WO2025242584A1 - A stable soft gelatin capsule formulation for elinzanetant - Google Patents

A stable soft gelatin capsule formulation for elinzanetant

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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
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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
French (fr)
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
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Filing date
Publication date
Application filed by Bayer Consumer Care AG filed Critical Bayer Consumer Care AG
Publication of WO2025242584A1 publication Critical patent/WO2025242584A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—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 .

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Abstract

The present disclosure 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-C10-fatty acid. The disclosure further relates to the manufacture of the pharmaceutical formulations according to the disclosure as well as soft gelatin capsules comprising the same, their medical uses, in particular for treating sex hormone-dependent diseases and disorders.

Description

A stable soft gelatin capsule formulation for elinzanetant
Field of the Invention
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.
Background of the Invention
The compound 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- yl}-N,2-dimethylpropanamide, herein also referred to by its INN: elinzanetant, is being developed for treatment of different diseases and conditions (WO 2007/028654 A1 ), including sex-hormone dependent diseases and disorders (WO 2016/184829 A1 ).
Different approaches have been carried out to obtain formulations suitable for administration of elinzanetant in the desired dosage. To mitigate slow dissolution 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. Reducing the size of the soft gelatin capsule would be desirable to ease oral application and to enhance the compliance with the recommended intake scheme of two capsules once daily. Further, it has surprisingly been found by the inventors that glyceride lipidic excipients (such as Capmul MCM) in formulations foster esterification of elinzanetant with the fatty acids of the excipients during manufacture and during storage. This effect is also enhanced by increased concentration of elinzanetant. These elinzanetant esters are undesired and require specification as degradation products with certain acceptance limits.
Hence, it is an object of the present invention to reduce the formation rate of elinzanetant esters to safeguard commercial shelf life of the drug product, while maintaining dissolution properties of the formulation and increasing drug load in the formulation to reduce the size of the capsules.
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.
In a development program investigating excipients that have not been included during previous formulation development programs it was surprisingly found that the excipient propylene glycol monocaprylate did show superior dissolution properties of the API while maintaining good emulsifying properties, physical and chemical stability of the fill mass, and safeguarding compatibility of the liquid fill mass with the capsule shell. Furthermore, technical experiments including stability testing of the fill mass and of soft gelatin capsules, respectively, revealed that the elinzanetant ester formation rate of different components with elinzanetant was substantially reduced using propylene glycol monoester of a saturated or un-saturated C2-C -fatty acid (e.g. 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.
Summary of the Invention
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. Accordingly, 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.
Moreover, 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.
Figure Legend
Figure 1 shows the geometric mean and standard deviation (SD) concentration-time profiles of elinzanetant for Reference and Soft Gelatin Capsules 3 (N=16) in log-linear (a) and linear scale (b); (triangles: Soft Gelatin Capsules 3, rectangles: Reference)
Figure 2 shows the geometric mean and standard deviation (SD) concentration-time profiles of elinzanetant for Reference and Soft Gelatin Capsules 1 (N=16) in log-linear (a) and linear scale (b); (circles: Soft Gelatin Capsules 1 , rectangles: Reference)
Detailed Description of the Invention
The details and embodiments of the present invention is further defined by the disclosure herein.
All numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about." “About” in a preferred embodiment refers to the quantities, percentages or proportions, and other numerical values ±5%.
The terms "a" and "an" as used herein refer to "one or more" of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise.
The term "excipient" as used herein 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.
The terms “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. The primary effect of the solubilizers and emulsifiers of the present pharmaceutical formulation is the solubilization of elinzanetant. They may further facilitate stabilizing that dissolved state by emulsifying elinzanetant in its hydrophobic/lipid-based formulation according to the disclosure in an aqueous environment, such as in the acidic aqueous environment in the stomach or in the neutral or basic aqueous environment after passage of the pylorus and duodenum. The naming as 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.
The term “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. In one embodiment 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. “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” or “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)-yl]-3-pyridinyl}-N,2-dimethylpropanamide” is also known under its INN “elinzanetant”. The terms are used interchangeably herein. Elinzanetant is, e.g., disclosed as Example 34 in WO 2007/028654 A1 , incorporated herein by reference.
In an embodiment elinzanetant refers to a compound of formula (I):
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
In one embodiment, 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.
In an embodiment propylene glycol monoester of a C2-C -fatty acid is a propylene glycol monoester of a Cs-fatty acid. In one embodiment the propylene glycol monoester of a C2-Cio-fatty acid is propylene glycol monocaprylate [also known under trade names Capryol 90 or Capryol PGMC].
In some embodiments, 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.
In one embodiment, 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.
Additional Solubilizers
In one embodiment the pharmaceutical formulation of the present disclosure comprises one or more further solubilizer. In an embodiment 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 (p-cyclodextrin sulfobutylether, sodium salt [182410-00-0]) 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]). Fumaric acid ((E)-2-butenedioic acid [110-17-8]). 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. Mono-, di and tri- glycerides of fatty acids [73398-61 -5] also called Imwitor 742. 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]) also called 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]) also called Anycoat C, Benecel hypromellose, BonuCel, Headeel Cellulose, Mecellose, Methocel, Metolose, Pharmacoat, Rutocel, Vivapharm HPMC. Lanolin alcohols [8027- 33-6] also called Argowax, Lanis AL, Lantrol 1780, Ritawax, Super Hartolan. Lecithin [8002-43-5; 8030-76-01 ; 93685-90-6] also called Coatsome NC, E322, Epikuron, Lecigran, Lipoid, Phosal MCT, Phospholipon 100 H, ProKote LSC, Sternfine, Sternpur, Topcithin, Yelkin. Linoleic acid ((Z,Z)-9,12-octadecadienoic acid [60-33-3]) also called Emersol 310, Emersol 315, Pamolyn, Polylin No. 515. 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 [4235-95-4] also called Coatasome MC-8181 , Lipoid PC 18: 1 /18: 1 (DOPC), PhospoLipid-DOPC; Dierucoyl phosphatidylcholine [51779-95-4] also called PhospoLipid-DERPC; Palmitoyloleoyl phosphatidylcholine [26853-31 -6] also called Coatasome MC-6081 , PhospoLipid-POPC; Dimyristoyl phosphatidylglycerol, sodium salt [67232-80-8] also called Coatasome MG-4040LS, Lipoid PG 14:0/14:0 (DMPG), PhospoLipid-DMPG; Dipalmitoyl phosphatidylglycerol, sodium salt [67232-81 -9] also called Coatasome MG-6060LS, Lipoid PG 16:0/16:0 (DPPG), PhospoLipid-DPPG; Distearoyl phosphatidylglycerol, sodium salt [67232-82-0] also called Coatasome MG- 8080LS, Lipoid PG 18:0/18:0 (DSPG), PhospoLipid-DSPG; Dioleoyl phosphatidylglycerol, sodium salt [62700-69-0] also called Lipoid PG 18:1/18:1 (DOPG), PhospoLipid-DOPG; Palmitoyloleoyl phosphatidylglycerol, sodium salt [81490-05-3] also called Lipoid PG 16:0/18:1 (POPG), PhospoLipid-POPG; Dimyristoyl phosphatidylethanolamine [998-07-02] also called Coatasome ME-4040, Lipoid PE 14:0/14:0 (DMPE); Dipalmitoyl phosphatidylethanolamine [923-61 -5] also called Coatasome ME-6060, Lipoid PE 16:0/16:0 (DPPE); Distearoyl phosphatidylethanolamine [1069-79-0] also called Coatasome ME-8080, Lipoid PE 18:0 /18:0 (DSPE); Dioleoyl phosphatidylethanolamine [4004-05-1 ] also called Coatasome ME-8181 , Lipoid PE 18:1/18:1 (DOPE); Dimyristoyl phosphatidic acid, sodium salt [80724-31 -8] also called Coatasome MA-4040LS; Dipalmitoyl phosphatidic acid, sodium salt [74427-52-4] also called Coatasome MA-6060LS, Lipoid PA 16:0/16:0 (DPPA); Distearoyl phosphatidic acid, sodium salt [108321 -18-2] also called Coatasome MA-8080LS, Lipoid PA 18:0/18:0 (DSPA); Dioleoyl phosphatidylserine, sodium salt [70614-14-1 ] also called Coatasome MS-8181 LS. 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, Eastacryl 30D, Kollicoat MAE 30 DP, Kollicoat MAE 100 P; Poly(methacrylic acid, methyl methacrylate) 1 :2 [25086-15-1 ] also called Eudragit S 100, Eudragit S 12.5, Eudragit FS 30D; Poly(ethyl acrylate, methyl methacrylate, methacrylic) 7:3:1 [33434-24-1 ] also called Eudragit RL 100, Eudragit RL PO, Eudragit RL 30 D, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS PO, Eudragit RS 30 D, Eudragit RS 12.5. 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, Lumulse CS-20, Ritacet 20; Polyoxyl 25 cetostearyl ether also called Brij CS25, Ceteareth 25, Cremephor A25, Hetoxol CS-25; Polyoxyl 2 cetyl ether also called Brij CZ, Hetoxol CA-2, Jeecol CA-10, Lipocol C-2, Nikkol BC-2, Procol CA-2; Polyoxyl 10 cetyl ether also called Brij 15 C10, Jeecol CA-10, Lipocol C-10, Nikkol BC-10TX, Procol CA-10; Polyoxyl 20 cetyl ether also called Brij C20, Hetoxol CA-20, Jeecol CA-20, Lipocol C-20, Nikkol BC-20TX; Polyoxyl 26 glyceryl ether also called Ethosperse G- 26, Genapol G-260, Glycereth-26, Hetoxide G-26, Jeechem GL-26; Polyoxyl 4 lauryl ether also called Brij L4, Ethosperse LA-4, Genapol LA 040, Hetoxol LA-4, Jeecol LA- 4, Lipocol L-4, Lumulse L-4, Nikkol BL-4.2, Procol LA-4; Polyoxyl 9 lauryl ether also called Brij L9, Hetoxol LA-9, Jeecol LA-9, Nikkol BL-9EX; Polyoxyl 12 lauryl ether also called Hetoxol LA-12, Jeecol LA-12, Lipocol L-12, Lumulse L-12, Procol LA-12; Polyoxyl 23 lauryl ether also called Brij L23, Ethosperse LA-23, Genapol LA 230, Hetoxol LA-23, Jeecol LA-23, Lipocol L-23, Lumulse L-23, Procol LA-23, Ritox 35; Polyoxyl 2 oleyl ether also called Brij 02, Genapol O 020, Jeecol OA-2, Lipocol 0-2, Nikkol BO-2V, Procol OA-2, Ritoleth 2; Polyoxyl 10 oleyl ether also called Brij 010, Genapol O 100, Hetoxol OA-10, Jeecol OA-10, Lipocol 0-10, Nikkol 8O-IOV, Procol OA-10, Ritoleth 10; Polyoxyl 20 oleyl ether also called Brij 020, Genapol O 200, Jeecol OA-20, Lipocol 0-20, Nikkol BO-20V, Procol OA-20, Ritoleth 20; Polyoxyl 2 stearyl ether also called Brij S2, Genapol HS 020, Hetoxol STA-2, Jeecol SA-2, Lipocol S-2, Nikkol BS-2, Procol SA-2; Polyoxyl 10 stearyl ether also called Brij S10, Hetoxol STA- 10, Jeecol SA-10, Lipocol S-10, Procol SA-10; Polyoxyl 20 stearyl ether also called Brij S20, Jeecol SA-20, Lipocol S-20; Polyoxyl 21 stearyl ether also called Brij S721 , Jeecol SA-21 , Lipocol S-21 , Ritox 721 ; Polyoxyl 100 stearyl ether also called Brij S100, Hetoxol STA-100, Jeecol SA-100. Polyoxyethylene castor oil derivatives (polyethoxylated castor oil [61791 -12-6]) 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 R40, Nikkol CO 40TX, Protochem CA-40; Polyoxyl 40 hydrogenated castor oil also called Croduret 40, Eumulgin HRE 40PH, Hetoxide HC40, Jeechem CAH-40, Kolliphor RH 40, Lipocol HCO-40, Lipocol LAV HCO-40, Lumulse HCO 40, Nikkol HCO 40 Pharma, Protachem CAH-40; Polyoxyl 60 castor oil also called Jeechem CA-60, Nikkol CO 60TX; Polyoxyl 60 hydrogenated castor oil also called Croduret 60, Eumulgin HRE 60, Hetoxide HC60, Jeechem CAH-60, Kolliphor RH 60, Lipocol HCO-60, Nikkol HCO 60, Protachem CAH-60; Polyoxyl 100 castor oil also called Jeechem CA-100; Polyoxyl 100 hydrogenated castor oil also called Jeechem CA-100, Nikkol HCO 100; Polyoxyl 200 castor oil also called Hetoxide C200, Jeechem CA200; Polyoxyl 200 hydrogenated castor oil also called Jeechem CAH-200. Polyoxyl 15 hydroxystearate (2-hydroxyethyl-12-hydroxyoctadecanoate [70142-34-6]) also called Solutol HS 15. Polyoxylglycerides with specific examples Caprylocaproyl polyoxylglycerides [73398-61 -5; 223129-75-7] also called caprylocaproyl polyoxyl-8 glycerides, DUBCARE GPE 810, Labrasol ALF; Lauroyl polyoxylglycerides [57107-95- 6] also called lauroyl polyoxyl-6 glycerides Gelucire 44/14, Labrafil M2130CS; Linoleoyl polyoxylglycerides [61789-25-1] also calledlinoleoyl polyoxyl-6 glycerides, Labrafil M212SCS; Oleoyl polyoxylglycerides [68424-61 -3; 9004-96-0] also called oleoyl polyoxyl-6 glycerides, DUBCARE OLGA SF, 10 Labrafil Ml 944CS; Stearoyl polyoxylglycerides [1323-83-7; 9005-08-07] also called stearoyl polyoxyl-32 glycerides, Gelucire 50/13, Simulsol L165 PHA. Polyvinyl acetate phthalate [34481 - 48-6], Povidone (1-ethenyl-2-pyrrolidinone homopolymer [9003-39-8]) also called E1201 , Kollidon, Plasdone, Povipharm. Propylene glycol dilaurate (2- dodecanoyloxypropyl dodecanoate [22788-19-9]) also called Capmul PG-2L, E477, Emalex 15 PG di-L. 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]) also called Kollisolv PYR, Soluphor P. Sodium Bicarbonate(carbonic acid monosodium salt [144-55-8]) also called ESOO, Effer-Soda. 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. Sorbitan esters with specific examples Sorbitan diisostearate (sorbitan diisooctadecanoate [68238-87-9]); Sorbitan dioleate ((Z,Z)-sorbitan di-9- octadecanoate [29116-98-1 ]); Sorbitan monoisostearate (sorbitan monoisooctadecanoate [71902-01-7]) also called Arlacel 987, Crill 6, Montane 70; Sorbitan monolaurate (sorbitan monododecanoate [1338-39-2]) also called Alkamuls SML, Arlacel 20, Armotan ML, Crill 1 , Dehymuls SML, E493, Emsorb 2515, Glycomul L, Hodag SML, Liposorb L-80, Montane 20, Protachem SML, Sorbester P12, Sorbirol L, Span 20, Tega SML; Sorbitan monooleate ((Z)-sorbitan mono-9-octadecenoate [1338-43-8]) also called Ablunol S-80, Alkamuls SMO, Arlacel 80, Armotan MO, Capmul 0, Crill 4, Crill SO, Dehymuls SMO, Drewmulse SMO, Drewsorb BOK, E494, Glycomul 0, Emsorb 2500, Glycomul 0, Hodag SMO, Lamesorb SMO, Liposorb 0, Montane 80, Nikkol SO-10, Nissan nonion OP-SOR, Norfox Sorbo S-80, Polycon SBO K, Protosorb SMO, Protachem SMO, S-Maz BOK, Sorbester PI 7, Sorbirol 0, Sorgen 40, Sorgen S-40-H, Span 80, Tega SMO; Sorbitan monopalmitate (sorbitan monohexadecanoate [26266-57-9])also called Ablunol S-40, Arlacel 40, Armotan MP, Crill 2, Dehymuls SMP, E495, Glycomul P, Hodag SMP, Lamesorb SMP, Liposorb P, Montane 40, Nikkol SP-10, Nissan nonion PP-40R, Protachem SMP, Protosorb SMP, Sorbester P16, Sorbirol P, Span 40; Sorbitan monostearate (sorbitan monooctadecanoate [1338-41-6]) also called Ablunol S-60, Alkamuls SMS, Arlacel 60, Armotan MS, Atlas 11 OK, Capmul S, Crill 3, Dehymuls SMS, Drewmulse SMS, Drewsorb 60K, Durtan 60, Durtan 60K, E491 , Famodan MS Kosher, Glycomul S FG, Glycomul S KFG, Hodag SMS, Lamesorb SMS, Liposorb S, Liposorb SC, Liposorb S- K, Montane 60, Nikkol SP-60R, Norfox Sorbo S-60FG, Polycon S60K, Protachem SMS, Prote-sorb SMS, S-Maz 60K, S-Maz 60KHS, Sorbester P18, Sorbirol S, Sorgen SO, Span 60, Span 60K, Span 60 VS, Tega SMS; Sorbitan sesquiisostearate (sorbitan sesquiisooctadecanoate [71812-38-9]) also called Protachem SQI; Sorbitan sesquioleate ((Z)-sorbitan sesqui-9-octadecanoate [8007-43-0]) also called Arlacel C, Arlacel 83, Crill 43, Glycomul SOC, Hodag SSO, Liposorb SQO, Montane 83, Nikkol SO-15, Nissan nonion OP-83RAT, Protachem SOC, Sorgen 30, Sorgen 30, Sorgen S- 30-H; Sorbitan sesquistearate (sorbitan sesquioctadecanoate [51938-44-4]); Sorbitan tri isostearate (sorbitan triisooctadecanoate [54392-27-7]); Sorbitan trilaurate (sorbitan tridodecanoate [71217-21 -5]) also called Span 25; Sorbitan trioleate ((Z,Z,Z)-sorbitan tri-9-octadecenoate [26366-58-0]) also called Ablunol S-85, Arlacel 85, Crill 45, Glycomul TO, Hodag STO, Liposorb TO, Montane 85, Nissan nonion OP-8SR, Protachem STO, Prote-sorb STO, S-Maz 85K, Sorbester P37, Span 85, Tega STO; Sorbitan tristearate (sorbitan tri-octadecanoate [26658-19-5]) also called Alkamuls STS, Crill 35, Crill 41 , Drewsorb 65K, E492, Famodan TS Kosher, Glycomul TS KFG, Hodag STS, Lamesorb STS, Liposorb TS, Liposorb TS-K, Montane 65, Protachem STS, Prote-sorb STS, Sorbester P38, Span 65, Span 65K. 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. 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, Sistema 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, Sistema SP, STELLIESTERS SE SS, Surfhope SE, Tegosoft TE. Tricaprylin (1 ,3-di( octanoyloxy)propan-2-yl octanoate [538-23-8]) also called Captex 8000, Hest TC, Miglyol 808, Rofetan GTC, Trivent OC-G. Trimethyl- Pcyclodextrin (tri-O-methyl-p-cyclodextrin [55216-11 -0]). Triolein (2,3-bis[[(Z)-octadec- 9-enoyl]oxy]propyl (Z)-octadec-9-enoate [122-32-7] also called Captex GTO. 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.
In one embodiment 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. In an embodiment, the concentration of caprylocaproyl macrogol-8 glycerides (e.g., Labrasol ALF) 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. In one embodiment the concentration of caprylocaproyl macrogol-8 glycerides (e.g., Labrasol ALF) is from about 8% w/w to about 10% w/w. In an embodiment the concentration of caprylocaproyl macrogol-8 glycerides (e.g., Labrasol ALF) 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.
In some embodiments, the concentration of the Glycerol monooleate (e.g., Peceol) 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.
In one embodiment, 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.
In an embodiment, 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.
In an embodiment, 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.
Emulsifiers
In some embodiments, the pharmaceutical formulation of the present disclosure comprises an emulsifier.
In some embodiments, 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.
In some embodiments, 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|3,20|3)- 20-carboxy-11 -oxo-30-norlean-12-en-3-yl-2-O-[3-D-glucopyranuronosyl- monoammonium salt; anhydrous [53956-04-0]; (a-D-glucopyranosiduric acid, (3[3,20[3)-20-carboxy-11 -oxo 30-norlean-12-en-3-yl-2-O-[3-D-glucopyranuronosyl-, monoammonium salt; pentahydrate [1407-03-0]) also called Magnasweet. 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. Lanolin, hydrous [8020-86-4], Laurie acid (dodecanoic acid [143- 07-7]) also called C-1297, Hydrofol acid 1255, Hydrofol acid 1295, Hystrene 9512, Kortacid 1299, Lunac L70, Neo-fat 12, Neo-fat 12-43, Ninol AA62 Extra, Prifac 2920, Univol U314, Wecoline 1295. 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. Mineral oil [8012-95-1 ] and lanolin alcohols [8027-33-6] also called Amerchol L-101 , Protalan M-16, Protalan M-26, Vilvanolin. 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. OSA modified gum acacia [455885- 22-0], Palmitic acid (hexadecanoic acid [57-10-13]) also called Edenor C16 98-100, Emersol 140, Emersol 143, Hydrofol, Hystrene 9016, Industrene 4516, Lunac P-95. Pectin [9000-69-5]) also called E440, Genu, Unipectine U. Polycarbophil [9003-97-8] also called Noveon AA-1. 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; Polysorbate 21 (polyoxyethylene ( 4) sorbitan monolaurate [9005-64-5]) also called Crillet 11 , Hodag PSML-4, Protasorb L-5, Tween 21 ; Polysorbate 40 (polyoxyethylene 20 sorbitan monpalmitate [9005-66-7]) also called Atmer 112, Crillet 2, E434, Eumulgin SMP, Glyosperse S-20, Hodag-PSMP-20, Lamesorb SMP-20, Liposorb P-20, Lonzest SMP- 20, Montanax 40, Protosorb P-20, Ritabate 40, Sorbax PMP-20, Tween 40; Polysorbate 60 (polyoxyethylene 20 sorbitan monostearate [9005-67-8]) also called Alkest 20 TW 60, Atlas 70K, Atlas Armotan PMS 20, Cremophor PS-60, Crillet 3, Crillet 3HP, Crillet 3 Super, Drewpone 60K, Durfax 60, Durfax 60K, E435, Emrite 6125, Eumulgin SMS, Glyosperse S-20 KFG, Hetsorb S-20E, Hodag PSMS-20, Hodag SVS- 18, Kaopan TWS120, Lamsorb SMS-20, Liposorb S-20, Liposorb S-20K, Lonzest SMS-20, Montanox 60, Nikkol TS-10, Norfox Sorbo T-60, Polycon T60K, Protsorb S- 20, Ritabate 60, Sorbax PMS-20, T-Maz 60, T-max 60KHS, Tega SMS60, Tween 60, Tween 60K, Tween 60 Veg, Tween 60 VS; Polysorbate 61 (polyoxyethylene ( 4) sorbitan monostearate [9005-67-8]) also called Crillet 31 L02, Hetsorb S-4, Hodag PSMS-4, Liposorb S-4, Protasorb S-4, Tween 61 , Tween 61 N, Tween 61 V, Tween 61 Veg; Polysorbate 65 (polyoxyethylene 20 sorbitan tristearate [9005-71 -4]) also called Alkamuls PSTS-20, Crillet 35, E436, Glyosperse TS-20 KFG, Hodag-PSTS-20, Lamsorb STS-20, Lanzet STS-20, Liposorb TS-20, Montonax 65, Protasorb STS-20, Sorbax PTS-20, T-Maz 65K, Tween 65, Tween 65K, Tween 65 V; Polysorbate 80 (polyoxyethylene 20 sorbitan monooleate [9005-65-6]) also called Alkest TW 80, Atlas E, Atmer 116, Armotan PMO 20, Cremophor PS 80, Crillet 4, Crillet 4 HP, Crillet 4 Super, Crillet SO, Drewmulse POE-SMO, Drewpone BOK, Durfax 80, Durfax BOK, E433, Emrite 6120, 35 Eumulgin SMO, Glyosperse 0-20, Hetsorb O-20E, Hodag PSMO-20, Liposorb 0-20, Liposorb O-20K, Montanox 80, Olethytan 20, Polysorbat 80, Protasorb 0-20, Ritabate 80, Sepitrap 80, Tega SMO-80, Tega SMO-BOV, Tween 80, Tween 80 HP, Tween BOK, Tween 80 LM, Tween 80 SP, Tween 80 V, Tween 80 Veg; Polysorbate 81 (polyoxyethylene (5) sorbitan monooleate [9005-65-6]) also called Crillet 41 , Hetsorb-OSE, Hodag PSMO-5, Protsorb 0-5, Sorbax PMO-5, T-Maz 81 , Tega SMO 81 , Tween 81 , Tween 81 N; Polysorbate 85 (polyoxyethylene 20 sorbitan trioleate [9005-70-3]) also called Alkamuls PSTO-20, Atmer 118, Crillet 45, Crillet 4SLD, Glyosperse TO-20, Hetsorb TO-ZOE, Hodag PSTO-20, Liposorb TO-20, Lonzest STO-20, Montanox 85, Protasorb TO-20, Sorbax PTO-20, Tega STO 85, Tween 85, Tween BSLM, Tween BSN, Tween BSV; Polysorbate 120 (polyoxyethylene sorbitan monoisostearate [66794-58-9]) also called Crillet 6. 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, Myrj 45, Pegosperse 400 MS, Protomate 400-DPS, Ritapeg 400 MS; Polyoxyl 12 stearate also called Hodag 60-S, Kessco PEG-600 Monostearate, Lipopeg 6-S, Pegosperse 600 MS, Protomate 600- DPS; Polyoxyl 20 stearate also called Cerasynt 840, Hodag 100-S, Kessco PEG-1000 Monostearate, Lipopeg 10-S, Myrj 49, Pegosperse 1000MS, Protomate 1000-DPS; Polyoxyl 30 stearate also called Myrj 51 ; Polyoxyl 40 stearate also called Crodet S40, E431 , Emerest 2672, Hodag POE (40) MS, Lipal 395, Lipopeg 39-S, Myrj 52, Protamate 2000-DPS, Ritox 52, Simusol MS2; Polyoxyl SO stearate also called Atlas G-202153, Crodet SSO, Lipal SOS, Myrj 53; Polyoxyl 100 stearate also called Lipopeg 100-S, Myrj 59, Protomate 4400-DPS, Ritox 53; Polyoxyl 150 stearate also called Hodag 600-S, Ritox 59; Polyoxyl 4 distearate also called Hodag 22-S; Polyoxyl 8 distearate also called Hodag 42-S, Kessco PEG 400 OS, Protamate 400-DS; Polyoxyl 12 distearate also called Hodag 62-S, Kessco PEG 600 Distearate, Protamate 600- DS; Polyoxyl 32 distearate also called Hodag 25 154-S, Kessco PEG 1540 Distearate; Polyoxyl 150 distearate also called Hodag 602-S, Kessco PEG 6000 OS, Lipopeg 6000DS, Protamate 6000-DS. 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. Safflower glycerides [79982- 97-1 ], Saponite [1319-41 -1 ] also called Afrodit, lmvite 1016, Ionite P, Laponite, SapCa- 1 , Smectiton SA, SMI 200H, Stevensonite, Sumecton SA, SY 5, Veegum S6198. 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 ]) also called E413. Triethanolamine (2, 2', 2" - nitrilotriethanol [102-71 -6]) also called Tealan. 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.
In one embodiment, 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.
In some embodiments, 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.
In an embodiment, 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.
Antioxidants
In some embodiments, the pharmaceutical formulation of the present disclosure comprises an antioxidant. In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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 ]) also called E311. Phosphoric acid (orthophosphoric acid [7664-38-2]) also called E338. Potassium metabisulfite (dipotassium pyrosulfite [16731 -55-8]) also called E224. 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]) also called Ametox, Sodothiol, Sulfothiorine. Sulfur dioxide [7446-09- 05] also called E220. Thymol ([89-83-8]; m-thymol [3228-0303]) also called Flavinol, Intrasol, Medophyll.
In some embodiments, the antioxidant is selected from dl-Alpha tocopherol (Vitamin E), butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA), and mixtures thereof.
In some embodiments, the antioxidant is butylated hydroxytoluene (BHT).
In some embodiments, 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.
In some embodiments, the antioxidant is butylated hydroxyanisole (BHA).
In some embodiments, 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.
In an embodiment the antioxidant is dl-Alpha tocopherol (Vitamin E, also referred to as dl-a tocopherol, DL-alpha tocopherol, or DL-a tocopherol herein).
In some embodiments, 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.
The antioxidants according to the disclosure are commercially available. Thus, for example dl-alpha-tocopherol (Vitamin E) is available from BASF SE, Ludwigshafen, Germany; Butylated hydroxyanisole (BHA) is available from Sigma Aldrich, St. Louis, MO, USA; and Butylated hydroxytoluene (BHT) is available from Merck KGaA, Darmstadt, Germany.
In an embodiment the pharmaceutical formulation according to the disclosure comprises a mixture of solubilizers comprising propylene glycol monocaprylate.
In an embodiment 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.
In an embodiment, 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.
In an embodiment, 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. In an embodiment, 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. In another embodiment, 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.
In an embodiment, 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.
In an embodiment the disclosure relates to 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.
In one embodiment 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;
(b1 ) propylene glycol monocaprylate present at a concentration ranging from 10% w/w to 40% w/w;
(b2) caprylocaproyl macrogol-8 glycerides present at a concentration ranging from 5% w/w to 50% w/w;
(b3) glycerol monooleate present at a concentration ranging from about 10% w/w to 40% w/w;
(c) 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.
In one embodiment the disclosure relates to a pharmaceutical formulation comprising: (a) elinzanetant at a concentration of about 7% w/w;
(b1 ) propylene glycol monocaprylate present at a concentration of about 36.27% w/w; (b2) caprylocaproyl macrogol-8 glycerides present at a concentration of about 9.3% w/w;
(b3) glycerol monooleate present at a concentration of about 37.2% w/w;
(c) polysorbate 80 present at a concentration about 9.3% w/w; and
(d) dl-rac-alpha tocopherol present at a concentration of about 0.93% w/v.
In one embodiment the disclosure relates to a pharmaceutical formulation comprising: (a) elinzanetant at a concentration of about 7% w/w;
(b1 ) propylene glycol monocaprylate present at a concentration of about 18.69% w/w; (b2) caprylocaproyl macrogol-8 glycerides present at a concentration of about 46.5% w/w;
(b3) Glycerol monooleate present at a concentration of about 17.58% w/w;
(c) Polysorbate 80 present at a concentration about 9.3% w/w; and
(d) dl-rac-alpha tocopherol present at a concentration of about 0.93% w/v.
Methods of Treatment
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 ). In particular, sex hormone-dependent diseases and disorders have been proofed to be ameliorated by administration of elinzanetant in various clinical studies.
Accordingly, 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. In an embodiment of the present disclosure the disease or disorder is a sex hormone-dependent disease or disorder. In one embodiment, 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.
Examples 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 adolescents’ precocious puberty.
Examples of such 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. In women the condition may be menopause- associated conditions, such as penmenopause, the menopause, or the postmenopause. When referring to 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.
In men, sex hormone-dependent diseases or disorders may be associated with adrenopause.
Accordingly, in a preferred embodiment of the present disclosure, the disease or disorder, preferably the sex hormone-dependent disease or disorder, is a disease or disorder that is associated with menopause or adrenopause.
Further, sex hormone-dependent diseases or disorders, e.g., vasomotor symptoms, 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. by adjuvant endocrine therapy or androgen deprivation therapy by a compound or drug selected from the group consisting of 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) such as bazedoxifene, clomifene, cyclofenil, tamoxifen, ormeloxifene, toremifene, raloxifene, lasofoxifene and ospemifene; selective estrogen receptor degraders (SERDs) such as fulvestrant, brilanestrant and elacestrant; CYP17 Al inhibitors such as abiraterone, ketoconazole and seviteronel; and androgen deprivation therapy; combined androgen receptor blockers and CYP17 Al inhibitors, such as galeterone.
In an embodiment of the disclosure, 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. In yet a further embodiment in which the disease or disorder is vasomotor symptoms.
In an embodiment these sex hormone-dependent diseases or disorders are associated with menopause or caused by adjuvant endocrine therapy. Accordingly, a particular embodiment of the disclosure is 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. Yet more preferred, the disease or disorder is vasomotor symptoms associated with menopause. In a further embodiment of the disclosure is 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. In yet a further embodiment, the disease or disorder is vasomotor symptoms associated or caused by adjuvant endocrine therapy.
In some embodiments, 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.
In some embodiments, 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. In one embodiment 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. In a particular embodiment, 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. In a particular embodiment, 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. In one embodiment, 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.
In one embodiment 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.
It is understood that the required daily dose of 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.
Additional Therapeutic Agents
It is understood that 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.
Thus, in some embodiments, the pharmaceutical formulation of the present disclosure comprises elinzanetant or a pharmaceutical acceptable salt thereof, and the one or more additional therapeutic agents. Alternatively, elinzanetant and the one or more additional therapeutic agents may be formulated in separated pharmaceutical formulations. In some embodiments, the separated pharmaceutical formulations may be included in a pharmaceutical kit.
Examples of 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 rimonabant, and MC4 receptor agonists such as bremelanotide, modimelanotide, PF-00446687, PL-6983, PL-8905, setmelanotide, and 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 5 peptidase-4 (DPP-4) inhibitors such as anagliptin, aloglitin, dutogliptin, linagliptin, omarigliptin, saxagliptin, sitagliptin, teneligliptin, trelagliptin and vildagliptin, and GLP-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, and glycoside hydrolase inhibitors such as acarbose and miglitol, and meglitinides such as repaglinide and nateglinide, and sulfonylureas such as glibenclamide (glyburide), glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide and glyclopyramide, and thiazolidinediones such as pioglitazone and rosiglitazone, by also achieving glycaemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin- mediated glucose uptake such as metformin, and psychostimulants/ anticonvulsants such as phenterm ine/topiramate, and norepinephrine-dopamine reuptake inhibitor (NORI), nicotinic receptor antagonist/ opiate antagonists such as bupropion/naltrexone, and selective serotonin 2c receptor agonists such as lorcaserin, and phosphodiesterase type-4 inhibitors such as apremilast, cilomilast, ibudilast, piclamilast and roflumilast; kappa opioid agonists such as dynorphin analogues, nalfurafine and pentazocine; aromatase inhibitors such as anastrozole, exemestane, letrozole and testolactone; gonadotropin-releasing hormone receptor agonists such as leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin and triptorelin; gonadotropin-releasing hormone receptor antagonists such as ASP1707, elagolix, relugolix and linzagolix (OBE2109); and antiandrogens (androgen receptor blockers) such as cyproterone acetate, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide; CYPI 7 Al inhibitors such as abiraterone, ketoconazole and seviteronel; and combined androgen receptor blockers and CYPI 7 Al inhibitors such as galeterone, and hormone replacement therapies such as estrogen-only medications including conjugated estrogens, estradiol, esterified estrogen, estropipate and synthetic conjugated estrogens; progestin-only medications including micronized progesterone and medroxyprogesterone acetate; combination estrogen and progestin medicines including estradiol/norethindrone acetate, estradiol/drospirenone, estradiol/levonorgestrel, ethinyl estradiol/norethindrone acetate, estradiol/norgestimate, conjugated estrogen/medroxyprogesterone; combination estrogen and SERMS including conjugated estrogen/bazedoxifene; selective estrogen receptor modulators (SERMs) such as bazedoxifene, clomifene, cyclofenil, tamoxifen, ormeloxifene, toremifene, raloxifene, lasofoxifene and ospemifene; selective estrogen receptor degraders (SERDs) such as fulvestrant, brilanestrant and elacestrant.
In some embodiments, 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 bazedoxifene, clomifene, cyclofenil, tamoxifen, ormeloxifene, ospemifene, toremifene, raloxifene and lasofoxifene; selective estrogen receptor degraders (SERDs) such as fulvestrant, brilanestrant and elacestrant.
In some embodiments, 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, and glycoside hydrolase inhibitors such as acarbose and miglitol, and meglitinides such as repaglinide and nateglinide, and sulfonylureas such as glibenclamide (glyburide ), glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide and glyclopyramide, and thiazolidinediones such as pioglitazone and rosiglitazone, by also achieving glycaemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin-mediated glucose uptake such as metformin.
Further Aspects of the Formulation An object of the present invention is the provision of a pharmaceutical formulation having the desired bioavailability. 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, whereas Cmax is the maximum concentration of elinzanetant found in the bloodstream after administration. The area under the curve (AUC(O-tiast)) represents the total amount of elinzanetant which was in the bloodstream over the period studied, or extrapolated to infinity to obtain the total AUC. In one embodiment, 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. In one embodiment “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. In one embodiment, 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. In one embodiment 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. In one embodiment, the pharmaceutical formulation, the pharmaceutical formulation of the present disclosure, such as provided in a soft gelatin capsule, when administered at a single dose of 120 mg under fasted conditions, exhibits a Cmax, of between 1000 pg/L and 2000 pg/L, such as between 1000 pg/L and 1900 pg/L or between 1050 pg/L and 2000 pg/L. In one embodiment the Cmax is 1457 pg/L ±25%, such as between - 20% and +25% of 1457 pg/L. In one embodiment the Cmax is 1522 pg/L ±25%, such as between 80% and 125% of 1522 pg/L.
In one embodiment, the pharmaceutical formulation, such as provided in a soft gelatin capsule, 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. In one embodiment the total AUC is 6241 pg*h/L ±25%, such as between 80% and 125% of 6241 pg*h/L. In one embodiment the total AUC is 6402 pg*h/L ±25%, such as between 80% and 125% of 6402 pg*h/L.
In one embodiment the values herein for Cmax and total AUC refer to the geometric mean.
It is understood that the pharmaceutical formulation of the present disclosure may be formulated for enteral/gastrointestinal administration, parenteral administration, or topical administration. In one embodiment, 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. In one embodiment the pharmaceutical formulations according to the present disclosure are presented as liquids. Particularly, formulations of the present disclosure are in one embodiment liquid oral unit dosage forms, more preferably filled soft capsules, e. g. gelatin capsules. In one embodiment the pharmaceutical formulation according to the present disclosure is a filling of a soft gelatin capsule. Hence, in such an embodiment the pharmaceutical formulation according to the disclosure is a soft gelatin capsule formulation.
It will be understood by those of ordinary skill in the art that 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.
The present disclosure also relates to a soft gelatin capsule comprising the pharmaceutical formulation according to the present disclosure.
In some embodiments, 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.
In some embodiments, 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.
In an embodiment 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.
In a typical procedure for the preparation of the pharmaceutical formulation according to the present disclosure, 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.
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.
Thus, 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.
In some embodiments, 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 ).
Specifically, 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).
In some embodiments, 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.
It is understood that, where the formulations of the disclosure are presented as soft gelatin capsules, 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. In a preferred embodiment, 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. In some embodiments, 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. In some embodiments, 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 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, or about 120 mg of Elinzanetant. In one embodiment, the capsule contains about 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, or 120 mg elinzanetant. In a further embodiment the soft gelatin capsule according to the present disclosure contains about 60 mg elinzanetant.
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.
In a preferred embodiment, 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.
In a preferred embodiment, 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.
In one preferred embodiment, 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. In one embodiment 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. In a preferred embodiment the soft gelatin capsule shell comprises 0.03% w/w ferric oxide red and 0.42% ferric oxide yellow.
Further, 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. Hence, the soft gelatin capsule shell may also contain lecithin and/or triglycerides.
In a preferred embodiment 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..
It is understood that the soft gelatin capsule may be prepared by methods and techniques that are known to a skilled artisan. For example, 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).
Specifically, during the encapsulation process, 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. Once the level of gelatin in the box is reduced, the compressed air is deactivated allowing the gelatin to flow through the modulator valve. 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. Immediately after the gelatin ribbon is lubricated, it passes through the inline print unit, which applies the print logo to the ribbon. Next, 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. Additionally, 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.
Before starting encapsulation, several in process checks are performed. Once all parameters are within the acceptable range as per the Master Batch Record, encapsulation process is initiated. 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). After encapsulation, 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.
Commercial manufacturing follows the same process but on a much larger scale. Timelines for production of a single batch of ~1 , 000, 000 soft gelatin capsules could range from 4-5 days up to 14+ days, depending primarily on the capsule drying time stage. Thus, 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.
EXAMPLES
Analytical Method
Reversed phase high performance liquid chromatography (HPLC)
HPLC analysis of the formulations in the Examples were performed using the following method:
The quantitation for assay and related substances of Elinzanetant is done by external calibration using a reference standard of Elinzanetant. For determination of degradation products, reference solutions containing potential degradation products and other identified impurities are injected to assure peak assignment, resolution, and detection sensitivity (as part of the system suitability test). Development of alternative pharmaceutical formulations for gelatin capsules (soft gelatin capsule formulations)
Alternate excipients screening
In a first step five alternate solubilizers to Capmul MCM were investigated for their ability to dissolve elinzanetant (also referred to as API herein). API was added to the thermally liquified (35°C ± 5°C) solubilizer in small increments and stirred mechanically until no further API was dissolved. The API concentration in the liquid supernatant was determined by HPLC. The results are shown below:
In a second step the above listed 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.
- “Dry” = without addition of water. o The lipid fill mass contains water only in very low amounts being controlled by the quality of excipients and API.
- “wet” = addition of 10% (w/w) water. o Water potentially enters the fill mass following the softgel encapsulation process due to the excess of water present in the wet gelatin shell.
- “acid gel” = under addition of gelatin gel swatch processed with acid. o A small swatch of acid-type gelatin shell mass was added to the lipid fill mass to investigate compatibility.
- “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.
Solutions comprising 5% w/w elinzanetant in the respective excipients were subjected to thermic stress at 40°C/75% relative humidity (RH) in hermetically sealed amber glass vial and tested for assay and related substances (Assay/RS) using HPLC method as described above at the time of storage and after 4, 8, and 12 weeks, respectively. Results are detailed below:
Elinzanetant compatibility with excipients:
Table 1: Stability of elinzanetant
% Recovery Summary % Recovery Summary
Table 2: HPLC analysis of degradation products
RRT = relative retention time; values given are% of Adjusted Area; elinzanetant fatty acid esters are indicated in brackets
The results showed that the use of a propylene glycol monoester of a C2-C -fatty acid, and in particular propylene glycol monocaprylate, the number and total amount of degradation products can be significantly reduced and elinzanetant showed the highest stability in combination with these monoesters.
Summary
Results surprisingly revealed that by using a propylene glycol monoester of a C2-C10- fatty acid a yet significantly increased solubility of the elinzanetant in the developed alternate lipid fill mass, good compatibility with soft gelatin shell components in terms of stability by a clearly reduced ester formation kinetics, e.g., at a concentration of 5% (w/w) of elinzanetant in the formulation are obtained. Due to this increased stability at 5% (w/w) concentration, the decision was taken to proceed with soft gelatin capsule formulation 1 and soft gelatin capsule formulation 3, infra, into manufacturing of soft gelatin capsules at the 7% (w/w) drug load level.
Development of a new soft gelatin capsule with increased drug load
Methods and Results:
Based on the solubility and compatibility experiments described above the decision was taken to proceed with development of a soft gelatin capsule formulation containing 60 mg of elinzanetant for an attempt to reduce the size of the soft gelatin capsules to size 12 by increasing the elinzanetant drug load to 7% (w/w), making use of the superior dissolution power with increased stabilization of elinzanetant by the propylene glycol monoesters of C2-C10 fatty acids as solubilizers. We identified glycerol mono-caprylocaprate as the main source and enhancer of transesterification of fatty acid residues with elinzanetant in the current clinical study formulation. Without being bound by hypothesis, it is considered that the free hydroxyl group of elinzanetant is prone for this transesterification. Four soft gelatin capsule formulations (lipidic fill mass) comprising a propylene glycol monoester of fatty acids (Capryol 90 or Lauroglycol 90) were manufactured under nitrogen atmosphere at a temperature of 35°C±5°C. The respective formulations are detailed in the tables below:
all values in the tables are % 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.
Sample Max Solubility at 25°C Max Solubility at 5°C
Comparative example 64.1 mg/g 59.8 mg/g soft gelatin capsule formulation 1 92.6 mg/g 81 .2 mg/g soft gelatin capsule formulation 2 63.6 mg/g 53.4 mg/g soft gelatin capsule formulation 3 88.6 mg/g 86.5 mg/g soft gelatin capsule formulation 4 73.0 mg/g 62.8 mg/g
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.
Since soft gelatin capsule formulations 1 and 3 showed the highest solubility, they were used for further experiments.
Soft gelatin capsule formulations 1 and 3 were investigated for stability under different conditions.
Holding study:
The respective soft gelatin capsule formulation was stored at ambient conditions over 7 days.
Result for soft gelatin capsule formulations 1 and 3: no visible signs of precipitation after 7 days.
Water challenge:
10% (w/w) water was added to the soft gelatin capsule formulations 1 and 3. The mixture was stored under ambient conditions for 7 days. Result for soft gelatin capsule formulations 1 and 3: no visible sign of precipitation after 7 days
Plasticizer challenge:
5% (w/w) plasticizers sorbitol special - glycerol were added to the soft gelatin capsule formulations 1 and 3 and stored under ambient conditions for 7 days.
Result for soft gelatin capsule formulations 1 and 3: no visible sign of precipitation after 7 days.
Thermal cycling:
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.
Result for soft gelatin capsule formulations 1 and 3: no visible sign of precipitation after 6 days.
Thermal stability:
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.
Results in the table below represent the % Recovery of elinzanetant obtained based on the respective formulation’s label claim (5% w/w). Satisfactory recovery was obtained for all formulations as shown in the following table:
Formulation Initial 2 Weeks 4 weeks 12 Weeks
Comparative example 97.9% 96.8% 98.0% 96.9% soft gelatin capsule formulation 1 99.1 % 97.8% 97.5% 95.9% soft gelatin capsule formulation 2 97.7% 97.1 % 95.5% 94.8% soft gelatin capsule formulation 3 98.7% 95.9% 98.2% 97.8% soft gelatin capsule formulation 4 98.6% 99.1 % 97.9% 96.1 % Results reported below represent the %-adjusted area of the respective impurity peak/RRT in respective to the peak of elinzanetant. Soft gelatin capsule formulations 1 to 4 showed satisfactory stability with significantly reduced ester formation rate compared to the comparative example. Slightly reduced recovery of elinzanetant was found for soft gelatin capsule formulation 2.
Sample Initial 2 Weeks 4 weeks 12 Weeks
Comparative RRT RRT 1.05: 0.10 RRT 1.37: 0.05 RRT 2.59: 0.27 example 0.52: 0.38 RRT 1.61 : 0.07 RRT 1.61: 0.08 (C8 Ester)
RRT 2.59: 0.05 RRT 2.59: 0.10 RRT 1.37: 0.05
(C8 Ester) (C8 Ester) RRT 1.61 : 0.08
Soft gelatin RRT RRT 0.52: 0.74 RRT 0.52: 1.11 RRT 0.52: 2.18 capsule 0.52: 0.13 RRT 1.61: 0.06 RRT 1.61 : 0.09 formulation 1
Soft gelatin RRT RRT 0.5: 0.71 RRT 0.52: 1.07 RRT 0.52: 1.94 capsule 0.52: 0.10 RRT 1.61: 0.06 RRT 1.61 : 0.08 formulation 2 RRT 3-85. 0.17 RRT 3.85. 0.07
(C12 ester)
Soft gelatin RRT RRT 0.52: 0.72 RRT 0.52: 0.99 RRT 0.52: 1.32 capsule 0.52: 0.10 RRT 1.61: 0.08 RRT 1.61 : 0.13 formulation 3 RRT 2 59: 0 06
(C8 Ester)
Soft gelatin RRT RRT 0.52: 0.76 RRT 0.52: 1.10 RRT 0.52: 1.96 capsule 0.52: 0.12 RRT 1.61: 0.08 RRT 1.61 : 0.12 formulation 4 RRT 2 59: 0 06
(C8 Ester)
Conclusion:
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.
Stability Testing of Soft Gelatin Capsules
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.
Further, stability of the photosensitive elinzanetant was tested with capsules having a capsule shell without titanium dioxide (TiC ) as an opacifier.
Soft gelatin capsule with 60 mg elinzanetant based on soft gelatin capsule formulation 1 (Soft Gelatin Capsule 1)
Components Quantity per concentration% (w/w) capsule [mg] with respect to filling/formulation
Active pharmaceutical ingredient
Elinzanetant 60.00 7.00
Excipients capsule fill
DL-rac-a-Tocopherol 7.97 0.93
Caprylocaproylmacrogol-8 79.70 9.30 glycerides
Propylene glycol 310.83 36.27 monocaprylate
Glycerol monooleate 318.80 37.20
Polysorbate 80 79.70 9.30
Weight capsule fill 857.00 100.00
Capsule shell (dried) 432.764 w/o TiO2*
Weight capsule 1289.764 Soft gelatin capsule with 60 mg elinzanetant based on soft gelatin capsule formulation 3 (Soft Gelatin Capsule 3)
Component Quantity Concentration % (w/w) per with respect to capsule filling/formulation
[mg]
Active pharmaceutical ingredient elinzanetant 60.00 7.00
Excipients dl-rac-a-Tocopherol 7.97 0.93
Caprylocaproylmacrogol-8 glycerides 398.50 46.50
Propylene glycol mono-caprylate 160.17 18.69
Glycerol monooleate 150.66 17.58
Polysorbate 80 79.70 9.30
Weight formulation 857.00 100.00
Capsule shell (dried) w/o TiO2* 432.764
Total weight capsule 1289.764
*The qualitative and quantitative capsule shell composition w/o TiO2 is described below. Qualitative and quantitative capsule shell composition w/o TiCh
Component Amount in capsule concentration%
[mg] per capsule (w/w) with respect to shell
Ferric oxide red 0.121 0.03
Ferric oxide yellow 1.818 0.42
Gelatin 254.496 58.81
Lecithin trace trace
Sorbitol special - 176.329 40.74 glycerin
Triglycerides, trace trace medium chain
Water q.s.
Weight capsule 432.764 100.00 shell
60 mg elinzanetant soft gelatin capsule Comparative Example A
Component Quantity per Concentration% capsule (w/w)
[mg]
Active pharmaceutical ingredient
Elinzanetant 60.00 5.00
Excipients dl-rac-a-Tocopherol 11.40 0.95
Caprylocaproylmacrogol-8 glycerides 114.00 9.50
Glyceryl mono-caprylocaprate 444.60 37.05
Glycerol monooleate 456.00 38.00
Polysorbate 80 114.00 9.50
Weight formulation 1200.00 100.00
Capsule shell (dried) with TiO2** 640.129
Total weight capsule 1840.129
**The qualitative and quantitative shell composition with TiO2 is described below. Qualitative and quantitative capsule shell composition with TiO2
Component Amount in capsule Concentration %
[mg] per capsule (w/w) with respect to shell
Ferric oxide red 2.500 0.39
Ferric oxide yellow 0.179 0.03
Titanium dioxide 2.678 0.42
Gelatin 374.971 58.58
Lecithin trace trace
Sorbitol special - 259.801 40.59 glycerin
Triglycerides, trace trace medium chain
Water q.s.
Total weight 640.129 100.00 capsule shell
Reversed phase ultra-high performance liquid chromatography (UHPLC)
HPLC analysis of in connection with the soft gelatin capsules were performed using the following method:
Long term stability test
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.
For determination of degradation products, reference solutions containing potential degradation products and other identified impurities are injected to assure peak assignment, resolution, and detection sensitivity (as part of the system suitability test). Results
Elinzanetant-Cs- and -Cio-esters were detected in the amounts as given in the tables below.
0% relative humidity
Summary
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.
Photostability
Both investigated size 12 soft gelatin capsules with soft gelatin capsule formulation 1 and soft gelatin capsule formulation 3 were produced with capsule shell compositions with or without titanium dioxide as disclosed herein, supra.
Photostability of size 12 soft gelatin capsules with soft gelatin capsule formulation 1 and soft gelatin capsule formulation 3, respectively, was tested UHPLC as disclosed above.
Results
No significant changes were observed after light stress to the appearance and the assay of the softgels. No changes occurred to the degradation products of the investigated softgels due to light stress..
Summary
Four soft gelatin capsule formulations comprising Capryol 90 and/or Lauroglycol 90 were investigated for their stability, compatibility with typical gelatin shell components, and for their suitability in production of size-reduced soft gelatin capsules.
Two significantly size-reduced soft gelatin capsules containing 7% (w/w) of Elinzanetant were manufactured. Increased stability and significantly reduced ester formation kinetics were observed over six months storage in HDPE bottles at 25 °C I 60% RH and 40°C I 75%RH. Both formulations were shown to be photostable. GMP soft gelatin capsule batches containing these formulations were successfully manufactured for use in clinical relative bioavailability study in humans.
CLINICAL STUDIES
Randomized cross-over relative oral bioavailability study between soft gel capsules of Comparative Example A and Soft Gelatin Capsule 3
Study Design and Method:
A single dose, open-label, randomized, crossover study was conducted in healthy male participants to investigate the relative bioavailability of elinzanetant using soft gelatin capsule according to Comparative Example A, supra, (Reference) in comparison to Soft Gelatin Capsules 3, supra.
Sixteen (16) participants received a single dose of two capsules of either Reference or Soft Gelatin Capsules 3 on Day 1 . After a washout phase of 7 days in which frequent blood samples were collected for analyses of concentration of elinzanetant in plasma, all 16 participants received a second single dose of two capsules of the respective other type followed by a washout phase of 7 days during that frequent blood samples for pharmacokinetic analyses (PK) of elinzanetant were collected. Maximum concentration (Cmax) and total systemic exposure (AUC) were calculated for Reference and for Soft Gelatin Capsules 3 to determine relative oral bioavailability.
Results:
The geometric mean and standard deviation (SD) concentration-time profiles of elinzanetant for Reference and Soft Gelatin Capsules 3 are shown in Figure 1 . (N=16).
The geometric mean plasma concentrations and coefficient of variation (CV%) of elinzanetant for Cmax and AUC after single dose administration of Reference and Soft Gelatin Capsules 3 are presented in the following table:
Conclusions:
After administration of Soft Gelatin Capsules 3, mean AUC of elinzanetant was 6241 pg*h/L and mean Cmax was 1457 pg/L and after administration of Reference mean AUC was 5687 pg*h/L and mean Cmax was 1334 pg/L showing surprisingly higher oral bioavailability of Soft Gelatin Capsules 3 compared to Reference.
Fixed-sequence cross-over relative oral bioavailability study between soft gel capsules of Comparative Example A and Soft Gelatin Capsule 1
Study Design and Method:
A single dose, open-label, fixed-sequence, crossover study was conducted in healthy male participants to investigate the relative bioavailability of elinzanetant using soft gel capsules according to Comparative Example A (Reference), supra, in comparison to Soft Gelatin Capsule 1 , supra. Sixteen (16) participants received a single dose of two capsules of Reference on Day 1 . After a washout phase of 7 days in which frequent blood samples were collected for analyses of concentration of elinzanetant in plasma, all 16 participants received a second single dose of two capsules of Soft Gelatin Capsule 1 followed by a washout phase of 7 days during that frequent blood samples for pharmacokinetic analyses (PK) of elinzanetant were collected. Maximum concentration (Cmax) and total systemic exposure (AUC) were calculated for Reference and Soft Gelatin Capsule 1 to determine relative oral bioavailability.
Results:
The geometric mean and standard deviation (SD) concentration-time profiles of elinzanetant for Reference and Soft Gelatin Capsule 1 are shown in Figure 2. (N=16)
The geometric mean plasma concentrations + coefficient of variation (CV%) of elinzanetant for Cmax and AUC after single dose administration of Reference and Soft Gelatin Capsule 1 are presented in the following table:
Conclusions:
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.
In particular embodiments, the present disclosure relates to the following items.
Items
1 . A pharmaceutical formulation, comprising
(a) elinzanetant; and
(b) 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.
2. The pharmaceutical formulation of item 1 , wherein the solubilizer is propylene glycol monocaprylate.
3. The pharmaceutical formulation 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.
4. The pharmaceutical formulation of any one of items 1 to 3, wherein the concentration of elinzanetant in the pharmaceutical formulation ranges from 3% w/w to 10% w/w; preferably from 5% w/w to 7% w/w; more preferably the concentration of elinzanetant in the pharmaceutical formulation is about 7% w/w.
5. The pharmaceutical formulation of any one of items 1 to 4, further comprising an antioxidant.
6. The pharmaceutical formulation of any one of items 1 to 5, further comprising an emulsifier.
7. The pharmaceutical formulation of any one of items 1 to 8, comprising one or more further therapeutic agents. 8. The pharmaceutical formulation of any one of items 1 to 9, further comprising at least one emulsifier.
9. The pharmaceutical formulation of 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.
10. The pharmaceutical formulation of any one of items 1 to11 , wherein the pharmaceutical formulation comprises:
(a) elinzanetant at a concentration of from 5% w/w to 10% w/w
(b) 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
(c) Polysorbate 80 at a concentration of from 5% w/w to 15% w/w.
11. The pharmaceutical formulation according to item 10, 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 caprylocaproylmacrogol-8 glycerides is about 46.50% w/w, the concentration of the glycerol monooleate is about 17.58% w/w, and the concentration of Polysorbate 80 is about 9.3% w/w.
12. The pharmaceutical formulation according to item 10, 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 caprylocaproylmacrogol-8 glycerides is about 9.30% w/w, the concentration of the glycerol monooleate is about 37.20% w/w, and the concentration of polysorbate 80 is about 9.3% w/w. The pharmaceutical formulation according to any one of items 1 to 12, wherein the pharmaceutical formulation comprises an antioxidant. The pharmaceutical formulation according to item 13, wherein the antioxidant is selected from dl-rac-alpha tocopherol, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) and mixtures thereof. The pharmaceutical formulation according to item 13 or 14, wherein the antioxidant is dl-rac-alpha tocopherol present at a concentration ranging from 0.05% w/w to 1 .5% w/w. The pharmaceutical formulation of any one of items 1 to 15, comprising elinzanetant, propylene glycol monocaprylate (e.g. Capryol 90), caprylocaproyl macrogol-8 glycerides (e.g. Labrasol ALF), glycerol monooleate, dl-rac-alpha tocopherol, and Polysorbate 80. The pharmaceutical formulation of any one of items 1 to 16, comprising:
(a) elinzanetant from about 1 % w/w to about 10% w/w or from 5% w/w to 10% w/w;
(b1 ) propylene glycol monocaprylate (e.g. Capryol 90) present at a concentration ranging from 10% w/w to 40% w/w;
(b2) caprylocaproyl macrogol-8 glycerides (e.g. Labrasol ALF) present at a concentration ranging from 5% w/w to 50% w/w;
(b3) glycerol monooleate (e.g. Peceol) present at a concentration ranging from about 10% w/w to 40% w/w;
(c) polysorbate 80 (Tween 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 pharmaceutical formulation of item 17, comprising:
(a) elinzanetant at a concentration of about 7% w/w;
(b1 ) propylene glycol monocaprylate (e.g. Capryol 90) present at a concentration of about 36.27% w/w; (b2) caprylocaproyl macrogol-8 glycerides (e.g. Labrasol ALF) present at a concentration of about 9.3% w/w;
(b3) glycerol monooleate (e.g. Peceol) present at a concentration of about 37.2% w/w; and
(c) Polysorbate 80 (Tween 80) present at a concentration about 9.3% w/w;
(d) dl-rac-alpha tocopherol present at a concentration of about 0.93% w/v. The pharmaceutical formulation of any one of items 17, comprising:
(a) elinzanetant at a concentration of about 7% w/w;
(b1 ) propylene glycol monocaprylate (e.g. Capryol 90) present at a concentration of about 18.69% w/w;
(b2) caprylocaproyl macrogol-8 glycerides (e.g. Labrasol ALF) present at a concentration of about 46.5% w/w;
(b3) Glycerol monooleate (e.g. Peceol) present at a concentration of about 17.58% w/w; and
(c) Polysorbate 80 (Tween 80) present at a concentration about 9.3% w/w;
(d) dl-rac-alpha tocopherol present at a concentration of about 0.93% w/v. The pharmaceutical formulation according to any one of the items 1 to 19, wherein the pharmaceutical formulation is for oral administration. 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 soft gelatin capsule according to item 21 or 22, wherein the capsule shell comprises gelatin, sorbitol special - glycerin, and at least one pigment, preferably ferric oxide red and/or ferric oxide orange and/or ferric oxide black, and less than 0.4 % w/w TiO2, preferably the capsule is substantially free of TiO2. The soft gelatin capsule of item 23, wherein the capsule shell comprises, ferric oxide red, ferric oxide yellow, gelatin, and sorbitol special - glycerin. The pharmaceutical formulation of any one of items 1 to 20, or the soft gelatin capsule according to any one of items 21 to 24 for use in the treatment or prevention of a sex hormone dependent disease or disorder. The pharmaceutical formulation or the soft gelatin capsule for use according to item 25, wherein 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 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. The pharmaceutical formulation or the soft gelatin capsule for use according to item 26 or 27, wherein the sex-hormone dependent disease is vasomotor symptoms. The pharmaceutical formulation or the soft gelatin capsule for use according to anyone of items 25 to 28, wherein elinzanetant is administered in a daily dose of 40 mg to 160 mg, preferably 120 mg. A method for preparing the pharmaceutical formulations according to items 1 to 20, comprising mixing elinzanetant and one or more solubilizers, wherein one solubilizer is propylene glycol monocaprylate, with at least one or more excipients. 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. 32. A method according to item 30 or 31 , wherein elinzanetant is added in its anhydrous crystalline Form 1 .

Claims

Claims
1 . A pharmaceutical formulation comprising
(a) elinzanetant; and
(b) 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.
2. The pharmaceutical formulation of claim 1 , wherein the solubilizer is propylene glycol monocaprylate.
3. The pharmaceutical formulation of claim 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.
4. The pharmaceutical formulation of any one of claims 1 to 3, wherein the concentration of elinzanetant in the pharmaceutical formulation ranges from 3% w/w to 10% w/w; preferably from 5% w/w to 7% w/w; more preferably the concentration of elinzanetant in the pharmaceutical formulation is about 7% w/w.
5. The pharmaceutical formulation of any one of claims 1 to 4, further comprising an emulsifier.
6. The pharmaceutical formulation according to claim 5, wherein the emulsifier is a polyoxyethylene sorbitan fatty acid ester.
7. The pharmaceutical formulation of any one of claims 1 to 6, wherein the pharmaceutical formulation comprises:
(a) elinzanetant at a concentration of from 5% w/w to 10% w/w
(b) a mixture of solubilizers comprising propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, and glycerol monooleate (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 ranges from 10% w/w to 45%w/w; and
(c) Polysorbate 80 at a concentration of from 5% w/w to 15% w/w.
8. The pharmaceutical formulation according to any one of claims 1 to 7, wherein the pharmaceutical formulation comprises an antioxidant.
9. The pharmaceutical formulation according to claim 8, wherein the antioxidant is selected from dl-rac-alpha tocopherol, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) and mixtures thereof.
10. The pharmaceutical formulation of any one of claims 1 to 9, comprising elinzanetant, propylene glycol monocaprylate (Capryol 90), caprylocaproyl macrogol-8 glycerides (Labrasol ALF), glycerol monooleate, dl-rac-alpha tocopherol, and Polysorbate 80.
11 . The pharmaceutical formulation of any one of claims 1 to 10, comprising:
(a) elinzanetant from about 1 % w/w to about 10% w/w or from 5% w/w to 10% w/w;
(b1 ) propylene glycol monocaprylate (Capryol 90) present at a concentration ranging from 10% w/w to 40% w/w;
(b2) caprylocaproyl macrogol-8 glycerides (Labrasol ALF) present at a concentration ranging from 5% w/w to 50% w/w;
(b3) glycerol monooleate (Peceol) present at a concentration ranging from about 10% w/w to 40% w/w;
(c) polysorbate 80 (Tween 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.
12. The pharmaceutical formulation according to any one of the claims 1 to 11 , wherein the pharmaceutical formulation is for oral administration.
13. A soft gelatin capsule comprising a pharmaceutical formulation according to any one of claims 1 to 12, and a soft gelatin capsule shell.
14. The soft gelatin capsule according to claim 13, wherein the amount of elinzanetant per soft gelatin capsule ranges from 10 mg to 160 mg.
15. The pharmaceutical formulation of any one of claims 1 to 12, or the soft gelatin capsule according to claim 13 or 14 for use in the treatment or prevention of a sex hormone dependent disease or disorder.
16. The pharmaceutical formulation or the soft gelatin capsule for use according to claim 15, wherein the sex hormone-dependent disease or disorder, is a disease or disorder that is associated with menopause and/or adjuvant endocrine therapy.
17. The pharmaceutical formulation or the soft gelatin capsule for use according to claim 15 or 16, wherein the sex-hormone dependent disease is vasomotor symptoms.
18. The pharmaceutical formulation or the soft gelatin capsule for use according to anyone of claims 15 to 17, wherein elinzanetant is administered in a daily dose of 40 mg to 160 mg.
19. A method for preparing the pharmaceutical formulations according to claims 1 to 12, comprising mixing elinzanetant and one or more solubilizers, wherein one solubilizer is propylene glycol monocaprylate, with at least one or more excipients.
20. A method for producing a soft gelatin capsule according to claim 13 or 14 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.
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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 *
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