to produce C3(H2O), which associates with factor B to form the C3(H2O)B complex. Complement factor D acts to cleave factor B within the C3(H2O)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H2O) to form the alternative pathway C3 convertase, C3(H2O)Bb. Additionally, C3b generated by any of the C3 convertases also associates with factor B to form C3bB, which is cleaved by complement factor D to generate the later alternative pathway C3 convertase, C3bBb. This latter form of the alternative pathway C3 convertase provides important downstream amplification within all three of the defined complement pathways and may ultimately lead to the recruitment and assembly of additional factors in the complement cascade pathway, including cleavage of C5 into C5a and C5b, which acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing them.

[0005] Dysfunction or excessive activation of complement is associated with certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a, both of which are potent anaphylatoxins and play a role in many inflammatory disorders. Therefore, in some cases, it is desirable to reduce the response of complement pathways, including the alternative complement pathway.

[0006] Factor D is an attractive target for inhibition or modulation of the complement cascade due to its early, essential role in the alternative complement pathway and its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of factor D effectively blocks the pathway and attenuates membrane attack complex formation.

[0007] In view of the wide variety of medical disorders caused by adverse immune or inflammatory responses, it would be beneficial to provide additional advantageous compounds and formulations thereof for advantageous delivery that can increase therapeutic activity and / or stability. Summary of the Invention

[0008] The present disclosure features formulations and methods for administering danikopan. Formulations of danikopan can improve the oral bioavailability and / or storage stability of danikopan, a proximal complement alternative pathway factor D inhibitor.

[0009] [ka]

[0010] The present disclosure also features the use of these formulations to inhibit AP C3 convertase formation and to treat various conditions associated with complement factor D-mediated disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), e.g., PNH with clinically evident extravascular hemolysis (EVH), and geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

[0011] In a first aspect, the disclosure features a solid dispersion including (i) substantially amorphous danicopane and (ii) a pharmaceutically acceptable polymer, wherein the (w / w) ratio of substantially amorphous danicopane to pharmaceutically acceptable polymer in the solid dispersion is 10:1 to 1:4 (e.g., 10:1 to 1:1, 10:1 to 5:1, 5:1 to 1:2, 2:1 to 1:4, or 1:1 to 1:4).

[0012] In certain embodiments, the loading percentage of Danikopan in the solid dispersion is 25% to 90% (w / w) (e.g., 25% to 30%, 25% to 40%, 25% to 50%, 25% to 60%, 25% to 70%, 25% to 80%, 25% to 90%, 30% to 40%, 30% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30%-90%, 40%-50%, 40%-60%, 40%-70%, 40%-80%, 40%-90%, 50%-60%, 50%-70%, 50%-80%, 50%-90%, 60%-70%, 60%-80%, 60%-90%, 70%-80%, 70%-90%, 80%-90%, and 80%-90%. For example, in one embodiment, the loading percentage of Danicopan in the solid dispersion is 80%-90%.

[0013] In certain embodiments, the (w / w) ratio of substantially amorphous danicopan to pharmaceutically acceptable polymer in the solid dispersion is 3: 1 to 4: 1. For example, in one embodiment, the (w / w) ratio of substantially amorphous danicopan to pharmaceutically acceptable polymer is 4:1.

[0014] In certain embodiments, the solid dispersion contains at least 90% (e.g., at least 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, such as 90% to 99.9%, 90% to 99.5%, 90% to 99%, 90% to 98%, 90% to 97%, 90% to 96%, 90% to 95%, 95% to 99.9%, 95% to 99.5%, 95% to 99%, 95% to 98%, 95% to 97%, and 95% to 96%) of danicopan in amorphous form as determined by X-ray powder diffraction.

[0015] In certain embodiments, the pharmaceutically acceptable polymer in the solid dispersion includes a polymer selected from cellulose derivatives, polyacrylates, polyvinylpyrrolidone, polyvinyl acetate, copolymers of polyvinylpyrrolidone and polyvinyl acetate, and combinations thereof.

[0016] In further embodiments, the pharmaceutically acceptable polymer in the solid dispersion is present in an amount of 10% to 50% (e.g., 10% to 15%, 10% to 20%, 10% to 25%, 10% to 30%, 10% to 35%, 10% to 40%, 10% to 45%, 20% to 25%, 20% to 30%, 20% to 35%, 20% to 40%, 20% to 45%, 20% to 50%). , 25% to 30%, 25% to 35%, 25% to 40%, 25% to 45%, 25% to 50%, 30% to 35%, 30% to 40%, 30% to 45%, 30% to 50%, 35% to 40%, 35% to 45%, 35% to 50%, 40% to 45%, or 40% to 50% acetyl.

[0017] In further embodiments, the pharmaceutically acceptable polymer in the solid dispersion is an alkylcellulose (e.g., methylcellulose or ethylcellulose), a hydroxyalkylcellulose (e.g., hydroxymethylcellulose; hydroxyethylcellulose; hydroxypropylcellulose, such as that having 11% hydroxypropyl or 8% hydroxypropyl; or hydroxybutylcellulose), a hydroxyalkyl alkylcellulose (e.g., hydroxyethylmethylcellulose; or hydroxypropylmethylcellulose (HPMC) having 19-24% methoxyl / 7-12% hydroxypropoxyl, 28-30% methoxyl / 7-12% hydroxypropoxyl, 23% methoxyl / 10% hydroxypropoxyl, 23%-29% methoxyl / 8%-9% hydroxypropoxyl, 29% methoxyl / 9% hydroxypropoxyl, or 23% methoxyl / 6% hydroxypropoxyl), a hydroxyalkyl alkylcellulose ester (e.g., hydroxypropylmethylcellulose phthalate). phthalate, HPMCP), carboxyalkyl cellulose (e.g., carboxymethyl cellulose or an alkali metal salt thereof, such as sodium salt), carboxyalkyl alkyl cellulose (e.g., carboxymethyl ethyl cellulose), and carboxyalkyl cellulose esters (e.g., carboxymethyl cellulose butyrate, carboxymethyl cellulose propionate, carboxymethyl cellulose acetate butyrate, or carboxymethyl cellulose acetate propionate). In a further embodiment, the cellulose derivative in the solid dispersion is crosslinked or copolymerized (e.g., with any of the polymers described herein). In a further embodiment, the pharmaceutically acceptable polymer is a hydroxyalkyl alkyl cellulose, e.g., HPMC E3.

[0018] In further embodiments, the cellulose acetate in the solid dispersion is cellulose acetate phthalate (CAP) (e.g., 35% phthalyl / 24% acetyl), methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate, and hydroxypropyl methyl cellulose acetate succinate (HPMCAS) (e.g., 9% acetyl / 11% succinoyl, 12% acetyl / 6% succinoyl, and 8% acetyl / 15% succinoyl). In further embodiments, the HPMCAS polymer in the solid dispersion is selected from Grade L (HPMCAS-L), Grade H (HPMCAS-H), or Grade M (HPMCAS-M). The HPMCAS-L polymer can have a 5-9% acetyl, 14-18% succinoyl, 20-24% methoxyl, and 5-9% hydroxypropoxy content. The HPMCAS-M polymer may have a 7-11% acetyl, 10-14% succinoyl, 21-25% methoxyl, and 5-9% hydroxypropoxy content. The HPMCAS-H polymer may have a 10-14% acetyl, 4-8% succinoyl, 22-26% methoxyl, and 6-10% hydroxypropoxy content. In some embodiments, the average particle size of the solid dispersion particles in the solid dispersion is 1-80 μm. In some embodiments, the average particle size of the solid dispersion particles in the solid dispersion is 5-75 μm.

[0019] In some embodiments, the pharmaceutically acceptable polymer in the solid dispersion is a polyacrylate selected from polymethacrylate, methacrylate copolymers (e.g., methacrylic acid-methyl methacrylate copolymers having a 1:1 ratio of free carboxyl groups to ester groups, and a 1:2 ratio of free carboxyl groups to ester groups, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymers, and diethylaminoethyl methacrylic acid-methyl methacrylate copolymers), and ethacrylate copolymers (e.g., methacrylic acid ethacrylate copolymers having a 50:50 ratio of methacrylic acid to ethacrylate). In further embodiments, the pharmaceutically acceptable polymer is a methacrylate copolymer, e.g., Eudragit L-100.

[0020] In some embodiments, the pharmaceutically acceptable polymer in the solid dispersion is a polyvinyl acetate selected from polyvinylpyrrolidone (e.g., povidone), polyvinyl acetate esters (e.g., polyvinyl acetate phthalate (PVAP)), and polyethylene glycol polyvinyl acetate copolymers (e.g., polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymers) having a molecular weight of greater than 2,000 Da (e.g., 2,500, 9,000, 50,000, or 1,250,000 Da). In some embodiments, the pharmaceutically acceptable polymer is a polyvinyl acetate ester, e.g., polyvinyl acetate phthalate (PVAP).

[0021] In other embodiments, the pharmaceutically acceptable polymer in the solid dispersion is a copolymer of polyvinylpyrrolidone and polyvinyl acetate, wherein the copolymer has a ratio of N-vinyl-2-pyrrolidone to vinyl acetate of 10:90 to 70:30 (e.g., 20:80, 30:70, 40:60, 50:50, and 60:40).

[0022] In another aspect, the disclosure features a pharmaceutical composition in a capsule or tablet for oral administration, comprising any one of the solid dispersions disclosed herein. The pharmaceutical composition can be in a dosage form ranging from 20 mg to 900 mg (e.g., 20 mg to 30 mg, 20 mg to 40 mg, 20 mg to 50 mg, 20 mg to 75 mg, 20 mg to 100 mg, 20 mg to 125 mg, 20 mg to 150 mg, 20 mg to 175 mg, 20 mg to 200 mg, 20 mg to 225 mg, 30 mg to 40 mg, 30 mg to 50 mg, 30 mg to 75 mg, 30 mg to 100 mg, 30 mg to 125 mg, 30 mg to 150 mg, 30 mg to 175 mg, 30 mg to 200 mg, 30 mg to 225 mg, 30 mg to 250 mg). mg, 40mg~50mg, 40mg~75mg, 40mg~100mg, 40mg~125mg, 40mg~150mg, 40mg~175mg, 40mg~200mg, 40mg~225mg, 40mg~250mg, 50mg~75mg, 50mg~1 00mg, 50mg~125mg, 50mg~150mg, 50mg~175mg, 50mg~200mg, 50mg~225mg, 50mg~250mg, 60mg~75mg, 60mg~100mg, 60mg~125mg, 60mg~150mg, 60 mg~175mg, 60mg~200mg, 60mg~225mg, 60mg~250mg, 70mg~75mg, 70mg~100mg, 70mg~125mg, 70mg~150mg, 70mg~175mg, 70mg~200mg, 70mg~225m g, 70mg~250mg, 80mg~100mg, 80mg~125mg, 80mg~150mg, 80mg~175mg, 80mg~200mg, 80mg~225mg, 80mg~250mg, 90mg~100mg, 90mg~125mg, 90mg ~150mg, 90mg~175mg, 90mg~200mg, 90mg~225mg, 90mg~250mg, 100mg~125mg, 100mg~150mg, 100mg~175mg, 100mg~200mg, 100mg~225mg, 100mg~250mg, 200mg~225mg, 200mg~250mg, 200mg~275mg, 200mg~300mg, 200mg~325mg, and 200mg~350mg, 300mg~325mg, 300mg~350mg, 300mg~375mg,300mg~400mg, 300mg~425mg, 300mg~450mg, 400mg~425mg, 400mg~450mg, 400mg~475mg, 400mg~500mg, 400mg~525mg, 40 0mg~550mg, 500mg~525mg, 500mg~550mg, 500mg~575mg, 500mg~600mg, 500mg~625mg, 500mg~650mg, 600mg~625mg, 600mg The pharmaceutical composition may contain substantially amorphous danikopan (e.g., 600 mg to 675 mg, 600 mg to 700 mg, 600 mg to 725 mg, 600 mg to 750 mg, 700 mg to 725 mg, 700 mg to 750 mg, 700 mg to 775 mg, 700 mg to 800 mg, 700 mg to 825 mg, 700 mg to 850 mg, 800 mg to 825 mg, 800 mg to 850 mg, 800 mg to 875 mg, and 800 mg to 900 mg). In some embodiments, the pharmaceutical composition contains 100 mg of substantially amorphous danikopan. In some embodiments, the pharmaceutical composition contains 50 mg of substantially amorphous danikopan.

[0023] In some embodiments, the pharmaceutical composition further comprises a plasticizer. Exemplary plasticizers include polyalkylene oxides (e.g., polyethylene glycols such as PEG300, PEG400, PEG4000, and PEG8000, and polypropylene glycols), copolymers of ethylene oxide and propylene oxide (e.g., copolymers of the formula H(OCH2CH2) a (OCHCH3CH2) b (OCH2CH2) aOH, where a is 10-150 and b is 10-100 (e.g., a is 12, b is 20, a is 38, b is 29, a is 80, b is 27, a is 64, b is 37, a is 141, b is 44, a is 49, b is 57, a is 101, b is 56)), and polyethoxylated glyceryl esters (e.g., polyoxyl 35 castor oil and polyoxyl 40 castor oil having 40-45 moles of ethylene oxide).

[0024] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable binder, such as starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes.

[0025] In some embodiments, the pharmaceutical composition further comprises a filler (e.g., sucrose; sorbitol; mannitol; microcrystalline cellulose; starch, e.g., potato starch; kaolin, calcium carbonate; sodium chloride; lactose (e.g., Granulose 200 or Granulac 200); calcium phosphate; calcium sulfate; and sodium phosphate).

[0026] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Exemplary pharmaceutically acceptable carriers include, but are not limited to, sugar, starch, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils.

[0027] In some embodiments, the pharmaceutical composition further comprises pharmaceutically acceptable excipients (e.g., granulated alpha-lactose monohydrate (e.g., lactose monohydrate such as Tablettose 80); fumed silica such as Aerosil; magnesium stearate; croscarmellose sodium; colloidal silicon dioxide; and microcrystalline cellulose such as Avicel PH101 and Avicel PH102); colorants; flavorings; plasticizers; humectants; buffering agents; antioxidants; coating or film-forming agents; compression aids; emollients; emulsifiers; fragrances; preservatives; printing inks; adsorbents; suspending or dispersing agents; sweeteners; and water of hydration. In some embodiments, the pharmaceutical composition further comprises croscarmellose sodium. In some embodiments, the pharmaceutical composition further comprises magnesium stearate. In some embodiments, the pharmaceutical composition further comprises fumed silica, e.g., Aerosil. In some embodiments, the pharmaceutical composition further comprises granulated alpha-lactose monohydrate, e.g., Tablettose 80. In some embodiments, the pharmaceutical composition further comprises microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is Avicel PH101. In some embodiments, the microcrystalline cellulose is Avicel PH102. In some embodiments, the pharmaceutical composition further comprises croscarmellose sodium, magnesium stearate, fumed silica, lactose monohydrate, microcrystalline cellulose, microcrystalline cellulose, lactose, sodium lauryl sulfate, and colloidal silicon dioxide.

[0028] In some embodiments, the pharmaceutical composition further comprises a surfactant. Exemplary surfactants include those selected from polyethoxylated esters of one or more fatty acids (e.g., sodium lauryl sulfate, sodium laureth sulfate), polyethoxylated alkyl ethers, polyethoxylated glyceryl esters, polyoxyethylene glyceryl esters of one or more fatty acids, sorbitan esters, polyethoxylated sorbitan esters, polyethoxylated vitamin analogs (e.g., TPGS, e.g., D-alpha-tocopheryl PEG 1000 succinate), and ethoxylated propoxylated block copolymers. In some embodiments, the pharmaceutical composition further comprises sodium lauryl sulfate.

[0029] In other embodiments, the solid dispersion in the pharmaceutical composition is formed by spray drying a liquid mixture comprising danikopan, a pharmaceutically acceptable polymer (e.g., any one of the pharmaceutically acceptable polymers disclosed herein), a pharmaceutically acceptable solvent (e.g., acetone, dichloromethane, methanol, and / or water), and a pharmaceutically acceptable surfactant (e.g., sodium lauryl sulfate). In some embodiments, the polymer is HPMCAS-H, HPMCAS-L, HPMCAS-M, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate, HPMC E3, or Eudragit L-100.

[0030] In other embodiments, the pharmaceutical compositions are formulated as capsules (e.g., hard hydroxypropyl methylcellulose capsules and hard gelatin capsules), which contain a powder comprising the solid dispersion. In some embodiments, the pharmaceutical compositions are formulated as tablets.

[0031] In further embodiments, the disclosure features a pharmaceutical composition, wherein when tested according to the dissolution method defined herein using 0.1 N hydrochloric acid in water at 37°C with stirring at 50 rpm, at least 50% (w / w) of the pharmaceutical composition (e.g., 50-60%, 55-65%, 60-70%, or 65-90% (w / w)) dissolves within the first 8-90 minutes of the test.

[0032] In a further embodiment, the disclosure features a pharmaceutical composition, when tested according to the supersaturation profiling method defined herein using simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at 37°C, the pharmaceutical composition releases 0.027 or 0.8 mg / mL in SGF or SIF, respectively, within the first 4 hours of the test.

[0033] In another aspect, the disclosure features a pharmaceutical composition including danicopan dissolved in a glyceride fatty acid ester, a pharmaceutically acceptable organic solvent, and a D-α-tocopherol polyethylene glycol succinate (TPGS) compound contained in a liquid soft gelatin capsule for oral administration.

[0034] In a further embodiment, the pharmaceutical composition comprises a glyceride fatty acid ester, danicopan, a pharmaceutically acceptable organic solvent, and TPGS in a 16:2:1:1 ratio (w / w) within a liquid soft gelatin capsule.

[0035] In another aspect, the disclosure features a pharmaceutical composition including danicopan dissolved in Capmul MCM, propylene glycol, and D-α-tocopheryl PEG 1000 succinate, contained in a liquid soft gelatin capsule. The pharmaceutical composition may contain 50 mg to 400 mg (e.g., 50 mg to 75 mg, 50 mg to 100 mg, 50 mg to 125 mg, 50 mg to 150 mg, 50 mg to 175 mg, 50 mg to 200 mg, 50 mg to 225 mg, 50 mg to 250 mg, 60 mg to 75 mg, 60 mg to 100 mg, 60 mg to 125 mg, 60 mg to 150 mg, 60 mg to 175 mg). g, 60mg~200mg, 60mg~225mg, 60mg~250mg, 70mg~75mg, 70mg~100mg, 70mg~125mg, 70mg~150mg, 70 mg~175mg, 70mg~200mg, 70mg~225mg, 70mg~250mg, 80mg~100mg, 80mg~125mg, 80mg~150mg, 80mg~1 75mg, 80mg~200mg, 80mg~225mg, 80mg~250mg, 90mg~100mg, 90mg~125mg, 90mg~150mg, 90mg~175m g, 90mg~200mg, 90mg~225mg, 90mg~250mg, 100mg~125mg, 100mg~150mg, 100mg~175mg, 100mg~200m It may contain Danicopan (100mg-225mg, 100mg-250mg, 200mg-225mg, 200mg-250mg, 200mg-275mg, 200mg-300mg, 200mg-325mg, and 200mg-350mg, 300mg-325mg, 300mg-350mg, 300mg-375mg, 300mg-400mg).

[0036] In another aspect, the disclosure features a method of preparing any one of the solid dispersions disclosed herein. The method includes (i) dissolving danikopan and a pharmaceutically acceptable polymer (e.g., any one of the pharmaceutically acceptable polymers disclosed herein) in an organic solvent (e.g., one or more of acetone, methanol, ethanol, and dichloromethane) to form a solution, and (ii) spray-drying the solution to form the solid dispersion. In a further embodiment, the organic solvent is an organic solvent having a boiling point less than 80°C.

[0037] In other embodiments, the disclosure features a method of treating a condition regulated by complement factor D in a subject in need thereof. The method includes orally administering to the subject an effective amount of a pharmaceutical composition.

[0038] In further embodiments, the disclosure features methods, wherein the pharmaceutical composition is orally administered once, twice, or three times per day.

[0039] In further embodiments, the disclosure features methods in which the conditions being treated are paroxysmal nocturnal hemoglobinuria (PNH) and PNH with clinically evident extravascular hemolysis (EVH). In further embodiments, the methods include a capsule or tablet orally administered TID with 100-200 mg of Danicopan in a pharmaceutical composition.

[0040] In a further embodiment, the disclosure features a method in which the condition being treated is geographic atrophy (GA) secondary to age-related macular degeneration (AMD). In a further embodiment, the method includes a capsule or tablet containing 20 to 900 mg of Danicopan, administered orally three times daily.

[0041] definition By "pharmaceutically acceptable polymer" is meant a polymer that is suitable for pharmaceutical formulations and capable of forming a solid dispersion.

[0042] As used herein, the term "substantially amorphous" with respect to danicopan refers to a sample of danicopan in which less than 20% (w / w) of the danicopan is present in crystalline form (e.g., less than 15%, 12%, 10%, 8%, 5%, 3%, 2%, or 1% (w / w), such as 0.01% to 20%, 0.01% to 15%, 0.01% to 12%, 0.01% to 10%, 0.01% to 8%, 0.01% to 5%, 0.01% to 3%, and 0.01% to 1% (w / w)), as determined, for example, using X-ray powder diffraction methods as described in Example 3. In some embodiments, a substantially amorphous solid dosage form is a solid dosage form in which less than 2% (w / w) of the danicopan is present in crystalline form. Known crystalline forms of Danikopane are described in WO 2020 / 051538 and CN 113801189(A), the entire contents of which are incorporated herein by reference. In some embodiments, the absence of crystalline Danikopane is determined using differential scanning calorimetry (DSC), e.g., as described in WO 2020 / 051538, e.g., the absence of a melting endotherm at 155.3°C indicates the absence of crystalline Danikopane.

[0043] As used herein, the term "solid dispersion" refers to a solid formulation comprising (i) substantially amorphous danikopan dispersed in a polymer. In certain dosage forms of the present disclosure, the solid dispersion has a single glass transition temperature, T g The danikopane is dispersed homogeneously throughout the polymer in a manner that results in

[0044] As used herein, "bioavailability" refers to the proportion of a drug that is absorbed after administration to a subject or patient under fasting conditions.

[0045] The "coefficient of variation" is the arithmetic standard deviation divided by the arithmetic mean for a particular pharmacokinetic parameter, where the data are obtained from a pharmacokinetic study including 10, 12, or more subjects or patients.

[0046] "Mean" refers to the arithmetic mean of a particular pharmacokinetic parameter, where the data are obtained from pharmacokinetic studies including 10, 12, or more subjects or patients.

[0047] "C max " means the average peak concentration of drug achieved in plasma after administration.

[0048] "T max " refers to the maximum plasma concentration or C max This refers to the average time after oral administration of a drug when the

[0049] "AUC ∞ ", "A.U.C. 0-∞ " or "Area Under the Curve ∞ " means the mean integrated area under the curve for plasma concentration of a drug versus time from t=0 to t=∞ after administration.

[0050] "TPGS (tocopherol polyethylene glycol succinate)" refers to a compound or mixture of compounds containing one or more vitamin E moieties (e.g., tocopherol, tocomonoenol, tocodienol, or tocotrienol) attached (e.g., by an ester, amide, or thioester bond) to one or more polyethylene glycol (PEG) moieties via a linker (e.g., a dicarboxylic or tricarboxylic acid). The vitamin E moieties can be any naturally occurring or synthetic form of vitamin E, including the α, β, γ, and δ isoforms and all stereoisomers of tocopherol, tocomonoenol, tocodienol, and tocotrienol. Linkers include, for example, dicarboxylic acids (e.g., succinic acid, sebacic acid, dodecanedioic acid, suberic or azelaic acid, citraconic acid, methylcitraconate, itaconic acid, maleic acid, glutaric acid, glutaconic acid, fumaric acid, and phthalic acid). Exemplary tocopherol polyethylene glycol diesters are D-alpha-tocopheryl PEG succinate, polyethylene glycol tocopherol sebacate, polyethylene glycol tocopherol dodecanedioate, polyethylene glycol tocopherol suberate, polyethylene glycol tocopherol azelaate, polyethylene glycol tocopherol citraconate, polyethylene glycol tocopherol methylcitraconate, polyethylene glycol tocopherol itaconate, polyethylene glycol tocopherol maleate, polyethylene glycol tocopherol glutarate, polyethylene glycol tocopherol glutaconate, and polyethylene glycol tocopherol phthalate. Each PEG moiety of the TPGS compound can be any polyethylene glycol or any PEG derivative and can have a molecular weight of 200 to 6,000 kDa (e.g., 400 to 4,000 kDa, 500 to 2,000 kDa, 750 to 1,500 kDa, 800 to 1,200 kDa, 900 to 1,100 kDa, or 1,000 kDa). The PEG moieties can be polydisperse, i.e., have a variety of molecular weights.PEG derivatives include, for example, methylated PEG, propylene glycol, PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH2, PEG-CO2H, PEG-OMe and other ethers, branched PEG, and PEG copolymers (e.g., PEG-b-PPG-b-PEG-1100, PEG-PPG-PEG-1900, PPG-PEG-MBE-1700, and PPG-PEG-PPG-2000). Any known source of TPGS can be used in the present disclosure. An exemplary TPGS compound is tocopheryl PEG-1000 succinate (TPGS-1000), which has a PEG moiety with a molecular weight of 1,000 kDa. TPGS is a water-soluble form of vitamin E from natural sources. It is prepared by esterification of crystalline D-α-tocopheryl succinate with polyethylene glycol 1000 (PEG1000) and contains 260-300 mg / g of total tocopherols. Another exemplary TPGS compound is water-soluble natural vitamin E (ZMC-USA, The Woodlands, Texas). Methods for preparing PEGylated vitamin E are described in U.S. Patent Nos. 2,680,749 and 3,102,078, and U.S. Publication Nos. 2007 / 0184117 and 2007 / 0141203, which are incorporated herein by reference. TPGS compounds also contain one or more methylene (CH2) atoms. nIncluded are analogs that differ in chemical composition from tocopheryl PEG succinate (e.g., TPGS-1000) by substitution, addition, or removal of units or functional groups. TPGS compounds also include chromanol derivatives (e.g., 6-chromanol PEG-1000 succinate and 6-chromanol PEG-400 succinate), steroid derivatives (e.g., cholesteryl PEG-1000 succinate, PEG-1000 cholic acid, PEG-1000 dihydrocholic acid, PEG-1000 lithocholic acid, PEG-1000 ursodeoxycholic acid, PEG-1000 chenodeoxycholic acid), and others (e.g., indomethacin PEG-1000, chromone-2-carboxylic acid PEG-1000, chromone-2-carboxlic acid PEG-1000, chromone-2-carboxlic acid PEG-1000, chromone-2-carboxylic ... Examples of suitable PEG-1000 succinates include PEG-1100-OMe, PEG-1500 chromone-2-carboxylate, PEG-2000 chromone-2-carboxylate, naproxen PEG-1000, probenecid PEG-1000, 7-carboxymethoxy-4-methyl-coumarin PEG-1000, PEG-1000 5-(4-chlorophenyl)-2-furoate, probenecid tocopheryl PEG-1000 succinate, PEG-1000 lithocholic acid, and PEG-1000 chromone-3-carboxylate, PEG-1000 7-hydroxy-coumarinyl-4-acetate.

[0051] "Unit dosage form" means a unit administration of an active agent, such as Danikopan. Non-limiting examples of dosage forms include tablets, caplets, hard capsules, soft capsules, gelatin capsules, and liquid gelatin capsules.

[0052] As used herein, the term "administration" or "administering" refers to peroral (e.g., oral) administration of a drug to a subject or patient.

[0053] "Effective amount" refers to an amount of drug sufficient to treat, prevent, or ameliorate a condition in a subject or patient. The effective amount of Danicopan used to practice the methods disclosed herein for the therapeutic management of a condition will vary depending on one or more of the patient's age, weight, sex, and / or general health or problem state. The prescriber will primarily determine the appropriate amount and dosage regimen. Such an amount is referred to as an "effective amount."

[0054] As used herein, and as is well understood in the art, "treating" a condition (e.g., a condition described herein) such as a complement factor D-mediated disorder (e.g., paroxysmal nocturnal hemoglobinuria (PNH), e.g., PNH with clinically evident extravascular hemolysis (EVH), and geographic atrophy (GA) secondary to age-related macular degeneration (AMD)) or "treatment" of a condition is an approach for obtaining a beneficial or desired result, such as a clinical outcome. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; reduction in the severity of a disease, disorder, or condition; a stable (i.e., non-worsening) state of a disease, disorder, or condition; preventing the spread of a disease, disorder, or condition; delaying or slowing the progression of a disease, disorder, or condition; improvement or palliation of a disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. "Alleviating" a disease, disorder, or condition means reducing the severity and / or undesirable clinical symptoms of the disease, disorder, or condition and / or slowing or prolonging the time course of progression compared to the severity or time course in the absence of treatment.

[0055] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The recitation of ranges of values, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable.

[0056] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "etc.") is intended to be illustrative only and does not impose a limitation on the scope of the disclosure unless otherwise stated.

[0057] A "pharmaceutical composition" is a composition that includes at least one active agent, such as danicopan, and at least one other substance, such as a carrier. A pharmaceutical composition optionally contains more than one active agent.

[0058] The term "carrier" refers to a diluent, excipient, or vehicle for providing a solid dispersion of Danicopane.

[0059] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, sufficiently non-toxic, and not biologically or otherwise undesirable, and that is useful in preparing pharmaceutical compositions / combinations. As used in this application, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0060] A "subject," "patient," or "host" is a human or non-human animal in need of medical treatment, including, but not limited to, a monkey, bird, cat, dog, cow, horse, or pig. Medical treatment can include treatment of an existing condition, such as a disease or disorder, or prophylactic or diagnostic treatment. In certain embodiments, the patient or host is a human patient. In alternative embodiments, a patient, such as a host, is treated to prevent a disorder or disease described herein.

[0061] As used herein, the term "isolated" refers to a material in substantially pure form. An isolated compound is free of other components that materially affect the properties of the compound. In certain embodiments, the isolated form is at least 60, 70, 80, 90, 95, 98, or 99% pure.

[0062] Other features and advantages of the present disclosure will become apparent from the following detailed description, drawings, and claims. [Brief explanation of the drawings]

[0063] [Figure 1] FIG. 1 is a graph showing the XRPD diffractogram of an 80:20 Danicopane / HPMCAS-H solid dispersion. [Figure 2] 1 is a graph of the dissolution rate assay of Formulation 1 and Formulation 2. [Figure 3A] 1 is a graph of the pH shift dissolution rate of Formulation 1. [Figure 3B] 1 is a graph of the pH shift dissolution rate of Formulation 2. [Figure 4A] 1 is a graph of dissolution rate testing in 0.1 N HCl at 37° C. and 50 rpm for Formulation 1A (F1A) at various tablet hardness levels (100 Newtons, 150 Newtons, and 200 Newtons). [Figure 4B] 1 is a graph of dissolution rate testing in 0.1 N HCl at 37° C. and 50 rpm for Formulation 1B (F2A) at various tablet hardness levels (100 Newtons, 150 Newtons, and 200 Newtons). [Figure 4C]1 is a graph of dissolution rate testing in 0.1 N HCl at 37° C. and 50 rpm for Formulation 2A (F1B) at various tablet hardness levels (100 Newtons, 150 Newtons, and 200 Newtons). [Figure 4D] 1 is a graph of dissolution rate testing in 0.1 N HCl at 37° C. and 50 rpm for Formulation 2B (F2B) at various tablet hardness levels (100 Newtons, 150 Newtons, and 200 Newtons). [Figure 5A] 1 is a graph of the supersaturation rate of a 70:30 Danikopan / polymer solid dispersion and amorphous Danikopan (labeled "Amorphous API") in simulated intestinal fluid (SIF). [Figure 5B] 1 is a graph of the supersaturation rate of an 80:20 Danikopan / polymer solid dispersion and amorphous Danikopan (labeled "Amorphous API") in simulated intestinal fluid (SIF). [Figure 5C] 1 is a graph of the supersaturation rate of an 85:15 Danikopan / polymer solid dispersion and amorphous Danikopan (labeled "Amorphous API") in simulated intestinal fluid (SIF). [Figure 5D] 1 is a graph of the supersaturation rate of a 90:10 Danikopan / polymer solid dispersion and amorphous Danikopan (labeled "Amorphous API") in simulated intestinal fluid (SIF). [Figure 6A] 1 is a graph of the supersaturation rate of a 70:30 Danikopan / polymer solid dispersion and amorphous Danikopan (labeled "Amorphous API") in simulated gastric fluid (SGF). [Figure 6B] 1 is a graph of the supersaturation rate of an 80:20 Danikopan / polymer solid dispersion and amorphous Danikopan (labeled "Amorphous API") in simulated gastric fluid (SGF). [Figure 6C] 1 is a graph of the supersaturation rate of an 85:15 Danikopan / polymer solid dispersion and amorphous Danikopan (labeled "Amorphous API") in simulated gastric fluid (SGF). [Figure 6D] 1 is a graph of the supersaturation rate of a 90:10 Danikopan / polymer solid dispersion and amorphous Danikopan (labeled "Amorphous API") in simulated gastric fluid (SGF). [Figure 7A]1 is a graph of Cmax values ​​of Danicopane solid dispersion formulations in dogs. [Figure 7B] 1 is a graph of the AUC0-24 values ​​of Danikopan solid dispersion formulations in dogs. [Figure 8] 1 is a graph of overlaid XRPD diffractograms of various danikopane solid dispersions in different polymer systems at 25% danikopane loading. [Figure 9] 1 is a graph overlaid with the kinetic solubility profiles of various danikopan solid dispersions and crystalline danikopan in simulated gastric fluid (SGF) at 37°C over 30 minutes, followed by the kinetic solubility profiles of the subsequent conversion to fasted state simulated intestinal fluid (FaSSIF) over 20 minutes. [Figure 10] 1 is a graph overlaid with the kinetic solubility profiles of various Danikopan solid dispersions in simulated gastric fluid (SGF) at 37°C over 30 minutes and the subsequent kinetic solubility profiles upon conversion to fasted-state simulated intestinal fluid (FaSSIF) over 210 minutes. [Figure 11A] 1 is a graph of overlaid XRPD diffractograms of the following spray-dried solid dispersions: 40 / 60 Danicopane / HPMCAS-M, 60 / 40 Danicopane / HPMCAS-M, 80 / 20 Danicopane / HPMCAS-M, 40 / 60 Danicopane / HPMCAS-H, 60 / 40 Danicopane / HPMCAS-H, and 80 / 20 Danicopane / HPMCAS-H. [Figure 11B] 1 is a graph of overlaid XRPD diffractograms of the following spray-dried solid dispersions: 40 / 60 Danicopane / PVP VA64, 60 / 40 Danicopane / PVP VA64, 80 / 20 Danicopane / PVP VA64, 40 / 60 Danicopane / Eudragit, 60 / 40 Danicopane / Eudragit, and 80 / 20 Danicopane / Eudragit. [Figure 12A]Graph of the arithmetic mean plasma Danikopan concentration-time profile following administration of 200 mg Danikopan as a prototype PIC1 fed and fasted and as a tablet fed to healthy adult subjects (pharmacokinetic population) on a linear scale. [Figure 12B] Graph of arithmetic mean plasma Danikopan concentration-time profiles following administration of 200 mg Danikopan as prototype PIC1 fed and fasted and as a tablet to healthy adult subjects (pharmacokinetic population) on a semi-logarithmic scale. [Figure 13A] Graph of the arithmetic mean plasma Danicopan concentration-time profile following administration of 200 mg Danicopan as a prototype PIC2 fed and fasted and as a tablet fed to healthy adult subjects (pharmacokinetic population) on a linear scale. [Figure 13B] Graph of arithmetic mean plasma Danicopan concentration-time profiles following administration of 200 mg Danicopan as prototype PIC2 fed and fasted and as a tablet to healthy adult subjects (pharmacokinetic population) on a semi-logarithmic scale. DETAILED DESCRIPTION OF THE INVENTION

[0064] The present disclosure provides formulations of Danicopan and methods comprising the administration of the formulations to treat conditions associated with complement factor D-mediated disorders. Non-limiting examples of conditions treatable by this administration include paroxysmal nocturnal hemoglobinuria (PNH), e.g., PNH with clinically evident extravascular hemolysis (EVH), and geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

[0065] Danicopan is a factor D inhibitor capable of treating various factor D-mediated disorders, with no adverse effects at doses up to 1,600 mg. Danicopan was previously discovered to be capable of being prepared in a highly purified formulation exhibiting unexpectedly improved compound stability, as disclosed in International Publication No. 2020051538, assigned to Achillion Pharmaceuticals. The disclosed formulations of Danicopan have improved stability, making them suitable for various pharmaceutical formulations and compositions. However, these formulations of Danicopan were found to exhibit poor oral bioavailability, thereby rendering them unsuitable for therapeutic benefit (see, e.g., Table 9).

[0066] To overcome the low bioavailability of the formulation, a liquid soft gelatin capsule formulation of Danikopan was developed. However, it was discovered that the liquid soft gelatin capsule formulation had a limited shelf life, and large crystals of Danikopan were detected in the soft gelatin capsule after one month of storage in a blister package (Example 2).

[0067] Thus, the present disclosure provides formulations for increasing the oral bioavailability and / or reducing inter-patient variability in the pharmacokinetic behavior of danikopan. These formulations involve the use of solid dispersion systems that contain polymers capable of maintaining danikopan in an amorphous form, thereby providing improved storage stability over liquid soft gelatin capsules.

[0068] Solid dispersion pharmaceutical composition Pharmaceutically acceptable polymers for making solid dispersions Pharmaceutically acceptable polymers include one or more polymers capable of forming a solid dispersion containing danikopan. Two or more polymers can be used together, and may optionally contain one or more surfactants and / or plasticizers. Generally, the optimal T gValues ​​include 50°C to 180°C, which is above the melting point of Danikopane but below the temperature at which Danikopane decomposes. g The values ​​are from 50°C to 180°C (e.g., 50°C to 85°C, or 50°C to 80°C, or 50°C to 75°C, or 50°C to 70°C, or 50°C to 65°C, or 50°C to 60°C, or 75°C to 100°C, or 75°C to 95°C, or 75°C to 90°C, or 75°C to 85°C, or 75°C to 80°C, or 80°C to 110°C, or 80°C to 105°C, or 80°C to 100°C, or 80°C to 95°C, or 80°C to 90°C, or 80°C to 85°C, or 85°C to 125°C, or 85°C to 120°C, or 85°C to 115℃, or 85℃ to 110℃, or 85℃ to 105℃, or 85℃ to 100℃, or 85℃ to 95℃, or 85℃ to 90℃, or 90℃ to 125℃, or 90℃ to 120℃, or 90℃ to 115℃, or 90℃ to 110℃, or 90℃ to 105℃, or 90℃ to 100℃, or 90℃ to 95℃, or 95℃ to 125℃, or 95℃ to 120℃, or 95℃ to 115℃, or 95℃ to 110℃, or 95℃ to 105℃, or 95℃ to 100℃, or 100℃ to 135℃, or 10 0℃ to 130℃, or 100℃ to 125℃, or 100℃ to 120℃, or 100℃ to 115℃, or 100℃ to 110℃, or 100℃ to 105℃, or 110℃ to 150℃, or 110℃ to 145℃, or 110℃ to 140℃, or 110℃ to 135℃, or 110℃ to 130℃, or 110℃ to 125℃, or 110℃ to 120℃, or 110℃ to 115℃, or 120℃ to 145℃, or 120℃ to 140℃, or 120℃ to 135℃, or 120℃ to 130℃, or 12 0°C to 125°C, or 125°C to 150°C, or 125°C to 145°C, or 125°C to 140°C, or 125°C to 135°C, or 125°C to 130°C, or 130°C to 160°C, or 130°C to 150°C, or 130°C to 145°C, or 130°C to 140°C, or 130°C to 135°C, or 135°C to 150°C, or 135°C to 145°C, or 135°C to 140°C, or 150°C to 180°C, or 150°C to 170°C, or 150°C to 160°C, or 175°C to 180°C).

[0069] Exemplary T of a solid dispersion comprising Danikopan and one or more polymers g The values ​​are from 80°C to 150°C (e.g., 80°C to 145°C, or 80°C to 140°C, or 80°C to 135°C, or 80°C to 130°C, or 80°C to 125°C, or 80°C to 120°C, or 80°C to 115°C, or 80°C to 110°C, or 80°C to 105°C, or 80°C to 100°C, or 80°C to 95°C, or 80°C to 90°C, or 80°C to 85°C, or 85°C to 150°C, or 85°C to 145°C, or 85°C to 140°C, or 85°C to 150°C). °C to 135°C, or 85°C to 130°C, or 85°C to 125°C, or 85°C to 120°C, or 85°C to 115°C, or 85°C to 110°C, or 85°C to 105°C, or 85°C to 100°C, or 85°C to 95°C, or 85°C to 90°C, or 90°C to 150°C, or 90°C to 145°C, or 90°C to 140°C, or 90°C to 135°C, or 90°C to 130°C, or 90°C to 125°C, or 90°C to 120°C, or 90°C to 115°C, or 90℃ to 110℃, or 90℃ to 105℃, or 90℃ to 100℃, or 90℃ to 95℃, or 95℃ to 150℃, or 95℃ to 145℃, or 95℃ to 140℃, or 95℃ to 135℃, or 95℃ to 130℃, or 95℃ to 125℃, or 95℃ to 120℃, or 95℃ to 115℃, or 95℃ to 110℃, or 95℃ to 105℃, or 95℃ to 100℃, or 120℃ to 150℃, or 120℃ to 145℃, or 12 0℃ to 140℃, or 120℃ to 135℃, or 120℃ to 130℃, or 120℃ to 125℃, or 125℃ to 150℃, or 125℃ to 145℃, or 125℃ to 140℃, or 125℃ to 135℃, or 125℃ to 130℃, or 130℃ to 150℃, or 130℃ to 145℃, or 130℃ to 140℃, or 130℃ to 135℃, or 135℃ to 150℃, or 135℃ to 145℃, and 135℃ to 140℃).

[0070] An exemplary polymer is ethyl cellulose (T g =133℃), cellulose acetate phthalate (CAP, T g =171°C), hydroxypropyl methylcellulose acetate (T g =177℃), hydroxypropyl methylcellulose acetate succinate (HPMCAS, Tg =115℃), hydroxypropyl methylcellulose phthalate (HPMCP, T g =133℃), polyvinylpyrrolidone (T g =174°C), crospovidone (T g =190℃~195℃), polyvinyl alcohol (T g =75°C), and polyvinyl acetate phthalate (T g = 55°C). An exemplary solid dispersion is 20% (w / w) Danikopan and CMEC (T g =89.4℃), HPMCAS-M(T g =91.3℃), CAP(T g =129.9℃), or PVAP (T g =116.1℃).

[0071] Examples of polymers that can be used in the formulations of the present disclosure include, but are not limited to, cellulose derivatives, polyacrylates, polyvinylpyrrolidone, polyvinyl acetate, and copolymers thereof.

[0072] cellulose derivatives Formulations of the present disclosure may include one or more cellulose derivatives, which generally include those having any number of modifications to the free hydroxyl groups in the cellulose.

[0073] In some examples, the cellulose derivative is cellulose acetate with 10% to 50% acetyl. With respect to cellulose derivatives, the % refers to the percentage of free hydroxyl groups esterified with functional groups. For example, "10% acetyl" refers to a derivative in which 10% of the free hydroxyl groups in the cellulose are esterified with acetyl groups.

[0074] Specific examples of cellulose acetates include cellulose acetate phthalate (CAP) (available as Cellacefate), such as that with 35% phthalyl, 24% acetyl; methyl cellulose acetate phthalate; hydroxypropyl cellulose acetate; as well as M grades with 9% acetyl / 11% succinoyl (e.g., HPMCAS with an average particle size of 5 μm (i.e., HPMCAS-MF, fine powder grade) or HPMCAS with an average particle size of 1 mm (i.e., HPMCAS-MG, granular grade)), H grades with 12% acetyl / 6% succinoyl. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) such as grades (e.g., HPMCAS having an average particle size of 5 μm (i.e., HPMCAS-HF, fine powder grade) or HPMCAS having an average particle size of 1 mm (i.e., HPMCAS-HG, granule grade)), and L grades with 8% acetyl / 15% succinoyl (e.g., HPMCAS having an average particle size of 5 μm (i.e., HPMCAS-LF, fine powder grade) or HPMCAS having an average particle size of 1 mm (i.e., HPMCAS-LG, granule grade)).

[0075] Additional exemplary cellulose derivatives are alkylcelluloses such as methylcellulose (Methocel™ A) or ethylcellulose (Ethocel™); hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (hydroxypropyl cellulose, HPC, e.g., low-substituted HPC with 11% hydroxypropyl or 8% hydroxypropyl), and hydroxybutylcellulose; hydroxyethylmethylcellulose and hydroxypropylmethylcellulose (hypromellose, HPMC, e.g., with 19-24% methoxyl / 7-12% hydroxypropyl) (80-120 cP (Methocel™ K100), 3,000-5,600 cP (Methocel™ K100)). Methocel™ K, including those with apparent viscosities (2% in water at 20°C) of 11,250-21,000 cP (Methocel™ K4M), 11,250-21,000 cP (Methocel™ K15M), 80,000-120,000 cP (Methocel™ K100M), 28-30% methoxyl / 7-12% hydroxypropyl (with apparent viscosities (2% in water at 20°C) of 3,000-5,600 cP (Methocel™ E4M) and 7,500-14,000 cP (Methocel™ E10M), and Dow Examples of suitable hydroxypropyl methylcellulose include Methocel® E, available from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan; 23% methoxyl / 10% hydroxypropyl methylcellulose (Metolose® SR, available from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan); 23%-29% methoxyl / 8%-9% hydroxypropyl methylcellulose (also available from Shin-Etsu Chemical Co., Ltd., Tokyo, Japan);hydroxyalkyl alkylcelluloses such as Metolose®, available from Epson Corporation (29% methoxyl / 9% hydroxypropyl; Hypromellose USP, substitution 2910), and 23% methoxyl / 6% hydroxypropyl (Hypromellose USP, substitution 2208); hydroxyalkyl alkylcellulose esters such as hydroxypropyl methylcellulose phthalate (HPMCP) (e.g., HP55 grade, having a nominal phthalyl content of 31%, and HP-55S or HP-50 grade, having a nominal phthalyl content of 24%); carboxyalkylcelluloses such as carboxymethylcellulose and alkali metal salts thereof, such as the sodium salt; carboxyalkyl alkylcelluloses such as carboxymethylethylcellulose; and carboxyalkylcelluloses such as carboxymethylcellulose butyrate, carboxymethylcellulose propionate, carboxymethylcellulose acetate butyrate, and carboxymethylcellulose acetate propionate. Any of the cellulose derivatives herein may be further crosslinked or copolymerized (e.g., with any of the polymers described herein).

[0076] Polyacrylate Formulations of the present disclosure may include one or more polyacrylates or copolymers thereof. Exemplary polyacrylates include polymethacrylates; methacrylic acid-methyl methacrylate copolymers having a 1:1 ratio of free carboxyl groups to ester groups (e.g., Eudragit® L100, MW approximately 125,000 Da), and 1:2 ratio of free carboxyl groups to ester groups (Eudragit® S100, MW approximately 125,000 Da), dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymers (e.g., having a 2:1:1 ratio of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate, available in powder, granule, or solution form, i.e., Eudragit® E, respectively). PO, Eudragit® E100, or Eudragit® E12.5), and methacrylate copolymers such as diethylaminoethyl methacrylate-methyl methacrylate copolymer (e.g., Eudragit® E); and ethacrylate copolymers such as methacrylic acid ethacrylate copolymers having a 50:50 methacrylic acid to ethacrylate ratio (e.g., Kollicoat® MAE100P or Eudragit® L100-55, MW approximately 320,000 Da).

[0077] Polyvinylpyrrolidone and polyvinyl acetate Formulations of the present disclosure may include one or more polyvinylpyrrolidone, polyvinyl acetate, or copolymers thereof.

[0078] Exemplary polyvinylpyrrolidone and polyvinyl acetate include 2,500 Da (Kollidon® 12PF, weight average molecular weight of 2,000 to 3,000 Da), 9,000 Da (Kollidon® 17PF, weight average molecular weight of 7,000 to 11,000 Da), 25,000 Da (Kollidon® 25, weight average molecular weight of 28,000 to 34,000 Da), and 28,000 Da (Kollidon® 35PF, weight average molecular weight of 34,000 Da). polyvinylpyrrolidone (e.g., povidone, PVP, PVP) having a molecular weight of 50,000 Da (Kollidon® 30, weight average molecular weight of 44,000 to 54,000 Da), and 1,250,000 Da (Kollidon® 90 or Kollidon® 90F, weight average molecular weight of 1,000,000 to 1,500,000 Da); K30, or soluble povidone; polyvinyl acetate esters such as polyvinyl acetate phthalate (PVAP); polyethylene glycol-polyvinyl acetate copolymers such as polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymer (Soluplus®); and polyvinyl pyrrolidone-polyvinyl acetate copolymers (polyvinyl pyrrolidone-polyvinyl acetate, PVP VA) such as those having a ratio of N-vinyl-2-pyrrolidone to vinyl acetate of 60:40 (Copovidone, also available as Kollidon® VA64 or PVP VA64) and those having a ratio of N-vinyl-2-pyrrolidone to vinyl acetate of 20:80 (Kollidon® SR).

[0079] Method for preparing solid dispersion systems Pharmaceutical compositions comprising solid dispersions (e.g., spray dried dispersions (SDD) or hot melt extrusion (HME)) can be made using any useful method. Generally, one or more polymers and danikopane are combined with or without a solvent (e.g., one or more of dimethylacetamide, dimethylformamide, pyrrolidone, methylpyrrolidone, methanol, ethanol, dichloromethane, and acetone) to form a mixture (e.g., a liquid mixture) or a solution. Optionally, the polymer and danikopane, either with or without additional excipients, are heated to a temperature above the glass transition temperature T g or melting temperature T m The mixture can be heated to near or above a temperature of 1000 K to form a liquid mixture. The resulting solution can then be spray dried to form a solid dispersion. Alternatively, the method includes a hot melt extrusion process in which the mixture is heated to form a homogeneous molten mass, extruded, and cooled to form the solid dispersion. The extrudate can optionally be pelletized or milled to form a solid dispersion suitable for further processing into a suitable unit dosage form.

[0080] spray drying method The compositions of the present disclosure can be prepared by any useful process, such as spray drying to form a spray-dried dispersion (SDD). In one example, one or more polymers and danikopane are combined with one or more solvents (e.g., acetone) to form a solution having 4% (w / w) to 80% (w / w) total solids. The percentage (w / w) of total solids is determined by dividing the total mass of the compound and one or more polymers by the total mass of the compound, one or more polymers, and one or more solvents. The solution can then be spray-dried to form the SDD, which may optionally undergo a further drying step. In certain embodiments, the SDD comprises 80% (w / w) danikopane along with one or more polymers (i.e., the weight ratio of danikopane to polymer is 4:1).

[0081] For example, to produce 80% (w / w) danikopane in SDD, a solution of 8% (w / w) danikopane and 2% (w / w) pharmaceutically acceptable polymer or a combination of pharmaceutically acceptable polymers in acetone was prepared. The solution was then spray dried at an appropriate temperature (e.g., 40°C to 62°C for HPMCAS at an appropriate solution flow rate).

[0082] The resulting SDD can be blended with one or more excipients described herein and then granulated and / or compressed to produce a final blend for encapsulation or tableting. In certain embodiments, the one or more excipients include binders, fillers, disintegrants, wetting agents, glidants, and lubricants.

[0083] Other pharmaceutically acceptable excipients Pharmaceutically acceptable excipients useful in the formulations of the present disclosure may further include one or more other ingredients capable of maintaining danicopan in a substantially amorphous form. In certain embodiments, the excipient is a pharmaceutically acceptable polymer as described herein.

[0084] Exemplary excipients include anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration. Additional non-limiting exemplary excipients include colorants, flavors, plasticizers, humectants, and buffering agents. In some embodiments, the excipient comprises one or more of lactose monohydrate (e.g., Tablettose 80), fumed silica (e.g., Aerosil), magnesium stearate, croscarmellose sodium, and microcrystalline cellulose (e.g., Avicel PH101 and / or Avicel PH102).

[0085] Pharmaceutical formulations may include a solid dispersion of danikopane described herein in any pharmaceutically acceptable carrier. The solid dispersion may be used to fill any one of the unit dosage forms (e.g., capsules) described herein or for tableting. The solid dispersion may optionally be further processed before filling or tableting. Exemplary further processing includes spheronizing, pelletizing, milling, injection molding, sieving, and / or calendaring the solid dispersion. In one embodiment, the solid dispersion described herein is administered to a patient in need of treatment as a spray-dried dispersion (SDD). In another embodiment, the present disclosure provides a spray-dried dispersion (SDD) comprising danikopane and one or more pharmaceutically acceptable excipients as defined herein. In a further embodiment, the SDD comprises danikopane and one or more pharmaceutically acceptable excipients. In another embodiment, any of the spray-dried dispersions described can be coated to form a coated tablet. In an alternative embodiment, the spray-dried dispersion is formulated into a tablet but is not coated.

[0086] surfactants Formulations of the present disclosure optionally include one or more surfactants. Exemplary surfactants are liquid and solid polyethoxylated esters of fatty acids such as PEG 400 monostearate, also known as polyoxyl 40 stearate (Myrj® 52, hydrophobic-lipophilic balance (HLB) = 17), polyoxyl 8 stearate (Myrj® 45, HLB = 11), and PEG 660 hydroxystearate, also known as PEG 15 hydroxystearate (Solutol® HS15, HLB = 14-16); polyethoxylated esters of fatty acids such as polyoxyl 10 oleyl ether (Brij® 97, HLB = 12.4) and PEG 25 cetostearyl ether (Cremophor® A25, HLB = 15-17); alkyl ethers; polyethoxylated sorbitan esters such as polysorbate 20 (Tween® 20, HLB=15) and polysorbate 80 (Tween® 80, HLB=11.5); polyethoxylated glyceryl esters with high HLB values ​​(e.g., 10-20) such as polyoxyl 35 castor oil (Cremophor® EL, HLB=12-14) and polyoxyl 40 castor oil with 40-45 moles of ethylene oxide (Cremophor® RH-40, HLB=14-16); less than 2% C6 / 50%-80% C8 / 20%-50% C 10 / less than 3% C 12 / less than 1% C 14 PEG6 caprylic / capric acid glyceryl ester mixture (Softigen® 767, HLB=19), 50%-80% C8 / 20%-50% C 10 / less than 3% C 12 / less than 1% C 18 PEG8 caprylic / capric acid glyceryl ester mixture (Labrasol®, HLB=14), 40%-50% C 12 / 14%~24% C 14 / 4%~10% C8 / 3~9% C 10 / 4%~14% C 16 / 5%~15% C18 A mixture of PEG32 lauryl glyceryl esters (Gelucire® 44 / 14, HLB=14) with 40% to 50% C 16 / 48%~58% C 18 Polyethoxylated glyceryl esters of fatty acids with high HLB values ​​(e.g., 10-20), such as a mixture of PEG 32 stearyl glyceryl esters having the formula (Gelucire® 50 / 13, HLB=13); polyethoxylated vitamin analogs, such as D-alpha-tocopheryl PEG 1000 succinate (HLB=13); and polyethoxylated vitamin analogs of the formula H(OCH2CH2) a (OCHCH3CH2) b (OCH2CH2) a Ethoxylated propoxylated block copolymers having OH where a is 12 and b is 20 (Poloxamer® 124), where a is 38 and b is 29, where a is 80 and b is 27 (Poloxamer® 188), where a is 64 and b is 37 (Poloxamer® 237), where a is 141 and b is 44 (Poloxamer® 338), where a is 49 and b is 57, and where a is 101 and b is 56 (Poloxamer® 407).

[0087] plasticizer The formulations of the present disclosure optionally include one or more plasticizers. Generally, plasticizers have a glass transition temperature T g or to reduce the viscosity of the mixture of Danikopan and the polymer. Exemplary plasticizers are polyalkylene oxides such as polyethylene glycol (e.g., PEG300, PEG400, PEG4000, or PEG8000) and polypropylene glycol; a (OCHCH3CH2) b (OCH2CH2) aEthoxylated propoxylated block copolymers having OH where a is 12 and b is 20 (Poloxamer® 124), where a is 38 and b is 29, where a is 80 and b is 27 (Poloxamer® 188), where a is 64 and b is 37 (Poloxamer® 237), where a is 141 and b is 44 (Poloxamer® 338), where a is 49 and b is 57, and those where a is 101 and b is 56 (Poloxamer® 407); polyethoxylated glyceryl esters such as polyoxyl 35 castor oil (Cremophor® EL, HLB=12-14) and polyoxyl 40 castor oil with 40-45 moles of ethylene oxide (Cremophor® RH-40, HLB=14-16).

[0088] Hot Melt Extrusion Process In some embodiments, the compositions of the present disclosure are prepared by hot melt extrusion (HME). In one example, one or more polymers and danicopan are combined to form a mixture, which may optionally contain a surfactant. The mixture can then be fed into a preheated extruder (e.g., an extruder having temperature zones of 75°C to 145°C) to produce an initial extrudate. The extrudate can then be pelletized and ground (e.g., to a size of less than 500 μm) to produce a finely ground extrudate.

[0089] For example, to produce a 20% (w / w) danikopane extrudate, a preblend having 20% ​​(w / w) danikopane and 80% (w / w) pharmaceutically acceptable polymer, or a preblend having a combination of a pharmaceutically acceptable polymer and a surfactant (e.g., any pharmaceutically acceptable polymer and / or surfactant described herein), was prepared. Any component of the preblend can be pre-milled or pre-sieved. For example, the pharmaceutically acceptable polymer and / or surfactant can be milled through a burr rotor and rasp screen to reduce particle size (e.g., to 600 microns or less), and / or the danikopane can be pre-sieved. The preblend was then processed using a co-rotating twin-screw extruder, and the resulting extrudate was further processed by milling (pelletizing) to reduce its particle size (e.g., to 500 microns or less). The milled / pelletized extrudate was sieved and blended with various pharmaceutically acceptable excipients (e.g., any described herein), and the resulting blend was then co-milled. The co-milled blend can be further processed by adding a lubricant (e.g., magnesium stearate), and the resulting processed blend can be used to fill unit dosage forms (e.g., capsules).

[0090] Polymers for hot melt extrusion include cellulose derivatives such as HPMCAS, e.g., grades L, H, and M; polyvinylpyrrolidone (PVP), such as povidone having a molecular weight of 50,000 Da (Kollidon® 30, weight average molecular weight 44,000-54,000 Da); polyvinyl acetate; or copolymers of polyvinylpyrrolidone and polyvinyl acetate (PVP VA), such as those having a ratio of N-vinyl-2-pyrrolidone to vinyl acetate of 60:40 (copovidone, also available as Kollidon® VA 64) and those having a ratio of N-vinyl-2-pyrrolidone to vinyl acetate of 20:80 (Kollidon® SR).

[0091] In certain embodiments, any surfactant or wetting agent described herein can be included in the mixture to improve dissolution and / or improve stability. Exemplary surfactants include TPGS compounds, such as any described herein (e.g., D-alpha-tocopheryl PEG 1000 succinate) in useful amounts (e.g., 3%-10% (w / w), e.g., 5% (w / w)).

[0092] The resulting extrudate can be blended with one or more excipients described herein and then milled, blended, granulated, and / or compressed to produce a final blend for encapsulation or tableting. In certain embodiments, the one or more excipients include binders, fillers, surfactants (e.g., TPGS compounds), disintegrants, wetting agents, glidants, and lubricants.

[0093] Liquid gelatin capsule pharmaceutical composition Pharmaceutical Glycerides Glycerides can be used in the pharmaceutical composition of Danikopan's liquid gelatin capsule formulation. Glycerides are fatty acid mono-, di-, and tri-esters of glycerol. Glycerides include saturated and unsaturated monoglycerides, diglycerides (1,2- and 1,3-diglycerides), and triglycerides, including mixed and unmixed fatty acid compositions. Each glyceride is referred to herein as (Cn:m), where n is the length of the fatty side chain and m is the number of double bonds (cis- or trans-) in the fatty side chain. Examples of commercially available monoglycerides include monocaprylin (C8; i.e., glyceryl monocaprylate) (Larodan), monocaprin (C10; i.e., glyceryl monocaprate) (Larodan), monolaurin (C12; i.e., glyceryl monolaurate) (Larodan), monopalmitolein (C16:1) (Larodan), glyceryl monomyristate (C14) (Nikkol® MGM, Nikko), glyceryl monooleate (C16:1) (Larodan), and glyceryl monooleate (C14:1). Examples of commercially available mono / di- and triglycerides include Capmul MCM C8EP, (C8:C10 mono / diglyceride) and Capmul MCM (mono / diglyceride).Examples of commercially available diglycerides include glyceryl laurate (Imwitor® 312, Huls), caprylic / capric glyceride (Capmul® MCM, ABITEC), caprylic diglyceride (Imwitor® 988, Huls), caprylic / capric glyceride (Imwitor® 742, Huls), dicaprylin (C8) (Larodan), dicaprin (C10) (Larodan), dilaurin (C12) (Larodan), glyceryl dilaurate (C12) (Capmul® GDL, ABITEC®). Examples of commercially available triglycerides include tricaprylin (C8; i.e., glyceryl tricaprylate) (Larodan), capatex 100 (C10), tricaprin (C10; i.e., glyceryl tricaprylate) (Larodan), trilaurin (C12; i.e., glyceryl trilaurate) (Larodan), dimyristin (C14) (Larodan), dipalmitin (C16) (Larodan), distearin (Larodan), glyceryl dilaurate ( C12) (Capmul® GDL, ABITEC), glyceryl dioleate (Capmul® GDO, ABITEC®), glycerol esters of fatty acids (GELUCIRE® 39 / 01, Gattefosse), dipalmitorein (C16:1) (Larodan), 1,2 and 1,3-diolein (C18:1) (Larodan), dielaidin (C18:1) (Larodan), and dilinolein (C18:2) (Larodan).

[0094] TPGS compound D-α-tocopheryl polyethylene glycol succinate (tocopheryl PEG-1000 succinate) and related TPGS compounds can be used in the liquid gelatin capsule formulations of the present disclosure. Tocopheryl PEG-1000 succinate has the following structure:

[0095] [ka] where n is an integer.

[0096] Related TPGS compounds include additives formed using different diacid linkers, polyethylene glycol tails of different lengths, and different isoforms of tocopherol, tocomonoenol, tocodienol, and tocotrienol (e.g., α-, β-, γ-, or δ-), including α-tocopherol, α-tocomonoenol, α-tocodienol, α-tocotrienol, β-tocopherol, β-tocomonoenol, β-tocodienol, β-tocotrienol, γ-tocopherol, γ-tocomonoenol, γ-tocodienol, γ-tocotrienol, δ-tocopherol, δ-tocomonoenol, δ-tocodienol, δ-tocotrienol, and any stereoisomers thereof. Suitable vitamin E compounds of the present disclosure also include desmethyl-tocopherol, desmethyl-tocomonoenol, desmethyl-tocodienol, desmethyl-tocotrienol, and any stereoisomers thereof. Furthermore, if the compounds disclosed herein contain one or more chiral atoms whose stereochemistry is not specified, it will be understood that each stereoisomer of the compound is disclosed individually as if the structure of each stereoisomer were explicitly depicted. In certain embodiments of the present disclosure, the vitamin E compound can be the naturally occurring δ-stereoisomer of vitamin E.

[0097] The vitamin E moiety of the present disclosure can be naturally occurring or synthetic. Certain embodiments of the present disclosure include naturally occurring vitamin E compounds, such as extracts from food sources. For example, α-tocopherol, α-tocotrienol, β-tocopherol, β-tocotrienol, γ-tocopherol, γ-tocotrienol, δ-tocopherol, and δ-tocotrienol are naturally available from enriched grains, green vegetables, nuts, seeds, and vegetable oils. Methods for extracting vitamin E from natural sources are described, for example, in U.S. Patent Nos. 6,743,450, 6,838,104, 7,161,055, and 7,544,822, which are incorporated herein by reference.

[0098] TGPS compounds may contain synthetic vitamin E moieties. An exemplary method for producing α-tocopherol is the reaction of trimethylhydroquinone (TMHQ) with isophytol (3,7,11,15-tetramethylhexadec-1-en-3-ol) in a catalytic condensation reaction. Those skilled in the art will appreciate that other tocopherol, tocomonoenol, tocodienol, and tocotrienol isoforms and their derivatives can also be prepared using similar strategies starting from appropriate precursors. For example, the starting compounds can be TMHQ and 3,7,11,15-tetramethylhexadec-2-en-1-ol. An additional method for producing vitamin E using isophytol under relatively mild conditions is described by Wehrli et al., J. Org. Chem. 36:2910 (1971). Methods for synthesizing the unsaturated side chain of vitamin E are described in U.S. Patent No. 4,168,271, which is incorporated herein by reference. Additional methods for synthesizing vitamin E side chains are discussed by Stalla-Bourdillon, Ind. Chim. Belg. 35, 13 (1970). Additional methods for synthesizing tocopherols are described in U.S. Patent Nos. 5,523,420 and 6,005,122, each of which is incorporated herein by reference. Additional methods for synthesizing tocotrienols are described in U.S. Patent No. 7,038,067, which is incorporated herein by reference.

[0099] TGPS compounds can include different linkers, such as dicarboxylic acids (e.g., succinic acid, sebacic acid, dodecanedioic acid, suberic acid, or azelaic acid, citraconic acid, methylcitraconate, itaconic acid, maleic acid, glutaric acid, glutaconic acid, fumaric acid, and phthalic acid). Exemplary tocopherol polyethylene glycol diesters are TPGS, tocopherol sebacate, tocopherol dodecanedioate, tocopherol suberate, tocopherol azelate, tocopherol citraconic acid, tocopherol methylcitraconate, tocopherol itaconate, tocopherol maleate, tocopherol glutarate, tocopherol glutaconate, and tocopherol phthalate.

[0100] The PEG portion of the TPGS compound can be any polyethylene glycol or derivative thereof, having a molecular weight of 200 to 6000 kDa (e.g., 400 to 4000 kDa, 500 to 2000 kDa, 750 to 1500 kDa, 800 to 1200 kDa, 900 to 1100 kDa, or 1000 kDa). PEG derivatives include, for example, methylated PEG, polypropylene glycol (PPG), PEG-NHS, PEG-aldehyde, PEG-SH, PEG-NH2, PEG-CO2H, PEG-OMe and other ethers, branched PEG, and PEG copolymers (e.g., PEG-b-PPG-b-PEG-1100, PEG-PPG-PEG-1900, PPG-PEG-MBE-1700, and PPG-PEG-PPG-2000).

[0101] Any known source of TPGS compounds can be used in the present disclosure. TPGS typically has an HLB value of 13-18. An exemplary TPGS compound is tocopheryl PEG-1000 succinate (also referred to herein as "TPGS 1000"), which has a PEG moiety with a molecular weight of 1000 kDa. Food-grade TPGS 1000 is available, for example, under the trade name Eastman Vitamin E TPGS® (Eastman Chemical Company, Kingsport, TN). TPGS is a water-soluble form of naturally occurring vitamin E, prepared by esterification of crystalline D-α-tocopheryl succinate with polyethylene glycol 1000 (PEG 1000) and containing 260-300 mg / g of total tocopherols. Another exemplary TPGS compound is water-soluble natural vitamin E (ZMC-USA, The Woodlands, Texas). Methods for preparing TPGS are described in U.S. Patent Nos. 2,680,749 and 3,102,078, and U.S. Publication Nos. 2007 / 0184117 and 2007 / 0141203, which are incorporated herein by reference.

[0102] TPGS analogs also include chromanol derivatives (e.g., 6-chromanol PEG-1000 succinate and 6-chromanol PEG-400 succinate), steroid derivatives (e.g., cholesteryl succinate PEG-1000, cholic acid PEG-1000, dihydrocholic acid PEG-1000, lithocholic acid PEG-1000, ursodeoxycholic acid PEG-1000, chenodeoxycholic acid PEG-1000), and others (e.g., indomethacin PEG-1000, chromone-2-carboxylic acid PEG-1000, chromone-2-carboxlic acid PEG-1000, chromone-2-carboxylic ... Examples of suitable PEG-1000 succinates include PEG-1100-OMe, PEG-1500 chromone-2-carboxylate, PEG-2000 chromone-2-carboxylate, naproxen PEG-1000, probenecid PEG-1000, 7-carboxymethoxy-4-methyl-coumarin PEG-1000, PEG-1000 5-(4-chlorophenyl)-2-furoate, probenecid tocopheryl PEG-1000 succinate, PEG-1000 lithocholic acid, and PEG-1000 chromone-3-carboxylate, PEG-1000 7-hydroxy-coumarinyl-4-acetate.

[0103] Pharmaceutically acceptable organic solvents can be used in the liquid gelatin capsule formulations of the present disclosure, including propylene glycol, ethanol, N-methylpyrrolidone, or glycerol.

[0104] Unit dosage form For use in the treatment of human and animal subjects, Danicopan can be formulated as a pharmaceutical or veterinary composition. Depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prevention, prophylaxis, or therapy), the compound is formulated in a manner consistent with these parameters. Exemplary techniques for preparing pharmaceutical compositions can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0105] Danikopan may be present in a total amount of 10 to 95% by weight of the total weight of the composition. Compositions comprising danikopan and a pharmaceutically acceptable polymer may be provided in a dosage form suitable for oral administration. Alternatively, unit dosage forms of the present disclosure comprise substantially amorphous danikopan and pharmaceutically acceptable excipients (e.g., fillers, diluents, lubricants, and / or glidants). Thus, pharmaceutical compositions may be in the form of, for example, hard capsules (e.g., hard gelatin capsules or hard hydroxypropylmethylcellulose capsules), soft gelatin capsules, tablets, caplets, enteric-coated tablets, chewable tablets, enteric-coated hard gelatin capsules, enteric-coated soft gelatin capsules, minicapsules, lozenges, films, strips, gelcaps, dragees, suspensions, syrups, or sprinkles. The compositions may be formulated according to conventional pharmaceutical practice.

[0106] In certain embodiments, danikopan and a pharmaceutically acceptable polymer are contained in a capsule or compressed into a tablet. The danikopan in combination with a pharmaceutically acceptable polymer can be in any form, such as a semi-solid suspension, a solid suspension, a homogeneous melt, solid particles, or semi-solid particles. The form of danikopan can be determined based on the dosage. For example, capsules filled with a solid dispersion can be used for a drug load of approximately 10 to 95%.

[0107] Exemplary unit dosage forms are encapsulated powders, hard capsules (e.g., hard gelatin capsules or hard hydroxypropylmethylcellulose capsules), tablets, and soft gelatin capsules (e.g., liquid soft gelatin capsules). When soft gelatin capsules are used, if the composition contains propylene glycol or polyethylene glycol, it is preferred that the composition of the soft gelatin capsule shell contain a humectant, such as sorbitol, to prevent the soft gelatin capsule from becoming brittle.

[0108] Use of Danikopan for the treatment of selected disorders In one aspect, an effective amount of Danicopan formulated as a solid dispersion described herein is used to treat a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), including a complement factor D-associated disorder or an alternative complement pathway-associated disorder, a cellular disorder or abnormality that adversely affects the ability of a cell to participate in or respond to normal complement activity, or an undesired complement-mediated response to a medical treatment, such as surgery or other medical procedure, or pharmaceutical or biopharmaceutical drug administration, blood transfusion, or other allogeneic tissue or fluid administration.

[0109] In one embodiment, a method for treating paroxysmal nocturnal hemoglobinuria (PNH) is provided, comprising administering an effective amount of a solid dispersion formulation described herein, optionally in a pharmaceutically acceptable composition. PNH is a non-malignant hematological disorder characterized by the proliferation of hematopoietic stem cells and progeny mature blood cells that are deficient in several surface proteins. PNH red blood cells are unable to regulate their surface complement activation, which leads to the chronic activation of complement-mediated intravascular anemia, a typical feature of PNH.

[0110] In a further embodiment, there is provided a method for the treatment of PNH accompanied by clinically evident extravascular hemolysis (EVH), comprising the administration of an effective amount of a solid dispersion formulation described herein, optionally in a pharmaceutically acceptable composition. In a further embodiment, there is provided a method for the treatment of PNH accompanied by EVH, comprising the administration of an effective amount of a solid dispersion formulation described herein, optionally in a pharmaceutically acceptable composition, in combination with a complement component 5 (C5) inhibitor (e.g., an anti-C5 antibody such as eculizumab or ravulizumab).

[0111] In another embodiment, a method is provided for treating age-related macular degeneration (AMD) (e.g., wet AMD, dry AMD, or intermediate AMD) in a host, the method comprising administering an effective amount of a solid dispersion formulation described herein, optionally in a pharmaceutically acceptable composition. AMD is the leading cause of vision loss in industrialized countries. Based on numerous genetic studies, there is evidence of an association between the complement cascade and macular degeneration. Individuals with mutations in the gene encoding complement factor H have a five-fold increased risk of macular degeneration, and individuals with mutations in other complement factor genes also have an increased risk of AMD. Individuals with mutant factor H also have increased levels of C-reactive protein, a marker of inflammation. Without proper function of factor H, the alternative pathway of the complement cascade is overactivated, resulting in cellular damage. In a further embodiment, a method is provided for treating geographic atrophy (GA), secondary to AMD, in a host, the method comprising administering an effective amount of a solid dispersion formulation described herein, optionally in a pharmaceutically acceptable composition.

[0112] Other disorders associated with the complement cascade include acute respiratory distress syndrome (ARDS), arthropathy, asthma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), antibody-mediated graft rejection, antineutrophil cytoplasmic antibody-associated vasculitis, antiphospholipid syndrome, atypical hemolytic uremic syndrome (aHUS) or hemolytic uremic syndrome (HUS), chronic obstructive pulmonary disease (COPD), cirrhosis, cold agglutinin disease, and complement 3 (C3). 3, C3) glomerulopathies (e.g., C3 glomerulonephritis or compact deposit disease), diabetic macular edema, diabetic retinopathy, dermatomyositis, dermatitis, epidermolysis bullosa acquisita, fatty liver, focal segmental glomerulosclerosis, glomerulonephritis, graft-versus-host disease, Guillain-Barré syndrome, hemolytic anemia, hidradenitis suppurativa, IgA nephropathy, ischemia / reperfusion injury, liver failure, hepatitis, lupus nephritis, membranoproliferative glomerulonephritis, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis (MG), neuromyelitis optica (NMO), nonalcoholic steatohepatitis (NSHIP), These disorders include nonalcoholic steatohepatitis (NASH), pemphigoid, pemphigus vulgaris, preeclampsia, reduced glomerular filtration rate, respiratory disease, retinal detachment, retinopathy of prematurity, rheumatoid arthritis, scleroderma, sepsis, Shiga toxin-producing E. coli-associated hemolytic uremic syndrome, spinal cord injury, sickle cell disease, systemic lupus erythematosus (SLE), traumatic brain injury, ulcerative colitis, and uveitis. Accordingly, the present disclosure provides methods of treating any one of such disorders by administering to a subject in need thereof an effective amount of a solid dispersion formulation described herein, optionally in a pharmaceutically acceptable composition.

[0113] Dosage In some embodiments, the pharmaceutical compositions disclosed herein contain 20 mg to 900 mg of danikopan. In some embodiments, the pharmaceutical compositions disclosed herein contain 100 mg to 400 mg of danikopan. In some embodiments, the pharmaceutical compositions disclosed herein contain 100 mg to 200 mg of danikopan. In some embodiments, the pharmaceutical compositions disclosed herein contain 100 mg of danikopan. In some embodiments, the pharmaceutical compositions disclosed herein contain 50 mg of danikopan. In one embodiment, the pharmaceutical composition is formulated as a capsule and contains 50 mg to 900 mg (e.g., 50 mg to 75 mg, 50 mg to 100 mg, 50 mg to 125 mg, 50 mg to 150 mg, 50 mg to 175 mg, 50 mg to 200 mg, 50 mg to 225 mg, 50 mg to 250 mg, 60 mg to 75 mg, 60 mg to 100 mg, 60 mg to 125 mg, 60 mg to 150 mg, 60 mg to 175 mg, 60 mg to 2 00mg, 60mg~225mg, 60mg~250mg, 70mg~75mg, 70mg~100mg, 70mg~125mg, 70mg~150mg, 70mg~175mg, 70mg~200mg, 70m g~225mg, 70mg~250mg, 80mg~100mg, 80mg~125mg, 80mg~150mg, 80mg~175mg, 80mg~200mg, 80mg~225mg, 80mg~250mg , 90mg~100mg, 90mg~125mg, 90mg~150mg, 90mg~175mg, 90mg~200mg, 90mg~225mg, 90mg~250mg, 100mg~125mg, 100mg ~150mg, 100mg~175mg, 100mg~200mg, 100mg~225mg, 100mg~250mg, 200mg~225mg, 200mg~250mg, 200mg~275mg, 200m g~300mg, 200mg~325mg, and 200mg~350mg, 300mg~325mg, 300mg~350mg, 300mg~375mg, 300mg~400mg, 300mg~425mg, 3 00mg~450mg, 400mg~425mg, 400mg~450mg, 400mg~475mg, 400mg~500mg, 400mg~525mg, 400mg~550mg, 500mg~525mg,Contains Danicopan (500mg-550mg, 500mg-575mg, 500mg-600mg, 500mg-625mg, 500mg-650mg, 600mg-625mg, 600mg-650mg, 600mg-675mg, 600mg-700mg, 600mg-725mg, 600mg-750mg, 700mg-725mg, 700mg-750mg, 700mg-775mg, 700mg-800mg, 700mg-825mg, 700mg-850mg, 800mg-825mg, 800mg-850mg, 800mg-875mg, and 800mg-900mg). In one embodiment, the pharmaceutical composition is formulated as a tablet and contains 50 mg to 900 mg (e.g., 50 mg to 75 mg, 50 mg to 100 mg, 50 mg to 125 mg, 50 mg to 150 mg, 50 mg to 175 mg, 50 mg to 200 mg, 50 mg to 225 mg, 50 mg to 250 mg, 60 mg to 75 mg, 60 mg to 100 mg, 60 mg to 125 mg, 60 mg to 150 mg, 60 mg to 175 mg, 6 0mg~200mg, 60mg~225mg, 60mg~250mg, 70mg~75mg, 70mg~100mg, 70mg~125mg, 70mg~150mg, 70mg~175mg, 70mg~2 00mg, 70mg~225mg, 70mg~250mg, 80mg~100mg, 80mg~125mg, 80mg~150mg, 80mg~175mg, 80mg~200mg, 80mg~225mg , 80mg~250mg, 90mg~100mg, 90mg~125mg, 90mg~150mg, 90mg~175mg, 90mg~200mg, 90mg~225mg, 90mg~250mg, 10 0mg~125mg, 100mg~150mg, 100mg~175mg, 100mg~200mg, 100mg~225mg, 100mg~250mg, 200mg~225mg, 200mg~250m g, 200mg~275mg, 200mg~300mg, 200mg~325mg, and 200mg~350mg, 300mg~325mg, 300mg~350mg, 300mg~375mg, 300m g~400mg, 300mg~425mg, 300mg~450mg, 400mg~425mg, 400mg~450mg, 400mg~475mg, 400mg~500mg, 400mg~525mg,Contains 400mg to 550mg, 500mg to 525mg, 500mg to 550mg, 500mg to 575mg, 500mg to 600mg, 500mg to 625mg, 500mg to 650mg, 600mg to 625mg, 600mg to 650mg, 600mg to 675mg, 600mg to 700mg, 600mg to 725mg, 600mg to 750mg, 700mg to 725mg, 700mg to 750mg, 700mg to 775mg, 700mg to 800mg, 700mg to 825mg, 700mg to 850mg, 800mg to 825mg, 800mg to 850mg, 800mg to 875mg, and 800mg to 900mg).

[0114] Administration The formulations described herein can be administered in any amount and / or frequency that provides the host with an effective amount of danikopan to achieve the desired therapeutic result, thereby treating a disorder regulated by complement factor D, such as any of the disorders described herein. The amount and timing of the danikopan solid dispersion formulation administered will depend on the host being treated, the direction of the supervising medical professional, the time course of exposure, the mode of administration, the pharmacokinetic properties of danikopan, and the judgment of the prescribing physician. Therefore, due to variability between hosts, the dosages provided below are guidelines, and the physician can titrate the dose of the compound to achieve the treatment the physician deems appropriate for the host. When considering the degree of treatment desired, the physician can balance various factors, such as the age and weight of the host, the presence of existing diseases, and the presence of other diseases.

[0115] An effective amount of a formulation of danikopan described herein can be used in an amount sufficient to (a) inhibit the progression of an inflammatory disorder, an immune disorder, including autoimmune disease, or a disorder mediated by the complement pathway, including a disorder associated with complement factor D; (b) cause the regression of an inflammatory disorder, an immune disorder, including autoimmune disease, or a disorder associated with complement factor D; or (c) cause the cure of an inflammatory disorder, an immune disorder, including autoimmune disease, or a disorder associated with complement factor D, or inhibit or prevent the onset of an inflammatory disorder, an immune disorder, including autoimmune disease, or a disorder associated with complement factor D. Thus, an effective amount of a solid dispersion formulation or composition described herein provides a quantity of danikopan sufficient to provide a clinical benefit when administered to a patient.

[0116] The pharmaceutical composition can be formulated into any pharmaceutically useful form, such as pills, capsules (e.g., hard gelatin, soft gelatin, and liquid soft gelatin capsules), tablets, or powder. Some dosage forms, such as tablets and capsules, are subdivided into unit doses of suitable size containing an appropriate amount of active ingredient, for example, an effective amount of Danikopan to achieve the desired purpose.

[0117] The therapeutically effective dosage of the formulations described herein will be determined by a medical professional depending on the patient's condition, size, and age, as well as the route of delivery. In certain embodiments, the pharmaceutical composition is a dosage form containing 50 mg to 900 mg or 100 mg to 400 mg of danicopan. The dosage form may be administered, for example, once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), five times daily (OD), once every other day (Q2D), once every three days (Q3D), or any dosing schedule that provides treatment for the disorders described herein, as needed. In some embodiments, the dosage form is administered TID.

[0118] The formulations disclosed herein may be administered orally.

[0119] According to the methods of the present disclosure, the oral dosage form for administration can be any desired form in which the formulation is stable as a solid. The solid dispersion formulations disclosed in the present disclosure have good pharmacokinetic and pharmacodynamic properties when administered, for example, by the oral route. [Example]

[0120] Example 1. Preparation of Danikopan Liquid Soft Gelatin Capsule Formulation The active agent fill for the Danikopan liquid soft gelatin capsule formulation was prepared using a high-shear Silverson L4R homogenizer in a theoretical batch size of 740 g. Capmul MCM and D-alpha-tocopheryl PEG 1000 succinate were preheated to 45°C and melted for weighing and transfer prior to formulation preparation. No heat was applied to the formulation during homogenization, but the temperature of the mixture increased from room temperature to 64°C due to heat generated by the mixing blades and fill material.

[0121] A Danikopan liquid soft gelatin capsule formulation was prepared using a 16:2:1:1 ratio of Capmul MCM, Danikopan, propylene glycol, and D-alpha-tocopheryl PEG 1000 succinate. 592 g of Capmul MCM, 37 g of propylene glycol, and 37 g of D-alpha-tocopheryl PEG 1000 succinate were combined in a flask, and then 74 g of spray-dried Danikopan was added in approximately five portions during homogenization. After complete addition of Danikopan, the fill material was homogenized for 30 minutes. The resulting fill material was filtered through a 0.45 micron nylon filter to remove insoluble Danikopan and foreign particulates.

[0122] To encapsulate the active agent fill, the fill was transferred to a 7th generation Pilot encapsulation machine equipped with a separate heated tank containing the molten gel material. The gel material was cast into two ribbons. Both ribbons were then lubricated and passed between the rotary dies. Gravity fed the fill material to the encapsulation pump. The pump operated in positive displacement mode, delivering the fill material through a heated fill wedge (47°C) between the rotary dies, causing the gel ribbon to expand and form capsules. The die formed a seal in a continuous sealing process, separating the capsule from the ribbon. The target fill and shell weights were 1.0 g and 0.606 g, respectively. After encapsulation, the soft gel was dried using two drying steps.

[0123] Example 2. Stability study of Danikopan liquid soft gelatin capsule formulation A stability study of a 100 mg Danikopan liquid soft gelatin capsule formulation was conducted to determine the shelf life of the formulation. Clinical batches of soft gelatin capsules were stored in thermoformed blister packs and subjected to 40°C and 75% relative humidity. The soft gelatin capsules were inspected monthly to monitor API purity, as well as capsule appearance color, shape, and fill. After one month under the described conditions, large crystals of Danikopan were observed in the soft gelatin capsule fill, indicating that the liquid soft gelatin capsule formulation has a short shelf life.

[0124] Example 3. Preclinical spray-dried solid dispersion formulation of Danikopan Various solid dispersion formulations of Danikopan were prepared and characterized. The preferred polymers were found to be (i) 79% (w / w) Danikopan with 19% polyvinylpyrrolidone-vinyl acetate and 2% sodium lauryl sulfate in 95:5 acetone / water, and (ii) 80% (w / w) Danikopan with 20% HPMCAS-H polymer in acetone.

[0125] The following procedures were developed to prepare two spray-dried solid dispersion formulations of Danikopan: (i) Formulation 1 (79% (w / w) Danikopan with 19% polyvinylpyrrolidone-vinyl acetate and 2% sodium lauryl sulfate in 95:5 acetone / water) and (ii) Formulation 2 (80% (w / w) Danikopan with 20% HPMCAS-H polymer in acetone). Table 1 summarizes the amounts of reagents required to prepare the spray-dried solid dispersions.

[0126] [Table 1] a Danikopan concentrations were greater than 300 mg / mL. b Water was added to dissolve the sodium lauryl sulfate

[0127] A laboratory-scale spray dryer, SD46 (4M8-TriX Procept Spray Dryer), was used to dry the feed solution. The unit was equipped with either a two-fluid nozzle (1.0 mm, from Procept) or an ultrasonic nozzle (25 kHz, from Sono-Tek). The spray drying unit was operated with nitrogen in an open-loop configuration (i.e., without recirculation of dry nitrogen). A cyclone was used to collect the dried product. Before starting drying, (i) the drying gas was heated to an inlet temperature (T in ) to the temperature expected for the process, and then (ii) adjust the feed stream (F feed ) was adjusted to stabilize the spray dryer. During stabilization with the solvent mixture, T in Adjust the target outlet temperature (T out After stabilization, the feed to the spray dryer was switched from the solvent to the feed solution. feed Readjust the T outwas maintained at the target value. At the end of spray drying, the feed was switched to the stabilizing solvent mixture to rinse the feed lines and perform a controlled shutdown of the unit. All tests were performed under similar experimental conditions. The product collected from the cyclone was weighed and the yield was calculated as the mass percentage of wet product relative to the total solids in the solution fed to the spray dryer.

[0128] To perform secondary drying, a vacuum tray dryer EV52 was used to reduce the residual solvent content of the wet spray-dried solid dispersion. Drying was carried out under vacuum with a nitrogen sweep for at least 24 hours. The spray-dried material was amorphous after the spray-drying and secondary drying steps and did not form a phase-separated system.

[0129] Spray-dried samples were analyzed using X-ray powder diffraction (XRPD) to screen for crystalline material, and both formulations were found to be amorphous. As an example, XPRD analysis of Formulation 2 exhibited an amorphous halo with no evidence of crystallinity (Figure 1). The percent crystallinity of any solid dispersion can be calculated from the XRPD data integration of the crystalline and total observed XRPD diffraction peaks (% crystallinity = [(area under crystalline peak) / (area under all peaks)]). * 100).

[0130] Example 4. Preclinical tablet formulation and tableting of solid dispersion Danikopan Two tablet formulations using standard oral dosage form excipients were tested for each of the Danicopane solid dispersion formulations, resulting in a total of four Danicopane tablet formulations. The target tablet strength was 250 mg of Danicopane in a total tablet size of 600 mg. The two tablet formulations differed in the filler used (Tablettose 80 for Formulation A and Avicel PH102 for Formulation B). Three batches of tablets were produced for each of the four formulations: low, medium, and high tablet hardness. The blends prepared are listed in Table 2.

[0131] [Table 2]

[0132] The tablets were further characterized in terms of friability and disintegration (Tables 3 and 4). Hardness was tested at values ​​of approximately 100N, 150N, and 200N to obtain low, medium, and high hardness 600mg tablets.

[0133] [Table 3]

[0134] [Table 4]

[0135] Friability (weight loss) results were acceptable for medium- and high-hardness tablets, thus allowing these formulations to operate within the hardness range of 150-200 N. Low-hardness tablets tended to break during friability testing and were therefore deemed insufficient for manufacturing. Finally, all formulations exhibited short disintegration times of less than 5 minutes, even for the highest-hardness tablets. Tablet disintegration was consistently faster in Formulation B samples.

[0136] Example 5: Dissolution Rate Assay of Danicopane Preclinical Solid Dispersion Formulations A dissolution rate assay was performed to determine the dissolution rates of Formulations 1 and 2. Secondary dried samples of Formulations 1 and 2 were dissolved in 0.1 N aqueous hydrochloric acid at 37°C with stirring at 75 rpm, and HPLC was used to monitor the dissolution of Danicopan over time. Formulation 1 exhibited a faster dissolution rate compared to Formulation 2, taking approximately 40 minutes for at least 50% (w / w) of Formulation 1 to dissolve, and approximately 210 minutes for at least 50% (w / w) of Formulation 2 to dissolve (Figure 2).

[0137] A pH-shift dissolution assay was performed to monitor the dissolution rates of Formulations 1 and 2 as the pH of the dissolution medium was increased from pH 1 to pH 4-5 (Figures 3A and 3B). Secondary dried samples of Formulations 1 and 2 were dissolved in 0.1 N aqueous hydrochloric acid at 37°C with stirring at 75 rpm, and the dissolution of Danicopan was monitored over time using HPLC. After 30 minutes, the final pH of the dissolution medium was increased to pH 4-5 by adding 10 mM phosphate buffer and 1 M aqueous NaOH to the dissolution medium. After 30 minutes, approximately 23-30% of Formulation 1 had dissolved, and approximately 10-11% of Formulation 2 had dissolved. After adjusting the pH to pH 4-5, the dissolution of Formulation 1 remained at 5% over time, while the dissolution of Formulation 2 remained at 4-4.5% over time. The results demonstrate that Formulation 1 dissolves faster than Formulation 2, even when the pH of the solution was increased.

[0138] The dissolution rates of the tableted forms of Formulations 1 (A and B) and 2 (A and B) were also determined using a dissolution rate assay. Tablets were dissolved in 0.1 N aqueous hydrochloric acid at 37°C with stirring at 50 rpm, and HPLC was used to monitor the dissolution of Danicopan. The tableted form of Formulation 1 exhibited a faster dissolution rate compared to the tableted form of Formulation 2 (Figures 4A-4D). For example, after 2 hours, dissolution tests showed approximately 80% and 60% drug dissolution in Formulations 1 (A and B) and 2 (A and B), respectively.

[0139] Although Formulation 1 demonstrated faster drug dissolution than Formulation 2 based on preclinical studies, Formulation 2 was selected for subsequent scale-up strategies and GMP manufacturing.

[0140] Example 6: Supersaturation Profile of Danikopan / HPMCAS Solid Dispersions in Simulated Gastric Fluid (SGF) or Simulated Intestinal Fluid (SIF) A no-sink in vitro solubility screen was performed to determine the effect of HPMCAS grade and danicopan loading on the degree and duration of solid dispersion supersaturation and solubility. Samples were tested in 40 mL of simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at 37°C for 24 hours. Samples were taken at 10, 20, 30, and 45 minutes, and at 1, 2, 4, and 24 hours and analyzed using HPLC. Graphs showing the in vitro dissolution behavior of each solid dispersion composition in SIF are shown in Figures 5A-5D, and in vitro dissolution results in SGF are shown in Figures 6A-6D.

[0141] Figures 5A-5D and 6A-6D show that higher danikopane concentrations are reached in SGF than in SIF, consistent with the higher solubility of danikopane in acidic media. In SGF, solid dispersions made with M-grade polymers generally appeared to persist better than H-grade (at the same danikopane / HPMCAS ratio). This may not be relevant in vivo, since the solid dispersions likely only exist in the stomach for a relatively short time (less than 2 hours). In SIF, after 4 hours, comparable performance is seen between solid dispersions made with H- and M-grade polymers at each danikopane / HPMCAS ratio. This is perhaps most relevant, given that most of the absorption is expected to occur during this time frame. After 24 hours in SIF, the solid dispersions with higher danikopan loadings showed a significant decrease in danikopan concentration in solution, which in all cases still exceeded the solubility of the amorphous form, indicating that bioavailability should be improved compared to amorphous danikopan alone.

[0142] Example 7: Tablet formulation of 80:20 Danikopan / HPMCAS-H solid dispersion for large scale production A tablet formulation of the 80:20 Danikopan / HPMCAS-H spray-dried solid dispersion was optimized for large-scale production. The 100 mg formulation used a 1:1 intragranular ratio of spray-dried solid dispersion to filler (a combination of MCC and lactose) and had a total tablet size of 400 mg. The intragranular and extragranular filler was 50:50 MCC:lactose. The 100 mg tablet formulation composition is shown in Table 5.

[0143] [Table 5]

[0144] Example 8: Pharmacokinetics of Danikopan solid dispersion formulations in dogs Five Danicopane SDD compositions were tested in dogs to determine the pharmacokinetics (PK) of the following formulations: (1) 70:30 (Danicopane / HPMCAS-H), (2) 80:20 (Danicopane / HPMCAS-H), (3) 85:15 (Danicopane / HPMCAS-H), (4) 80:20 (Danicopane / HPMCAS-M), and (5) 85:15 (Danicopane / HPMCAS-M).

[0145] Danikopan solid dispersion formulations were administered to five dogs in a six-event crossover design with a washout period of approximately 7 days between successive doses, with approximately 3 weeks between dose events 2 and 3. In dose event 1, dogs were administered the solid dispersion as a 50 mg oral capsule. In dose events 2-6, the solid dispersion formulated as a suspension in 0.5% HPMC (w / w) and 0.1% Tween (w / v) was administered by oral gavage at a dose level of 50 mg / dog and a dose volume of 10 mL / dog. All dogs were fasted overnight and pretreated with 6 μg / kg pentagastrin 20 minutes prior to dosing. PK results are summarized in Table 6 and graphically depicted in Figures 7A and 7B. Results were compared for different Danikopan loads or HPMCAS polymer grades in the SDD administered as a suspension. maxThere were no significant differences in the mean or variability of the AUC. Danicopan SDD administered as powder-in-capsule (PIC) demonstrated approximately half the Cmax and three-quarters the AUC when compared to administration as a suspension. These data support that the current composition of Danicopan SDD is in a robust formulation space.

[0146] [Table 6]

[0147] Example 9. Additional spray-dried solid dispersion formulations of Danikopan The following spray-dried solid dispersion formulations of Danicopane were developed for screening purposes (Table 7). Based on solubility screening, the solvent system was chosen to be 80:20 dichloromethane:methanol (w / w) to prepare all solid dispersions under the same spraying conditions.

[0148] [Table 7]

[0149] The above spray-dried solid dispersions were characterized by XRPD, modulated differential scanning calorimetry (mDSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and polarized light microscopy (PLM), and are summarized in Table 8.

[0150] [Table 8]

[0151] The results of XRPD, mDSC, and microscopic physical characterization indicated that all spray-dried solid dispersions produced were completely amorphous. The XRPD diffractograms of each solid dispersion were devoid of sharp crystalline peaks, as can be seen in Figure 8. All mDSC thermograms indicated that each of the polymer systems exhibited a single Tg (single-phase system), indicating amorphous dispersions. However, Eudragit L100 SDD exhibited a Tg close to 180°C, which is higher than the polymer's onset decomposition temperature of 173-176°C and higher than the polymer's Tg measured at 127°C. Retest results confirmed that the Tg of the polymer system was higher than expected, approximately 180°C.

[0152] TGA showed that most polymer systems contained 2-4% residual solvent / moisture, which is the normal range for prototype solid dispersion formulations, but Eudragit L100 and PVP K30 SDD had residual solvent above the upper limit of 5%. Initial microscopic characterization data suggested that all of the solid dispersions were amorphous, exhibiting no detectable crystallinity. DSC data indicated that all were single-phase systems with a single Tg and no melting. All of the solid dispersion particles were shrunken and spherical, exhibiting no birefringence under a polarized microscope, indicating a lack of crystallinity. The particle sizes of the solid dispersions ranged anywhere from 2 to 25 μm.

[0153] A μDISS Profiler™ instrument from Pion, Inc. was used to quantify concentrations during kinetic solubility experiments. The unit consists of six photodiode array (PDA) spectrophotometers, each with its own dedicated fiber optic dip probe located in the center of a glass vial holding 10 mL of medium. Concentration measurements are performed directly in the assay medium, and processed results are plotted in "real time."

[0154] For the quantification of danikopan in solid dispersion formulations, and for the API, probes with 5 mm and 2 mm pathlength tips were selected (for solid dispersions composed of polymers: HPMCAS-M, Eudragit L100, and HPMCAS-H). The calibration curves generated were used to quantify danikopan in samples during kinetic solubility experiments at each time point. The above specific pathlength tips were selected to detect danikopan concentrations in simulated gastric fluid (SGF) and fasted-state simulated intestinal fluid (FaSSIF) buffers.

[0155] Approximately 42 mg of solid dispersion material, equivalent to 10 mg of Danikopan, was weighed into a 20 mL glass vial. The vial was then transferred to the instrument for analysis. A clean stir bar was added to the vial containing the sample. Prior to starting the experiment, 16 mL of SGF buffer was transferred to the vial to achieve an upper limit of approximately 650 μg / mL. Stirring was maintained at 220 RPM, and the temperature of the medium was maintained at 37°C. Kinetic solubility data were collected in the SGF medium for 30 minutes. The data showed that the solid dispersions had much higher solubility in the medium compared to Danikopan (Figure 9). The maximum solubility of most of the solid dispersion materials was at least two-fold higher than that of crystalline Danikopan. HPMCAS-M, HPMCAS-H, and Eudragit solid dispersions did not exhibit higher release at this low pH because they are acidic in nature and tend to ionize and release after pH 5.5 at higher pHs.

[0156] The media was converted to FaSSIF 6.5 using an in-house media conversion protocol at 30-minute intervals. The final volume in the vial was increased from 16 mL to 20 mL (500 μg / mL). The resulting samples were then analyzed in FaSSIF for approximately 18 hours using a μDiss Profiler. All solid dispersion formulations exhibited 2- to 5-fold higher equilibrium solubility compared to crystalline danikopan at 4 hours. The PVP VA64 solid dispersion exhibited a higher spring and slower fall (parachute effect), remaining supersaturated around 85 μg / mL, respectively, followed by the 80:20 danikopan / HPMCAS-H solid dispersion (control SDD), which stabilized at approximately 65 μg / mL (Figure 10). Spectral shifts were observed in the HPMCAS-M, HPMCAS-H, and Eudragit L100 solid dispersions (25% danikopan loading), which affected the data.

[0157] Experiments with solid dispersions that demonstrated problems were repeated by reducing the upper limit of Danikopan in FaSSIF to 0.25 mg / mL and changing the pathlength tip to 2 mm to allow for better detection and prevent light scattering from excess solid in the vial. While there was an improvement in the quality of data collected under the new experimental setup, there were still some small spectral shifts observed in the HPMCAS-M and Eudragit L100 solid dispersions. These shifts were not large and were within the wavelength range selected for quantification.

[0158] These formulations were evaluated based on their equilibrium solubility and maximum concentrations observed during the assay. The concentration profiles collected in SGF and FaSSIF are shown in Figures 9 and 10. All experiments were performed with N=2 replicates for each solid dispersion, and the results are summarized in Table 9 below. The data suggested that the HPMCAS-M solid dispersion was superior to the other solid dispersion systems in terms of achieving higher solubility and remaining supersaturated at approximately 200 μg / mL. The Eudragit solid dispersion reached approximately 120 μg / mL in FaSSIF and remained supersaturated for more than 4 hours. Most importantly, all of the solid dispersion formulations exhibited improved C solubility compared to crystalline Danikopan. max and kinetic solubility profiles (Table 9). The PVP VA64 solid dispersion and HPMCAS-H solid dispersion also performed better than the other solid dispersion systems by achieving approximately 85 μg / mL and approximately 65 μg / mL, respectively. The rationale behind considering a 4-hour time point is to mimic the transit time in an in vivo environment where the drug undergoes metabolism and excretion after this period as it passes through the GI tract.

[0159] [Table 9] * The simulated Cmax corresponds to the maximum concentration in the kinetic solubility profile. ** The data may be affected by slight spectral shifts seen in the solid dispersion samples during the assay.

[0160] Next, various loadings of Danikopan (40%, 60%, and 80% Danikopan) were tested in the solid dispersions to optimize the loading percentage of Danikopan in the solid dispersion formulation. Table 10 describes the composition of the various Danikopan loadings used in each solid dispersion.

[0161] [Table 10]

[0162] The results of physical characterization testing by XRPD showed that all spray-dried dispersions listed in Table 10 were completely amorphous. The XRPD diffractograms of each spray-dried solid dispersion were devoid of sharp crystalline peaks, as can be seen in Figures 11A and 11B.

[0163] Kinetic solubility experiments were performed using the same equipment and protocol described above in this example, using 2 mm pathlength tips for quantification of Danikopan in both SGF and FaSSIF, respectively.

[0164] The required amount of solid dispersion material, equivalent to 5 mg of Danikopan, was weighed into a 20 mL glass vial. The vial was then transferred to the instrument for analysis. A clean stir bar was added to the vial containing the sample. Before starting the experiment, 16 mL of SGF buffer was transferred to the vial to achieve an upper limit of approximately 300 μg / mL. Stirring was maintained at 220 RPM, and the temperature of the medium was maintained at 37°C. Kinetic solubility data was collected in SGF medium for 30 minutes. At 30-minute intervals, the medium was converted to FaSSIF pH 6.5 using an in-house medium conversion protocol. The final volume in the vial was increased from 16 mL to 20 mL (250 μg / mL). The resulting sample was then analyzed in FaSSIF for approximately 18 hours using a μDiss Profiler.

[0165] All solid dispersion formulations exhibited 2- to 5-fold higher equilibrium solubility compared to crystalline Danikopan at 4 hours. The PVP VA64 solid dispersion exhibited a higher spike and slower drop behavior, with three solid dispersions at different loadings reaching approximately 190 μg / mL in SGF but declining to lower concentrations after conversion to FaSSIF. In SGF medium, the 60 / 40 Danikopan / PVP VA64 solid dispersion achieved higher equilibrium solubility compared to the other two PVP VA64 solid dispersions at 40% and 80% Danikopan loading, respectively. The 80 / 20 Danikopan / HPMCAS-H solid dispersion also demonstrated the ability to reach a higher solubility of approximately 100 μg / mL in SGF compared to the other solid dispersions containing enteric polymers. In FaSSIF medium, all HPMCAS-M solid dispersions performed better by reaching approximately 100 μg / mL and remaining supersaturated at that concentration. The 40 / 60 Danicopane / Eudragit L100 solid dispersion reached approximately 120 μg / mL, but the data was significantly affected by spectral shifts and may therefore be unreliable. Kinetic solubility results are summarized in Table 11. The data suggested that the HPMCAS-M solid dispersion outperformed the other solid dispersions in terms of achieving higher solubility and remaining supersaturated at approximately 100 μg / mL. XRPD was performed on the remaining wet solid after the kinetic solubility test, and the results indicated that the sample did not exhibit any signs of crystallinity at detectable levels.

[0166] [Table 11] a The simulated Cmax corresponds to the maximum concentration in the kinetic solubility profile.

[0167] Example 10: Pharmacokinetics of Danikopan solid dispersion in healthy adult humans The pharmacokinetics of three Danicopane solid dispersions were studied in healthy human volunteers. The study was conducted in accordance with the International Council for Harmonisation (ICH) Harmonised Tripartite Guideline and in accordance with the ethical principles of Good Clinical Practice (GCP). This was a two-part, open-label, randomised, single-dose, three-sequence, three-period crossover, relative bioavailability (BA) and food effect study in healthy adult participants. Three Danicopane solid dispersions were used in this study: (1) a 60 / 40 Danicopane / PVP VA64 solid dispersion as 200 mg PIC (designated throughout as "PIC1"), (2) a 25 / 75 Danicopane / HPMCAS-M solid dispersion as 200 mg PIC (designated throughout as "PIC2"), and (3) an 80 / 20 Danicopane / HPMCAS-H solid dispersion in 100 mg tablets (designated throughout as "tablets").

[0168] Part of the research On Day 1 of each period, participants received a single oral dose of Danikopan in the prototype PIC1 formulation under fed conditions (Treatment A), the prototype PIC1 formulation under fasted conditions (Treatment B), or the tablet formulation under fed conditions (Treatment C). Participants were randomized in a 1:1:1 ratio to one of three sequences. All participants received Treatments A, B, and C, according to the treatment sequence that randomized participants to ABC, BCA, or CAB. PK blood samples were collected prior to Danikopan administration and for 72 hours after each Danikopan administration.

[0169] Part 2 of the study On Day 1 of each period, participants received a single oral dose of Danikopan in the prototype PIC2 formulation under fed conditions (Treatment D), the prototype PIC2 formulation under fasted conditions (Treatment E), or the tablet formulation under fed conditions (Treatment F). Participants were randomized in a 1:1:1 ratio to one of three sequences. All participants received Treatments D, E, and F, according to the treatment sequence that randomized participants to DEF, EFD, or FDE. PK blood samples were collected prior to and for 72 hours after each Danikopan dose.

[0170] Both parts In both parts 1 and 2 of the study, there was a washout period of at least 5 days between each Danicopan administration.

[0171] Research design considerations Participants were randomized to treatment sequence to minimize allocation bias. A three-period, three-sequence crossover design was used to reduce remaining variability, with every participant acting as their own control.

[0172] In each period, participants were confined to the clinic at the time indicated by the study site, from Day -1 of Period 1 through 72 hours after PK sample collection and study procedures on Day 4 of Period 3. Participants returned for study follow-up.

[0173] At any time, participants may be required to remain at the study site for longer periods at the discretion of the investigator or designee.

[0174] All participants who received at least one dose of study medication (including those who terminated the study early) returned to the study site 10 (±2) days after their last study medication dose for follow-up procedures and to determine whether any adverse events (AEs) had occurred since their last study visit.

[0175] Pharmacokinetics The mean plasma danicopan concentration-time profiles after a single 200 mg dose of danicopan administered as a prototype PIC1 formulation under fed and fasted conditions and as a tablet formulation under fed conditions are presented on a linear scale in Figure 12A and on a semi-logarithmic scale in Figure 12B.

[0176] Following a single oral dose of 200 mg danikopan, danikopan concentrations were generally quantifiable in plasma by 0.5 hours (the first post-dose time point) in all participants in each treatment group. Danikopan was readily absorbed following administration of the PIC1 formulation under fasted conditions (Treatment B) and the tablet formulation under fed conditions (Treatment C), with individual maximum plasma concentrations occurring between 1.00 and 4.00 hours post-dose. In comparison, delayed absorption was observed when the PIC1 formulation was administered under fed conditions (Treatment A), with individual maximum plasma concentrations observed between 3.00 and 10.00 hours post-dose. Post-peak concentrations declined in a multiphasic manner and remained quantifiable for up to 72 hours post-dose in the majority of participants in each treatment group. Peak mean concentrations were lower with the PIC1 formulation under fed conditions compared with the tablet formulation under fasted and fed conditions.

[0177] A summary of plasma Danicopane PK parameter estimates after each treatment is presented in Table 12. Statistical comparisons of plasma Danicopane PK parameter estimates are summarized in Tables 13 and 14.

[0178] [Table 12]

[0179] [Table 13]

[0180] [Table 14]

[0181] After a single oral dose of 200 mg Danikopan, the median T of Danikopan in plasma maxThe terminal elimination phase was easily characterized for all participants in each treatment group, and the apparent terminal half-life (t 1 / 2 ) estimates were comparable for each treatment, ranging from approximately 9.38 to 10.1 hours. Apparent total clearance (CL / F) and apparent volume of distribution (V z Estimates of HR / F were also comparable across treatments, ranging from 57.4 to 59.8 L / h and 765 to 843 L, respectively.

[0182] Exposure parameters of Danikopan in plasma (AUC and C max Between-participant variability (geometric CV%) for ) was generally low for each treatment, ranging from 25.1 to 28.9%, 32.7 to 39.8%, and 22.6% to 33.1% for PIC1 (fed), PIC1 (fasted), and tablet (fed), respectively.

[0183] Under fed conditions, the extent of danikopan exposure in plasma was similar between the PIC1 and tablet formulations, as measured by the geometric mean ratio (GMR, treatment A / C), AUC 0-t and AUC 0-inf In contrast, at peak exposure to Danicopan (C max ) was approximately 25% lower in PIC1 (fed) compared to the tablet (fed), and C max The lower limit of the 90% confidence interval (CI) for GMR was less than 80% (90% CI: 62.51-91.15). Compared with the tablet formulation under fed conditions, Danikopan in the PIC1 formulation significantly reduced median T max A statistically significant (p=0.0010) delay of approximately 3 hours was observed.

[0184] After PIC1 administration, (AUC 0-t and AUC 0-inf The extent of danicopan exposure in plasma (measured by C) was similar under fed and fasted conditions, but peak exposure was approximately 40% lower in the presence of food. maxThe GMR (treatment A / B) was 59.59, with a 90% CI completely below 80% (49.35-71.95). Compared to the fasted condition, the PIC1 formulation significantly increased median T max A statistically significant (p=0.0010) delay of approximately 4 hours was observed.

[0185] The extent of Danikopan exposure (AUC) was similar, with peak exposure (C max ) was approximately 27% higher for the PIC1 formulation under fasted conditions compared to the tablet formulation under fed conditions. max occurred approximately 1 hour earlier with the PIC1 formulation (fasted) compared to the tablet formulation (fed) (p=0.0342).

[0186] Of note, one participant (Participant 4) had measurable pre-dose concentrations in Treatment C (tablet, fed condition). max Because the PK data for this participant was ≤5% of the PK data, they were included in the PK summary and statistical analysis.

[0187] The mean plasma danicopan concentration-time profiles after a single 200 mg dose of danicopan administered as a prototype PIC2 formulation under fed and fasted conditions and as a tablet formulation under fed conditions are presented on a linear scale in Figure 13A and on a semi-logarithmic scale in Figure 13B.

[0188] Following a single oral dose of 200 mg danikopan, danikopan concentrations were quantifiable in plasma by 0.5 hours post-dose in all participants in each treatment group. Danikopan was readily absorbed following administration of the PIC2 formulation under fasted conditions (Treatment E) and the tablet formulation under fed conditions (Treatment F), with individual maximum plasma concentrations occurring between 1.50 and 6.00 hours post-dose. In comparison, delayed absorption was observed when the PIC2 formulation was administered under fed conditions (Treatment D), with individual maximum plasma concentrations observed between 4.01 and 16.00 hours post-dose. Post-peak concentrations declined in a multiphasic manner and remained quantifiable for up to 72 hours post-dose in the majority of participants in each treatment group. Peak mean concentrations were lower with the PIC2 formulation under fed conditions compared with the tablet formulation under fasted and fed conditions.

[0189] A summary of the plasma Danicopane PK parameters after each treatment is presented in Table 15. Statistical comparisons of the plasma Danicopane PK parameter estimates are summarized in Tables 16 and 17.

[0190] [Table 15]

[0191] [Table 16]

[0192] [Table 17]

[0193] After a single oral dose of 200 mg Danikopan, the median T of Danikopan in plasma max The terminal elimination phase was easily characterized for all participants in each treatment group, and the apparent terminal t 1 / 2Estimates were comparable after each treatment, ranging from approximately 9.34 to 10.8 hours. Danicopan's apparent CL / F and V were significantly greater for the PIC2 formulation under fed conditions compared to the tablet formulation under fasted and fed conditions. z / F estimates were higher.

[0194] Exposure parameters of Danikopan (AUC and C max Inter-participant variability (geometric CV%) for ) was generally low for the PIC2 formulation under fasted conditions and the tablet formulation under fed conditions (range: 28.8-36.0% and 23.2-34.6%, respectively). Moderate inter-participant variability, ranging from 75.5-81.0%, was observed for the PIC2 formulation under fed conditions.

[0195] AUC of Danikopan in plasma 0-t , AUC 0-inf , and C max The GMR (treatment D / F) showed approximately 10%, 11%, and 33% reductions in exposure with the PIC2 formulation compared to the tablet formulation under fed conditions, respectively. AUC 0-t and AUC 0-inf The 90% CI of the GMR of C max The 90% CIs for the GMRs of 100% (69.95-114.64 and 69.87-114.45, respectively) were 100%, in contrast to the 90% CIs for the GMRs of 49.57-89.92. However, the lower limits of the 90% CIs were less than 80% for each parameter. Compared with the tablet formulation under fed conditions, the median T max A statistically significant (p=0.0010) delay of approximately 3.5 hours was observed.

[0196] AUC and C of Danikopan max The GMR (treatment D / E) of PIC2 was reduced by approximately 19% and 60% when the PIC2 formulation was administered under fed compared to fasted conditions, respectively. AUC 0-t and AUC 0-inf The 90% CIs of the GMRs of C included 100% (62.93-103.13 and 62.98-103.16, respectively), but the lower bounds were less than 80%.max The 90% CI of GMR was completely below 80% (28.25-51.26). Compared to the fasted condition, the PIC2 formulation significantly reduced median T max A statistically significant (p=0.0005) delay of approximately 4.25 hours was observed.

[0197] AUC and C of Danikopan max were approximately 11% and 75% higher for the PIC2 formulation under fasted conditions compared with the tablet formulation under fed conditions, respectively, while median T max The estimates were not statistically different.

[0198] Pharmacokinetic conclusions from part one of the study Following a single 200 mg dose of Danikopan, the extent of exposure (AUC) to Danikopan in the prototype PIC1 and tablet formulations was comparable under fed (moderate fat) conditions. However, the peak exposure to Danikopan (C max ) was approximately 25% lower with the PIC1 formulation. Compared with the tablet formulation under fed conditions, the median T of Danikopan was significantly lower with the PIC1 formulation. max A delay of approximately 3 hours was observed.

[0199] Following a single 200 mg dose of Danikopan in the prototype PIC1 formulation, the extent of Danikopan exposure was similar under fed compared to fasted conditions. However, peak Danikopan exposure was approximately 40% lower under fed conditions. Compared to fasted conditions, the median T of Danikopan was significantly lower under fed conditions. max A delay of approximately 4 hours was observed.

[0200] The PIC1 formulation exhibits a reduced absorption rate (C) with similar systemic exposure to Danikopan compared to the tablet formulation under fed conditions. max (decrease in

[0201] Effect of food on PIC1 formulation (C max This decrease in danicopan systemic exposure is in contrast to the previously observed increase in danicopan systemic exposure when the tablet formulation was administered with food.

[0202] The extent of exposure to Danikopan was similar after administration of PIC1 under fasted conditions and the tablet under fed conditions. However, peak exposure to Danikopan was 27% higher with PIC1 (fasted) compared with the tablet (fed), and median T max was an hour early.

[0203] Pharmacokinetic conclusions from the two parts of the study Following a single 200 mg dose of Danikopan, the extent of exposure was slightly lower (10-11%) with the prototype PIC2 formulation compared to the tablet formulation under fed conditions. Peak exposure to Danikopan was approximately 33% lower with the PIC2 formulation compared to the tablet, with median T max was delayed by approximately 3.5 hours.

[0204] Administration of a single 200 mg dose of Danikopan in the prototype PIC2 formulation with food reduced both the magnitude and peak exposure to Danikopan by approximately 19% and 62%, respectively, compared to fasted conditions. Compared to fasted conditions, the median T of Danikopan was significantly lower under fed conditions. max A delay of approximately 4.25 hours was observed.

[0205] The PIC2 formulation resulted in a reduced overall systemic exposure to Danikopan and a decreased absorption rate (C) compared to the tablet formulation under fed conditions. max (decrease in the

[0206] The effect of food on PIC2 formulation (AUC and C max This decrease in danicopan systemic exposure contrasts with the previously observed increase in danicopan systemic exposure when the tablet formulation was administered with food.

[0207] Overall, a more pronounced food effect on danikopan exposure is observed with the PIC2 formulation compared to the PIC1 formulation.

[0208] The degree of exposure to Danikopan was slightly increased (11%) after administration of PIC2 under fasted conditions compared to the tablet formulation under fed conditions. Peak exposure to Danikopan was approximately 75% higher with PIC2 (fasted). max was similar for both treatments.

[0209] Other embodiments While the present disclosure has been described in relation to specific embodiments thereof, it is possible to make further modifications, and this application is intended to cover any variations, uses, or adaptations of the present disclosure; it will be understood that the principles of the present disclosure, including such departures from the disclosure, will generally be understood to be within known or customary practice in the art to which the present disclosure pertains and which may be applied to the essential features described hereinabove. All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A solid dispersion comprising (i) substantially amorphous danicopane and (ii) a pharmaceutically acceptable polymer, wherein the (w / w) ratio of substantially amorphous danicopane to pharmaceutically acceptable polymer in said solid dispersion is from 10:1 to 1:

4.

2. 2. The solid dispersion of claim 1, wherein the loading percentage of the substantially amorphous Danikopan is 25% to 90% (w / w).

3. 3. The solid dispersion of claim 2, wherein the (w / w) ratio of substantially amorphous danikopane to said pharmaceutically acceptable polymer is from 3:1 to 4:

1.

4. 4. A solid dispersion according to any one of claims 1 to 3, wherein by X-ray powder diffraction at least 90% of the Danikopan is in amorphous form.

5. 5. The solid dispersion of claim 1, wherein the pharmaceutically acceptable polymer comprises a polymer selected from the group consisting of cellulose derivatives, polyacrylates, polyvinylpyrrolidone, polyvinyl acetate, copolymers of polyvinylpyrrolidone and polyvinyl acetate, and combinations thereof.

6. 6. The solid dispersion of claim 5, wherein the pharmaceutically acceptable polymer is a cellulose derivative selected from the group consisting of cellulose acetate having 10% to 50% acetyl, alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, hydroxyalkyl alkyl cellulose ester, carboxyalkyl cellulose, carboxyalkyl alkyl cellulose, and carboxyalkyl cellulose ester.

7. 7. The solid dispersion of claim 6, wherein the pharmaceutically acceptable polymer is hydroxypropylmethylcellulose (HPMC) E3.

8. 7. The solid dispersion of claim 6, wherein the pharmaceutically acceptable polymer is a cellulose acetate selected from the group consisting of cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose (HPMC), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS).

9. 9. The solid dispersion of claim 8, wherein the pharmaceutically acceptable polymer is an HPMCAS polymer selected from Grade L (HPMCAS-L), Grade H (HPMCAS-H), or Grade M (HPMCAS-M).

10. 6. The solid dispersion of claim 5, wherein the pharmaceutically acceptable polymer is a polyacrylate selected from the group consisting of polymethacrylates, methacrylate copolymers, and ethacrylate copolymers.

11. 11. The solid dispersion of claim 10, wherein the pharmaceutically acceptable polymer is Eudragit L-100.

12. 6. The solid dispersion of claim 5, wherein the pharmaceutically acceptable polymer is a polyvinyl acetate selected from the group consisting of polyvinyl acetate esters and polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymers.

13. 13. The solid dispersion of claim 12, wherein the pharmaceutically acceptable polymer is polyvinyl acetate phthalate (PVAP).

14. 6. The solid dispersion of claim 5, wherein the pharmaceutically acceptable polymer is a copolymer of polyvinylpyrrolidone and polyvinyl acetate, the copolymer having a ratio of N-vinyl-2-pyrrolidone to vinyl acetate of 10:90 to 70:

30.

15. A pharmaceutical composition in a capsule or tablet for oral administration comprising the solid dispersion of any one of claims 1 to 14.

16. 16. The pharmaceutical composition of claim 15, containing 20 mg to 900 mg of substantially amorphous danikopan.

17. 17. The pharmaceutical composition of claim 15 or 16, further comprising a pharmaceutically acceptable plasticizer, binder, filler, carrier, excipient, and / or surfactant.

18. 18. The pharmaceutical composition of any one of claims 15 to 17, wherein the solid dispersion is formed by spray drying a liquid mixture comprising danikopane and the pharmaceutically acceptable polymer.

19. 19. The pharmaceutical composition of any one of claims 15 to 18, wherein the pharmaceutical composition is in the form of a capsule selected from a hard hydroxypropyl methylcellulose capsule, a hard gelatin capsule, or a soft gelatin capsule, and the capsule contains a powder comprising the solid dispersion.

20. The pharmaceutical composition according to any one of claims 15 to 18, wherein the pharmaceutical composition is in the form of a tablet.

21. 21. The pharmaceutical composition of any one of claims 15 to 20, wherein when tested according to the dissolution method defined herein using 0.1 N hydrochloric acid in water at 37°C with stirring at 50 rpm, at least 50% (w / w) of the pharmaceutical composition dissolves within the first 8 to 90 minutes of the test.

22. 21. The pharmaceutical composition of any one of claims 15 to 20, when tested according to the supersaturation profiling method defined herein using simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at 37°C, releases 0.027 or 0.8 mg / mL of said pharmaceutical composition in SIF or SGF, respectively, within the first 4 hours of the test.

23. A pharmaceutical composition for oral administration comprising danikopan dissolved in a glyceride fatty acid ester, a pharmaceutically acceptable organic solvent, and a D-α-tocopherol polyethylene glycol succinate (TPGS) compound contained in a liquid soft gelatin capsule.

24. 24. The pharmaceutical composition of claim 23, wherein the ratio (w / w) of glyceride fatty acid ester, danicopan, pharmaceutically acceptable organic solvent, and TPGS is 16:2:1:

1.

25. 25. The pharmaceutical composition of claim 24, wherein the danikopan is dissolved in Capmul MCM, propylene glycol, and D-alpha-tocopheryl PEG 1000 succinate.

26. A pharmaceutical composition according to any one of claims 23 to 25, comprising 20 mg to 900 mg of danikopan.

27. A method for preparing the solid dispersion according to any one of claims 1 to 14, said method comprising: (i) dissolving Danikopan and a pharmaceutically acceptable polymer in an organic solvent to form a solution; (ii) spray drying the solution to form the solid dispersion.

28. 28. The method of claim 27, wherein the organic solvent has a boiling point of less than 80°C.

29. 27. A method for treating a condition regulated by complement factor D, comprising orally administering to a subject in need thereof an effective amount of the pharmaceutical composition of any one of claims 15 to 26.

30. 30. The method of claim 29, wherein the pharmaceutical composition is orally administered once, twice, or three times per day.

31. 31. The method of claim 29 or 30, wherein the condition is paroxysmal nocturnal hemoglobinuria (PNH) and PNH with clinically evident extravascular hemolysis (EVH).

32. 32. The method of claim 31, wherein the pharmaceutical composition comprises 150-200 mg of danikopan and is administered orally three times a day.

33. 33. The method of claim 32, wherein the pharmaceutical composition comprises 150 mg of danikopan and is administered orally three times daily.

34. 31. The method of claim 29 or 30, wherein the condition is geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

35. 35. The method of claim 34, wherein the pharmaceutical composition comprises 100-200 mg of danikopan and is administered orally twice daily.

36. 35. The method of claim 34, wherein the pharmaceutical composition comprises 200 to 400 mg of danikopan and is administered orally once daily.

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