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WO2025265110A1 - Compositions pharmaceutiques orales renfermant un composé de naphtyridine - Google Patents

Compositions pharmaceutiques orales renfermant un composé de naphtyridine

Info

Publication number
WO2025265110A1
WO2025265110A1 PCT/US2025/034720 US2025034720W WO2025265110A1 WO 2025265110 A1 WO2025265110 A1 WO 2025265110A1 US 2025034720 W US2025034720 W US 2025034720W WO 2025265110 A1 WO2025265110 A1 WO 2025265110A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
amount
composition
present
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/034720
Other languages
English (en)
Inventor
Fernando Antonio ALVAREZ-NUNEZ
John Inn CHUNG
Behnoush KHORSAND
Yuan-Hon Kiang
Yicong LIANG
Hwee Jing ONG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc filed Critical Amgen Inc
Publication of WO2025265110A1 publication Critical patent/WO2025265110A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Naphthyridine compounds have been shown to be important in a number of biological applications, including modulating processes mediated by the enzyme protein arginine methyltransferase 5 (PRMT5). It is known that PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders.
  • PRMT5 arginine methyltransferase 5
  • (4(trifluoromethy Ijpheny Ijmorphol inojmethanone) is a small molecule PMRT5 inhibitor currently being evaluated for the treatment of cancers with methylthioadenosine phosphorylase (MTAP) deletion occurring in about 15% of human cancers, including for example, non-small lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, esophageal cancer, and cholangiocarcinoma in the second or third line of therapy.
  • MTAP methylthioadenosine phosphorylase
  • a goal in developing a drug is to provide dosage forms which make it possible to maintain a certain amount or concentration of drug in a subject's body that is clinically or therapeutically relevant, in a manner that provides suitable patient compliance. In some cases, this is complicated when the dosage forms comprise a high drug loading. Daily doses as high as 1600 mg/day or 1200 mg/day of Compound A currently being evaluated can pose a significant pill burden to a subject having to take many doses a day in order to achieve a recommended dosage. Another goal in developing a formulation of Compound A that is safe, effective, stable and convenient for patients.
  • the disclosure provides pharmaceutical compositions comprising 1-40 wt% Compound A, a diluent, a disintegrant, and a lubricant, wherein the pharmaceutical compositions are suitable for oral administration.
  • the disclosure further provides pharmaceutical compositions comprising Compound A, a diluent in an amount of 45- 75 wt%, a polyol in an amount of 3-25 wt%, a disintegrant in an amount of 1-10 wt%, and a lubricant in an amount of 0.5-7%, wherein the pharmaceutical compositions are free of a reducing sugar and suitable for oral administration.
  • the pharmaceutical compositions are in the form of a tablet.
  • the tablet comprises a coating, such as a film-coating.
  • the disclosure also provides methods of using the disclosed pharmaceutical compositions, including methods of treating cancer (e.g., ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, esophageal, gastroesophageal junction (GEJ) cancer, biliary tract cancer (BTC), pancreatic, bladder cancer, glioma, solid tumor, head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, and mesothelioma).
  • cancer e.g., ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, esophageal, gastroesophageal junction (GEJ) cancer, biliary tract cancer (BTC), pancreatic, bladder cancer, glioma, solid tumor, head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, and mesothelioma).
  • cancer e.g
  • the disclosure also provides a method of treating a disease or disorder responsive to inhibiting protein arginine methyltransferase 5 (PRMT5) comprising administering to the subject a therapeutically effective amount of the disclosed compositions.
  • PRMT5 protein arginine methyltransferase 5
  • Figure 1 shows a comparison of the dissolution profiles of tablets comprising 1 wt% Mg stearate and 1 .25 wt% Mg stearate.
  • Figure 3 shows particle size distribution (PSD) of granules for 1% DL and 20% DL final blends as described in Example 1.
  • Figure 5A shows impact of tablet hardness (kp) on the disintegration times of 5 mg tablets for three different hardnesses (low, target, and high).
  • the tablets comprised Compound A and were prepared as described in Example 1 .
  • QTPP quality target product profile
  • Figure 5B shows impact of tablet hardness (kp) on the disintegration times of 20 mg tablets for three different hardnesses (low, target, and high).
  • the tablets comprised Compound A and were prepared as described in Example 1 .
  • QTPP quality target product profile
  • Figure 8A shows the dissolution profiles of 200 mg tablets having different hardness values (17.5, 24, and 29.5 kp), as described in Example 2.
  • Figure 9 shows a comparison of bulk and tapped density of tablets having a DL of 20%, 25%, and 32%, as described in Example 2.
  • Figure 10 shows a comparison of Carr's index of tablets having a DL of 20%, 25%, and 32%, as described in Example 2.
  • Figure 11 shows a comparison of the PSD of the initial blends from 25% and 32% DL, as described in Example 2.
  • Figure 12 shows a PSD comparison of the PSD of the final blends from 25% and 32% DL, as described in Example 2.
  • Figure 13 shows a PSD comparison of the dissolution profiles of the 25% and 32% DL, as described in Example 2.
  • Figure 14 shows the preliminary mean (+SD) plasma Compound A concentration-time profiles after once daily administration of Compound A cycle 1 day 1 .
  • Figure 15 shows the preliminary mean (+SD) plasma Compound A concentration-time profiles after once daily administration of Compound A cycle 1 day 15.
  • Figure 16 shows dose normalized C ma x at Cycle 1 Day 1 for 100 mg and 200 mg tablets.
  • Figure 17 shows dose normalized C ma x at Cycle 1 Day 15 for 100 mg and 200 mg tablets.
  • Figure 18 shows dose normalized AUG at Cycle 1 Day 1 for 100 mg and 200 mg tablets.
  • Figure 19 shows dose normalized AUG at Cycle 1 Day 15 for 100 mg and 200 mg tablets.
  • Figure 20 shows the dissolution profile for 300 mg IR film-coated tablets in 50 mM phosphate buffer pH
  • compositions comprising Compound A: , wherein the compositions are suitable for oral administration.
  • compositions for providing 1-40 wt% are provided herein.
  • the disclosed pharmaceutical compositions comprise 1-40 wt% Compound A, a diluent, a disintegrant, and a lubricant.
  • the disclosed pharmaceutical compositions further comprise a polyol.
  • provided herein are pharmaceutical compositions comprising Compound A, a diluent in an amount of 45-75 wt%, a polyol in an amount of 3-25 wt%, a disintegrant in an amount of 1-10 wt%, and a lubricant in an amount of 0.5-7%, wherein the pharmaceutical compositions are free of a reducing sugar.
  • the pharmaceutical compositions further comprise a coating (e.g., a film-coating).
  • the disclosed pharmaceutical compositions are suitable for oral administration.
  • the disclosed pharmaceutical compositions are a tablet.
  • the disclosed pharmaceutical compositions advantageously are capable of providing a high drug loading of Compound A in solid dosage forms suitable for oral administration (e.g., tablets).
  • the disclosed pharmaceutical compositions provide a high drug loading (DL) of Compound A.
  • a high drug loading refers to dosage forms comprising more than 20 wt% Compound A, such as at least 25 wt% Compound A per unit dosage (e.g., 25-40 wt% Compound A).
  • a high DL dosage form may comprise 25, 30, 32, 35, 37.5, or 40 wt% Compound A.
  • the disclosure provides tablets comprising 40 wt% Compound A.
  • compositions having a high drug loading reduce the pill burden of patients administered high dosages of Compound A using conventional dosage forms.
  • pharmaceutical compositions disclosed herein provide improved handling during manufacture and provide suitable in vivo pharmacokinetics (PK).
  • PK in vivo pharmacokinetics
  • the 200 mg tablets (25% DL) show suitable in vivo PK. See, for example, Figures 16-19.
  • the disclosed composition advantageously reduces or prevents chemical degradation of the composition by including a polyol, such as mannitol, as a brittle diluent, while overcoming the unfavorable higher sticking propensity that typically accompanies the inclusion of polyol in such compositions by including an increased amount of lubricant, all without affecting compression or dissolution.
  • a polyol such as mannitol
  • a brittle diluent such as a brittle diluent
  • IVIVC In vitro-in vivo correlation
  • a delivery system must be selected/designed for each active ingredient followed by evaluation of the PK properties (e.g., absorption, plasma exposure, and target site exposure) and the PD properties (target binding/activation, transducer process, biological effects and response).
  • the PK/PD properties are evaluated in preclinical studies, wherein the results are used to development a suitable dosing regimen which can be further evaluated in clinical studies, wherein the ultimate goal is the development of an approved drug product.
  • the disclosed pharmaceutical compositions are an immediate release composition.
  • immediate release refers to a pharmaceutical composition developed to dissolve without delaying or prolonging dissolution or absorption of a drug.
  • an IR tablet or capsule is swallowed whole and instantaneously disintegrates to make the drug available for absorption and subsequent pharmacologic action.
  • Immediate-release products are used when the rapid onset of action of a drug is advantageous and usually include disintegrants (e.g., croscarmellose sodium) as excipients.
  • disintegrants e.g., croscarmellose sodium
  • 70% to 80% of a drug in an IR formulation should be released, preferably within an hour, and certainly within 4 hours, after ingestion. For poorly soluble drugs, a longer dissolution time may be considered normal. In certain embodiments, 70% to 80% of the drug in an IR formulation is released within one hour. In certain embodiments, at least 85% of the drug in an IR formulation is released within 60 min in an aqueous medium. In certain embodiments, 70% to 80% of the drug in an IR formulation is released within 4 hours.
  • the disclosed pharmaceutical compositions comprise Compound A.
  • the disclosed pharmaceutical compositions comprise Compound A as the free base.
  • the disclosed pharmaceutical compositions comprise Compound A as a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, and which do not possess any own properties that are undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyru
  • preferred “pharmaceutically acceptable salts” include the acetate, bromide, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate and tosylate salt of Compound A.
  • the disclosed pharmaceutical compositions comprise 1-40 wt% Compound A. Accordingly, in some embodiments, the pharmaceutical compositions comprise 1 wt% Compound A, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 1-20 wt% Compound A, for example, 3-17 wt% Compound A, 5-15 wt% Compound A and 8-12 wt% Compound A.
  • the disclosed pharmaceutical compositions comprise 20-40 wt% Compound A, for example, 23-38 wt%, 25-35 wt%, and 28-32 wt% Compound A.
  • the disclosed pharmaceutical compositions comprise 1 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 20 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 25 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 30 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 32 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 37.5 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 40 wt% Compound A. DILUENT
  • the disclosed pharmaceutical compositions comprise a diluent.
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used without limitation to increase the bulk of a potent drug whose mass is too small for manufacture or administration and/or to improve the consistency of a composition for processing and handling, and/or to improve stability, and binding ability of a composition comprising the drug.
  • suitable diluents include, for example, lactose, lactose monohydrate, microcrystalline cellulose, and a combination thereof.
  • the disclosed pharmaceutical compositions comprise microcrystalline cellulose.
  • the pharmaceutical compositions comprise more than one diluent.
  • the pharmaceutical compositions comprise lactose monohydrate.
  • the diluent comprises microcrystalline cellulose.
  • the diluent comprises lactose monohydrate and microcrystalline cellulose.
  • the disclosed pharmaceutical compositions are free of a reducing sugar (e.g., lactose).
  • the pharmaceutical composition comprises a polyol (e.g., mannitol), as described herein.
  • the disclosed pharmaceutical compositions comprise a suitable amount of diluent.
  • the pharmaceutical compositions disclosed herein comprise about 50-80 wt% diluent of the composition (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, and 80 wt%, including amounts in between the listed point values).
  • the disclosed pharmaceutical compositions comprise 45-75 wt% diluent, 50-70 wt%, 50-65 wt%, or 55-65 wt% diluent.
  • the disclosed pharmaceutical compositions comprise 71.25 wt% diluent.
  • the disclosed pharmaceutical compositions comprise 57 wt% diluent.
  • the disclosed pharmaceutical compositions comprise 58.25 wt% diluent.
  • the disclosed pharmaceutical compositions comprise 55.75 wt% diluent.
  • the disclosed pharmaceutical compositions comprise 45-75 wt%, 50-70 wt%, 50-65 wt%, or 55-65 wt% of microcrystalline cellulose. In some cases, the disclosed pharmaceutical compositions comprise 55.75 wt% of microcrystalline cellulose. In some cases, the disclosed pharmaceutical compositions comprise 57 wt% of microcrystalline cellulose. In some cases, the disclosed pharmaceutical compositions comprise 58.25 wt% of microcrystalline cellulose. In some cases, the disclosed pharmaceutical compositions comprise 71 .25 wt% of microcrystalline cellulose.
  • the disclosed pharmaceutical compositions further comprise a polyol.
  • suitable polyols e.g., sugar alcohols
  • suitable polyols include mannitol, sorbitol, xylitol, erythritol, isomalt, lactitol, hydrogenated starch hydrolysates, or a combination thereof.
  • the disclosed pharmaceutical compositions comprise mannitol, sorbitol, or a combination thereof.
  • the disclosed pharmaceutical compositions comprise mannitol.
  • the disclosed pharmaceutical compositions comprise a suitable amount of polyol.
  • the polyol is present in an amount of 3-25 wt% (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25 wt% of the composition, including amounts in between the recited values (e.g., 8.75, 13.75, 23.75 wt% of the composition),.
  • the polyol is present in 3-15 wt%, 8-10 wt%, and 15-20 wt% of the composition.
  • the polyol is present in 5-15 wt% or 13-15 wt% of the composition.
  • the disclosed pharmaceutical compositions comprise 23.75 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 19 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 14 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 13.75 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 7 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 8.75 wt% polyol.
  • the disclosed pharmaceutical compositions comprise 23.75 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 19 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 14 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 13.75 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 7 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 8.75 wt% mannitol.
  • the amount of polyol present is considered relative to the amount of diluent present.
  • the diluent and polyol are present in a weight ratio of 1 :10 to 10:1 (e.g., 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2, 1 :1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1).
  • the diluent and polyol are present in a weight ratio of 1 :5 to 5:1.
  • the diluent and polyol are present in a weight ratio of 8:1. In some embodiments, the diluent and polyol are present in a weight ratio of 3:1.
  • the 5 mg, 20 mg, and 100 mg tablets comprise, inter alia, a 3:1 weight ratio of diluent to polyol (e.g., see Tables 1 and 2 of Example 1). In some cases, the diluent and polyol are present in a weight ratio of 4: 1 . In some cases, the diluent and polyol are present in a weight ratio of 6.5:1.
  • the disclosed pharmaceutical compositions comprise a disintegrant.
  • a “disintegrant” refers to an ingredient added to solid dosage forms to facilitate their breakup or disintegration when exposed to moisture or fluids in the body.
  • suitable disintegrants include, for example, croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellose sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low- substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.
  • the disintegrant comprises a cellulose derivative.
  • the disintegrant comprises croscarmellose sodium.
  • the disclosed pharmaceutical compositions comprise a suitable amount of disintegrant.
  • the disintegrant is present in an amount of 1-10 wt% of the composition (e.g., 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, and 10 wt% disintegrant).
  • the disclosed compositions comprise 1-9 wt% disintegrant (e.g., 2-8, 3-7, 3-6, 3-5, and 3-4 wt% disintegrant).
  • the disclosed compositions comprise 2-5 wt% (e.g., 2-3, 2-4, 3-4, 3-5, and 4-5 wt%) distintegrant. In some embodiments, the disclosed compositions comprise 3 wt% disintegrant. In some embodiments, the disclosed compositions comprise 3 wt% croscarmellose sodium.
  • the disclosed pharmaceutical compositions comprise a lubricant.
  • a "lubricant” refers to a substance added to solid dosage forms to reduce friction during manufacturing processes thereby preventing sticking of the formulation to the equipment facilitating the release of tablets from molds or punches and ensuring uniformity in tablet weight and helping to maintain the integrity of the dosage form.
  • suitable lubricants include, for example, magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof.
  • the lubricant comprises a stearate.
  • the lubricant comprises magnesium stearate.
  • the disclosed pharmaceutical compositions comprise a suitable amount of lubricant.
  • the lubricant is present in an amount of 0.5-7 wt% of the composition (e.g., 0.5-7, 1-6.5, 1.5-6.0, and 2.0-5.5 wt%).
  • the lubricant is present in an amount of 1-5 wt% of the composition (e.g., 1-4, 1-3, 1-2, 1.1-1.5 wt% lubricant).
  • the lubricant is present in an amount 1 to 1.3 wt% (e.g., 1.0, 1.1, and 1.3 wt% lubricant).
  • the lubricant is present in an amount of 0.5- 1.5 wt%. In some embodiments, the disclosed compositions comprise 1 wt% lubricant. In some embodiments, the disclosed compositions comprise 1 .25 wt% lubricant.
  • the lubricant can be intragranular and/or extragranular. In some embodiments, the lubricant is intragranular. In some embodiments, the lubricant is extragranular. In some embodiments, the lubricant is both extragranular and intragranular. In some embodiments, the amount lubricant is equally distributed intra- and extragranular (e.g., 1 :1). In some embodiments, more of the lubricant is extragranular (e.g., 1.5:1). Without wishing to be bound to any particular theory, it is believed that embodiments comprising more lubricant extragranularly provide improved handling properties during manufacturing of tablets using compression. For example, in some instances the compressed tablet blends were observed to stick to the tooling equipment.
  • the pharmaceutical compositions comprise 0.5 wt% intragranular lubricant and 0.75 wt% extragranular lubricant. In some embodiments, the pharmaceutical compositions comprise 0.5 wt% intragranular magnesium stearate and 0.75 wt% extragranular magnesium stearate.
  • the pharmaceutical composition disclosed herein include Compound A (e.g., in an amount of 1-40 wt%) bear a diluent (e.g., in an amount of 45-75 wt%), optionally a polyol (e.g., in an amount of 3-25 wt%), a disintegrant (e.g., in an amount of 1-10 wt%), and a lubricant (e.g., in an amount of 0.5-7%).
  • the disclosed pharmaceutical compositions are free of a reducing sugar.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) 1-40 wt% Compound A; (2) 45-75 wt% microcrystalline cellulose; (3) 3-25 wt% mannitol; (4) 1-10 wt% croscarmellose; and (5) 0.5-7 wt% magnesium stearate, in the form of a tablet.
  • the pharmaceutical composition is free of reducing sugars and suitable for oral administration.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) 1 wt% Compound A free base; (2) 71.25 wt% microcrystalline cellulose; (3) 23.75 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 wt% magnesium stearate, in the form of a tablet.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) 20 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 19 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 wt% magnesium stearate, in the form of a tablet.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) 25 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 14 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 wt% magnesium stearate, in the form of a tablet.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) 25 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 13.75 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 .25 wt% magnesium stearate, in the form of a tablet.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) 30 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 8.75 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 .25 wt% magnesium stearate, in the form of a tablet.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) 32 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 7 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 wt% magnesium stearate, in the form of a tablet.
  • the disclosure provides a pharmaceutical composition comprising (1) 37.5 wt% Compound A free base; (2) 58.25 wt% microcrystalline cellulose; (3) 3 wt% croscarmellose; and (4) 1 .25 wt% magnesium stearate, in the form of a tablet.
  • the disclosure provides a pharmaceutical composition comprising (1) 40 wt% Compound A free base; (2) 55.75 wt% microcrystalline cellulose; (3) 3 wt% croscarmellose; and (4) 1 .25 wt% magnesium stearate, in the form of a tablet.
  • the disclosed pharmaceutical compositions comprise a coating.
  • a coating may contain, for example, a film-coating (e.g., membrane forming agent such as a polymer), a plasticizer (which provides plasticity, flexibility, and extensibility to a coating membrane), a water-soluble base (e.g., lactose or sodium chloride), a dispersing agent (which prevents particles or tablets from adhering and aggregating after the coating).
  • a film-coating e.g., membrane forming agent such as a polymer
  • plasticizer which provides plasticity, flexibility, and extensibility to a coating membrane
  • a water-soluble base e.g., lactose or sodium chloride
  • a dispersing agent which prevents particles or tablets from adhering and aggregating after the coating.
  • Exemplary membrane forming agents include, for example, a water-insoluble polymer or a water- soluble polymer.
  • the membrane forming agent is not particularly limited, so long as it is pharmaceutically acceptable and biocompatible. These membrane forming agents may be added alone or as a combination thereof in an appropriate amount(s).
  • Exemplary water-insoluble polymer include, but are not limited to, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, beeswax, carnauba wax, cetyl alcohol, cetyl stearyl alcohol, glyceryl behenate, lipids, fats, resins such as shellac or the like, cellulose derivatives such as ethyl cellulose, cellulose acetate, polyacrylate derivatives such as aminoalkylmethacryl copolymer (product name: Eudragit RS), polymethacrylate derivatives such as methacrylate copolymer (product name: Eudragit L), hydroxypropylmethyl cellulose acetate succinate, polylactic acid, and polyglycolic acid.
  • dibenzyl phthalate dihexyl phthalate
  • butyl octyl phthalate beeswax
  • carnauba wax cetyl alcohol
  • Exemplary water-soluble polymers include, but are not limited to, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, carmellose sodium, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol.
  • the coating comprises polyvinyl alcohol.
  • the coating further comprises one or more of titanium dioxide, polyethylene glycol, talc, and a coloring agent.
  • Some exemplary coating compositions include ethylcellulose, polymethacrylates, as well as coating products sold by OPADRYTM.
  • the coating agent is Opadry Clear, Opadry Blue 13B50579, Opadry White 33628707, Opadry QX 321 A180025, or Opadry II (33G28707).
  • the coating agent is Opadry White 33628707.
  • the coating agent is Opadry QX 321 A180025.
  • the weight percentages of the excipients discussed throughout are with respect to the total weight of the composition before the coating composition is applied.
  • the disclosed pharmaceutical compositions comprise a coating in an amount of 3 wt% of the composition before the coating composition is applied. FREE OF REDUCING SUGARS
  • the disclosed pharmaceutical compositions are free of a reducing sugar (e.g., lactose).
  • Reducing sugars include those sugars comprising a free aldehyde or ketone functional group which can act as a reducing agent.
  • Nonlimiting examples of reducing sugars include, for example, glucose, fructose, galactose, lactose, maltose, and combinations thereof.
  • compositions free of a reducing sugar disclosed herein minimize the likelihood of the compositions undergoing decomposition via the Maillard reaction thereby improving stability of the disclosed compositions.
  • compositions were shown to produce Compound A- lactose adducts under various conditions - see, e.g., Example 9.
  • free of a reducing sugar refers to the composition comprising less than 5 wt% of a reducing sugar (e.g., 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, or 1.0 wt% or less of a reducing sugar).
  • the disclosed compositions comprise less than 1 wt% of a reducing sugar (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, or 0.01 wt% or less of a reducing sugar).
  • the disclosed compositions are devoid of a reducing sugar.
  • the disclosed pharmaceutical compositions comprise mannitol as a nonreducing sugar.
  • mannitol can be used in lieu of lactose.
  • use of mannitol in the pharmaceutical compositions disclosed herein results in tablets having comparable compactability as tablets comprising lactose but withimproved compressibility and flow properties as compared to lactose.
  • the disclosure provides methods of treating a disease or disorder responsive to inhibiting protein arginine methyltransferase 5 (PRMT5) comprising administering to the subject a therapeutically effective amount of the disclosed compositions comprising Compound A.
  • PRMT5 protein arginine methyltransferase 5
  • a “therapeutically effective amount” of Compound A means an amount effective to treat or to prevent development of, or to alleviate the existing symptoms of, the patient being treated. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, a “therapeutically effective amount” refers to that amount of Compound A described herein that results in achieving the desired effect.
  • a therapeutically effective amount of Compound A described herein decreases MTAP activity by at least 5%, compared to control, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%.
  • the disclosure provides a method of treating a cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of the composition of the disclosed compositions comprising Compound A.
  • the cancer is a MTAP-null cancer.
  • MTAP-null cancer refers to a cancer that lacks expression of the enzyme methylthioadenosine phosphorylase (MTAP).
  • MTAP-null cancers include MTAP-deficiency in at least 1% of disease cells, and in some cases, at least 20% of disease cells.
  • MTAP-null and “MTAP-deleted” are used interchangeably.
  • Nonlimiting examples of suitable cancer include ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic, and bladder cancer.
  • the cancer is ovarian cancer.
  • the cancer is lung cancer.
  • the cancer is lymphoid.
  • the cancer is glioblastoma.
  • the cancer is colon.
  • the cancer is melanoma.
  • the cancer is gastric.
  • the cancer is pancreatic.
  • the cancer is bladder cancer.
  • the cancer is MTAP-null ovarian cancer, MTAP-null lung cancer, MTAP-null lymphoid cancer, MTAP-null glioblastoma, MTAP-null colon cancer, MTAP-null melanoma, MTAP-null gastric cancer, MTAP-null esophageal cancer, MTAP-null gastroesophageal junction (GEJ) cancer, MTAP-null biliary tract cancer (BTC), MTAP-null pancreatic cancer, MTAP-null bladder cancer, MTAP-null glioma, an MTAP-null solid tumor, MTAP-null head and neck squamous cell carcinoma (HNSCC), MTAP-null gallbladder cancer, and MTAP-null mesothelioma.
  • HNSCC MTAP-null head and neck s
  • the MTAP-null cancer is lung cancer. In some embodiments, the MTAP-null lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the MTAP-null NSCLC is squamous. In some embodiments the MTAP- null NSCLC is non-squamouns. In some embodiments, the MTAP-null cancer is pancreatic cancer. In some embodiments, the MTAP-null pancreatic cancer is MTAP-null pancreatic adenocarcinoma (e.g., MTAP-null pancreatic ductal adenocarcinoma).
  • the MTAP-null cancer is esophageal cancer. In some embodiments, the MTAP-null esophageal cancer is esophageal squamous cell carcinoma or esophageal adenocarcinoma.
  • the methods comprise administering Compound A in an amount ranging from 40 mg to 1600 mg. In some cases, Compound A is administered in a divided daily dose, such as two, three, four, five, or six times a day. In some embodiments, the methods comprise administering 40 mg, 120 mg, 240 mg, 480 mg, 960 mg, or 1600 mg of Compound A to the patient once daily. In some embodiments, the methods comprise administering 40 mg, 120 mg, 240 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 960 mg, 1000 mg, 1100 mg, 1200 mg, or 1600 mg of Compound A to the patient once daily.
  • the methods comprise administering 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 960 mg, 1000 mg, 1100 mg, or 1200 mg of Compound A to the patient once daily. In some embodiments, the methods comprise administering 800 mg, 900 mg, or 1200 mg of Compound A to the patient once daily.
  • the efficacy of a given treatment for cancer can be determined by the skilled clinician. However, a treatment is considered "effective treatment," as the term is used herein, if any one or all of the signs or symptoms of e.g., a tumor are altered in a beneficial manner or other clinically accepted symptoms are improved, or even ameliorated, e.g., by at least 10% following treatment with an agent as described herein. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and/or described herein. EMBODIMENTS
  • a pharmaceutical composition comprising
  • composition of embodiment 1 wherein the diluent is selected from lactose, lactose monohydrate, microcrystalline cellulose, and a combination thereof.
  • composition of embodiment 4, wherein the polyol comprises mannitol, sorbitol, or a combination thereof.
  • composition of embodiment 4 or 5, wherein the polyol comprises mannitol.
  • the disintegrant comprises croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellose sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.
  • lubricant comprises magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof.
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • composition of any one of embodiments 1-49 free of a reducing sugar (e.g., lactose).
  • a reducing sugar e.g., lactose
  • a method of treating a cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of the composition of any one of embodiments 1-50.
  • cancer selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic and bladder cancer.
  • a pharmaceutical composition comprising
  • composition of embodiment 1 A, wherein the diluent is selected from lactose, lactose monohydrate, microcrystalline cellulose, and a combination thereof.
  • composition of embodiment 4A, wherein the polyol comprises mannitol, sorbitol, or a combination thereof.
  • the disintegrant comprises croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellosoe sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.
  • a pharmaceutical composition comprising
  • a lubricant in an amount of 0.5-7 wt%, wherein the pharmaceutical composition is free of a reducing sugar and is suitable for oral administration.
  • composition of embodiment 35A comprising 1-40 wt% Compound A, or a pharmaceutically acceptable salt thereof.
  • composition of embodiment 36A comprising 20-40 wt% Compound A, or a pharmaceutically acceptable salt thereof.
  • composition of embodiment 37 A comprising 20 wt% of Compound A, or a pharmaceutically acceptable salt thereof.
  • composition of embodiment 37 A comprising 30 wt% of Compound A, or a pharmaceutically acceptable salt thereof.
  • composition of any one of embodiments 35A-49A comprising 0.5 wt% intragranular lubricant and 0.75% extragranular lubricant.
  • the disintegrant is croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellose sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.
  • the lubricant is magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof.
  • a pharmaceutical composition comprising:
  • Compound (Compound A) or a pharmaceutically acceptable salt thereof, in an amount of 1-40%;
  • microcrystalline cellulose in an amount of 45-75 wt%
  • croscarmellose in an amount of 1-10 wt%
  • magnesium stearate in an amount of 0.5-7 wt%; wherein the pharmaceutical composition is free of reducing sugars and is suitable for oral administration.
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • a pharmaceutical composition comprising
  • composition of any one of embodiments 1 A-69A, further comprising a coating is provided.
  • a method of treating a cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of the composition of any one of embodiments 1 A-72A.
  • embodiment 75A The method of embodiment 73A or 74A, wherein the cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, esophageal, gastroesophageal junction (GEJ) cancer, biliary tract cancer (BTC), pancreatic, bladder cancer, glioma, solid tumor, head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, and mesothelioma.
  • the cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, esophageal, gastroesophageal junction (GEJ) cancer, biliary tract cancer (BTC), pancreatic, bladder cancer, glioma, solid tumor, head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, and mesothelioma.
  • 76A The method of embodiment 75A, wherein the lung cancer is non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • pancreatic cancer is pancreatic adenocarcinoma.
  • esophageal cancer is esophageal squamous cell carcinoma or esophageal adenocarcinoma.
  • Mg stearate refers to magnesium stearate
  • MCC refers to microcrystalline cellulose
  • DL refers to drug loading
  • QTPP refers to quality target product profile
  • RRT refers to relative retention time
  • RH refers to relative humidity
  • PSD particle size distribution
  • SDS sodium dodecyl sulfate.
  • Dry Granulation Process An illustrative dry granulation manufacturing process (e.g., roller compaction) suitable for preparing the disclosed dosage forms is described herein.
  • De-lumping (sieving): During manufacturing a suitable metal screen was used to de-lump Compound A, microcrystalline cellulose, mannitol, and croscarmellose sodium. It was observed that the Compound A agglomerates and sticks to the screen even after a microcrystalline wash was performed. A similar observation of screen sticking was made using the Vorti-Siev during lead lot manufacturing for both the 1% drug load and 20% drug load formulations which made the delumping step time consuming. Although sticking to the sieve was observed, the assay values and content uniformity for the lead lot 5 mg, 20 mg and 100 mg tablets all met the QTPP criteria. In some instances, co-milling was used to reduce the time for the de-lumping step.
  • This example demonstrates tablets in accordance with embodiments of the disclosure and illustrative manufacturing processes therefor. Tablets comprising Compound A, mannitol, croscarmellose sodium, magnesium stearate were prepared as shown in Tables 1 and 2.
  • T able 1 Composition of 5 mg IR T ablets a The quantity used was adjusted to correct for the assay value of the drug substance batch used. MCC and mannitol was adjusted to maintain a 3:1 ratio. a The quantity used was adjusted to correct for the assay value of the drug substance batch used. MCC and mannitol was adjusted to maintain a 3:1 ratio.
  • Tablets comprising 5 mg (1% DL), 20 mg and 100 mg (20% DL) of Compound A were manufactured via dry granulation using the roller compaction (RC) process described herein and illustrated in Figure 2.
  • RC roller compaction
  • Step 1 The tablet components (Compound A, MCC, mannitol, and croscarmellose sodium) were delumped using a suitable metal screen and blender.
  • the de-lumping step was performed using either preblending and de-lumping or co-milling.
  • Step 5 The final blend from Step 4 was compressed into tablets on a rotary tablet press. The tablet appearance, weight, thickness, and hardness were tested throughout compression.
  • Figure 4 shows the impact of tablet hardness on the friability of the three tablet strengths (5 mg, 20 mg, and 100 mg). For all tablet hardnesses evaluated, the QTPP criteria for friability ( ⁇ 1%) was met for all three tablet strengths. However, the lowest evaluated tablet hardness of 3 kp for the 20 mg strength tablet approached the limit of the QTPP criteria.
  • Figures 5A-C show the impact of tablet hardness on the disintegration time for the three tablet strengths.
  • the QTPP criteria for disintegration ⁇ 300 s
  • the highest evaluated tablet hardness of 9 kp for the 20 mg strength tablet approached the limit of the QTPP criteria.
  • the stability of the dosage forms was evaluated using a bracketing strategy.
  • the 5 mg (1 % drug load) and 100 mg (20% drug load) tablets were packaged in high-density polyethylene (HDPE) bottles (30 count) with child-resistant closures (CRC) containing a foil induction seal liner.
  • Bottles also contained 1 gram of desiccant (2 x 0.5 g sachets).
  • the bottles were stored at the long term (2-8 °C), accelerated (30 °C/65% RH and 40 °C/75%RH), and contingency (-20 °C) storage conditions. Stability results up to one month are summarized in Tables 6 and 7.
  • Stability data for the clinical lot showed no significant changes in appearance, assay, total impurities, morpholine, water content and dissolution after 1 month under -20 °C, 24 months at 30 °C/65% RH, and 6 months at 40 °C/75% RH storage conditions (Tables 5 and 6).
  • the stability indicates that tablets comprising Compound A were stable for at least 36 months at the recommended storage condition (2 to 8 °C). All dissolution profiles after 24 month storage were consistent with an immediate release profile.
  • Compound A has a single CF3 moiety. Due to rotational dynamics of the CF3 and the presence of two unique molecular conformers in Free Base From 1, two fluorine resonances are observed by solid-state NMR that are specific to Compound A Free Base Form 1 . The crystalline form of Compound A was selectively monitored by 19 F solid-state NMR spectroscopy excluding out all excipients. The drug substance in the 5 mg and 20 mg lead lot tablets largely conformed to Compound A Free Base Form 1 by 19 F solid-state NMR. However, a third minor 19 F resonance was observed that was unidentified.
  • This third resonance appeared to broaden in only the 5 mg 1% DL DP tablet, but not in the drug substance (uncompressed and compressed) and 20 mg 20% DL tablet.
  • the apparent broadening of the third resonance for the 5 mg tablet also was observed in the final blend used to compress the 5 mg tablet (post-roller compaction step) but did not appear in the pre-blend (pre-roller compaction step).
  • the broadening of the third resonance decreased in tablets that were stored for 2 days under a 40 °°C/75% RH open condition.
  • Example 2 Film-Coated 200 mg IR Tablet (25% DL)
  • Step 1 Compound A and pre-screened (using suitable metal screen) microcrystalline cellulose, mannitol and croscarmellose sodium were blended using a suitable blender.
  • Step 2 The blend from Step 1 was de-lumped using a conical mill.
  • Step 3 The mixture from Step 2 was blended using a suitable blender.
  • Step 4 The blend from Step 3 was lubricated by adding pre-screened (using suitable metal screen) magnesium stearate to the blender in Step 3.
  • Step 5 The blend was compacted into ribbons using roller compaction and subsequently milled into granular blend using a roller compactor equipped with an oscillating mill.
  • Step 6 The granular blend was lubricated with pre-screened magnesium stearate (using suitable metal screen) using a suitable blender.
  • Step 7 The final blend from Step 6 was compressed into tablets on a rotary tablet press. The tablet appearance, weight, thickness and hardness were tested throughout compression.
  • Step 8 The tablets from Step 7 were film-coated in a pan coater using a suspension of Opadry® II in purified water. The tablet appearance and weight were tested throughout compression.
  • Step 9 The film-coated tablets were packaged into HDPE bottles and/or blister cards.
  • the stability of the 200 mg IR film-coated tablets was evaluated as described herein.
  • the tablets were packaged into 50 count 325 cc HDPE bottles and polypropylene child resistant closure with foil induction seals without desiccant.
  • the bottled tablets were placed on stability at 30 °C/65 %RH (long term storage) and 40 °C/75 %RH (accelerated storage).
  • Stability data show no significant changes in description, assay, organic impurities, water content and dissolution after 6-month under 40 °C/75% RH storage conditions and up to 12-month at long term storage condition of 30 °C/65% RH and 30 °C/75% RH for clinical packaging bottle, for 9-month for commercial packaging bottle and for 9-month for blister packaging ( Figures 8B- E respectively).
  • Example 4 Film-Coated IR Tablets (30%) and Uncoated IR Tablets (37.5%, and 40% DL)
  • This example demonstrates tablets (30%, 37.5%, and 40% DL) in accordance with embodiments of the invention comprising Compound A, a diluent, a disintegrant, and a lubricant.
  • the 30% DL tablet further comprised a polyol (i.e., mannitol) and a film-coating.
  • This example demonstrates a pharmacokinetic comparison of 100 mg and 200 mg dosage forms.
  • the C1D1 dose-normalized C ma x geometric mean was 4.48 (48% CV) and 4.12 (40%) for 100 mg and 200 mg tablets, respectively.
  • the C1D15 dose-normalized Cmax geometric mean was 5.80 (41%) and 5.68 (42%) for 100 mg and 200 mg tablets, respectively.
  • the C1D1 dose-normalized AUCo-24h geometric mean was 55.0 (53%) and 55.9 (42%) for 100 mg and 200 mg tablets, respectively.
  • the C1D15 dose-normalized AUCo-24h geometric mean was 67.0 (46% CV) and 79.8 (45%) for 100 mg and 200 mg tablets, respectively.
  • the geometric least squares mean ratio for C ma x on cycle 1 day 1 and cycle 1 day 15 were 0.919 (90% Cl: 0.789, 1.07) and 0.978 (0.782, 1 .22), respectively.
  • the geometric least squares mean ratio for AUCo-24h on cycle 1 day 1 and cycle 1 day 15 were 1.02 (0.870, 1.19) and 1.19 (0.953, 1.49), respectively.
  • the preliminary data suggest the C ma x and AUC 0 -24h are comparable between 100 mg and 200 mg tablet strength.
  • Example 7 Film-Coated 300 mg IR Tablet (30% DL)
  • This example demonstrates an oral dosage form and its manufacture according in accordance with embodiments of the invention. Immediate-release tablets comprising 300 mg Compound A (30% DL) and a filmcoating were prepared as shown in Table 17.
  • Compound A 300 mg film-coated tablets were stable for 3 months at 30 °C/65% RH (RSC), 30 °C/75 % RH and 40 °C/75% RH (ASC) conditions.
  • Composition 2 comprising Compound A and mannitol exhibited the best stability during the evaluations showing the least amount of degradation and impurity formation.
  • Compound A was formulated in various composition formats, as shown in Table 21, then subjected to room temperature or stress conditions of 70°C/75% RH. Compound A with lactose in a solution was used as a control to confirm the LCMS signal for the expected adduct. Under both room temperature and stress conditions, the formulations containing lactose showed formation of the Compound A lactose adduct:

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Abstract

L'invention concerne des compositions pharmaceutiques renfermant un composé A, notamment 1 à 40 % en poids de composé A, les compositions pharmaceutiques étant appropriées pour une administration par voie orale. Dans certains modes de réalisation, les compositions de l'invention conviennent à une charge médicamenteuse élevée. Les compositions de l'invention sont appropriées pour traiter des maladies ou des troubles sensibles à l'inhibition de la protéine arginine méthyltransférase 5 (PRMT5) (p. ex. un cancer).
PCT/US2025/034720 2024-06-21 2025-06-23 Compositions pharmaceutiques orales renfermant un composé de naphtyridine Pending WO2025265110A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022132914A1 (fr) 2020-12-16 2022-06-23 Amgen Inc. Inhibiteurs de prmts
WO2023196545A1 (fr) * 2022-04-08 2023-10-12 Amgen Inc. Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022132914A1 (fr) 2020-12-16 2022-06-23 Amgen Inc. Inhibiteurs de prmts
WO2023196545A1 (fr) * 2022-04-08 2023-10-12 Amgen Inc. Traitements du cancer à l'aide d'inhibiteurs de prmt5 à coopération mta

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* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "A study of AMG 193 in subjects with advanced MTAP-null solid tumors (MTAP)", CLINICALTRIALS.GOV, 10 February 2023 (2023-02-10), XP093231692, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT05094336?tab=history&a=21#version-content-panel> *
LUYINGSUNGWON KIMKINAM PARK: "In vitro-in vivo correlation: Perspectives on model development.", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 418, no. 1, 2011, pages 142 - 148, XP028293178, DOI: 10.1016/j.ijpharm.2011.01.010
ZOUHUIXI ET AL.: "Application of pharmacokinetic-pharmacodynamic modeling in drug delivery: development and challenges", FRONTIERS IN PHARMACOLOGY, vol. 11, 2020, pages 543082

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