WO2024073072A1 - Formulations pharmaceutiques topiques pour bromodomaine préférentiel de bd2 et inhibiteur terminal supplémentaire - Google Patents

Formulations pharmaceutiques topiques pour bromodomaine préférentiel de bd2 et inhibiteur terminal supplémentaire Download PDF

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WO2024073072A1
WO2024073072A1 PCT/US2023/034163 US2023034163W WO2024073072A1 WO 2024073072 A1 WO2024073072 A1 WO 2024073072A1 US 2023034163 W US2023034163 W US 2023034163W WO 2024073072 A1 WO2024073072 A1 WO 2024073072A1
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formulation
ointment
cream
cream formulation
aqueous gel
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PCT/US2023/034163
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English (en)
Inventor
Jason TAO
Jason Carbol
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Bp Asset Iii, Inc.
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Publication of WO2024073072A1 publication Critical patent/WO2024073072A1/fr

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

Definitions

  • Psoriasis is a chronic inflammatory disease mediated by aberrant immune responses and driven by chronic cytokine stimulation. Psoriasis is a skin condition having 4 main forms: plaque type, generalized pustular psoriasis, guttate and erythroderma.
  • TCS topical corticosteroids
  • TCS topical corticosteroids
  • the following compound referred to herein as the “Compound” (see U.S. Patent No.9,637,456) is being developed as a potential topical treatment for psoriasis:
  • the Compound is a potent BD2-preferential bromodomain and extra terminal (BET) inhibitor that targets multiple pathways critical to psoriasis pathogenesis, including IL-17 and IL-23.
  • BET bromodomain and extra terminal
  • the Compound has been tested topically on humans in a 2% w/w cream formulation 1 ME146188668v.1 137589-00120 (hereinafter the “Original Formulation” or Original Cream Formulation) for safety and efficacy.
  • the cream formulation contains polyethylene glycol 400 (“PEG 400”) and propylene glycol.
  • an ointment formulation of the Compound is disclosed herein.
  • One embodiment of the invention is an ointment comprising: a) the Compound, which is 1-5 % w/w of the ointment; b) an emollient, which is at least 50% w/w of the ointment; c) one or more dissolution solvents; and d) one or more surfactants and/or emulsion stabilizers. Suitable emollients, dissolution solvents and surfactants and/or emulsion stabilizer are provided below in the Detailed Description.
  • the one or more dissolution solvents are propylene glycol and dimethyl sulfoxide and in another aspect the one or more dissolution solvents (such as propylene glycol and dimethyl sulfoxide) are 4-30% w/w of the ointment.
  • the emollient is petrolatum and in another aspect the emollient (such as petrolatum) is 50-90% w/w/ of the ointment.
  • the one or more surfactants and/or stabilizers are glyceryl monostearate, one or more mono- and di- glycerides, PEG2 stearate or sorbitan monostearate.
  • the one or more surfactants and/or stabilizers are 5-20% w/w of the ointment.
  • the one or more dissolution solvents are 10-20% w/w of the ointment
  • the emollient is 70-80% w/w of ointment
  • the one or more surfactants and/or stabilizers are 5- 2 ME146188668v.1 137589-00120 20% of the ointment.
  • the emollient is 70-80% w/w of the ointment
  • the one or more dissolution solvents are is 14-17% w/w of the ointment
  • the one or more surfactants and/or emulsion stabilizers are 5-12% w/w of the ointment.
  • Specific examples of ointment formulations of the invention are provided in Example 4.
  • Another embodiment of the invention is an anhydrous gel formulation comprising: a) the Compound, which is 10-30% w/w of the formulation; b) one or more dissolution solvents; c) a non-aqueous solvent miscible in the dissolution solvent; and d) a gelling agent.
  • the one or more dissolution solvents are mixture of dimethyl sulfoxide, diethylene glycol monomethyl ether, and dimethyl isosorbide.
  • the one or more dissolution solvents e.g., a mixture of dimethyl sulfoxide, diethylene glycol monomethyl ether, and dimethyl isosorbide
  • the non-aqueous solvent is glycerin.
  • the non-aqueous solvent is 10-50% w/w of the anhydrous gel formulation.
  • the gelling agent is hydroxypropyl cellulose.
  • the gelling agent e.g., hydroxypropyl cellulose
  • the one or more dissolution solvents are 50-70% w/w of the formulation
  • the non-aqueous solvent is 10-20% w/w of the solvent
  • the gelling agent is 0.5-3% w/w of. Specific examples of anhydrous gel formulations of the invention are provided in Example 6.
  • Another embodiment of the invention is an aqueous gel formulation, comprising: a) the Compound, which is 2-10% w/w of the aqueous gel formulation; b) one or more dissolution solvents; c) a non-aqueous solvent miscible in the one or more dissolution solvents; d) water; and e) a gelling agent Suitable dissolution solvents, non-aqueous solvents and gelling agents are provided in the Detailed Description.
  • the one or more dissolution solvents are a mixture of dimethyl sulfoxide, benzyl alcohol or dimethyl isosorbide.
  • the one or more dissolution solvents are 10-60% w/w of the aqueous gel formulation.
  • the non- 3 ME146188668v.1 137589-00120 aqueous solvent miscible in the one or more dissolution solvents is glycerin.
  • the non-aqueous solvent miscible in the one or more dissolution solvents is 10-50% w/w of the aqueous gel formulation.
  • the gelling agent is hydroxyethyl cellulose, a mixture comprising polyethoxylated sorbitan monooleate and an acrylamide/acryloyldimethyl taurate copolymer dispersed in a C14-18 hydrocarbon such as isohexadecane (e.g., SEPINEO P600TM) or a crosslinked polyacrylic acid such as a carbopol (e.g., carbopol 980).
  • the gelling agent e.g., one of the aforementioned gelling agents
  • the water is 2-50% w/w of the aqueous gel formulation.
  • the dissolution solvent is 40-50% w/w of the aqueous gel formulation
  • the non-aqueous solvent is 10-20% w/w of the aqueous gel formulation
  • water is 25-35% w/w of the aqueous gel formulation.
  • Specific examples of aqueous gel formulations of the invention are provided in Example 5.
  • cream formulation comprising: a) the Compound, which is 25-35% w/w of the cream formulation; b) one or more dissolution solvents; c) one or more surfactants and/or emulsion stabilizers; d) an emollient; e) a gelling agent; and f) water, which is at least 15% w/w of the cream formulation, e.g., 20-40% w/w of the cream formulation.
  • Suitable dissolution solvents, surfactants and/or emulsion stabilizers, emollients and gelling agents are provided in the Detailed Description.
  • the one or more dissolution solvents are a mixture of dimethyl isosorbide, diethylene glycol monomethyl ether and dimethyl sulfoxide.
  • the one or more dissolution solvents e.g., a mixture of dimethyl isosorbide, diethylene glycol monomethyl ether and dimethyl sulfoxide
  • the emollient is petrolatum, white soft paraffin, lanolin, white wax, mineral oil, microcrystalline wax, petroleum jelly, coco butter or shea butter.
  • the emollient is petrolatum.
  • the emollient e.g., petrolatum, white soft paraffin, lanolin, white wax, mineral oil, microcrystalline wax, petroleum jelly, coco butter or shea butter
  • the gelling agent is a mixture comprising polyethoxylated sorbitan monooleate and an acrylamide/acryloyldimethyl taurate copolymer dispersed in a C 14-18 hydrocarbon such as isohexadecane (e.g., SEPINEO P600TM), xanthan 4 ME146188668v.1 137589-00120 gum or a crosslinked copolymer of acrylic acid and a C10-C30 alkyl acrylate (e.g., PEMULEN TM TR-1), xanthan gum.
  • a C 14-18 hydrocarbon such as isohexadecane (e.g., SEPINEO P600TM), xanthan 4 ME146188668v.1 137589-00120 gum or a crosslinked copolymer of
  • the gelling agent e.g., one of the aforementioned gelling agents
  • the one or more surfactants and/or emulsion stabilizers is glyceryl monostearate, one or more mono- and di- glycerides, PEG2 stearate or sorbitan monostearate.
  • the one or more surfactants and/or emulsion stabilizers is a mixture of a C 10 -C 20 alcohol or a mixture thereof and a polyethylene glycol ether of a C 10 -C 20 alcohol or a mixture thereof (e.g., polyethylene glycol ethers of cetyl alcohol or polyethylene glycol ethers of oleyl alcohol).
  • the one or more surfactants and/or emulsion stabilizers e.g., one of the aforementioned surfactants and/or emulsion stabilizers
  • the one or more dissolution solvents are a mixture of diethylene glycol monoethyl ether, dimethyl isosorbide and dimethyl sulfoxide; the emollient is white petrolatum; and the one or more surfactants and/or emulsion stabilizers is a C 10 -C 20 alcohol or a mixture of C10-C20 alcohols and one or more polyethylene glycol ethers of a C10- C20 alcohol, wherein the polyethylene glycol is a 1-20mer.
  • the one or more dissolution solvents are 35-45% w/w of the cream formulation; the emollient is 5-20% w/w of the cream formulation; the one or more surfactants and/or emulsion stabilizers are 50-10% w/w of the cream formulation and water is 20-40% w/w of the cream formulation.
  • cream formulations of the invention are provided in Example 3.
  • Yet another embodiment of the invention is a method of treating psoriasis in a subject. The method comprises applying an effective amount of a formulation disclosed herein to a portion of skin on the subject that is showing the symptoms of psoriasis.
  • Figure 1 depicts a Franz cell used in in vitro permeation testing (IVPT).
  • Figure 2 is a bar graph showing the amount of the Compound in ug/cm 2 that permeated the skin over time into the receptor fluid over time in the IVPT study.
  • Figure 3 is a bar graph showing the amount of the Compound in ug/cm 2 in the different skin layers 22 hours after dosing from the IVPT study.
  • Figure 4 is a bar graph showing the percentage delivery of the Compound potency that permeated through the skin and into the receptor fluid over time, and the percentage of the Compound potency in the different skin layers 22 hours after dosing.
  • Figure 5 is a graph of the Compound concentration in ng/mL over time in hours determined ex vivo by open flow microperfusion study in pig skin.
  • Figure 6 is a bar graph of the Compound concentration in ng/mL determined in an ex vivo biopsy by LCMS in the lower dermis of pig skin.
  • Figure 7 is a graph of the Compound concentration in ng/mL over time in hours determined ex vivo by open flow microperfusion study in human skin.
  • Figure 8 is a bar graph of the Compound concentration in ng/mL determined in an ex vivo biopsy by LCMS in the lower dermis of human skin.
  • Figure 9 is a bar graph of the Compound concentration in ng/mL determined in an ex vivo biopsy by MALDI in the lower dermis of human skin.
  • DETAILED DESCRIPTION OF THE INVENTION Disclosed herein are formulations of the Compound suitable for topical application to the skin of a subject with psoriasis.
  • An effective amount of a disclosed formulation is applied topically to portions of the skin (including the scalp) that exhibit the signs and/or symptoms of psoriasis, including rashes or patches of red, inflamed skin, often covered with loose, silver-colored scales. Patches of skin afflicted with psoriasis are also often itchy and/or painful that can crack or bleed.
  • Psoriasis can also be characterized by discoloration and pitting with fingernails and toenails.
  • An “effective amount” refers to a quantity that alleviates the symptoms of psoriasis when applied to affected areas of the skin.
  • the disclosed formulations are applied in an amount sufficient to cover the affected area of skin.
  • a first embodiment of the invention is the ointment formulation of the Compound, which comprises: a) the Compound, which is 1-5 % w/w of the ointment; b) white petrolatum, which is at least 65% w/w, e.g., 70-80% w/w of the ointment; c) propylene glycol; d) one or more mono and/or diglycerides; and e) dimethyl sulfoxide.
  • the one or more mono and/or diglycerides is a stearate ester of glycerol.
  • the stearate ester of glycerol is GMS Pure.
  • the ointment comprises propylene glycol, which is 7-13% w/w of the ointment; the mixture of one or more mono and diglycerides, which is 5-10% w/w of ointment; and dimethyl sulfoxide, which is 3-7% w/w of the ointment; and the other ingredients are as described in the first embodiment.
  • propylene glycol is 9-11% w/w of the ointment; the mixture of one or more mono and diglycerides is 6-8% w/w of the 6 ME146188668v.1 137589-00120 ointment; and dimethyl sulfoxide is 4-6% w/w of the ointment; and the other ingredients are as described in the first embodiment.
  • propylene glycol is 10% or 11% w/w of the ointment; the mixture of mono and diglycerides is 7% w/w of the ointment; and dimethyl sulfoxide is 5% w/w of the ointment; and the other ingredients are as described in the first embodiment or first aspect.
  • the one or more mono and/or diglycerides is a stearate ester of glycerol.
  • the stearate ester of glycerol is GMS Pure.
  • the ointment is as described in the first embodiment or the first or second aspect, and the ointment additionally comprises sorbitan monostearate.
  • the ointment additionally comprises sorbitan monostearate, which is 1-8% w/w of the ointment.
  • sorbitan monostearate is 2-4% w/w of the ointment.
  • sorbitan monostearate is 3% w/w of the ointment.
  • the ointment is as described in the first embodiment or the first or second aspect, and the ointment additionally comprises a polyethylene glycol ether of stearyl alcohol.
  • the polyethylene glycol ether of stearyl alcohol is 2-(2- octadecoxyethoxy)ethanol (steareth-2).
  • the ointment additionally comprises steareth-2, which is 1-8% w/w of the ointment.
  • steareth-2 is 3-5% w/w of the ointment.
  • steareth-2 is 4% w/w of the ointment.
  • the ointment is as described in the first embodiment and the ointment comprises a mixture of a stearate ester of glycerin and a salt of stearic acid, for example, the stearic acid salt is potassium stearate.
  • the mixture is GMS-SE.
  • GMS SE is the reaction product of glycerin and stearic acid combined with potassium stearate.
  • the mixture 5-10% w/w of ointment, or, alternatively, 7% w/w of the ointment.
  • the ointment comprises a mixture of a stearate ester of glycerin and a salt of stearic acid
  • the ointment in one example comprises propylene glycol, which is 7-13% w/w of the ointment; GMS-SE, which is 5-10% w/w of the ointment; and dimethyl sulfoxide, which is 3-7% w/w of the ointment.
  • the ointment comprises a mixture of a stearate ester of glycerin and a salt of stearic acid
  • the ointment comprises propylene glycol, which is 9-11% w/w of the ointment; GMS-SE, which is 6-8% w/w of the ointment; and dimethyl sulfoxide, which is 4- 6% w/w of the ointment.
  • the ointment comprises a mixture of a stearate ester of glycerin and a slat of stearic acid
  • the ointment comprises propylene glycol, which is 10% w/w of the ointment
  • GMS-SE which is 7 ME146188668v.1 137589-00120
  • the ointment is as described in the first embodiment or the first, second, third, fourth or fifth aspect
  • the Compound is 1-4% w/w of the ointment, alternatively, 1.5-2.5% w/w of the ointment and in another alternative 2.0% w/w of the ointment.
  • a second embodiment of the invention is an anhydrous gel formulation comprising: a) the Compound, which is 10-30% w/w of formulation; b) glycerin, which is 10-20% w/w of the formulation; c) diethylene glycol monomethyl ether; d) dimethyl isosorbide; e) dimethyl sulfoxide; and f) hydroxypropyl cellulose.
  • dimethyl sulfoxide is 10-40% w/w of the formulation; diethylene glycol monomethyl ether is 10-40% w/w of the formulation; dimethyl isosorbide is 7-20% w/w of the formulation; and hydroxypropyl cellulose is 0.5% to 5% w/w of the formulation; and the remainder of the ingredients are as described in the second embodiment.
  • dimethyl sulfoxide is 20-30% w/w of the formulation; diethylene glycol monomethyl ether is 20-30% w/w of the formulation; dimethyl isosorbide is 10-16% w/w of the formulation; and hydroxypropyl cellulose is 0.5 % to 3% w/w of the formulation; and the remainder of the ingredients are as described in the second embodiment.
  • dimethyl sulfoxide is 25% w/w of the formulation; diethylene glycol monomethyl ether is 25% w/w of the formulation; dimethyl isosorbide is 13% w/w of the formulation; glycerin is 16% w/w of the formulation; and hydroxypropyl cellulose is 1% w/w of the formulation; and the remainder of the ingredients are as described in the second embodiment.
  • the anhydrous gel formulation is as described in the second embodiment or seventh aspect, and the Compound is 17-23% w/w of the formulation. Alternatively, the Compound is 20% w/w of the formulation.
  • a third embodiment of the invention is an aqueous gel formulation, comprising: a) the Compound, which is 2-10% w/w of the aqueous gel formulation; b) glycerin, which is 15- 25% w/w of the aqueous gel formulation; c) water; d) dimethyl isosorbide; e) dimethyl sulfoxide; and f) benzyl alcohol.
  • water is 15-45% w/w of the aqueous gel formulation; dimethyl isosorbide is 8-20% w/w of the aqueous gel formulation; dimethyl sulfoxide is 15-45% w/w of the aqueous gel formulation; and benzyl alcohol is 0.5-4% w/w of the aqueous gel formulation; and the remainder of the ingredients are as described in the third embodiment.
  • water is 25-35% w/w of the aqueous gel formulation; dimethyl isosorbide is 12-18% w/w of the aqueous gel formulation; dimethyl sulfoxide is 25-35% w/w of the aqueous gel formulation; and benzyl alcohol is 0.5-2% w/w of the aqueous gel formulation; and the remainder of the ingredients are as described in the third embodiment.
  • water is 30% w/w of the aqueous gel formulation; dimethyl isosorbide is 15% w/w of the aqueous gel formulation; dimethyl sulfoxide is 30% w/w of the aqueous gel formulation; and benzyl alcohol 1% w/w of the aqueous gel formulation; and the remainder of the ingredients are as described in the third embodiment.
  • the aqueous gel formulation is as described in the third embodiment or ninth aspect and comprises a gelling agent which is a mixture polyethoxylated sorbitan monooleate and an acrylamide/acryloyldimethyl taurate copolymer dispersed in a C14-C18 hydrocarbon, wherein the gelling agent is 0.5-6% w/w of the aqueous gel formulation.
  • a gelling agent which is a mixture polyethoxylated sorbitan monooleate and an acrylamide/acryloyldimethyl taurate copolymer dispersed in a C14-C18 hydrocarbon, wherein the gelling agent is 0.5-6% w/w of the aqueous gel formulation.
  • the gelling agent is a mixture comprising polyethoxylated sorbitan monooleate and an acrylamide/acryloyldimethyl taurate copolymer dispersed in a C14-C18 hydrocarbon such as isohexadecane, wherein the gelling agent is 1-3% w/w of the gel formulation.
  • the gelling agent a mixture comprising polyethoxylated sorbitan monooleate and an acrylamide/acryloyldimethyl taurate copolymer dispersed in a C14-18 hydrocarbon such isohexadecane, which is 2% w/w of the aqueous gel formulation.
  • the aqueous gel formulation is as described in the third embodiment or ninth aspect, and comprises a gelling agent which is a mixture of polyethoxylated sorbitan monooleate and an acrylamide/acryloyldimethyl taurate copolymer dispersed in a C 14-18 hydrocarbon, wherein the gelling agent is 3-5% w/w of the aqueous gel formulation; or 4% w/w of the aqueous gel formulation.
  • the polyethoxylated sorbitan monooleate is polysorbate 80 and the C14-18 hydrocarbon is isohexadecane.
  • the mixture is SEPINEO P600 TM .
  • the aqueous gel formulation is as described in the third embodiment or ninth aspect, and comprises a gelling agent which is a crosslinked polyacrylic acid (e.g., carbopol 980), which is 0.25-2.5% w/w of the aqueous gel formulation, and aqueous base in an amount so that the pH of the formulation is between 5.0 and 6.0.
  • a gelling agent which is a crosslinked polyacrylic acid (e.g., carbopol 980), which is 0.25-2.5% w/w of the aqueous gel formulation, and aqueous base in an amount so that the pH of the formulation is between 5.0 and 6.0.
  • the gel aqueous formulation additionally comprises a crosslinked polyacrylic acid (e.g., carbopol 980), which is 0.5-1.25% w/w of the aqueous gel formulation and aqueous sodium hydroxide in an amount so that the pH of the formulation is between 5.25 and 5.75.
  • the aqueous gel formulation additionally comprises a crosslinked polyacrylic acid (e.g., carbopol 980), which is 0.75% w/w of the aqueous gel formulation and sodium hydroxide in an amount so that the pH of the formulation is between 5.5.
  • the aqueous gel formulation is as described in the third embodiment or ninth aspect, and additionally comprises hydroxyethyl cellulose (e.g., NATROSOLTM 250 HHX), which is 1-5% w/w of the aqueous gel formulation; hydroxyethyl cellulose (e.g., NATROSOLTM 250 HHX), which is 1.5-2.5% w/w of the aqueous gel formulation.
  • hydroxyethyl cellulose e.g., NATROSOLTM 250 HHX
  • NATROSOLTM 250 HHX is 2.0% w/w of the aqueous gel formulation.
  • the aqueous gel formulation is as described in the third embodiment or ninth, tenth, eleventh, twelfth or thirteenth aspect, and the Compound is 4-6% w/w of the aqueous gel formulation, alternatively 5% w/w.
  • a fourth embodiment of the invention is a cream formulation, comprising: a) w the Compound, which is 1-5% w/ cream formulation; b) diethylene glycol monoethyl ether; c) dimethyl isosorbide; d) white petrolatum; e) a C10-C20 alcohol or a mixture of C10-C20 alcohols; f) dimethyl sulfoxide; g) one or more polyethylene glycol ethers of a C 10 -C 20 alcohol, wherein the polyethylene glycol is a 1-20 mer; and h) water, which is at least 15% w/w of the cream formulation, e.g., 20-40% w/w of the cream formulation.
  • the cream formulation comprises: a) the Compound, which is 1- 5% w/w of the cream formulation; b) diethylene glycol monoethyl ether, which is 15-25% w/w of the cream formulation; c) dimethyl isosorbide, which is 10-20% w/w of the cream formulation; d) white petrolatum, which is 5-20% w/w of the cream formulation; e) the C 10 - C 20 alcohol or the mixture of C 10 -C 20 alcohols, which is 5-10% w/w of the cream formulation; f) dimethyl sulfoxide, which is 3-10% w/w of the cream formulation; g) the one or more polyethylene glycol ethers of a C10-C20 alcohol, which are 4-10% w/w of ⁇ the cream formulation; and the remainder of the ingredients are as described for the fourth embodiment.
  • the cream formulation comprises: a) the Compound, which is 1-3% w/w of the cream formulation; b) diethylene glycol monoethyl ether, which is 18-22% w/w of the cream formulation; c) dimethyl isosorbide, which is 14-16% w/w of the cream formulation; d) white 10 ME146188668v.1 137589-00120 petrolatum, which is 5-20% w/w of the cream formulation; e) the C10-C20 alcohol or the mixture of C10-C20 alcohols, which is 6-8% w/w of the cream formulation; f) dimethyl sulfoxide, which is 4-6% w/w of the cream formulation; g) the one or more polyethylene glycol ethers of a C10-C20 alcohol, which are 5-7% w/w of the cream formulation; and the remainder of the ingredients are as described for the fourth embodiment.
  • the cream comprises: a) the Compound, which is 2% w/w of the cream formulation; b) diethylene glycol monoethyl ether, which is 20.5% w/w of the cream formulation; c) dimethyl isosorbide, which is 15% w/w of the cream formulation; d) white petrolatum, which is 5-20% w/w of the cream formulation; e) the C10-C20 alcohol or the mixture of C 10 -C 20 alcohols, which is 7% w/w of the cream formulation; f) dimethyl sulfoxide, which is 5% w/w of the cream formulation; g) the one or more polyethylene glycols of a C10-C20 alcohol, which are 6% w/w of the cream formulation; and the remainder of the ingredients are as described for the fourth embodiment.
  • the C10-C20 alcohol or the mixture of C10-C20 alcohols in the fourth embodiment or fifteenth aspect are cetostearyl alcohol; and the one or more polyethylene glycol ethers is a polyethylene glycol ether of cetyl alcohol and a polyethylene glycol ether of oleyl alcohol.
  • the polyethylene glycol ether of cetyl alcohol and the polyethylene glycol ether of oleyl alcohol are, both 2 mers, such ceteth-20 and oleth- 2.
  • the cream formulation is as described in the fourth embodiment or fifteenth or sixteenth aspects and additionally comprises mineral oil, which is 2-10% w/w of the cream formulation.
  • the mineral oil is 5-7% w/w of the cream formulation. In yet another alternative, the mineral oil is 6% w/w of the cream formulation.
  • the cream formulation is as described in the fourth embodiment or fifteenth, sixteenth or seventeenth aspects and additionally comprises a mixture of mono and diglycerides, which is 1-4% w/w of the cream formulation.
  • the mixture of mono and diglycerides, (e.g., wherein the one or more mono and/or diglycerides is a stearate ester of glycerol, such as GMS Pure) is 2% w/w of the cream formulation.
  • the cream formulation is as described in the fourth embodiment or fifteenth, sixteenth, seventeenth or eighteenth aspects and additionally comprises white petrolatum, which is 6-10% w/w of the cream formulation; benzyl alcohol, which is 0.5-3% w/w of the cream formulation; and xanthan gum, which is .25-1.0% w/w of the cream 11 ME146188668v.1 137589-00120 formulation.
  • white petrolatum is 8% w/w
  • benzyl alcohol is 1.0% w/w
  • xanthan gum is 0.5% w/w of the cream formulation.
  • the cream formulation is as described in the fourth embodiment or fifteenth, sixteenth, seventeenth or eighteenth aspects and additionally comprises white petrolatum, which is 6-10% w/w of the cream formulation; xanthan gum, which is 0.25-1.0% w/w of the cream formulation; and one or more C 1 -C 4 alkyl parabens, which are 0.1-0.5% w/w of the cream formulation.
  • the one or more C 1 -C 4 alkyl parabens are methyl paraben and propyl paraben, e.g., 0.15-0.25% w/w methylparaben and 0.015-0.025% w/w propylparaben.
  • the cream formulation is as described in the fourth embodiment or fifteenth or sixteenth aspects and additionally comprises a mixture of mono and diglycerides, which is 1-4% w/w of the cream formulation; white petrolatum, which is 12-16% w/w of the cream formulation; benzyl alcohol, which is 0.5-3% w/w of the cream formulation; and xanthan gum, which is .25-1.0% w/w of the cream formulation.
  • the mixture of mono and diglycerides is 2% w/w, white petrolatum is 14% w/w, benzyl alcohol is 1.0% w/w, and xanthan gum is 0.5% w/w of the cream formulation.
  • the cream formulation is as described in the fourth embodiment or fifteenth, sixteenth, seventeenth or eighteenth aspects and additionally comprises white petrolatum, which is 6-10% w/w of the cream formulation; benzyl alcohol, which is 0.5-3% w/w of the cream formulation; and of crosslinked copolymer of acrylic acid and a C10-30 alkyl acrylate co-monomer, which is 0.25-1.5% w/w.
  • white petrolatum is 8% w/w of the cream formulation
  • benzyl alcohol is 1% w/w of the cream formulation
  • the crosslinked copolymer of acrylic acid and a C 10-30 alkyl acrylate co- monomer is 0.25-1.5% w/w.
  • the crosslinked copolymer of acrylic acid and the C10-30 alkyl acrylate is 0.75% w/w of the cream formulation.
  • the crosslinked copolymer of acrylic acid and the C 10-30 alkyl acrylate is PEMULEN TM TR-1.
  • the cream formulation is as described in the fourth embodiment or fifteenth, sixteenth, seventeenth or eighteenth aspects and additionally comprises white petrolatum, which is 6-10% w/w of the cream formulation; benzyl alcohol which is 0.5-3% w/w of the cream formulation; and acrylamide/sodium acryloyldimethyl taurate copolymer, which is 1-5% w/w of the cream formulation.
  • white petrolatum is 16-20% w/w
  • benzyl alcohol is 0.5-3% w/w
  • acrylamide/sodium 12 ME146188668v.1 137589-00120 acryloyldimethyl taurate copolymer is 1-5% w/w of the cream formulation.
  • the cream formulation is as described in the fourth embodiment or fifteenth, sixteenth, seventeenth or eighteenth aspects and additionally comprises comprising white petrolatum, which is 8% w/w of the cream formulation; benzyl alcohol, which 1.0% w/w; and acrylamide/sodium acryloyldimethyl taurate copolymer, which is 2% w/w of the cream formulation.
  • the cream formulation is as described in the fourth embodiment or fifteenth, sixteenth, seventeenth or eighteenth aspects and additionally comprises white petrolatum, which is 18.5% w/w of the cream formulation; benzyl alcohol, which is 1.0% w/w of the cream formulation; and acrylamide/sodium acryloyldimethyl taurate copolymer, which is 2% w/w of the cream formulation.
  • the cream formulation is as described in the fourth embodiment or fifteenth, sixteenth or seventeenth aspects and additionally comprises glycerol monostearate, which is 1-3% w/w of the cream formulation; petrolatum, which is 6-10% w/w of the cream formulation, benzyl alcohol, which is 0.5-3.0% w/w of the cream formulation; and acrylamide/sodium acryloyldimethyl taurate copolymer, which is 1-3% w/w.
  • glycerol monostearate is 2% w/w; petrolatum, which is 8% w/w of the cream formulation; benzyl alcohol is 1% w/w; and acrylamide/sodium acryloyldimethyl taurate copolymer is 2% w/w of the cream formulation.
  • the cream formulation the cream formulation comprises a mixture of a stearate ester of glycerin and a salt of stearic acid (e.g., 1-3% w/w or 2% w/w), such as a potassium salt of stearic acid, for example, GMS-SE.
  • the acrylamide/sodium acryloyldimethyl taurate copolymer described in the previous aspects is SEPINEO P600 TM .
  • the disclosed formulations comprise the Compound as a solvate, e.g., an ethanolate, such as an ethanolate represented by the following structural formula: 13 ME146188668v.1 137589-00120
  • w/w means weight/ weight, or the weight of a component of the formulation divided by the weight of the formulation.
  • Preservatives may be added to the disclosed formulations to prevent, for example, microbial contamination that can affect the stability of the formulation and/or cause infection in the patient.
  • preservatives suitable for use in the disclosed formulations include parabens (such as methyl, ethyl, propyl, p-hydroxybenzoate, butyl, isobutyl, and isopropyl paraben), potassium sorbate, sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol, bronidox, MDM hydantoin, iodopropynyl butylcarbamate, benzalconium chloride, cetrimide, and benzylalcohol.
  • parabens such as methyl, ethyl, propyl, p-hydroxybenzoate, butyl, isobutyl, and isopropyl paraben
  • potassium sorbate such as methyl, ethyl, propyl,
  • the formulations can additionally comprise an anti-oxidant.
  • anti-oxidants suitable for use in the present invention include ascorbic acid, ascorbyl linoleate, ascorbyl dipalmitate, ascorbyl palmitate, ascorbyl tocopherol maleate, butylated hydroxytoluene, butylated hydroxyanisole (BHA), calcium ascorbate, carotenoids, kojic acid and its pharmaceutically acceptable salts, propyl gallate, sodium thiosulfate, thioglycolic acid and its pharmaceutically acceptable salts (e.g., ammonium), tocopherol, tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth-18, or tocophereth-80.
  • BHA butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • calcium ascorbate carotenoids
  • kojic acid and its pharmaceutically acceptable salts propy
  • a dissolution solvent is a solvent in which the Compound is soluble and which is suitable for topical pharmaceutical use.
  • the dissolution comprises one solvent.
  • the dissolution solvent is a mixture of solvents.
  • dissolution solvents suitable for use in the disclosed formulations include ethanol, isopropyl alcohol, dimethyl isosorbide, oleic acid, oleyl alcohol, castor oil, diisopropyl adipate, laureth-4, oleth- 2, propylene carbonate benzyl alcohol, PEG 400, phenoxyethanol, propylene glycol, 14 ME146188668v.1 137589-00120 diethylene glycol monomethyl ether, TANSCUTOL®P, dimethyl sulfoxide and mixtures thereof.
  • An emollient is a substance that helps soothe, soften, and increase moisture levels, especially in the skin.
  • emollients suitable for use in the disclosed formulations include petrolatum, white soft paraffin, lanolin, white wax, mineral oil, microcrystalline wax, petroleum jelly, coco butter or shea butter.
  • a gelling agent is a substance that promotes or facilitates the formation of a gel when added to a liquid phase.
  • gelling agents suitable for use in the disclosed formulations include hydroxyethyl cellulose, fumed silica, a mixture comprising polyethoxylated sorbitan monooleate and an acrylamide/acryloyldimethyl taurate copolymer dispersed in a C14-18hydrocarbon such as isohexadecane (e.g., SEPINEO P600TM) or a crosslinked polyacrylic acid such as a carbopol (e.g., carbopol 980).
  • a non-aqueous solvent miscible in the one or more dissolution solvents is a solvent suitable for topical pharmaceutical use and miscible with a dissolution solvent.
  • non-aqueous solvents miscible in the dissolution solvent suitable for use in the disclosed formulations include glycerin, sorbitol, diethyl sebicate, butyl stearate, isopropyl myristate, isopropyl palmitate, miglyol 810 (caprylic/capric triglyceride), propylene glycol dicaprylate/dicaprate or glyceryl monooleate.
  • An emulsion stabilizer is a substance that prevents droplets within an emulsion from coming together, or coalescing.
  • a surfactant is a compound that lowers the surface tension (or interfacial tension) between two liquids, between a gas and a liquid, or between a liquid and a solid.
  • Surfactants may act as detergents, wetting agents, emulsifiers, foaming agents, or dispersants.
  • surfactants and/or emulsion stabilizers suitable for use in the disclosed formulations include an ethoxylated esterified fatty acid, an ethoxylated sugar esterified with a fatty acid, ethoxylated alcohol, mono or diglyceride (e.g., mono or di stearate ester of glycerol) a sugar esterified with fatty acid, including a sorbitan ester, a tween surfactant, glyceryl monostearate, ethoxylated castor oil, a sodium phosphate surfactant (such as sodium laurel sulfate, sodium laurel ether sulfate), an amine surfactants (such as cocamide DEA), C10-C20 alcohol or a mixture thereof (e.g., stearyl alcohol, cetyl alcohol or a mixture thereof) or a C 10 -C 20 fatty acid (e.g., steric acid).
  • IVPT In Vitro Permeation Test
  • the IVPT studies were carried out with human cadaver skin; and the receptor fluid was phosphate buffered saline at pH 7.4 with 2% hydroxypropyl-beta-cyclodextrin and 0.01% w/w NaN3 preservative.
  • the temperature of the receptor well was 32 ⁇ 0.5°C; and the temperature of the skin surface was maintained at 30 ⁇ 1.0°C.
  • the receptor well was sampled at 2, 4, 8 and 24 hours. Samples tested are shown in Table 1 below.
  • Figure 2 shows the amount of drug substance that permeated through the skin and into the receptor fluid over time.
  • the Cream 2% in Water Phase (Table 1, Formulation 1) and the 20% Anhydrous Gel (with DMSO) (Table 1, Formulation 4) demonstrate the highest amounts of the Compound in the receptor fluid 22 hours after dosing.
  • the 5% Aqueous Gel (Table 1, Formulation 3) demonstrates slightly higher amounts of the Compound in the receptor fluid 8 hours after dosing, then slightly lower amounts of the Compound in the receptor fluid 22 hours after dosing than the Cream 2% in Water Phase (Table 1, Formulation 1) and the 20% Anhydrous Gel (with DMSO) (Table 1, Formulation 4) platforms.
  • Figure 3 displays the amount of drug substance in the different skin layers 22 hours after dosing.
  • the 20% Anhydrous Gel (with DMSO) (Table 1, Formulation 4) demonstrates the highest amount of the Compound in the epidermis and among the highest with the 5% Aqueous Gel (Table 1, Formulation 3) in the dermis 22 hours after dosing.
  • the 5% Aqueous Gel (Table 1, Formulation 3), the 15% Anhydrous Gel (with PEG 400) (Table 1, Formulation 5) and the 2% Ointment (in Internal Phase) (Table 1, Formulation 6) demonstrate comparable amounts of the Compound in the epidermis 22 hours after dosing.
  • Figure 4 displays both the percentage of the drug substance potency that permeated through the skin and into the receptor fluid over time, and the percentage of the drug substance potency in the different skin layers 22 hours after dosing.
  • the Cream 2% in Water Phase (Table 1, Formulation 1) delivered the highest percentage of the Compound into the receptor fluid 22 hours after dosing.
  • the 2% Ointment (in Internal Phase) (Table 1, Formulation 6) delivered the highest percentage of the Compound in the epidermis 22 hours after dosing, followed by the Cream 2% in Water Phase (Table 1, Formulation 1), the Cream 1% Oil Phase (Table 1, Formulation 2), the Original Cream Formulation (Table 1, 17 M E146188668v.1 137589-00120 Formulation 8) and the 5% Aqueous Gel (Table 1, Formulation 3).
  • Table 1, Formulation 6 The above IVPT data was investigated to further identify lead formulations and potential next steps. The data was evaluated by skin layer, allowing comparison of formulations at each level of penetration. The skin used in the study was 300 ⁇ m thick. Below in Table 2 is the data for each formulation and the penetration through the stratum corneum and into the epidermis.
  • Table 2 – IVPT Epidermis Data Evaluation As seen in Table 2 above the penetration of the Compound into the epidermis of the selected formulations is relatively similar. When comparing the formulations to the Original Formulation, the relative improvement of penetration is up to three times more Compound in the epidermis for the best formulations and no improvement for other formulations. Penetration through the stratum corneum and through the epidermis and into the dermis was then evaluated for each formulation using the IVPT data and the results shown in Table 3 below. 18 ME146188668v.1 137589-00120 Table 3 – IVPT Dermis Data Evaluation As seen in Table 3 above, select formulations penetrate significantly better, and up to four to five times more than the Original Formulation into the dermis.
  • the 5% Aqueous Gel showed a five fold improvement
  • the 20% Anhydrous Gel showed a four fold improvement
  • the 2% Ointment in Internal Phase
  • the Cream 2% in Water Phase in Water Phase
  • the final depositing of the Compound into the receptor solution was evaluated for each formulation. This would be representative of the amount of the Compound penetrating through the stratum corneum, through the epidermis, and through the first 10% of the dermis and starting to enter the remaining 90% of the dermis. The results are shown in Table 4 below.
  • the five formulations were 1) the Original Cream Formulation (Table 1, Formulation 8); 2) Cream 2% in Water Phase (Table 1, Formulation 1); 3) 20% Anhydrous Gel (with DMSO) (Table 1, Formulation 4); 4) 5% Aqueous Gel (Table 1, Formulation 3); and 5) 2% Ointment (in Internal Phase) (Table 1, Formulation 6).
  • 20 ME146188668v.1 137589-00120 The results are shown in Figures 5-9. OFM and biopsy results showed all four formulations had better penetration into the dermis than the Original Cream Formulation in both human and pig skin (up to 8.8-fold better by MALDI and 72-fold better by OFM).
  • Example 3 Stable Modified Cream Formulation
  • the cream formula used in Examples 1 and 2 (Cream 2% in Water Phase (Table 1, Formulation 1) was found to have some observable syneresis following storage at 40°C. A study was undertaken identify a formulation with a more stable structure. This was performed by altering the preservative system, oil phase composition, viscosity modifying excipients, and total amount of water.
  • Example 4 Ointment Formulations With Improved Texture
  • the ointment formulations used in Examples 1 and 2 (Original Ointment Formulation in Table 6 below (Table 1, Formulation 6)) had a noticeable slick/glossy texture that is uncharacteristic of ointments.
  • the ointment formulations shown below in Table 6 were tested to identify an ointment formulation with improved texture. 22 M E146188668v.1 137589-00120 Table 6 –Tested Modified Ointment Formulations of the Compound All the ointments formulations that were produced resulted in visually similar smooth, thick, light yellow ointments.
  • Example 5 Alternate Aqueous Gel Formulations While the aqueous gel formulation used in Examples 1 and 2 (Original Aqueous Gel Formulation in Table 7 (Table 1, Formulation 3)) was stable when stored at 40° C and did not have any negative rheological properties, several alternate aqueous gel batches were made to determine how different types and concentrations of gelling agents could impact the gel. The aqueous gel formulations tested are shown below in Table 7. Table 7 – Alternate Aqueous Gel Formulations of the Compound 23 M E146188668v.1 137589-00120 All the alternate formulations produced similar thick, clear, yellow gels that were not pourable.
  • Example 6 Alternate Anhydrous Gel Formulations
  • the anhydrous gel formula used in Examples 1 and 2 (Original Anhydrous Gel Formulation in Table 8, (Table 1, Formulation 4)) was stable when stored at 40°C and did not have any negative rheological properties.

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Abstract

L'invention concerne des formulations topiques d'un composé représenté par la formule développée suivante : (I). Sont incluses une formulation d'onguent du composé, une formulation de gel anhydre du composé, une formulation de gel aqueux du composé et une formulation de crème du composé. Les formulations sont décrites plus en détail dans la description.
PCT/US2023/034163 2022-09-30 2023-09-29 Formulations pharmaceutiques topiques pour bromodomaine préférentiel de bd2 et inhibiteur terminal supplémentaire WO2024073072A1 (fr)

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Publication number Priority date Publication date Assignee Title
US9637456B2 (en) 2013-03-14 2017-05-02 Glaxosmithkline Intellectual Property (No. 2) Limited 2,3-disubstituted 1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9637456B2 (en) 2013-03-14 2017-05-02 Glaxosmithkline Intellectual Property (No. 2) Limited 2,3-disubstituted 1-acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors
US10034881B2 (en) * 2013-03-14 2018-07-31 Glaxosmithkline Intellectual Property (No. 2) Limited 2,3-disubstituted 1 -acyl-4-amino-1,2,3,4-tetrahydroquinoline derivatives and their use as bromodomain inhibitors

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Title
NADEEM AHMED ET AL: "Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation", PHARMACOLOGICAL RESEARCH, vol. 99, 1 September 2015 (2015-09-01), AMSTERDAM, NL, pages 248 - 257, XP093121725, ISSN: 1043-6618, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S1043661815001140/pdfft?md5=60c7be844ee660149e2bb331787852e8&pid=1-s2.0-S1043661815001140-main.pdf> DOI: 10.1016/j.phrs.2015.06.001 *

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