WO2025242583A1 - Nouvelle formulation comprenant de l'élinzanétant dans une dispersion solide - Google Patents

Nouvelle formulation comprenant de l'élinzanétant dans une dispersion solide

Info

Publication number
WO2025242583A1
WO2025242583A1 PCT/EP2025/063648 EP2025063648W WO2025242583A1 WO 2025242583 A1 WO2025242583 A1 WO 2025242583A1 EP 2025063648 W EP2025063648 W EP 2025063648W WO 2025242583 A1 WO2025242583 A1 WO 2025242583A1
Authority
WO
WIPO (PCT)
Prior art keywords
elinzanetant
solid dispersion
pharmaceutical composition
tablet
composition according
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/EP2025/063648
Other languages
English (en)
Inventor
Johanna Anlahr
Andre PREUSS
Gabriele Winter
Afra TORGE-FRANZEN
Corinna BODE
Maximilian Franz Ludwig KARL
Marcus-Hillert SCHULTZE-MOSGAU
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.)
Bayer Consumer Care AG
Original Assignee
Bayer Consumer Care AG
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 Bayer Consumer Care AG filed Critical Bayer Consumer Care AG
Publication of WO2025242583A1 publication Critical patent/WO2025242583A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a pharmaceutical composition comprising a solid dispersion, the solid dispersion comprising elinzanetant and at least one solid dispersion matrix comprising a neutral polymer as a solid dispersion matrix agent, its process of preparation and its use for treating diseases and disorders.
  • WO 2011/023733 A1 page 31, line 6 discloses the formulation of the crystalline anhydrate Form 1 in a solid pharmaceutical composition.
  • drug substance and excipients were dry mixed and thereafter granulated using water; see WO 2011/023733 A1, page 32, lines 7 to 10.
  • the granules were dried and milled in a conical mill to reduce the size of the granules.
  • compositions according to WO 2011/023733 A1 exhibit insufficient dissolution in biorelevant media; see e.g. composition 26 of Example 2, Figure 1 and Table 2 of the present disclosure. Therefore, the solid compositions of prior art also exhibit an unfavorable high variability in bioavailability.
  • a liquid formulation in a soft gelatin capsule was provided (WO 2019/175253 A1). These soft gelatin capsules are used in clinical development and are planned for launch of the commercial drug product.
  • the disadvantage of the capsules described is the fact, that due to the limited drug load, the size of the capsules is large (Size-20) and for a desired daily dose of 120 mg, two soft gelatin capsules containing 60 mg each have to be taken.
  • amorphous solid dispersions Another inherent issue of amorphous solid dispersions is the instability of the solid state which results in a tendency for recrystallisation of the drug and/or excipients during storage (Andrews et al., Journal of Pharmacy and Pharmacology; 62: 1580–1590 (2010)). This may be accompanied by a break-down of dissolution and bioavailability.
  • the stability of the API should be preserved, e.g. avoiding degradation or esterification of the API.
  • some APIs like elinzanetant tend to react with the matrix.
  • the inventors have surprisingly found that elinzanetant free base is instable within a matrix of acidic polymer matrix agents.
  • the problem to be solved by the present invention is to provide a pharmaceutical composition containing elinzanetant showing sufficient bioavailability and stability of elinzanetant.
  • the pharmaceutical composition according to the invention shows desired stabilization of the active ingredient elinzanetant as well as sufficient bioavailability.
  • the inventors have unexpectedly found that the pharmaceutical compositions according to the invention were stable and exhibited increased dissolution behavior in biorelevant media as compared to solid pharmaceutical compositions of prior art, e.g. the ones disclosed in WO 2011/023733 A1.
  • the formulation of WO 2011/023733 A1 relates to a solid pharmaceutical composition not being a solid dispersion, as mixing and wet granulation using water does not lead to embedding of the drug substance into the matrix, i.e. not resulting in a solid dispersion. Further, it has been shown that the pharmaceutical composition according to the invention shows a pharmacokinetic AUC that is approx. 12% higher than with the formulation (soft gelatin capsules) of prior art used in Phase III clinical studies and used for approval and launch of elinzanetant. This was surprising as the soft gelatin capsules contained elinzanetant in solubilized form.
  • compositions according to the present disclosure reach the pharmacokinetic exposures and bioavailability of the soft gelatin capsule formulation as used in clinical Phase III studies at lower doses, such as at a daily dose of 100 mg or higher and lower than 120 mg.
  • the invention pertains to a pharmaceutical composition comprising a solid dispersion comprising elinzanetant or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition according to the invention comprises elinzanetant or a pharmaceutically acceptable salt thereof, and a solid dispersion matrix; wherein the solid dispersion matrix comprises a neutral polymer as a solid dispersion matrix agent.
  • the invention further relates to granules, pellets, tablets, dragées, sachets, pills, or melts comprising the pharmaceutical composition according to the invention.
  • the invention also relates to a method for treating a sex hormone-dependent disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition according to the invention, or granules, pellets, a tablet, a dragée, a sachet, a pill, or a melt according to the invention, comprising a therapeutically effective dose of elinzanetant.
  • FIGURE LEGEND Figure 1 Dissolution of ASD compositions in 2 stage dissolution in biorelevant media; Composition numbers according to Example 1 are indicated
  • SD standard deviation
  • elinzanetant refers to 2-[3,5-bis(trifluoromethyl)phenyl]-N- ⁇ 4-(4-fluoro-2- methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)- yl]pyridin-3-yl ⁇ -N,2-dimethylpropanamide.
  • elinzanetant is the compound of formula (I) O (I).
  • compound of the invention or “active agent” or “active pharmaceutical ingredient” or “active ingredient” refer to elinzanetant.
  • compositions according to the disclosure include but are not limited to granules, pellets, tablets, dragées, pills, melts or solid dispersions and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • Solid dispersion The solid dispersion of the present disclosure comprises elinzanetant or a pharmaceutically acceptable salt thereof and a solid dispersion matrix, comprising a solid dispersion matrix agent, and optionally a carrier.
  • elinzanetant or the pharmaceutically acceptable salt thereof is present in the solid dispersion in amorphous form.
  • elinzanetant or the pharmaceutically acceptable salt thereof being in amorphous form means that in the final pharmaceutical composition, the active pharmaceutical ingredient may be molecularly dispersed in the solid dispersion matrix or be present as amorphous particles within the solid dispersion matrix.
  • amorphous form within the solid dispersion matrix can be achieved by methods known in the art, such as e.g. solvent evaporation or cooling of the melt.
  • the solid dispersion matrix is a very effective solid-state stabilizer.
  • a solid dispersion matrix can be formed by one or more components, such as a solid dispersion matrix agent and optionally a further component, such as a carrier.
  • a “solid dispersion matrix” are polymeric excipients, non- polymeric excipients, or combinations thereof, capable of dissolving or dispersing the active ingredient (I).
  • the “solid dispersion matrix” may consist of a “solid dispersion matrix agent”, or may consist of the combination of a “solid dispersion matrix agent” and a “carrier” used during the manufacturing process of the amorphous solid dispersion (ASD).
  • the “solid dispersion matrix” and the amorphous elinzanetant or the pharmaceutically acceptable salt thereof become integral parts of the amorphous solid dispersion (ASD).
  • neutral polymers show superior properties with respect to dissolution behavior and in particular stability of elinzanetant in the pharmaceutical composition.
  • non-neutral solid dispersion matrix agents such as those comprising recurring carboxylate groups, foster transesterification with elinzanetant and found that neutral polymers as solid dispersion matrix agents unexpectedly increase the chemical and physical stability of elinzanetant in ASD compositions, e.g., as compared to non-neutral solid dispersion matrix agents.
  • the solid dispersion matrix agent is a neutral polymer.
  • “Neutral polymer” in context with the present disclosure relate to a polymer containing only non-deprotonable functional groups and/or deprotonable functional groups (contain hydrogen atoms that could potentially be donated) with a pKa of 7 or more showing superior properties with respect to dissolution behavior and stability of the pharmaceutical composition.
  • the solid dispersion matrix agent is a pharmaceutically acceptable polymer containing only non-deprotonatable recurring functional groups or deprotonatable recurring functional groups having a pK a of 7 or more.
  • the polymer does not contain a recurring functional group with a pKa of less than 7, such as a carboxylate group, a sulfonate group, a phosphate group, a sulfate group, and a phosphonate group. In one embodiment the polymer does not contain a recurring carboxylate group.
  • “Recurring group” refers a group present in two or more constitutional repeating units (mer) of the polymer.
  • “Functional group” - for repeating units of polymers – are attached to their nonpolar core of carbon atoms and thus add chemical character to carbon chains. Functional groups can also be charged, depending on the ambient pH conditions, this is indicated by its pKa.
  • the pharmaceutical composition does not contain a surfactant.
  • an ionic surfactant such as SDS may interfere with the dissolution behavior.
  • the pharmaceutical composition does not contain an ionic surfactant.
  • the pharmaceutical composition does not contain sodium dodecyl sulfate (SDS).
  • the solid dispersion matrix agent is selected from the group consisting of polyethylene oxide, polyvinylpyrrolidone (PVP), vinylpyrrolidone/vinylacetate copolymer (copovidone) (e.g. Kollidon VA64), polyalkylene glycol (e.g. polyethylene glycol), hydroxyalkyl cellulose (e.g. hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (e.g.
  • PVP polyvinylpyrrolidone
  • copovidone e.g. Kollidon VA64
  • polyalkylene glycol e.g. polyethylene glycol
  • hydroxyalkyl cellulose e.g. hydroxypropyl cellulose
  • hydroxyalkyl methyl cellulose e.g.
  • solid dispersion matrix is selected from the group consisting of polyvinylpyrrolidone (PVP), vinylpyrrolidone/vinylacetate copolymer (copovidone), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyethylene glycol and polyethylene oxide.
  • PVP polyvinylpyrrolidone
  • copovidone vinylpyrrolidone/vinylacetate copolymer
  • HPMC hydroxypropyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • the neutral polymer is vinylpyrrolidone/vinylacetate copolymer (copovidone).
  • copovidone vinylpyrrolidone/vinylacetate copolymer
  • the solid dispersion comprises elinzanetant or the pharmaceutically acceptable salt thereof and the solid dispersion matrix agent in a weight ratio of from 1:0.5 to 1:4, such as from 1:1 to 1:3 or from 1:1.5 to 1:2.5.
  • the solid dispersion comprises elinzanetant or the pharmaceutically acceptable salt thereof and the solid dispersion matrix agent in a weight ratio of 1:2.
  • the solid dispersion comprises elinzanetant and the solid dispersion matrix agent in a weight ratio of from 1:0.5 to 1:4, such as from 1:1 to 1:3 or from 1:1.5 to 1:2.5. In an embodiment the solid dispersion comprises elinzanetant and the solid dispersion matrix agent in a weight ratio of 1:2.
  • Carrier The solid dispersion matrix may optionally further comprise a carrier. In the context of the present disclosure the carrier is selected from the groups of disintegration promoters, fillers, lubricants, sweeteners, antioxidants, plasticizers, flavoring agents and/or colorants or a combination thereof.
  • the pharmaceutically acceptable solid dispersion matrix comprises a solid dispersion matrix agent and a carrier.
  • the solid dispersion matrix consists of a solid dispersion matrix agent and a carrier.
  • the carrier according to the present invention is a disintegration promoter.
  • the carrier is a disintegration promoter selected from the group consisting of cross-linked polyvinylpyrrolidone, maize starch, modified starch, and starch derivatives such as sodium carboxymethyl starch and sodium starch glycolate, cellulose derivatives, such as carmellose calcium (carboxymethylcellulose calcium) and croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium), or microcrystalline cellulose, or a combination of croscarmellose sodium and microcrystalline cellulose, or mixtures thereof.
  • the disintegration promoter is croscarmellose sodium or cross-linked polyvinylpyrrolidone. In an embodiment, the disintegration promoter is croscarmellose sodium.
  • the carrier according to the present invention is a filler selected from the group consisting of microcrystalline cellulose, cellulose powder, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose or maltodextrins or mixtures thereof.
  • the filler is microcrystalline cellulose or lactose or a combination thereof.
  • the solid dispersion matrix does not contain a filler.
  • the solid pharmaceutical composition does not contain a filler.
  • the carrier according to the present invention is a lubricant selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, glycerin monostearate, glycerin, monobehenate, calcium behenate, hydogenated vegetable fat or oil, polyethylenglycol and talc, or mixtures thereof.
  • the lubricant is selected from the list consisting of magnesium stearate, stearic acid and talc.
  • the carrier is magnesium stearate.
  • the carrier according to the present invention is a sweetener selected from the group consisting of sucralose, saccharin, sodium-, potassium- or calcium saccharin, potassium acesulfame, neotame, alitame, glycyrrhizin or thaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol, or mixtures thereof.
  • sweeteners are added in amounts known for persons skilled in the art.
  • the carrier according to the present invention is a flavoring agent selected from the group consisting of synthetic/artificial flavoring agents, such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural counterpart, or mixtures thereof.
  • synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through
  • the carrier according to the present invention is a colorant selected from the group consisting of dyes, lakes, or pigment such as indigo carmine, riboflavin and titanium dioxide, or mixtures thereof.
  • colorants are added in amounts known for persons skilled in the art according to the desired color and/or color intensity.
  • the carrier according to the present invention is an antioxidant selected from the group consisting of citric acid, butylated hydroxyanisole, butylated hydroxytoluene, ethylenediaminetetraacetic acid (EDTA), tocopherol (Vitamine E), ascorbic acid, glutathione, cysteine, sulfite (such as sodium sulfite or sodium hydrogen sulfite), di-sulfite (such as sodium di-sulfite), esters of ascorbic acid, and salts or esters of gallic acid, or mixtures thereof.
  • an antioxidant selected from the group consisting of citric acid, butylated hydroxyanisole, butylated hydroxytoluene, ethylenediaminetetraacetic acid (EDTA), tocopherol (Vitamine E), ascorbic acid, glutathione, cysteine, sulfite (such as sodium sulfite or sodium hydrogen sulfite), di-sulfite (such as sodium di
  • the carrier according to the present invention is plasticizers, selected from the group consisting of polyethylene glycol, propylene glycol, sorbitol, glycerol, maltitol, xylitol, mannitol, erythritol, glycerol trioleate, tributyl citrate, triethyl citrate acetyl triethyl citrate, glyceryl triacetate, stearic acid, medium chain triglycerides or a mixture thereof.
  • plasticizers selected from the group consisting of polyethylene glycol, propylene glycol, sorbitol, glycerol, maltitol, xylitol, mannitol, erythritol, glycerol trioleate, tributyl citrate, triethyl citrate acetyl triethyl citrate, glyceryl triacetate, stearic acid, medium chain trig
  • the solid dispersion matrix comprises a mixture of one or more of the above disclosed disintegration promotors, fillers, lubricants, sweeteners, antioxidants, plasticizers, flavoring agents and/or colorants.
  • Pharmaceutical compositions according to the disclosure is in the form of a solid dispersion or a pharmaceutical composition comprising a solid dispersion.
  • the solid dispersion may be a solid solution, glass solution, glass suspension, amorphous precipitation in a crystalline carrier, eutectic or monotectic, compound or complex formation or combinations thereof.
  • the inventors have unexpectedly found that the dissolution behavior of the solid pharmaceutical composition according to the present disclosure can be further optimized by adapting the weight ratio of elinzanetant to the solid dispersion matrix agent and to the carrier, or the weight ratio of the sum of elinzanetant and solid dispersion matrix to carrier, or the weight ratio of elinzanetant to carrier.
  • the solid dispersion comprises elinzanetant or a pharmaceutically acceptable salt thereof, the solid dispersion matrix agent and the carrier in a weight ratio of from 1:0.5:0.15 to 1:4:10, such as from 1:1:0.5 to 1:3:6 or from 1:1.5:1 to 1:2.5:3.5.
  • the solid dispersion comprises elinzanetant or a pharmaceutically acceptable salt thereof elinzanetant and the solid dispersion matrix agent and the carrier in a weight ratio of 1:2:2.
  • the solid dispersion comprises elinzanetant, the solid dispersion matrix agent and the carrier in a weight ratio of from 1:0.5:0.15 to 1:4:10, such as from 1:1:0.5 to 1:3:6 or from 1:1.5:1 to 1:2.5:3.5.
  • the solid dispersion comprises elinzanetant and the solid dispersion matrix agent and the carrier in a weight ratio of 1:2:2.
  • the solid dispersion comprises elinzanetant or a pharmaceutically acceptable salt thereof, the solid dispersion matrix agent and the carrier in a weight ratio for the sum of elinzanetant or a pharmaceutically acceptable salt thereof and the solid dispersion matrix agent to carrier of from 1:0.1 to 1:2, such as from 1:0.25 to 1:1.5 or from 1:0.4 to 1:1.
  • the solid dispersion comprises elinzanetant and the solid dispersion matrix agent to carrier in a weight ratio of 1:2.
  • the solid dispersion comprises elinzanetant, the solid dispersion matrix agent and the carrier in a weight ratio for the sum of elinzanetant and the solid dispersion matrix agent to carrier of from 1:0.1 to 1:2, such as from 1:0.25 to 1:1.5 or from 1:0.4 to 1:1.
  • the solid dispersion comprises elinzanetant and the solid dispersion matrix agent to carrier in a weight ratio of 1:2.
  • the solid dispersion comprises elinzanetant or a pharmaceutically acceptable salt thereof and the carrier in a weight ratio of from 1:0.15 to 1:10, such as from 1:0.5 to 1:6 or from 1:1 to 1:3.5.
  • the solid dispersion comprises elinzanetant or a pharmaceutically acceptable salt thereof and the carrier in a weight ratio of 1:2.
  • the solid dispersion comprises elinzanetant and the carrier in a weight ratio of from 1:0.15 to 1:10, such as from 1:0.5 to 1:6 or from 1:1 to 1:3.5.
  • the solid dispersion comprises elinzanetant and the carrier in a weight ratio of 1:2.
  • the solid dispersion is substantially homogeneous.
  • the present invention achieves a stable formulation in which elinzanetant or a pharmaceutically acceptable salt thereof is stabilized in its amorphous form through its shelf life and maintains supersaturation of elinzanetant in solution and resulting in a maximum bioavailability of elinzanetant in vivo after administration.
  • Excipients of the pharmaceutical composition outside the solid dispersion may further comprise pharmaceutically acceptable excipients that do not form integral part of solid dispersion of the solid dispersion matrix and elinzanetant or the pharmaceutically acceptable salt thereof. Such pharmaceutically acceptable excipient may for example be blended with the solid dispersion before further processing of the pharmaceutical composition, such as tableting.
  • the pharmaceutical composition according to the disclosure may comprise further pharmaceutically acceptable excipients, such as selected from the group consisting of fillers, lubricants, disintegration promoters, sweeteners, antioxidants, plasticizers, flavoring agents and/or colorants or a combination thereof.
  • the embodiments for the fillers, lubricants, disintegration promoters, sweeteners, antioxidants, plasticizers, flavoring agents and/or colorants, or mixtures thereof, comprised in the pharmaceutical composition are as disclosed for the respective excipients as carriers in the solid dispersion herein.
  • the pharmaceutical composition consists of a blend of the solid dispersion according to the present disclosure and one or more further pharmaceutically excipients, altogether mixed and formulated into tablets which are optionally finally coated.
  • the solid pharmaceutical composition comprises a lubricant.
  • the lubricant is selected from the group consisting of magnesium stearate, stearic acid, lecithin, soy lecithin, mineral oil, carnauba wax, acetylated monoglycerides, and polysorbate; or a mixture thereof.
  • the lubricant is magnesium stearate.
  • the lubricant may be blended with the solid dispersion comprising elinzanetant and the solid dispersion matrix.
  • the lubricant does not form part of the solid dispersion but is blended with the solid dispersion before further processing of the pharmaceutical composition, such as tableting. Coating
  • the solid pharmaceutical composition is optionally coated.
  • the pharmaceutical composition according to the disclosure is a tablet.
  • the tablet is coated.
  • the optional coating is carried out with addition of customary coating and film-forming agents familiar to the person skilled in the art, such as hydroxy-propylcellulose, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polyvinyl- pyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), shellac, acrylic and/or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol (e.g.
  • polyethylene glycol 3350 polyethylene glycol 3350
  • glycerol triacetate or triethyl citrate and/or colorants/pigments such as, for example, titanium dioxide, rice starch, calcium sulfate, calcium carbonate, iron oxide (e.g. red iron oxide, yellow iron oxide, black iron oxide), indigotin or suitable color lakes, and/or anti-tacking agents such as talc, and/or opacifiers such as titanium dioxide, rice starch, calcium sulfate, calcium carbonate.
  • An optional coating may comprise HPMC and polyethylene glycol, and iron oxide, such as iron oxide red and/or iron oxide yellow.
  • the coating may comprise an opacifier, such titanium dioxide or rice starch or calcium sulfate.
  • a mixture of the coating substances mentioned herein may also be used as a ready-to-use coating system such as commercially available coatings.
  • the coating is about 0.5% to 10% by weight of the coated tablet, preferably 0.5% to 4.5% by weight of the coated tablet formulation, more preferably about 1.5% to 4.5% by weight of the coated tablet.
  • the solid pharmaceutical composition is coated with a lacquer containing HPMC and polyethylene glycol, and iron oxide, such as iron oxide red, iron oxide yellow and titanium dioxide.
  • the solid pharmaceutical composition is coated with a lacquer containing HPMC and polyethylene glycol, and iron oxide, such as iron oxide red, iron oxide yellow, and one or more opacifier selected from the group consisting of rice starch, calcium sulfate, and calcium carbonate.
  • Amount of elinzanetant in the solid pharmaceutical composition can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient, for the purpose of this invention is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable excipient and a pharmaceutically effective amount of elinzanetant.
  • a pharmaceutically acceptable excipient is any excipient which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of elinzantent is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the pharmaceutical composition according to the invention demonstrates improved pharmacokinetic properties compared to compositions of prior art, in particular the soft gelatin capsules used in Phase III clinical studies. Specifically, the pharmaceutical composition according to the present invention achieves comparable pharmacokinetic exposure at a reduced dose.
  • the total amount of elinzanetant to be administered using the pharmaceutical composition of the present invention will generally range from about 5 mg to about 300 mg per day.
  • the amount of the administered elinzanetant can vary widely according to considerations as the compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.
  • the amount of elinzanetant in a dosage unit, such as one tablet, of the pharmaceutical composition is from 5 mg to 300 mg, in an embodiment from 60 to 240 mg, in an embodiment from 90 mg to 160mg, in an embodiment 100 to 160 mg.
  • the amount of elinzanetant in a dosage unit of the pharmaceutical composition, such as one tablet is 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, or 120 mg.
  • An embodiment of the disclosure is a pharmaceutical composition, such as a tablet, comprising elinzanetant in an amount of 5 mg to 300 mg, such as from 60 to 200 mg, such as from 90 mg to 160 mg, such as from 100 to 160 mg.
  • An embodiment of the disclosure is a pharmaceutical composition, such as a tablet, comprising elinzanetant in an amount of 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, or 120 mg.
  • the amount of elinzanetant in a single dosage unit of the pharmaceutical composition, such as a tablet, is 120 mg.
  • a single dosage unit may comprise the daily dose of elinzanetant.
  • the daily dose of elinzanetant is from 40 to 300 mg, such as 60 to 200 mg, such as 60 to 160 mg, e.g.60, 80, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, or 160 mg.
  • the daily dose of elinzanetant is 100 mg, 105 mg, 110 mg, 115 mg or 120 mg. In an embodiment the daily dose of elinzanetant is 100 mg. In an embodiment the daily dose of elinzanetant is 105 mg. In an embodiment the daily dose of elinzanetant is 110 mg. In an embodiment the daily dose of elinzanetant is 115 mg. In an embodiment the daily dose of elinzanetant is 120 mg.
  • a single dosage unit may contain an integer fraction of the daily dose of elinzanetant. For illustrative purpose a single dosage unit may contain half of the daily dose so that two dosage units are to be taken for administration of the daily dose.
  • a single dosage unit may contain a third of the daily dose so that three dosage units are to be taken for administration of the daily dose, and so on.
  • the amount of elinzanetant in the pharmaceutical composition is an integer fraction of 120 mg, such as 20 mg, 30 mg, 40 mg, 60 mg, or 120 mg.
  • a single dosage unit of the pharmaceutical composition comprises a daily dose of elinzanetant, preferably 120 mg.
  • the amount of elinzanetant in the pharmaceutical composition is an integer fraction of 110 mg, such as 55 mg.
  • a single dosage unit of the pharmaceutical composition comprises a daily dose of elinzanetant, preferably 110 mg.
  • the amount of elinzanetant in the pharmaceutical composition is an integer fraction of 100 mg, such as 50 mg.
  • a single dosage unit of the pharmaceutical composition comprises a daily dose of elinzanetant, preferably 100 mg
  • the pharmaceutical composition according to the invention is administered once or more daily, such as up to three times daily, or up to two times per day.
  • the solid pharmaceutical composition is administered once daily.
  • the pharmaceutical composition is administered via the oral route.
  • the amounts specified may in some cases be advantageous to deviate from the amounts specified, depending on body weight, individual behavior toward the active ingredient, type of preparation and time or interval over which the administration is affected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases. In the case of administration of relatively large amounts, it may be advisable to divide these into several individual doses over the day.
  • the pharmaceutical composition will be utilized to achieve the desired pharmacological effect by, e.g., oral administration to a patient in need thereof and will have advantageous properties in terms of stability, drug release, bioavailability, and/or compliance in mammals.
  • a patient, for the purpose of this invention is a mammal, including and in particular a human, in need of treatment for the particular condition or disease.
  • the pharmaceutical composition according to the invention is in an embodiment a solid pharmaceutical composition and is administered orally or rectally.
  • the pharmaceutical composition according to the invention is in an embodiment a solid pharmaceutical composition and is administered orally.
  • Dissolution and Pharmacokinetic Features of the pharmaceutical composition is an immediate release pharmaceutical composition, including an immediate release tablet, immediate release granules, immediate release pellets, immediate release solid mixture immediate release dragées, immediate release sachets, immediate release pills, and immediate release melts.
  • the pharmaceutical composition is a tablet, such as an immediate release tablet.
  • “Immediate release” in one embodiment relates to a rapid dissolution of elinzanetant from the composition occurring in vitro.
  • the pharmaceutical composition When administered, the pharmaceutical composition first enters the acidic environment of the stomach before entering the more neutral environment of the duodenum. Accordingly, it may be desirable for the solid pharmaceutical composition, such as a tablet, to allow dissolution of elinzanetant in vitro within a certain time after adding it to a solution of acidic conditions for a certain time and rebuffering from that acidic to a more neutral condition.
  • rapidly dissolution is defined as the in vitro dissolution of elinzanetant is such that at least 50% is dissolved within 120 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37° and 75 rpm as stirring rate for 30 min and then rebuffering to FaSSIF at a pH 6.5 as a medium at 37° and 75 rpm as stirring rate.
  • rapid dissolution is defined as the in vitro dissolution of elinzanetant is such that at least 60% is dissolved within 120 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37° and 75 rpm as stirring rate for 30 min and then rebuffering to FaSSIF at a pH 6.5 as a medium at 37° and 75 rpm as stirring rate.
  • the in vitro dissolution of at least 75% of the comprised elinzanetant within 210 minutes as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37°C ⁇ 0.5°C and 75 rpm as stirring rate for 30 min, and then rebuffering to Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH 6.5 as a medium at 37°C ⁇ 0.5°C and 75 rpm as stirring rate.
  • FaSSIF Fasted State Simulated Intestinal Fluid
  • At least 80% of the comprised elinzanetant is dissolved in vitro within 210 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37°C ⁇ 0.5°C and 75 rpm as stirring rate for 30 min, and then rebuffering to Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH 6.5 as a medium at 37°C ⁇ 0.5°C and 75 rpm as stirring rate.
  • FaSSIF Fasted State Simulated Intestinal Fluid
  • Bioavailability in one embodiment is defined as the fraction (percentage) of an administered dose or the concentration ( ⁇ g drug per L blood) of elinzanetant that reaches the blood stream (systemic circulation) within a time period after administration of the pharmaceutical composition, e.g. the solid pharmaceutical composition according to the present disclosure.
  • Tmax is the time where the highest concentration of elinzanetant is found in the bloodstream after administration
  • C max is the maximum concentration of elinzanetant found in the bloodstream after administration.
  • the area under the curve (AUC(0-tlast)) represents the total amount of elinzanetant which was in the bloodstream over the period studied, or extrapolated to infinity to obtain the total AUC.
  • the present disclosure relates to a pharmaceutical composition, such as a solid pharmaceutical composition, comprising elinzanetant or a pharmaceutical acceptable salt thereof, wherein the pharmaceutical composition essentially exhibits a bioavailability of elinzanetant as a solid pharmaceutical composition according to the present disclosure, such as tablets having the composition of Composition 5 of Example 1 of the present disclosure.
  • a pharmaceutical composition such as a solid pharmaceutical composition, comprising elinzanetant or a pharmaceutical acceptable salt thereof, wherein the pharmaceutical composition essentially exhibits a bioavailability of elinzanetant as a solid pharmaceutical composition according to the present disclosure, such as tablets having the composition of Composition 5 of Example 1 of the present disclosure.
  • “Essentially” in context with the present disclosure refers to values that are within a range of ⁇ 30% from the respective value, such as within a range of ⁇ 25% from the respective value.
  • “essentially” refers to bioequivalence, such as the bioequivalence according to the US Food and Drug Administration (FDA),
  • the upper and lower 90% confidence intervals of the mean value is within the ranges.
  • the upper and lower 90% confidence intervals of the mean value are within the range of -20% and +25% from the respective value, in other words between 80% and 125% of the respective value.
  • Bioavailability is in one embodiment evaluated by determining Cmax and/or total AUC after administration of the pharmaceutical composition to a subject, such as a human subject.
  • administration for determining is performed in the morning, during the day or in the evening.
  • administration for determining is performed under fasted conditions, such as in the morning before food uptake.
  • the pharmaceutical composition of the present disclosure when administered at a single dose of 120 mg under fasted conditions, exhibits a C max of between 600 ⁇ g/L and 1200 ⁇ g/L, such as between 650 ⁇ g/L and 1150 ⁇ g/L. In one embodiment the Cmax is 901 ⁇ g/L ⁇ 25%, such as between 80% and 125% of 901 ⁇ g/L. In one embodiment, the pharmaceutical composition of the present disclosure, when administered at a single dose of 120 mg under fasted conditions, exhibits a geometric mean of Cmax of between 600 ⁇ g/L and 1200 ⁇ g/L, such as between 650 ⁇ g/L and 1150 ⁇ g/L.
  • the C max is 941 ⁇ g/L ⁇ 25%, such as between 80% and 125% of 941 ⁇ g/L.
  • the pharmaceutical composition of the present disclosure when administered at a single dose of 120 mg, exhibits a C max of between 80% and 125% of the C max as observed after a single dose of 120 mg with a tablet of Composition 5 of Example 1 of the present disclosure.
  • the single doses are administered under fasted conditions.
  • the pharmaceutical composition when administered at a single dose of 120 mg fasted conditions, exhibits a total AUC of between 5000 ⁇ g*h/L and 10000 ⁇ g*h/L, such as between 5700 ⁇ g*h/L and 9600 ⁇ g*h/L.
  • the total AUC is 7602 ⁇ g*h/L ⁇ 25%, such as between 80% and 125% of 7602 ⁇ g*h/L.
  • the pharmaceutical composition when administered at a single dose of 120 mg fasted conditions, exhibits a geometric mean of total AUC of between 5000 ⁇ g*h/L and 10000 ⁇ g*h/L, such as between 5700 ⁇ g*h/L and 9600 ⁇ g*h/L.
  • the total AUC is 7480 ⁇ g*h/L ⁇ 25%, such as between 80% and 125% of 7480 ⁇ g*h/L.
  • the pharmaceutical composition of the present disclosure when administered at a single dose of 120 mg, exhibits a total AUC of between 80% and 125% of the total AUC as observed after a single dose of 120 mg with a tablet of Composition 5 of Example 1 of the present disclosure.
  • the single doses are administered under fasted conditions.
  • the pharmaceutical composition of the present disclosure when administered at a single dose of 110 mg, exhibits a total AUC of between 80% and 125% of the total AUC as observed after a single dose of 100 mg, 105 mg,110 mg, or 115 mg with a tablet of Composition 5 of Example 1 of the present disclosure.
  • the values herein for Cmax and total AUC refer to the geometric mean.
  • the pharmaceutical composition comprises: (i) elinzanetant at a concentration of 5 % w/w to 50 % w/w, (ii) copovidone at a concentration of 4% w/w to 77% w/w, (iii) optionally croscarmellose sodium at a concentration of 4% w/w to 87% w/w, and (iv) Magnesium stearate at a concentration of 0.1% w/w to 1.5% w/w.
  • the pharmaceutical composition comprises: (i) elinzanetant at a concentration of 5 % w/w to 50 % w/w, (ii) copovidone at a concentration of 4% w/w to 77% w/w, (iii) Magnesium stearate at a concentration of 0.1% w/w to 1.5% w/w.
  • the pharmaceutical composition comprises: (i) elinzanetant at a concentration of 5 % w/w to 50 % w/w, (ii) copovidone at a concentration of 4% w/w to 77% w/w, (iii) croscarmellose sodium at a concentration of 4% w/w to 87% w/w, and (iv) Magnesium stearate at a concentration of 0.1% w/w to 1.5% w/w.
  • the pharmaceutical composition comprises: (i) elinzanetant at a concentration of 10 % w/w to 40 % w/w, (ii) copovidone at a concentration of 30% w/w to 50% w/w, (iii) croscarmellose sodium at a concentration of 30% w/w to 50% w/w, and (iv) Magnesium stearate at a concentration of 0.2% w/w to 1.0% w/w.
  • the pharmaceutical composition comprises: (i) elinzanetant at a concentration of about 19.9% w/w, (ii) copovidone at a concentration of about 39.8% w/w, (iii) croscarmellose sodium at a concentration of about 39.8 % w/w, and (iv) Magnesium stearate at a concentration of about 0.5 % w/w.
  • Methods of treatment Elinzanetant is suited for the treatment of diseases and disorder, such as psychotic disorders (WO 2007/028654 A1), and sex hormone-dependent diseases and disorders (WO 2016/184829 A1).
  • disease or disorder is a sex hormone-dependent disease or disorder.
  • the sex hormone-dependent disease or disorder is selected form the group consisting of vasomotor symptoms, pathological gain of excess body fat and/or excess body weight, insomnia, sleep disturbances, night-time awakenings, anxiety, depression, urinary symptoms of urgency, dysuria.
  • the term "sex hormone-dependent disease or disorder” as used herein means a disease or disorder which is exacerbated by, or caused by, excessive, inappropriate, or unregulated sex hormone production.
  • Sex hormone-dependent diseases or disorders may occur in both sexes/genders, men and women. Accordingly, in one embodiment of the present invention, the subject is man. In a further embodiment of the present invention the subject is a woman.
  • Example of such diseases or disorders in men include but are not limited to benign prostatic hyperplasia (BPH), metastatic prostatic carcinoma, testicular cancer, breast cancer, androgen dependent acne, seborrhea, hypertrichosis, male pattern baldness, vasomotor symptoms and in boys’ precocious puberty.
  • Example of such diseases or disorders in women include but not limited to endometriosis, adenomyosis, abnormal puberty, uterine fibroids, heavy menstrual bleeding, hormone- dependent cancers (ovarian cancer, breast cancer), hyperandrogenism, hirsutism, hypertrichosis, female androgenetic alopecia, androgen dependent acne, seborrhea, virilization, polycystic ovary syndrome (PCOS), HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans ), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized the ca cells in ovarian stroma), other manifestations of high intra ovarian androgen concentrations (e.g.
  • follicular maturation arrest atresia, an ovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen producing tumor (virilizing ovarian or adrenal tumor), pathological gain of excess body fat and/or excess body weight, pre-eclampsia, diabetes, fatigue, irritability, cognitive decline, hair-loss, dry skin, insomnia, sleep disturbances, night-time awakenings, anxiety and depression, decreases in sexual desire, vaginal dryness and pain, connective tissue loss and muscle bulk reduction, urinary symptoms of urgency, hidradenitis suppurativa, dysuria, osteoporosis.
  • Sex hormone-dependent diseases or disorders may be caused and/or associated with different conditions, which can have natural (such as menopause or adrenopause), surgical (such as bilateral oophorectomy in women, or orchiectomy or prostatectomy in men), radiological (i.e. radiation therapy) or chemical causes (e.g. adjuvant endocrine therapy).
  • vascular symptoms or sleep disturbances or night-time awakenings can for example be caused by different conditions.
  • the condition may be menopause-associated conditions, such as peri-menopause, the menopause, or the post-menopause.
  • menopause When referring to association with menopause herein, it is preferably meant to include peri- menopause, menopause and post-menopause, more preferably peri-menopause and menopause.
  • sex hormone-dependent diseases or disorders may be associated with adrenopause.
  • the disease or disorder preferably the sex hormone-dependent disease or disorder, is a disease or disorder is associated with menopause or adrenopause.
  • sex hormone-dependent diseases or disorders may be caused in men and women by certain types of therapy interfering with hormone signaling and/or regulation, e.g., adjuvant endocrine therapy, aromatase inhibitors such as anastrozole, exemestane, letrozole and testolactone; gonadotropin-releasing hormone receptor agonists such as such as leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin and triptorelin; gonadotropin-releasing hormone receptor antagonists such as ASP1701, elagolix, relugolix and linzagolix (OBE2109); selective estrogen receptor modulators (SERMs) such as apeldedoxifene, clomifene, cyclofenil, tamoxifen, ormeloxifene, toremifene, raloxifene, lasofoxifen
  • hormone signaling and/or regulation e.g.
  • the disease or disorder is a sex hormone-dependent disease or disorder selected from the group consisting of vasomotor symptoms, insomnia, sleep disturbances, and night-time awakenings. Yet, particularly preferred is the embodiment in which the disease or disorder is vasomotor symptoms. In a preferred embodiment these sex hormone-dependent diseases or disorders are associated with menopause or caused by adjuvant endocrine therapy. Accordingly, in a preferred wherein the vasomotor symptoms are caused or induced by therapy with an aromatase inhibitor and/or selective estrogen receptor modulators (such as tamoxifen).
  • an aromatase inhibitor and/or selective estrogen receptor modulators such as tamoxifen.
  • the disease or disorder is selected from the group consisting of vasomotor symptoms associated with menopause, insomnia associated with menopause, sleep disturbances associated with menopause, and night-time awakenings associated with menopause. Yet more preferred, the disease or disorder is vasomotor symptoms associated with menopause. Associated with menopause includes peri-menopause, menopause and post-menopause. Process for manufacturing The solid dispersion of the invention can be prepared according to methods known to the art for the manufacture of solid dispersions, such as fusion/melt technology, hot melt extrusion, solvent evaporation (i.e.
  • a solvent suitable for manufacture of solid dispersions by solvent evaporation processes such as spray-drying, layering or fluid-bed granulation can be any solvent, wherein the compound of the invention can be dissolved.
  • Preferred solvents include alcohols (e.g. methanol, ethanol, n-propanol, isopropanol, and butanol), ketones (e.g.
  • esters e.g. ethyl acetate and propyl acetate
  • various other solvents such as acetonitrile, methylene chloride, chloroform, hexane, toluene, tetrahydrofurane, cyclic ethers, and 1,1,1-trichloroethane.
  • Lower volatility solvents such as dimethyl acetamide or dimethyl sulfoxide can also be used.
  • solvents such as 20% ethanol and 80% acetone
  • the solvent used for manufacture of the solid dispersion is methanol, ethanol, n-propanol, isopropanol, acetone or a mixture thereof.
  • a mixture of ethanol and acetone (1:4) is used as solvent.
  • acetone is used as solvent.
  • the pharmaceutical composition according to the invention is optionally coated according to methods known to the art as described e.g. in WO 2014/039677 like spraying the coating liquid in a pan or perforated drum coater onto the pharmaceutical composition.
  • Example 1 Preparation of Compositions Materials and Methods Elinzanetant-solvent mixture
  • the crystalline anhydrate Form 1 of elinzanetant and the polymer were dissolved within an organic solvent (acetone, or a mixture of acetone and ethanol (4:1)).
  • organic solvent acetone, or a mixture of acetone and ethanol (4:1)
  • polymers polyvinylpyrrolidone (PVP), copovidon, hydroxypropylmethylcellulose- phthalate (HPMC-P), HPMC-acetylsuccinate (HPMC AS), Polyacrylic acid and Hydroxypropylcellulose (HPC) were used.
  • a surfactant e.g.
  • Macrogol 15 hydroxystearate, sodium dodecyl sulfate (SDS)) was added to the elinzanetant-polymer solution.
  • Carrier addition Croscarmellose sodium was used as carrier.
  • the carrier was added to the compositions either using rotavapor-preparation or fluid bed granulation. In the case for rotavapor-preparation, croscarmellose sodium was suspended within the elinzanetant-polymer solution and the suspension filled into a round bottomed flask and acetone evaporated on a rotavapor instrument (Büchi, ⁇ 40°C, ⁇ 100 mbar).
  • Dryed film material was removed from the glass flask and crushed by mortar and pestle or using a coffee mill (IKA, 8000 rpm, 30 sec) to obtain the amorphous solid dispersion material (ASD material).
  • ASD material amorphous solid dispersion material
  • croscarmellose sodium was fluidized within a granulator (Glatt GPCG 2) and the elinzanetant-polymer solution was sprayed onto it and dried to obtain the ASD material as granules.
  • the granules were roller compacted with a Gerteis Minipactor and directly grinded down to granules to increase bulk density, if needed.
  • Amorphous state of the ASD material was confirmed via DSC and XRPD measurements as follows:
  • the X-Ray Powder Diffraction (XRPD) data was recorded on a Bruker D2 PHASER diffractometer with a LYNXEYE-2 detector using Cu K 1 radiation (1.54060 ⁇ ). All samples were prepared and measured at ambient temperature, on open Si-single-crystal low background sample holders. The data were collected in the Bragg-Brentano ( /2 ) horizontal geometry between either 3° and 40° (2 ) in 0.02° steps at 0.3 s step-1.
  • the X- ray tube was operated at 30 kV and 10 mA.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • Tablets were compressed out of the prepared ASD material using either a compression simulator (StylOne Evolution, Medelpharm), an eccentric press (EK2, Korsch), or a rotary die press (Fette 102i, Fette compacting; XL-100, Korsch). Oval tablets with a length between 16 mm and 19 mm length were produced, depending on the composition mass needed to obtain tablets with the indicated amount of elinzanetant. Compression force was set to target a resistance to crushing between 150 N -190 N per tablet, depending on tablet size. Resistance to crushing of the tablets was tested on a conventional hardness tester (Sotax MT50 und UTS4.1-12FSr Kraemer). Table 1 Overview ASD tablet compositions Composition 1 2 3 4 5 6 7 8 No.
  • Copovidone ASD ratio 1:1.5:2.5 (elinzanetant:polymer:carrier) 12.6 g copovidone were dissolved in 42 g of acetone.8.4 g elinzanetant were added and shaken until a clear solution resulted. Afterwards 21 g croscarmellose sodium was added. The solvent was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a mortar. 10.2 g of the ASD material was blended with 0.06 g sieved magnesium stearate and compressed into 17*7 mm tablets each with a total weight of 603.5 mg.
  • composition 3 Copovidone ASD ratio 1:2:3 (elinzanetant:polymer:carrier) 8.3 g elinzanetant were dissolved in 13.7 g of solvent mixture (acetone/ethanol (4:1)). 16.6 g Copovidone and additional 27.5 g of the solvent mixture were added and heated to 40°C until a clear solution resulted. Afterwards 24.9 g croscarmellose sodium were added and dispersed. The solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a mortar.
  • composition 5 Copovidone ASD ratio 1:2:2 (elinzanetant:polymer:carrier) 208.44 g elinzanetant and 416.91 copovidone were dissolved in 625.7 g acetone and added to 416.9 croscarmellose sodium using fluid bed granulation. 300 g of the ASD material as granules were blended with 1.5 g sieved magnesium stearate and compressed into 18*8 mm tablets each with a total weight of 603 mg. Tablets were coated within a drum coater with a yellow HPMC lacquer.
  • composition 7 Copovidone ASD ratio 1:3:4 (elinzanetant:polymer:carrier) 25.2 g copovidone were dissolved in 77 g of acetone.8.4 g elinzanetant were added and shaken until a clear solution resulted. Afterwards 58.81 g croscarmellose sodium were added. The solvent was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a mortar. 16.32 g of the ASD material was blended with 0.085g sieved magnesium stearate and compressed into 19*8 mm tablets each with a total weight of 965 mg.
  • Composition 8 PVP ASD ratio 1:1:2 (elinzanetant:polymer:carrier) 12.5 g Polyvinylpyrrolidone (PVP) were dissolved in 101.1 g solvent mixture (acetone/ethanol (4:1)).12.5 g elinzanetant were added and shaken until a clear solution was obtained. Afterwards 25 g croscarmellose sodium were added and dispersed. The solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C.
  • solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C.
  • the solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a coffee mill. 29.65 g of the ASD material were blended with 0.185g sieved magnesium stearate and compressed into 16*7 mm tablets each with a total weight of 483 mg.
  • Composition 10 HPC ASD ratio 1:2:3 (elinzanetant:polymer:carrier) 7.5 g elinzanetant were dissolved in 16.8 g of the solvent mixture (acetone/ethanol (4:1)). 15 g Hydroxypropylcellulose (HPC SL) were together with additional 147.2 g solvent mixture added and shaken until a clear solution resulted.
  • composition 14 Copovidone ASD ratio 1:2:3 (elinzanetant:polymer:carrier) with SDS 16.8 g Copovidone were dissolved in 52.5 g of acetone. 8.4 g elinzanetant were added and shaken until a clear solution resulted. Afterwards 1.68 g SDS suspended within in 13.13 g ethanol were added, succeeded by the addition of 25.2 g croscarmellose sodium. The solvents were removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a mortar and a coffee mill.
  • the solvent was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a coffee mill.25 g of the ASD material was blended with 0.094 g sieved magnesium stearate and compressed into 18*8 mm tablets each with a total weight of 783 mg. Composition 16 Copovidone ASD ratio 1:2:3 (elinzanetant:polymer:carrier) with SDS 16.8 g Copovidone were dissolved in 52.5 g of acetone.
  • Composition 17 PVP ASD ratio 1:2:3 (elinzanetant:polymer:carrier) with SDS 16.8 g PVP 25 were dissolved in 52.5 g solvent mixture (acetone/ethanol (4:1)). 8.4 g elinzanetant were added and shaken until a clear solution resulted. The solution was mixed with 1.7 g SDS dissolved in 885.1 g solvent mixture (acetone/ethanol (4:1)), succeeded by the addition of 25.2 g croscarmellose sodium. The solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a mortar and a coffee mill.
  • composition 18 PVP ASD ratio 1:2:3 (elinzanetant:polymer:carrier) with SDS 16.8 g PVP 25 were dissolved in 52.5 g solvent mixture (acetone/ethanol (4:1)). 8.4 g elinzanetant were added and shaken until a clear solution resulted. 4.2 g SDS were suspended in the solution, succeeded by the addition of 25.2 g croscarmellose sodium. The solvent mixture was afterwards removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C.
  • Comparative Compositions Composition 19 HPMC-P ASD ratio 1:1:2 (elinzanetant:polymer:carrier) 7.53 g elinzanetant were dissolved in 13.97 g of solvent mixture (acetone/ethanol (4:1)). 7.55 g Hydroxypropylmethylcellulose-phthalate (HPMC-P) and 56.61 g of solvent mixture (acetone/ethanol (4:1)) were added and dissolved.
  • HPMC-P ASD ratio 1:1.5:2.5 (elinzanetant:polymer:carrier) 10.8 g Hydroxypropylmethylcellulose-phthalate (HPMC-P) were dissolved in 91.85 g solvent mixture (acetone/ethanol (4:1)). 7.2 g elinzanetant were added and dissolved. Afterwards 18 g croscarmellose sodium were added and dispersed. The solvent mixture was afterwards removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C.
  • solvent mixture was afterwards removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C.
  • composition 21 HPMC-P ASD ratio 1:2:3 (elinzanetant:polymer:carrier) 5.06 g elinzanetant were dissolved in 11 g solvent mixture (acetone/ethanol (4:1)).10.07 g Hydroxypropylmethylcellulose-phthalate (HPMC-P) and 56.61 g of the solvent mixture (acetone/ethanol (4:1)) were added and dissolved.
  • HPMC-P ASD ratio 1:3:4 (elinzanetant:polymer:carrier) 21.6 g Hydroxypropylmethylcellulose-phthalate (HPMC-P) were dissolved in 110 g acetone.7.2 g elinzanetant were added and dissolved. Afterwards 28.8 g croscarmellose sodium were added and dispersed. The solvent was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a mortar.8.4 g of the ASD material was blended with 0.05 sieved magnesium stearate and compressed into 19*8 mm tablets each with a total weight of 965 mg.
  • composition 23 HPMC-AS ASD ratio 1:1:2 (elinzanetant:polymer:carrier) 7.57 g elinzanetant were dissolved in 16.65 g solvent mixture (acetone/ethanol (4:1)). 7.57 g HPMC-acetylsuccinate (HPMC-AS) were added with 158.13 solvent mixture (acetone/ethanol (4:1)) and heated to 40°C until a clear solution was obtained. Afterwards 15.12 g croscarmellose sodium and 10.2 g solvent mixture (acetone/ethanol (4:1)) were added and dispersed. The solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C.
  • composition 24 HPMC-AS ASD ratio 1:1.5:2.5 (elinzanetant:polymer:carrier) 7.57 g elinzanetant were dissolved in 94.67 g solvent mixture (acetone/ethanol (4:1)). 11.34 g HPMC-acetylsuccinate (HPMC-AS) were added and stirred until a clear solution was obtained. Afterwards 18.99 g croscarmellose sodium were added and dispersed.
  • the solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a coffee mill. 12 g of the ASD material was blended with 0.06 g sieved magnesium stearate and compressed into 18*8 mm tablets each with a total weight of 603 mg.
  • composition 25 HPMC-AS ASD ratio 1:2:3 (elinzanetant:polymer:carrier) 7.6 g elinzanetant were dissolved in 13.4 g solvent mixture (acetone/ethanol (4:1)).15.2 g HPMC-acetylsuccinate (HPMC-AS) and 164.0 g solvent mixture (acetone/ethanol (4:1)) were added and heated to 40°C until a clear solution was obtained. Afterwards 22.7 g croscarmellose sodium and 20 g solvent mixture (acetone/ethanol (4:1)) were added and dispersed. The solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C.
  • solvent mixture was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C.
  • composition 26 crystalline tablet formulation 14.3 g elinzanetant, 9.1 g lactose monohydrate. 6.4 g microcrystalline cellulose. 1.6 g hydroxyproylmethylcellulose, 0.5 g croscarmellose sodium were blended within a high shear granulator and granulated with 6.4 g water. Wet granules were dried with in a fluid bed instrument.
  • This composition was prepared in accordance with WO 2011/023733 A1; page 31 to page 32. 21 g of granules were blended with 4.2 g lactose anhydrate, 6.6 g microcrystalline cellulose and 1g croscarmellose sodium. This blend was mixed with 0.3 g sieved magnesium stearate and compressed into 10 mm round tablets resulting in a resistance to crushing of around 90 N. Tablets were finally coated with a hydroxypropyl methylcellulose based lacquer within a drum coater.
  • Example 2 Dissolution behavior: Material and Methods Dissolution biorelevant media Fasted State Simulated Intestinal Fluid (Double concentrated FaSSIF; herein referred to as FaSSIF) Powder (biorelevant.com Ltd) sodium taurocholate 3.0 mM, lecithin 0.75 mM, sodium chloride 106 mM, monobasic sodium phosphate 28.4 mM, sodium hydroxide 8.7 mM Buffer In about 0.9L of purified water 0.84 g of sodium hydroxide, 7.9 g of monobasic sodium phosphate monohydrate, and 12.38 g sodium chloride was dissolved, and adjust the pH to 6.5 with 1 N sodium hydroxide or 1 N hydrochloride acid.
  • Fasted State Simulated Gastric Fluid (herein referred to as FaSSGF) Powder (biorelevant.com Ltd) Sodium taurocholate 0.08 mM, lecithin 0.02 mM, -sodium chloride 34.2 mM, hydrochloride acid 25.1 mM Buffer
  • FaSSGF Fasted State Simulated Gastric Fluid
  • Tablets of amorphous solid dispersions showed increased dissolution rates as compared to crystalline IR tablet formulation in the 2-stage biorelevant dissolution set-up resembling the physiological conditions for oral application.
  • Example 3 Stability of ASD compositions comprising neutral polymers or non-neutral polymers (polymers containing recurring functional groups having a pKa of less than 7), with or without surfactants, was compared.
  • ASD material was stored open within a climate chamber at 40°C and 75 % relative humidity (rH) and samples were analyzed with regard to degradation products of elinzanetant and stability of the amorphous state of elinzanetant at different timepoints.
  • compositions comprising an amorphous solid dispersion of elinzanetant and a solid dispersion matrix comprising a neutral polymer showed surprisingly increased stability of elinzanetant, in particular with respect to a surprisingly decreased amounts of degradation products.
  • Compositions comprising a surfactant showed a higher tendency for recrystallisation of elinzanetant within the ASD.
  • Example 4 Relative Bioavailability between Soft Gelatin Capsule and Tablet according to the present disclosure
  • Study Design and Method A combined single- and multiple-dose, open-label, fixed sequence, crossover study was conducted in healthy female and male participants to investigate the relative bioavailability of elinzanetant using soft gelatin capsules as disclosed herein above and used in phase III clinical studies with a composition according to the present disclosure.
  • Soft gelatin capsules consisting of a shell and a soft gelatin capsules formulation (fill mass) were used.
  • composition of the fill mas was as follows: elinzanetant 5.00% w/w; Glycerol Monocaprylocaprate (Capmul MCM) 37.05% w/w; Caprylocaproyl polyoxyl-8 glycerides (Labrasol ALF) 9.50% w/w; Polysorbate 80 (Tween 80) 9.50% w/w; Glyceryl Monooleate (Peceol) 38.00% w/w; and DL-Alpha tocopherol (Vitamin E) 0.95% w/w; with a total amount of 60 mg elinzanetant per capsule.
  • WO 2019/175253 A1 The soft gelatin capsules and manufacture of the same are disclosed in WO 2019/175253 A1 in particular as Example 1a.
  • WO 2019/175253 A1 is incorporated herein by reference.
  • the above disclosed soft gelatin capsules (Reference) were compared to tablets of Composition no 5, supra, (Tablet), coated with a non-functional lacquer. Twenty-four (24) participants received a single dose of two capsules (60 mg elinzanetant in each capsule) of Reference (total dose 120 mg elinzanetant) on Day 1.
  • a solid pharmaceutical composition according to the present disclosure would reach the pharmacokinetic exposures and bioavailability of the soft gelatin capsule formulation as used in clinical Phase III studies at a daily dose of between 100 mg to below 120 mg instead of 120 mg.
  • Example 5 Multiple Dosing To further investigate the optimal dose (reaching the pharmacokinetic exposures of the soft gelatin capsule formulation of the Phase III clinical studies (Reference)), a clinical study comparing elinzanetant exposures after single administration and after 7 days of once-daily administration of tablets having the relative amounts of the Composition no.5, supra, containing either a 100 mg dose (100 mg Tablet) or a 120 mg dose (120 mg Tablet) of elinzanetant in comparison to once-daily administration of a 120 mg dose elinzanetant (2x60 mg) using Reference formulation (see Example 4) is conducted: In a combined single- and multiple-dose, open-label, full randomized 3 x 3 crossover study the relative bioavailability of elinzanetant after administration of 100 mg Tablet and 120 mg Tablet against Reference (see Example 4) is investigated in healthy female participants.
  • Plasma exposures of elinzanetant after multiple dose in terms of AUC(0-24) ss, C max,ss, and C min,ss is determined of both Tablet doses and compared against the respective exposures of the 120 mg dose using Reference.
  • Interpolation of the optimal dose is performed by using inverse regression techniques with confidence regions determined using parametric bootstrap techniques.
  • a daily dose of 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, or 119 mg, or one of the tested doses 100 and 120 mg as daily dose is identified to provide exposure values closest to the Reference.
  • Example 6 Investigation of additional compositions Further amorphous and crystalline formulations were prepared with compositions listed in Table 6. Amorphous samples were prepared in accordance with Example 1, using a further polymer hydroxypropyl methylcellulose (HPMC). Table 6 presents an overview of the individual compositions.
  • compositions Composition 27 19.9 g HPMC-P were dissolved in 94.5 g of acetone.10 g elinzanetant were added and shaken until a clear solution resulted. Afterwards 19.9 g croscarmellose sodium was added. The solvent was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a tube mill (IKA). Crushed material was sieved through a 1.25 mm sieve. 30 g of the ASD material was blended with 0.15 g sieved magnesium stearate and compressed into 18*8 mm tablets each with a total weight of 603 mg.
  • IKA tube mill
  • Composition 28 19.9 g HPMC were dissolved in 94.5 g of acetone. 10 g elinzanetant were added and shaken until a clear solution resulted. Afterwards 19.9 g croscarmellose sodium was added. The solvent was removed using a rotavapor under reduced pressure while rotating the flask within a water bath at 40°C. After drying the formed film was removed from the flask and crushed down using a tube mill (IKA). Crushed material was sieved through a 1.25 mm sieve 30 g of the ASD material was blended with 0.15 g sieved magnesium stearate and compressed into 18*8 mm tablets each with a total weight of 603 mg.
  • IKA tube mill
  • Crystalline compositions Composition 29 crystalline tablet formulation 10 g elinzanetant, 19.9 g copovidon and 19.9 g croscarmellose sodium were blended The blend was wet granulated by adding water consistency q.s. in the mortar and blending it manually with a pistil. Wet granules were dried overnight and crushed in a tube mill (IKA) and sieved through a 1.25 mm sieve. 30 g of the granule material was blended with 0.15 g sieved magnesium stearate and compressed into 18*8 mm tablets each with a total weight of 603 mg.
  • IKA tube mill
  • composition is the same as Composition 5, with the difference that elinzanetant is crystalline and not embedded in the polymer (not a solid dispersion).
  • the preparation method resembles the preparation of the pharmaceutical compositions disclosed in WO 2011/023733 A1, pages 31 and 32 and does not lead to a solid dispersion.
  • Composition 30 crystalline tablet formulation 9.96 g elinzanetant, 19.9 g HPMC-P and 19.9 g croscarmellose sodium were blended. The blend was wet granulated by adding water q.s. in the mortar and blending it manually with a pistil. Wet granules were afterwards dried overnight and crushed in a tube mill (IKA) and sieved though a 1.25 mm sieve.
  • IKA tube mill
  • composition No. 1 30 g of the granule material was blended with 0.15 g sieved magnesium stearate and compressed into 18*8 mm tablets each with a total weight of 603 mg.
  • This composition is the same as Composition 27, with the difference that elinzanetant is crystalline and not embedded in the polymer (not a solid dispersion).
  • the preparation method resembles the preparation of the pharmaceutical compositions disclosed in WO 2011/023733 A1, pages 31 and 32 and does not lead to a solid dispersion.
  • Table 7 Overview release of additional compositions within 2 stage biorelevant dissolution test 27 28 29 30 release 30 min 2.8 25.3 23.9 6.9 [%] release 120 min 92.9 76.8 23.0 16.7 [%] release 210 93.2 86.0 16.2 16.9 min[%]
  • the dissolution test shows that providing an amorphous solid dispersion with results in drastically increase dissolution under basic conditions in the two stage biorelevant dissolution test (c.p., e.g., results for Composition 29 with results for Composition 5 (Table 2)).
  • the composition according to the invention (comprising a neutral polymer; Composition 28 in this example) exhibits an increased dissolution rate in gastric environment (release 30 min) as compared to Composition 27.
  • stability was investigated as described in Example 3.
  • Results are presented in Table 8.
  • Table 8 Overview chemical and physical stability of Compositions, a (amorphous elinzanetant), c (crystalline elinzanetant) 2 weeks 4 weeks Composition Sum of Sum of No. chemical solid chemical solid degradation state degradation state products [%] products [%] 27 18.1 a 19.4 a 28 ⁇ 0.05 a ⁇ 0.05 a 29 0.1 c 0.1 c 30 25.3 c 25.6 c
  • the results unexpectedly show that the combination of providing elinzanetant in an amorphous form in solid dispersion with a neutral polymer provides for a superior pharmaceutical composition with respect to chemical and physical stability and dissolution behavior.

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Abstract

La présente divulgation concerne une composition pharmaceutique comprenant une dispersion solide, la dispersion solide comprenant de l'élinzanétant (I) et au moins une matrice de dispersion solide comprenant un polymère neutre en tant qu'agent de matrice de dispersion solide, son procédé de préparation et son utilisation pour le traitement de maladies et de troubles.
PCT/EP2025/063648 2024-05-24 2025-05-19 Nouvelle formulation comprenant de l'élinzanétant dans une dispersion solide Pending WO2025242583A1 (fr)

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