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WO2020109965A1 - Collyre contenant un extrait d'agrumes sous forme liposomale - Google Patents

Collyre contenant un extrait d'agrumes sous forme liposomale Download PDF

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Publication number
WO2020109965A1
WO2020109965A1 PCT/IB2019/060123 IB2019060123W WO2020109965A1 WO 2020109965 A1 WO2020109965 A1 WO 2020109965A1 IB 2019060123 W IB2019060123 W IB 2019060123W WO 2020109965 A1 WO2020109965 A1 WO 2020109965A1
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WO
WIPO (PCT)
Prior art keywords
solution
biosecur
collyrium
liposomes
phospholipids
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.)
Ceased
Application number
PCT/IB2019/060123
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English (en)
Inventor
Alessandro Zanini
Marco VELLANTE
Eugenio Sodo
Giovanni Cavallo
Fulvio FOSCHINI
Roberto GIUVA
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Offhealth SpA
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Offhealth SpA
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 Offhealth SpA filed Critical Offhealth SpA
Priority to EP19831879.2A priority Critical patent/EP3870151A1/fr
Publication of WO2020109965A1 publication Critical patent/WO2020109965A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • the present invention relates to the ophthalmic use of mixtures of natural origin, based on citrus extracts, which provide excellent antibacterial protection and are certified organic preservatives, such as the product marketed by the Canadian company BIOSECUR Lab. Inc. under the registered trademark BIOSECUR® and which is the subject of patent application US 2017/0079281, to which reference should be made for completeness.
  • the antimicrobial compositions which are described generally comprise citrus extract as the main ingredient as well as a relatively low concentration of lauric arginate as an additive, which enhances the effect of citrus extracts.
  • Biosecur product on the market is used as an agent to disinfect surfaces and for food storage.
  • Biosecur® The active ingredient of Biosecur® is represented by flavonoids extracted from the peel and the pulp of different types of citrus fruit which due to their chemical structure are poorly absorbed by cell membranes .
  • An object of the invention is an ophthalmic preparation consisting of an aqueous solution, or collyrium, consisting of a dispersion of liposomes containing BIOSECUR® or in any case a mixture of flavonoid-rich citrus extracts.
  • a collyrium in borate isotonic buffer, is made viscous to improve its stability and mucoadhesiveness, with the addition of hydroxypropyl-methylcellulose (hypromellose) .
  • An object of the invention is also an industrial method for preparing a solution for ophthalmic use comprising a dispersion of liposomes containing Biosecur® or of liposomes containing a composition based on extracts of citrus fruits rich in flavonoid, which method does not damage, in its different operating steps, the liposomal structure and the active ingredients contained therein, and which allows obtaining liposomes of such a size as to make the same ophthalmic solution sterilizable by 0.2 micron filtration .
  • BIOSECUR® product is characterized by the presence of a powerful citrus extract in glycerin of natural origin which, due to the strong concentration of flavonoids, provides an excellent antibacterial protection against bacteria, in particular against the Gram (-) and Gram (+) bacteria.
  • BIOSECUR® trademark different formulations are marketed containing extracts of different types of citrus fruit in different concentrations, in glycerin, of natural origin, admixed with acids such as ascorbic acid, citric acid and lactic acid, but these formulations are always and only usable as disinfectants which act on surfaces, and not really suitable for use in the ophthalmic field, due to the low capacity of the flavonoids to be absorbed by the ocular membranes.
  • the citrus extracts which bring bioflavonoids are: mandarin fruit extract, bitter orange fruit extract, and sweet orange peel extract.
  • BIOSECUR® product for ease of description, in the following description reference will be made in particular to the BIOSECUR® product, but included within the scope of the invention are also similar mixtures of natural citrus extracts comprising mandarin fruit extract, bitter orange fruit extract, and sweet orange peel extract, where the possible presence of glycerin does not interfere with the antibacterial activity, but is used to make the preparation more viscous and therefore with greater permanence on the surfaces and to solubilize the flavonoids.
  • collyrium is a liquid containing various medicinal substances which is applied in drops to the eye to treat eye diseases.
  • Collyrium may contain excipients:
  • BIOSECUR as a disinfectant agent
  • the inventors have set themselves the task of developing a collyrium containing this agent, which meets all the above requirements, also to exploit the antioxidant and anti-inflammatory features of the flavonoids themselves even inside the membranes and not only at the superficial level, as is widely reported in the literature, also at the level of the ocular membranes.
  • the activity carried out for this purpose has led in a first stage to the development of an aqueous ophthalmic solution, with a buffer system to adjust the pH, slightly hypotonic or isotonic with an osmolality of between 260 and 310 mOsm/Kg, containing Biosecur® in a percentage concentration by weight, based on the total weight of the composition, ranging from 0.05 to 0.2%, which was stable, provided with remarkable antibacterial activity, but which proved to be cytotoxic at in vitro toxicity tests and therefore unusable .
  • an aqueous ophthalmic solution preferably in borate, isotonic buffer, in which Biosecur®, in a concentration of between 0.1% and 0.2% by weight, is in liposomal form, with phospholipids in a range of between 0.6 and 1.50% w/w, where the size of the liposomes, obtained through a high pressure extrusion as described below, result in a size smaller than 200nm.
  • This formulation while being less active than the previous one which included the simple presence of Biosecur®, was non-cytotoxic, allowing sterilization of the collyrium by filtration at 0.2 micron .
  • the partial and limited decrease in antibacterial activity is probably due to the peculiarity (polyphenols/flavonoids ) of the Biosecur® product which interact with phospholipids .
  • This modulating effect of the phospholipids is carried out also at the level of the cytotoxicity of the Biosecur® product, which loses any effect of cellular stress.
  • the liposomal formulation of Biosecur® was admixed with Hypromellose, in a percentage not higher than 0.3% w/w, as a viscosizing agent.
  • Hypromellose does not derive from pure chance but from an articulated research which has involved a wide experimental activity, since the addition of other viscosizing agents of common use and widely used as the hyaluronic acid sodium salt or the cross-linked hyaluronic acid have proved completely unusable as they cause the precipitation of Biosecur®, with complete loss of its antibacterial activity.
  • Hypromellose added in a percentage not higher than 0.15% w/w to the liposomal preparation containing Biosecur® at 0.2%, does not cause any precipitation, and the antibacterial activity is good, as coded by the Pharmacopoeia, always allowing the possibility of sterilizing the eye drops by 0.2 micron filtration.
  • the experimentation carried out allowed the development of a liposomal formulation of Biosecur® containing 0.15% w/w hypromellose, which has all the features of significantly improving the absorption of flavonoids at the level of the ocular membranes.
  • liposomes allow improving the absorption of flavonoids especially at the level of the ocular membrane .
  • the patent document CN 103 860 625 A describes ophthalmic compositions comprising the extract of Pericarpium Citri tangerinae, which is rich in anthocyanidin, a strong antioxidant.
  • the compositions can be in the form of liposomes. However, no specific activity or procedure is indicated to produce sterile citrus extract liposomes by 0.2 micron filtration.
  • WO 2017/161387 A1 describes a liposomal composition
  • a liposomal composition comprising an orange extract, prepared by mixing an aqueous and an organic phase containing phospholipids, evaporation of organic solvents, filtration (without any indication of the pore size of the filter used), and lyophilization of liposomes.
  • the activity of obtaining nanosized liposomes does not occur spontaneously, but the action of at least one high-energy source, such as ultrasounds or an ultra-high-pressure extruder (at least 900-1200 atm) is required.
  • the patent document US 2010/143451 A1 describes eye gel compositions comprising an Osage orange extract which is encapsulated in a liposomal composition and then in an eye gel composition comprising polyacrylates and xanthan gum.
  • a liposomal formulation (called EYE Gel Composition) is illustrated which, in addition to not being fully described, results in a composition which is not a collyrium: in fact, due to the presence of Carbopol, Xanthan gum and Dimethicone, as indicated, it is a gel/cream for topical use which due to the presence of phenoxyethanol and caprylyl glycol chlorphenesin (preservatives used in cosmetics) cannot be used on the eyes due to its toxicity.
  • fig. 1 is a graph illustrating the logarithmic reduction of the concentration of microorganisms which survived as a function of time for a sample of aqueous collyrium in isotonic borate buffer with Biosecur® at a concentration of 0.2% w/w;
  • fig. 5 is a graph like the previous one relating to a sample of collyrium with Biosecur® at 0.1% w/w in liposomal form with phospholipids S80 at 1% w/w;
  • fig. 6 is a graph like the previous one relating to a sample of collyrium with Biosecur® at 0.1% w/w in liposomal form with phospholipids S80 at 1% w/w and hypromellose at 0.15% w/w;
  • fig. 7 is a graph like the previous one related to a sample of collyrium with Biosecur® at 0.2% w/w in liposomal form with phospholipids S80 at 1% w/w and hypromellose at 0.15%.
  • the Biosecur® is proposed in liposomal form, in a concentration not less than 1% by weight of non-hydrogenated phospholipids S80 and not higher than 0.2% by weight of Biosecur®, or equivalent extract of flavonoids from mandarin, bitter orange and sweet orange, with respect to the total weight of the aqueous collyrium, resorting or not to the addition of Hypromellose to improve its stability and mucoadhesiveness, in a quantity not exceeding 0.15% by weight on the total weight, to always allow sterilization by (sterilizing) filtration of the liposomal solution without incurring the possible occlusion of the filters used.
  • An aqueous collyrium sample was prepared in isotonic borate buffer, with Biosecur® at a concentration of 0.2%, 0.1% and 0.05% w/w.
  • the preparation of the collyrium did not involve particular difficulty. The only specific attention was to subject the aqueous collyrium with Biosecur® for ophthalmic use, to filtration at 0.2 micron to ensure sterility .
  • the product has shown a remarkable anti-bacterial capacity following the evaluation prescribed by the 12th edition of the Pharmacopoeia, and all the preparations were found to comply with criteria A recommended by the F.U.I. XII ed.
  • Candida albicans ATCC 10231 Candida albicans ATCC 10231, and
  • the possibility of viscosizing the collyrium was evaluated by preparing the following aqueous collyrium in which Biosecur is present in different percentages, using cross-linked Hyaluronic acid or Hyaluronic acid sodium salt as the viscosity agent.
  • Hypromellose as a viscosizing agent in a percentage not higher than 0.15%. Unlike the other viscosizing agents used in the previous procedure, such as Hyaluronic acid, the addition of Hypromellose does not cause any precipitation, and the antibacterial activity is good, as codified by the Pharmacopoeia, always allowing the possibility of sterilizing the collyrium by filtration 0.2 microns.
  • the cells are grown in plates until an almost confluent monolayer is obtained.
  • Three cell culture plates are prepared for each sample. Furthermore, three plates are prepared for the negative control, three for the positive control and three for the control of the culture medium (MEM control) . In the plates to be treated with the sample, an aliquot of the test sample was placed in contact with the cellular monolayer.
  • Cells BSCL 56/L929 (connective tissue of mouse) Culture medium: Minimum Essential Medium (MEM) , with Earle's salts admixed with 5% fetal bovine serum, 1% L-glutamine, 0.6% penicillin/ streptomycin and 0.3% fungizone (complete MEM) .
  • MEM Minimum Essential Medium
  • an aliquot of the sample is placed in direct contact with the cell culture.
  • Negative control aliquot of sterile physiological solution .
  • Control medium Complete MEM cell culture medium.
  • the plates treated with the sample under examination, those with the positive and negative controls and those with the culture control are incubated for 48 hours at 37 ⁇ 1 °C.
  • Cytotoxicity is assessed qualitatively by microscopic examination of the cells after 24 and 48 hours of incubation. The general morphology, the presence of vacuolization, detachments, cell lysis and integrity of the membranes are evaluated. The deviations from the normal morphology highlighted by the negative control are assigned a score from 0 to 4 (see scoring system) . Furthermore, for the plates treated with the sample, the confluence of the monolayer is evaluated, and the color of the culture medium is compared with that of the medium of the negative control plates.
  • the score varies from grade 0, which corresponds to no Reactivity i.e. a fair amount of intracellular granulations and no cell lysis, to grade 4 which indicates a severe Reactivity, i.e. the almost complete destruction of the cellular layer.
  • the cells treated with the sample after 24 and 48 hours of incubation showed deviations from the normal morphology highlighted by the negative control.
  • the sample under examination shows a severe reactivity.
  • Table 4 refers to an NIOLIP collyrium S80, consisting of liposomes with Phospholipids S80 at 1% containing Biosecur 0.2%
  • Niolip S80 liposomes prepared with
  • Table 5 refers to an NIOLIP collyrium S80, with liposomes prepared with Phospholipids S80 at 1% containing Biosecur 0.1%
  • Niolip S80 liposomes prepared with
  • the partial and limited decrease of the antibacterial activity compared to the use of the Biosecur not in liposomal form, can be ascribed perhaps to the peculiarity of the polyphenols/flavonoids of the Biosecur® product which probably interact with the phospholipids which form the liposome structure.
  • phospholipids S80 have always been used in which phosphatidylcholine has a concentration not higher than 80% by weight, in particular between 73 and 79
  • Niolip S80 liposomes prepared with
  • Niolip S80 liposomes prepared with Phospholipids S80
  • Biosecur 0.1% Biosecur 0.1%
  • cross-linked Hyaluronic acid 0.1% Borate Buffer
  • Niolip S80 liposomes prepared with Phospholipids S80
  • Biosecur 0.05% cross-linked
  • Niolip S80 (with liposomes prepared with phospholipids S80) 1%, Biosecur 0.1%, Hypromellose 0.15%, Borate Buffer
  • the liposomal product containing 0.1% Biosecur® showed a weak/ fair anti-bacterial capacity, the preparation was found to comply with the B criteria recommended by the F.U.I. XII. In the continuation of the experiment the product fell into the type A classification according to the Pharmacopoeia. (see fig. 6)
  • the liposomal product containing 0.2% Biosecur has instead shown a good anti-bacterial capacity following the evaluation prescribed by the Pharmacopoeia XII edition. All preparations comply with criteria A recommended by the F.U.I. XII ed.
  • the challenge test was carried out on a sterile sample of Niolip with liposomes S80 1% Biosecur ®
  • the present invention also provides a method for making an aqueous collyrium of Biosecur® or of a mixture of flavonoid-rich citrus extracts, in the form of a liposomal preparation having antibacterial activity which provides for the steps as specified below:
  • the mixture of phospholipids and Biosecur® is dried under vacuum, using a rotavapor, at a temperature not higher than 45-50 °C.
  • a dry powder is obtained, where the Biosecur®, the flavonoids and the other lipophilic and hydrophilic components are in direct contact with phospholipids.
  • the solution containing Proliposomes is extruded at high pressure (800 1000 atm) using a high-pressure mechanical extruder, to obtain liposomes with a size less than 200 nm; the high pressure extrusion procedure is repeated 4-6 times (100 liters x 4-6 times) as needed to obtain liposomes with a size smaller than 200 nm (limit for the 0.2 micron filterability required for sterilization) .
  • the forming process is not a spontaneous process but requires the application of great energy to obtain a real inclusion of the active ingredients and the desired size of the liposomes .
  • Controls pH, isotonicity.
  • Biosecur® is sterilized in line by filtration through a 0.2 micron filter.
  • Controls pH, isotonicity, sterility, size, residual ethanol titer

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Natural Medicines & Medicinal Plants (AREA)
  • Ophthalmology & Optometry (AREA)
  • Inorganic Chemistry (AREA)
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  • Alternative & Traditional Medicine (AREA)
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Abstract

L'invention porte sur une préparation ophtalmique constituée d'une solution aqueuse, ou d'un collyre, contenant une dispersion de liposomes BIOSECUR® d'un mélange contenant des extraits d'agrumes riches en flavonoïdes, sous la forme d'une préparation liposomale, qui fournit une excellente protection antibactérienne, selon les paramètres indiqués par la classification de la pharmacopée XII éd, de péférence, un tel collyrium, dans un tampon isotonique à base de borate, est rendu visqueux pour améliorer sa stabilité et la mucoadhésivité, avec l'ajout d'hydroxypropy1-méthylcellulose (hyprothése). L'invention porte également un procédé de préparation d'une telle solution à usage ophtalmique comprenant du Biosecur® ou une composition à base d'extraits d'agrumes riches en flavonoïdes, sous forme liposomale, les liposomes ayant une taille inférieure à 200 nm.
PCT/IB2019/060123 2018-11-26 2019-11-25 Collyre contenant un extrait d'agrumes sous forme liposomale Ceased WO2020109965A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP19831879.2A EP3870151A1 (fr) 2018-11-26 2019-11-25 Collyre contenant un extrait d'agrumes sous forme liposomale

Applications Claiming Priority (2)

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IT201800010576 2018-11-26
IT102018000010576 2018-11-26

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WO2020109965A1 true WO2020109965A1 (fr) 2020-06-04

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100143451A1 (en) * 2008-07-31 2010-06-10 Gruber James V Composition for Improving Skin Condition and Appearance
CN103860625A (zh) * 2013-02-20 2014-06-18 成都尖卡斌科技有限公司 越橘提取物眼用制剂及其制备方法和用途
WO2015006863A1 (fr) * 2013-07-16 2015-01-22 Vasudevan Harish Procédé pour extraire des flavonoïdes et/ou polyphénols d'écorces d'orange séchées et en poudre, ses compositions, et procédés de traitement de maladies associées à une inflammation chronique
US20160303033A1 (en) * 2013-04-02 2016-10-20 Air Products And Chemicals, Inc. Compositions of delivery systems for personal care products
WO2017161387A1 (fr) * 2016-03-18 2017-09-21 Reid Christopher Brian Compositions à base d'extraits naturels et leur utilisation dans des méthodes destinées à prévenir ou à traiter des maladies

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100143451A1 (en) * 2008-07-31 2010-06-10 Gruber James V Composition for Improving Skin Condition and Appearance
CN103860625A (zh) * 2013-02-20 2014-06-18 成都尖卡斌科技有限公司 越橘提取物眼用制剂及其制备方法和用途
US20160303033A1 (en) * 2013-04-02 2016-10-20 Air Products And Chemicals, Inc. Compositions of delivery systems for personal care products
WO2015006863A1 (fr) * 2013-07-16 2015-01-22 Vasudevan Harish Procédé pour extraire des flavonoïdes et/ou polyphénols d'écorces d'orange séchées et en poudre, ses compositions, et procédés de traitement de maladies associées à une inflammation chronique
WO2017161387A1 (fr) * 2016-03-18 2017-09-21 Reid Christopher Brian Compositions à base d'extraits naturels et leur utilisation dans des méthodes destinées à prévenir ou à traiter des maladies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
O GORTZI ET AL: "Enhanced bioactivity of Citrus limon (Lemon Greek cultivar) extracts, essential oil and isolated compounds before and after encapsulation in liposomes", PLANTA MEDICA, vol. 73, no. 09, 1 January 2007 (2007-01-01), DE, pages P_184, XP055674209, ISSN: 0032-0943, DOI: 10.1055/s-2007-986965 *

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