WO2014196943A1 - Systèmes de gel contenant des microsphères de vancomycine permettant une libération contrôlée du médicament et de la serrapeptase - Google Patents

Systèmes de gel contenant des microsphères de vancomycine permettant une libération contrôlée du médicament et de la serrapeptase Download PDF

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Publication number
WO2014196943A1
WO2014196943A1 PCT/TR2014/000211 TR2014000211W WO2014196943A1 WO 2014196943 A1 WO2014196943 A1 WO 2014196943A1 TR 2014000211 W TR2014000211 W TR 2014000211W WO 2014196943 A1 WO2014196943 A1 WO 2014196943A1
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WO
WIPO (PCT)
Prior art keywords
serratiopeptidase
thermosensitive gel
vancomycin
thermosensitive
gel system
Prior art date
Application number
PCT/TR2014/000211
Other languages
English (en)
Other versions
WO2014196943A4 (fr
Inventor
Sema ÇALIŞ
Bülent ATILA
Meral ÖZALP
Sibel PEHLIVAN
Elif SARIGÖL
Original Assignee
Çaliş Sema
Atila Bülent
Özalp Meral
Pehlivan Sibel
Sarigöl Elif
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 Çaliş Sema, Atila Bülent, Özalp Meral, Pehlivan Sibel, Sarigöl Elif filed Critical Çaliş Sema
Priority to EP14755429.9A priority Critical patent/EP3003382A1/fr
Publication of WO2014196943A1 publication Critical patent/WO2014196943A1/fr
Publication of WO2014196943A4 publication Critical patent/WO2014196943A4/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
    • A61K9/0012—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/2404—Serralysin (3.4.24.40)

Definitions

  • This invention is related to gel systems containing vancomycin microspheres for controlled drug release and serratiopeptidase in order to inject to the area of medical device-related infection.
  • biofilm causes a high resistance to used antibiotics and slow or incomplete penetration of antibiotic to infected area. Therefore, it is needed that the drug delivery systems which do not require surgical procedure and provide biofilm eradication and local, sustained and desired amount of drug in the site of infection for the treatment of biofilm-based medical device-related osteomyelitis.
  • the prior art vancomycin loaded microspheres and pluronic thermosensitive gel formulations are known. But, subject of this invention which is a gel system containing vancomycin HCI, vancomycin HCI loaded microspeheres and serratiopeptidase in the same formulation, which can be administered directly to the infection area is not available.
  • Designed thermosensitive gel system characterized in that it comprises antibiotic loaded microspheres, free antibiotic and proteolytic enzyme, wherein the proteolytic enzyme is serratiopeptidase.
  • a biodegradable polymer was selected to prepare of the microspheres.
  • Various biodegradable natural polymers such as polysaccharides (dextran or cellulose), chitin, chitosan, proteins (collagen.fibrin, gelatin, albumin) and synthetic polymers such as aliphatic polyesters [ poly(glycolide) (PGA), poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA), poly(e-caprolactone) (PCL), poly(3-hydroxybutyrate(PHB), poly (3-hydroxybutyrate-co-3- hydroxyvalerate) (P(HBco-HV)), Poly (anhydrides) can be used.
  • PGA poly(glycolide)
  • PLA poly(lactide)
  • PLA poly(lactide-co-glycolide)
  • PCL poly(e-caprolactone)
  • P(HBco-HV) poly(HBco-HV)
  • PCL poly(E-caprolactone) (Sigma Aldrich) which is biodegradable, biocompatible and FDA approved polymer was selected.
  • This synthetic and non-toxic polymer is a member of aliphatic polyesters and it has semicrystalline structure.
  • thermosensitive gel which utilize temperature change as the trigger that determines their gelling behavior without any additional external factor such as organic solvent, copolymerization or gelling agent is foreseed.
  • Poloxamer is chosen to obtain thermosensitive gel. Poloxamers are non ionic copolymers of polyoxyethylene -polyoxypropylene. Poloxamer 407 has thermosensitive gelling properties in water and it is also known by the BASF trade name Pluronic F127 (Sigma Aldrich). Poloxamer 407 was used in sample formulations.
  • Serratiopeptidase (Speciality Enzymes and Biochemicals Co.) is a proteolitic enzyme which is isolated from non-patgogenic Serratia spp. It is used in dose of 5-10 mg (10 000-20 000 units) three times a day to reduce inflammation and edema which is caused by trauma, infection, airway obstruction or chronic venous insufficiency. Optimal pH values are between pH 8,5-9,5 and optimal temperature is 40 °C for its activity. Serratiopeptidase is also stable between pH 5.5-9.5 at 40 °C, however it looses its activity at 60 °C in 10 minutes.
  • Vancomycin is a glycopeptide antibiotic. It is preferred first-line therapy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. Hydrochloride salt of vancomycin (vancomycin HCI) (Sandoz) was used in this invention. Preparation of Microspheres
  • Polymer (600 mg) was dissolved in 3 mL of dichlorometane to obtain organic phase for acquiring inner phase of multiple emulsion.
  • This organic phase was added to 1 mL of aqueous phase including 0.05 or 0.1 % (w/v) polyvinyl alcohol) (PVA) and drug ( 0 or 20 % (w/w) of polymer amount) and was wortexed for 2 minutes.
  • PVA polyvinyl alcohol
  • drug 0 or 20 % (w/w) of polymer amount
  • This dispersion was injected to 150 mL of distilled water including 0.1 % (w/v) PVA in two minutes and was mixed (Silverson L4RT) at 1000 rpm for 1 hour in order to obtain multiple emulsion.
  • this emulsion was diluted with distilled water including 0.05 % (w/v) PVA and was mixed (Silverson L4RT) at 800 rpm for 1 hour at room temperature. The microsphere suspension was then vacuum filtered and washed with distilled water two times to remove PVA residue. The microspheres were frozen at -20°C followed by 48 hours lyophilization.
  • Blank and drug loaded PCL microspheres were sterilized at a dose of 25kGy (fix dose rate 3.62 kGy/h ) using a 60 Co source at room temperature.
  • thermosensitive Pluronic F127 gels were prepared using cold method. Pluronic F127 (20 % w/v) was dissolved in phosphate buffered saline (PBS) and was stirred with magnetic stirrer at +4°C for 12 hours. Blank thermosensitive Pluronic F127 gel formulations were sterilized in autoclave at 121 °C for 15 minutes.
  • Pluronic F127 (20 % w/v) was dissolved in phosphate buffered saline (PBS) and was stirred with magnetic stirrer at +4°C for 12 hours. Blank thermosensitive Pluronic F127 gel formulations were sterilized in autoclave at 121 °C for 15 minutes.
  • PBS phosphate buffered saline
  • thermosensitive gel formulations were placed inside the dialysis membrane (MWCO 300,000 Da). The bags were fitted into the tube containing 2 mL of PBS and the tubes were fully immersed in a thermostated shaker (50 rpm) bath system at 37°C. At 1., 3., 6., 12., 24., 48. hours, the whole release medium was withdrawn and vancomycin hydrochloride content was determined by HPLC.
  • thermosensitive pluronic gels including different amount of vancomycin HCI, serratiopeptidase and vancomycin HCI loaded PCL microspheres were added to 96 well plates containing biofilm. Then the plates were incubated at 37 °C on a horizontal shaker at 60 rpm for 24 hours. The wells without gels were used as a control group. After incubation, the wells were washed with PBS twice to remove planktonic cells and then the low-energy sonication was applied to the plates to take up the biofilm.
  • the survived cells were serially diluted and were seeded into the plates including TSA (Tryptic Soy Agar). After 24 hours of incubation, colonies formed were counted.
  • TSA Traptic Soy Agar

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Neurosurgery (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Wood Science & Technology (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des systèmes de gel contenant des microsphères de vancomycine permettant une libération contrôlée du médicament et de la serrapeptase pour une injection dans la zone d'une infection liée à un dispositif médical.
PCT/TR2014/000211 2013-06-07 2014-06-05 Systèmes de gel contenant des microsphères de vancomycine permettant une libération contrôlée du médicament et de la serrapeptase WO2014196943A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP14755429.9A EP3003382A1 (fr) 2013-06-07 2014-06-05 Systèmes de gel contenant des microsphères de vancomycine permettant une libération contrôlée du médicament et de la serrapeptase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2013/06905 2013-06-07
TR201306905 2013-06-07

Publications (2)

Publication Number Publication Date
WO2014196943A1 true WO2014196943A1 (fr) 2014-12-11
WO2014196943A4 WO2014196943A4 (fr) 2015-01-15

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Family Applications (1)

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PCT/TR2014/000211 WO2014196943A1 (fr) 2013-06-07 2014-06-05 Systèmes de gel contenant des microsphères de vancomycine permettant une libération contrôlée du médicament et de la serrapeptase

Country Status (2)

Country Link
EP (1) EP3003382A1 (fr)
WO (1) WO2014196943A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108309941A (zh) * 2018-03-20 2018-07-24 南京工业大学 一种舍雷肽酶外用粉剂及其制备方法
WO2019064290A1 (fr) 2017-09-29 2019-04-04 Lifebond Ltd. Composition et procédé de libération contrôlée de médicament à partir d'un tissu

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MAHESHWARI M ET AL: "DEVELOPMENT OF TETRACYCLINE-SERRATIOPEPTIDASE-CONTAINING PERIODONTAL GEL: FORMULATION AND PRELIMINARY CLINICAL STUDY", AAPS PHARMSCITECH, SPRINGER NEW YORK LLC, US, vol. 7, no. 3, 1 January 2006 (2006-01-01), pages E1 - E10, XP002547740, ISSN: 1530-9932, [retrieved on 20060915], DOI: 10.1208/PT070376 *
THALLER ET AL: "A comparative in vitro evaluation of different therapeutic protocols for vascular graft infections", EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY, SAUNDERS, LONDON, GB, vol. 14, 1 December 1997 (1997-12-01), pages 35 - 37, XP005068343, ISSN: 1078-5884, DOI: 10.1016/S1078-5884(97)80151-7 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019064290A1 (fr) 2017-09-29 2019-04-04 Lifebond Ltd. Composition et procédé de libération contrôlée de médicament à partir d'un tissu
CN108309941A (zh) * 2018-03-20 2018-07-24 南京工业大学 一种舍雷肽酶外用粉剂及其制备方法
CN108309941B (zh) * 2018-03-20 2023-08-11 南京工业大学 一种舍雷肽酶外用粉剂及其制备方法

Also Published As

Publication number Publication date
WO2014196943A4 (fr) 2015-01-15
EP3003382A1 (fr) 2016-04-13

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