EP4003353A1 - Bromocriptine à utiliser dans le traitement de maladies oculaires associées à un niveau élevé de vegf et composition pharmaceutique comprenant de la bromocriptine - Google Patents

Bromocriptine à utiliser dans le traitement de maladies oculaires associées à un niveau élevé de vegf et composition pharmaceutique comprenant de la bromocriptine

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Publication number
EP4003353A1
EP4003353A1 EP20775397.1A EP20775397A EP4003353A1 EP 4003353 A1 EP4003353 A1 EP 4003353A1 EP 20775397 A EP20775397 A EP 20775397A EP 4003353 A1 EP4003353 A1 EP 4003353A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
bromocriptine
use according
vegf
amd
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Withdrawn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
EP20775397.1A
Other languages
German (de)
English (en)
Inventor
Anna SWIECH-ZUBILEWICZ
Katarzyna SALADZIAK
Maciej OSEKA
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.)
Individual
Original Assignee
Individual
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Filing date
Publication date
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Publication of EP4003353A1 publication Critical patent/EP4003353A1/fr
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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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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

  • the present invention relates to bromocriptine for use in treating eye diseases associated with elevated level of vascular endothelial growth factor (VEGF) and a pharmaceutical composition for use in treating eye diseases associated with elevated level of VEGF comprising bromocriptine and a pharmaceutically acceptable carrier.
  • VEGF vascular endothelial growth factor
  • Angiogenesis means formation of new blood vessels.
  • Angiogenesis is associated with many physiological and pathological processes, e.g., formation of collateral circulation in the myocardium or formation of solid tumor vascularization.
  • the angiogenesis process is mediated by VEGF.
  • VEGF is released by many cells and tissues, including endothelial cells of blood vessels, which is mediated by various factors, e.g., an inflammatory factor, and in response to hypoxia.
  • the released VEGF acting through the receptors, causes loosening of junctions between vascular endothelial cells and migration of the endothelial cells through the vascular wall.
  • Migrating vascular endothelial cells arrange themselves into tubular structures, which form primordia of the new blood vessels.
  • VEGF-mediated loosening of junctions between endothelial cells forming a natural barrier in blood vessels is associated with the penetration of fluid into the extravascular space, which leads to swelling of the surrounding tissues.
  • pathological angiogenesis plays an important role in diseases such as AMD (age- related macular degeneration), including, in particular, exudative AMD, retinal artery embolism, retinal vein occlusion, diabetic macular edema, or diabetic retinopathy.
  • AMD age-related macular degeneration
  • retinal artery embolism CAD
  • retinal vein occlusion CAD
  • diabetic macular edema CAD
  • diabetic retinopathy diabetic macular edema
  • Diabetic macular edema develops in patients with long-standing diabetes and more advanced form of diabetic retinopathy. It occurs in approximately 14% of diabetics. The incidence of DME depends on severity of retinopathy and the duration and type of diabetes. Approximately 30% of patients with type 1 and type 2 diabetes treated with insulin and approximately 15% of patients with type 2 diabetes treated with oral antidiabetic drugs, after 25 years of having diabetes, develop DME. Diabetic macular edema is defined as the presence of fluid or hard exudates within 1 dd (disc diameter) from the macular center.
  • Diabetic retinopathy is currently the most common cause of blindness in developed countries. The reason for that is the increased incidence of diabetes in these countries. According to WHO, in 2002, diabetic retinopathy caused blindness in 1.8 million people (4.8%) worldwide. In the USA, it causes blindness in 12-24 thousand diabetics every year. Clinically, DR takes several forms such as non-proliferative retinopathy, pre-proliferative retinopathy, diabetic maculopathy, proliferative retinopathy, and advanced diabetic retinopathy. In most of these forms, it comes to retinal edema and in case of proliferative forms, to abnormal blood vessel overgrowth as well.
  • Embolism of the central retinal artery or its branch is relatively rare. It is characterized by a sudden, painless vision loss. With prompt treatment, vision is fully or partially restored.
  • One of the complications of central retinal artery embolism is the formation of pathological blood vessels within the eye tissue.
  • Retinal vein occlusion means blockade of the main retinal vein (central retinal vein occlusion, CRVO) or a branch thereof (branch retinal vein occlusion, BRVO). It leads to various degrees of visual impairment. CRVO and BRVO are the second most common retinal vascular condition. The ischemic form is less common than the non-ischemic form. Retinal vein occlusions occur with a frequency of about 2 per 1000 in people over the age of 40, and more than 5 per 1000 in people over 64 years of age. As in case of central retinal artery embolism, in case of retinal vein occlusion, there may be late complications involving formation of new pathological blood vessels within retina and other eye tissues, e.g., in the filtration angle or in the iris.
  • AMD is the leading cause of vision loss in people over the age of 50. It occurs in 8.8% of the population, more often in women, its frequency increases with age and it affects almost 28% of people over the age of 75. Worldwide, the number of patients reaches 50 million. Due to population aging, the problem of AMD is increasing, and about 10% of people over 45 are at risk of suffering from this condition. 90% of AMD cases consist of the dry form of AMD, with atrophic lesions within macula and gradual vision loss. 10% of patients with AMD have wet (exudative) AMD, where new blood vessels are formed in the retina and choroid (choroidal neovascularization, CNV), which rapidly leads to severe visual impairment or vision loss.
  • CNV choroidal neovascularization
  • Exudative AMD is responsible for most cases of vision loss. It is related to the retinal edema that occurs as a result of the disruption of the blood-retina barrier and growth of new pathological blood vessels. Newly formed vessels are brittle and leaky, which aggravates the pathological retinal edema and can lead to retinal detachment. In case of such changes which occur within central area of the retina, called the macula, a central scotoma appears in the patient’s field of view, which prevents functioning in everyday life. Also in the course of diabetes there is an increased release of VEGF due to increased blood sugar level (hyperglycemia) and the action of the so-called advanced (protein) glycation end products (AGEs).
  • VEGF blood sugar level
  • AGEs advanced (protein) glycation end products
  • VEGF inhibitors or VEGF receptors inhibitors such as ranibizumab (fragment of recombinant humanized anti-VEGF-A monoclonal antibody), bevacizumab (recombinant humanized anti-VEGF-A monoclonal antibody) and aflibercept (VEGF receptor Fc fragment) are used to reduce swelling of the eye tissues and to inhibit angiogenesis. They are given as repeated intravitreal injections, usually at intervals of one or two months. The injectable form of VEGF inhibitor administration requires sterile administration conditions, limits the number of potential patients and is associated with the complication risk.
  • bromocriptine has an inhibitory effect on VEGF release and action, and VEGF-A and VEGF-A receptor (VEGF-R2) gene expression in an angiogenesis model, which is significantly more potent than inhibitory effect of the known agents, including other type 2 dopaminergic receptor agonists such as cabergoline and pergolide.
  • Bromocriptine (Formula 1) is a semisynthetic derivative of the ergot alkaloid ergocriptine. It is used in the prevention or inhibition of postpartum lactation for medical reasons, in hyperprolactinemia, amenorrhea, galactorrhea or menstrual cycle disorders, galactorrhea with normoprolactinemia, pituitary adenomas such as prolactinoma, acromegaly, and Parkinson's disease. Bromocriptine stimulates D2 type dopaminergic receptors.
  • the present invention therefore provides bromocriptine for use in treating eye diseases associated with elevated level of vascular endothelial growth factor (VEGF), increased vascular permeability and abnormal angiogenesis processes.
  • VEGF vascular endothelial growth factor
  • the eye disease is age-related macular degeneration (AMD), diabetic macular edema, and diabetic retinopathy, and retinal vascular occlusion or embolism.
  • AMD is exudative AMD.
  • the invention provides also a pharmaceutical composition for use in treating eye diseases associated with elevated level of VEGF, increased vascular permeability and abnormal angiogenesis processes, characterized in that it comprises bromocriptine and a pharmaceutically acceptable carrier.
  • the eye disease is AMD, diabetic macular edema, and diabetic retinopathy, and retinal vascular occlusion or embolism.
  • AMD is exudative AMD.
  • the invention provides also a pharmaceutical composition for the above-mentioned use, which is in form of a microemulsion comprising an internal phase, an external phase and an emulsifying agent, wherein the internal phase is formed by a non-aqueous, oxygen atom-containing pharmaceutically acceptable polar solvent, and the external phase is formed by C1-C10 alkyl ester of Cs-Cn fatty acid, medium-chain triglyceride or vegetable oil.
  • the pharmaceutical composition additionally comprises a monoglyceride, such as monomyristoyl glycerol.
  • a monoglyceride such as monomyristoyl glycerol.
  • the composition comprises a solvent selected from propylene glycol, ethylene glycol, polyethylene glycol, and glycerol.
  • the external phase contains a purified vegetable oil selected from corn oil and peanut oil.
  • the invention provides also a pharmaceutical composition for the above-mentioned use, which consists of two parts mixed together before use, the first part containing a lyophilized powder consisting of bromocriptine and mannitol, and the second part containing the carrier in the form of an aqueous buffered solution.
  • the aqueous buffered solution contains citric acid, disodium EDTA, benzalkonium chloride and water, and the pH of this solution is adjusted to 3.0 with HCI and NaOH solutions.
  • the invention also relates to a pharmaceutical composition for the above-mentioned use, which comprises bromocriptine, sodium chloride, sodium EDTA, benzalkonium chloride and water, the pH of this solution is adjusted to 3.0 with HCI and NaOH solutions.
  • the pharmaceutical composition additionally comprises a buffer system such as a phosphate buffer, an acetate buffer or an oxoborate buffer, a preservative such as benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, ethylparaben, disodium EDTA, sorbic acid, phenylethyl alcohol, and a viscosity enhancing agent, such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose.
  • a buffer system such as a phosphate buffer, an acetate buffer or an oxoborate buffer
  • a preservative such as benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, ethylparaben, disodium EDTA, sorbic acid, phenylethy
  • the pharmaceutical composition comprises a preservative in an amount of 0.001 % to 1.0% by weight and a viscosity enhancing agent in an amount of 0.01 % to 2.0% by weight.
  • Fig. 1 shows plots of VEGF-A gene expression levels after a 5-day D. rer/ ' o culture in the presence of dopaminergic substances after pretreatment with cobalt chloride;
  • Fig. 2 shows plots of VEGFR-2 gene expression levels after a 5-day D. rer/ ' o culture in the presence of dopaminergic substances after pretreatment with cobalt chloride.
  • a laboratory zebrafish (Danio rer/ ' o) model is used, among others.
  • VEGF-A and VEGFR-2 genes were determined by quantitative DNA polymerase chain reaction (qPCR), i.e. realtime PCR on the 5th day of life.
  • qPCR quantitative DNA polymerase chain reaction
  • Fig. 1 shows plots of VEGF-A gene expression levels after a 5-day D. rer/ ' o culture in the presence of dopaminergic substances after pretreatment with cobalt chloride, where:
  • Fig. 2 shows plots of VEGFR-2 gene expression levels after a 5-day D. rer/ ' o culture in the presence of dopaminergic substances after pretreatment with cobalt chloride, where:
  • bromocriptine has the strongest inhibitory effect on the VEGF-A and VEGFR-2 gene expression.
  • a pharmaceutical composition comprising bromocriptine in the form of a microemulsion was prepared by dissolving 1 g of chicken lecithin in 8 g of isopropyl myristate and sonication. 1 g 1 wt.% solution of bromocriptine in ethylene glycol was added with stirring to the resulting mixture to obtain a stable, clear microemulsion.
  • Example 3
  • a pharmaceutical composition comprising bromocriptine in the form of a microemulsion was prepared in the same way as in Example 2, except that 0.5 g of monomyristoyl glycerol was added additionally to the mixture of lecithin and isopropyl myristate and the mixture was heated at 50°C for 5 minutes, cooled to room temperature and 2 g 1 wt.% solution of bromocriptine in glycerol was added with stirring to obtain a stable, clear microemulsion.
  • a pharmaceutical composition in the form of two parts to be mixed together before use is a pharmaceutical composition in the form of two parts to be mixed together before use
  • the first part of the composition was prepared as a lyophilized powder consisting of 0.5 g of bromocriptine and 9 g of mannitol.
  • the second part of the composition was prepared as a buffered to pH 3.0 aqueous solution containing 0.2 g of citric acid (monohydrate), 0.02 g of disodium EDTA, 0.02 g of benzalkonium chloride, and water to 200 g.
  • the pH of this solution was adjusted to 3.0 with HCI and NaOH solutions.
  • the resulting pharmaceutical composition is usable for up to 2 weeks after mixing the two parts of the composition together.
  • a pharmaceutical composition in the form of two parts to be mixed together before use is a pharmaceutical composition in the form of two parts to be mixed together before use
  • the first part of the composition was prepared as a lyophilized powder consisting of 0.25 g of bromocriptine and 4.5 g of mannitol.
  • the second part of the composition was prepared as an aqueous solution buffered with phosphate buffer (0.1 g) to pH 3.0, containing 0.01 g of disodium EDTA, 0.01 g of thimerosal, 0.05 g of polyvinyl alcohol, and water to 100 g.
  • the pH of this solution was adjusted to 3.0 with HCI and NaOH solutions.
  • the resulting pharmaceutical composition is usable for up to 2 weeks after mixing the two parts of the composition together.

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

Abstract

La présente invention concerne de la bromocriptine à utiliser dans le traitement de maladies oculaires associées à un taux élevé de facteur de croissance endothéliale vasculaire (VEGF), une perméabilité vasculaire accrue et des processus d'angiogenèse anormaux. L'invention concerne également une composition pharmaceutique à utiliser dans le traitement de maladies oculaires associées à un niveau élevé de VEGF et une angiogenèse anormale, caractérisée en ce qu'elle comprend de la bromocriptine et un support pharmaceutiquement acceptable.
EP20775397.1A 2019-07-23 2020-07-22 Bromocriptine à utiliser dans le traitement de maladies oculaires associées à un niveau élevé de vegf et composition pharmaceutique comprenant de la bromocriptine Withdrawn EP4003353A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL430675A PL430675A1 (pl) 2019-07-23 2019-07-23 Bromokryptyna do zastosowania w leczeniu chorób oczu związanych z podwyższonym poziomem śródbłonkowego czynnika wzrostu naczyń (VEGF) oraz kompozycja farmaceutyczna zawierająca bromokryptynę
PCT/IB2020/056885 WO2021014372A1 (fr) 2019-07-23 2020-07-22 Bromocriptine à utiliser dans le traitement de maladies oculaires associées à un niveau élevé de vegf et composition pharmaceutique comprenant de la bromocriptine

Publications (1)

Publication Number Publication Date
EP4003353A1 true EP4003353A1 (fr) 2022-06-01

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Application Number Title Priority Date Filing Date
EP20775397.1A Withdrawn EP4003353A1 (fr) 2019-07-23 2020-07-22 Bromocriptine à utiliser dans le traitement de maladies oculaires associées à un niveau élevé de vegf et composition pharmaceutique comprenant de la bromocriptine

Country Status (3)

Country Link
EP (1) EP4003353A1 (fr)
PL (1) PL430675A1 (fr)
WO (1) WO2021014372A1 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8426922D0 (en) * 1984-10-24 1984-11-28 Sandoz Ltd Galenic formulation
US20100168085A1 (en) * 2003-05-22 2010-07-01 Yesa Research And Development Co. Ltd. At The Weizmann Institute Of Science Dopamine and agonists and antagonists thereof for modulation of suppressive activity of CD4+CD25+ regulatory T cells
AU2016206366B2 (en) * 2008-01-14 2017-03-02 Veroscience, Llc Parenteral formulations of dopamine agonists
EP2296624A1 (fr) * 2008-06-09 2011-03-23 Boehringer Ingelheim International GmbH Nouvelles émulsions pour la préparation de médicaments
PL232974B1 (pl) * 2015-12-09 2019-08-30 Ofta Spolka Z Ograniczona Odpowiedzialnoscia Zastosowanie agonistów receptorów dopaminergicznych typu 2 w leczeniu schorzeń oczu wywołanych przez podwyższony poziom śródbłonkopochodnego czynnika wzrostu naczyń

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Publication number Publication date
PL430675A1 (pl) 2021-01-25
WO2021014372A1 (fr) 2021-01-28

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