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WO2025009608A1 - Régulateur de concentration pour substance in vivo ou médicament dans un système semi-fermé in vivo - Google Patents

Régulateur de concentration pour substance in vivo ou médicament dans un système semi-fermé in vivo Download PDF

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Publication number
WO2025009608A1
WO2025009608A1 PCT/JP2024/024382 JP2024024382W WO2025009608A1 WO 2025009608 A1 WO2025009608 A1 WO 2025009608A1 JP 2024024382 W JP2024024382 W JP 2024024382W WO 2025009608 A1 WO2025009608 A1 WO 2025009608A1
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drug
concentration
semi
aqueous humor
closed system
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Japanese (ja)
Inventor
秀徳 高橋
良太 高橋
悟 伊野田
卓也 高山
健一 相澤
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Jichi Medical University
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Jichi Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to regulating the concentration of a substance or drug in a semi-closed system in the body, such as increasing or suppressing the intraocular concentration of an intravitreal preparation, such as an anti-VEGF drug or other intravitreal injection preparation.
  • nAMD Exudative age-related macular degeneration
  • VEGF vascular endothelial growth factor
  • Treatment for nAMD involves intravitreal injection of anti-VEGF drugs, but the effect lasts for one to three months, and the only way to maintain the effect at present is through frequent injections.
  • the reason why the effect of anti-VEGF drugs lasts for a short time is thought to be because the drug passes through an outflow pathway via the aqueous humor circulation and is transported to the entire body (see non-patent documents 1, 5, and 6).
  • Intravitreal injections have major problems in terms of complications and costs.
  • intravitreal injections are extremely expensive, with the cost of a single dose exceeding 100,000 yen.
  • Another problem is that medical costs become very high. For this reason, it is desirable to have as few injections as possible.
  • Eye drops for glaucoma Drugs that control the dynamics of aqueous humor production and outflow are widely used as eye drops for glaucoma.
  • Aqueous humor is produced in the ciliary body and excreted through two outflow pathways (trabecular pathway and uveoscleral pathway).
  • Eye drops for glaucoma are classified according to their mechanism of action into parasympathomimetics, sympathomimetics, sympatholytics, prostaglandin drugs, and carbonic anhydrase inhibitors, and act to suppress aqueous humor production and promote outflow, thereby lowering intraocular pressure (Non-Patent Document 1).
  • Eye drops for glaucoma cost less than 3,000 yen for one month of use, which is less than 1/30 the price of anti-VEGF drugs.
  • sympathomimetics promote aqueous humor regeneration.
  • PVD posterior vitreous detachment
  • the human body also has semi-closed systems such as the spinal cavity and joint cavities, similar to the eyeball.
  • the present invention aims to regulate the concentration of an in vivo substance or drug in a semi-closed system in the body, such as by increasing or suppressing the anterior chamber concentration of an intravitreal preparation, such as an anti-VEGF drug or other intravitreal injection preparation.
  • an intravitreal preparation such as an anti-VEGF drug or other intravitreal injection preparation.
  • the inventors have considered whether it is possible to maintain the concentration of intravitreal preparations, such as drugs for intravitreal injection, for a long period of time by controlling the dynamics of aqueous humor production and outflow.
  • intravitreal preparations such as drugs for intravitreal injection
  • intraocular drug concentration for a longer period of time.
  • drugs that promote or suppress the production or outflow of body fluids in a semi-closed system in the body such as aqueous humor production inhibitors or aqueous humor outflow promoters, such as glaucoma treatment drugs, improve or suppress the anterior chamber concentration of intravitreal preparations, such as anti-VEGF drugs for intravitreal injection.
  • the anterior chamber and the vitreous body communicate with each other within the same eye, and the concentration of intravitreal preparations in the anterior chamber is about 1/40 of the concentration in the vitreous body.
  • a concentration regulator for a substance or drug in a semi-closed system in the body which comprises as an active ingredient a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed system in the body.
  • Aspect 2 The concentration regulator according to Aspect 1, wherein the body fluid in the semi-closed system in the body is aqueous humor, and the semi-closed system in the body is the anterior chamber.
  • Aspect 3 The concentration regulator according to Aspect 1, wherein the drug that promotes or inhibits the production or excretion of body fluids in a semi-closed system in the body is an aqueous humor production inhibitor or an aqueous humor outflow promoter, and the concentration regulator of an in vivo substance or drug in the semi-closed system in the body is an agent that enhances or inhibits the concentration of an in vivo substance or drug in the anterior chamber.
  • the aqueous humor production inhibitor or aqueous humor outflow promoter is a therapeutic agent for glaucoma.
  • the concentration regulator according to aspect 4 wherein the therapeutic agent for glaucoma is an ⁇ 2 agonist, a sympathetic ⁇ -blocker, a carbonic anhydrase inhibitor, or a prostanoid receptor associated drug.
  • the drug is an intravitreal formulation.
  • the concentration adjusting agent according to Aspect 6 wherein the intravitreal preparation is an anti-VEGF drug.
  • the anti-VEGF drug is an anti-VEGF-A drug, an anti-VEGF-B drug, or an anti-PlGF drug.
  • Aspect 9 The concentration regulator according to Aspect 8, wherein the anti-VEGF drug is aflibercept.
  • Aspect 10 The concentration regulator according to Aspect 1, wherein the biological substance is a physiologically active substance.
  • Aspect 11 The concentration regulator according to Aspect 10, wherein the physiologically active substance is a cytokine.
  • Aspect 12 The concentration regulator according to aspect 11, wherein the cytokine is CXCL1 or TNF- ⁇ .
  • the concentration of a substance or drug in a semi-closed system in the body can be adjusted by promoting or inhibiting the production or discharge of body fluids in the semi-closed system in the body, such as controlling the drug concentration in the anterior chamber by controlling the dynamics of the production or discharge of aqueous humor.
  • the number of intravitreal injections is reduced, and the occurrence of complications due to intravitreal injections is reduced, thereby improving the prognosis of nAMD, leading to a reduction in medical expenses for nAMD, and reducing the number of hospital visits, thereby easing the burden on patients.
  • glaucoma eye drops as a drug concentration control for anti-VEGF drugs, as in a more specific embodiment of the present invention, leads to drug repositioning, and has the advantages of certainty due to confirmed safety and pharmacokinetics at the clinical level, and low cost due to the use of a large amount of existing data (see Non-Patent Document 3 above).
  • FIG. 1 is a graph showing the results of univariate analysis of eye drop scores and Eylea concentrations.
  • FIG. 2 is a graph showing the results of multivariate analysis of age, sex, axial length, and eye drop score with Eylea concentration as the objective variable.
  • the present invention provides a concentration regulator for a substance or drug in a semi-closed system in the body, the concentration regulator containing as an active ingredient a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed system in the body.
  • Examples of semi-closed systems in the body include the eyeball, anterior chamber, abdominal cavity, skull, spinal cavity, joint cavity, etc.
  • Examples of body fluids in semi-closed systems in the body include aqueous humor, cerebrospinal fluid, intra-articular fluid, etc.
  • the present invention provides an agent for adjusting the concentration of an endogenous substance or drug in a semi-closed system in the body, which contains as an active ingredient a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed system in the body.
  • the drug that promotes or inhibits the production or excretion of body fluids in the semi-closed system in the body is, for example, an aqueous humor production inhibitor or an aqueous humor outflow promoter
  • the agent for adjusting the concentration of an endogenous substance or drug in a semi-closed system in the body is, for example, an agent that enhances or inhibits the concentration of the endogenous substance or drug in the anterior chamber.
  • An aqueous humor production inhibitor is an agent that inhibits the production of aqueous humor or is expected to inhibit the production of aqueous humor
  • an aqueous humor outflow promoter is an agent that promotes the outflow of aqueous humor or is expected to promote the outflow of aqueous humor.
  • aqueous humor production inhibitors or aqueous humor outflow promoters include glaucoma treatments such as glaucoma eye drops, carbonic anhydrase inhibitors (e.g., powder or tablet) such as acetazolamide, and intracranial pressure reducing or osmotic diuretics such as mannitol infusion. Similar effects can be expected from oral medications, injections, inhalants, etc. that match the mechanism of action, without being limited to the drug form of eye drops. Since they act on the whole body, they are not worth the side effects, but for example, oral administration of Diamox (acetazolamide) significantly suppresses aqueous humor production.
  • aqueous humor production inhibitors or aqueous humor outflow promoters examples include aqueous humor production inhibitors, aqueous humor main outflow promoters, aqueous humor accessory outflow promoters, aqueous humor production inhibitors and accessory outflow promoters.
  • aqueous humor production inhibitors include sympathetic beta-blockers, carbonic anhydrase inhibitors, alpha beta-blockers, etc.
  • aqueous humor main outflow promoters include Rho kinase inhibitors and parasympathetic stimulants.
  • aqueous humor accessory outflow promoters include prostanoid receptor-related drugs such as prostaglandins.
  • aqueous humor production inhibitors and accessory outflow promoters include adrenergic alpha 2 receptor agonists, etc.
  • glaucoma therapeutic agents include prostaglandins (PGs), prostanoid receptor-associated drugs such as latanoprost, travoprost, tafluprost, and bimatoprost; sympathetic beta-blockers (beta-blockers) such as timolol maleate, carteolol hydrochloride, and betaxolol hydrochloride; carbonic anhydrase inhibitors (CAIs) such as dorzolamide hydrochloride, brinzolamide, and diamox (acetazolamide); alpha 2 agonists such as brimonidine and brimonidine tartrate; sympathetic alpha 2 stimulants; ROCK inhibitors (Rho kinase inhibitors) such as ripasudil hydrochloride hydrate; and beech.
  • PGs prostaglandins
  • Examples of such drugs include sympathetic alpha-1 blockers such as Zosyn hydrochloride; sympathetic alpha-1 beta blockers such as nipradilol; ion channel openers such as isopropyl unoprostone; parasympathomimetics such as pilocarpine hydrochloride; parasympathomimetics; sympathomimetics such as dipivefrine hydrochloride; osmotic diuretics such as mannitol; selective EP2 receptor agonists such as omidenepag isopropyl; and combination eye drops of the respective drugs, and preferred examples include alpha-2 agonists such as brimonidine; sympathetic beta blockers; carbonic anhydrase inhibitors; and prostanoid receptor related drugs such as prostaglandins.
  • sympathetic beta-blockers such as timolol maleate, carteolol hydrochloride, and betaxolol hydrochloride
  • carbonic anhydrase inhibitors CAIs
  • alpha-2 agonists such as brimonidine and brimonidine tartrate
  • the concentration of a substance or drug in the body can be adjusted in the semi-closed system by administering a drug that promotes or inhibits the production or discharge of body fluids in the semi-closed system in the body. That is, for example, the concentration of an intravitreal preparation in the anterior chamber can be improved or inhibited by administering an aqueous humor production inhibitor or an aqueous humor outflow promoter, such as a glaucoma treatment agent. It is also possible to apply the present invention to promote the outflow of substances that have specific adverse effects in the ophthalmic field, such as intraocular inflammatory cytokines, or conversely, to retain physiologically active substances that have a protective effect on nerves, etc., in the eye.
  • the intravitreal preparation is, for example, a preparation that is localized inside the vitreous body, and the preparation may be administered by eye drops, vitreous injection, intraarterial injection, intravenous injection, subcutaneous injection, subconjunctival injection, etc., as well as intranasally, transbronchially, intramuscularly, transdermally, or orally, but is preferably administered by vitreous injection. That is, the intravitreal preparation is preferably a vitreous injection preparation.
  • Intravitreal preparations include, for example, anti-VEGF drugs, anti-cancer drugs, and antibodies against various uveitis, many of which are already on the market, but according to the knowledge of the present inventors, intravitreal preparations are not limited to these already on the market, and will also include new drugs that will be developed in the future.
  • anti-VEGF drugs include anti-VEGF-A drugs, anti-VEGF-B drugs, and anti-PlGF drugs.
  • anti-VEGF drugs include Eylea (aflibercept), pegaptanib, bevacizumab, ranibizumab, brolucizumab, and faricimab.
  • Eylea is an anti-VEGF-A drug, an anti-VEGF-B drug, and an anti-PlGF drug.
  • the anterior chamber concentration of the intravitreal preparation can be measured, for example, by anterior chamber paracentesis.
  • the biological substance may be, for example, a physiologically active substance, and examples of the physiologically active substance include cytokines.
  • cytokines include CXCL1 and TNF- ⁇
  • examples of cytokines include interleukin (IL), hematopoietic factors (CSF, EPO, TPO), interferon (IFN), tumor necrosis factor (TNF), growth factors, growth factors (EGF, FGF, PDGF), and chemokine (IL-8).
  • the subject When administering to a subject a drug that promotes or inhibits the production or excretion of bodily fluids in a semi-closed system in the body, which is the active ingredient of the concentration regulator in a semi-closed system in the body of a substance or drug in the body of the present invention, the subject is preferably a person who has been administered a drug such as an intravitreal preparation.
  • the dosage of a drug such as an intravitreal preparation is, for example, generally 0.5 mg to 6.0 mg of the active ingredient per dose for an adult (body weight 60 kg).
  • examples of the subject include subjects suffering from exudative age-related macular degeneration (nAMD) as well as subjects suffering from other diseases that can be treated with anti-VEGF drugs.
  • nAMD exudative age-related macular degeneration
  • Examples of other diseases that can be treated with anti-VEGF drugs include diabetic retinopathy, retinal vein occlusion, myopic choroidal neovascularization, neovascular glaucoma, retinopathy of prematurity, and other intraocular neovascular diseases in general, including other rare diseases.
  • diseases include diabetic retinopathy, retinal vein occlusion, myopic choroidal neovascularization, neovascular glaucoma, retinopathy of prematurity, and other intraocular neovascular diseases in general, including other rare diseases.
  • the subject include mammals such as humans, mice, rats, cows, pigs, monkeys, dogs, and cats, but preferably humans.
  • the concentration regulator of an in vivo substance or drug in a semi-closed in vivo system of the present invention may be a drug that promotes or inhibits the production or excretion of body fluids in the semi-closed in vivo system, or may be formulated as a pharmaceutical composition mixed with a pharma- ceutically acceptable carrier.
  • the pharmaceutical composition may be formulated in a dosage form for oral use, such as tablets, capsules, elixirs, and microcapsules, or in a dosage form for parenteral use, such as eye drops, injections, ointments, and patches.
  • Examples of pharma- ceutically acceptable carriers include solvents such as sterilized water and saline; binders such as gelatin, cornstarch, gum tragacanth, and gum arabic; excipients such as crystalline cellulose; and leavening agents such as cornstarch, gelatin, and alginic acid.
  • Pharmaceutically acceptable carriers include additives.
  • additives include lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, and saccharin; flavorings such as peppermint and saffron oil; stabilizers such as benzyl alcohol and phenol; buffers such as phosphates and sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; preservatives; surfactants; and emulsifiers.
  • lubricants such as magnesium stearate
  • sweeteners such as sucrose, lactose, and saccharin
  • flavorings such as peppermint and saffron oil
  • stabilizers such as benzyl alcohol and phenol
  • buffers such as phosphates and sodium acetate
  • solubilizers such as benzyl benzoate and benzyl alcohol
  • antioxidants preservatives
  • surfactants such as surfactants; and emulsifier
  • the pharmaceutical composition can be formulated by combining the above-mentioned carriers appropriately and mixing them in a unit dosage form required for generally accepted pharmaceutical practice.
  • examples of the solvent for the injection include isotonic solutions containing adjuvants such as physiological saline, glucose, D-sorbitol, D-mannose, D-mannitol, and sodium chloride.
  • the solvent for the injection may contain alcohol such as ethanol; polyalcohol such as propylene glycol and polyethylene glycol; nonionic surfactants such as polysorbate 80 (trademark) and HCO-50; etc.
  • administration of the concentration regulator of the present invention in a semi-closed biological system of a biological substance or drug to a subject is not particularly limited and can be appropriately selected depending on the organ in which the target symptom is manifested.
  • administration can be by eye drop, intra-arterial injection, intravenous injection, subcutaneous injection, subconjunctival injection, etc., as well as intranasal, transbronchial, intramuscular, transdermal, or oral administration by methods known to those skilled in the art.
  • the dosage of the concentration regulator of the present invention in a semi-closed biological system for a substance or drug in the body varies depending on the symptoms, but in the case of oral administration, the dosage is generally, for example, 250 mg to 1,000 mg of active ingredient per day for an adult (body weight 60 kg) (especially when Diamox (acetazolamide) is taken orally according to the package insert).
  • the single dose of the concentration regulator of the present invention in a semi-closed biological system of a biological substance or drug in the present invention varies depending on the subject, target organ, symptoms, and administration method, but for example, in the form of eye drops, it can be administered to an adult (body weight 60 kg) by instilling one drop at a time, once or twice a day, and in the form of an injection, it can be administered to an adult (body weight 60 kg) by intravenous or local injection, for example, at about 60 mg to 180 mg of the active ingredient per day (particularly when 20% mannitol is administered by infusion as instructed in the package insert).
  • the administration of the concentration regulator in a semi-closed in vivo system of a substance or drug in the body of the present invention to a subject is, for example, before administration of the drug to the subject, simultaneously with administration of the drug to the subject, or after administration of the drug to the subject.
  • the administration of the concentration regulator in a semi-closed in vivo system of a substance or drug in the body of the present invention to a subject is before administration of the drug to the subject
  • the administration of the concentration regulator in a semi-closed in vivo system of a substance or drug in the body of the present invention to a subject is, for example, 1 hour to 6 hours before administration of the drug to the subject.
  • the administration of the concentration regulator in a semi-closed in vivo system of a substance or drug in the body of the present invention to a subject is after administration of the drug to the subject
  • the administration of the concentration regulator in a semi-closed in vivo system of a substance or drug in the body of the present invention to a subject is, for example, 1 hour to 6 hours after administration of the drug to the subject.
  • the present invention provides a method for regulating the concentration of an endogenous substance or drug in an in vivo semi-closed system, characterized by administering to a subject a drug that promotes or inhibits the production or excretion of body fluids in the in vivo semi-closed system.
  • the present invention also provides a pharmaceutical composition for use in regulating the concentration of an endogenous substance or drug in an in vivo semi-closed system, which contains as an active ingredient a drug that promotes or inhibits the production or excretion of body fluids in the in vivo semi-closed system.
  • the present invention provides the use of a drug that promotes or inhibits the production or excretion of body fluids in an in vivo semi-closed system in the manufacture of a pharmaceutical composition for use in regulating the concentration of an endogenous substance or drug in an in vivo semi-closed system.
  • Example 1 Subjects and selection criteria: The inventors have been collecting aqueous humor during intravitreal injections of nAMD for over 10 years, and have frozen and stored tens of thousands of samples. Therefore, subjects were 13 people who used glaucoma eye drops and could measure the aqueous humor concentration 28 days after Eylea vitreous injection. In addition, subjects who could measure the aqueous humor concentration 28 days after Eylea vitreous injection, matched by age and sex, were used as controls.
  • the glaucoma eye drops used were specifically Xalatan (latanoprost), Lumigan (bimatoprost), Cosopt (dorzolamide hydrochloride-timolol maleate solution), Aiphagan (brimonidine tartrate), Tapros (tafluprost), Duotrava (travoprost-timolol maleate solution), etc.
  • the age, sex, axial length, and eye drop score were examined for the above subjects and controls.
  • Eylea is an anti-VEGF drug.
  • As for the eye drop score glaucoma eye drops that act to suppress aqueous humor production are thought to increase the concentration of the vitreous injection, so each drug was given a +1.
  • glaucoma eye drops that act to promote aqueous humor outflow are thought to decrease the concentration of the vitreous injection, so each drug was given a -1.
  • Example 2 Regulation of the concentration of a substance or drug in the body by a drug that promotes or inhibits the production or excretion of body fluids in a semi-closed system in the body: An increase in aflibercept concentration in the anterior chamber was observed after topical brimonidine instillation. The mean aflibercept concentration was 18 (standard deviation (SD) 6.4) and 6.5 (6.6) pg/mL, respectively, in 6 eyes vs. 74 eyes, respectively, p ⁇ 0.0001.
  • Brimonidine instillation primarily suppresses aqueous humor production to lower intraocular pressure, and this is thought to have suppressed the aqueous humor production and reduced the outflow of aflibercept from the main outflow pathway via the trabecular meshwork-Schlemm's canal and the accessory outflow pathway via the uveosclera, thereby suppressing the decrease in aflibercept concentration.
  • An increase in aflibercept concentration in the anterior chamber was observed with topical administration of beta-blockers and carbonic anhydrase inhibitors (CAIs), which have a purely aqueous humor production-inhibiting effect.
  • CAIs carbonic anhydrase inhibitors
  • Beta-blockers aflibercept concentrations were 15 (9.3) and 6.2 (6,2) pg/mL in 10 eyes vs. 70 eyes, p ⁇ 0.0001.
  • TNF- ⁇ was selected and its concentration was measured because these are not related to inflammation.
  • Example 3 As shown in Table 1 below, it has been found that the present invention can reduce drug prices by several tens of thousands of yen per year.
  • the vitreous concentration (pg/mL) on day 0 is calculated by administering 2 mg of aflibercept to a vitreous volume of 4.5 mL. Since the measurement is performed in the anterior chamber, where it is easy to do, the concentration in the anterior chamber is 1/40 of that in the vitreous, so it is set to 1/40.
  • the concentration (pg/mL) on day 28 is the concentration actually collected from patients with and without brimonidine eye drops, which have both the effects of suppressing production and promoting outflow, reducing flow rate by 37%.
  • the concentration (pg/mL) on day 84 when the effect is calculated to be no longer effective, can be calculated. Since brimonidine is still effective, the value on day 84, 2.22446E-12, is copied into the column for brimonidine eye drops, and the number of days is calculated to be 90.42 days. From this, it can be seen that the number of times per year for Eylea will be reduced from 4.345 to 4.037, and the drug price will be reduced by 42,862 yen per year. The price of generic brimonidine is low at 129 yen/mL, so if the eye dropper bottle is discarded after one month as recommended by the pharmaceutical company, the annual cost will be 7,740 yen. Therefore, the present invention is expected to reduce the drug price by 42,862 yen per year and reduce the risk, invasiveness, and discomfort associated with eye puncture, such as endophthalmitis.

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Abstract

La présente invention permet de réguler la concentration d'une substance in vivo ou d'un médicament dans un système semi-fermé in vivo, par exemple, pour améliorer ou supprimer la concentration intraoculaire d'une formulation intravitréenne, par exemple, une formulation d'injection de corps vitré, telle qu'un médicament anti-VEGF. La présente invention concerne un régulateur de concentration pour une substance in vivo ou un médicament dans un système semi-fermé in vivo, le régulateur de concentration contenant, comme principe actif, un médicament qui favorise ou supprime la production ou l'évacuation d'un fluide corporel dans le système semi-fermé in vivo.
PCT/JP2024/024382 2023-07-06 2024-07-05 Régulateur de concentration pour substance in vivo ou médicament dans un système semi-fermé in vivo Pending WO2025009608A1 (fr)

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* Cited by examiner, † Cited by third party
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JP2016502502A (ja) * 2012-10-05 2016-01-28 カドモン コーポレイション，リミティド ライアビリティ カンパニー 眼疾患の治療
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ENGEL LISA A., MUETHER PHILIPP S., FAUSER SASCHA, HUEBER ARNO: "The effect of previous surgery and topical eye drops for primary open-angle glaucoma on cytokine expression in aqueous humor", GRAEFE'S ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, SPRINGER BERLIN HEIDELBERG, BERLIN/HEIDELBERG, vol. 252, no. 5, 1 May 2014 (2014-05-01), Berlin/Heidelberg, pages 791 - 799, XP093258957, ISSN: 0721-832X, DOI: 10.1007/s00417-014-2607-5 *
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YANG QING, LI YING, LUO LIN: "Effect of myricetin on primary open-angle glaucoma", TRANSLATIONAL NEUROSCIENCE, vol. 9, no. 1, 12 November 2018 (2018-11-12), pages 132 - 141, XP093258958, ISSN: 2081-6936, DOI: 10.1515/tnsci-2018-0020 *

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