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WO2022260667A1 - Formes posologiques orales d'ibrutinib - Google Patents

Formes posologiques orales d'ibrutinib Download PDF

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Publication number
WO2022260667A1
WO2022260667A1 PCT/US2021/036712 US2021036712W WO2022260667A1 WO 2022260667 A1 WO2022260667 A1 WO 2022260667A1 US 2021036712 W US2021036712 W US 2021036712W WO 2022260667 A1 WO2022260667 A1 WO 2022260667A1
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WO
WIPO (PCT)
Prior art keywords
dosage form
oral dosage
ibrutinib
weight percent
amount
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.)
Ceased
Application number
PCT/US2021/036712
Other languages
English (en)
Inventor
Mahmoud Ghannam
Shahin Fesharaki
Mohammad Al HREEBAT
Ahmad Arif MOHAMMAD
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.)
Hikma Pharmaceuticals USA Inc
Original Assignee
Hikma Pharmaceuticals USA 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 Hikma Pharmaceuticals USA Inc filed Critical Hikma Pharmaceuticals USA Inc
Priority to PCT/US2021/036712 priority Critical patent/WO2022260667A1/fr
Priority to MA63498A priority patent/MA63498A1/fr
Priority to TNP/2023/000295A priority patent/TN2023000295A1/en
Publication of WO2022260667A1 publication Critical patent/WO2022260667A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K31/539—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 having two or more oxygen atoms in the same ring, e.g. dioxazines
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to stable oral dosage forms of ibrutinib as an active ingredient and, in particular, oral dosage forms comprising ibrutinib and acidifying agent.
  • Ibrutinib is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue in the BTK active site, leading to the inhibition of BTK enzymatic activity, thus blocking B-cell receptor signaling, which drives B-cells into apoptosis and/or disrupts cell migration and adherence to protective tumor microenvironments.
  • BTK tyrosine kinase
  • ibrutinib is approved to treat a variety of blood cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia and marginal zone lymphoma, as both a first and second line therapy. Ibrutinib is also indicated as a second line therapy for the treatment of chronic graft versus host disease.
  • the active drug substance is practically insoluble in aqueous solutions of pH 4.5-8, and only slightly soluble in HC1 at pH 1.2.
  • ibrutinib is classified as a BCS Class 2 compound (low solubility and high permeability) which presents a challenge in developing orally bioavailable formulations.
  • the IMBRUVICA ® capsule formulation comprises ibrutinib, croscarmellose sodium, microcrystalline cellulose , magnesium stearate and sodium lauryl sulfate encapsulated in a hard gelatin capsule.
  • the IMBRUVICA ® tablet formulation comprises ibrutinib, colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium lauryl sulfate with a film coating.
  • ibrutinib that include an acidifying agent such as tartaric acid or citric acid.
  • the dosage forms may further include a binder such as sodium alginate.
  • the inclusion of the acidifying agent is believed to make the microenvironment more acidic, thereby enhancing the dissolution profile of the drug.
  • a first aspect of the invention is an oral dosage form comprising ibrutinib and an acidifying agent.
  • the acidifying agent is present in an amount of from about 0.5 to about 5.0 weight percent.
  • the acidifying agent is present in an amount of from about 1.0 to about 3.0 weight percent.
  • the acidifying agent is selected from the group consisting of tartaric acid and citric acid.
  • the acidifying agent is tartaric acid.
  • the dosage from further comprises a binder.
  • the binder is present in an amount of from about 0.5 to about 10.0 weight percent.
  • the binder is present in an amount of from about 1.0 to about 5.0 weight percent.
  • the binder comprises sodium alginate.
  • the ibrutinib has a particle size having a d9o of from about 75 to about 105 microns.
  • the ibrutinib is Form I ibrutinib.
  • the oral dosage form is a capsule.
  • the oral dosage form releases about 70% or more of the ibrutinib within about 45 minutes when tested in 900 mL of 3.0% w/v Polysorbate 20 in 50 mM phosphate buffer, pH 6.8, paddles at 75 rpm.
  • the oral dosage form releases about 90% or more of the ibrutinib within about 45 minutes when tested in 900 mL of 3.0% w/v Polysorbate 20 in 50 mM phosphate buffer, pH 6.8, paddles at 75 rpm.
  • the oral dosage form releases about 90% or more of the ibrutinib within about 30 minutes when tested in 900 mL of 3.0% w/v Polysorbate 20 in 50 mM phosphate buffer, pH 6.8, paddles at 75 rpm.
  • the oral dosage form releases about 70% or more of the ibrutinib within about 45 minutes when tested in 900 mL of 0.1 N HC1, paddles at 50 rpm.
  • the oral dosage form releases about 90% or more of the ibrutinib within about 45 minutes when tested in 900 mL of 0.1 N HC1, paddles at 50 rpm.
  • the oral dosage form releases about 90% or more of the ibrutinib within about 30 minutes when tested in 900 mL of 0.1 N HC1, paddles at 50 rpm.
  • the first aspect is a method of treating a cancer by administering to a patient in need thereof the oral dosage form of the first aspect.
  • the method of treating cancer is a method of treating a blood cancer by administering to a patient in need thereof the oral dosage form of the first aspect.
  • the method of treating cancer is a method of treating a blood cancer selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia and marginal zone lymphoma by administering to a patient in need thereof the oral dosage form of the first aspect.
  • the first aspect is a method of treating a graft versus host disease by administering to a patient in need thereof the oral dosage form of the first aspect.
  • an oral dosage form comprising ibrutinib, an acidifying agent present in an amount of about 1.0 to about 5.0 weight percent and a binder present in an amount of from about 1.0 to about 10 weight percent.
  • the acidifying agent is selected from tartaric acid and citric acid and the binder is sodium alginate.
  • the oral dosage form further comprises a surfactant, a lubricant, a filler, and a disintegrant.
  • the method of treating cancer is a method of treating a blood cancer by administering to a patient in need thereof the oral dosage form of the second aspect.
  • the method of treating cancer is a method of treating a blood cancer selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia and marginal zone lymphoma by administering to a patient in need thereof the oral dosage form of the second aspect.
  • the second aspect is a method of treating a graft versus host disease by administering to a patient in need thereof the oral dosage form of the second aspect.
  • a third aspect of the disclosure is an oral dosage form consisting essentially of ibrutinib, an acidifying agent, a binder, a surfactant, a lubricant, a filler, and a disintegrant.
  • the acidifying agent is present in an amount of from about 1.0 weight percent to about 3.0 weight percent.
  • the oral dosage form consists essentially of, or consists of, ibrutinib, tartaric acid or citric acid, sodium alginate, sodium lauryl sulfate, magnesium stearate, a microcrystalline cellulose and croscarmellose sodium.
  • tartaric acid or citric acid is present in an amount of from about 1.0 to about 3.0 weight percent.
  • sodium alginate is present in an amount of from about 1.0 to about 5.0 weight percent.
  • the oral dosage form releases about 70% or more of the ibrutinib within about 45 minutes when tested in 900 mL of 3.0% w/v Polysorbate 20 in 50 mM phosphate buffer, pH 6.8, paddles at 75 rpm.
  • the oral dosage form releases about 90% or more of the ibrutinib within about 45 minutes when tested in 900 mL of 3.0% w/v Polysorbate 20 in 50 mM phosphate buffer, pH 6.8, paddles at 75 rpm.
  • the oral dosage form releases about 90% or more of the ibrutinib within about 30 minutes when tested in 900 mL of 3.0% w/v Polysorbate 20 in 50 mM phosphate buffer, pH 6.8, paddles at 75 rpm [0044] In another example of the third aspect, the oral dosage form releases about 70% or more of the ibrutinib within about 45 minutes when tested in 900 mL of 0.1 N HC1, paddles at 50 rpm. [0045] In still another example of the third aspect, the oral dosage form releases about 70% or more of the ibrutinib within about 45 minutes when tested in 900 mL of 0.1 N HC1, paddles at 50 rpm.
  • the oral dosage form releases about 90% or more of the ibrutinib within about 30 minutes when tested in 900 mL of 0.1 N HC1, paddles at 50 rpm.
  • the third aspect is a method of treating a cancer by administering to a patient in need thereof the oral dosage form of the third aspect.
  • the method of treating cancer is a method of treating a blood cancer by administering to a patient in need thereof the oral dosage form of the third aspect.
  • the method of treating cancer is a method of treating a blood cancer selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia and marginal zone lymphoma by administering to a patient in need thereof the oral dosage form of the third aspect.
  • the third aspect is a method of treating a graft versus host disease by administering to a patient in need thereof the oral dosage form of the third aspect.
  • the term “about” means that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors.
  • the term “about” is used in describing a value or an end-point of a range, the disclosure should be understood to include the specific value or end-point referred to.
  • weight percent is a relative measure of the amount of one excipient or ingredient relative to the total weight of the dosage form and is based on the total weight of the dosage form.
  • Total weight of the dosage form refers to the total weight of the tablet if the dosage form, including any coating included thereon or to the total weight of the capsule fill. To be clear, the total weight of the dosage form when the dosage form is a capsule does not include the weight of the capsule shell or any coating included thereon.
  • the present disclosure is directed to oral dosage forms of ibrutinib having good stability and bioavailability compared to commercially available dosage forms.
  • the dosage forms of the present disclosure comprise ibrutinib and an acidifying agent, such as tartaric acid or citric acid.
  • the dosage forms can further comprise a binder, such as sodium alginate.
  • the formulations of ibrutinib of the present disclosure are formulated for oral administration.
  • the pharmaceutical formulations described herein include, but are not limited to, tablets, capsules, pills, powders, fast melts and multiparticulate formulations; the dosage forms can be formulated for immediate release, controlled release, delayed release, extended release, pulsatile release or mixed immediate and controlled release.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Such processing methods include conventional dry or wet mixing, dissolving, granulating, milling, encapsulating, or compression processes.
  • the oral formulations are made via a standard mixing and blending process.
  • pharmaceutical formulations for oral use can be obtained by mixing ibrutinib with one or more solid excipients described herein. The resulting mixture can be compressed into tablets or can be capsulized into hard or soft capsules, such as gelatin capsules.
  • the oral formulation can by prepared in push-fit capsules, such as a two-piece capsule made of gelatin, hydroxymethylcellulose (HPMC), starch or the like.
  • the capsule formulation can comprise one or more pH adjusting agents, binders, carriers, fillers, lubricants, disintegrants, surfactants, wetting agents, stabilizers, antioxidants, preservatives, colorants, flavorings, and/or other pharmaceutically acceptable excipients used in the art.
  • the oral dosage forms described herein may also include a film coating, such as a delayed release coating, which disintegrates upon oral ingestion or upon contact with a biological fluid.
  • Ibrutinib is a kinase inhibitor first reported in US Patent No. 7,514,444. Subsequently, a number of polymorphic forms of ibrutinib have been reported, including Forms A, B, C, D, E and F, disclosed in US Patent No. 9,540,382 and Form I in WO 2015/081180, herein incorporated by reference.
  • the dosage forms of the present disclosure are suitable for use with any polymorphic form of ibrutinib.
  • the ibrutinib for use with the disclosed dosage form is Form I of ibrutinib.
  • Ibrutinib can be included in the dosage form in any amount as would be suitable for therapeutic use.
  • Ibrutinib is currently approved in the US to treat a variety of blood cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia and marginal zone lymphoma, as both a first - and second-line therapy. Ibrutinib is also indicated as a second line therapy for the treatment of chronic graft versus host disease. Ibrutinib can be administered sequentially with or concurrently in combination with one or more other chemotherapeutics. Conventional dosing regimens for ibrutinib are known in the art, but the drug is typically administered orally once per day in a dose amount considered to be therapeutic.
  • IMBRUVICA ® tablets are currently available in dosage amounts of 140 mg, 280 mg, 420 mg, and 560 mg of active pharmaceutical ingredient per tablet.
  • IMBRUVICA ® capsules are currently available in dosage amounts of 70 mg and 140 mg of ibrutinib per capsule.
  • the IMBRUVICA ® capsules contain Form A ibrutinib and the inactive ingredients of croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate in a gelatin shell.
  • the dosage forms of the present disclosure include a pH adjusting agent.
  • the pH adjusting agent can be any pharmaceutically acceptable acid or base.
  • Suitable pharmaceutically acceptable acids include both inorganic acids, for example, hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid, as well as organic acids, for example citric, fumaric, maleic, malic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid, etc.
  • Pharmaceutically acceptable bases can include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g.
  • the dosage forms of the present disclosure can include one or more pH adjusting agents, for example, a combination of one, two, three or more suitable acids.
  • the dosage form includes a pharmaceutically acceptable acid, in particular, tartaric acid or citric acid.
  • the pH adjusting agent can be present in any amount as necessary to affect the pH of the surrounding microenvironment.
  • the pH adjusting agent (acid or base) can be present in an amount of about 0.5 to about 10.0 weight percent, for example about 0.5 weight percent, about 1.0 weight percent, about 1.5 weight percent, about 2.5 weight percent, about 3.0 weight percent, about 3.5 weight percent, about 4.0 weight percent, about 4.5 weight percent, about 5.0 weight percent, about 5.5 weight percent, about 6.0 weight percent, about 6.5 weight percent, about 7.0 weight percent, about 7.5 weight percent, about 8.0 weight percent, about 8.5 weight percent, about 9.0 weight percent, about 9.5 weight percent, or about 10.0 weight percent, of the total weight of the dosage form.
  • the pH adjusting is a pharmaceutically acceptable acid present in an amount of from about 0.5 to about 5.0 weight percent of the total weight of the dosage form.
  • the pH adjusting agent is a pharmaceutically acceptable acid present in an amount of from about 0.5 to about 3.0 weight percent of the total weight of the dosage form.
  • the pH adjusting agent is a pharmaceutically acceptable acid present in an amount of from about 1.0 to about 2.0 weight percent of the total weight of the dosage form.
  • the pH adjusting agent is citric acid or tartaric acid present in an amount of about 0.5 weight percent, about 1.0 weight percent, about 1.5 weight percent, about 2.5 weight percent, or about 3.0 weight percent of the total weight of the dosage form.
  • the pH adjusting agent is tartaric acid present in an amount of about 0.5 to about 3.0 weight percent. In another embodiment, the pH adjusting agent is tartaric acid present in an amount of about 0.5 weight percent of the total weight of the dosage form. In another embodiment, the pH adjusting agent is tartaric acid present in an amount of about 1.0 weight percent. In yet another embodiment, the pH adjusting agent is tartaric acid present in an amount of about 1.5 weight percent. In still another embodiment, the pH adjusting agent is tartaric acid present in an amount of about 2.0 weight percent of the total weight of the dosage form. In another embodiment, the pH adjusting agent is tartaric acid present in an amount of about 2.5 weight percent. In still another embodiment, the pH adjusting agent is tartaric acid present in an amount of about 3.0 weight percent.
  • Suitable binders according to the present invention include, e.g., amylose, bentonites, cellulose and cellulose derivatives such as carboxymethylcellulose, methylcellulose, HPMC, HPMCAS, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, and microcrystalline cellulose (MCC), crospovidone, dextrin, gelatin, natural or synthetic gums, magnesium aluminum silicate, microcrystalline dextrose, pregelatinized starch, polyethylene glycol, polysaccharide acids, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, povidone, sodium alginate, starches, sugars (e.g., amylose, bentonites, cellulose and cellulose derivatives such as carboxymethylcellulose, methylcellulose, HPMC, HPMCAS, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, and microcrystalline cellulose (MCC), crospovidone,
  • the dosage form includes sodium alginate.
  • Binders can be included in the dosage form in any amount useful for holding together the ingredients of the dosage form.
  • the amount of binder included in an oral dosage form, and in particular for a capsule dosage form, is typically more than about 20 weight percent based on the total weight of the dosage form, e.g. 20 to 70 weight percent. It was surprisingly found that the inclusion of a pH adjusting agent in the form of an acid in combination with a lower amount of binder than would be otherwise be expected provided an oral dosage form having an in vitro dissolution profile that is highly similar to that of the brand product.
  • the dosage forms according to the present disclosure can include much lower amounts of binder, for example, about 1.0 to about 10.0 weight percent, for example, about 1.0 weight percent, about 1.5 weight percent, about 2.5 weight percent, about 3.0 weight percent, about 3.5 weight percent, about 4.0 weight percent, about 4.5 weight percent, about 5.0 weight percent, about 5.5 weight percent, about 6.0 weight percent, about 6.5 weight percent, about 7.0 weight percent, about 7.5 weight percent, about 8.0 weight percent, about 8.5 weight percent, about 9.0 weight percent, about 9.5 weight percent, or about 10.0 weight percent, of the total weight of the dosage form.
  • the dosage forms according to the present disclosure include a binder in an amount of about 1.0 to about 5.0 weight percent.
  • the binder is sodium alginate present in an amount of about 1.0 weight percent, about 1.5 weight percent, about 2.5 weight percent, about 3.0 weight percent, about 3.5 weight percent, about 4.0 weight percent, about 4.5 weight percent, or about 5.0 weight percent of the total weight of the dosage form. In one embodiment, the binder is sodium alginate present in an amount of about 3.0 weight percent.
  • Suitable carriers for use in the oral dosage forms described herein include, but are not limited to, gelatin, colloidal silicon dioxide, silicified colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, microcrystalline cellulose (MCC), lactose, mannitol and the like.
  • the pharmaceutical dosage forms of the present disclosure can comprise from about 1 to about 70 weight percent of a carrier.
  • Suitable filling agents, or fillers, for use in the solid dosage forms described herein include, but are not limited to, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, lactose, microcrystalline cellulose (MCC), silicified MCC (e.g.
  • ProSolv ® HD90 cellulose powder, dextrose, dextran, starches, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • the filler is silicified MCC.
  • the pharmaceutical compositions provided herein may contain from about 1 to about 70 weight percent of a filler.
  • Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, bentonite, a cellulose such as microcrystalline cellulose, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a gum, e.g.
  • the disintegrating agent is croscarmellose sodium.
  • the amount of disintegrant varies depending on the type of formulation.
  • the pharmaceutical compositions provided herein may contain, in one example, from about 0.5 to about 15 weight percent or from about 10 to about 15 weight percent of a disintegrant.
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
  • the lubricant is magnesium stearate.
  • the pharmaceutical compositions provided herein may
  • Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, cellulose and cellulose derivatives (such as microcrystalline cellulose, silicified MCC, microcellulose, etc.), cyclodextrins, polyols (including mannitol, xylitol, and sorbitol), polysaccharides (for example dextrates and maltodextrin), starches, modified starches, sugars (e.g. lactose, sucrose, and dextrose), talc, and the like.
  • the amount of diluent varies depending on the type of formulation.
  • the pharmaceutical compositions provided herein may contain from about 1.0 to about 70 weight percent of a diluent.
  • Suitable surfactants or wetting agents include copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), glyceryl monostearate, magnesium stearate, oleic acid, polaxomers, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbates, quaternary ammonium compounds (e.g., Polyquat 10 ® ), sodium lauryl sulfate, sodium oleate, sorbitan monolaurate, sorbitan monooleate, triacetin, triethanolamine oleate, vitamin E TPGS and the like.
  • the surfactant is sodium lauryl sulfate.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5 weight percent of a surfactant or wetting agent.
  • the ibrutinib dosage forms can include a stabilizer, including but not limited to an antioxidant or a preservative.
  • Suitable stabilizers for use in the solid dosage forms described herein include but are not limited to butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
  • BHT butylated hydroxytoluene
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5 weight percent of a stabilizer.
  • the particle size of the API was selected to obtain the desired dissolution and to ensure smooth processing of the final dosage form to obtain a finished dosage form that meets specifications.
  • All capsules were manufacturing via a dry granulation method by slugging followed by capsule filling. Prosolv HD90 and SLS were first sifted using a 500-micron sieve, and then mixed with ibrutinib in a plastic bag. The resulting mixture was passed through a 500-micron sieve. Sodium alginate was sifted into the sifted API mixture, followed by Ac-di-sol ® (croscarmellose sodium), acidifying agent (tartaric acid or citric acid).
  • the resulting mixture was sieved and loaded into a Matcon container and mixed. To this mixture was added part of the magnesium stearate and sieved through a 500-micron filter. The prepared powder mix was then prepared into slugs. The resulting slugs were passed through mesh R.25 using a Glatt crushing machine and collected. The resulting mixture was passed through mesh S1.0 using a Glatt crushing machine before being transferred to the Matcon container and mixed. The remaining magnesium stearate was mixed with a small quantity of the premix and the entire mixture combined and mixed to obtain a powder blend. The powder blend was filled into empty gelatin capsules (size 0) using a filling machine.
  • FDA drug release medium 3.0% w/v Polysorbate 20 in 50 mM phosphate buffer, pH 6.8, paddles, 75 rpm, 900 mL
  • 0.1 N HC1 paddles, 50 rpm, 900 mL
  • a similarity factor (F2) was calculated for each test capsule relative to a Comparative Example, the Comparative Example capsule being the 140 mg RLD product which is branded as IMBRUVICA ® and contains ibrutinib, croscarmellose sodium, microcrystalline cellulose, magnesium stearate and sodium lauryl sulfate encapsulated in a hard gelatin capsule.
  • An F2 value closer to 100 indicates performance closer to the brand product, and above 50 is considered “passing”.
  • Table 1 Formulation composition for API particle size determination
  • Table 7 Formulation composition for acid effect
  • Table 8 Percent drug release for acid effect in 3% w/v Polysorbate in phosphate buffer
  • Croscarmellose sodium was selected as the disintegrant for the development of the ibrutinib capsules according to the present disclosure, and the dissolution profile was monitored for capsules comprising 10%, 11.8% and 14% by weight.
  • the capsules detailed in Table 13 below were prepared as described above and tested in the 3.0% w/v Polysorbate 20 in 50 mM phosphate buffer and in 0.1 N HC1. The results of the dissolution tests are shown in Tables 14 and 15.
  • Table 16 Formulation composition for binder variation
  • Table 17 Percent drug release for binder amount variation in 3% w/v Polysorbate in phosphate buffer
  • SLS Sodium lauryl sulfate
  • Magnesium stearate was selected as the lubricant for the development of the ibrutinib capsules. Magnesium stearate levels were tested at 1.5 wt %, 2.0 wt %, and 2.5 wt % (Table 22). The release profile of each capsule was monitored as described above (Tables 23 and 24).
  • Table 22 Formulation composition for magnesium stearate amount variation
  • Table 23 Percent drug release for magnesium stearate amount variation in 3% w/v Polysorbate in phosphate buffer
  • Capsules according to the formulation provided in Table 25 (below) were prepared as described above.

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  • Public Health (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Formes posologiques orales stables et biodisponibles d'ibrutinib, les formes posologiques comprenant de l'ibrutinib et un agent acidifiant. Les formes posologiques peuvent en outre comprendre un liant, tel que de l'alginate de sodium, un tensioactif, un lubrifiant, une charge et/ou un délitant. L'invention concerne également des procédés de traitement de cancers, en particulier de cancers du sang, et la maladie du greffon contre l'hôte comprenant l'administration à un patient qui a besoin d'une forme posologique comprenant de l'ibrutinib et un agent acidifiant.
PCT/US2021/036712 2021-06-10 2021-06-10 Formes posologiques orales d'ibrutinib Ceased WO2022260667A1 (fr)

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PCT/US2021/036712 WO2022260667A1 (fr) 2021-06-10 2021-06-10 Formes posologiques orales d'ibrutinib
MA63498A MA63498A1 (fr) 2021-06-10 2021-06-10 Formes posologiques orales d'ibrutinib
TNP/2023/000295A TN2023000295A1 (en) 2021-06-10 2021-06-10 Oral dosage forms of ibrutinib

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