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EP4580600A1 - Compositions ophtalmiques - Google Patents

Compositions ophtalmiques

Info

Publication number
EP4580600A1
EP4580600A1 EP23765459.5A EP23765459A EP4580600A1 EP 4580600 A1 EP4580600 A1 EP 4580600A1 EP 23765459 A EP23765459 A EP 23765459A EP 4580600 A1 EP4580600 A1 EP 4580600A1
Authority
EP
European Patent Office
Prior art keywords
silica
composition
hydrogel
microparticles
pharmaceutically acceptable
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
EP23765459.5A
Other languages
German (de)
English (en)
Inventor
Minna VAAHTIO
Lasse Leino
Mika KAIMAINEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Optifye Therapeutics Ag
Original Assignee
Optifye Therapeutics Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Optifye Therapeutics Ag filed Critical Optifye Therapeutics Ag
Publication of EP4580600A1 publication Critical patent/EP4580600A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • This invention relates to a sustained or controlled release ophthalmic composition for topical delivery. More specifically a sustained or controlled release ophthalmic composition comprising an active pharmaceutical ingredient in a hydrogel silica composition is disclosed herein, which is especially feasible to administer as a topical eye drop, and is suitable for once-a-day administration of the active pharmaceutical ingredient.
  • Topical ophthalmic drug delivery systems for treatment of ocular inflammation are typically available in the form of dosage forms such as solutions, suspensions, gels and ointments. While these have been found suitable, thus far, for delivery of the required active ingredient to the eye, there are several disadvantages associated with these conventional dosage forms, the most common being the need to administer multiple times a day.
  • the conventional gel and ointment dosage forms are also known to impact vision, or acuity of it, while solution dosage forms are too easily washed off from the surface of the eye. Further, suspension products, if not formulated appropriately, can be gritty, causing injury to the cornea.
  • Drugs, or active ingredients, that are typically used for treatment of ocular inflammation such as those arising from disease conditions of the conjunctiva, cornea and anterior segment of the eye, like anterior uveitis, ulceris, cyclitis, allergic and vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis and non-specific superficial keratitis; corneal injury from chemical, radiation or thermal burns or following penetration by foreign bodies; postoperative use to reduce inflammatory reactions; graft reaction, and the like, include corticosteroids such as dexamethasone and its pharmaceutically acceptable salts, prostaglandins such as bimatoprost, latanoprost and others.
  • corticosteroids such as dexamethasone and its pharmaceutically acceptable salts
  • prostaglandins such as bimatoprost, latanoprost and others.
  • Maxidex® a 0.1%w/v suspension containing dexamethasone is indicated for treatment of steroid responsive inflammatory conditions of the conjunctiva, cornea and anterior segment of the eye, such as, anterior uveitis, ulceris, cyclitis, allergic and vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis and non-specific superficial keratitis. It is also indicated for the treatment of corneal injury from chemical, radiation or thermal burns or following penetration by foreign bodies, and for post-operative use to reduce inflammatory reactions and suppress graft reaction.
  • EP 1904108 discloses generally the use of a composition with a permeation enhancer, methyl sulfonylmethane, for treatment of disorders, diseases, and other adverse medical conditions, including the adverse ocular conditions disorders often associated with aging.
  • EP3265096 relates to compositions and methods useful for the treatment and/or prevention of conditions of the eye, including dexamethasone as an active ingredient.
  • WO2019126176 relates to a novel mixed transition metal oxide and its use as a catalyst or catalyst precursor such as a hydrocarbon conversion catalyst or catalyst precursor or specifically a hydroprocessing catalyst or catalyst precursor, along with an active ingredient such as dexamethasone. None of these disclosures provide a composition suitable for once daily administration to the eye, in the form of eye drops that can be conveniently administered in the subconjunctival sac.
  • An objective of the present disclosure is to provide a hydrogel silica composition comprising an active pharmaceutical ingredient for topical ophthalmic administration.
  • a first aspect relates to a hydrogel silica composition comprising: a) silica microparticles comprising an active pharmaceutical ingredient, and having a maximum diameter in a range of about 0.5 pm to about 40 pm, and b) a silica sol comprising solid nanoparticles of ⁇ 50 nm; wherein, i) said silica sol has a solid content of ⁇ 1% by weight, ii) said hydrogel silica composition comprises up to 30% by weight of the composition of said silica microparticles, and iii) said hydrogel silica composition is for topical administration.
  • the hydrogel silica composition is provided in the form of topical eye drops. In another preferred embodiment, the hydrogel silica composition is provided in a single dose container.
  • the disclosure provides a silica hydrogel composition for use in the treatment of an eye disorder or eye disease.
  • the silica hydrogel composition is for topical ophthalmic administration. More preferably, the hydrogel silica composition is topically administered once-a-day.
  • the eye disorder or eye disease is ocular inflammation.
  • the ocular inflammation is selected from anterior uveitis, ulceris, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or non-specific superficial keratitis, or post-operative ocular inflammation or inflammatory reactions.
  • ocular inflammation is post-operative ocular inflammation or inflammatory reaction.
  • the eye disorder or eye disease is corneal injury from chemical, radiation or thermal bums or following penetration by foreign bodies.
  • Another aspect relates to a method of treatment of an eye disorder or an eye disease in a patient in need thereof, the method comprising topically administering to the patient the said hydrogel silica composition.
  • the eye disease or eye disorder is ocular inflammation selected from anterior uveitis, ulceris, cyclitis, allergic or vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis or non-specific superficial keratitis or post-operative ocular inflammation or inflammatory reaction, preferably the ocular inflammation is post-operative ocular inflammation or inflammatory reaction.
  • the hydrogel silica composition comprises dexamethasone or its pharmaceutically acceptable salt as active ingredient.
  • a yet another aspect relates to the use of the said silica hydrogel composition for treatment of an eye disorder or an eye disease.
  • the silica microparticles are obtained by a process of spray drying the silica with the active pharmaceutical ingredient.
  • a hydrogel silica composition comprising: a) silica microparticles containing about ⁇ 15 wt-%, preferably 10 wt-%, more preferably ⁇ 7.5 wt-% of dexamethasone or its pharmaceutically acceptable salt, wherein the silica microparticles have an average diameter DIO in a range of 0.9 - 10 pm and/or average diameter D50 in a range of 0.5 - 15 pm and/or average diameter D90 in a range of 5 - 40 pm, preferably 5 - 20 pm; and b) a silica sol comprising solid nanoparticles of ⁇ 50 nm, wherein the silica sol has a solid content of ⁇ 1% by weight , and wherein the hydrogel silica composition comprises up to 30% by weight of the composition of said silica microparticles.
  • the silica sols (SS) to be mixed with the spray-dried silica microparticles (MP) with encapsulated dexamethasone were prepared using TEOS as a precursor.
  • R of 400 (corresponding to about 0.9%w/w of silica in the silica sol) was prepared.
  • the initial pH of every sample was adjusted to pH 2 using 0.1 M HC1.
  • the hydrolysis was allowed to occur at room temperature (i.e. at about 2°C to about 23°C) for 25 minutes under continuous mixing.
  • the pH was then raised to about 5.8 to about 6.2 by adding 0.1 M NaOH with continuous stirring.
  • the silica sols were immediately mixed with the spray-dried microparticles.
  • Rheological measurements were conducted with a rheometer (AR 2000 Ex, with a plastic plate measuring head having diameter of 60 mm, TA instruments, Germany) to measure storage (elastic) and loss (viscous) modulus (with oscillatory mode), and dynamic viscosity and thixotropic behaviour (with rotational mode) for the different compositions.
  • the hydrogel composites were injected directly from the single-dosing unit (SDU) onto the measuring plate of the rheometer in order to simulate the properties of the hydrogel composite in real operating situation.
  • SDU single-dosing unit
  • Storage modulus G’ (see Figure 3) for 3 different formulations (Formulations #04D-0.3, #06D-0.25, #06D-0.3) at room temperature (about 25 °C) were relatively low, at about 100- 4000 Pa at strain of 0.001-0.01 and angular frequency of 1Hz. Depending on the formulation, they were, during injection, either flowing (viscous, but still easily flowing) or directly easily extrudable hydrogels. Also, the loss moduli G” were low for #04D-0.3, #06D-0.25, #06D- 0.3.
  • Tear fluid (2 pl) was collected from rabbit eye at time points 0 (prior to dosing), Ih, 2h, 6h, 12h, 24h and 48 h after the dosing.
  • the tear fluid was collected using 2 pl capillary (Microcaps®).
  • the tear fluid was removed from the capillary to the plastic vials using a pipette (pressure technology).
  • 48 pl of 30% acetonitrile solution was added immediately after sample taking into the vials and the vial was sacked in order to mix the tear fluid and acetonitrile.
  • the samples were stored at 4-8°C until testing.
  • Table 5B Dexamethasone concentrations in tear fluids for Test Item #06D-0.25
  • Table 5C Dexamethasone concentrations in tear fluids for Test Item #06D-0.3
  • Tear fluid (2 pl) was collected from rabbit eye at time points shown in Table 13 below.
  • the tear fluid was collected using 2 pl capillary (Microcaps®).
  • the tear fluid was removed from the capillary to the plastic vials using a pipette (pressure technology).
  • the samples were stored at -20°C until testing in dry ice.
  • Tables 13A - 13D illustrate dexamethasone concentration in tear fluids for all compositions studied in vivo, showing parallel samples in both eyes.
  • Table 13C Dexamethasone concentration in tear fluids forMaxidex® single dose.
  • Table 13D Dexamethasone concentration in tear fluids forMaxidex® multiple dose. Clinical observations
  • Purity-% is calculated as a relation of main peak area to total area of main peak and area of peaks of related substances (peaks which area percent are under 0.05% are not included in the calculations). 2): Co-eluting impurity peaks in 25 °C and 40°C samples, which cannot be separated with current method.
  • Table 20 Storage stability data of Formulation #09 Table 21. Related substances analysis during storage stability of Formulation #09 detected but area percent is under 0.05%.
  • Purity-% is calculated as a relation of main peak area to total area of main peak and area of peaks of related substances (peaks which area percent are under 0.05% are not included in the calculations).
  • silica hydrogel compositions of ofloxacin were prepared by combining (i) silica microparticle with the formulation of R3-200 at pH 4.0 (using 80% ethanol as diluent for dilution from R3 to 200) with 5%w/w of encapsulated ofloxacin (calculated in relation to the theoretical silica amount) with (ii) R400 silica sol (0.3 g of silica microparticles in 1 ml of silica sol (Ofloxacin #04 D-0.3) and 0.4 g of silica microparticle in 1 ml of silica sol (Ofloxacin #04 D-0.4)).
  • This suspension was then transferred into the single dose units (SDU) through a 20 G needle. After the filling, the SDUs are allowed to gel for 1 day.
  • compositions and methods provided herein can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent to the persons of skill in the art that other embodiments exist, and that the described embodiments are illustrative and should not be construed as restrictive.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composition de silice d'hydrogel comprenant : a) des microparticules de silice comprenant un principe actif pharmaceutique, et présentant un diamètre maximal dans une plage de 0,5 à 40 µm, et b) un sol de silice comprenant des nanoparticules solides < 50 nm ; i) ledit sol de silice présentant une teneur en solides < 1 % en poids, ii) ladite composition de silice d'hydrogel comprenant jusqu'à 30 % en poids de la composition desdites microparticules de silice, et iii) ladite composition de silice d'hydrogel étant destinée à une administration ophtalmique topique.
EP23765459.5A 2022-09-01 2023-09-01 Compositions ophtalmiques Pending EP4580600A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI20225766 2022-09-01
PCT/EP2023/074034 WO2024047230A1 (fr) 2022-09-01 2023-09-01 Compositions ophtalmiques

Publications (1)

Publication Number Publication Date
EP4580600A1 true EP4580600A1 (fr) 2025-07-09

Family

ID=87971941

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23765459.5A Pending EP4580600A1 (fr) 2022-09-01 2023-09-01 Compositions ophtalmiques

Country Status (5)

Country Link
EP (1) EP4580600A1 (fr)
JP (1) JP2025529178A (fr)
KR (1) KR20250092172A (fr)
CN (1) CN120152697A (fr)
WO (1) WO2024047230A1 (fr)

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006270035A1 (en) 2005-07-15 2007-01-25 Chakshu Research Inc. Formulation and method for administration of ophthalmologically active agents
AU2014300888B2 (en) 2013-06-24 2019-01-17 Delsitech Oy Silica hydrogel composite
CN106660812B (zh) * 2014-06-30 2017-10-27 日挥触媒化成株式会社 多孔二氧化硅系粒子、其制造方法及配合其的化妆料
EP3265096B9 (fr) 2015-03-05 2023-10-04 TheiaNova Limited Compositions ophtalmiques et leurs procédés d'utilisation
HK1248570A1 (zh) * 2015-05-29 2018-10-19 西德奈克西斯公司 D2o稳定化的药物制剂
KR102228986B1 (ko) 2015-10-22 2021-03-18 델시테크 오와이 하이드로겔 복합체 데포 제형
CN107260655B (zh) * 2017-06-09 2021-03-09 金陵科技学院 一种维生素e改性的硅基水凝胶隐形眼镜载药体系及其制备方法
US10843176B2 (en) 2017-12-20 2020-11-24 Uop Llc Highly active quaternary metallic materials using short-chain alkyl quaternary ammonium compounds
US20220211800A1 (en) * 2018-09-21 2022-07-07 Cornell University Processes and agents for glaucoma
US20220265832A1 (en) * 2019-08-26 2022-08-25 University Of Montana Thixotropic delivery systems

Also Published As

Publication number Publication date
JP2025529178A (ja) 2025-09-04
CN120152697A (zh) 2025-06-13
KR20250092172A (ko) 2025-06-23
WO2024047230A1 (fr) 2024-03-07

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