WO2019143971A2 - Formulations pour l'administration dermique de conjugués polymères de composés indolocarbazole à exposition réduite - Google Patents

Formulations pour l'administration dermique de conjugués polymères de composés indolocarbazole à exposition réduite Download PDF

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WO2019143971A2
WO2019143971A2 PCT/US2019/014241 US2019014241W WO2019143971A2 WO 2019143971 A2 WO2019143971 A2 WO 2019143971A2 US 2019014241 W US2019014241 W US 2019014241W WO 2019143971 A2 WO2019143971 A2 WO 2019143971A2
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cream formulation
sna
formulation
cream
formulations
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WO2019143971A3 (fr
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Valentina Mainero
Silvio Traversa
Majed KHEIR
Kirby WONG-MOON
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Sienna Biopharmaceuticals Inc
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Sienna Biopharmaceuticals Inc
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    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6903—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
    • 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

Definitions

  • Skin care formulations which include for example, primers, serums, lotions, ointments, gels, creams, foams and other products, are used on the skin for various purposes.
  • Formulations can contain one or more active agents, including in some embodiments, indolocarbazole compounds conjugated to polymer(s).
  • a cream formulation for dermal delivery of a polymer conjugate of an indolocarbazole compound with reduced exposure is disclosed in accordance with one embodiment.
  • the cream formulation includes or consists essentially of, for example a polymer conjugate of an indolocarbazole compound in a solvent system comprising an aqueous phase (containing the indolocarbazole), an oil phase and surfactants.
  • the polymer conjugate of an indolocarbazole compound is SNA-125.
  • the SNA-125 may be present at about 0.05% to about 25% (w/w) (e.g., 0.05-5%, 5-15%, 15-25%, and overlapping ranges therein).
  • the SNA-125 may be present at about 0.05% to about 10% (w/w) of the cream formulation.
  • the SNA- 125 may be present at about 2% (w/w) of the cream formulation.
  • Other reduced exposure compounds disclosed herein may be used with or instead of SNA- 125.
  • the aqueous phase of the cream formulation may include solvents, preservatives, solubilizing agents, etc.
  • the aqueous phase may include, for example, one or more of 2-(2-ethoxyethoxy)ethanol (tradename TRANSCUTOL P - penetration enhancer), high purity grade, low molecular weight polyethylene glycol 400 (tradename SR (Super Refmed)PEG 400 - commonly used as a partitioning agent because it is strongly hydrophilic, purified water, phenoxyethanol (used as a preservative), propylene glycol (water-miscible co-solvent/drug stabilizer), isopropyl alcohol (co-solvent), benzyl alcohol (preservative/solvent), one or more antioxidants, including for example, butylated hydroxyanisole (‘BHA’), butylated hydroxytoluene (‘BHT’), and propyl gallate, and ethanol (solvent).
  • BHA butylated hydroxyanisole
  • BHT buty
  • the oil phase of the solvent system for the cream formulation may include, for example, one or more of isopropyl myristate (‘IPM’ emollient), cetostearyl alcohol (emollient/thickener), Caprylic/Capric Triglyceride (‘GTCC’ emollient/moisturizer), liquid paraffin and/or white soft paraffin (emollient/skin lubricant), dimethicone 350 (moisturizer/skin protectant), beeswax (skin protectant/thickening agent), stearyl alcohol (skin conditioner/emulsifier), cholesterol (skin conditioner/moisturizer), stearic acid (emulsifier/emollient/lubricant) and castor oil, mineral oil, butyl stearate, IPA and IPP.
  • IPM isopropyl myristate
  • cetostearyl alcohol emollient/thickener
  • GTCC Caprylic/Capric Triglyceride
  • the surfactants used in the cream formulation may be used to stabilize oil- in-water emulsions, and may include, for example, one or more of Brij S2 (polyoxyethylene fatty ethers derived from stearyl alcohols), Brij S20 (polyoxyethylene fatty ethers derived from stearyl alcohols), Span 60 (emulsifier/surfactant derived from stearic acid and used in combination with Tween 60) and Tween 60 (polysorbate emulsifier/surfactant), and Cetomacrogol 1000 (emulsifier/surfactant).
  • Brij S2 polyoxyethylene fatty ethers derived from stearyl alcohols
  • Brij S20 polyoxyethylene fatty ethers derived from stearyl alcohols
  • Span 60 emulsifier/surfactant derived from stearic acid and used in combination with Tween 60
  • Tween 60 polysorbate emulsifier/surfactant
  • a cream formulation for dermal delivery of SNA- 125 with reduced exposure is disclosed, wherein the cream formulation includes about 2% w/w SNA- 125 and a combination of aqueous phase components, oil phase components and surfactants as set forth below in Table 1.
  • a method of treating a skin condition associated with TrkA, Janus Kinase (JAK1, JAK2 and/or JAK3), Tyrosine Kinase 2 (TYK2), Mitogen-Activated Protein Kinase (MAP2K and/or MAP3K) signaling is disclosed in accordance with another embodiment.
  • the method comprises: applying, or instructing application of, a topical cream formulation to a skin region, wherein the cream formulation fully or partially inhibits signaling in the skin region, and thereby treats the skin condition.
  • the cream formulation comprises: a polymer conjugate of an indolocarbazole compound in an oil-in-water emulsion.
  • the polymer conjugate of an indolocarbazole in the cream formulation is SNA-125 having reduced exposure; examples are set forth below in Table 1. Other reduced exposure compounds disclosed herein may be used with or instead of SNA-125.
  • Table 1 provides the compositions of four non-limiting embodiments of SNA-125 cream formulations. Each of the percentages in the table can be adjusted by +/- 20%.
  • the skin condition is inflammation, pain, atopic dermatitis, psoriasis, pruritus associated with psoriasis, or another dermatologic condition.
  • Figure 1 depicts the mean percent applied dose of SNA-125 recovered from epidermis and dermis following application of a representative SNA-125 cream prototype formulation (CR045) and a SNA- 125 gel formulation. No formulation was applied to a control blank cell.
  • Figures 2A and 2B depict the data with error bars (standard deviation) and without error bars, respectively.
  • Figures 5B and 5C depict connecting letters reports summarizing significant differences (Tukey-Kramer, p ⁇ 0.05) between the formulations with respect to epidermis and dermis, respectively.
  • Figure 6 depicts an individual model graph for BHA (A) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 7 depicts an individual model graph for BHT (B) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 8 depicts an individual model graph for propyl gallate (C) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 9 depicts an individual model graph for ascorbic acid (D) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 10 depicts an individual model graph for ascorbic palmitate (E) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 11 depicts an interaction model graph for BHT and BHA (AB) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 12 depicts an interaction model graph for BHA and propyl gallate (AC) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 13 depicts an interaction model graph for BHT and ascorbic palmitate (BE) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 14 depicts an interaction model graph for propyl gallate and ascorbic palmitate (CE) in the CR045 solvent system and average percentage recovery (%) of SNA-125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • Figure 15 depicts an interaction model graph for propyl gallate and alpha tocopherol (CF) in the CR045 solvent system and average percentage recovery (%) of SNA- 125 under stress conditions (6% H 2 O 2 spiking at 70°C for 24 hours) in the solvent system.
  • CF propyl gallate and alpha tocopherol
  • C propyl gallate
  • F alpha tocopherol
  • A BHA
  • Effective delivery of pharmacologically active agents may be hindered by unwanted exposure of those agents to non-desired locations (such as the systemic circulation and/or lymphatic system).
  • topical agents useful in treating various skin disorders may result in toxic side effects because of systemic exposure.
  • One issue with delivering compositions comprising one or more active agents topically (or non-topically) is the concern that such agents need to be delivered in an amount and at a location sufficient to have a therapeutic effect.
  • exposure e.g., absorption or longevity of the composition in the systemic circulation, lymphatic system, or other non-targeted sites
  • compositions described herein are both therapeutically efficacious and minimize non-target (e.g., systemic or bloodstream) exposure.
  • the active agents are PEGylated or otherwise coupled to large molecules, and surprisingly, are effective in crossing biological membranes such that the active agents are effectively delivered to the target location. Inflammatory and non-inflammatory conditions are contemplated herein.
  • Reduced exposure compounds and compositions are provided in several embodiments.
  • “Reduced exposure” compounds are those compounds that, when delivered to a target location, are formulated to act at the target location with reduced exposure (e.g., entry and/or longevity) in non-target sites. Exposure is reduced as compared to active agents not formulated according to the embodiments described herein. As a non-limiting example, a PEGylated topical dermal active agent has reduced exposure to the bloodstream as compared to the active agent alone.
  • Reduced exposure compounds include topical compounds that can be delivered to body surfaces and cavities such as the skin, eyes, ears, nose, mouth, vagina, rectum, etc.
  • Non-desired target sites include, for example, the systemic system, the lymphatic system, non-target tissue, etc.
  • “Reduced exposure compositions” comprise or consist essentially of one or more“reduced exposure compounds.”
  • Reduced exposure topical compositions are provided in many embodiments.
  • less or none of the active agent is absorbed into the non-target site (e.g., systemic circulation and/or lymphatic system).
  • the non-target site e.g., systemic circulation and/or lymphatic system.
  • clearance e.g., by the kidney
  • One or more of the advantages of (i) reduced absorption into the non-target site (e.g., systemic circulation and/or lymphatic system), (ii) slower absorption into the non-target site (e.g., systemic circulation and/or lymphatic system), and (iii) faster clearance rates from the non-target site (e.g., systemic circulation and/or lymphatic system) are also achieved when using the compositions (e.g., via dermal topical formulations as described herein) for treating the skin.
  • a polymer conjugate comprising a warhead (e.g., at least one active agent) linked to a polymer, wherein the warhead comprises an indolocarbazole compound.
  • the polymer conjugate comprises an indolocarbazole compound of formula (I) or of formula (II):
  • R 1 and R 2 are the same or a different residue and are each independently selected from the group consisting of:
  • R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, - (CH 2 ) a CO 2 R 10 (wherein a is 1 or 2, and wherein R 10 is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl) and -(CH 2 ) a CO 2 NR 5 R 6 ,
  • R 8 is selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
  • R is hydrogen, -CONR R , or -CO 2 R , wherein R is hydrogen or a wherein substituted or unsubstituted lower alkyl, and R 12 is hydrogen or a substituted or unsubstituted lower alkyl;
  • (f) -CH CH(CH 2 ) m R 16 , wherein m is 0 to 4, and R 16 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -COOR 15 , -OR 15 (wherein R 15 is as defined above) -CONR 5 R 6 or - NR 5 R 6 (wherein R 5 and R 6 are as defined above);
  • R 3 is hydrogen, halogen, acyl, carbamoyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted lower alkynyl or amino;
  • W 1 and W 2 are independently hydrogen, hydroxy or W 1 and W 2 together represent oxygen;
  • X is a polymer moiety, either linear or branched
  • A represents -L 1 -X' and B represents -L 2 -Y', wherein at least one of X' and Y' is a polymer moiety, either linear or branched, which is bound by L 1 and/or L 2 to the tetrahydrofuran ring of the compound of formula (II); L 1 and/or L 2 are a covalent chemical bond or a linker group;
  • R 19 or R 20 are each independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl or R 19 or R 20 are independently the residue of an a-amino acid in which the hydroxy group of the carboxyl group is excluded, or R 19 or R 20 are combined with a nitrogen atom to form a heterocyclic group; and
  • the polymer moiety X, X' or/and Y' covalently attached to the indolocarbazole compound of formulae (I) and (II) has to be biocompatible, can be of natural or semi -synthetic or synthetic origin and can have a linear or branched structure.
  • the polymer moiety X, X' or/and Y' is selected from poly(alkylene oxides), in particular from (polyethylene) oxides.
  • polymers include without limitation polyacrylic acid, polyacrylates, polyacrylamide or N-alkyl derivatives thereof, polymethacrylic acid, polymethacrylates, polyethylacrylic acid, polyethylacrylates, polyvinylpyrrolidone, poly(vinylalcohol), polyglycolic acid, polylactic acid, poly(lactic-co- glycolic) acid, dextran, chitosan, polyaminoacids, hydroxyethyl starch.
  • the polymer moiety X, X' or/and Y' is a polyethylene glycol (PEG) moiety, wherein the terminal OH group can optionally be modified e.g. with C 1 -C 5 alkyl or C 1 -C 5 acyl groups. In some embodiments, the terminal OH group is optionally modified with C 1 -, C 2 - or C 3 -alkyl groups or C 1 -, C 2 - or C 3 groups. In some embodiments, the modified polyethylene glycol is a terminally alkoxy-substituted polyethylene glycol. In some embodiments, the polymer moiety is methoxy-polyethylene- glycol (mPEG).
  • mPEG methoxy-polyethylene- glycol
  • lower alkyl when used alone or in combination with other groups, means a straight chained or branched lower alkyl group containing from 1-6 carbon atoms, preferably from 1-5, more preferably from 1-4 and especially preferably 1-3 or 1-2 carbon atoms.
  • These groups include, in some embodiments, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, amyl, isoamyl, neopentyl, 1 -ethylpropyl, hexyl, and the like.
  • lower alkyl moiety of the "lower alkoxy”, the “lower alkoxycarbonyl”, the “lower akylaminocarbonyT, “lower hydroxyalkyf and of the “tri-lower alkylsilyT groups has the same meaning as "lower alkyl” defined above.
  • the "lower alkenyl” groups are defined as C 2 -C 6 alkenyl groups which may be straight chained or branched and may be in the Z or E form. Such groups include vinyl, propenyl, 1 -butenyl, isobutenyl, 2-butenyl, 1 -pentenyl, (Z)-2- pentenyl, (E)-2- pentenyl, (Z)-4-methyl-2 -pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1 , 3 or 2,4- pentadienyl, and the like.
  • the C2-C 6 - alkenyl groups are C 2 -C 5 -, C 2 - C 4 -alkenyl groups. In other embodiments, the C 2 -C 6 - alkenyl groups are C 2 -C 3 -alkenyl groups.
  • lower alkynyl groups refers to C 2 -C 6 -alkynyl groups which may be straight chained or branched and include ethynyl, propynyl, 1 -butynyl, 2- butynyl, 1 -pentynyl, 2-pentynyl, 3 -methyl- 1 -pentynyl, 3-pentynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl and the like.
  • C 2 -C 6 -alkynyl groups are C 2 -C 5 -, C 2 -C 4 -alkynyl groups.
  • C 2 -C 6 -alkynyl groups are C 2 -C 3 -alkynyl groups.
  • aryl group refers to C 6 -C 14 -aryl groups which contain from 6 up to 14 ring carbon atoms. These groups may be mono-, bi- or tricyclic and are fused rings. In some embodiments, the aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like. The aryl moiety of the "arylcarbonyl” and the “arylaminocarbonyl” groups has the same meaning as defined above.
  • heteroaryl groups may contain 1 to 3 heteroatoms independently selected from nitrogen, sulfur or oxygen and refers C 3 -C 13 -heteroaryl groups. These groups may be mono-, bi- or tricyclic. In some embodiments, the C 3 -C 13 heteroaryl groups include heteroaromatics and saturated and partially saturated heterocyclic groups. These heterocyclics may be monocyclic, bicyclic, tricyclic. In some embodiments, the 5 or 6- membered heterocyclic groups are thienyl, furyl, pyrrolyl, pyridyl, pyranyl, morpholinyl, pyrazinyl, methyl pyrrolyl, and pyridazinyl.
  • the C 3 -C 13 -heteroaryl may be a bicyclic heterocyclic group.
  • the bicyclic heterocyclic groups are benzofuryl, benzothienyl, indolyl, imidazolyl, and pyrimidinyl.
  • the C 3 -C l3 - heteroaryls are furyl and pyridyl.
  • lower alkoxy includes alkoxy groups containing from 1 to 6 carbon atoms, in some embodiments from 1 to 5, in other embodiments from 1 -4 and in yet other embodiments 1 to 3 or 1 to 2 carbon atoms and may be straight chained or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isopropoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • acyl includes lower alkanoyl containing 1 to 6 carbon atoms, in some embodiments from 1 to 5, from 1 to 4, from 1 to 3 or from 1 to 2 carbon atoms and may be straight chained or branched. These groups include, in some embodiments, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and hexanoyl.
  • the acyl moiety of the "acyloxy" group has the same meaning as defined above.
  • halogen includes fluoro, chloro, bromo, iodio, and the like.
  • aralkyl refers C 7 -C 15 -aralkyl wherein the alkyl group is substituted by an aryl.
  • the alkyl group and aryl may be selected from the C 1 -C 6 alkyl groups and the C 6 -C 14 -aryl groups as defined above, wherein the total number of carbon atoms is between 7 and 15.
  • the C 7 -C 15 -aralkyl groups are benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1 , 1 -diphenylethyl, 1 ,2- diphenyl ethyl.
  • the aralkyl moiety of the "aralkyloxy" groups has the same meaning as defined above.
  • the substituted lower alkyl, alkenyl and alkynyl groups have 1 to 3 independently selected substituents, such as lower alkyl, hydroxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, nitro, halogen, amino, mono- or di- lower alkylamino, dioxolane, dioxane, dithiolane, and dithione.
  • the lower alkyl substituent moiety of the substituted lower alkyl, alkenyl and alkynyl groups, and the lower alkyl moiety of the lower alkoxy, the lower alkoxycarbonyl, and the mono- or di-lower alkylamino substituents of the substituted lower alkyl, alkenyl and alkynyl groups have the same meaning as "lower alkyl” defined above.
  • the substituted aryl, the substituted heteroaryl and the substituted aralkyl groups each has 1 to 3 independently selected substituents, such as lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, and halogen.
  • substituents such as lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, and halogen.
  • the lower alkyl moiety of the lower alkyl, the lower alkoxy, the lower alkoxycarbonyl, and the mono- or di- lower alkylamino groups among the substituents has the same meaning as Tower alkyl’ defined above.
  • the heterocyclic group formed by R 5 and R 6 combined with a nitrogen atom includes pyrrolidinyl, piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino, N-methylpiperazinyl, indolyl, and isoindolyl.
  • each of R 1 and R 2 is hydrogen.
  • the residue R 14 is selected from phenyl, pyridyl, imidazolyl, thiazolyl, tetrazolyl, -COOR 15 , -OR 15 (wherein R 15 is in some embodiments selected from hydrogen, methyl, ethyl, phenyl or acyl), -SR 7 (wherein R 7 is in some embodiments selected from substituted or unsubstituted lower alkyl, 2-thiazoline and pyridyl) and -NR 5 R 6 (wherein R 5 and R 6 are in some embodiments selected from hydrogen, methyl, ethyl, phenyl, carbamoyl and lower alkylaminocarbonyl).
  • the residue R 16 is selected from hydrogen, methyl, ethyl, phenyl, imidazole, thiazole, tetrazole, -COOR 15 , -OR 15 and -NR 5 R 6 (wherein the residues R 15 , R 5 and R 6 have the meanings as described above).
  • the residue R 7 is selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, thiazole and tetrazole.
  • k is 2, 3 or 4
  • j is 1 or 2
  • m and n are independently 0 or 1.
  • R 3 is hydrogen or acetyl. Furthermore, in some embodiments, each W 1 and W 2 is hydrogen.
  • X' when Y' is a polymer moiety and X' is not a polymer moiety, X' is selected from carboxy, hydroxymethyl or a lower alkoxy carbonyl. In some embodiments X' is selected from methoxycarbonyl.
  • Y' is selected from hydroxy or acetyloxy.
  • the warhead of the polymer conjugate is a derivative of K252a, which has the formula:
  • the polymer conjugate is SNA-125 (also referred to as CT340), wherein the composition has the formula:
  • SNA-125 also referred to as CT340
  • a non-target site such as the systemic circulation and/or lymphatic system
  • exposure at a non target site is less than 90%, 75%, 50%, 25%, 15%, 10%, 5% or 2% (or less) of the polymer conjugate as compared to a similar active entity that has not been produced according to the embodiments described herein.
  • desirable rate of clearance from the non-target site (e.g., systemic circulation and/or lymphatic system) for the compositions described herein is increased by at least 10%, 25%, 50%, or 75% or more as compared to non-conjugated controls.
  • a PEGylated active agent described herein not only penetrates the desired membranes to reach a desired target, but has reduced non-target exposure by at least 20-80% or more as compared to the non-PEGylated active agent.
  • blood concentrations measured post administration of the compositions described herein are less than about 0.1 ng/ml, less than 1 ng/ml, or less than 10 ng/ml after, e.g., 15 minutes, 30 minutes, 1 hour, 6 hours or 12 hours.
  • reduced exposure at non-target sites contributes to enhanced efficacy.
  • Efficacy may be enhanced because lower concentrations/amounts/dosing schedules are required to achieve the same or similar therapeutic efficacy at the target site (because, for example, the active ingredient stays at the desired target site for a longer time).
  • concentrations/amounts/dosing schedules are reduced by 25%-75% or more.
  • More rapid clearance rates of the active agent once in the non-target site(s) are also beneficial because this may allow for a higher concentration or more doses to be delivered. This is especially beneficial for active agents in which a subject would benefit from a higher dose but cannot tolerate the higher dose due to toxicity at the non-target site (e.g., systemic toxicity).
  • Faster clearance rates would permit the desired higher dose to be delivered according to the desired schedule. For example, a subject may be able to tolerate daily doses rather than weekly doses because of the reduced exposure.
  • the active agents of the compositions described herein are measured in non-target sites (e.g., the systemic circulation and/or lymphatic system) at less than amounts found when the active agent is delivered without conjugation (e.g., less than 0.5%, 1% or 2% after 6 or 12 hours, as compared with 3-15% (e.g., 3-6%) when the active agent is delivered without conjugation).
  • non-target sites e.g., the systemic circulation and/or lymphatic system
  • the active agents of the compositions described herein are measured in non-target sites (e.g., the systemic circulation and/or lymphatic system) at less than 0.5%, 1% or 2% after 3-24 hours, as compared to an amount 2-20 times greater when the active agent is delivered without conjugation.
  • non-target sites e.g., the systemic circulation and/or lymphatic system
  • clearance of the compositions occurs within minutes of exposure to the non-target site (e.g., systemic circulation and/or lymphatic system), as opposed to hours.
  • 50% clearance of the conjugated polymer compounds occurs in less than 5 minutes, 15 minutes, 30 minutes, 1 hour, 6 hours, and 12 hours of exposure to the systemic circulation and/or lymphatic system. Clearance times of the conjugated polymer compounds are reduced by more than 25%, 50%, 75% and 90%, as compared to the non-conjugated active agents or other formulations. These reduced clearance times are beneficial to reduce toxicity and undesired side effects.
  • an active agent may be increasingly toxic as it is metabolized in the non-target site (e.g., systemic circulation and/or lymphatic system) because the metabolites exhibit more toxicity than the original agent.
  • the non-target site e.g., systemic circulation and/or lymphatic system
  • faster clearance rates in some cases even before the toxic metabolites are created, are especially beneficial.
  • the term“active entity” or“active agent” as used herein should not be understood as limiting the participation of the polymer itself and/or the chemical linking moiety between the polymer and the warhead in defining the pharmacology of the polymer conjugate.
  • the polymer influences the selectivity and/or inhibitory activity of the polymer conjugate.
  • the chemical linking moiety between the polymer and warhead influences the selectivity and/or inhibitory activity of the polymer conjugate.
  • the polymer conjugates exhibit no change in selectivity or inhibitory activity against the therapeutic target in comparison with the unconjugated active agent.
  • the polymer conjugates exhibit a significant increase in selectivity against the therapeutic target in comparison with the unconjugated active agent. In some embodiments, the polymer conjugates exhibit a significant increase in inhibitory activity against the therapeutic target in comparison with the unconjugated active agent. In some embodiments, the polymer conjugates exhibit a significant increase in selectivity and inhibitory activity against the therapeutic target in comparison with the unconjugated active agent. In some embodiments, the increased selectivity and/or inhibitory activity of the polymer conjugate against the therapeutic target in comparison with the unconjugated active agent causes decrease in undesired biological effects. In some embodiments, the increased selectivity of the polymer conjugate is caused by an increase of the hydrodynamic volume resulting from the conjugated polymer chain. In some embodiments, the polymer chain creates a higher steric hindrance which allows discrimination among the diverse shapes and sizes of the binding sites of different proteins, thus improving selectivity with respect to the active agent alone.
  • various inflammatory skin diseases are treated.
  • the inflammatory skin disease comprises, in some embodiments, psoriasis, psoriasis guttata, inverse psoriasis, pustular psoriasis, psoriatic erythroderma, pruritis associated with any of the various forms of psoriasis, acute febrile neutrophilic dermatosis, eczema, xerotic eczema, dyshidrotic eczema, vesicular palmar eczema, acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatomyositis, exfoliative dermatitis, hand eczema, pompholyx, keloids, rosacea, rosacea due to sarcoidosis, rosacea due to scleroderma, rosacea due to Sweet syndrome, rosacea
  • various skin neoplasias are treated.
  • the skin neoplasia comprises, in some embodiments, squamous cell carcinoma, basal cell carcinoma, malignant melanoma, malignant cutaneous lymphoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • various vascular tumors are treated.
  • the vascular tumor comprises, in some embodiments, hemangiomas, Kaposi's sarcoma, lymphangioma, glomangioma, angiosarcoma, hemangioendothelioma, and infantile hemangiomas.
  • bullous diseases are treated.
  • the bullous disease comprises, in some embodiments, bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, epidermolysis bullosa acquisita, linear Immunoglobulin A disease, mucous membrane pemphigoid, pemphigoid gestationis, pemphigus foliaceus, and pemphigus vulgaris.
  • hair growth and cycling are modulated.
  • alopecia is treated.
  • the polymer conjugates are administered in combination with UV irradiation therapy.
  • polymer conjugates wherein the polymer is polyethylene glycol (PEG) or methoxy -polyethylene glycol (m-PEG).
  • PEG polyethylene glycol
  • m-PEG methoxy -polyethylene glycol
  • a pharmaceutical composition comprising or consisting essentially of a polymer conjugate disclosed herein that is formulated for topical administration.
  • methods of making and using the compositions described herein are provided.
  • the invention comprises a reduced exposure composition comprising at least one active entity linked to at least one polymer, wherein the composition has reduced exposure at a non-target site as compared to the active entity delivered without the polymer.
  • the non-target site comprises the systemic system, the lymphatic system and/or another non-target tissue site in some embodiments.
  • the active entity binds to a kinase.
  • the active entity binds to Tropomyosin receptor kinase A (TrkA).
  • the active entity binds to a Janus Kinase (JAK) family member in some embodiments.
  • the active entity binds to one or more of Janus Kinase 1 (JAK1), Janus Kinase 2 (JAK2), Janus Kinase 3 (JAK3), and/or Tyrosine kinase 2 (TYK2) in some embodiments.
  • the active entity binds to mitogen-activated protein kinase kinase 2 (MAP2K) and/or mitogen-activated protein kinase kinase 3 (MAP2K3).
  • MAP2K mitogen-activated protein kinase kinase 2
  • MAP2K3 mitogen-activated protein kinase kinase 3
  • the polymer used in the reduced exposure compounds comprises polyethylene glycol (PEG) and/or methoxy-polyethylene glycol (m- PEG).
  • PEG polyethylene glycol
  • m- PEG methoxy-polyethylene glycol
  • the active entity has one or more carboxyl, hydroxyl, amino and/or sulfhydryl groups
  • the active entity is PEGylated (or conjugated/coupled to another polymer) at one or more of said carboxyl, hydroxyl, amino and/or sulfhydryl groups.
  • the reduced exposure compositions described herein are formulated for topical administration in several embodiments.
  • methods of treating one or more of the following are provided: inflammatory skin disease, vascular tumors, skin neoplasia, bullous diseases, alopecia, wounds, scars, autoimmune disorders, and cancerous or pre-cancerous lesions.
  • Methods for modulating hair growth and cycling are provided in some embodiments.
  • a method of treating any of the above-mentioned skin diseases or any other skin condition in need of treatment includes: applying, or instructing application of, a topical formulation to a skin region, wherein the formulation fully or partially inhibits signaling in the skin region, and thereby treats the skin condition, wherein the formulation comprises: a polymer conjugate of an indolocarbazole compound in an oil- in-water emulsion.
  • the topical formulation applied in accordance with the method may be any of the cream formulations of SNA- 125 as more fully described herein.
  • the compositions may be administered via at least two routes of administration, either simultaneously or sequentially according to some embodiments.
  • the composition is administered via a first (e.g. topical dermal) route to a subject, wherein the subject further receives an additional agent via a second (e.g., non-dermal) route to achieve synergetic effects.
  • the active agent (SNA-125/CT340) may be synthesized as follows:
  • K252b 1 molar equivalent of K252b was pre-dried by suspending in 10 vol of dichloromethane and concentrating to dryness on the rotary evaporator at ⁇ 25°C then holding under reduced pressure to afford a yellowish solid.
  • the dried K252b was re-suspended in 160 vol of dichloromethane at ambient temperature ( ⁇ 20°C) and 2 molar equivalents of 4- methylmorpholine were added. The resulting suspension was stirred for ⁇ 35-45 minutes.
  • Methanol (0.01 vol) was added to quench the reaction and the mixture was stirred for -1-1.5 hours at ambient temperature. 30 vol of saturated sodium bicarbonate solution were added and the biphasic mixture was then stirred for -20 minutes. The phases were separated and the lower (organic) phase was washed with 15 vol of saturated sodium bicarbonate solution. The organic phase was concentrated to dryness under reduced pressure at ⁇ 25°C, protected from light.
  • the product from Step 2 is purified by preparative column chromatography using silica gel which has been pretreated with ethyl acetate containing 5% tri ethyl amine.
  • the Step 2 product was dissolved in dichloromethane/ethyl acetate for application to the column. Elution with ethyl acetate enabled residual K252a and UV- inactive species to be eluted (as monitored by TLC).
  • the column was then conditioned with dichloromethane and eluted with dichloromethane/MeOH (98.5: 1.5 -> 95.5:4.5). Fractions were collected and analyzed by HPLC and TLC, and pooled according to their purity. Evaporation of the combined desired product fractions led to CT340 of purity >95% by HPLC area.
  • a precipitation step is performed to transform it from a semisolid concentrate into a readily handled free- flowing solid.
  • the active agent is formulated for topical delivery.
  • the active agent may be a reduced exposure composition.
  • the active agent is a polymer conjugate of an indolocarbazole compound, thereby providing a reduced exposure indolocarbazole compound.
  • the polymer conjugate is the indolocabazole depicted in Formula (II).
  • the polymer conjugate is SNA-125 (formerly referred to as CT340; both terms are used interchangeably herein).
  • the topical delivery formulation can be in any form, including for example, an ointment, a gel, a balm, a cream, a lotion, a primer, a serum, a liquid, a spray, etc.
  • the topical delivery formulation is a cream.
  • the weight percentage (w/w) of active agent to the total weight of the topical delivery formulation may range from about 0.001% to about 20%, from about 0.005% to about 15%, from about 0.01% to about 12%, or from about 0.1% to about 10%, including any weight percentages within the disclosed ranges. In other embodiments, the weight percentage (w/w) of the active agent may be greater than or equal to about 1.00% w/w. In certain embodiments, the weight percentage (w/w) of the active agent to the total weight of the topical delivery formulation may fall within any range defined by any two of the above weight percentages.
  • the weight percentage (w/w) of the active agent may be less than or equal to about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% w/w.
  • the weight percentage (w/w) of the active agent to the total weight of the topical delivery formulation may fall within any range defined by any two of the above weight percentages.
  • a cream formulation for dermal delivery of a polymer conjugate of an indolocarbazole compound with reduced exposure.
  • the cream formulation includes a polymer conjugate of an indolocarbazole compound in a solvent system comprising an aqueous phase (containing the indolocarbazole), an oil phase and surfactants.
  • the polymer conjugate of an indolocarbazole compound is SNA-125.
  • the SNA-125 may be present at about 0.05% to about 25% (w/w) of the cream formulation. In a variation, the SNA-125 may be present at about 0.05% to about 10% (w/w) of the cream formulation.
  • a cream formulation for dermal delivery of SNA-125 with reduced exposure wherein the cream formulation includes about 2% w/w SNA- 125 and a combination of aqueous phase components, oil phase components and surfactants as set forth below in Table 1 (reproduced again below).
  • the aqueous phase may include solvents, preservatives, solubilizing agents, etc.
  • the aqueous phase may include, for example, one or more of 2-(2-ethoxyethoxy)ethanol (tradename TRANSCUTOL P - penetration enhancer), high purity grade, low molecular weight polyethylene glycol 400 (tradename SR (Super Refmed)PEG 400 - commonly used as a partitioning agent because it is strongly hydrophilic, purified water, phenoxyethanol (used as a preservative), propylene glycol (water-miscible co-solvent/drug stabilizer), isopropyl alcohol (co-solvent), benzyl alcohol (preservative/solvent), butylated hydroxytoluene (‘BHT’ - antioxidant), propyl gallate (antioxidant), and ethanol (solvent).
  • 2-(2-ethoxyethoxy)ethanol tradename TRANSCUTOL P - penetration enhancer
  • high purity grade, low molecular weight polyethylene glycol 400 tradename SR (Super Refmed)PEG 400 - commonly used as a partitioning agent because it
  • the oil phase of the solvent system for the cream formulation may include, for example, one or more of isopropyl myristate (‘IPM’ emollient), cetostearyl alcohol (emollient/thickener), Caprylic/Capric Triglyceride (‘GTCC’ emollient/moisturizer), liquid paraffin and/or white soft paraffin (emollient/skin lubricant), dimethicone 350 (moisturizer/skin protectant), beeswax (skin protectant/thickening agent), stearyl alcohol (skin conditioner/emulsifier), cholesterol (skin conditioner/moisturizer), and stearic acid (emulsifier/emollient/lubricant).
  • IPM isopropyl myristate
  • cetostearyl alcohol emollient/thickener
  • GTCC Caprylic/Capric Triglyceride
  • liquid paraffin and/or white soft paraffin emollient/skin
  • the surfactants used in the cream formulation may be used to stabilize oil- in-water emulsions, and may include, for example, one or more of Brij S2 (polyoxyethylene fatty ethers derived from stearyl alcohols), Brij S20 (polyoxyethylene fatty ethers derived from stearyl alcohols), Span 60 (emulsifier/surfactant derived from stearic acid and used in combination with Tween 60) and Tween 60 (polysorbate emulsifier/surfactant), and Cetomacrogol 1000 (emulsifier/surfactant).
  • Brij S2 polyoxyethylene fatty ethers derived from stearyl alcohols
  • Brij S20 polyoxyethylene fatty ethers derived from stearyl alcohols
  • Span 60 emulsifier/surfactant derived from stearic acid and used in combination with Tween 60
  • Tween 60 polysorbate emulsifier/surfactant
  • Table 1 provides the compositions of four non-limiting embodiments of SNA-125 cream formulations. Each of the percentages in the table can be adjusted by +/- 20%.
  • the target preferred maximum feasible dose is 5% (based on a clinical concentration of 2% w/w SNA- 125)
  • the data in Table 9 highlights that all the cream formulations had a SNA-125 solubility of >20% w/w (therefore 4 times the target preferred maximum feasible dose).
  • the SNA-125 ointment formulation (low BA) had a saturated solubility of 16.72%, which is still significantly higher than the preferred maximum feasible dose.
  • SNA- 125 cream formulations have a maximum feasible concentration of less than 20% (w/w). In several embodiments, SNA-125 cream formulations have a maximum feasible concentration of about 10% to about 15% (w/w). In several embodiments, SNA- 125 cream formulations have a maximum feasible concentration of about 5% to about 10% (w/w). In several embodiments, SNA-125 cream formulations have a maximum feasible concentration of less than 5%. In some embodiments, the CR062 and CR054 formulations have a maximum feasible concentration of less than 20% (w/w). Table 10 depicts the composition of manufactured formulations for evaluation of the maximum feasible concentration of CR054 and CR062. Table 11 depicts the characterization of the manufactured formulations for evaluation of the maximum feasible concentration of CR054 and CR062.
  • the residual formulation was removed from the surface of the skin and then the skin surface was taped striped up to 5 times to remove the skin surface layers ( Stratum Corneum).
  • the epidermis was then heat-separated from the dermis by placing the skin into an incubator at 60°C for 2 min, followed by manual separation using curved forceps.
  • the amount of drug delivered to epidermis and dermis was then determined by HPLC-FLD.
  • FIG. 3 depicts the mean flux (ng/cm 2 /hr) of SNA-125 permeated through the 1 cm 2 skin dosing area (i.e. drug detected in receiver fluid) following application of each of the ten prototype formulations.
  • a difference in flux profiles between the low-BA ointment formulation and the cream formulation was observed. While the low-BA ointment formulation exhibited a maximum flux at about 4 hours, the cream formulations tended to have bi-phasic flux patterns with maxima near 4 hours and after about 18 hours.
  • FIG. 4 depicts the mean amount of SNA-125 (ng) recovered from epidermis and dermis following application of the ten prototype formulations
  • Figure 5 depicts the mean percent of applied dose of SNA-125 recovered from epidermis and dermis (ng) following application of the ten formulations.
  • CR045 showed comparable epidermal ( ⁇ 3%) & dermal levels ( ⁇ l%) as observed in the small-scale study described above.
  • Creams CR061 and CR062 delivered the greatest amount of SNA- 125 to both epidermis and dermis based both on amount (ng) and percent applied dose (%).
  • This criterion is based upon change in percentage recovery from initial testing. Formulations with a SNA-125 percentage recovery of 95-105% after 4 weeks storage were scored 1, formulations with a percentage recovery of 90-95% or 105-110% SNA-125 were scored 2, and formulations with a recovery ⁇ 90 or >110 % SNA- 125 were scored 3. Second Criterion: Purity after 4 Weeks (25°C and 40°C)
  • the SNA- 125 ointment formulation (low BA) has fewer excipients (6 excipients) as compared to the prototype cream formulations; however, the ointments take longer on average to stir to cool.
  • small particles of cholesterol were initially observed in the ointment formulation due to the high melting point of the excipients.
  • the small particles of cholesterol sat at the bottom of the vessel; while these particles were later solubilized by the benzyl alcohol in the liquid phase, this may be an issue with a larger batch size.
  • This criterion is based upon the delivery of SNA-125 into the epidermal/dermal layers, measured as amount (ng) recovered from the epidermis/dermis after 24 hours following application of the formulation.
  • the epidermal and dermal delivery has been ranked via absolute values.
  • the statistical analyses depicted in Figures 4B-4C and Figures 5B-5C indicate which formulations are statistically similar to each other. Rankings of numbers which are not connected by the same number are significantly different.
  • the formulations can be ranked from most to least favorable as follows: (1) CR061 and CR062; (3) CR054; (4) CR047 and SNA-125 ointment (Low BA); (6) CR053 and CR058; (8) CR045; (9) CR042; (10) CR043.
  • Table 14 depicts the top four top 4 SNA- 125 formulations under consideration when incorporating an aesthetic preference (e.g., ethanol content) criterion.
  • the formulation CR045 was selected for the antioxidant screening study as a representative formulation with 30% w/w water content in the formulation (adjusted to 37.50% w/w in the solvent system).
  • the CR045 solvent system could solubilize all the antioxidants selected for investigation (BHA, BHT, propyl gallate, ascorbic acid, ascorbyl palmitate and alpha tocopherol).
  • Table 15 depicts the theoretical composition (% w/w) of the solvent system from formulation CR045, which is adjusted to total 100%.
  • the recovery (% w/w) of SNA-125 was investigated after the being stored in the stress conditions determined in the preliminary study above (6% H 2 O 2 spiking at 70°C).
  • Figure 8 shows individual model graph for propyl gallate, indicating that its presence in the solvent system resulted in an increase in the average percentage recovery (%) of SNA-125 under the stress conditions.
  • the individual model graph for ascorbic acid ( Figure 9) indicates that having this antioxidant in the solvent system resulted in a decrease in the average percentage recovery (%) of SNA-125 under the stress conditions.
  • the individual model graph for ascorbic palmitate ( Figure 10) indicates that this antioxidant resulted in a slight decrease in the average percentage recovery (%) of SNA-125 under the stress conditions.
  • Figure 11 depicts the interaction model graph for BHT and BHA (AB), indicating there is an interaction between BHA and BHT.
  • BHA BHA in the solvent system
  • the average percentage recovery (%) of SNA-125 is higher without BHT.
  • the average percentage recovery (%) of SNA-125 is higher with BHT.
  • the average percentage recovery (%) of API is highest when there is BHA and no BHT.
  • the interaction model graph for BHA and propyl gallate indicates there is an interaction between BHA and propyl gallate.
  • the average percentage recovery (%) of SNA- 125 remains constant with and without BHA.
  • the combination of BHA without propyl gallate, BHA with propyl gallate and propyl gallate without BHA all yielded similar results of percentage recovery (%) of SNA-125.
  • the average percentage recovery (%) of SNA-125 is slightly higher with BHA alone. When neither BHA nor propyl gallate are in the solvent system, the average percentage recovery (%) of SNA-125 is lower.
  • Figure 13 depicts the interaction model graph for BHT and ascorbic palmitate (BE), which indicates there is an interaction between BHT and ascorbic palmitate.
  • BE ascorbic palmitate
  • the average percentage recovery (%) of SNA-125 is highest with BHT, but lowest without BHT.
  • the average percentage recovery (%) of SNA- 125 remains similar with and without BHT.
  • the combination of BHT and ascorbic palmitate results in the highest average percentage recovery (%) of SNA- 125.
  • the interaction model graph for propyl gallate and ascorbic palmitate indicates there is an interaction between propyl gallate and ascorbic palmitate.
  • ascorbic palmitate is in the solvent system
  • the average percentage recovery (%) of SNA-125 is lower than when it is not.
  • propyl gallate is in the solvent system
  • the average percentage recovery (%) of SNA-125 is much higher without ascorbic palmitate.
  • the combination of propyl gallate without ascorbic palmitate results in the highest average percentage recovery (%) of SNA- 125.
  • Figure 15 depicts the interaction model graph for propyl gallate and alpha tocopherol (CF), which indicates there is an interaction between propyl gallate and alpha tocopherol.
  • CF propyl gallate and alpha tocopherol
  • Table 22 depicts the general trend observed regarding the effect of the six selected antioxidants on SNA- 125 percentage recovery following 24 hours and 5 days storage with 6% H 2 O 2 spiking at 70°C.
  • BHA and propyl gallate in the solvent system of CR045 were both found to increase the average percentage recovery of SNA- 125.
  • BHA and propyl gallate can be used alone, and can also be used in combination to achieve the best outcome.
  • the SNA-125 formulation contains at least one of BHA and propyl gallate.
  • alpha tocopherol was found to increase the effectiveness of propyl gallate.
  • BHA and propyl gallate are incorporated in the SNA- 125 formulations. Both BHA and propyl gallate have USP and EU monographs available.

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Abstract

L'invention concerne des formulations topiques servant à traiter des affections cutanées, telles que la dermatite atopique, le psoriasis, le prurit dans lesquelles un conjugué polymère d'un indolocarbazole présente une exposition systémique réduite. Une formulation donnée à titre d'exemple comprend l'antagoniste de la kinase TrkA/JAK/MAP, du SNA-125, dans une formulation de crème.
PCT/US2019/014241 2018-01-18 2019-01-18 Formulations pour l'administration dermique de conjugués polymères de composés indolocarbazole à exposition réduite Ceased WO2019143971A2 (fr)

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CN116134038A (zh) * 2020-06-30 2023-05-16 德米拉公司 Irak4抑制剂及其局部用途
US20240382502A1 (en) * 2020-11-17 2024-11-21 Arcutis Biotherapeutics, Inc. Compositions and methods for deep dermal drug delivery

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KR101379693B1 (ko) * 2005-08-25 2014-04-10 크리어빌리스 쎄라퓨틱스 에스.피.에이. Ｋ-252ａ 및 그의 유도체의 중합체 컨쥬게이트
AU2014293013A1 (en) * 2013-07-26 2016-03-17 Race Oncology Ltd. Combinatorial methods to improve the therapeutic benefit of bisantrene
CA2932123C (fr) * 2013-12-05 2022-05-31 Nian WU Conjugues polymeres-hydrates de carbone pour technologie d'administration pharmacologique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116134038A (zh) * 2020-06-30 2023-05-16 德米拉公司 Irak4抑制剂及其局部用途
EP4172163A4 (fr) * 2020-06-30 2024-07-24 Dermira, Inc Inhibiteurs d'irak4 et utilisations topiques
US20240382502A1 (en) * 2020-11-17 2024-11-21 Arcutis Biotherapeutics, Inc. Compositions and methods for deep dermal drug delivery

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