WO2018234407A1 - Composition contenant des nanoparticules d'argent métallique et un sel hyaluronate à titre d'intermédiaire dans la préparation de formulations pharmaceutiques à usage topique - Google Patents

Composition contenant des nanoparticules d'argent métallique et un sel hyaluronate à titre d'intermédiaire dans la préparation de formulations pharmaceutiques à usage topique Download PDF

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Publication number
WO2018234407A1
WO2018234407A1 PCT/EP2018/066475 EP2018066475W WO2018234407A1 WO 2018234407 A1 WO2018234407 A1 WO 2018234407A1 EP 2018066475 W EP2018066475 W EP 2018066475W WO 2018234407 A1 WO2018234407 A1 WO 2018234407A1
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WO
WIPO (PCT)
Prior art keywords
composition
aqueous solution
pellets
weight
salt
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Application number
PCT/EP2018/066475
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English (en)
Inventor
Giovanna ADELIZZI
Piersandro Pallavicini
Celestino RICCIARDI
Original Assignee
Sakura Italia S.R.L.
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Application filed by Sakura Italia S.R.L. filed Critical Sakura Italia S.R.L.
Publication of WO2018234407A1 publication Critical patent/WO2018234407A1/fr

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • 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
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to a process for preparing an aqueous composition (A) containing silver metal nanoparticles and a pharmaceutically acceptable hyaluronate salt, the use of said composition (A) as intermediate in the preparation of pellets (B) wherein silver metal nanoparticles are dispersed in said pharmaceutically acceptable hyaluronate salt, a film (C) or gel (C ') obtained by addition of respectively a suitable filming or gelling polymer to said composition (A) previously neutralized with an organic acid.
  • compositions comprising as the active ingredient the pellets (B), the film (C) or the gel (C) as the active ingredient in combination with suitable excipients and /or diluents in particular for use in the treatment of cutaneous lesions wounds, vaginal mucosal lesions, vaginal infections and dryness, respiratory mucosa infections and dryness.
  • Medical devices for favoring wound healing, promoting revascularization, absorbing exudate and, where necessary, exert an antibacterial/ antimicrobial action are generally applied on skin lesions, but also mucosal lesions, like for example caused by vaginal dryness.
  • Silver inhibits the synthesis of structural proteins composing the bacterial wall preventing its formation, and binds to enzymatic proteins of bacterial DNA, disrupting its functionality.
  • silver prevents the proliferation of keratinocytes and fibroblasts (fundamental components of dermis and epidermis), slow down the regeneration of the wound bed on which it is applied, and this is so detrimental to complete healing of the lesion, that some authors suggest to avoid the application of silver based devices (Lam, P.K.
  • silver is a sensitizing agent, mainly when applied for long periods, in general ("Chronic exposure to Silver or Silver salts, Patty's Industrial Hygiene and Toxicology, Vol. 2, G.D. Clayton, F.E. Clayton, Eds. Wiley- Interscience, New York, 3rd Ed., 1981, p. 1881-1894).
  • the biological effects of hyaluronic acid is well known, and is a function both of the molecular structure and molecular weight of this substance.
  • Hyaluronic acid characterized by having an average low molecular weight favoring cell mobility plays a key role in wound healing processes (West et al, Science, 1985, 228, 1324-6; Deed et al, Int. J. Cancer, 1997, 71, 251-6).
  • High molecular weight fractions characterized by having high viscosity find particular specific application in ocular surgery and also in particular cases of soft tissue filling, for both surgical and dermocosmetic purposes.
  • aqueous compositions containing very small amounts of silver metal of very small dimension and a hyaluronate salt having a high weight average molecular weight.
  • This aqueous composition is used in the preparation of further compositions having both antibacterial and wound healing properties.
  • Object of the present invention is therefore a process for preparing a composition (A), containing an aqueous dispersion of a pharmaceutically acceptable hyaluronic acid salt, having a weight average molecular weight ranging from 1,000,000 and 1,400,000 Da in an amount of from 0.4 to 2% by weight based on the total composition weight and metal silver particles, having an average size of from 4 to 10 nm in a concentration of from 0.004 to 0.02% comprising the following steps:
  • step c) Letting react the mixture coming from step b) at temperature ranging from 20 to 65°C. d) Neutralizing the reacted mixture of step c) with an organic acid.
  • a further object of the present invention are pellets B), obtained by removing water from the composition A), wherein said pellets metal silver consist of nanoparticles dispersed within said hyaluronate salt.
  • a further object of the present invention are: the composition (C) in film form obtained by adding a filming polymer to the aqueous composition (A), and the composition (C) in the form of a gel/hydrogel, obtained by adding a gelling polymer to said composition (A).
  • the present invention further relates to formulations or medical formulations comprising the pellets B), the film C) or the hydrogel C) in combination with suitable excipients and/or diluents.
  • formulations are in particular destined to the treatment of cutaneous or vaginal mucosal lesions and/or wounds and for the treatment of dryness and infections of respiratory mucosa.
  • Figure 1 reports the localized surface plasmonic resonance (LPSR) peak increase in the absorbance spectrum diagram as an indication of the nanoparticles formation according to the process of the present invention carried out at room temperature for 24 hours in a 0.5% sodium hyaluronate aqueous solution by using a 0.001 M of AgN03.
  • LPSR localized surface plasmonic resonance
  • Figures 2-7 reports the same absorbance spectrum diagram of the reaction evolution of the process of the present invention according to the operating conditions followed in the experiment B.
  • Figures 10-13 report the absorbance spectre of the reaction progression according to the operating conditions reported in Experiment C.
  • Figures 14-16 report the absorption spectra of the metal silver nanoparticles before and after addition of 1M HC1, 1M acetic acid, 1M citric acid,
  • Figure 17 reports the TEM (Transmission Electronic microscopy) photos (magnification 50000 and 100000) of the metal silver nanoparticles (AgNP), following to neutralization with citric acid.
  • respiratory mucosa we mean the mucous membrane lining the respiratory tract, including the nasal cavity; the larynx; the trachea; and the bronchi tree. Preferably it is the nasal mucosa.
  • the hyaluronate salt is an alkaline metal salt and more preferably it is the sodium hyaluronate salt.
  • the Ag salt added in step b) in the process of the invention is the nitrate salt, although other water soluble salt may be used such as sulphate, fluoride, acetate.
  • the final concentration of the Ag ion in the aqueous solution of step b) preferably ranges from 0.005 to 0.01%.
  • the pH in the aqueous solution of step b) is preferably higher than 11 and more preferably is comprised between 11.4 and 12.5.
  • step c) The redox reaction occurring in step c) is preferably carried out at 60°C for 6 hours.
  • Rl-(OH)HC-CH(OH)-R2 to obtain 2R1R2CHO, wherein Rl and R2 are residues forming together a glucuronic and/or glucosamine ring, both constituting the repeating unit of the hyaluronic acid molecule.
  • the preferred organic acid used in step (d) to neutralize the aqueous alkaline solutions is acetic or citric acid, more preferably is citric acid.
  • the aqueous composition (A) obtained with the process according to the present invention may be used as intermediate for preparing compositions in the form of films (C) or in the form of gel or hydrogel.
  • compositions are respectively prepared by addition of filming polymer such as polyvinyl alcohols ammonium polyacrilates and ethylcellulose or gelling polymer like for example pectin, chitosan, collagen, and polysaccharides.
  • filming polymer such as polyvinyl alcohols ammonium polyacrilates and ethylcellulose or gelling polymer like for example pectin, chitosan, collagen, and polysaccharides.
  • the aqueous composition (A) may be used in the preparation of the pellets (B) wherein the Ag metal silver nanoparticles are dispersed in the pharmaceutically acceptable hyaluronic acid salt.
  • pellets once coming in contact with water (like for example also that contained in the body fluids), form an aqueous solution with the same characteristics as those of the aqueous composition (A) used in the preparation of these pellets.
  • pellets are preferably prepared from the aqueous composition (A) that is diluted up to 5 times its volume with a polar aprotic solvent, preferably acetone, thereby obtaining a turbid suspension that is centrifuged preferably at 13000 rpm for 10 minute, the centrifuged product i.e. these pellets are isolated and dried under nitrogen flow.
  • a polar aprotic solvent preferably acetone
  • a further object of the present invention are the formulations containing the pellets (B), the film (C) or the gel/ hydrogel (C) in combination with suitable excipients and or diluents.
  • the formulations containing the films (C) are preferably in the form of medical devices destined to the treatment of essentially cutaneous lesions.
  • the formulations containing the hydrogel (C) are preferably medical devices that may be destined both to the treatment of cutaneous lesions, but also to the treatment of vaginal and respiratory mucosal lesions and vaginal and respiratory mucosal dryness and vaginal and respiratory mucosal infections.
  • the formulations containing the pellets (B) are preferably medical devices more preferably in the form sprayable anhydrous compositions placed in pressurized containers containing anhydrous propellants such as lower hydrocarbons and are destined to the treatment of cutaneous lesions.
  • pellets may also be formulated as anhydrous vaginal ovules or suppositories, preferably based on synthetic triglycerides.
  • the aqueous composition (A) after 3 weeks tends to form aggregates.
  • aqueous composition (A) or formulation thereof are extemporaneously prepared at the moment of use by adding to the formulation (Al) coming from step (c) of the process according to the present invention the organic acid solution (A2) for neutralizing the alkaline aqueous solution (Al).
  • a further object of the present invention is a kit for preparing extemporaneously the composition (A), said kit containing the aqueous solution (Al) coming from step (c) of the process according to the present invention and the organic acid aqueous solution (A2) in predetermined amounts for neutralizing the alkaline aqueous solution (A 1 ) thereby obtaining the aqueous composition (A).
  • This extemporaneous formulation may be prepared in a suitable sprayer o syringe to direct said composition (A) inside vagina or nose as this composition is mainly used as washing vaginal or nasal solution.
  • said sprayer or syringe contains the composition Al) to which the organic acid A2) is added for preparing the extemporaneous solution A.
  • step 1 the progressive growth is observed of the localized surface plasmonic resonance (LPSR) absorption band of the redox reaction wherein the starting aqueous solution coming from step b) and utilized in step c) of the process of the invention has a sodium hyaluronate concentration of 0.5%, a 0.001M concentration of Ag + corresponding to 0.01% by weight calculated on the total aqueous solution weight at room temperature.
  • LPSR localized surface plasmonic resonance
  • EXPERIMENT B Monitoring the progression of the redox reaction of step c) of the process of the invention by Absorbance Spectre and Ag + analysis: comparation using different parameters in the redox reaction of step c) of the process according to the invention.
  • this analysis was replicated on the same solutions 1 month after The data may be compared with the absorbance spectra detected for every preparation sample.
  • the absorbance detection was conducted on the solutions as such (sample 0.300 ml, in 1 mm cuvette) with the exception of 2% sodium hyaluronate, where the excessive viscosity of the solution renders impossible the cuvette filling.
  • 0.300 ml have been diluted in bi- distilled water to 3.00ml and the detection was conducted by using 1cm cuvette.
  • AgNPs silver metal nanoparticles
  • sodium hyluronate concentration and AgN03 concentrations a) 0.10% sodium hyaluronate, 0.001 M AgN03, b) 0.25% sodium hyaluronate, 0.001 M AgN03, c) 0.5% sodium hyaluronate, 0.002 M AgN03, d) 0.5% sodium hyaluronate, 0.0005 M AgN03,
  • step c) of the process of the invention was carried out either at 60°C for 6 h or at the same temperature, but for 24 h.
  • Figure 9-13 report the spectra experiment of the reaction carried at 60°C for 6 and 24 hours by using the starting concentrations reported in a)-b)
  • the acidification with citric avid is optimal as it brings to a completely tolerable pH.
  • the AgNPS solution prepared as described in the previous experiments was treated with respectively polyvinylalcohol thereby obtaining a film that can be applied on wounds or cutaneous lesions.
  • the same AgNPS solution may be treated with a polymer having gelling properties such as pectin or collagen.
  • Precipitation of a solid product The addition of acetone of AgNps prepared according to the following conditions 0.5% HyNa, O.OOIM AgN03, 60°C, 6h , renders the solution so turbid that it can be centrifuged.
  • the 1 :5 dilution ratio: aqueous solution volume/acetone volume and the centrifugation of this turbid solution for 10 minutes at 13000 rpm allow to obtain pellets that after being isolated dried under nitrogen flow and thereafter re-dissolved in water allows to obtain a solution with absorbance spectrum similar to that of the starting solution.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un procédé de préparation d'une composition (A) contenant une dispersion aqueuse d'un sel d'acide hyaluronique pharmaceutiquement acceptable, ayant un poids moléculaire moyen en poids dans la plage de 1 000 000 à 1 400 000 en une quantité de 0,4 à 2 % en poids sur la base du poids total de la composition et des particules d'argent métallique, ayant une taille moyenne de 4 à 10 nm à une concentration dans la plage de 0,004 à 0,02 %, comprenant les étapes suivantes : a) préparer une solution aqueuse dudit sel d'acide hyaluronique pharmaceutiquement acceptable ayant le poids moléculaire ci-dessus à une concentration comprise dans la plage précitée, b) ajouter une solution aqueuse de sel d'argent à la solution aqueuse et un hydroxyde de métal alcalin jusqu'à obtention d'un pH dans la plage de 9,8 à 12,5, et d'une concentration d'ions Ag de 0,004 à 0,02 %; c) laisser réagir le mélange de l'étape b) à une température dans la plage de 20 à 65°C; et d) neutraliser le mélange réactionnel de l'étape c) avec un acide organique. Cette composition A) est utilisée comme intermédiaire pour préparer des granulés (B), où lesdites nanoparticules d'argent métallique sont dispersées dans ledit sel ou un film de hyaluronate pharmaceutiquement acceptable (C) ou un gel (C) obtenu par ajout d'un polymère filmogène ou gélifiant à ladite composition (A) avant sa neutralisation avec un acide organique. Des compositions topiques contenant : • les granulés (B) • le film (C) ou le gel (C) en combinaison avec des excipients et/ou diluants appropriés, à utiliser en particulier dans le traitement des plaies et des lésions, notamment de la peau, et de la muqueuse vaginale sont en outre décrites.
PCT/EP2018/066475 2017-06-20 2018-06-20 Composition contenant des nanoparticules d'argent métallique et un sel hyaluronate à titre d'intermédiaire dans la préparation de formulations pharmaceutiques à usage topique WO2018234407A1 (fr)

Applications Claiming Priority (2)

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EP17177003 2017-06-20
EP17177003.5 2017-06-20

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WO2018234407A1 true WO2018234407A1 (fr) 2018-12-27

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150011501A1 (en) * 2012-02-17 2015-01-08 Kimflexor, S.L. Partially depolymerized glycosaminoglycan silver and gold salts
WO2016156788A1 (fr) * 2015-03-31 2016-10-06 Lancaster University Business Enterprises Ltd Nanoparticules métalliques revêtues de glycosaminoglycane et utilisations de celles-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150011501A1 (en) * 2012-02-17 2015-01-08 Kimflexor, S.L. Partially depolymerized glycosaminoglycan silver and gold salts
WO2016156788A1 (fr) * 2015-03-31 2016-10-06 Lancaster University Business Enterprises Ltd Nanoparticules métalliques revêtues de glycosaminoglycane et utilisations de celles-ci

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Chronic exposure to Silver or Silver salts, Patty's Industrial Hygiene and Toxicology", vol. 2, WILEY-INTERSCIENCE, pages: 1881 - 1894
ABDEL-MOHSEN A M ET AL: "Antibacterial activity and cell viability of hyaluronan fiber with silver nanoparticles", CARBOHYDRATE POLYMERS, APPLIED SCIENCE PUBLISHERS, LTD. BARKING, GB, vol. 92, no. 2, 12 September 2012 (2012-09-12), pages 1177 - 1187, XP028972926, ISSN: 0144-8617, DOI: 10.1016/J.CARBPOL.2012.08.098 *
BRUN ET AL., OSTEOARTHRITIS CARTILAGE, vol. 11, 2003, pages 208 - 16
DEED ET AL., INT. J. CANCER, vol. 71, 1997, pages 251 - 6
J. COLLOID INTERF. SCI., vol. 498, 2017, pages 271 - 281
LAM, P.K. ET AL., BR. J. BIOMED. SCI., vol. 61, 2004, pages 125 - 127
WEST ET AL., SCIENCE, vol. 228, 1985, pages 1324 - 6

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