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WO2025147698A1 - Dispositifs et procédés d'administration transdermique d'ozanimod - Google Patents

Dispositifs et procédés d'administration transdermique d'ozanimod Download PDF

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Publication number
WO2025147698A1
WO2025147698A1 PCT/US2025/010414 US2025010414W WO2025147698A1 WO 2025147698 A1 WO2025147698 A1 WO 2025147698A1 US 2025010414 W US2025010414 W US 2025010414W WO 2025147698 A1 WO2025147698 A1 WO 2025147698A1
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WO
WIPO (PCT)
Prior art keywords
ozanimod
pharmaceutically acceptable
acceptable salt
day
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/010414
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English (en)
Inventor
Niraj Vasisht
Eun Soo Lee
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Corium Innovations Inc
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Corium Innovations Inc
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Filing date
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Publication of WO2025147698A1 publication Critical patent/WO2025147698A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • S1P sphingosine 1-phosphate
  • RMS sphingosine 1-phosphate
  • S1P receptor modulators may have safety and tolerability risks, such as elevation in hepatic transaminase, resulting headaches, and prolongation of bradyarrhythmia and QTc.
  • treatment using oral delivery of S1P receptor modulators require titration before treatment initiation.
  • Ozanimod is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis.
  • Ozanimod acts as a sphingosine-1-phosphate receptor agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.
  • Ozanimod is available as an oral therapy administered daily, however, orally delivered ozanimod can result in slow heart rate (bradyarrhythmia) and/or atrioventricular conduction delays in patients. Further, patients suffering from certain disorders such as MS may have difficulty in swallowing and therefore oral administration may not be viable for those patients.
  • a therapeutic transdermal patch comprising: a release liner; a drug matrix comprising ozanimod or a pharmaceutically acceptable salt thereof; and a skin permeation enhancer; and optionally a backing layer; wherein the transdermal patch delivers the ozanimod with a transdermal flux rate of about 0.29 ⁇ g/cm 2 h to about 0.5 ⁇ g/cm 2 h at 32°C.
  • the drug matrix comprises ozanimod free base.
  • the drug matrix comprises about 1% dry wt. to about 5% dry wt., based on the Attorney Docket No.
  • the drug matrix comprises the ozanimod or pharmaceutically acceptable salt thereof in an amount to transdermally deliver to a patient 0.23 mg/day, 0.46 mg/day, or 0.92 mg/day of the ozanimod over 1 to 10 days. In some embodiments, the drug matrix comprises the ozanimod or pharmaceutically acceptable salt thereof in an amount to transdermally deliver to a patient 0.23 mg/day, 0.46 mg/day, or 0.92 mg/day of the ozanimod over 7 days.
  • the amount of the ozanimod or pharmaceutically acceptable salt thereof is from about 11.78 mg to about 17.62 mg for a transdermal patch having a planar cross-sectional area of about 49 cm 2 .
  • the skin permeation enhancer is selected from the group consisting of oleic acid, levulinic acid, methyl laurate, n-methyl pyrrolidone, and any combination thereof. In some embodiments, the skin permeation enhancer is oleic acid and one or more of: methyl laurate or n-methyl pyrrolidone.
  • the drug matrix further comprises one or more of : glycerol monooleate, pyrrolidone, dimethyl sulfoxide, transcutol, or any combination thereof.
  • the drug matrix further comprises a pressure sensitive adhesive.
  • the therapeutic transdermal patch has a drug utilization from about 10% to about 50%, or from about 15% to about 35%, wherein the drug utilization corresponds to a percentage of an amount of ozanimod transdermally delivered with respect to a total amount of ozanimod initially present in the drug matrix.
  • the transdermal patch further comprises a planar cross- sectional area from about 20 cm 2 to about 80 cm 2 .
  • the drug matrix has a thickness from about 3 mil to about 7 mil.
  • a method for transdermal delivery of ozanimod or a pharmaceutically acceptable salt thereof in a patient in need of ozanimod administration comprising: transdermally administering a therapeutic patch having a planar cross-sectional area to the patient, the therapeutic patch comprising: a release liner; a drug matrix comprising comprises about 1% dry wt. to about 5% dry wt.
  • the planar cross-sectional area is from about 20 cm2 to about 80 cm2 and the drug matrix comprises from about 5 mg to about 29 mg of the ozanimod or pharmaceutically acceptable salt thereof.
  • the therapeutic patch is configured to transdermally deliver from about 60 ⁇ g/cm 2 to about 90 ⁇ g/cm 2 of the ozanimod or pharmaceutically acceptable salt thereof to the patient over 7 days at 32°C.
  • the patient upon the transdermal delivery, the patient is less at risk of hepatic transaminase elevation, headache and/or bradyarrhythmia and QtC prolongation as compared to oral administration of ozanimod to a patient.
  • the method provides administration of substantially the same daily dose of the ozanimod or pharmaceutically acceptable salt thereof to the patient over at least 7 days.
  • the drug matrix comprises the ozanimod or pharmaceutically acceptable salt thereof in an amount to transdermally deliver to a patient 0.23 mg/day, 0.46 mg/day, or 0.92 mg/day of the ozanimod or pharmaceutically acceptable salt thereof over one to 10 days.
  • the drug matrix comprises the ozanimod or pharmaceutically acceptable salt thereof in an amount to transdermally deliver to a patient 0.23 mg/day, 0.46 mg/day or 0.92 mg/day of the ozanimod or pharmaceutically acceptable salt thereof over 7 days.
  • the amount of the ozanimod or pharmaceutically acceptable salt thereof is from about 11.78 mg to about 17.62 mg for a transdermal patch having a planar cross-sectional area of about 49 cm 2 .
  • the planar cross-sectional area is from about 20 cm2 to about 80 cm 2 and the drug matrix comprises from about 5 mg to about 29 mg of the ozanimod or pharmaceutically acceptable salt thereof.
  • the therapeutic patch is configured to transdermally deliver from about 60 ⁇ g/cm 2 to about 90 ⁇ g/cm 2 of the ozanimod or pharmaceutically acceptable salt thereof to the patient over 7 days at 32°C.
  • the composition further comprises the ozanimod or pharmaceutically acceptable salt thereof in an amount to transdermally deliver to a patient 0.23 mg/day, 0.46 mg/day, or 0.92 mg/day of the ozanimod or pharmaceutically acceptable salt thereof over 7 days.
  • the amount of the ozanimod or pharmaceutically acceptable salt thereof is from about 11.78 mg to about 17.62 mg for a transdermal patch having a planar cross-sectional area of about 49 cm 2 .
  • the composition further comprises one or more of: glycerol monooleate, pyrrolidone, dimethyl sulfoxide, transcutol, or any combination thereof.
  • the composition further comprises a pressure sensitive adhesive.
  • FIG.1B depicts a top cross-sectional view of a transdermal patch, in accordance with an embodiment.
  • FIG.2 depicts a comparison of the transdermal flux achieved by various drug matrices, in accordance with an embodiment.
  • Attorney Docket No. CPS-100WO depicts a comparison of the cumulative skin permeation achieved by the various drug formulations from FIG.3, in accordance with an embodiment.
  • FIG.4 depicts an exemplary model output for a sensitization prediction for ozanimod base, in accordance with an embodiment. DETAILED DESCRIPTION OF THE INVENTION Definitions [0025] Terms used in the claims and specification are defined as set forth below unless otherwise specified.
  • S1P1 compound or “S1P1 agonist” or “S1P1 activator” or “S1P1 inhibitor” or “S1P1 antagonist” as the terms are used herein refer to compounds that interact in some way with the S1P receptor subtype 1. They can be agonist or activators, or they can be antagonists or inhibitors.
  • S1P1 compound can be selective for action on subtype 1 of the S1P receptor family; for example, a compound of the invention can act at a lower concentration on subtype 1 of the S1P receptor family than on other subtypes of the S1P receptor family; more specifically, an “S1P1 compound” of the invention can selectively act on subtype 1 receptors compared to its action on subtype 3, or “S1P3” receptors.
  • compositions comprising a formulation or compound described herein (e.g., ozanimod), and physiologically compatible with the recipient thereof.
  • pharmaceutically acceptable indicates that the designated carrier, vehicle, diluent, excipient(s), and/or salt is generally chemically and/or physically compatible with the other ingredients comprising a formulation or compound described herein (e.g., ozanimod), and physiologically compatible with the recipient thereof.
  • a drug formulation e.g., a pharmaceutically acceptable patch, and/or a drug matrix, configured for transdermal delivery of a sphingosine-1-phosphate (S1P) receptor modulator, such as for example, ozanimod or a pharmaceutically acceptable salt thereof.
  • Contemplated drug matrices include the S1P receptor modulator (e.g., ozanimod) and a permeation enhancer.
  • a contemplated drug formulation or matrix is configured to transdermally Attorney Docket No.
  • CPS-100WO deliver an effective amount of ozanimod to a subject, wherein such effective amount may correspond to a dosage rate of 0.23 mg/day, 0.46 mg/day, and/or 0.92 mg/day of ozanimod.
  • a provided drug formulation may be configured to deliver the S1P receptor modulator transdermally with a transdermal flux rate from about 0.29 ⁇ g/cm 2 h to about 0.5 ⁇ g/cm 2 h at 32°C, as described herein.
  • Contemplated drug matrices may be as part of, or a patch configured to be placed about a subject’s skin, so as to effectuate transdermal delivery of the S1P receptor modulator to the subject.
  • a disclosed patch includes a drug matrix layer that contains the contemplated drug formulation or matrix, as described herein.
  • Contemplated S1P receptor modulators for use in the disclosed drug matrices may include one or more of: ozanimod, fingolimod, siponimod, and ponesimod.
  • Also provided herein are methods of treating patients suffering from e.g., one or more of the following diseases: multiple sclerosis (MS), irritable bowel syndrome (IBS), and ulcerative colitis (UC), the method comprising transdermally administering a disclosed drug matrix.
  • MS multiple sclerosis
  • IBS irritable bowel syndrome
  • UC ulcerative colitis
  • methods of treatment provided herein may help to decrease the action of immune cells that may cause nerve damage as a treatment for MS in a patient in need thereof.
  • Drug Matrices Provided herein, for example, is a drug matrix that may be used for transdermal delivery of ozanimod, wherein the drug matrix comprises ozanimod and a permeation enhancer.
  • a contemplated drug matrix (e.g., for any drug formulation described herein) comprises ozanimod base and/or a pharmaceutically acceptable salt of ozanimod.
  • a non- limiting example of a pharmaceutically acceptable salt of ozanimod includes ozanimod hydrochloride.
  • a contemplated drug matrix includes one or more permeation enhancers.
  • a contemplated permeation enhancer may be configured to solubilize the ozanimod into a solution.
  • the solution is at least a partially liquid solution, which may be also partially solid.
  • the amount of the ozanimod (e.g., ozanimod free base) in the drug matrix is such that a resulting solution thereof is free or substantially free of crystalline formation (e.g., crystalline polymorph(s)).
  • the amount of ozanimod found in the drug matrix is from about 0.5% by weight (wt.) to about Attorney Docket No. CPS-100WO 10% by wt., such as from about 1% by wt.
  • the drug matrix has minimal or is substantially free of crystalline ozanimod.
  • skin barrier e.g., skin membrane
  • the one or more permeation enhancers may be selected from the group consisting of oleic acid, levulinic acid, methyl laurate, n-methyl pyrrolidone, and any combination thereof.
  • the one or more permeation enhancers include oleic acid and one or more of methyl laurate and n-methyl pyrrolidone.
  • the one or more permeation enhancers include either oleic acid or levulinic acid, but not both.
  • the one or more permeation enhancers include either methyl laurate or n-methyl pyrrolidone, but not both.
  • the one or more permeating enhancers comprise oleic acid, levulinic acid, capric acid, palmitic acid, ascorbic acid, other acid groups able to solubilize oleic free base, or any combination thereof.
  • drug matrix that comprises ozanimod and about 0.5% by weight (wt.) to about 3.0% by wt. % of oleic acid, such as from about 1% by wt. to about 2.5% by wt., from about 1.3% by wt.
  • a contemplated drug matrix may alternatively or additionally include about 0.25% by weight (wt.) to about 2.0% by wt. of levulinic acid such as from about 0.5% by wt. to about 1.0% by wt., from about 0.7% by wt.
  • a contemplated drug matrix may also include one or more of: transcutol, dimethyl sulfoxide (DMSO), a glycerol oleate (e.g., glycerol monoleate), and crospovidone.
  • the drug matrix may further comprise transcutol, e.g., may comprise 1.0% by weight (wt.) to about 10.0% by wt. transcutol, e.g., about 2.5% by wt. to about 7.5% by wt., or about 4.4% by wt., wherein wt.% is on a dry or wet basis of the drug matrix, and/or is based on the total weight of the drug matrix.
  • DMSO is provided in a contemplated drug matrix in an amount from about 1.0% by weight (wt.) to about 10.0% by wt., such as from about 2.5% by wt. to about 7.5% by wt., or about 5.6% by wt., wherein wt.% is on a dry or wet basis of the drug matrix, and/or is based on the total weight of the drug matrix.
  • a glycerol oleate (e.g., glycerol monoleate) is provided in a contemplated drug matrix in an amount from about 1.0% by weight (wt.) to about 10.0% by wt., such as from about 2.5% by wt. to about 7.5% by wt., or about 6% by wt., wherein wt.% is on a dry or wet basis of the drug matrix, and/or is based on the total weight of the drug matrix.
  • wt.% is on a dry or wet basis of the drug matrix, and/or is based on the total weight of the drug matrix.
  • such pressure sensitive adhesive is configured to help aid the drug matrix, including as part of a patch, to be secured to the skin of a subject.
  • the pressure sensitive adhesive is provided in a contemplated drug matrix in an amount from about 25.0% by weight (wt.) to about 75.0% by wt., such as from about 40% by wt. to about 65% by wt., from about 50% by wt. to about 60% by wt., about 55% by wt., or about 57% by wt., wherein wt.% is on a dry or wet basis of the drug matrix, and/or is based on the total weight of the drug matrix.
  • a drug matrix that includes about 1 to about 5 wt. percent ozanimod free base, and about 0.25 to about 10 weight percent of a permeation Attorney Docket No. CPS-100WO enhancer, about 6 to about 40% by weight crospovidone, and about 20% to about 90% of a pressure adhesive.
  • a drug matrix may further comprise one or more of transcutol, DMSO, glycerol and/or crospovidone.
  • Transdermal Patch [0057] As described herein, in some embodiments, a contemplated drug matrix may be as part of, or a patch configured to be placed about a subject’s skin, so as to effectuate transdermal delivery of ozanimod to a subject.
  • FIG.1A provides an exemplary side cross- section view of a patch 100
  • FIG.1B provides an exemplary top cross-section view of a patch 100
  • the patch includes a drug matrix layer 102 (FIG.1B) that comprises a contemplated drug matrix described herein.
  • the patch further comprises a release liner 104 configured to be coupled to a distal end of the drug matrix 102, wherein the distal end of the drug matrix is configured to be disposed against a skin of the subject to effectuate the transdermal delivery of the ozanimod.
  • the release liner 104 is configured to help provide protection for the drug matrix 102, including the pressure sensitive adhesive properties.
  • the release liner 104 is configured to be removably coupled to the drug matrix 102, so as to be removed from the patch prior to placing the drug matrix 102 onto the skin of a subject.
  • the release liner 104 comprises paper, poly-coated paper, polyester film, polyethylene, polypropylene, or other materials known in the art.
  • the release liner 104 comprises siliconized polyethylene terephthalate (PET).
  • PET polyethylene terephthalate
  • the patch optionally includes a backing layer 106, which may be coupled to a proximal end of the drug matrix 102.
  • the backing layer 106 helps provide protection to the drug matrix 102 prior to and/or during placement of the patch 100 on the skin of a subject.
  • the backing layer 106 comprises a polyester film laminate, and/or other materials as known in the art.
  • a cross-section of the patch (viewed in a proximal to distal direction, and vice versa, e.g., top view in FIG.1B) is configured in any shape, such as a square, rectangle, circle, oval, triangle, etc.
  • FIG.1B depicts an exemplary top cross-section view of the proximal end of a patch 100, having a square shape with rounded corners.
  • the patch has a cross-sectional area (e.g., a planar cross-sectional area as shown in FIG.1B) of about 6.45 cm 2 , about 15 cm 2 , about 30 cm 2 , about 49 cm 2 , about 65 cm 2 , or about 80 cm 2 .
  • each layer e.g., drug matrix layer 102, release liner 104, backing layer 106
  • the drug matrix layer 102 has a thickness from about 1 mil to about 10 mil, such as from about 2 mil to about 8 mil, from about 3 mil to about 6 mil, or from about 4 mil to about 5 mil.
  • the drug matrix layer 102 has a thickness of about 4 mil, about 4.7 mil, or about 5.5 mil.
  • the release liner 104 has a thickness from about 1 mil to about 5 mil, such as from about 2 mil to about 4 mil, or about 3 mil.
  • the backing layer 106 has a thickness from about 0.5 mil to about 3 mil, such as from about 1 mil to about 2 mil, or about 1.7 mil.
  • the units “mil” refer to 0.001 inch.
  • the OZD-22 formulation listed in Table 2 of Example 2 herein, using a 49 cm 2 size patch was observed as having an average flux rate of Attorney Docket No. CPS-100WO 0.5 ug/cm 2 h, and may correlate with a dosage rate of 0.92 mg/day over a time period, such as 7 days. In some cases, varying the patch size will thereby vary the dosage rate, based on the average flux rate.
  • the transdermal dosage delivery rate is constant or substantially constant over a minimum number of days, such as from about 1 day to about 10 days, or about 7 days.
  • the transdermal flux rate corresponds to a rate at which an amount of the ozanimod can cross the skin barrier of a subject’s skin for delivery thereto.
  • the transdermal flux rate is based on the type and/or amount of permeation enhancers provided with the drug matrix. See Example 1, where four exemplary ozanimod compositions having varying amounts of ozanimod base, and varying amounts and types of the permeation enhancers, resulted in different transdermal flux profiles (at 32°C).
  • a contemplated drug matrix is prescribed to obtain a minimum transdermal flux rate for the ozanimod.
  • the transdermal flux rate at 32°C, is about 0.3 ⁇ g/cm 2 h, about 0.4 ⁇ g/cm 2 h, about 0.5 ⁇ g/cm 2 h, or about 0.6 ⁇ g/cm 2 h.
  • the above listed transdermal flux rates correspond to a minimum transdermal flux rate, a maximum transdermal flux rate, and/or an average transdermal flux rate, over a minimum number of days.
  • the minimum number of days is about 1 Attorney Docket No. CPS-100WO day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, or 30 days.
  • the cumulative skin permeation of ozanimod delivered transdermally after 8 days of administering the drug matrix to a skin of a subject, at 32°C is from about 40 ⁇ g/cm 2 to about 100 ⁇ g/cm 2 , such as from about 60 ⁇ g/cm 2 to about 95 ⁇ g/cm 2 h, from about 85 ⁇ g/cm 2 to about 95 ⁇ g/cm 2 h, from about 65 ⁇ g/cm 2 to about 80 ⁇ g/cm 2 h, or from about 60 ⁇ g/cm 2 to about 70 ⁇ g/cm 2 h.
  • the transdermal flux rate and cumulative skin permeation corresponds to a rate of amount of ozanimod per a delivery area (e.g., a surface area of skin interfacing with the drug matrix).
  • said delivery area corresponds to a cross-sectional area of the drug matrix as part of, or as a patch, that is in contact or otherwise coupled to the skin of the subject, wherein said cross-sectional area of the patch may specifically correspond to a planar cross-sectional area of the patch (as described herein). Accordingly, in some embodiments, as the cross-sectional area of the patch increases, the amount of ozanimod delivered may increase due to the larger delivery area.
  • the transdermal patch includes a planar cross-sectional area from about 5 cm 2 to about 100 cm 2 , such as from about 10 cm 2 to about 80 cm 2 , from about 20 cm 2 to about 70 cm 2 , from about 30 cm 2 to about 60 cm 2 , or from about 40 cm 2 to about 50 cm 2 .
  • the patch has a cross-sectional area (e.g., a planar cross-sectional area as shown in FIG.1B) of about 6.45 cm 2 , about 15 cm 2 , about 30 cm 2 , about 49 cm 2 , about 65 cm 2 , or about 80 cm 2 .
  • a drug utilization value may also be a function of the transdermal flux rate and/or the cross-sectional area of the patch, among others.
  • drug utilization refers to a percentage of the amount of ozanimod (e.g., by weight, volume, etc.) that was delivered transdermally (e.g., that crossed Attorney Docket No. CPS-100WO the skin barrier) with respect to the total amount of ozanimod that was provided initially in the drug matrix.
  • a contemplated drug matrix contained 2 mg of ozanimod (e.g., ozanimod base, and/or a pharmaceutically acceptable salt thereof), and 1 mg of ozanimod is determined to have been transdermally delivered to a subject, the drug utilization would be 50% (1 mg delivered / 2 mg found in the ozanimod drug formulation).
  • the drug utilization may be based at least partially on the transdermal flux rate, a delivery area for the composition (e.g., cross-sectional area of the patch), a duration of time, and/or temperature.
  • Example 2 provides exemplary drug matrices having differing drug utilizations values.
  • the duration of time is reflective of the cumulative amount of ozanimod transdermally delivered, such that the drug utilization will continue to increase over time until reaching a maximum amount transferred.
  • the drug utilization is measured with respect to a prescribed treatment period (as described herein), such as 7 days.
  • a prescribed treatment period as described herein
  • the drug utilization over 7 days is from about 5 % to about 60%, such as from about 10 % to about 50%, from about 15 % to about 40%, from about 15 % to about 20%, from about 20 % to about 30%, or from about 30 % to about 40%.
  • a contemplated drug matrix is configured to transdermally deliver an effective amount of the ozanimod to a subject, which may be, for example, 0.23 mg/day, 0.46 mg/day, or 0.92 mg/day (which may be an average dosage rate, a substantially constant dosage rate, or both, over a span of a treatment period).
  • the amount of ozanimod found in the drug matrix to achieve the effective amount is specified based on the estimated transdermal flux rate of ozanimod, the delivery area of the ozanimod drug formulation (e.g., which may be based on the cross-sectional area of a contemplated patch), and estimated drug utilization.
  • a contemplated drug matrix that is a part of, or a transdermal patch having a cross-sectional area of 6.45 cm 2 , wherein the amount of ozanimod provided in the patch ranges from about 1.55 mg to about 2.32 mg of the ozanimod free base.
  • a contemplated drug matrix that is a part of, or a patch having a cross-sectional area of 49 cm 2 , wherein the amount of ozanimod provided with the patch (e.g., as part of the drug matrix) may be from about 11.78 mg to about 17.62 mg of ozanimod free base.
  • a method of treating MS comprises transdermally administering an effective amount of ozanimod using a disclosed transdermal patch, to deliver 0.23 mg/day, 0.46 mg/day, or 0.92 mg/day of ozanimod, to a subject over 1 to 10 days, such as over 7 days.
  • the ozanimod is transdermally administered by administering a contemplated patch (as described herein) to the skin of a subject, wherein the patch includes a contemplated drug matrix described herein.
  • administering the patch to the skin of a subject includes placing and/or at least partially securing the patch to the skin of the subject.
  • a contemplated patch may include a release liner, which may be removed prior to placing the patch on the skin, thereby coupling the drug matrix with the skin to effectuate transdermal delivery of ozanimod to the subject.
  • the method of treatment comprises transdermally delivering the effective amount of ozanimod for a treatment period, which may be from 1 to 10 days, such as 7 days.
  • the method comprises transdermally delivering the effective amount of ozanimod at a constant rate, or substantially constant rate over the treatment period.
  • the method comprises transdermally delivering the effective amount of ozanimod at a constant rate, or substantially constant rate over the treatment period, such that titration of the prescribed dosage of ozanimod is not required.
  • the time to reach steady state delivery of ozanimod transdermally is reduced as compared to traditional oral delivery of ozanimod, which may require about 104 hours (for example) to reach steady state, and also require frequent titration.
  • Attorney Docket No. CPS-100WO [0081]
  • the transdermal patch is administered once every treatment period.
  • the effective amount of ozanimod may be varied across different treatment periods.
  • a first treatment period may include transdermally delivering the ozanimod to the subject at 0.23 mg/day, while a subsequent treatment period may include transdermally delivering the ozanimod to the subject at 0.46 mg/day or 0.92 mg/day.
  • transdermal delivery of ozanimod results in lower liver function test abnormalities as compared with traditional oral delivery of ozanimod. In some cases, such lower liver function test abnormalities is due to avoiding first pass metabolism of the ozanimod that may occur with traditional oral delivery of ozanimod.
  • the C max through transdermal delivery of ozanimod is lower compared with traditional oral delivery of ozanimod.
  • transdermal delivery of ozanimod results in reduced incidences of macular edema, and/or reduced adverse events as compared with traditional oral delivery of ozanimod.
  • placement of the drug matrix as described herein on the skin of a subject may not result in any concerns for skin irritation, toxicity, and/or sensitization (see Example 3).
  • Example 1 Comparison of transdermal flux between exemplary drug matrices
  • Table 1 depicts four exemplary compositions for a contemplated drug matrix described herein: i) the OZD-4 formulation, ii) the OZD-15 formulation, iii) the OZD- 16 formulation, and iv) the OZD-22 formulation.
  • the OZD-4 and OZD-15 formulations included 3.0 wt.% (dry) of ozanimod (based on the total weight of the formulation, i.e., 77.4 mg), while the OZD-16 and OZD-22 formulations included 2.0 wt.% (dry) of ozanimod.
  • the drug matrices were provided as part of a transdermal patch having a cross-sectional area of Attorney Docket No. CPS-100WO 6.45 cm 2 .
  • the drug matrices varied between either oleic acid and levulinic acid, and either methyl laurate and n-methyl pyrrolidone.
  • FIG.2 depicts a comparison of the transdermal flux (skin flux) profile over time. As depicted, aside from the OZD-4 formulation, all the other drug matrices had a transdermal flux of at least 0.3 ⁇ g/cm 2 h over the entire time period (approximately 170 hours).
  • FIG.3 depicts the cumulative skin permeation (e.g., transdermal delivery) of ozanimod to a subject, wherein the increase in the cumulative ozanimod skin permeation tracked relatively close to that of the respective skin flux profile over time.
  • all of the drug matrices are capable of delivering ozanimod with a transdermal flux of at least 0.3 ⁇ g/cm 2 h at least partially across a given time period.

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Abstract

Des modes de réalisation de l'invention comprennent, dans certains modes de réalisation, une formulation de médicament, par exemple, un timbre pharmaceutiquement acceptable, et/ou une matrice de médicament, conçue pour l'administration transdermique d'ozanimod ou d'un sel pharmaceutiquement acceptable de celui-ci. Les matrices médicamenteuses envisagées comprennent l'ozanimod et un activateur de perméation. Selon certains modes de réalisation, une formulation ou une matrice de médicament envisagée est conçue pour administrer par voie transdermique une quantité efficace d'ozanimod à un sujet, une telle quantité efficace pouvant correspondre à une vitesse de dosage de 0,23 mg/jour, 0,46 mg/jour et/ou 0,92 mg/jour d'ozanimod. Dans certains modes de réalisation, une formulation de médicament fournie peut être conçue pour administrer l'ozanimod par voie transdermique avec un débit transdermique d'environ 0,29 µg/cm 2 h à environ 0,5 µg/cm 2 h à 32 °C. Les matrices de médicament envisagées peuvent faire partie de, ou un timbre conçu pour être placé autour de la peau d'un sujet, de façon à effectuer une administration transdermique de l'ozanimod au sujet.
PCT/US2025/010414 2024-01-04 2025-01-06 Dispositifs et procédés d'administration transdermique d'ozanimod Pending WO2025147698A1 (fr)

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Publication number Priority date Publication date Assignee Title
US20220265568A1 (en) * 2019-07-29 2022-08-25 Lts Lohmann Therapie-Systeme Ag Process for preparing pressure sensitive adhesive compounds for use in a transdermal therapeutic system

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220265568A1 (en) * 2019-07-29 2022-08-25 Lts Lohmann Therapie-Systeme Ag Process for preparing pressure sensitive adhesive compounds for use in a transdermal therapeutic system

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TRAN J.Q. ET AL.: "Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study", CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, WILEY-BLACKWELL PUBLISHING LTD, GB, vol. 7, no. 3, 7 August 2017 (2017-08-07), pages 263 - 276, XP072469888, ISSN: 2160-763X, DOI: 10.1002/CPDD.383 *

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