WO2024258300A1 - Méthode d'amélioration de l'effet hypoglycémique systémique de l'insuline par voie topique avec utilisation d'analogues de la prostaglandine : nouvelle combinaison fixe de gouttes ophtalmiques d'insuline et d'analogues de la prostaglandine pour réduction du taux de glycémie - Google Patents

Méthode d'amélioration de l'effet hypoglycémique systémique de l'insuline par voie topique avec utilisation d'analogues de la prostaglandine : nouvelle combinaison fixe de gouttes ophtalmiques d'insuline et d'analogues de la prostaglandine pour réduction du taux de glycémie Download PDF

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Publication number
WO2024258300A1
WO2024258300A1 PCT/PH2024/050008 PH2024050008W WO2024258300A1 WO 2024258300 A1 WO2024258300 A1 WO 2024258300A1 PH 2024050008 W PH2024050008 W PH 2024050008W WO 2024258300 A1 WO2024258300 A1 WO 2024258300A1
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Prior art keywords
insulin
treatment
pharmaceutical composition
diabetes mellitus
application according
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PCT/PH2024/050008
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English (en)
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David Harold GOSIENGFIAO
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Priority to AU2024302192A priority Critical patent/AU2024302192A1/en
Priority to KR1020257043748A priority patent/KR20260016557A/ko
Priority to CN202480039450.3A priority patent/CN121368490A/zh
Publication of WO2024258300A1 publication Critical patent/WO2024258300A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • 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
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • This invention relates to a method of increasing the systemic hypoglycemic effect of insulin when applied topically to the eye through the use of prostaglandin analogues as penetration enhancers, more specifically, to an ophthalmic composition of insulin and prostaglandin analogue for the lowering of blood glucose level.
  • Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia or elevated blood sugar levels, affecting millions of individuals worldwide (International Diabetes Federation, 2019).
  • diabetes According to the International Diabetes Federation (IDF), as of 2021 , an estimated 537 million adults worldwide are living with diabetes, which represents approximately one in eleven adults. Due to factors such as aging populations, urbanization, and lifestyle changes, including unhealthy diets and reduced physical activity, the prevalence of diabetes is increasing globally. Diabetes is a significant cause of morbidity and mortality, with complications such as cardiovascular disease, kidney disease, nerve damage, and blindness. The IDF estimates that diabetes was responsible for 4.2 million deaths in 2019, making it one of the leading causes of death worldwide.
  • Insulin therapy is the cornerstone of treatment for type 1 diabetes and often required for advanced type 2 diabetes.
  • Insulin is a hormone used to lower blood glucose to normal levels. It achieves its hypoglycemic effect by promoting the uptake and storage of glucose in the body's tissues.
  • insulin products There are several types of insulin products available, which can be classified based on their onset, peak, and duration of action. These differences in action profiles allow healthcare providers to tailor insulin therapy to the individual needs of patients with diabetes.
  • the main types of insulin include:
  • Rapid-acting insulins start working within 15 minutes of administration, peak at approximately 1 hour, and last for 2-4 hours. They are typically taken just before or with meals to help control post-meal blood sugar spikes. Examples include insulin lispro (Humalog), insulin aspart (NovoLog), and insulin glulisine (Apidra).
  • short-acting insulin begins to work within 30 minutes to an hour, peaks at 2-4 hours, and lasts for 5-8 hours. It is usually taken 30 minutes before meals. Examples include Humulin R and Novolin R.
  • Intermediate-acting insulins have a slower onset and longer duration of action compared to short-acting insulin. They start working within 1-2 hours, peak at 4-12 hours, and last for 12- 18 hours. They are typically used to provide basal insulin coverage throughout the day.
  • NPH insulin Neuronal Protamine Hagedorn
  • Humulin N and Novolin N.
  • Long-acting insulins provide a slow, steady release of insulin with no pronounced peak, lasting for 15 up to 24 hours or longer. They are used to provide basal insulin coverage and are often combined with rapid- or short-acting insulin to cover mealtime blood sugar spikes. Examples include insulin glargine (Lantus, Toujeo), insulin detemir (Levemir), and insulin degludec (Tresiba).
  • Insulin molecules exist as monomers or can aggregate into dimers or hexamers. These aggregation states influence the rate of insulin absorption. Insulin monomers are more soluble and are absorbed more rapidly than dimers or hexamers.
  • Rapid-acting insulins are engineered to have minor alterations in their amino acid sequences compared to human insulin. These changes result in altered insulin molecules that do not self-aggregate into hexamers as readily as regular insulin, promoting faster absorption into the bloodstream.
  • Insulin lispro (Humalog) has a reversal of proline and lysine at positions B28 and B29. This change disrupts the hexamer formation and enhances its solubility, leading to faster absorption.
  • Insulin aspart has a proline at position B28 replaced with an aspartic acid, which also reduces hexamer formation and increases the rate of absorption.
  • Insulin glulisine (Apidra) has asparagine at position B3 replaced with a lysine and a lysine at position B29 replaced with a glutamic acid, which results in faster dissociation into monomers and quicker absorption.
  • Short-acting insulin (Regular insulin):
  • Regular insulin which is structurally identical to human insulin, forms hexamers in the presence of zinc ions. These hexamers must dissociate into dimers and then monomers before they can be absorbed into the bloodstream. This dissociation process slows down the absorption of regular insulin compared to rapid-acting analogs.
  • NPH insulin is a suspension of human insulin combined with protamine, a protein that forms a complex with insulin.
  • the protamine-insulin complex has reduced solubility, which slows down the absorption of insulin from the injection site into the bloodstream, resulting in an intermediate duration of action.
  • Insulin glargine (Lantus, Toujeo) has a glycine substituted for asparagine at position A21 and two arginines added to the B-chain. These changes make insulin glargine less soluble at physiological pH, causing it to precipitate at the injection site. The precipitate slowly dissolves over time, providing a slow, steady release of insulin.
  • Insulin detemir has a myristic acid fatty acid chain attached to lysine at position B29. This modification increases the binding of insulin detemir to albumin in the bloodstream and at the injection site, slowing down its absorption and prolonging its duration of action.
  • Insulin degludec has a hexadecanedioic acid side chain at position B29, which facilitates the formation of multi-hexamers. These multi-hexamers slowly release monomers, resulting in a prolonged and stable action profile.
  • Insulin is primarily administered by subcutaneous injections.
  • the delivery of insulin via the ocular route has been challenging because of ocular barriers.
  • These ocular barriers while essential for the eye's protection and homeostasis, present significant challenges for delivering insulin via eye drops. Overcoming these barriers is crucial for the development of a viable ocular insulin delivery system.
  • Insulin is a large molecule that consists of 51 amino acids. It has a molecular weight of approximately 5.8 kD. Its relatively large size results in poor passive diffusion across the ocular barriers — the corneal epithelium, tight junctions between cells, active efflux transporters — significantly reducing its absorption and bioavailability when delivered via eye drops.
  • the conjunctiva and sclera contribute to ocular drug absorption limitations. While these tissues are more permeable to hydrophilic molecules than the cornea, their ability to permit the passage of large molecules like insulin is still limited.
  • Insulin is typically administered through injections or an insulin pump, as it needs to be delivered directly into the bloodstream to be effective.
  • the present invention leverages a previously undescribed effect of prostaglandin and prostaglandin analogues on the permeability of the cornea and conjunctiva to large molecules for use as a penetration enhancer for insulin.
  • Prostaglandin and prostaglandin analogues have been used clinically as ocular hypotensives since 1998.
  • the first prostaglandin analogue to be approved by the FDA for clinical ophthalmic use is Latanoprost.
  • Later drugs include Unoprostone, Travoprost, Bimatoprost, Tafluprost, Latanoprostene.
  • Prostaglandin analogues are prodrugs which are hydrolyzed in the cornea into their active form to selectively stimulate the prostaglandin F2 alpha receptor to cause upregulation of matrix metalloproteinases and remodeling of the extracellular matrix in the structures of the eye adjacent to Schlemm’s canal where aqueous humor drains. These actions result in higher tissue permeability of these structures, thereby decreasing outflow resistance to aqueous which results in a drop in intraocular pressure.
  • Aqueous contains cells and large proteins
  • latanoprost has been shown to increase corneal hysteresis not correlated with the drug-induced decrease in the intraocular pressure. This suggests a direct effect of latanoprost on the viscoelastic corneal propertiespn 1 -
  • prostaglandin analogues travoprost, latanoprost and bimatoprost have likewise been associated with different extents of reduction in tissue stiffness and changes in corneal microstructureTM.
  • SUBSTITUTE SHEET (RULE 26) have been performed to confirm this.
  • the present invention leverages this effect to increase the ocular absorption of topical insulin.
  • the '418 patent discloses a method and composition for treating metabolic syndrome, or a disorder associated with metabolic syndrome, e.g. obesity, dyslipidemia, and/or a diabetic condition.
  • An F-series prostaglandin (/.e., latanoprost) according to the following formulas (I) and (II) are used:
  • a pharmaceutical composition of the formulas can be prepared, packaged, and/or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops.
  • the ‘800 reference teaches a non-hypoglycemic or euglycemic combination of insulin and prostaglandin analogues through invasive methods such as injecting, implanting and/or inserting in/ or adjacent to the Schlemm's canal or at other ocular tissues and sites related to or surrounding the Schlemm's canal for the purpose of lowering intraocular pressure.
  • This reference fails to teach the use of prostaglandin analogues as a penetration enhancer to enhance ocular absorption of topically applied insulin. It also fails to teach a combination of insulin and prostaglandin analogues for topical ocular application to lower blood glucose levels.
  • the disclosure specifically excludes hypoglycemic compositions by specifically limiting itself to euglycemic insulin.
  • the primary objective of this invention is to :
  • a formulation comprising an insulin and a prostaglandin analogue that causes a significant systemic hypoglycemic effect in order to manage diabetes mellitus;
  • the present invention is directed to a novel insulin delivery system that utilizes the ocular application of the insulin.
  • the present invention is directed to a novel insulin delivery system that provides at least an insulin, in a form of rapid- or short-acting type, and at least a prostaglandin analogue.
  • the present invention is directed to a novel insulin formulation that comprises at least an insulin, in a form of rapid- or short-acting type, and at least a prostaglandin analogue.
  • the present invention is directed to an insulin with a prostaglandin analogue formulation further comprising excipients used in ocular application.
  • SUBSTITUTE SHEET (RULE 26) The present invention is directed to a process of manufacturing an ocular application solution with insulin and prostaglandin analogue.
  • This invention has the potential to revolutionize the management of diabetes mellitus by offering a convenient method of insulin administration while avoiding the complications and challenges associated with traditional subcutaneous injections.
  • the present invention is directed to a novel ocular insulin delivery system that utilizes prostaglandin analogue as penetration enhancer.
  • the present invention utilizes insulin identified as rapid-acting or short-acting insulin.
  • the present invention utilizes short-acting insulin such as but not limited to Regular insulin (insulin R).
  • short-acting insulin such as but not limited to Regular insulin (insulin R).
  • the present invention utilizes prostaglandin analogues as penetration enhancers.
  • the present invention utilizes prostaglandin analogues such as, but not limited to, the following: latanoprost, bimatoprost, travoprost, or tafluprost.
  • the present invention leverages the corneal penetration-enhancing properties of prostaglandin analogues to facilitate the transport of insulin across the corneal and conjunctival barriers, resulting in a significant systemic hypoglycemic effect.
  • the present invention utilizes the excipients and other ingredients which are commonly used in the preparation of an ocular medication such as, but not limited to:
  • Preservatives benzalkonium chloride (final concentration range can be from 0.005% to 0.08%);
  • Surfactants polysorbate 80, polyoxyl 40 hydrogenated castor oil, metacresol;
  • Chelating agents disodium edetate, tromethamine
  • Buffering agents sodium phosphate dibasic, sodium phosphate monobasic, citric acid monohydrate, sodium hydrogen phosphate dihydrate, hydrochloric acid, sodium hydroxide, boric acid, sodium borate;
  • Viscosity enhancers HPMC 4000 cps, PVA, Carbomer, PEG, Na hyaluronate, glycerin;
  • Tonicity agents sodium chloride, glycerol, zinc chloride, zinc oxide pH adjusting agents: HCI / NaOH q.s. to pH 6.4 to 7.4; and
  • Solvent water for injection.
  • the concentration of insulin in the present invention ranges from 1 .735 mg/mL to 69.4 mg/mL or a percentage of 0.1735% to 6.94%.
  • the concentration of prostaglandin analogue in the present invention ranges are different depending on which analogue will be used.
  • the final concentration range is from 0.000625% to 0.2%.
  • the final concentration range is from 0.015% to 0.6%.
  • the final concentration range can be from 0.002% to 0.16%.
  • the final concentration range can be from 0.00125% to 0.12%.
  • the final concentration range can be from 0.00018775% to 0.06%.
  • Prostaglandin analogues are relatively insoluble and must be dissolved together with a surfactant at a high temperature typically at 80 degrees C then cooled down before mixing with insulin because insulin denatures above 40 degrees Celsius.
  • Insulin itself is relatively insoluble at pH 6.4 to 7.4 and must be dissolved in water at pH 2 - 3. The pH is then adjusted through buffering until the desired pH of 6.4 to 7.4 is achieved.
  • the present invention is prepared by mixing a solution of the selected insulin in water at the appropriate concentration with its pH adjusted to 6.4 to 7.4, with a solution of the selected prostaglandin analogue, likewise dissolved in water together with the selected surfactant at the appropriate concentration with its pH similarly adjusted.
  • the selected excipients are added to the combination while maintaining the pH through buffering. The mixture is gently agitated until the components are thoroughly combined, resulting in a homogeneous insulin eye drop solution.
  • the present invention is administered topically onto the eye depending on the amount as recommended by the user’s health care professional.
  • Insulin As a relatively large molecule, insulin poses a significant challenge for ocular absorption. Insulin also has 18 hydrophilic residues on its surface which renders it difficult to be absorbed through the lipophilic barriers of the eye. Tear turnover
  • This mechanism also allows the increased uptake of insulin that is applied topically onto the eye, thus resolving the problems of the prior arts.
  • Buffering agent q.s buffer capacity nmt 0.5% Tonicity agent 0.5-2% NaCI ‘quantity sufficient to osmolality approx. 308 mOsMol/Kg*

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Abstract

La présente invention concerne plus précisément une méthode permettant d'augmenter l'absorption de l'insuline appliquée par voie topique sur l'œil, grâce à l'utilisation d'analogues de la prostaglandine en tant que promoteur de pénétration, améliorant ainsi son effet hypoglycémique systémique pour la réduction du taux de glycémie. Plus particulièrement, la présente invention concerne une composition composée d'insuline, d'un analogue de prostaglandine en tant que promoteur de pénétration, et d'un ensemble d'excipients, sous forme de gouttes ophtalmiques pouvant être appliquées de manière non invasive, sans nécessiter d'injection.
PCT/PH2024/050008 2023-06-13 2024-06-13 Méthode d'amélioration de l'effet hypoglycémique systémique de l'insuline par voie topique avec utilisation d'analogues de la prostaglandine : nouvelle combinaison fixe de gouttes ophtalmiques d'insuline et d'analogues de la prostaglandine pour réduction du taux de glycémie Pending WO2024258300A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2024302192A AU2024302192A1 (en) 2023-06-13 2024-06-13 Method of enhancing the systemic hypoglycemic effect of topically applied insulin with the use of prostaglandin analogues: a novel fixed combination eye drop formulation of insulin and prostaglandin analogue for the lowering of blood glucose level
KR1020257043748A KR20260016557A (ko) 2023-06-13 2024-06-13 프로스타글란딘 유사체의 사용을 통해 국소 적용된 인슐린의 전신 혈당강하 효과를 증강시키는 방법: 혈당 수준의 감소를 위한 인슐린 및 프로스타글란딘 유사체의 신규한 고정 조합 점안액 제형
CN202480039450.3A CN121368490A (zh) 2023-06-13 2024-06-13 使用前列腺素类似物来增强局部应用的胰岛素的全身性降血糖作用的方法：一种用于降低血糖水平的胰岛素和前列腺素类似物的新颖固定组合滴眼剂配制品

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PH12023050274 2023-06-13
PH12023050274 2023-06-13

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US19/403,706 Continuation-In-Part US20260083822A1 (en) 2024-06-13 2025-11-28 Topical Ocular Insulin Delivery Enhanced by Prostaglandin Analogues

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WO2024258300A1 true WO2024258300A1 (fr) 2024-12-19

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PCT/PH2024/050008 Pending WO2024258300A1 (fr) 2023-06-13 2024-06-13 Méthode d'amélioration de l'effet hypoglycémique systémique de l'insuline par voie topique avec utilisation d'analogues de la prostaglandine : nouvelle combinaison fixe de gouttes ophtalmiques d'insuline et d'analogues de la prostaglandine pour réduction du taux de glycémie

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KR (1) KR20260016557A (fr)
CN (1) CN121368490A (fr)
AU (1) AU2024302192A1 (fr)
WO (1) WO2024258300A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2493474B1 (fr) * 2009-10-30 2019-09-04 Intratus, Inc. Méthodes et compositions pour une libération prolongée de médicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2493474B1 (fr) * 2009-10-30 2019-09-04 Intratus, Inc. Méthodes et compositions pour une libération prolongée de médicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WU NA, CHEN YUHONG, YU XIAOBO, LI MENGWEI, WEN WEN, SUN XINGHUAI: "Changes in Corneal Biomechanical Properties after Long-Term Topical Prostaglandin Therapy", PLOS ONE, PUBLIC LIBRARY OF SCIENCE, US, vol. 11, no. 5, 17 May 2016 (2016-05-17), US , pages e0155527, XP093256336, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0155527 *

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AU2024302192A1 (en) 2025-11-27
KR20260016557A (ko) 2026-02-03

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