Alpelisib formulation

Abstract

Alpelisib Formulations The present invention features granular formulations and related invention embodiments that include an internal phase consisting of free-flowing granules comprising alpelisib or a pharma- ceutical salt thereof as the active pharmaceutical ingredient and at least one pharma- ceutical acceptable carrier material, and an external phase free of said API, preferably additionally comprising at least one pharma- ceutical acceptable carrier material.

Description

[Technical field]

[0001] The present invention relates to novel granular formulations comprising the compound (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide), also known as (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide, also known as BYL719 or alpelisib or a pharma- ceutically acceptable salt thereof, and said granular formulations for use or for use in the treatment of PIK3CA-associated overgrowth spectrum (PROS) and other related inventive embodiments. [Background technology]

[0002] Tissue growth is a tightly controlled process in organisms from embryonic development to adulthood. One of the major regulators of cell growth is the PI3K / AKT / mTOR signaling pathway. Overactivation of the PI3K / AKT / mTOR pathway results in significant dysregulation of cellular functions, resulting in a competitive growth advantage. Somatic mutations and gains or losses of these genes are associated with many different solid and hematological tumors. In addition to the well-known role of PIK3CA in cancer, postzygotic somatic mutations of PIK3CA have also been identified in various overgrowth disorders. These disorders comprise a broad group of clinically recognizable mutation-driven morphological abnormalities, termed the PIK3CA-associated overgrowth spectrum (PROS). PROS is associated with overgrowth of tissues including, but not limited to, fat, muscle, skin, bone, nerves, blood or lymphatic vessels. PROS is characterized by congenital or early childhood onset overgrowth, sporadic onset and mosaic distribution. Segmental overgrowth is often congenital in onset, but is usually present by the age of 1 year, and in some cases progressive tissue overgrowth persists into adulthood. Complications of PROS vary by anatomical location and extent of overgrowth, but may include, among other symptoms, functional impairment (e.g., walking or swallowing), pain, cardiac dysfunction, pulmonary hypertension, seizures, neurodevelopmental disorders, recurrent superficial infections, thromboembolism, and / or hemorrhage, all of which can be debilitating and cause premature death. Current treatment relies primarily on debulking surgery, such as amputation and / or endovascular occlusion. Regrowth after surgery is frequent and often requires reoperation. There is a large unmet need for new targeted therapeutic approaches and effective treatments to address PROS.

[0003] Alpelisib (BYL719) is approved in the United States for use in combination with the endocrine therapy fulvestrant to treat postmenopausal women and men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated advanced or metastatic breast cancer detected by an FDA-approved test after progression or after an endocrine-based regimen (US FDA: May 24, 2019). In addition, alpelisib has been administered to patients suffering from severe clinical symptoms of PROS. Patients who showed significant improvement were associated with partial or complete resolution of complications related to PROS. As a result of the favorable effect of alpelisib, it has become possible to avoid rescue surgery in a small number of patients for whom surgery was considered an option before the start of treatment.

[0004] The formulations of the present invention are novel, preservative-free, wet granulated products containing alpelisib or a pharma- ceutically acceptable salt thereof in the form of granules, which have a good dissolution profile and allow for patient-tailored dosing that can be conveniently and safely taken at pharmacologically effective daily doses, especially by the pediatric population. Summary of the Invention

[0005] The present invention provides a granular formulation suitable for administration to patients with swallowing disorders, geriatric patients and especially pediatric patients comprising (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (or alpelisib or BYL719) or a pharma- ceutically acceptable salt thereof, particularly for use in the treatment of PIK3CA-Associated Overgrowth Spectrum (PROS). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] The present invention provides in a first embodiment a free-flowing (meaning droppable) granular formulation comprising (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide (also known as alpelisib or BYL719) or a pharma- ceutically acceptable salt thereof, preferably alpelisib as the free base, as an active pharmaceutical ingredient (API) for the treatment of patients, in particular those with dysphagia, geriatric patients or especially pediatric patients, and at least one pharma- ceutical acceptable carrier material and an exogranular phase free of said API, preferably comprising in addition at least one pharma- ceutical acceptable carrier material.

[0007] In a second embodiment, the present invention provides a pharmaceutical single-dose unit receptacle comprising a granular formulation according to the first embodiment or as defined elsewhere herein.

[0008] In a third embodiment, the invention relates to a granular formulation or a pharmaceutical single unit dose receptacle according to the previous embodiments or as defined elsewhere herein for use in the treatment of a human patient, in particular any patient with dysphagia, an elderly patient or in particular a pediatric patient, said use comprising the administration of said granular formulation, preferably comprising a unit dose from a pharmaceutical single unit dose receptacle comprising a granular formulation according to the first invention embodiment or as defined elsewhere herein, in the treatment of (or to a patient suffering from) a proliferative disease, in particular a mutation-driven morphological disorder termed PIK3CA-associated overgrowth spectrum (PROS).

[0009] In a fourth embodiment, the present invention relates to the use of a granular formulation or a pharmaceutical single unit dose receptacle according to the first or second embodiment above or as defined elsewhere herein in the treatment of a human patient, in particular any patient with dysphagia, an elderly patient or in particular a pediatric patient, said use comprising the administration of said granular formulation, preferably comprising a unit dose from a pharmaceutical single unit dose receptacle comprising a granular formulation according to the first invention embodiment or as defined elsewhere herein, in the treatment of (or to a patient suffering from) a proliferative disease, in particular a mutation-driven morphological disorder termed PIK3CA-associated overgrowth spectrum (PROS).

[0010] In a fifth embodiment, the present invention provides a method for the treatment of a proliferative disease or in particular a mutation-driven morphological disorder referred to as PIK3CA-associated overgrowth spectrum (PROS), comprising administering to a human patient, in particular any patient with dysphagia, an elderly patient or in particular a pediatric patient, in particular in need of such treatment, a therapeutically effective amount of a granular formulation as defined in the first embodiment or elsewhere herein, preferably using a pharmaceutical single-dose unit receptacle as defined in the second embodiment or elsewhere herein.

[0011] In a sixth embodiment, the present invention provides the use of a granule formulation as defined in the first embodiment or elsewhere herein for the manufacture of a medicinal product comprising said granule formulation in the form of free-flowing granules for use in the treatment of a proliferative disease, in particular a mutation-driven morphological disorder termed PIK3CA-associated overgrowth spectrum (PROS), in particular for use in the manufacture of a pharmaceutical single unit dose receptacle as defined in the second embodiment or elsewhere herein for said treatment.

[0012] In a seventh embodiment, the present invention provides a process for producing a granular formulation of the present invention, comprising the steps of: (i) preparing an inner phase comprising (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide (also referred to as alpelisib) or a pharma- ceutical acceptable salt thereof, in particular alpelisib as a free base, by wet granulation, adding one or more diluents, adding a disintegrant, and adding a binder, and then drying the mixture; (ii) preparing an external phase comprising a diluent and a lubricant, and preferably (iii) filling the resulting granular (dry) formulation into pharmaceutical single-dose unit receptacles; The present invention provides a process for forming a

[0013] In preferred embodiments of the first to seventh embodiments above and other embodiments herein, a disintegrant is not required to release the active pharmaceutical ingredient alpelisib from the internal phase, and therefore the granular formulation more preferably comprises an external phase that does not contain a disintegrant.

[0014] In another embodiment, in particular all embodiments, the free flowing granular formulation, in particular when filled into pharmaceutical single dose receptacles, in particular stick packs, may further comprise a diluent, in particular lactose, sorbitol or in particular microcrystalline cellulose, e.g. Avicel PH101, in an amount of 25% to 45%, preferably 28% to 42%, such as 30 to 40%, for example 36.17%, and / or mannitol (in particular Mannitol) in an amount of 25% to 45%, preferably 28% to 42%, such as 30 to 40%, for example 34%. in an internal phase comprising a disintegrant, especially croscarmellose sodium, crospovidone or preferably carboxymethyl starch sodium, in an amount of 2% to 7%, preferably 3% to 6%, such as 3% to 7%, for example 5%, and a binder, especially hydroxypropylcellulose, povidone, starch or preferably hydroxypropylmethylcellulose, in an amount of 1 to 5%, preferably 1.5 to 4.5%, such as 2 to 4%, for example 3%, or alternatively 20 mg to 200 mg, preferably 25 mg to 150 mg, such as 20 mg, or 25 mg, or 50 mg, or 100 mg, of alpelisib or a pharma- ceutical acceptable salt thereof (the stated amounts therefore refer, in the case of a salt of alpelisib, to the alpelisib portion of the salt), especially alpelisib in free form, the external phase contains a diluent, in particular lactose, sorbitol, mannitol or in particular (preferably microcrystalline) cellulose, for example cellulose MKGR, in an amount of 10-30%, preferably 10-25%, such as 15-20%, for example 17.5%, and a lubricant, for example compritol 888, sodium stearyl fumarate or preferably magnesium stearate, in an amount of 0.25-4%, preferably 0.3-3%, for example 0.5-1.5%, for example 1%; All amounts are selected to add up to 100% each in the final granulated formulation (powder including the inner phase and, if present, the outer phase).

[0015] When percentages of ingredients are given, this means the weight percentage of the total granular formulation.

[0016] An embodiment having the same definition level scope (level 1) = no priority, level 2) = after "especially", level 3) = after "preferably", level 4) = after "for example", level 5) = after "for example") defines a preferred embodiment of the scope defined in the immediately preceding embodiment.

[0017] In a further embodiment, the free flowing granular formulation comprises an internal phase and an external phase packaged in a stick pack pharmaceutical single dose receptacle, the internal phase being: (i) 1% to 5%, 2 to 5%, 3% to 4% or 3.33% of alpelisib or a pharma- ceutical acceptable salt thereof; or alternatively 20 mg to 200 mg, 25 mg to 150 mg, 20 mg, or 25 mg, or 50 mg, or 100 mg of alpelisib or a pharma- ceutical acceptable salt thereof. (ii) a diluent selected from lactose, sorbitol and microcrystalline cellulose in an amount of 25% to 45%, 28 to 42%, 30 to 40% or 36.17% and / or mannitol in an amount of 25% to 45%, 28 to 42%, 30 to 40% or 34%; (i) a disintegrant selected from croscarmellose sodium, crospovidone and sodium carboxymethyl starch in an amount of 2-7%, 3-6%, 3-7% or 5%; and (iv) a binder selected from hydroxypropylcellulose, povidone, starch and hydroxypropylmethylcellulose in an amount of 1-5%, 1.5-4.5%, 2-4% or 3%; the outer phase contains (i) a diluent selected from lactose, sorbitol, mannitol and microcrystalline cellulose in an amount of 10-30%, 10-25%, 15-20% or 17.5%; and (ii) a lubricant selected from compritol 888, sodium stearyl fumarate and magnesium stearate in an amount of 0.25-4%, 0.3-3%, 0.5-1.5% or 1%; all amounts selected to total 100% in the final granular formulation.

[0018] In a further embodiment, the free flowing granular formulation comprises an internal phase and an external phase packed in a stick pack pharmaceutical single dose receptacle, the internal phase comprising: (i) 3% to 4% or 3.33% of alpelisib or a pharma- ceutical acceptable salt thereof; or alternatively 20 mg, or 25 mg, or 50 mg, or 100 mg of alpelisib or a pharma-ceutical acceptable salt thereof (the recited amounts therefore refer to the alpelisib portion of the salt, in the case of a salt of alpelisib), in particular alpelisib in free form; (ii) a diluent selected from lactose, sorbitol and microcrystalline cellulose in an amount of 30 to 40% or 36.17%, and / or mannitol in an amount of 30 to 40% or 34%; (iii) 3 to 7% of a pharma-ceutical acceptable salt thereof; % or 5%; and (iv) a binder selected from hydroxypropylcellulose, povidone, starch and hydroxypropylmethylcellulose in an amount of 2-4% or 3%; the outer phase contains (i) a diluent selected from lactose, sorbitol, mannitol and microcrystalline cellulose in an amount of 15-20% or 17.5%; and (ii) a lubricant selected from compritol 888, sodium stearyl fumarate and magnesium stearate in an amount of 0.5-1.5% or 1%; all amounts selected to total 100% in the final granulated formulation.

[0019] In a further embodiment, the free flowing granular formulation comprises an internal phase and an external phase packed in a stick pack pharmaceutical single dose receptacle, the internal phase comprising: (i) 3% to 4% or 3.33% of alpelisib or a pharma- ceutical acceptable salt thereof; or alternatively 20 mg, or 25 mg, or 50 mg, or 100 mg, or 125 mg of alpelisib or a pharma-ceutical acceptable salt thereof (the recited amounts thus refer to the alpelisib portion of the salt, in the case of a salt of alpelisib), in particular alpelisib in free form; and (ii) microcrystalline cellulose (e.g., Avicel PH101) in an amount of 30 to 40% or 36.17% and / or mannitol (e.g., Mannitol PH101) in an amount of 30 to 40% or 34%. (iii) a disintegrant which is sodium carboxymethyl starch in an amount of 3-7% or 5%; and (iv) a binder which is hydroxypropyl methylcellulose in an amount of 2-4% or 3%; the outer phase contains (i) a diluent which is microcrystalline cellulose (e.g., cellulose MK GR) in an amount of 15-20% or 17.5%; and (ii) a lubricant which is magnesium stearate in an amount of 0.5-1.5% or 1%; all amounts selected to total 100% in the final granular formulation.

[0020] In a further embodiment, the free flowing granular formulation comprises an internal phase and an external phase filled into a stick pack pharmaceutical single dose receptacle, the internal phase containing (i) 3% to 4% or 3.33% of alpelisib or a pharma- ceutical acceptable salt thereof; or alternatively 20 mg, or 25 mg, or 50 mg, or 100 mg of alpelisib or a pharma-ceutical acceptable salt thereof (hence the amounts stated refer to the alpelisib portion of the salt, in the case of a salt of alpelisib), in particular alpelisib in free form; (ii) a diluent which is microcrystalline cellulose (e.g., Avicel PH101) in an amount of 36.17% and / or mannitol (e.g., Mannitol Pharma) in an amount of 34%; (iii) a disintegrant which is sodium carboxymethyl starch in an amount of 5%; and (iv) a binder which is hydroxypropyl methylcellulose in an amount of 3%; and the external phase containing (i) microcrystalline cellulose (e.g., cellulose MK101) in an amount of 17.5%. (ii) a diluent, which is magnesium stearate, in the amount of 1%; all amounts selected to total 100% in the final granulated formulation.

[0021] In one embodiment, the present invention relates to a free flowing granular formulation of the present invention for use in the treatment of a proliferative disorder.

[0022] In one embodiment, the present invention relates to a free-flowing granular formulation of the present invention for use in the treatment of PROS.

[0023] In one embodiment, the present invention relates to a method of treating a proliferative disorder, preferably PROS, comprising administering to a patient in need thereof a free flowing granular formulation of the present invention comprising a therapeutically effective amount of (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (or alpelisib) or a pharma- ceutical acceptable salt thereof.

[0024] In one embodiment, the present invention further relates to a pharmaceutical receptacle comprising a granular formulation according to the present invention and printed instructions for administration of the granular formulation of the present invention containing (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (or alpelisib) or a pharma- ceutically acceptable salt thereof.

[0025] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following general definitions apply unless otherwise specified:

[0026] The term "alpelisib" refers to (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide or BYL719. Alpelisib and pharma- ceutically acceptable salts thereof are described in PCT Patent Application WO 2010 / 029082, which is incorporated herein by reference in its entirety. A method for preparing alpelisib is described therein in Example 15. Preferably, alpelisib is in the form of the free base (i.e., has not formed a salt with another distinct acid or base). Alpelisib or a pharma- ceutical acceptable salt thereof, in particular alpelisib itself, is the essential active pharmaceutical ingredient (API) of the granular formulation according to the invention.

[0027] As used herein, the terms "comprise," "include," and "contain" are used in an open-ended and open-ended sense, unless otherwise indicated.

[0028] The terms "a" and "an" as well as "the" and similar references in the context of describing the present invention (particularly in the context of the claims which follow) are to be construed as including both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural is used for compounds, salts, etc., this is deemed to mean a single compound, salt, etc.

[0029] The term "pharmaceutical acceptable" refers to compounds, materials, excipients, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for contact with the tissues of a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problems commensurate with a reasonable benefit / risk ratio.

[0030] The term "geriatric patient" is preferably a patient aged 60 years or older, such as aged 70 years or older.

[0031] By "pediatric patient" is meant a patient under the age of 21, or between the ages of 12 and 16 (adolescent), or between the ages of 2 and 12 (child), or between the ages of 1 month and 2 (infant), or newborn to 1 month (neonatal). Preferably, a pediatric patient is a child or adolescent patient under the age of 21, 18 or younger, 15 or younger, 12 or younger, 9 or younger, 6 or younger, or 5 or younger.

[0032] A "patient with swallowing disorders" is a patient who has difficulty swallowing pharmaceutical preparations in the form of tablets, capsules, etc. due to physical and / or psychological inhibitions.

[0033] The term "(free-flowing) granular formulation" (also referred to herein as "formulation of the invention" etc.) means that the formulation according to the invention is free-flowing in a dry state during administration (although it may be administered into a fluid such as juice, tea, coffee, soup, milk, yogurt, water or other food or drink for administration to a patient).

[0034] The term "free flowing granules" refers specifically to a dry powder consisting of granules such that the resulting powder is capable of flowing freely in the dry state.

[0035] The term "internal phase" refers to a granular phase comprising the active ingredient (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (alpelisib) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier material, such as one or in particular two diluents, a disintegrant and a binder.

[0036] The term "external phase" refers to the external phase of a granule that does not contain any API, but only at least one pharma- ceutical acceptable carrier material, including, for example, diluents and lubricants.

[0037] The term "pharmaceutical single dose unit receptacle" refers to any container (preferably sealed after filling with a granular formulation) containing one single dose, in particular a flask (e.g. made of metal, glass or plastic or any combination thereof; preferably sealed after filling, e.g. by a lid or foil), a bottle (e.g. made of metal, glass or plastic or any combination thereof; preferably sealed after filling, e.g. preferably by a lid or foil) (e.g. made of metal, glass or plastic or any combination thereof; preferably sealed after filling, e.g. by a lid or foil), a bag made e.g. from a sheet of plastic (preferably metallized) and / or metal, a pouch made e.g. from a sheet of plastic (preferably metallized) and / or metal, a sachet made e.g. from a plastic (preferably metallized) or metal or in particular a stick pack, wherein the bag, pouch, sachet or stick pack is preferably sealed, e.g. by a heat treatment, to form a hermetically sealed receptacle.

[0038] The term "stick pack" refers to a pharmaceutical single dose unit container which is highly preferred in the embodiment of the present invention. Also called "granules in a single dose container", this term may specifically include or may specifically refer to an aluminium sachet.

[0039] Receptacle encapsulated formulations, particularly stick pack encapsulated formulations according to the invention, offer advantages in terms of storage and transportation compared to suspension formulations for children, which are bulkier and more problematic to transport, for example. Stick pack formulations do not require dosing cups, spoons, bottles, dispensers, etc. to measure the dose. Preferred stick packs are small, single-dose sachets in a relatively robust, child-resistant aluminium packaging containing the granular formulations of embodiments of the invention.

[0040] The term "unit dose" means the dose administered to a patient at a time of administration.

[0041] The term "daily dose" refers to the total dose of a therapeutic agent administered to a particular patient in any one day or 24 hour period. Said daily dose may preferably be administered using one or more of the pharmaceutical single dose unit receptacles according to the invention.

[0042] The phrases "effective amount" or "therapeutically effective amount" are used herein to mean an amount sufficient to preferably reduce, and most preferably prevent, a clinically significant deficit in activity, function and response in a subject in need thereof, particularly by at least about 5%, particularly at least 15%, preferably at least 50%, more preferably at least 90%. Alternatively, an effective amount or therapeutically effective amount is an amount sufficient to provide an observable improvement over baseline in clinically observable signs and symptoms of a disease when compared to a patient not receiving the treatment.

[0043] Administration of the granular formulations of the invention can be by direct application into each patient's mouth (either from a receptacle or, for example, via a spoon) or by pouring the granular formulation into liquid or food and then orally ingested.

[0044] When the term "treatment" is used, this means in particular therapeutic treatment aimed at complete cure, partial cure, symptomatic relief, or other therapy or other useful form of treatment.

[0045] The term "about" is preferably intended to mean within ±10%, more preferably within ±5%, and even more preferably within ±2% or within ±1% of a given value or range.

[0046] (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) is a specific 2-carboxamide cycloaminourea derivative compound that potently and selectively targets the (α)-isoform of class IA P3K and has the following chemical structure: [ka]

[0047] This compound is also known as (S)-N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide or BYL719 or alpelisib.

[0048] (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) and pharma- ceutically acceptable salts thereof are described in PCT Patent Application WO 2010 / 029082, which is incorporated herein by reference in its entirety, and methods for its preparation are described therein, for example, in Example 15. Preferably, alpelisib is in the form of the free base.

[0049] Suitable pharma- ceutical acceptable carrier materials for use in the internal and / or external phase of the granular formulation of the present invention include diluents and fillers, disintegrants, binders and / or lubricants.

[0050] The diluent is preferably selected from the group consisting of mannitol (including alpha, beta and delta polymorphs), sorbitol, malodextrin, lactose (e.g. lactose monohydrate), microcrystalline cellulose, maltitol, xylitol and any combination thereof, preferably microcrystalline cellulose and / or mannitol is used in the internal phase and cellulose, especially microcrystalline cellulose, is used in the external phase.

[0051] The disintegrant is preferably selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, sodium croscarmellose, calcium croscarmellose, cross-linked polyvinylpyrrolidone (e.g. commercially available under the trade names Crospovidone® or Polyplasdone® or Kollidone® CL), cross-linked alginic acid, sodium alginate, potassium alginate, gellan gum, corn starch, pregelatinized starch, sodium carboxymethylcellulose, sodium carboxymethyl starch glycine, and any combination thereof. Preferably, sodium carboxymethyl starch is used.

[0052] The binder is preferably selected from celluloses such as hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, starch, Starch 1500, polyvinylpyrrolidone (=povidone) and any combination thereof. Preferably, hydroxypropylmethylcellulose is used.

[0053] The lubricant is preferably selected from sodium stearyl fumarate, magnesium stearate, stearic acid, hydrogenated castor oil, calcium stearate, aluminum stearate, PEG 4000-8000, talc, glyceryl monostearate, glyceryl dibehenate (e.g., available under the trade name Compritol® 888 ATO from Gattefosse), glyceryl palmitostearate (e.g., available under the trade name Precerol® from Gattefosse), hydrogenated cottonseed oil, castor oil, and any combination thereof. Preferably, magnesium stearate is used.

[0054] Other pharma- ceutically acceptable excipients for the granular formulation (which is flowable in the final filled state) are also possible, such as pharma- ceutically acceptable sweeteners, pharma- ceutically acceptable colorants (dyes or pigments), pharma- ceutically acceptable flavors, preservatives, and the like, or mixtures of two or more thereof.

[0055] Formulations for geriatric patients, especially pediatric patients, may usually contain preservatives and flavorings. The stick pack formulation of the present invention does not contain preservatives. Furthermore, since alpelisib is a neutral molecule with no unpleasant taste, flavorings are not required in the granule formulation of the present invention.

[0056] Pharmacology and Usefulness The granular formulation of the present invention is useful for treating proliferative diseases, particularly cancer or PIK3CA mutation-driven morphology referred to as PIK3CA-associated overgrowth spectrum (PROS), preferably for treating patients with dysphagia, geriatric patients or pediatric patients, particularly pediatric patients. Examples of cancers suitable for treatment with the granular formulation of the present invention include, but are not limited to, breast cancer, ovarian cancer, head and neck cancer, pancreatic cancer and colorectal cancer. Preferably, the proliferative disease treated with the granular formulation of the present invention is a cancer selected from the group consisting of breast cancer, ovarian cancer and head and neck cancer. Preferably, the proliferative disease treated with the granular formulation of the present invention is PROS.

[0057] Tissue proliferation is a tightly controlled process in organisms from embryonic development to adulthood. One of the major regulators of cell proliferation is the PI3K / AKT / mTOR signaling pathway, which is a well-known target for multiple therapeutic strategies. Overactivation of the PI3K / AKT / mTOR pathway leads to significant dysregulation of cellular functions, resulting in a competitive growth advantage. Somatic mutations and gains or losses of these genes have been associated with many different solid and hematological tumors (De Santis MC et al.,(2017)PI3K Signaling in Tissue Hyper-Proliferation:From Overgrowth Syndromes to Kidney Cysts.Cancers(Basel);9(4):30). In addition to the well-known role of PIK3CA in cancer, postzygotic somatic mutations of PIK3CA have also been identified in various overgrowth disorders, including a broad group of clinically recognizable mutation-driven morphological abnormalities, termed the PIK3CA-associated overgrowth spectrum (PROS). PIK3CA-related overgrowth spectrum (PROS) designates a heterogeneous group of rare asymmetric overgrowth disorders caused by postzygotic variants in the PIK3CA gene (Keppler-Noreuil KM, Sapp JC, Lindhurst MJ et al., (2014) Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am. J. Med. Genet. p. 1713-33). PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which transduces activation of tyrosine kinase growth factor and hormone receptors into activation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) signaling, promoting tissue growth.In PROS, activation of this pathway is associated with overgrowth that may involve adipose tissue, muscle, skin, bone, blood or lymphatic vessels, or nerve tissue (Kurek KC et al., (2012) Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am. J. Hum. Genet. 90(6): 1108-15; Lindhurst MJ, Parker VE, Payne F et al., (2012) Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat. Genet; 44(8): 928-33). The prevalence of PROS is difficult to estimate due to its rarity, recent characterization (i.e., by the US National Institutes of Health in 2014), variability in ascertainment, wide phenotypic spectrum, and occurrence of atypical or mild phenotypes leading to misdiagnosis (Keppler-Noreuil KM et al., Am. J. Med. Genet. Ap. 1713-33; Mirzaa GM et al., (2013) Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP. Am J Med Genet C Semin Med Genet p. 122-30). PROS is characterized by congenital or early childhood onset overgrowth, sporadic onset, and mosaic distribution. Segmental overgrowth is often congenital in onset, but is usually present by the age of 1 year, and in some cases progressive tissue overgrowth persists into adulthood.Although genotype-phenotype correlations in PROS have been suggested (Mirzaa G et al.,(2016)PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.JCI Insight;1(9):e87623;Keppler-Noreuil KM et al.,(2014)Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.Am.J.Med.Genet.A p.1713-33), the primary determinant of the phenotype is the timing and location of the pathogenic mutation. As a result, PROS is characterized by a high degree of phenotypic heterogeneity between individuals. The characteristics of the overgrowth are highly variable for unknown reasons, i.e., some lesions show overgrowth limited to childhood, while other individuals may have progressive soft tissue overgrowth in adulthood. Complications of PROS vary depending on the anatomical location and the degree of overgrowth, but may include, among other symptoms, functional impairment (e.g., walking or swallowing), pain, cardiac dysfunction, pulmonary hypertension, seizures, neurodevelopmental disorders, recurrent superficial infections, thromboembolism, and / or bleeding, all of which can be debilitating and cause premature death. Current treatment relies primarily on debulking surgeries such as amputation and / or endovascular occlusion. Regrowth after surgery is frequent and often requires reoperation. There is a large unmet need for new targeted therapeutic approaches and effective treatments to address PROS.

[0058] Alpelisib, also known as (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or BYL719, is an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor that belongs to the 2-aminothiazole family of compounds. In biochemical assays, alpelisib potently inhibits the p110α subunit of PI3K (IC50=4.6nM) 50-fold more potently than other class IPI3K isoforms (e.g., p110β IC50=1156nM, p110δ IC50=290nM, p110γ IC50=250nM) and is inactive against most other kinases (Fritsch C et al.,(2014)Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials.Mol.Cancer Ther.,p.1117-29).

[0059] Alpelisib has been administered to patients with PROS under a compassionate use program. It was administered to two patients (one adult and one pediatric) with confirmed PIK3CA mutations and suffering from severe clinical symptoms of PROS. The adult participant was a 29-year-old man who had progressed on previous treatment with sirolimus. The pediatric patient was a 9-year-old girl with confirmed PIK3CA c.3140A>G (H1047R) mutation who had not received targeted systemic therapy for PROS / CLOVES syndrome. Both patients tolerated the treatment well and had no side effects except for hyperglycemia, which was seen in the adult patient, but was well controlled with nutritional therapy, and alpelisib did not affect the growth of the pediatric patient. In both patients, the volume reduction of the PROS lesions was associated with improved function of the affected organs and improved performance status. Several adult and pediatric PROS patients have been successfully treated with alpelisib under compassionate use.

[0060] The granular formulations of the present invention are particularly useful for the treatment of PIK3CA-Associated Overgrowth Spectrum (PROS) in pediatric patients.

[0061] In one embodiment, the granular formulation of the present invention can be used to treat fibroadipose hyperplasia (FH), a PROS disorder that, although not malignant, can cause health and medical problems such as walking problems due to leg length discrepancy, limb movement problems due to overgrowth, and challenges in regular daily living due to deformity.

[0062] In another embodiment, the granular formulation of the present invention can be used to treat congenital, lipomatous, overgrowths, vascular malformations, epidermal nevi, and spinal / skeletal abnormalities and / or scoliosis (collectively known as CLOVES syndrome), a rare, progressive congenital disorder that involves multiple organs including the skin, vascular system, and musculoskeletal system.

[0063] In another embodiment, the granular formulation of the present invention can be used to treat megalencephaly-capillary malformation syndrome, a rare developmental disorder characterized by overgrowth of the brain and several somatic tissues, accompanied by capillary skin malformations, macrocephaly (MEG) or hemimegalencephaly (HMEG), corticocerebral abnormalities such as hypertrichosis, facial dysmorphism, somatic growth abnormalities with body and brain asymmetry, developmental delay and digital abnormalities.

[0064] In another embodiment, the granular formulation of the present invention can be used to treat hemihyperplasia-multiple lipomatosis syndrome, a rare genetic overgrowth syndrome characterized by non-progressive, asymmetric, moderate hemihyperplasia with slow-growing, painless, multiple, recurrent, subcutaneous lipomatous masses distributed over the entire body, especially the back, trunk, limbs, fingers, and axillae.

[0065] In another embodiment, the granular formulation of the present invention can be used to treat hemimegalencephaly. Hemimegalencephaly is a rare malformation that involves one side of the brain. Children with this disorder may have a large, asymmetric head, accompanied by seizures, partial paralysis and impaired cognitive development, and often require hemispherectomy surgery.

[0066] In another embodiment, the granular formulation of the present invention can be used to treat congenital infiltrative lipomatosis of the face (CILF), a very rare disorder in which mature adipocytes invade adjacent tissues in the facial area, resulting in facial asymmetry.

[0067] In a further embodiment, the present invention relates to a method for treating a PIK3CA-associated overgrowth spectrum (PROS) disorder, comprising administering to a patient in need thereof a granular formulation of the present invention comprising a therapeutically effective amount of alpelisib or a pharma- ceutical acceptable salt thereof.

[0068] The activity and properties of the granular formulations of the present invention may be demonstrated in standard clinical and / or animal tests.

[0069] In adult patients (e.g., geriatric patients or other adult patients with dysphagia), alpelisib may be orally administered at a daily effective dose of about 1 to 6.5 mg / kg in human adults. Alpelisib may be orally administered to a human adult weighing 50 to 70 kg at a daily dose of about 70 mg to 455 mg, for example, about 100 mg to 400 mg, about 240 mg to 400 mg, about 125 mg to 400 mg, or about 125 mg to 300 mg, in a single dose or in divided doses up to four times a day. Preferably, alpelisib is administered to a human adult weighing 50 to 70 kg (e.g., geriatric patients or adults with dysphagia) at a daily dose of about 125 mg, 200 mg, 250 mg, 300 mg / day, or 350 mg to about 400 mg. In adult patients, alpelisib is preferably orally administered at 250 mg once a day with a meal.

[0070] In pediatric patients, alpelisib may be administered orally at an effective daily dose of about 10 mg / day, or 20 mg / day (preferred), or 25 mg / day (preferred), or 30 mg / day, or 40 mg / day, or 50 mg / day (preferred), or 60 mg / day, or 70 mg / day, or 75 mg / day, or 80 mg / day, or 90 mg / day, or 100 mg / day, or 110 mg / day, or 120 mg / day, or 125 mg / day (preferred), or 130 mg / day, 140 mg / day, or 150 mg / day, or 175 mg / day, or 200 mg / day (preferred), or 250 mg / day per patient. In pediatric patients, alpelisib is preferably administered orally at 50 mg once daily with a meal.

[0071] It will be understood that the specific dose level for any particular patient will depend on a variety of factors, including age, weight, general health, drug combination with one or more active agents, and the type and severity of the disease. Armed with the teachings of the present invention, one of ordinary skill in the art will have the experience and skill to select the appropriate dose level of treatment for a particular patient.

[0072] In another embodiment, the present invention further relates to a pharmaceutical single-dose unit receptacle comprising a granular formulation according to the present invention and printed instructions directing the administration of alpelisib or a pharma- ceutical acceptable salt thereof for the treatment of PROS. EXAMPLES

[0073] The following examples are illustrative of the invention described above, but are not intended to limit the scope of the invention in any way.

[0074] Example 1 Manufacturing of 20mg or 50mg granule formulations Granular formulations of 20 mg and 50 mg were manufactured using the unit amounts in Table 1 below. The environmental conditions for the manufacturing process were 22° C.±3° C. and 55% RH±10% RH.

[0075] Mannitol Pharma, alpelisib, sodium carboxymethyl starch (NA-carboxymethyl starch) and Avicel PH101 (cellulose, microcrystalline PH101) were blended in a high shear granulator. HPMC-603 (HPMC, hypromellose) was dissolved in purified water while stirring in a stainless steel container. Swelling and degassing were allowed until a clear solution was obtained (approximately 5 hours). The dissolved HPMC-603 was then added at a rate of 0.8 kg / min to 1.0 kg / min in the high shear granulator and granules were produced at an impeller speed of 130 to 203 rpm and a chopper speed of 1450 rpm. The liquid feed system was flushed with the amount of water required to meet the target water addition amount at a rate of 0.8 kg / min to 1.0 kg / min. The wet mass was kneaded in a high shear granulator with impeller speed of 150-203 rpm and chopper speed of 1450 rpm for 10-60 seconds. The granules were dried in a fluid bed dryer until a loss on drying (%LOD) of about 1.7% or less was achieved. The dried granules were screened through a screening mill (screen size 1 mm, round wire). The external phase excipient Cellulose MK GR (PH102) was sieved through a screening mill (screen size 1 mm / round wire) and added to the granules and blended in a blender for 18 minutes at a target speed of 9 rpm. Magnesium stearate was sieved (0.5 mm), added to the granules and mixed in a blender for 11 minutes at a target speed of 9 rpm. The final blend was ready to use and used for filling stick packs using packaging material (stick pack dimensions 90 mm x 25 mm for both strengths). The shelf life of the final blend was 30 days and the storage temperature did not exceed 25°C.

[0076] [Table 1]

[0077] The granular formulation of the present invention has good flowability and, as a result, is uniformly filled into containers such as stick packs. The granular formulation of the present invention is characterized by a reduced proportion of fine powder (amount of powder remaining in the granules), which helps to avoid dust generation due to fine particles adhering to the seal of the stick pack packaging, which prevents the stick pack from being sealed.

Claims

1. 1. A free-flowing granular formulation comprising an inner phase in the form of granules comprising alpelisib or a pharma- ceutical acceptable salt thereof as an active pharmaceutical ingredient and at least one pharma-ceutical acceptable carrier material, and additionally an outer granular phase free of said active pharmaceutical ingredient, said outer granular phase comprising at least one pharma-ceutical acceptable carrier material.

2. 10. The free-flowing granular formulation of claim 1 for use in treating a patient having dysphagia, said patient being selected from geriatric and pediatric patients.

3. 3. The free-flowing granular formulation of claim 2, wherein the patient is a pediatric patient.

4. The present invention relates to a stick pack pharmaceutical single dose receptacle comprising an internal phase and an external phase, the internal phase comprising: (i) 1% to 5%, 2 to 5%, 3% to 4%, or 3.33% of alpelisib or a pharma- ceutical acceptable salt thereof; or alternatively 20 mg to 200 mg, 25 mg to 150 mg, 20 mg, or 25 mg, or 50 mg, or 100 mg, or 125 mg of alpelisib or a pharma-ceutical acceptable salt thereof; and (ii) lactose, sorbitol ... (iii) a disintegrant selected from croscarmellose sodium, crospovidone, and sodium carboxymethyl starch in an amount of 2-7%, 3-6%, 3-7%, or 5%; and (iv) a binder selected from hydroxypropylcellulose, povidone, starch, and hydroxypropylmethylcellulose in an amount of 1-5%, 1.5-4.5%, 2-4%, or 3%; 2. The free flowing granular formulation of claim 1, wherein the external phase contains: (i) a diluent selected from lactose, sorbitol, mannitol and microcrystalline cellulose in an amount of 10-30%, 10-25%, 15-20% or 17.5%; and (ii) a lubricant selected from Compritol 888, sodium stearyl fumarate and magnesium stearate in an amount of 0.25-4%, 0.3-3%, 0.5-1.5% or 1%; all amounts selected to add up to 100% in the final granular formulation.

5. The present invention relates to a stick pack pharmaceutical single dose receptacle comprising an internal phase and an external phase, the internal phase comprising: (i) 3% to 4% or 3.33% of alpelisib or a pharma- ceutical acceptable salt thereof; or alternatively 20 mg, or 25 mg, or 50 mg, or 100 mg of alpelisib or a pharma- ceutical acceptable salt thereof; (ii) diluents selected from lactose, sorbitol, and microcrystalline cellulose in an amount of 30-40% or 36.17%, and / or mannitol in an amount of 30-40% or 34%; and (iii) croscarmellose sodium, crospovidone, and carboxymethyl starch sodium in an amount of 3-7% or 5%.

2. The free flowing granular formulation of claim 1, wherein the external phase contains (i) a diluent selected from lactose, sorbitol, mannitol and microcrystalline cellulose in an amount of 15-20% or 17.5%; and (ii) a lubricant selected from completel 888, sodium stearyl fumarate and magnesium stearate in an amount of 0.5-1.5% or 1%; all amounts selected to add up to 100% in the final granular formulation.

6. The present invention relates to a stick pack pharmaceutical single dose receptacle comprising an internal phase and an external phase, the internal phase comprising: (i) 3% to 4% or 3.33% alpelisib or a pharma- ceutical acceptable salt thereof; or alternatively 20 mg, or 25 mg, or 50 mg, or 100 mg alpelisib or a pharma- ceutical acceptable salt thereof; and (ii) microcrystalline cellulose (e.g., Avicel PH101) in an amount of 30-40% or 36.17% and / or mannitol (e.g., Mannitol PH101) in an amount of 30-40% or 34%.

2. The free flowing granular formulation of claim 1, wherein the outer phase contains (i) a diluent which is microcrystalline cellulose (e.g., Cellulose MK GR) in an amount of 15-20% or 17.5%; and (ii) a lubricant which is magnesium stearate in an amount of 0.5-1.5% or 1%; all amounts selected to add up to 100% in the final granular formulation.

7. 1. A stick pack pharmaceutical single dose receptacle comprising an internal phase and an external phase, the internal phase containing: (i) 3%-4% or 3.33% of alpelisib or a pharma- ceutical acceptable salt thereof; or alternatively 20 mg, or 25 mg, or 50 mg, or 100 mg of alpelisib or a pharma-ceutical acceptable salt thereof; (ii) a diluent which is microcrystalline cellulose (e.g., Avicel PH101) in an amount of 36.17% and / or mannitol (e.g., Mannitol Pharma) in an amount of 34%; (iii) a disintegrant which is sodium carboxymethyl starch in an amount of 5%; and (iv) a binder which is hydroxypropyl methylcellulose in an amount of 3%; the external phase containing: (i) microcrystalline cellulose (e.g., cellulose MK101) in an amount of 17.5%.

2. The free-flowing granular formulation of claim 1, comprising: (i) a diluent which is magnesium stearate in the amount of 1%; and (ii) a lubricant which is magnesium stearate in the amount of 1%; all amounts selected to total 100% in the final granular formulation.

8. 8. The granular formulation of any one of claims 1 to 7, for use in the treatment of a human patient with dysphagia, selected from a geriatric or pediatric patient, said treatment comprising administration of said granular formulation in the treatment of a proliferative disease with mutation-driven morphological abnormalities associated with PIK3CA-associated overgrowth spectrum (PROS).

9. The granular formulation of claim 8, wherein the granular formulation is administered to the patient using a stick pack pharmaceutical single dose unit receptacle of claim 4 containing the granular formulation.

10. Use of a granular formulation according to any one of claims 1 to 7 in the treatment of a pediatric patient with dysphagia, comprising administration of said granular formulation in the treatment of a proliferative disorder with mutation-driven morphological abnormalities associated with PIK3CA-associated overgrowth spectrum (PROS).

11. 11. The use according to claim 10, wherein the granular formulation is administered using a stick pack pharmaceutical single dose unit receptacle according to claim 4, comprising the granular formulation.

12. Use of a granular formulation according to any one of claims 1 to 4 in the manufacture of a medicament comprising said formulation in the form of free-flowing granules for use in the treatment of a proliferative disease or PROS.

13. 13. The use according to claim 12, wherein the pharmaceutical product is manufactured to contain the granular formulation in a pharmaceutical single dose unit receptacle according to claim 4.

14. A process for producing a granular formulation according to any one of claims 1 to 7, comprising the steps of: (i) preparing an internal phase comprising alpelisib or a pharma- ceutical acceptable salt thereof by wet granulation, adding one or more diluents, adding a disintegrant, and adding a binder, and then drying the mixture; (ii) preparing the external phase comprising a diluent and a lubricant; The process includes forming by

15. 15. The process of claim 14, further comprising filling the resulting dry granular formulation into stick pack pharmaceutical single dose unit receptacles in step (iii).