WO2020111960A1 - Composition implantable comprenant de la cystatine et son utilisation en implantologie osseuse - Google Patents

Composition implantable comprenant de la cystatine et son utilisation en implantologie osseuse Download PDF

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Publication number
WO2020111960A1
WO2020111960A1 PCT/PL2019/050069 PL2019050069W WO2020111960A1 WO 2020111960 A1 WO2020111960 A1 WO 2020111960A1 PL 2019050069 W PL2019050069 W PL 2019050069W WO 2020111960 A1 WO2020111960 A1 WO 2020111960A1
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Prior art keywords
composition
weight
cystatin
poloxamer
amount
Prior art date
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Ceased
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PCT/PL2019/050069
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English (en)
Inventor
Przemysław Baranowski
Krzysztof GOŁĄB
Jakub GBUREK
Janusz Pluta
Bożena Karolewicz
Joanna ANTOSZEWSKA-SMITH
Katarzyna Jadwiga JUSZCZYŃSKA
Tadeusz Przemysław SEBZDA
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Akademia Medyczna
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Akademia Medyczna
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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising cystatin and poloxamer P407 and carbomer 971 P or carbomer 974P, as well as other compounds, such as nipagins, and use thereof in bone implantology, in particular for coating implants or for application on an implant fixation site in order to promote effective osseointegration thereof.
  • Cystatins have inhibitory properties towards proteases involved in bone resorption, they stimulate bone formation and mineralization, they also have immunosuppressive and antimicrobiological activity. Due to all of these properties, coating of TSADs (Temporary Skeletal Anchorage Devices) with a cystatin layer or applying it to the fixation site may at the same time prevent bone resorption events in the vicinity of the TSAD, promote its overgrowth with new bone tissue, inhibit its rejection through an immunological route, as well as prevent microbiological superinfections (Goto T, Yamaza T, Tanaka T.: Cathepsins in the osteoclast.
  • TSADs Temporal Skeletal Anchorage Devices
  • cysteine proteases of the papain family are involved, mainly cathepsin B, L and K, which are secreted into the extracellular matrix by osteoclasts.
  • Cysteine proteases are also utilized by a variety of bacteria ( Pseudomonas aeruginosa, Staphylococcus aureus, Perphyromonas gingivalis), parasites ( Trypanosoma cruzi, Leishmania donovani) and fungi ( Candida albicans, Candida parapsilosis and Candida tropicaiis) in an invasive process to degrade host tissues and they are essential for proliferation in some viruses (Polio, Picornavirus).
  • cystatins are considered as potential pharmaceuticals in therapy of diseases, in the course of which excessive proteolytic activity is found or of diseases associated with an infection with microorganisms. It was also found that cystatins stimulate osteoblast differentiation, as well as formation and mineralization of bones. Cystatins also have immunosuppressive properties by inhibiting legumain and cathepsin S involved in presentation of antigens mediated by MHCs class II.
  • cystatins in medicine was the object of patents and patent applications globally.
  • Polish patent document PAT.217192 a use of cysteine protease inhibitor monomer lyophilizate, being ovocystatin, as an active substance of a pharmaceutical agent used on preventing and/or treating of dementia, including preventing and inhibiting cognitive functions deterioration, especially those progressing along with development of dementia, in particular in Alzheimer’s disease and in aging process.
  • a protein composition was disclosed comprising angiogenin and/or its degradation products in an amount of 2 to 15 mg/100 mg and cystatin and/or its degradation products with a mass ratio to angiogenin in range of 0.003 to 0.6.
  • the oral composition comprises zinc and a copper salt capable of coating and closing dental tubules by protein agglomeration providing in a short period of time an effect on preventing and reducing teeth hypersensitivity symptoms.
  • the composition comprises a foaming agent (an anionic surfactant such as sodium alkyl sulfate and sodium lauryl sulfate), a nonionic surfactant (copolymer (poloxamer) polyoxyethylene-polyoxypropylene, polyoxyethylated hydrogenated castor oil or polyoxyethylene sorbitan) and a fatty acid ester.
  • the foaming agent can be present in the amount of 0.5 to 5% by weight in relation to the total mass of the oral composition and preferably 0.5 to 3.5% by weight.
  • Polish patent PAT.219098 discloses a pharmaceutical composition for treating periodontal diseases in open and inpatient dental treatment, as well as in dental surgery.
  • the pharmaceutical composition is in a gel form with adjusted viscosity.
  • Its active ingredient is a base consisting of an inhibitor of cysteine peptidases derived from egg whites, urea, human and animal amniotic fluid, human and animal placenta and from plants, with an activity of 1-50 inhibitor units, being suspended in 50 g of a polyhydric alcohol and 50 g of a 0.05 molar solution of phosphate buffer with a pH of 6.0 to 7.5, in the amount of 20 to 50% by weight, with its carrier being gelling agents in the amount of 7 to 20% by weight and water making up to 100% by weight.
  • the gelling agents are methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, gelatin, citrus-apple pectin or dextran. It is preferable to use additives in the form of polyhydric alcohols and the Nipagin composition.
  • preparations are being sought that would support bone remodeling, sustain the osseointegration process and inhibit or even thwart superinfections with microorganisms during surgical procedures.
  • this kind of preparation should also be easy to use, easy to administer locally, nonirritating to mouth tissues and exhibiting good adherence to implant surfaces or solid tissues.
  • this kind of preparation should be characterized with long term stability.
  • the first object of the invention is an implantological composition comprising cystatin, a carrier, a neutralizing agent, deionized water or buffer, characterized in that it comprises cystatin with specific activity of at least 10 inhibitor units per milligram of protein in the amount of 0.02% (by weight), a carrier substance in the amount of 15.0% to 20.0% (by weight) and a neutralizing agent in the amount of no more than necessary to obtain a suitable pH value, preferably selected from the group comprising: NaOH or TEA, and the composition comprising deionized water or PBS buffer making up to 100% (by weight) of the weight of the composition.
  • the carrier substance is poloxamer 407.
  • the composition comprises a gelling agent in the amount of no more than 0.25% (by weight) of the weight of the composition.
  • the composition may be applied to soft tissues as well as solid tissues and implants, depending on the content of the gelling agent. When it is absent from the composition then the composition shows better adhesive properties towards a soft tissue surface, e.g. epithelium. In contrast, after the addition of a gelling agent, the composition adheres better to solid tissue or implants.
  • an adhesive properties enhancing substance is carbomer 974P or carbomer 971P.
  • the composition comprises additives.
  • the additives constitute from 0% to 25% (by weight) of the weight of the composition.
  • the additives are selected from the group comprising: parabens (nipagins), glycerol, polyoxyethylene glycol 200, propylene glycol.
  • cystatin is of animal or plant origin or it is human recombinant.
  • the suitable pH of the composition is 7.40 ⁇ 0.05.
  • the composition is in a liquid form in temperature of 20°C.
  • the composition is in a gel form in temperature of 37°C.
  • the second object of the invention is a use of the implantological composition for coating implants or for local administration to promote osseointegration.
  • Fig. 1 shows the activity of cystatin released in time from the formulation of the following composition: 17% poloxamer 407 and 0.02% cystatin, in a base of deionized water
  • Fig. 2 shows the activity of cystatin released in time from the formulation of the following composition: 17% poloxamer 407, 0.1% carbomer 974P and 0.02% cystatin, in a base of deionized water
  • Fig. 3 shows shear stress as a function of shear rate for the prepared gels in temperature of 20°C
  • Fig. 4 shows shear stress as a function of shear rate for the prepared gels in temperature of 37°C
  • Figs 5-8 show viscosity as a function of temperature for the prepared gels.
  • cystatin at the concentration of 0.2 mg/ml is stable in the conditions of the preparation of the formulation. Also, the presence of poloxamer 407 (at the concentration of 15%-20%> w/w) and carbomer 974P (at the concentration of 0.1-0.25% w/w) has no adverse effect on cystatin activity (Example 8). Moreover, it was found that the formulation with the concentration of 0.2 mg/ml is stable for the period of at least 12 months (Example 9). To summarize, both the method of preparation of the formulation and its composition provide a fully active and stable cystatin formulation.
  • the prepared hydrogels are characterized by an initial (until about 10 hours) rapid release of cystatin, whereas in the following hours the release rate is gradually decreasing (Fig. 1 and 2).
  • Hydrogels based on poloxamer 407 and carbomers 971 P/974P can be used as a sustained release form for a biologically active protein such as cystatin.
  • poloxamer 407 To a weighted portion of the solvent 17 g of poloxamer 407 are added, followed by adding the rest of deionized water to the mass of 99.98 g. The whole mixture is agitated in order to provide wetting of the introduced poloxamer, and then it is placed in temperature of 2-8°C for 24h to obtain a clear solution. After this time, the poloxamer solution is transferred to 0.02 g of freeze dried cystatin, it is mixed until the cystatin is dissolved and a homogenous mixture is obtained having a pH of 7.4. Next, the solution is filtered through a syringe filter with pore diameter of 0.22 pm in aseptic conditions. The filtered solution is sealed in ampoules having a volume of 2 ml in aseptic conditions. The obtained agent is intended for coating of bone implants.
  • the gel is cooled and then in aseptic conditions 20 g of 17% poloxamer 407 solution comprising 0.02 g of freeze dried cystatin, filtered through a syringe filter with pore diameter of 0.22 pm, is added therein. The whole mixture is agitated until a homogenous mixture is obtained. The ready solution is sealed in ampoules having a volume of 2 ml in aseptic conditions. The obtained agent is intended for coating of bone implants.
  • the gel is cooled and then in aseptic conditions 20 g of 17% poloxamer 407 solution comprising 0.02 g of freeze dried cystatin, filtered through a syringe filter with pore diameter of 0.22 pm, is added therein. The whole mixture is agitated until a homogenous mixture is obtained. The ready solution is sealed in ampoules having a volume of 2 ml in aseptic conditions. The obtained agent is intended for coating of bone implants.
  • poloxamer 407 To a weighted portion of the solvent 15 g of poloxamer 407 are added, followed by adding the rest of deionized water to the mass of 99.98 g. The whole mixture is agitated in order to provide wetting of the introduced poloxamer, and then it is placed in temperature of 2-8°C for 24h to obtain a clear solution. After this time, the poloxamer solution is transferred to 0.02 g of freeze dried cystatin, it is mixed until the cystatin is dissolved and a homogenous mixture is obtained having a pH of 7.4. Next, the solution is filtered through a syringe filter with pore diameter of 0.22 pm in aseptic conditions. The filtered solution is sealed in ampoules having a volume of 2 ml in aseptic conditions. The obtained agent is intended for coating of bone implants.
  • the gel is cooled and then in aseptic conditions 20 g of 15% poloxamer 407 solution comprising 0.02 g of freeze dried cystatin, filtered through a syringe filter with pore diameter of 0.22 pm, is added therein. The whole mixture is agitated until a homogenous mixture is obtained. The ready solution is sealed in ampoules having a volume of 2 ml in aseptic conditions. The obtained agent is intended for coating of bone implants.
  • poloxamer 407 To a weighted portion of the solvent 20 g of poloxamer 407 are added, followed by adding the rest of deionized water to the mass of 99.98 g. The whole mixture is agitated in order to provide wetting of the introduced poloxamer, and then it is placed in temperature of 2-8°C for 24h to obtain a clear solution. After this time, the poloxamer solution is transferred to 0.02 g of freeze dried cystatin, it is mixed until the cystatin is dissolved and a homogenous mixture is obtained having a pH of 7.4. Next, the solution is filtered through a syringe filter with pore diameter of 0.22 pm in aseptic conditions. The filtered solution is sealed in ampoules having a volume of 2 ml in aseptic conditions. The obtained agent is intended for coating of bone implants.
  • Deionized water ad 100.0 g To about 60 g of deionized water 0.175 g of carbomer 974P is added, and then it is mixed until a homogenous mixture is obtained. Next, with constant agitation, 20 g of poloxamer 407 are added in small portions to the mass of about 77 g. After wetting the introduced poloxamer, the whole mixture is placed in temperature of 2-8°C for 24h for it to dissolve. Then, the mixture is adjusted to pH 7.40 ⁇ 0.05 using 2-5 drops (as needed) of 10 NaOH solution and with deionized water to the mass of 80 g.
  • the prepared gel is sterilized in an autoclave in the following conditions: 121 °C and overpressure of 1 atm for 15 minutes. After the sterilization process, the gel is cooled and then in aseptic conditions 20 g of 20% poloxamer 407 solution comprising 0.02 g of freeze dried cystatin, filtered through a syringe filter with pore diameter of 0.22 pm, is added therein. The whole mixture is agitated until a homogenous mixture is obtained. The ready solution is sealed in ampoules having a volume of 2 ml in aseptic conditions. The obtained agent is intended for coating of bone implants.
  • Example 8 Compositions of the formulations and their anti-papain activity
  • Example 9 Stability of an example formulation in the period of 12 months.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Le premier objet de l'invention est une composition implantable comprenant de la cystatine, un support, un agent neutralisant, de l'eau désionisée ou un tampon, caractérisé par le fait qu'elle comprend de la cystatine ayant une activité spécifique d'au moins 10 unités inhibitrices par milligramme de protéine dans la quantité de 0,02 % (en poids), une substance support dans la quantité de 15,0 % à 20,0 % (en poids) et un agent neutralisant dans la quantité de pas plus que nécessaire pour obtenir une valeur de pH appropriée, de préférence choisie dans le groupe comprenant : NaOH ou TEA, et la composition comprenant de l'eau désionisée ou du tampon PBS constituant jusqu'à 100 % (en poids) du poids de la composition. Le second objet de l'invention est une utilisation de la composition implantable pour revêtir des implants ou pour une administration locale pour favoriser l'ostéointégration.
PCT/PL2019/050069 2018-11-28 2019-11-27 Composition implantable comprenant de la cystatine et son utilisation en implantologie osseuse Ceased WO2020111960A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP.427909 2018-11-28
PL427909A PL239917B1 (pl) 2018-11-28 2018-11-28 Kompozycja zawierająca cystatynę oraz jej zastosowanie w implantologii kostnej

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Publication Number Publication Date
WO2020111960A1 true WO2020111960A1 (fr) 2020-06-04

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WO (1) WO2020111960A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056627A1 (fr) * 2000-01-12 2001-08-09 Am-Pharma B.V. Dispositif medical revetu de peptides antimicrobiens
PL195665B1 (pl) * 2000-06-13 2007-10-31 Przed Farmaceutyczne Jelfa Sa Środek farmaceutyczny w postaci żelu do stosowania miejscowego w leczeniu chorób przyzębia
PL218970B1 (pl) * 2008-01-15 2015-02-27 Akademia Medyczna Im Piastów Śląskich We Wrocławiu Kompozycja farmaceutyczna do leczenia chorób skórnych
PL219098B1 (pl) * 2008-08-28 2015-03-31 Akademia Medyczna Im Piastów Śląskich We Wrocławiu Kompozycja farmaceutyczna do leczenia chorób przyzębia

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056627A1 (fr) * 2000-01-12 2001-08-09 Am-Pharma B.V. Dispositif medical revetu de peptides antimicrobiens
PL195665B1 (pl) * 2000-06-13 2007-10-31 Przed Farmaceutyczne Jelfa Sa Środek farmaceutyczny w postaci żelu do stosowania miejscowego w leczeniu chorób przyzębia
PL218970B1 (pl) * 2008-01-15 2015-02-27 Akademia Medyczna Im Piastów Śląskich We Wrocławiu Kompozycja farmaceutyczna do leczenia chorób skórnych
PL219098B1 (pl) * 2008-08-28 2015-03-31 Akademia Medyczna Im Piastów Śląskich We Wrocławiu Kompozycja farmaceutyczna do leczenia chorób przyzębia

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PL427909A1 (pl) 2020-06-01
PL239917B1 (pl) 2022-01-24

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