WO2025242584A1 - Formulation de capsule de gélatine molle stable pour élinzanétant - Google Patents

Formulation de capsule de gélatine molle stable pour élinzanétant

Info

Publication number
WO2025242584A1
WO2025242584A1 PCT/EP2025/063649 EP2025063649W WO2025242584A1 WO 2025242584 A1 WO2025242584 A1 WO 2025242584A1 EP 2025063649 W EP2025063649 W EP 2025063649W WO 2025242584 A1 WO2025242584 A1 WO 2025242584A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
elinzanetant
soft gelatin
concentration
propylene glycol
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/EP2025/063649
Other languages
English (en)
Inventor
Jens Gysler
Michael Krause
Jorma Hassfeld
Marcus-Hillert SCHULTZE-MOSGAU
Lindsay SCHAEFER VACCA
Wai SHEUNG MA
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 WO2025242584A1 publication Critical patent/WO2025242584A1/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin

Definitions

  • the present invention relates to the field of pharmaceutical formulations, in particular pharmaceutical formulations comprising elinzanetant and at least one solubilizer, wherein the solubilizer is a propylene glycol monoester of a C2-C -fatty acid.
  • a liquid formulation in a soft gelatin capsule was provided (WO 2019/175253 A1 ).
  • These soft gelatin capsules comprising glyceryl mono-caprylocaprate (e.g. Capmul MCM) as a solubilizer are used in clinical development and are prepared for commercial drug product launch.
  • the disadvantage of these capsules is the fact, that due to the limited drug load, the size of the capsules is large (Size-20; 1840.129 mg per capsule). As this is of low convenience to the patients that must take the drug a potential non- compliance of the patients is created, because of a potential discomfort when ingesting large sized capsules.
  • glyceride lipidic excipients such as Capmul MCM
  • Capmul MCM glyceride lipidic excipients
  • the shell of the soft gelatin capsule currently used comprises titanium dioxide. Titanium dioxide is thought to be needed to maintain the (photo)stability of elinzanetant. Omission of titanium dioxide as opacifier while maintaining photostability would be desirable to reduce the total number of components in pharmaceutical formulations comprising elinzanetant.
  • Capryol 90 instead of glycerol monocapryloparate as solubilizer and emulsifier, even with higher concentrations of elinzanetant. Furthermore, it was surprisingly found that the solubility of Elinzanetant in lipidic fill mass formulations containing varying amounts of propylene glycol monocaprylate exceeded the solubility previously observed with glyceryl mono- caprylocaprate. Moreover, it was surprisingly found that the pharmaceutical formulations of the present disclosure exhibit a higher bioavailability as compared to the pharmaceutical formulations of prior art.
  • the inventors of the present invention have unexpectedly found that the use of propylene glycol monoesters of fatty acids results in a surprisingly higher stability. It has been found that transesterification of elinzanetant with the fatty acid moiety is significantly reduced when propylene glycol monoesters of fatty acids are present in the formulation as compared to a glycerol monoester of a fatty acid. In addition, it has been found that by using C2-C10 fatty acids in these propylene glycol monoesters the solubility of elinzanetant can be further enhanced while maintaining stability.
  • the present invention relates to a pharmaceutical formulation, comprising (a) 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(1 H )-y l]py ridin-3-y l ⁇ -N , 2- dimethylpropanamide (elinzanetant); and (b) at least one solubilizer which is a propylene glycol monoester of a saturated or un-saturated C2-C -fatty acid.
  • the invention further relates to a soft gelatin capsule comprising the pharmaceutical formulation according to the disclosure and a soft gelatin capsule shell.
  • the present invention also relates to a method for preparing the pharmaceutical formulations according to the disclosure, comprising mixing elinzanetant and one or more solubilizers, and optionally at least one or more further excipient, wherein one solubilizer is a propylene glycol monoester of a saturated or un-saturated C2-C -fatty acid.
  • the invention relates to a method for producing a soft gelatin capsule according to the disclosure comprising the steps of providing a capsule shell, mixing a soft gelatin capsule formulation comprising elinzanetant and one or more solubilizers, and optionally at least one further excipient, propylene glycol monoester of a C2-C10- fatty acid and incorporating the formulation into the capsule shell.
  • SD standard deviation
  • SD standard deviation
  • excipient refers to any ingredient of a pharmaceutical formulation other than the active pharmaceutical ingredient(s) (API(s)), such as solubilizer, antioxidant, emulsifier, pigments, or opacifier.
  • solubilizer and “emulsifier” refer to surface-active excipients, i.e., excipients that decrease the surface tension or interfacial tension between two components, such as liquids and/or solid compounds, that are non-miscible, i.e., one being hydrophilic and the other being hydrophobic.
  • solubilizers and emulsifiers of the present pharmaceutical formulation is the solubilization of elinzanetant.
  • solubilizer and/or emulsifier in the present application is made according to the believed function, but not intended to be limiting as to their actual function(s) in the formulation and/or during uptake in the human body. Accordingly, a solubilizer can also take over emulsifying function and vice versa.
  • soft gelatin capsule formulation is to be understood as referring to the (liquid) fill mass formulation of a soft gelatin capsule.
  • a soft gelatin capsule hence comprises the soft gelatin capsule formulation as a filling encapsulated by a shell, i.e., a soft gelatin capsule shell.
  • the pharmaceutical formulation according to the present disclosure is a soft gelatin capsule formulation.
  • the pharmaceutical formulation according to the disclosure comprises 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(1 H )-y l]py rid in-3-y l ⁇ -N , 2- dimethylpropanamide (elinzanetant); and a propylene glycol monoester of a C2-C10- fatty acid.
  • elinzanetant refers to a compound of formula (I):
  • the concentration of elinzanetant in the pharmaceutical formulation ranges from about 0.1 % w/w to about 50% w/w, from about 0.2% w/w to about 40% w/w, from about 0.3% w/w to about 30% w/w, from about 0.5% w/w to about 20% w/w, from about 0.8% w/w to about 15% w/w, or from about 1 % w/w to about 10% w/w; particularly, from 5% w/w to 10% w/w, even more preferred the concentration of elinzanetant in the pharmaceutical formulation according to the disclosure is 7% w/w.
  • the concentration of the propylene glycol monoester a C2-C10- fatty acid ranges from about 70% w/w to about 99.9% w/w, from about 75% w/w to about 99.7% w/w, from about 80% w/w to about 99.5% w/w, from about 85% w/w to about 99.2% w/w, or from about 90% w/w to about 99% w/w.
  • the concentration of the propylene glycol monoester a C2-C10- fatty acid ranges from about 10% w/w to about 90% w/w, preferably from about 15% w/w to about 60% w/w, more preferably from about 18% w/w to about 38% w/w.
  • the concentration of the propylene glycol monoester a C2-C10- fatty acid ranges from about 10% w/w to about 90% w/w, from about 12% w/w to about 65% w/w, from about 15% w/w to about 60% w/w, from about 15% w/w to about 50% w/w, from about 15% w/w to about 40% w/w.
  • the concentration of the propylene glycol monoester a C2-Cio-fatty acid ranges from about 15% w/w to about 60% w/w, from about 20% w/w to about 65% w/w, from about 20% w/w to about 55% w/w, from about 25% w/w to about 50% w/w, from about 30% w/w to about 45% w/w, or from about 32% w/w to about 42% w/w.
  • the concentration of the propylene glycol monoester a C2-C -fatty acid ranges from about 10% w/w to about 50% w/w, from about 15% w/w to about 45% w/w, from about 15% w/w to about 40% w/w, from about 18% w/w to about 38% w/w.
  • C2-Cio-fatty acid in context of the present disclosure refers to any fatty acid with two to ten carbon atoms. Unless stated otherwise, the term refers to saturated and unsaturated fatty acids with two to ten carbon atoms.
  • the propylene glycol monoester a C2-C -fatty acid is selected from the group consisting of propylene glycol propionate, propylene glycol monobutyrate, propylene glycol mono valerate, propylene glycol monocaproate, propylene glycol monoenanthate, propylene glycol monocaprylate, propylene glycol monopelargonate, and propylene glycol monocaprate, or a mixture thereof.
  • propylene glycol monoester of a C2-C -fatty acid is a propylene glycol monoester of a Cs-fatty acid.
  • the propylene glycol monoester of a C2-Cio-fatty acid is propylene glycol monocaprylate [also known under trade names Capryol 90 or Capryol PGMC].
  • the concentration of propylene glycol monocaprylate ranges from about 10% w/w to about 50% w/w, from about 15% w/w to about 40% w/w, from about 18% w/w to about 38% w/w.
  • the pharmaceutical formulation comprises one or more further excipients, preferably selected from the group consisting of one or more further solubilizer, one or more emulsifier, and one or more antioxidant, or mixtures thereof.
  • the pharmaceutical formulation of the present disclosure comprises one or more further solubilizer.
  • the pharmaceutical formulation of the present disclosure comprises a mixture of solubilizers comprising propylene glycol monocaprylate and one or more further solubilizer.
  • Further solubilizer may be selected by the skilled persons according to the needs.
  • Solubilizers in connection with the present disclosure are substances that facilitate solubilization of substances; in particular the solubilization of a substance that is poorly soluble in water, preferably the solubilization of elinzanetant.
  • Suitable further solubilizers include, but are not limited to, any one or mixture of [with CAS numbers shown in parentheses]: Anionic emulsifying wax [8014-38-8] also called Collone HV, Crodex A, Cyclonette Wax, Kerawax, Lanette SX, Lanette W. Benzalkonium chloride (alkyldimethyl(phenylmethyl) ammonium chloride [8001 -54-5]) also called Hyamine 3500, Pentonium, Zephiran.
  • Benzethonium chloride N,N- Dimethyl-N-[2-[2-4-(1 , 1 ,3,3-tetramethylbutyl)phenoxy]ethoxy]ethyl]-benzene- methanaminium chloride [121 -54-0], p-diisobutylphenoxyethoxyethyl dimethyl benzyl ammonium chloride monohydrate [5929-09-9]).
  • Benzyl alcohol benzenemethanol [100-51 -6]
  • Benzyl benzoate benzoic acid phenylmethyl ester [120-51 -4]).
  • Betadex sulfobutyl ether sodium also called ADVASEP-7, Capitsol
  • Cetylpyridinium chloride (1 -hexadecylpyridinium chloride [123-05-5], 1 -hexadecylpyridinium chloride monohydrate [6004-24-6]) also called Cepacol, Cepacol Chloride, Cetamiun, Dobendan, Medilave, Pristacin, Pyrisept.
  • Cholestyramine Resin (cholestyramine [11041 -12-6]) also called DUOLITE AP143, Purolite A430MR.
  • Cyclodextrins (a-cyclodextrin [10016-20-3], [3-cyclodextrin [7585-39- 9], y-cyclodextrin [17465-86-0]) also called Cavitron, Encapsin, CavamaxW6 Pharma, CavamaxW7 Pharma, Cavamax W8 Pharma, E459, Kleptose).
  • Diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol [111 -90-0]) also called Carbitol, Transcutol HP, Transcutol P.Dimethyl-p-cyclodextrin ( di-O-methyl-p-cyclodextrin [S 1166-71 -3]).
  • Glyceryl monocaprylate (1 ,3-dihydroxy-2-propanyloctanoate [26402-26-6]) also called Imwitor 308.
  • Glyceryl laurate (2,3-dihyroxypropyldodecanoate [142-18-7]) also called Aldo MLD KFG, Cithrol GML, Colonial Monolaurin, Imwitor 312, Lauricidin, Lumulse GML K, Ultrapure GML.
  • Glyceryl dilaurate (2-dodecanoyloxy-3-hydroxypropyl) dodecanoate [17598-94-6; 27638-00-2]) also called Capmul GDL.
  • Glyceryl linoleate (2,3-dihydroxypropyl (9Z,12Z)-octadeca-9,12-dienoate [2277-28-3; 26545-74-4]) also called Maisine.
  • Glyceryl monostearate (octadecanoic acid monoester with 1 ,2,3-propanetriol [31566- 31 -1 ]) also called Capmul GMO-SOK, Cutina GMS V, Dermowax GMS, DUBCARE GMS, Emalex GMS, Imwitor 191 , Imwitor 491 , Imwitor 900, Imwitor 900K, Kessco GMS, Lonzest GMS, Myvaplex 600P, Myvatex, Protachem GMS-450, Rheodol MS- 16SV, Starfol GMS, Stepan GMS, Tegin 90, Tegin 503, Tegin 515, Tegin 4100, Tegin M, Ultimate GMS.
  • Glycerol monooleate (9-octadecenoic acid (Z), monoester with 1 ,2,3- propane-triol [25496-72-4]) also called Aldo MO, Capmul GMO, Drewmulse GMO, DUB OG, DUBCARE OG, Hallstar GMO, Inwitor 948, Kessco GMO, Ligalub, Monomuls 90-018, Peceol.
  • Hydroxypropyl betadex P-cyclodextrin, 2-hydroxypropyl ether [94035-02-6; 128446-35-5]
  • Cavasol W7 HP Pharma Kleptose HPB.
  • Hydroxyethyl-p-cyclodextrin p-cyclodextrin, 2-hydroxyethyl ether [98513-20-3; 128446-32-2]
  • Hypromellose cellulose, 2-hydroxypropyl methyl ether [9004-65-3]
  • Anycoat C Benecel hypromellose, BonuCel, Headeel Cellulose, Mecellose, Methocel, Metolose, Pharmacoat, Rutocel, Vivapharm HPMC.
  • Meglumine (1 -deoxy-1- (methylamino)-D-gluitol [6284-40-8]).
  • Methylpyrrolidone (1 -methylpyrrolidin-2-one [872-50-4]) also called M-Pyrol, Pharmasolve.
  • Niacinamide (3-pyridinecarboxamide [98-92-0]) also called vitamin 83.
  • Nonionic emulsifying wax [97069-99-0] also called Collone Nl, Crodex N, Emulgade 1000NI, Kerawax, Lipowax P, Masurf EmulisfyingWax, Permulgin D, Polawax, Ritachol 2000, T-Wax.
  • Oleic acid ((Z)-9- octadecenoic acid [112-80-1 ]) also called Crodolene, Crossential 094, Emersol, Glycon, Groco, Hy-Phi, Industrene, Metaupon, Neo-Fat, Priolene.
  • Oleyl alcohol ((Z)-9- octadecen-1-ol [143-28-2]) also called HD-Eutanol V PH, Naval, Ocenol.
  • Phospholipids also called Coatsome, Lipoid, PhosphoLipid with specific examples Dilauroyl phosphatidylcholine [18194-25-7] also called Coatasome MC-2020, PhosphoLipid-DPAPC; Dimyristoyl phosphatidylcholine [18194-24-6] also called Coatasome MC-4040, Lipoid PC 14:0/14:0 (DMPC), PhospoLipid-DMPC; Dipalmitoyl phosphatidylcholine [63-89-8] also called Coatasome MC-6060, Lipoid PC 16:0/16:0 (DPPC), PhospoLipid-DPPC; Distearoyl phosphatidylcholine [816-94-4] also called Coatasome MC-8080, Lipoid PC 18:0/18:0 (DSPC), PhospoLipid-DSPC; Dioleoyl phosphatidylcholine [4235
  • Polacrilex resin copolymer of methacrylic acid and divinylbenzene [50602-21 -6; 80892-32-6] also called Amberlite IRP-64.
  • Poloxamers a-hydro- whydroxypoly(oxyethylene)poly(oxypropylene)poly-(oxyethylene) block copolymer [9003-11-6] also called Lutrol, Monolan, Pluracare, Pluronic, Supronic, Surfonic, Synperonic.
  • Polymethacrylates also called Acryl-EZE, Drugcoat, Eastacryl, Eudragit, Kollicoat MAE with specific examples Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 :2: 1 [24938-16-7] also called Eudragit E 100, Eudragit E 12.5, Eudragit E PO; Poly(ethyl acrylate, methyl methacrylate) 2:1 [9010- 88-2] also called Eudragit NE 30 D, Eudragit NE 40 D, Eudragit NM 30 D; Poly(methacrylic acid, methyl methacrylate) 1 :1 [25806-15-1 ] also called Eudragit L 100, Eudragit L 12.5; Poly(methacrylic acid, ethylacrylate) 1 :1 [25212-88-8] also called Acryl-EZE 93A, Acryl-EZE MP, Eudragit L 30 D-55, Eudragit L 100-55
  • Polyoxyethylene alkyl ethers (polyethylene glycol monocetyl ether [9004-95-9], polyethylene glycol monolauryl ether [9002-92-01 ], polyethylene glycol monooley [9004-98-2] ether, polyethylene glycol monostearyl ether [9005-00-9]) also called Brij, Cremophor A, Cyclogol 1000, Emalex, Emulgen, Ethosperse, Genapol, Hetoxol, Hostacerin, Jeecol, Lipocol, Lumulse, Nikkol, Procol, Ritholeth, Ritox with specific examples Cetomacrogol 1000 also called Cresmer 1000; Polyoxyl 6 cetostearyl ether also called Ceteareth 6, Cremephor A6; Polyoxyl 20 cetostearyl ether also called Brij CS-20, Ceteareth 20, Cremephor A20 polyether, Genapol T200, Hetoxol CS-20, Jeecol CS-20, Lipocol SC- 20, Lumuls
  • Polyoxyethylene castor oil derivatives also called Acconon, Etocas, Eumulgin, Jeechem, Kolliphor, Lipocol, Lumulse, Nikkol, Protachem, Simulsol with specific examples Polyoxyl 5 castor oil also called Etocas 5, Hetoxide C-5, Jeechem CA-5, Lumulse CO-5; Polyoxyl 9 castor oil also called Jeechem CA-9, Protachem CA-9; Polyoxyl 15 castor oil also called Etocas 15, Jeechem CA-15, Protochem CA-15; Polyoxyl 35 castor oil also called Etocas 35, Super refined Etocas 35, Emulgin RO 35 PH, Kolliphor EL, Kolliphor ELP; Polyoxyl 40 castor oil also called Acconon CA-40, Croduret 40, Etocas 40, Eumulgin RO 40, Hetoxide C40, Jeechem CA-40, Lumulse CO-40, Marlowet R
  • Propylene glycol monolaurate (1 ,2-propanediol monolaurate [27194-74-7; 142-55-2]) also called Capmul PG-12, Cithrol PGML, E-477, Emalex PGML, Imwitor 412, Lauroglycol 90, Lauroglycol FCC, Schercemol PGML, STELLIESTERS LPG.
  • Pyrrolidone (2-pyrrolidinone [616-45-5]
  • Kollisolv PYR Soluphor P.
  • Sodium lauryl sulfate (sulfuric acid monododecyl ester sodium salt (1 :1 ) [151 -21-3]) also called Elfan 240, Texapon K12P.
  • Sodium polystyrene sulfonate (divinylbenzene copolymer with styrene, sulfonated, sodium salt [63182-08-1 ]) also called AMBERLITE IRP69, Kayexalate, Kionex, Resonium A, Solystat.
  • Stearic acid (octadecanoic acid [57-11-4]) also called Crodacid ES70, Cristal G, Cristal S, Dermofat 4919, Dervacid, DUBCARE STEA, ES70, Edenor, Emersol, Extra AS, Extra P, Extra S, Extra ST, Hystrene, Industrene, Kortacid 1895, Pearl Steric, Pristerene, Speziol L2SM GF, Stellipress Micro, Tegostearic, TriStar.
  • Crodacid ES70 also called Crodacid ES70, Cristal G, Cristal S, Dermofat 4919, Dervacid, DUBCARE STEA, ES70, Edenor, Emersol, Extra AS, Extra P, Extra S, Extra ST, Hystrene, Industrene, Kortacid 1895, Pearl Steric, Pristerene, Speziol L2SM GF, Stellipress Micro, Tegostearic, TriStar.
  • Sucrose palmitate ([ 6-[3 ,4-di hydroxy-2, 5- bis(hydroxymethyl) oxlan-2-yl] oxy-3,4,5-trihydroxyoxan-2-yl]methyl hexadecanoate [26446-38-8]) also called E473, Ryoto, Navia PS750-C, STELLIESTERS SE 15P, Surfhope SE Cosme, Surfhope SE Pharma.
  • Sucrose stearate (sucrose monostearate [25168-73-4]; sucrose distearate [27195-16-0]; sucrose tristearate [27923-63-3])) also called Crodesta F, E473, zucchinia SP, STELLIESTERS SE SS, Surfhope SE, Tegosoft TE.
  • Tricaprylin (1 ,3-di( octanoyloxy)propan-2-yl octanoate [538-23-8]
  • Captex 8000 also called Captex 8000
  • Hest TC Miglyol 808, Rofetan GTC, Trivent OC-G.
  • Trimethyl- Pcyclodextrin (tri-O-methyl-p-cyclodextrin [55216-11 -0]).
  • Vitamin E polyethylene glycol succinate (4-O-(2-hydroxyethyl-1 -O-[2,5,7,8- tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydrochrome dihydrochromen-6- yl)butanedioate [9002-96-4; 30999-06-5]) also called Speziol TPGS Pharma, VEGS.
  • the pharmaceutical formulation of the present disclosure comprises one or more further solubilizer selected from the group consisting of caprylocaproyl macrogol-8 glycerides (e.g., Labrasol ALF), glycerol monooleate (e.g., Peceol), or mixtures thereof.
  • caprylocaproyl macrogol-8 glycerides e.g., Labrasol ALF
  • glycerol monooleate e.g., Peceol
  • the concentration of caprylocaproyl macrogol-8 glycerides ranges from about 1 % w/w to about 80% w/w, from about 3% w/w to about 70% w/w, from about 5% w/w to about 60% w/w, from about 7% w/w to about 55% w/w, or from about 8% w/w to about 50% w/w.
  • the concentration of caprylocaproyl macrogol-8 glycerides is from about 8% w/w to about 10% w/w.
  • the concentration of caprylocaproyl macrogol-8 glycerides is about 9.5% w/w. In a further embodiment the concentration of caprylocaproyl macrogol-8 glycerides (Labarsol ALF) is from about 40% w/w to about 55% w/w. In an embodiment the concentration of caprylocaproyl macrogol-8 glycerides (e.g., Labrasol ALF) is about 47.5% w/w.
  • the concentration of the Glycerol monooleate ranges from about 15% w/w to about 60% w/w, from about 20% w/w to about 65% w/w, from about 20% w/w to about 55% w/w, from about 25% w/w to about 50% w/w, from about 30% w/w to about 45% w/w, or from about 33% w/w to about 43% w/w.
  • the pharmaceutical formulation of the present disclosure comprises a mixture of solubilizers comprising propylene glycol monocaprylate, and caprylocaproyl macrogol-8 glycerides, glycerol monooleate (Peceol); wherein the concentration of propylene glycol monocaprylate ranges from 10% w/w to 60% w/w, the concentration of caprylocaproyl macrogol-8 glycerides ranges from 5% w/w to 60% w/w, and the concentration of the glycerol monooleate (Peceol) ranges from about 15% w/w to about 70% w/w.
  • solubilizers comprising propylene glycol monocaprylate, and caprylocaproyl macrogol-8 glycerides, glycerol monooleate (Peceol); wherein the concentration of propylene glycol monocaprylate ranges from 10% w/w to 60% w/w, the concentration of caprylocaproyl macrogol-8
  • the pharmaceutical formulation of the present disclosure comprises a mixture of solubilizers comprising propylene glycol monocaprylate, and caprylocaproyl macrogol-8 glycerides, glycerol monooleate (e.g., Peceol); wherein the concentration of propylene glycol monocaprylate ranges from 30% w/w to 45% w/w, the concentration of caprylocaproyl macrogol-8 glycerides ranges from 8% w/w to about 15% w/w, and the concentration of the glycerol monooleate (e.g., Peceol) ranges from about 30% w/w to about 45% w/w.
  • solubilizers comprising propylene glycol monocaprylate, and caprylocaproyl macrogol-8 glycerides, glycerol monooleate (e.g., Peceol); wherein the concentration of propylene glycol monocaprylate ranges from 30% w/w to 45% w
  • the pharmaceutical formulation of the present disclosure comprises a mixture of solubilizers comprising propylene glycol monocaprylate, and caprylocaproyl macrogol-8 glycerides, glycerol monooleate (e.g., Peceol); wherein the concentration of propylene glycol monocaprylate ranges from 10% w/w to 25% w/w, the concentration of caprylocaproyl macrogol-8 glycerides ranges from 30% w/w to about 60% w/w, and the concentration of the glycerol monooleate (e.g., Peceol) ranges from about 10% w/w to about 30% w/w.
  • solubilizers comprising propylene glycol monocaprylate, and caprylocaproyl macrogol-8 glycerides, glycerol monooleate (e.g., Peceol); wherein the concentration of propylene glycol monocaprylate ranges from 10% w/w to 25% w/w, the
  • the pharmaceutical formulation of the present disclosure comprises an emulsifier.
  • the concentration of the emulsifier ranges from about 15% w/w to about 70% w/w, from about 20% w/w to about 65% w/w, from about 25% w/w to about 60% w/w, from about 30% w/w to about 55% w/w, from about 35% w/w to about 50% w/w, or from about 38% w/w to about 48% w/w.
  • the concentration of the emulsifier ranges from about 15% w/w to about 60% w/w, from about 20% w/w to about 65% w/w, from about 20% w/w to about 55% w/w, from about 25% w/w to about 50% w/w, from about 30% w/w to about 45% w/w, or from about 33% w/w to about 43% w/w.
  • Suitable emulsifiers include, but are not limited to, any one of mixture of [with CAS numbers shown in parentheses]: Acacia [9000-01 -5], Agar [9002-18-0], Ammonium alginate [9005-34-9], Ammonium glycyrrhizate (a-D-glucopyranosiduric acid, (3
  • Calcium alginate [9005-35-0] also called (alginate, Kaltostat. Calcium stearate (octadecanoic acid calcium salt [1592-23-0]) also called Ceasit PC, Kemistab EC-F, Synpro.
  • Capric acid [334-48-5] Carbomer ([9003-01 -4] alternative names (carbomer 934 [9007-16-3]; carbomer homopolymer Type C [9007-17-4]; carbomer 941 [9062-04-08]; carbomer carboxypolymethylene [9007-20-9])) also called Acrypol, Acritamer, Carbopol, Pemulen, Tega Carbomer.
  • Ceratonia (carob gum [9000-40-2]) also called Meyprofleur.
  • Cetostearyl alcohol [67762-27-0; 8005-44-5] also called Crodacol CS90, DUB SC 20D, Kolliwax CSA, Lanette 0, Speziol C16-18 Pharma, Tega Alkanol 1618, Tega Alkanol 6855.
  • Cetyl alcohol (hexadecane-1 -ol [36653-82-4]) also called Aval, Cachalot, Cetanol, Crodacol C70, Crodacol C90, Crodacol C95, HallStar CO-1695, Hyfatol 16- 95, Kessco CA, Lanette 16, Lipocol C, Nacol 16-95, Rita CA, Speziol C16 Pharma, Tega Alkanol 16, Vegarol 1695, Vegarol 1698.
  • Cetyl palmitate (hexadcyl hexadecanoate [540-10-3]) also called Crodamol CP, DUBCARE PC, Dynacerin CP, Estol 3694, Hallstar 653, Kessco CP, Palmil C, Pelemol CP, Sabowax CP, Stepan 653. Cholesterol (cholest-5-en-3[3-ol [57-88-5]). Colophony ((2R,3S,4S,SR,6R)-2- (hydroxymethyl)-6-[E]-3-phenylprop-2-enoxy]oxane-3,4,5-triol [8050-09-7; 8050-10- 0]).
  • Diethanolamine (2,2'-iminobisethanol [111 -42-2]).
  • Hydrogenated Palm Oil [68514- 74-9; 8033-29-2] also called Cegesoft, Dynasan P60, Softisan 154.
  • Hydroxypropyl cellulose (cellulose, 2-hydroxypropyl ether [9004-62-2]) also called Aero Whip, Coatcel, Klucel, Nissa HPC. Hydroxypropyl starch [113894-92-1 ]).
  • Lanolin anhydrous lanolin [8006-54-0] also called Coronet, E913, Lanis, Lantrol 1650, Pharmalan, Protalan anhydrous.
  • Magnesium oxide [1309-48-4] also called Descote, ES30, Magcal, Magchem 100, Magnyox, Marmag, Oxymag.
  • Medium-chain triglycerides [ 438544-49-1 ] also called Bergabest, Captex 300, Captex 355, Coconad, Crodamol GTCC, Delios, Kollisolv MCT, Labrafac CC, Labrafac Lipa, Labrafac WL1349, Miglyol 810, Miglyol 812, Myritol, Neobee MS, Nesatol, ProKote 2855, Stelliesters MCT, Waglinol 3/9280.
  • Methylcellulose (cellulose methyl ester [9004-67-5] also called Benecel, BonuCel, Cellacol, Culminal MC, E461 , Mapolose, Methocel, Metolose, Rutocel A 55 RT, Tylose, Viscol.
  • Modified starch (includes acetylated distarch adipate [65996-63-6]; acid treated waxy com starch [68909-37-5]; distarch phosphate, waxy corn basis [55963-33-2]; oxidized waxy corn starch [65996-62-5]; sodium octenyl succinate starch [66829-29-6]) also called Amprac, C*Pharm, Capsul, Clearam, Cleargum, El 401-1452, Hi-Cap, Instant Pure-Cote, Lycoat, Pure-Cote, Pure-Gel, Purity, Purity Gum, Uni-Pure. Monoethanolamine (2-aminoethanol [141 -43-5]).
  • Myristic acid (tetradecanoic acid [544-63-8] also called Edenor C14 98-100.
  • Myristyl alcohol (tetradecan-1 -ol 112-72-1 ]) also called Dytol R-52, Lanette Wax KS, Loral C14-95, Loxanol V, Nacol 14-95, Nacol 14-98, Unihydag WAX-14.
  • Octyldodecanol [5333-42-6] also called Euthanol G PH, Jarcol 1 -20, Jeecol ODD, STELLIESTERS ODOL.
  • Polyoxyethylene sorbitan fatty acid esters with specific examples Polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate [9005-64-5]), also called Alkest TW20, Armotan PML20, Atmer 110, Cremophor PS 20, Crillet 1 , Crillet 1 HP, Crillet 1 HPW, Drewmulse, Durfax 20, E432, Eumilgin SML 20, Glyosperse L-20, Hetsorb L-20E, Hodag PSML-20, Kaopan TW L120, Lamsorb SML-20, Liposorb L-20, Liposorb L-20K, Montanox 20, Nissan Nonion LT-221 , Norfox Sorbo T20, POE-SML, Protasorb L-20-K, Ritabate 20, Sorbax PML-20, Sorgen TW-20, T-Maz 20, T-Maz 20K, Protasorb L-20, Tega SML-20, Tween 20, Tween20HP, Tween 20L; Polysorb
  • Polyoxyethylene stearates (polyoxyethylene stearate [9004-99-3]; polyoxyethylene distearate [9005-08- 7]) also called Marlosol with specific examples Polyoxyl 2 stearate also called Hodag DGS, Lipa DGS, Lipopeg 2-DEGS; Polyoxyl 4 stearate also called Acconon 200-MS, Hodag 20-S, Lipopeg 2-DEGS, Protamate 200-DPS; Polyoxyl 6 stearate also called Cerasynt 616, DUB SPEG, Kessco PEG 300 Monostearate, Lipal 300S, Lipopeg 3-S, Polystate C, Protamate 300-DPS; Polyoxyl 8 stearate also called Acconon 400-MS, Cerasynt 660, Cithrol 4MS, Crodet SB, Emerest 2640, Grocor 400, Hodag 40-S, Kessco PEG-400 Monostearate, Lipopeg 4-S
  • Potassium alginate [9005-36-1 ] also called Improved Kelmar, Protanal.
  • Propylene glycol alginate [9005-37-2] also called E405, Kelcoloid, Kimiloid, Manucol Ester, PGA, Profoam, TIC Pretested.
  • Sodium borate (disodium tetraborate decahydrate [1303-96-4]) also called E285.
  • Sodium citrate dihydrate trisodium 2-hydroxypropane-1 ,2,3-tricarboxylate dihydrate [6132-0403]).
  • Sodium lactate [72-17-3] also called E325, Lacolin, Patlac, Purasal, Ritalac NAL.
  • Sodium stearate (sodium octadecenoate [822-16-2]) also called Kemilub ES, Prodhygine, STELLIESTERS SE SS.
  • Stearyl alcohol (1 -octadecanol [112-9 2-5]) also called Alfol 18, Cachalot, Crodacol S95, Hyfatol 18-95, Hyfatol 18-98, Kolliwax SA, Lanette 18, Lipocol S, Nacol 18-94, Nacol 18-98, Nacol 18-99, Rita SA, Speziol C18 Pharma, Stearol, Stenol, Tega Alkanol 18, Vegarol 1895, Vegarol 1898.
  • Tragacanth tragacanth gum [9000-65-1 ]
  • Triethanolamine (2, 2', 2" - nitrilotriethanol [102-71 -6]
  • Tealan Triethanolamine
  • Xanthan gum [11138-66-2] also called Grindsted, Keldent, Keltrol, Rhodicare S, Rhodigel, Rhodopol, Satiaxane U, Vanzan NF, Xantural.
  • the emulsifiers according of the disclosure are commercially available.
  • the emulsifier is a polyoxyethylene sorbitan fatty acid ester, preferably selected from the group consisting of polysorbate 20, polysorbate 60, polysorbate 80, and polysorbate 120. In an embodiment, the emulsifier is polysorbate 80.
  • the concentration of the polyoxyethylene sorbitan fatty acid ester ranges from about 1 % w/w to about 70% w/w, from about 2% w/w to about 50% w/w, from about 3% w/w to about 40% w/w, or from about 5% w/w to about 15% w/w. In an embodiment the concentration of the polyoxyethylene sorbitan fatty acid ester is about 9.50% w/w.
  • the emulsifier is polysorbate 80, present at a concentration from about 1 % w/w to about 70% w/w, from about 2% w/w to about 50% w/w, from about 3% w/w to about 40% w/w, or from about 5% w/w to about 15% w/w. In an embodiment, the emulsifier is polysorbate 80, present at a concentration of about 9.50% w/w.
  • the pharmaceutical formulation of the present disclosure comprises an antioxidant.
  • the concentration of the antioxidant ranges from about 0.02% w/w to about 5% w/w, from about 0.05% w/w to about 4% w/w, from about 0.1 % w/w to about 3% w/w, from about 0.2% w/w to about 2% w/w, from about 0.3% w/w to about 1 .8% w/w, or from about 0.5% w/w to about 1 .5% w/w.
  • the concentration of the antioxidant ranges from about 0.005% w/w to about 3% w/w, from about 0.01 % w/w to about 2% w/w, from about 0.02% w/w to about 1 % w/w, from about 0.05% w/w to about 0.5% w/w, from about 0.08% w/w to about 0.4% w/w, or from about 0.1 % w/w to about 0.3% w/w.
  • the concentration of the antioxidant ranges from about 0.002% w/w to about 2% w/w, from about 0.005% w/w to about 1 % w/w, from about 0.01 % w/w to about 0.5% w/w, from about 0.02% w/w to about 0.3% w/w, from about 0.03% w/w to about 0.2% w/w, or from about 0.05% w/w to about 0.15% w/w.
  • the concentration of the antioxidant ranges from about 0.0005% w/w to about 1 % w/w, from about 0.001 % w/w to about 1 % w/w, from about 0.002% w/w to about 1 % w/w, from about 0.005% w/w to about 1 % w/w, from about 0.01 % w/w to about 1 % w/w, or from about 0.02% w/w to about 1 % w/w.
  • Suitable antioxidants include, but are not limited to, any one or mixture of [CAS numbers shown in parentheses]: Acetone sodium bisulfite (2-hydroxy-2- propanesulfonic acid, sodium salt [540-92-1 ]).
  • Alpha tocopherol a racemic mixture ( ⁇ )- (2RS,4'RS,8'RS)-2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanol [10191 -41 -0]) - also called DL-Alpha tocopherol, and the naturally occurring form D- alpha tocopherol (2R,4'R,8'R)alpha-tocopherol)) also called Copherol F1300, E307, Vitamin E.
  • Ascorbic acid (L-( + )ascorbic acid [50-81 -7]) also called C-97, E300.
  • Ascorbyl palmitate (L-ascorbic acid 6-hexdecanoate [137-66-6]) also called E304).
  • Butylated hydroxyanisole (BHA) (2-tert-butyl-4-methoxyphenol [25013-16-5]) also called E320, Nipanox BHA, Nipantiox 1 -F, Tenox BHA Butylated hydroxytoluene (BHT) (2,6-di-tert-butyl-4-methylphenol [128-37-0] also called Agidol, Dalpac, E321 , Embanox BHT, Impruvol, Ionol CP, Nipanox BHT, OHS28890, Sustane, Tenox BHT, Topanol, Vianol. Carbon dioxide [124-38-9] also called E290.
  • Citric acid monohydrate (2-hydroxy-1 ,2,3-propanetricarboxylic acid mono hydrate [5949-29-1 ] also called E330.
  • Dodecyl gallate (dodecyl 3,4,5-trihydroxybenzoate [1166-52-5]) also called E312, Nipagallin LA, Progallin LA.
  • Erythorbic acid (D-isoascorbic acid [89-65-6]) also called E315.
  • Ethyl oleate ((Z)-9-octadecenoic acid, ethyl ester [111 -62-6]) also called Crodamol EO, DUBCARE OE, Kessco EO.
  • Histidine (S)-2-amino-3-(imidazol-4- yl)propanoic acid [71-00-1 ]) also called Ajipure.
  • Malic acid hydroxybutanedioic acid [6915-15-7 ; (RS)-( ⁇ )hydroxybutanedioic acid [617-48-1 ]) also called E296.
  • D-Mannose ((3S,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol [3458-28-4] also called MannoTab. Monothioglycerol(3-mercapto-1 ,2-propanediol [96-27-5]).
  • Niacinamide 3- pyridinecarboxamide [98-92-0]
  • Octyl gallate octyl 3,4,5-trihydroxybenzoate [1034- 01 -1 ]
  • Phosphoric acid orthophosphoric acid [7664-38-2]
  • Potassium metabisulfite dipotassium pyrosulfite [16731 -55-8]
  • Propionic acid [79-09-4] also called E280.
  • Propyl gallate (3,4,5- trihydroxybenzoic acid propyl ester [121-79-9] also called E310, Progallin P, Tenox PG.
  • Sodium ascorbate (monosodium L-(+)-ascorbate [134-03-2] also called E301 , SA- 99.
  • Sodium formaldehyde sulfoxylate ([149-44-0]; sodium formaldehyde sulfoxylate dihydrate [6035-47-8]) also called Rongalite.
  • Sodium metabisulfite (sodium pyrosulfite [7681 -57-4]) also called E221.
  • Sodium sulfite [7757-83-7] also called E221.
  • Sodium thiosulfate sodium thiosulfate anhydrous [7772-98-7]; sodium thiosulfate pentahydate [1010 2-17-7]
  • Ametox Sodothiol
  • Sulfothiorine Sulfur dioxide [7446-09- 05] also called E220.
  • Thymol [89-83-8]; m-thymol [3228-0303]
  • Flavinol Intrasol, Medophyll.
  • the antioxidant is selected from dl-Alpha tocopherol (Vitamin E), butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA), and mixtures thereof.
  • Vitamin E dl-Alpha tocopherol
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • the antioxidant is butylated hydroxytoluene (BHT).
  • the concentration of the butylated hydroxytoluene (BHT) ranges from about 0.0005% w/w to about 1 % w/w, from about 0.001 % w/w to about 0.5% w/w, from about 0.002% w/w to about 0.2% w/w, from about 0.005% w/w to about 0.1 % w/w, from about 0.01 % w/w to about 0.05% w/w, or from about 0.02% w/w to about 0.04% w/w.
  • BHT butylated hydroxytoluene
  • the antioxidant is butylated hydroxyanisole (BHA).
  • the concentration of the butylated hydroxyanisole (BHA) ranges from about 0.0005% w/w to about 1 % w/w, from about 0.001 % w/w to about 0.5% w/w, from about 0.002% w/w to about 0.2% w/w, from about 0.005% w/w to about 0.1 % w/w, from about 0.01 % w/w to about 0.05% w/w, or from about 0.02% w/w to about 0.04% w/w.
  • the antioxidant is dl-Alpha tocopherol (Vitamin E, also referred to as dl-a tocopherol, DL-alpha tocopherol, or DL-a tocopherol herein).
  • the concentration of the dl-alpha tocopherol (Vitamin E) ranges from about 0.02% w/w to about 5% w/w, from about 0.05% w/w to about 4% w/w, from about 0.1 % w/w to about 3% w/w, from about 0.2% w/w to about 2% w/w, from about 0.3% w/w to about 1.8% w/w, from about 0.5% w/w to about 1.5% w/w, or from 0.05 w/w to 1 .5 w/w.
  • antioxidants according to the disclosure are commercially available.
  • dl-alpha-tocopherol (Vitamin E) is available from BASF SE, Ludwigshafen, Germany;
  • Butylated hydroxyanisole (BHA) is available from Sigma Aldrich, St. Louis, MO, USA;
  • Butylated hydroxytoluene (BHT) is available from Merck KGaA, Darmstadt, Germany.
  • the pharmaceutical formulation according to the disclosure comprises a mixture of solubilizers comprising propylene glycol monocaprylate.
  • the pharmaceutical formulation according to the disclosure comprises propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, and glycerol monooleate; wherein the concentration of propylene glycol monocaprylate ranges from 10% w/w to 50% w/w, the concentration of caprylocaproyl macrogol-8 glycerides ranges from 5% w/w to 20% w/w, the concentration of the glycerol monooleate ranges from 10% w/w to 45% w/w.
  • the disclosure relates to a pharmaceutical formulation comprising elinzanetant, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, and glycerol monooleate, wherein the concentration of elinzanetant is about 7% w/w, the concentration of propylene glycol monocaprylate ranges from 30% w/w to 45% w/w, the concentration of caprylocaproyl macrogol-8 glycerides ranges from 8% w/w to about 15% w/w, and the concentration of the glycerol monooleate (e.g., Peceol) ranges from about 30% w/w to about 45% w/w.
  • the concentration of glycerol monooleate e.g., Peceol
  • the disclosure relates to a pharmaceutical formulation comprising elinzanetant, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, and glycerol monooleate, wherein the concentration of elinzanetant is about 7% w/w; wherein the concentration of propylene glycol monocaprylate ranges from 10% w/w to 25% w/w, the concentration of caprylocaproyl macrogol-8 glycerides ranges from 30% w/w to about 60% w/w, and the concentration of the glycerol monooleate (e.g., Peceol) ranges from about 10% w/w to about 30% w/w.
  • the concentration of glycerol monooleate e.g., Peceol
  • the disclosure relates to a pharmaceutical formulation comprising elinzanetant, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, and glycerol monooleate, wherein the concentration of elinzanetant is about 7% w/w, the concentration of propylene glycol monocaprylate is about 18.69% w/w, the concentration of caprylocaproyl macrogol-8 glycerides is about 46.50% w/w, the concentration of the glycerol monooleate is about 17.58% w/w.
  • the disclosure relates to a pharmaceutical formulation comprising elinzanetant, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, and glycerol monooleate, wherein the concentration of elinzanetant is about 7% w/w, the concentration of propylene glycol monocaprylate is about 36.27% w/w, the concentration of caprylocaproyl macrogol-8 glycerides is about 9.30% w/w, the concentration of the glycerol monooleate is about 37.20% w/w.
  • the pharmaceutical formulation comprises Polysorbate 80 at a concentration ranging from 5% w/w to 10% w/w. In an embodiment the pharmaceutical formulation comprises dl-rac-alpha tocopherol at a concentration ranging from 0.05% w/w to 1 .5% w/w.
  • the disclosure relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising elinzanetant, propylene glycol monocaprylate (e.g., Capryol 90), caprylocaproyl macrogol-8 glycerides, glycerol monooleate, dl-rac-alpha tocopherol and Polysorbate 80.
  • the disclosure relates to a pharmaceutical formulation comprising: (a) elinzanetant from about 1 % w/w to about 10% w/w or from 5% w/w to 10% w/w;
  • caprylocaproyl macrogol-8 glycerides present at a concentration ranging from 5% w/w to 50% w/w;
  • glycerol monooleate present at a concentration ranging from about 10% w/w to 40% w/w;
  • polysorbate 80 present at a concentration from 5% w/w to 15% w/w; and (d) dl-rac-alpha tocopherol present at a concentration ranging from 0.05% w/w to 1 .5% w/w or ranging from 0.5% w/v to 1 .0% w/v.
  • the disclosure relates to a pharmaceutical formulation comprising: (a) elinzanetant at a concentration of about 7% w/w;
  • the disclosure relates to a pharmaceutical formulation comprising: (a) elinzanetant at a concentration of about 7% w/w;
  • Elinzanetant and its pharmaceutically acceptable salts are 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 ).
  • diseases and disorder such as psychotic disorders (WO 2007/028654 A1 ), and sex hormone-dependent diseases and disorders (WO 2016/184829 A1 ).
  • sex hormone-dependent diseases and disorders have been proofed to be ameliorated by administration of elinzanetant in various clinical studies.
  • the present disclosure also relates to a pharmaceutical formulation according to the disclosure for use in the treatment and/or prevention of a disease or disorder.
  • the 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, and 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 human sexes/genders, men and women. Accordingly, in one embodiment of the present disclosure, the disease or disorder is a disease or disorder in a human. In one embodiment of the present disclosure the disease is a sex hormone-dependent disease or disorder in males. In another embodiment of the present disclosure the disease is a sex hormone-dependent disease or disorder in females.
  • BPH benign prostatic hyperplasia
  • metastatic prostatic carcinoma testicular cancer
  • breast cancer breast cancer
  • androgen dependent acne seborrhea
  • hypertrichosis male pattern baldness
  • vasomotor symptoms in adolescents’ precocious puberty.
  • diseases or disorders in women include but are 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, nighttime 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).
  • Vasomotor 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 penmenopause, the menopause, or the postmenopause.
  • association with menopause herein, it is meant to include penmenopause, menopause, and post-menopause. In an embodiment it is meant to include 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 that 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., cancer therapy for treating breast cancer or prostate cancer, e.g.
  • 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
  • GnRH analogues or GnRH antagonists gonadotropinreleasing hormone receptor antagonists such as ASP1701 , elagolix, relugolix and linzagolix (OBE2109)
  • selective estrogen receptor modulators SERMs
  • SERMs selective estrogen receptor modulators
  • 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.
  • the disease or disorder is vasomotor symptoms.
  • these sex hormone-dependent diseases or disorders are associated with menopause or caused by adjuvant endocrine therapy.
  • the disease or disorder being 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.
  • the disease or disorder is vasomotor symptoms associated with menopause.
  • the disease or disorder being selected from the group consisting of vasomotor symptoms associated or caused by adjuvant endocrine therapy, insomnia or caused by adjuvant endocrine therapy, sleep disturbances or caused by adjuvant endocrine therapy, and night-time awakenings or caused by adjuvant endocrine therapy.
  • the disease or disorder is vasomotor symptoms associated or caused by adjuvant endocrine therapy.
  • the present disclosure further relates to a method for the treatment and/or prophylaxis of diseases, in particular the aforementioned diseases, comprising administering to a subject the pharmaceutical formulation according to the disclosure.
  • the present disclosure further relates to a method for the treatment and/or prophylaxis of sex hormone dependent disease or disorder, comprising administering to a subject in need thereof the pharmaceutical formulation according to the disclosure.
  • the present disclosure further relates to a method for the treatment and/or prophylaxis of a sex hormone-dependent disease or disorder selected from the group consisting of vasomotor symptoms, insomnia, sleep disturbances and night-time awakenings; comprising administering to a subject in need thereof the pharmaceutical formulation according to the disclosure.
  • the disclosure relates to a method for the treatment and/or prophylaxis of a sex hormone-dependent disease or disorder associated with menopause selected from the group consisting of vasomotor symptoms, insomnia, sleep disturbances and night-time awakenings; comprising administering to a subject in need thereof the pharmaceutical formulation according to the disclosure.
  • the disclosure relates to a method for the treatment and/or prophylaxis of a sex hormone-dependent disease or disorder associated or caused by adjuvant endocrine therapy selected from the group consisting of vasomotor symptoms, insomnia, sleep disturbances and night-time awakenings; comprising administering to a subject in need thereof the pharmaceutical formulation according to the disclosure.
  • the daily dose of elinzanetant may be adapted to the need.
  • the daily dose of elinzanetant is between 10 mg and 300 mg, more preferably between 40 mg and 200 mg, yet more preferred between 100 mg and 160 mg.
  • the daily dose is particularly preferred 100 mg, 120 mg, or 160 mg. In a most preferred embodiment, the daily dose of elinzanetant is about 120 mg.
  • the disclosure relates to a pharmaceutical formulation according to the present disclosure for use in the treatment of a sex hormone-dependent disease or disorder selected from the group consisting of vasomotor symptoms, insomnia, sleep disturbances, and night-time awakenings, wherein elinzanetant is administered at a daily dose of between 10 mg to 300 mg, such as between 40 mg and 200 mg, or between 100 mg and 160 mg. In one embodiment, elinzanetant is administered at a daily dose of about 120 mg.
  • elinzanetant and amount of elinzanetant in the pharmaceutical formulation of the present disclosure will depend upon several factors including the seventy of the condition to be treated and the age and condition of the recipient and will ultimately be at the discretion of the attendant physician.
  • Elinzanetant or a pharmaceutically acceptable salt is used in combination with one or more additional therapeutic agents for treating or preventing a disease or condition disclosed herein.
  • the pharmaceutical formulation of the present disclosure comprises elinzanetant or a pharmaceutical acceptable salt thereof, and the one or more additional therapeutic agents.
  • elinzanetant and the one or more additional therapeutic agents may be formulated in separated pharmaceutical formulations.
  • the separated pharmaceutical formulations may be included in a pharmaceutical kit.
  • Suitable additional therapeutic agents include, but are not limited to, a2- adrenergic agonists and imidazoline receptor agonists such as clonidine; antidepressants including selective serotonin reuptake inhibitors (SSRis) such as citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, and selective serotonin-norepinephrine reuptake inhibitors (SNRis) such as desvenlafaxine, duloxetine, levomilnacipran, milnacipran and venlafaxine, and serotonin modulator and stimulators (SMSs) such as vortioxetine and vilazodone, also serotonin-noradrenaline-dopamine reuptake inhibitors such as tesofensine; antiobesity/ weight loss medications including inverse agonists for the cannabinoid receptor CBI such as rimon
  • the one or more additional therapeutic agents is selected from aromatase inhibitors such as anastrozole, exemestane, letrozole and testolactone; selective estrogen receptor modulators (SERMs) such as apeledoxifene, clomifene, cyclofenil, tamoxifen, ormeloxifene, ospemifene, toremifene, raloxifene and lasofoxifene; selective estrogen receptor degraders (SERDs) such as fulvestrant, brilanestrant and elacestrant.
  • SERMs selective estrogen receptor modulators
  • SELDs selective estrogen receptor degraders
  • the one or more additional therapeutic agents is selected from drugs that improve glycaemic control such as insulin and long-acting forms of this hormone such as aspart, detemir, glargine, isophane and lispro, and dipeptidyl peptidase-4 (DPP-4) inhibitors such as anagliptin, aloglitin, dutogliptin, linagliptin, omarigliptin, saxagliptin, sitagliptin, teneligliptin, trelagliptin and vildagliptin, and G LP- 1 receptor agonists such as albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide and semaglutide, subtype 2 sodium-glucose transport (SGLT-2) inhibitors such as canagliflozin, dapagliflozin, empagliflozin and ipragliflozin
  • Bioavailability in one embodiment is defined as the fraction (percentage) of an administered dose or the concentration (pg drug per mL 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
  • Cmax is the maximum concentration of elinzanetant found in the bloodstream after administration.
  • the area under the curve 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 pharmaceutical formulation according to the present disclosure, such as Soft Gelatin Capsule 1 or Soft Gelatin Capsule 3 as disclosed in the Examples herein below.
  • 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, e.g. a range between -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 AUC after administration of the pharmaceutical formulation to a subject, such as a human subject.
  • the administration may be performed with the desired dose.
  • Cmax and/or AUC are determined after administration of a single dose of 120 mg elinzanetant to a subject, such as after single administration of two soft gelatin capsules according to the present disclosure, each capsule containing 60 mg elinzanetant, e.g. under fasted conditions.
  • administration for determining is performed in the morning, during the day or in the evening. In one embodiment administration for determining is performed under fasted conditions, such as in the morning before food uptake.
  • the Cmax is 1457 pg/L ⁇ 25%, such as between - 20% and +25% of 1457 pg/L.
  • the Cmax is 1522 pg/L ⁇ 25%, such as between 80% and 125% of 1522 pg/L.
  • the pharmaceutical formulation when administered at a single dose of 120 mg under fasted conditions, exhibits a totalAUC of between 4000 pg*h/L and 8500 pg*h/L or between 1050 pg/L and 2000 pg/L, such as between 4000 pg*h/L and 8200 pg*h/L.
  • the total AUC is 6241 pg*h/L ⁇ 25%, such as between 80% and 125% of 6241 pg*h/L.
  • the total AUC is 6402 pg*h/L ⁇ 25%, such as between 80% and 125% of 6402 pg*h/L.
  • the values herein for Cmax and total AUC refer to the geometric mean.
  • the pharmaceutical formulation of the present disclosure may be formulated for enteral/gastrointestinal administration, parenteral administration, or topical administration.
  • the pharmaceutical formulation of the present disclosure is formulated for oral administration (i.e., oral pharmaceutical formulation).
  • the pharmaceutical formulations for oral administration according to the present disclosure may be liquid or semi-solid at ambient temperatures.
  • the pharmaceutical formulations according to the present disclosure are presented as liquids.
  • formulations of the present disclosure are in one embodiment liquid oral unit dosage forms, more preferably filled soft capsules, e. g. gelatin capsules.
  • the pharmaceutical formulation according to the present disclosure is a filling of a soft gelatin capsule.
  • the pharmaceutical formulation according to the disclosure is a soft gelatin capsule formulation.
  • the pharmaceutical formulation may contain further excipients, such as preservatives, and pigments. Without being bound by hypothesis, it is believed that due to the presence of solubilizers and emulsifier which have also a preservative effect, no additional preservatives are needed. But it is to be understood that the pharmaceutical formulation according to the present disclosure may also contain such further excipients, e.g. preservatives, in addition to the excipients, e.g., solubilizers and/or emulsifier, disclosed herein.
  • further excipients e.g. preservatives
  • the present disclosure also relates to a soft gelatin capsule comprising the pharmaceutical formulation according to the present disclosure.
  • the pharmaceutical formulation of the present disclosure may be made using methods and techniques that are commonly employed in preparing such preparations within the pharmaceutical industry.
  • the pharmaceutical formulation of the present disclosure may be prepared in conventional manner, for example, by appropriate mixing of the ingredients in one or more vessels, the ingredients being dissolved using established pharmaceutical techniques.
  • the disclosure relates to a method for preparing the pharmaceutical formulations according to the disclosure, comprising mixing elinzanetant and one or more solubilizers, wherein one solubilizer is propylene glycol monocaprylate, and optionally with one or more excipients.
  • the active ingredient is dissolved in the mixture of the excipients maintaining the temperature at 30°C to 40°C under an inert atmosphere, e.g., nitrogen gas blanket, and under yellow light or protected from light, until the active ingredient is completely solubilized and then stored in the sealed containers until further use.
  • an inert atmosphere e.g., nitrogen gas blanket
  • the active ingredient is selected from elinzanetant or a pharmaceutically acceptable salt thereof, or elinzanetant as anhydrous crystalline form (Form 1 ) or the active ingredient is elinzanetant or a pharmaceutically acceptable salt thereof, or elinzanetant as anhydrous crystalline form (Form 1 ) with one or more additional therapeutic agents.
  • the present disclosure also provides a method for preparing the pharmaceutical formulations according to the present disclosure by dissolving the active ingredient into at least of one excipient.
  • the active ingredient is elinzanetant or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient is elinzanetant. In some embodiments, the active ingredient is elinzanetant as anhydrous crystalline form (Form 1 ).
  • WO 2011/023733 A1 discloses elinzanetant in a crystalline anhydrate form (Form 1 ), having certain characteristic 2 theta angles occurring at 4.3 ⁇ 0.1 , 7.9 ⁇ 0.1 , 9.8 ⁇ 0.1 , 10.7 ⁇ 0.1 , 10.8 ⁇ 0.1 , 13.3 ⁇ 0.1 , 14.0 ⁇ 0.1 , 15.1 ⁇ 0.1 degrees, which correspond respectively to d-spacing at 20.4, 11.1 , 9.0, 8.3, 8.2, 6.6, 6.3 and 5.9 Angstroms (A).
  • the active ingredient is elinzanetant or a pharmaceutically acceptable salt thereof, or Elinzanetant as anhydrous crystalline form (Form 1 ) with one or more additional therapeutic agents.
  • the capsule shell may suitably be made of gelatins such as Gelatin, NF, EP and may include plasticizers such as anidrisorb, glycerin or sorbitol, water, preservatives, colorants(s), and opacifying agent(s) such as titanium dioxide.
  • the capsule shell does not contain titanium dioxide.
  • the soft gelatin capsule may be of any shape, suitably the capsules may be elongated such as ellipsoidal, oblong, oval, or cylindrical with rounded ends.
  • a soft gelatin capsule contains from about 1 mg to about 500 mg, from about 1 mg to about 250 mg, from about 1 mg to about 160 mg, from about 2 mg to about 150 mg, from about 3 mg to about 120 mg, from about 4 mg to about 100 mg, or from about 5 mg to about 80 mg of Elinzanetant.
  • the capsule contains about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about
  • the disclosure also relates to a method for producing a soft gelatin capsule comprising the steps of providing a soft gelatin capsule shell, mixing a soft gelatin capsule formulation comprising elinzanetant and one or more solubilizers, wherein one solubilizer is propylene glycol monocaprylate and at least one excipient, and incorporating the formulation into the capsule shell.
  • the soft gelatin capsule shell may comprise different proportions of gelatin, glycerine, a blend of sorbitol special and glycerin (sorbitol special - glycerin), and water. Further, the soft gelatin capsule shell may contain further excipients as desired, such as including but not limiting to lubricants and/or anti-sticking agents.
  • the soft gelatin capsule shell comprises gelatin in a concentration from 10% w/w to 99% w/w, preferably from 20% w/w to 80% w/w, more preferred from 40% w/w to 70% w/w. In a particular embodiment the soft gelatin capsule shell comprises gelatin at a concentration of about 58.81 % w/w.
  • the soft gelatin capsule shell comprises sorbitol special - glycerin in a concentration from 10% w/w to 99% w/w, preferably from 20% w/w to 60% w/w, more preferred from 30% w/w to 50% w/w. In a particular embodiment the soft gelatin capsule shell comprises sorbitol special - glycerin at a concentration of about 40.74% w/w.
  • the soft gelatin capsule shell comprises at least one pigment, selected from the group consisting of ferric oxide pigments, such as ferric oxide red and/or ferric oxide yellow, and/or ferric oxide black, and less than 0.4% w/w with respect to the shell of TiO2, preferably the capsule is substantially free of TiO2.
  • the total concentration of pigments may range from 0.01 % w/w to 1 % w/w.
  • the total concentration of ferric oxide red and ferric oxide yellow ranges from 0.01 % w/w to 1 % w/w, preferably from 0.3% w/w to 0.7% w/w, more preferably from 0.4% w/w to 0.5% w/w, yet more preferred about 0.45% w/w.
  • the soft gelatin capsule shell comprises 0.03% w/w ferric oxide red and 0.42% ferric oxide yellow.
  • the soft gelatin capsule shell may contain water as needed (q.s.) and traces of other compounds, e.g., those used as lubricants for mold release purposes during production.
  • the soft gelatin capsule shell may also contain lecithin and/or triglycerides.
  • the soft gelatin capsule shell comprises gelatin at a concentration of about 58.81 % w/w, sorbitol special - glycerin at a concentration of about 40.47% w/w, ferric oxide red at a concentration of about 0.03% w/w, ferric oxide yellow a concentration of about 0.42% w/w, and optionally traces of medium chain triglycerides, and lecithin, and water q.s..
  • the soft gelatin capsule may be prepared by methods and techniques that are known to a skilled artisan.
  • the soft gelatin capsule may be prepared by the rotary-die encapsulation process.
  • the rotary die process involves the continuous formation of a heat seal between two ribbons of gelatin, simultaneous with dosing of the fill liquid into each capsule (J.P. Stanley, the Theory and Practice of Industrial Pharmacy, 3rdEd.,1986, p398-412).
  • the gelatin receiver is stationed above the encapsulation machine.
  • the converted gelatin mass is gravity fed through two heated gelatin hoses into heated gelatin spreader boxes.
  • At the end of each gelatin hose is a modulator valve.
  • the modulator valve is equipped with a diaphragm that is connected to compressed air.
  • a 100-micron mesh filter bag is attached at the end of the modulator value filtering any particulates from the gel mass.
  • the level of the gelatin within the spreader box activates a proximity switch allowing the compressed air to close the diaphragm within the modulator valve, thereby stopping the flow of the gelatin mass.
  • the spreader boxes are mounted above the casting drum on each side of the encapsulation machine and are secured by mounting brackets.
  • the spreader box spreads the gelatin mass onto the casting drum evenly at the desired thickness.
  • the encapsulation machine casts a thin ribbon of molten gelatin onto a water-cooled, circular casting drum that rotates at a speed directly proportional to the machine/die speed.
  • the gelatin ribbon is cooled on the casting drum, then pulled off and threaded through a series of sparge tubes, which lubricate the inside and outside of the gelatin ribbon.
  • the gelatin ribbon passes through the inline print unit, which applies the print logo to the ribbon.
  • the gelatin ribbon is threaded through the encapsulation machine between the wedge and the rotary dies.
  • the wedge is positioned on top of the gelatin ribbon and the rotary dies.
  • the wedge is utilized to heat the gelatin ribbon before the rotary dies cut the soft gelatin shell halves.
  • the heat from the wedge is utilized to facilitate the sealing of the two soft gelatin shell halves.
  • the wedge is employed in the filling (soft gelatin capsule formulation) of the soft gelatin capsules, via the positive displacement medicine pump, which doses the fill material through the wedge into the forming soft gelatin capsules.
  • in-process checks are performed at regular intervals during encapsulation to examine process responses and the results are documented.
  • the electronic data system automatically records the sample collecting time, in process results, and any deviations or production events during encapsulation.
  • the in- process checks include fill weight, shell weight, and seal thickness (leading and trailing seals).
  • Visual checks are performed at the machine, including soft gelatin shape and print quality during the encapsulation process.
  • the soft gelatin shell weights are measured and recorded at the same time the fill weights are measured.
  • Fill and shell weights are recorded at regular intervals with seal thickness checks (leading and trailing seals).
  • the soft gelatin capsules are tumbled until they can be spread onto shallow trays to enable capsules to cool and lose water.
  • the shallow trays with soft gelatin capsules are then dried in a drying tunnel at controlled humidity and temperature to reduce the shell moisture content to inhibit growth of mold and bacteria, prevent capsules from sticking together, and provide capsule rigidity and consistent shape.
  • the drying endpoint is typically determined through hardness testing. Upon reaching a nominal hardness target, soft gelatin capsules are then transferred from shallow trays into deep trays after release from drying for bulk packing.
  • the present disclosure provides a method for producing a soft gelatin capsule comprising the steps of providing a capsule shell, mixing a formulation comprising Elinzanetant or pharmaceutically acceptable salts thereof and at least one excipient, and incorporating the formulation into the capsule shell.
  • HPLC analysis of the formulations in the Examples were performed using the following method:
  • solubilizers were tested for their compatibility with API elinzanetant at a concentration of approx. 5% (w/w) applying selected parameters typical for softgel formulations and their respective manufacturing process.
  • Samples containing 5% (w/w) elinzanetant dissolved in the respective solubilizer were filled in amber glass vials, blanketed with nitrogen, sealed hermetically, and tested after storage at elevated temperature.
  • the lipid fill mass contains water only in very low amounts being controlled by the quality of excipients and API.
  • base gel under addition of gelatin gel swatch processed with base/lime. o A small swatch of base-type gelatin shell mass was added to the lipid fill mass to investigate compatibility.
  • RRT relative retention time; values given are% of Adjusted Area; elinzanetant fatty acid esters are indicated in brackets
  • % w/w Tocopherol refers to dl-rac-a tocopherol Solubility of elinzanetant in the comparative example and in the soft gelatin capsule formulations 1 to 4 w/o API as disclosed above was determined.
  • Elinzanetant (API) was added to the soft gelatin capsule formulations denoted as “w/o API” at two different temperatures (25°C and 5°C) until no further API was dissolved. The clear supernatant was analyzed by HPLC, supra. Results are presented in the following table.
  • Soft gelatin capsule formulation 2 containing propylene glycol monolaurate instead of a propylene glycol mono ester of a C2-C10 fatty acid surprisingly did not show the increased solubility of a propylene glycol mono ester of a C2-C10 fatty acid containing soft gelatin capsule formulations 1 , 3 and 4.
  • Soft gelatin capsule formulations 1 and 3 were investigated for stability under different conditions.
  • the respective soft gelatin capsule formulation was stored at ambient conditions over 7 days.
  • Soft gelatin capsule formulations 1 and 3 were exposed to three 48-hour thermal cycle from -20°C to 40°C, i.e. , the soft gelatin capsule formulations were kept at -20°C and 40°C over six alternating periods of 24 hours each.
  • Comparative examples and soft gelatin capsule formulations 1 to 4 with 5% (w/w) elinzanetant were placed sealed in amber glass vials in an oven at 40°C. The samples were analyzed using HPLC initially and after 2, 4 and 12 weeks.
  • Soft gelatin capsule formulations comprising a propylene glycol monoester of C2 to C10 fatty acids exhibited clearly enhanced stability with respect to prevention of transesterification when compared to the comparative example formulation containing glycerol monoester of C2 to C10 fatty acids. Furthermore, the use of propylene glycol monoester of fatty acids with less than 12 carbon atoms, e.g., 8 carbon atoms (Soft gelatin capsule formulations 1 , 3 and 4), showed clearly increased solubility as compared to e.g., propylene glycol monolaurate (Soft gelatin capsule formulation 2) reaching levels above the comparative example. These data show that soft gelatin capsule formulation according to the disclosure has surprisingly beneficial properties with respect to increasing drug load while maintaining stability of elinzanetant.
  • Soft gelatin capsule formulations with 7% drug load to reduce size Because of the increased stability of the soft gelatin capsule formulations according to the disclosure, and in particular soft gelatin capsule formulations 1 and 3 of above, respective formulations containing a concentration of elinzanetant of 7% (w/w) were produced and encapsulated in gelatin shells.
  • the so manufactured soft gelatin capsules contained 60 mg of elinzanetant each and had a reduced size of 12 as compared to the size of 20 of the currently used soft gelatin capsules, e.g., used in clinical Phase II and III studies.
  • Soft gelatin capsule with 60 mg elinzanetant based on soft gelatin capsule formulation 1 Soft Gelatin Capsule 1
  • Titanium dioxide 2.678 0.42
  • HPLC analysis of in connection with the soft gelatin capsules were performed using the following method:
  • the soft gelatin capsules were packaged in HDPE bottles with induction seal and subsequently stored at long-term storage conditions (25°C I 60% relative humidity (RH)) and at accelerated storage conditions (40°C/75% RH) for 6 months, respectively.
  • the quantitation for assay and related substances of elinzanetant is done by external calibration using a reference standard of elinzanetant.
  • Stability data showed improved stability after 6 months storage at long-term storage condition and at accelerated storage condition. Formation of elinzanetant esters in soft gelatin capsules containing a pharmaceutical formulation according to the present disclosure is reduced significantly compared with Comparative Example A . Hence, substituting the Capmul MCM being the main constituent of the soft gelatin capsule formulation with a propylene glycol monoester C2-C10 fatty acid showed significantly higher stability.
  • Mean AUC of elinzanetant was 6402 pg*h/L and mean Cmax was 1522 pg/L after administration of Soft Gelatin Capsule 1 and mean AUC was 5689 pg*h/L and mean Cmax was 1334 pg/L after administration of Reference showing surprisingly higher oral bioavailability of Soft Gelatin Capsules 1 compared to Reference.
  • the present disclosure relates to the following items.
  • a pharmaceutical formulation comprising
  • At least one solubilizer which is a propylene glycol monoester of a saturated or un-saturated C2-C -fatty acid, preferably selected from the group consisting of propylene glycol propionate, propylene glycol monobutyrate, propylene glycol mono valerate, propylene glycol monocaproate, propylene glycol monoenanthate, propylene glycol monocaprylate, propylene glycol monopelargonate, and propylene glycol monocaprate, or a mixture thereof.
  • a solubilizer which is a propylene glycol monoester of a saturated or un-saturated C2-C -fatty acid, preferably selected from the group consisting of propylene glycol propionate, propylene glycol monobutyrate, propylene glycol mono valerate, propylene glycol monocaproate, propylene glycol monoenanthate, propylene glycol monocaprylate, propylene glycol monopelargonate, and propy
  • composition of item 1 or 2 wherein the concentration of the at least one solubilizer in the pharmaceutical formulation ranges from about 10% w/w to about 90% w/w, preferably from about 15% w/w to about 60% w/w, more preferably from about 18% w/w to about 38% w/w.
  • any one of items 1 to 10 wherein the formulation comprises one or more further solubilizer selected from the group consisting of caprylocaproyl macrogol-8 glycerides (e.g. Labrasol ALF), glycerol monooleate (e.g. Peceol), or a mixture thereof, and one or more emulsifier.
  • caprylocaproyl macrogol-8 glycerides e.g. Labrasol ALF
  • glycerol monooleate e.g. Peceol
  • emulsifier emulsifier
  • a mixture of solubilizers comprising propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, and glycerol monooleate (e.g. Peceol), wherein the concentration of propylene glycol monocaprylate ranges from 10% w/w to 50% w/w, the concentration of caprylocaproyl macrogol-8 glycerides ranges from 5% w/w to 20% w/w, and the concentration of the glycerol monooleate (e.g. Peceol) ranges from 10% w/w to 45%w/w; and
  • the pharmaceutical formulation of any one of items 1 to 16 comprising:
  • propylene glycol monocaprylate e.g. Capryol 90
  • concentration ranging from 10% w/w to 40% w/w;
  • caprylocaproyl macrogol-8 glycerides e.g. Labrasol ALF
  • Labrasol ALF Labrasol ALF
  • glycerol monooleate e.g. Peceol
  • concentration ranging from about 10% w/w to 40% w/w;
  • propylene glycol monocaprylate e.g. Capryol 90
  • caprylocaproyl macrogol-8 glycerides e.g. Labrasol ALF
  • glycerol monooleate e.g. Peceol
  • propylene glycol monocaprylate e.g. Capryol 90
  • concentration about 18.69% w/w
  • caprylocaproyl macrogol-8 glycerides e.g. Labrasol ALF
  • Labrasol ALF labrasol ALF
  • Glycerol monooleate e.g. Peceol
  • a soft gelatin capsule comprising a pharmaceutical formulation according to any one of items 1 to 20, and a soft gelatin capsule shell.
  • the soft gelatin capsule according to item 21 wherein the amount of elinzanetant per soft gelatin capsule ranges from 10 mg to 160 mg.
  • the pharmaceutical formulation or the soft gelatin capsule for use according to item 25 or 26, wherein the sex hormone-dependent disease or disorder is a disease or disorder that is associated with menopause and/or adjuvant endocrine therapy.
  • a method for producing a soft gelatin capsule according to any one of items 21 to 24 comprising the steps of providing a capsule shell, mixing a soft gelatin capsule formulation comprising elinzanetant and one or more solubilizers, wherein one solubilizer is propylene glycol monocaprylate and at least one excipient, and incorporating the formulation into the capsule shell.
  • a method according to item 30 or 31 wherein elinzanetant is added in its anhydrous crystalline Form 1 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne le domaine des formulations pharmaceutiques, en particulier des formulations pharmaceutiques comprenant de l'elinzanétant et au moins un agent de solubilisation, l'agent de solubilisation étant un monoester de propylène glycol d'un acide gras C2-C10. L'invention concerne en outre la fabrication des formulations pharmaceutiques selon l'invention ainsi que des capsules de gélatine molle les comprenant, leurs utilisations médicales, en particulier pour le traitement de maladies et de troubles dépendant de l'hormone sexuelle.
PCT/EP2025/063649 2024-05-24 2025-05-19 Formulation de capsule de gélatine molle stable pour élinzanétant Pending WO2025242584A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP24177851.3 2024-05-24
EP24177851 2024-05-24

Publications (1)

Publication Number Publication Date
WO2025242584A1 true WO2025242584A1 (fr) 2025-11-27

Family

ID=91247376

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/063649 Pending WO2025242584A1 (fr) 2024-05-24 2025-05-19 Formulation de capsule de gélatine molle stable pour élinzanétant

Country Status (1)

Country Link
WO (1) WO2025242584A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007028654A1 (fr) 2005-09-09 2007-03-15 Smithkline Beecham Corporation Dérivés de pyridine et utilisation de ceux-ci dans le traitement de troubles psychotiques
WO2011023733A1 (fr) 2009-08-27 2011-03-03 Glaxosmithkline Llc Formes anhydrates d'un dérivé de pyridine
WO2016184829A1 (fr) 2015-05-18 2016-11-24 Nerre Therapeutics Limited Antagonistes doubles des récepteurs nk-1/nk-3 pour le traitement de maladies dépendant des hormones sexuelles
WO2019175253A1 (fr) 2018-03-14 2019-09-19 KaNDy Therapeutics Limited Nouvelle formulation pharmaceutique comprenant des antagonistes doubles des récepteurs nk-1/nk-3
WO2023147135A1 (fr) * 2022-01-31 2023-08-03 Acer Therapeutics, Inc. Antagonistes du récepteur de la nk pour le traitement du cancer de la prostate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007028654A1 (fr) 2005-09-09 2007-03-15 Smithkline Beecham Corporation Dérivés de pyridine et utilisation de ceux-ci dans le traitement de troubles psychotiques
WO2011023733A1 (fr) 2009-08-27 2011-03-03 Glaxosmithkline Llc Formes anhydrates d'un dérivé de pyridine
WO2016184829A1 (fr) 2015-05-18 2016-11-24 Nerre Therapeutics Limited Antagonistes doubles des récepteurs nk-1/nk-3 pour le traitement de maladies dépendant des hormones sexuelles
WO2019175253A1 (fr) 2018-03-14 2019-09-19 KaNDy Therapeutics Limited Nouvelle formulation pharmaceutique comprenant des antagonistes doubles des récepteurs nk-1/nk-3
WO2023147135A1 (fr) * 2022-01-31 2023-08-03 Acer Therapeutics, Inc. Antagonistes du récepteur de la nk pour le traitement du cancer de la prostate

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J.P. STANLEY: "Theory and Practice of Industrial Pharmacy", 1986, pages: 398 - 412
PAWSEY STEVE ET AL: "Elinzanetant (NT-814), a Neurokinin 1,3 Receptor Antagonist, Reduces Estradiol and Progesterone in Healthy Women", vol. 106, no. 8, 24 February 2021 (2021-02-24), US, pages e3221 - e3234, XP093192078, ISSN: 0021-972X, Retrieved from the Internet <URL:http://academic.oup.com/jcem/article-pdf/106/8/e3221/38939391/dgab108.pdf> [retrieved on 20241108], DOI: 10.1210/clinem/dgab108 *
SASSARINI JENIFER ET AL: "Elinzanetant: a phase III therapy for postmenopausal patients with vasomotor symptoms", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 33, no. 1, 2 January 2024 (2024-01-02), UK, pages 19 - 26, XP093221859, ISSN: 1354-3784, DOI: 10.1080/13543784.2024.2305122 *

Similar Documents

Publication Publication Date Title
US11767328B2 (en) Method of treatment of symptoms of menopause
EP0184942B1 (fr) Compositions pharmaceutiques contenant de l&#39;acide 13-Cis vitaminique A comme ingrédient actif
US10532059B2 (en) Steroid hormone pharmaceutical composition
US20170281646A1 (en) Steroid hormone pharmaceutical composition
JP2002503686A (ja) 経口投与可能な吸収促進剤を含む即時遊離且つ延長遊離剤形およびこの吸収促進剤の使用
UA120508C2 (uk) Комплекси сиролімусу і його похідних, спосіб їх отримання і фармацевтичні композиції, що містять зазначені комплекси
CN104363899A (zh) [(1s)-1-{[(2s,4r)-4-(7-氯-4-甲氧基异喹啉-1-基氧基)-2-({(1r,2s)-1-[(环丙基磺酰基)氨甲酰基]-2-乙烯基环丙基}氨甲酰基)吡咯烷-1-基]羰基}-2,2-二甲基丙基]氨基甲酸1,1-二甲基乙基酯的增溶的胶囊制剂
KR100679582B1 (ko) 경질 쉘 캡슐용 이부프로펜 용액
WO2025242584A1 (fr) Formulation de capsule de gélatine molle stable pour élinzanétant
HK40120902A (zh) 含有双重nk-1/nk-3受体拮抗剂的新颖的药物制剂
CN119789850A (zh) 包含异维甲酸的药物组合物及其制备方法和用途
HK40037077A (en) Novel pharmaceutical formulation comprising dual nk-1/nk-3 receptor antagonists
EA042709B1 (ru) Новый фармацевтический препарат, содержащий двойные антагонисты рецептора nk-1/nk-3
BR112020017388B1 (pt) Formulação de cápsula de gelatina macia compreendendo antagonistas duplos dos receptores nk-1/nk-3, e método para produção de uma cápsula de gelatina macia
WO2005046651A1 (fr) Capsules remplies de liquide et renfermant de la doxycycline
BR122024026592A2 (pt) Formulação farmacêutica de cápsula de gelatina mole compreendendo antagonistas duplos dos receptores nk-1/nk-3, seu uso e seu método de preparação
US20240050416A1 (en) Stable Pharmaceutical Compositions of Apixaban
WO2000037083A1 (fr) Composition pharmaceutique orale anti-oestrogenique
TWI525086B (zh) 決奈達隆醫藥組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25725031

Country of ref document: EP

Kind code of ref document: A1