EP2968328A1 - Compositions destinées à être utilisées en traitement de troubles oculaires à l'aide de dipyridamole - Google Patents

Compositions destinées à être utilisées en traitement de troubles oculaires à l'aide de dipyridamole

Info

Publication number
EP2968328A1
EP2968328A1 EP14764673.1A EP14764673A EP2968328A1 EP 2968328 A1 EP2968328 A1 EP 2968328A1 EP 14764673 A EP14764673 A EP 14764673A EP 2968328 A1 EP2968328 A1 EP 2968328A1
Authority
EP
European Patent Office
Prior art keywords
dipyridamole
eye
composition
topically
effective amount
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.)
Withdrawn
Application number
EP14764673.1A
Other languages
German (de)
English (en)
Other versions
EP2968328A4 (fr
Inventor
Moshe Rogosnitzky
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.)
Od Ocular Discovery
Original Assignee
Remedeye Inc
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 Remedeye Inc filed Critical Remedeye Inc
Publication of EP2968328A1 publication Critical patent/EP2968328A1/fr
Publication of EP2968328A4 publication Critical patent/EP2968328A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • 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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the present invention relates to compositions for use in treating eye disorders using dipyridamole.
  • dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface associated with symptoms of ocular discomfort.
  • dry eye includes two major classes: (i) aqueous tear deficient dry eye (ADDE), and (ii) evaporative dry eye (EDE).
  • ADDE refers mainly to a failure of sufficient tear secretion due to lacrimal dysfunction.
  • ADDE has two major subclasses: (i) Sjogren's Syndrome dry eye (SSDE), and (ii) non-SS dry eye (such as in Graft-versus-Host Disease (GvHD) or in diabetes mellitus).
  • EDE may be: (i) intrinsic, due to diseases affecting lid structures or dynamics, or (ii) extrinsic, in which ocular surface disease occurs due to some extrinsic exposure, such as topical drug preservatives, contact lens wear, pterygium, or vitamin A deficiency.
  • corneal ulcer usually refers to the medical condition in which the corneal epithelium, stroma, or both are lysed and deleted by the activation and
  • collagenolytic enzyme causing corneal ulcer, bacterial collagenase, and matrix metalloproteases (MMPs) are known to be involved in the ulcerative process.
  • MMPs matrix metalloproteases
  • the corneal/conjunctival diseases including a repeated erosion of the cornea and a prolonged corneal epithelial deficiency, are associated with such disorders.
  • the repairing process of the corneal/conjunctival epithelial disorders involves the coverage of the epithelial deficiency by the migration of corneal epithelial cells, followed by a subsequent cell division and differentiation, resulting in reconstitution of normal cornea and conjunctiva.
  • Corneal anesthesia and congenital corneal anesthesia usually develop into neurotrophic keratopathy.
  • Neurotrophic keratopathy is a degenerative corneal disease induced by an impairment of the trigeminal nerve. Impairment or loss of corneal sensory innervation is responsible for corneal epithelial defects, ulcers, and perforations.
  • a pterygium is a non-cancerous growth that starts in the clear, thin tissue (conjunctiva) of the eye. This growth covers the white part of the eye (sclera), and extends onto the cornea. It is often slightly raised, and contains visible blood vessels. The problem may occur in one or both eyes. Pterygium may become inflamed and cause burning, irritation, or a feeling like there's something foreign in the eye. Vision may be affected if the grows extends far enough onto the cornea. There is at present no known curative treatment for pterygium other than surgery.
  • a Pinguecula is a yellowish, slightly-raised thickening of the conjunctiva on the sclera, close to the edge of the cornea. Pingueculae typically occur on the part of the sclera that is between the eyelids, and therefore is exposed to the sun. In some cases, Pingueculae become swollen and inflamed, a condition called pingueculitis. Frequently, Pingueculae can lead to the formation of pterygia. There is at present no known curative treatment for Pinguecula other than surgery.
  • Uveitis is inflammation of the middle layer of the eye, called the uvea or uveal tract.
  • the uvea consists of the middle, pigmented, vascular structures of the eye, and includes the iris, ciliary body, and choroid.
  • anterior uveitis accounts for between 50% and 90% of uveitis cases, while in Asian countries the proportion drops to be between 28% and 50%.
  • Uveitis is estimated to be responsible for approximately 10-20% of the cases of blindness in the United States. The cause is generally infectious (bacterial or viral infection) or autoimmune. Genetic factors act as a predisposing factor for this difficult- to-treat condition.
  • Fischer '450 dipyridamole was introduced as a coronary vasodilator in the early 1960s, and is well known to have platelet aggregation inhibitor properties due to the inhibition of adenosine uptake. Subsequently, dipyridamole was shown to reduce thrombus formation in a study of arterial circulation of the brain in a rabbit model. These investigations led to its use as an anti-thrombotic agent. Dipyridamole soon became the therapy of choice for such applications as stroke prevention, maintaining the patency of coronary bypass and valve-replacement, as well as for treatment prior to coronary angioplasty.
  • Leung ⁇ 81 there was a negligible effect on cAMP after the addition of dipyridamole in comparison to a control. Only a combination of caffeine and dipyridamole yielded the desired effect of decreasing cAMP in-vitro, which is assumed to indicate increased cellular levels of cAMP.
  • compositions for use in treating eye disorders using dipyridamole would, inter alia, overcome the problems mentioned above associated with such ailments.
  • compositions and treatment indications for use in treating eye disorders using dipyridamole.
  • eye disorder is specifically defined for use herein to include, but not be limited to, any ailment of Scleritis, Graft-versus-Host Disease (GvHD), keratitis, corneal ulcer, corneal abrasion, snow blindness, Thygeson's superficial punctuate keratopathy, corneal neovascularization, Fuch's dystrophy, keratoconus, keratoconjunctivitis sicca (dry eye), ulceris, corneal anesthesia, neurotrophic keratopathy, red eye, pink eye, keratomycosis, xeropthalmia, retinoblastoma, uveitis, pterygium, keratopathy, and Pingueculae.
  • GvHD Graft-versus-Host Disease
  • exemplary is used herein to refer to examples of embodiments and/or implementations, and is not meant to necessarily convey a more-desirable use-case.
  • preferred is used herein to refer to an example out of an assortment of contemplated embodiments and/or implementations, and is not meant to necessarily convey a more-desirable use-case. Therefore, it is understood from the above that "exemplary” and “preferred” may be applied herein to multiple
  • Dipyridamole is readily absorbed from the gastrointestinal tract, reaching peak plasma levels in humans 1 -3 hours following oral administration. Peak plasma levels are dose dependent and range from about 0.5 g/mL after a 25mg dose to 1 .6 g/mL after a 75mg dose. Blood levels are quite variable, possibly depending on food intake and gastrointestinal peristalsis. Ingestion on an empty stomach may result in higher blood levels. Following intravenous (IV) administration, the distribution half-life in humans is about 25 minutes, and after oral administration, is about 3 hours. When plasma levels of drug are followed for up to 60 hours after IV or oral administration of 20-50mg, plasma levels decline tri-exponentially with half-lives of 5 minutes (IV only), 53 minutes, and about 10-12 hours. The volume of distribution is about 140L with about 92 to 99% binding to plasma proteins, primarily alphal -acid glycoprotein. Typical daily oral doses of dipyridamole range from 100- 400mg.
  • Dipyridamole is practically insoluble in water (water solubility is 8.17mg/L (Meylan, WM ET AL. (1996))), and very soluble in methanol. This creates a challenge for finding a suitable method for ocular application in which an aqueous solution delivered via single drops is preferred.
  • Embodiments of the present invention provide compositions and treatment indications for use in treating eye disorders using dipyridamole. It was determined that by adjusting the pH of the aqueous solution to -6.6 (6.5-6.7), dipyridamole fully dissolves in the aqueous solution.
  • dipyridamole was found to be effective in treating ocular medical conditions when applied topically in physiological saline formulations.
  • Topical application of dipyridamole may serve to treat dry eye caused by, for example, Graft-versus-Host Disease (GvHD), diabetes, allergic conjunctivitis, contact lens-related dry eye, and Sjorgen's syndrome.
  • GvHD Graft-versus-Host Disease
  • diabetes for example, diabetes, allergic conjunctivitis, contact lens-related dry eye, and Sjorgen's syndrome.
  • topical dipyridamole may also be used to treat corneal ulcers resulting from, for example: viral infection, bacterial infection, fungal infection, injury resulting from wearing contact lenses, traumatic injury, and parasite infection. Moreover, topical dipyridamole may also be used for the treatment of pterygium, corneal anesthesia, and corneal neovascularization. [0021] Therefore, according to the present invention, there is provided for the first time a composition for use in treating eye disorders, the composition including: (a) an effective amount of a topically-administered dipyridamole.
  • the topically-administered dipyridamole is formulated as a solution.
  • the topically-administered dipyridamole is at least one agent selected from the group consisting of: dipyridamole and a
  • the effective amount corresponds to a concentration of at least about 10 "5 molarity.
  • the effective amount is based on a treatment administration of at least once every other day.
  • the present invention relates to compositions for use in treating eye disorders using dipyridamole.
  • the aspects, uses, and advantages for such compositions, according to the present invention may be better understood with reference to the accompanying description.
  • the description is not to be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles of the invention, since the scope of the present invention is best defined by the appended claims.
  • Exemplary embodiments of the present invention are detailed below in the following exemplary formulations.
  • Dipyridamole eye drops were prepared as follows. 1 g of citric acid was mixed in 10OmL saline (0.9% w/v sodium chloride in sterile water) to obtain a pH of 6.7. 8.5mg of dipyridamole was weighed, irradiated by UVB for 30 minutes for sterility, and diluted in the 10OmL saline. This solution was then filtered through a 0.22 micron filter for sterilization, resulting in a solution containing 85mcg of dipyridamole per ml_. Using a dropper, one drop (equivalent to approximately 0.05mL) was applied to the eye.
  • Dipyridamole eye drops were prepared as follows. 1 g of citric acid was mixed in " l OOmL saline (0.9% w/v sodium chloride in sterile water) to obtain a pH of 6.7. 2.125mg of dipyridamole was weighed, irradiated by UVB for 30 minutes for sterility, and diluted in the 10OmL saline. This solution was then filtered through a 0.22 micron filter for sterilization, resulting in a solution containing 21 .25mcg of dipyridamole per mL. Using a dropper, one drop (equivalent to approximately 0.05mL) was applied to the eye.
  • a human female suffering from diabetes-related dry eye was treated with one drop of Formulation B bilaterally once every other day. Relief from the dry-eye symptoms was attained within twenty minutes. The patient required subsequent application once every other day. After 10 days of use, redness in the eye (or pink eye) disappeared. Maintenance continued with administration once every other day.
  • a human male suffering from a deep corneal ulcer with stromal involvement in one eye was treated with one drop of Formulation A three times daily. Relief from pain and irritation was attained within 24 hours. The patient required subsequent application twice daily. After 7 days of use, the cornea had completely reepithelialized.
  • a human female suffering from a corneal ulcer in one eye was treated with one drop of Formulation A twice daily. Relief from pain and irritation was attained within one day. The patients required subsequent application twice daily. After 7 days of use, the ulcer had healed completely.
  • a human male suffering from diabetes-related neovascularization was treated with one drop of Formulation C twice daily.
  • the patient required subsequent application twice daily.
  • the abnormal vessels were no longer visible by slit-lamp photography examination.
  • a human male suffering from anterior uveitis in both eyes was treated with one drop of Formulation C three times daily. Relief from pain was attained within three days. Blurred vision was resolved within 7 days. Inflammation appeared to be completely resolved within 14 days. The patient continued subsequent application twice daily to maintain remission.
  • a human male suffering from anterior uveitis in both eyes was treated with one drop of Formulation B three times daily. Relief from pain was attained within two days. Blurred vision was resolved within 14 days. Inflammation appeared to be completely resolved within 18 days. The patient continued subsequent application twice daily to maintain remission.
  • Dipyridamole eye drops were prepared by dissolving dipyridamole in sterile water. pH was adjusted, as needed, to achieve solubility. Several concentrations were prepared, ranging from 5mcg/ml to 200mcg/ml. Sterile procedures were followed.
  • Dipyridamole eye ointment was prepared by mixing dipyridamole in a base of yellow soft paraffin, liquid paraffin and wool fat at a ratio of (8:1 :1 ). Several concentrations were prepared, ranging from 5mcg/ml to 200mcg/ml. Sterile procedures were followed.
  • Sjorgen's related dry eye A slight transient stinging sensation was experienced upon application of the drops/ointment. Partial relief of dry eye symptoms set in within one hour of application. The relief became complete after about seven days of continuous use and continues with daily administration in some patients and period (every 3 - 4 days) administration in others.
  • Keratoconus Daily administration (once to twice daily) for three months led to an improvement in astigmatism enabling lowering of cylinder by a quarter to half a number in two subjects.
  • Conjunctivitis non-specific: A slight transient stinging sensation was experienced upon application of the drops/ointment. Partial relief of conjunctivitis symptoms (itchiness, burning or excessive tearing) set in within one hour of application. Application continued once to twice daily. After two to four days of use all symptoms including exudation had relieved.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention porte sur des compositions destinées à être utilisées en traitement de troubles oculaires, les compositions comprenant une quantité efficace d'un dipyridamole administré par voie topique. De préférence, le dipyridamole administré par voie topique est formulé sous forme d'une solution. De préférence, le dipyridamole administré par voie topique est au moins un agent choisi entre le dipyridamole et un sel pharmaceutiquement acceptable de celui-ci. De préférence, la quantité efficace correspond à une concentration de molarité d'au moins environ 10-5. De préférence, la quantité efficace est basée sur une administration pour traitement au moins une fois tous les deux jours.
EP14764673.1A 2013-03-12 2014-03-11 Compositions destinées à être utilisées en traitement de troubles oculaires à l'aide de dipyridamole Withdrawn EP2968328A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL225179A IL225179A (en) 2013-03-12 2013-03-12 Compounds for use in ocular disorders using dipyridamole
PCT/IB2014/059645 WO2014141079A1 (fr) 2013-03-12 2014-03-11 Compositions destinées à être utilisées en traitement de troubles oculaires à l'aide de dipyridamole

Publications (2)

Publication Number Publication Date
EP2968328A1 true EP2968328A1 (fr) 2016-01-20
EP2968328A4 EP2968328A4 (fr) 2016-11-23

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ID=48916407

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14764673.1A Withdrawn EP2968328A4 (fr) 2013-03-12 2014-03-11 Compositions destinées à être utilisées en traitement de troubles oculaires à l'aide de dipyridamole

Country Status (14)

Country Link
EP (1) EP2968328A4 (fr)
JP (1) JP6820658B2 (fr)
KR (2) KR20210010638A (fr)
CN (1) CN105188702B (fr)
AU (1) AU2014229371B2 (fr)
BR (1) BR112015022084A2 (fr)
CA (1) CA2905594A1 (fr)
CL (1) CL2015002627A1 (fr)
EA (1) EA035966B1 (fr)
IL (1) IL225179A (fr)
MX (1) MX2015012716A (fr)
MY (1) MY182591A (fr)
SG (2) SG11201507092QA (fr)
WO (1) WO2014141079A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180015090A1 (en) * 2015-01-28 2018-01-18 Realinn Life Science Limited COMPOUNDS FOR ENHANCING PPARy EXPRESSION AND NUCLEAR TRANSLOCATION AND THERAPEUTIC USE THEREOF
US20180092776A1 (en) 2016-09-30 2018-04-05 Sara Heikali Method and device for treating and managing diseased ocular tissue
WO2021001806A1 (fr) 2019-07-04 2021-01-07 Ocular Discovery Ltd. Formulations de dipyridamole stables avec des impuretés réduites
WO2021001805A1 (fr) 2019-07-04 2021-01-07 Ocular Discovery Ltd. Formulations de dipyridamole stables et leurs procédés de préparation

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07258084A (ja) * 1994-03-17 1995-10-09 Rohto Pharmaceut Co Ltd ジピリダモールを必須成分とする眼圧降下剤
US5780450A (en) * 1995-11-21 1998-07-14 Alcon Laboratories, Inc. Use of adenosine uptake inhibitors for treating retinal or optic nerve head damage
US20060104968A1 (en) * 2003-03-05 2006-05-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases
RU2008122978A (ru) * 2005-11-09 2009-12-20 Комбинаторкс, Инкорпорейтед (Us) Способы, композиции и наборы для лечения медицинских состояний
WO2010056710A1 (fr) * 2008-11-11 2010-05-20 Biovista, Inc. Compositions et procédés pour traiter des maladies ophtalmiques
EP2363126A1 (fr) * 2010-03-04 2011-09-07 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Composition comprenant une L-carnitine en tant que principe actif en combinaison avec le glucoside de l'hydroxykynurénine, pour la prévention et/ou le traitement de pathologies de l'oeil dues au rayonnement ultraviolet

Also Published As

Publication number Publication date
CL2015002627A1 (es) 2016-03-11
KR20150126021A (ko) 2015-11-10
IL225179A0 (en) 2013-06-27
MX2015012716A (es) 2016-07-06
MY182591A (en) 2021-01-26
CA2905594A1 (fr) 2014-09-18
KR20210010638A (ko) 2021-01-27
SG11201507092QA (en) 2015-10-29
IL225179A (en) 2017-01-31
EA035966B1 (ru) 2020-09-07
WO2014141079A1 (fr) 2014-09-18
EP2968328A4 (fr) 2016-11-23
AU2014229371B2 (en) 2018-05-10
BR112015022084A2 (pt) 2017-07-18
JP2016514123A (ja) 2016-05-19
SG10201706937UA (en) 2017-09-28
AU2014229371A1 (en) 2015-10-29
JP6820658B2 (ja) 2021-01-27
EA201591653A1 (ru) 2017-05-31
CN105188702B (zh) 2019-03-26
CN105188702A (zh) 2015-12-23

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