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WO2015093995A1 - Procédé de fabrication d'un revêtement protecteur polymère multicouche pour matériaux d'implant avec fonction de libération pharmacologique contrôlée - Google Patents

Procédé de fabrication d'un revêtement protecteur polymère multicouche pour matériaux d'implant avec fonction de libération pharmacologique contrôlée Download PDF

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Publication number
WO2015093995A1
WO2015093995A1 PCT/PL2014/000145 PL2014000145W WO2015093995A1 WO 2015093995 A1 WO2015093995 A1 WO 2015093995A1 PL 2014000145 W PL2014000145 W PL 2014000145W WO 2015093995 A1 WO2015093995 A1 WO 2015093995A1
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WO
WIPO (PCT)
Prior art keywords
parylene
layer
implant
coating
treated
Prior art date
Application number
PCT/PL2014/000145
Other languages
English (en)
Inventor
Monika Brzychczy-Włoch
Katarzyna GĘBAROWSKA
Monika GOŁDA-CĘPA
Janusz Kasperczyk
Andrzej Kotarba
Monika MUSIAŁ-KULIK
Original Assignee
Uniwersytet Jagielloński
Centrum Materiałów Polimerowych I Węglowych Polskiej
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 Uniwersytet Jagielloński, Centrum Materiałów Polimerowych I Węglowych Polskiej filed Critical Uniwersytet Jagielloński
Priority to DE112014005909.9T priority Critical patent/DE112014005909B4/de
Publication of WO2015093995A1 publication Critical patent/WO2015093995A1/fr

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Classifications

    • 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
    • A61L27/54—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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Definitions

  • the subject of the invention is a method of forming a multilayer coating with a controlled drug release function intended for the functionalization of implant materials.
  • a dynamic growth in demand for implant materials is being observed both in Poland and globally. This is associated with a number of factors: the aging of the population, the desire to maintain quality of life, the increased number of traffic accidents, and civilization progress. A significant increase in demand is particularly seen with respect to metal implants, which effectively restore the role of damaged bones and allow for the proper functioning of patients in everyday life. Available data indicate that in Poland about 25,000 hip joint replacement surgeries, 13,000 spine surgeries involving the use of implants, and 13,000 knee repair surgeries using fixation implants are performed each year.
  • the most popular alloys used in orthopaedics are stainless steel, TiAlV and NiTi, which contain heavy metals, even toxic ones. Due to the conditions inside the body promoting corrosion (36.6°C, physiological fluids of a composition similar to sea water and therefore characterised by high ionic strength) (Injury 27 (1996) S/C16), the surface of implants undergoes slow destruction, and heavy metal ions migrate to the body at levels up to 10 ⁇ L/rrlL/week (Corros. Sci 51 (2009) 1 157). This concentration may be harmful to patients, leading to a number of diseases, including cancer (Mater. Sci. Eng. C, 24 (2004) 745). The negative effect of released metal ions on the human body continues to be the subject of many studies.
  • Implantation procedures are complicated and associated with the risk of implant rejection by the host, due to a number of complex processes on the implant-tissue interface (J Pharm Sci, 97 (2008) 2892).
  • the most common post-operative complications include prolonged inflammation persisting for about 3 weeks, and infection (Biomol. Eng, 19 (2002) 21 1).
  • patients receive a variety of oral and intramuscular anti-inflammatory and anti-infective drugs.
  • solutions are considered that rely on controlled local drug release from the surface of the inserted implant, bringing a number of benefits to patients.
  • the most important benefits include the application of lower doses of the drug, and their activity limited to the target tissue, which reduces the risk of side effects associated with the oral administration of high doses of medication.
  • parylene C poly(chloro-para-xylene)
  • stents to limit the formation of blood clots on their surface, as disclosed in US patent no. 6776792.
  • US patent no. 2013001 1456A1 discloses the use of parylene C as a carrier for an antibacterial agent on the surface of a cochlear implant, an ocular implant, and a pacemaker.
  • parylene C is used in multilayer polymer coatings intended for drug release. According to the description in US patent no.
  • parylene C is a solid foundation for such a coating, to which in the next step a mixture of drug and copolymer is attached, and another layer of suitably prepared parylene is deposited.
  • a polymer layer prepared in such a way successfully prolongs drug release time inside the body.
  • biodegradable polymers are used for drug encapsulation.
  • controlled drug release can be successfully achieved using copolymers of PEG (polyethylene glycol) and another polymer.
  • PEG polyethylene glycol
  • a copolymer composed of PEG and a lactic acid copolymer can create an efficient barrier preventing rapid drug release to the body.
  • the degradation time of the copolymer and drug release kinetics can be adjusted.
  • Copolymers of L-lactide and glycolide (PLGA) are biocompatible and biodegradable.
  • PGLA loaded with an immunosuppressive drug is used as a biodegradable polymer layer on a non-biodegradable polyamide coating protecting biocorrosive implants, as disclosed in patent EP 2433660 Al .
  • US patent no. 20120303057 Al discloses a method of manufacturing an ibuprofen-loaded PGLA film in order to coat resorbable sutures made of the same resorbable material, i.e. PGLA. Deposition of a drug- loaded PGLA film on both degradable and non-degradable materials ensures stable drug release thanks to the gradual process of hydrolytic degradation.
  • the major problem related to drug release from the implant surface is the engineering of its surface.
  • the amount and speed of drug release is associated with the composition of the implant surface, its morphology, the adherence power of cells and susceptibility to the formation of bacterial biofilm. Therefore, there is an ongoing need to improve the surface of implants in order to achieve drug release at the appropriate therapeutic level and within a sufficiently long time.
  • chemical passivity determining parylene application as a protective layer is problematic at the same time, because bioactive substances and a biodegradable polymer cannot be bound directly to it.
  • Parylene C is a crystalline polymer and has a non-porous structure, with poor permeability to small molecules.
  • the method of forming a multilayer protective coating for implant materials with a controlled drug release function is characterised in that a 6 to 20 ⁇ -thick parylene layer is applied onto the surface of an implant by chemical vapour deposition, and then treated with oxygen plasma under 0.2 to 1 mbar pressure for 15 to 60 minutes, using a plasma generator of 10 to 60 W power.
  • a mixture of lactide and glycolide solutions is deposited in the molar ratio of lactide to glycolide from 1 : 1 to 100: 1, together with the drug substance in the amount of 5% to 10% w/w of the polymer material and a polymerisation initiator, and then the polymerisation is performed, and the obtained layer is dried.
  • poly(monochloro-p-xylylene) (parylene C) is used for the formation of the layer.
  • the formation of the polymer layer is carried out in a process wherein the parylene coating is prepared by chemical vapour deposition.
  • a starting substance (dimer) is used: [2,2]-paracyclophane (dimer of parylene N), dichloro-[2,2]-paracyclophane (dimer of parylene C).
  • the dimer is vaporised from the solid phase to the gaseous phase.
  • the vapour is heated up to 650°C. At this temperature the dimer is degraded to monomer molecules.
  • the monomer molecules are passed into the next chamber, where the substrate is exposed for deposition. In the coating chamber, at room temperature and under low vacuum of 10 "3 mbar, monomer molecules deposit spontaneously on the surface of the implant and the polymerisation occurs. The thickness of the deposited coating is controlled throughout the deposition time.
  • the parylene coating before oxygen plasma treatment is cleaned using organic solvents such as isopropanol, ethanol or acetone, preferably ethanol.
  • oxygen plasma treatment is performed in a chamber with a quartz vessel fitted in a rotor, in order to ensure uniform plasma distribution and to optimise the concentration of excited oxygen forms.
  • oxygen plasma treatment is carried out at 0.2 mbar pressure for 60 minutes, using a plasma generator of 50 W power.
  • the mixture of lactide and glycolide solutions with the drug substance and the initiator is applied onto the treated layer of parylene by immersion or spraying.
  • Copolymers loaded with the drug substance are bound with the substrate and form a biodegradable layer on the surface of parylene.
  • the molar ratio of lactide to glycolide is from 7: 1 to 4: 1, most preferably
  • Zr(acac) 4 is used as an initiator.
  • the drug substances used are anti-inflammatory, anti-infective, analgesic and antithrombotic agents, preferably ibuprofen.
  • an 8 to 10 ⁇ -thick parylene layer and an 0.12 to 0.19 mm-thick copolymer layer are applied onto the surface of the implant.
  • the coating according to the invention i.e. a parylene layer with a copolymer layer
  • the thickness of the therapeutic layer is a compromise between the need to store an adjusted amount of the drug substance and to minimize thickness - an excessively thick layer leaves a void after degradation, which may result in loosening of the implant.
  • the copolymer matrix loaded with the drug substance is obtained by the method wherein copolymers are dissolved in organic solvent, preferably methylene chloride, and the drug substance in a relevant solvent (chloroform for ibuprofen), and then both solutions are brought together under vacuum and adjusted to an appropriate density.
  • organic solvent preferably methylene chloride
  • a relevant solvent chloroform for ibuprofen
  • a coating manufactured using the method according to the invention comprises two parylene layers, wherein the first layer (near the surface of an implant) is a solid, non-porous and hydrophobic parylene, and the second is a non-porous hydrophilic parylene modified by the method according to the invention.
  • the layer of solid parylene protects the metallic surface against corrosion and increases its biocompatibility.
  • oxygen plasma treatment of the parylene surface leads to the formation of micro- and nanopores and insertion of functional groups containing oxygen, which are the adsorption sites facilitating binding with a degradable copolymer responsible for the function of drug release. It should be emphasized that the declared effect can be achieved only for the surface of parylene treated with oxygen plasma, as this is the only type of plasma ensuring the insertion of functional groups containing oxygen.
  • the hydrophilic parylene layer is formed as a result of modification of the first layer of hydrophobic parylene deposited on the implant.
  • the plasma treatment of the first parylene layer is limited only to the supraficial part of this layer, while the part in direct contact with the implant remains untreated. With such a modification, the oxygen adsorption sites and pores are distributed only on the surface and serve for connecting of the copolymer layer, while the deeper part of the layer maintains its initial hydrophobic properties. Oxygen functional groups generated in the process of oxygen plasma treatment act as binding sites between the parylene C layer and the copolymer layer.
  • the therapeutic layer combined with the polymer layer ensures controlled drug release for 3-7 weeks.
  • the coating manufactured by the method according to the invention forms an integrated anticorrosive and therapeutic system.
  • the therapeutic layer combined with the polymer layer can be deposited onto orthopaedic implants for both short-term (screws, nails) and long-term use (hip joint or knee joint prostheses) made of various alloys, e.g. SS 316L (stainless steel) or titanium alloys (e.g. T.6A1V).
  • various alloys e.g. SS 316L (stainless steel) or titanium alloys (e.g. T.6A1V).
  • Example 1 The subject of the invention is presented in more detail in examples of manufacture.
  • Example 1 The subject of the invention is presented in more detail in examples of manufacture.
  • Samples prepared in such a manner were cleaned with ethanol, and then treated with oxygen plasma inside a specially adapted chamber with a quartz vessel fitted in a rotor in order to ensure uniform plasma distribution and optimise the concentration of excited oxygen forms.
  • Process conditions were as follows: pressure 0.2 mbar, time: 60 min, plasma generator power: 50 W.
  • a similar treatment effect can be obtained using the following parameters: oxygen pressure: 0.2 mbar, time: 5 min, generator power: 50 W, without the use of a rotor and placing samples in a glass container.
  • copolymer matrices comprising lactide and glycolide (85: 15) obtained in the process of ring-opening polymerisation using non-toxic Zr(acac) 4 as an initiator, and loaded with ibuprofen as a model drug, in a dose 5% and 10% w/w of copolymer according to the following procedure.
  • Copolymers were dissolved in methylene chloride, and the drug in chloroform. Next, the two solutions were brought together and mixed. The mixture without air bubbles was poured onto the surface of parylene C treated according to Example 1. Gas bubbles released during mixing were removed under vacuum conditions.
  • the prepared matrices on parylene C treated according to Example 1, of 0.12 to 0.19 mm thickness, were air-dried for 7 days, and then dried for another week in a vacuum dryer in order to completely remove the solvent. Next, the samples were exposed to hydrolytic degradation in phosphate buffer, pH 7.4, at 37°C.
  • the thickness of coatings was measured using Scanning Electron Microscopy, for treated parylene it was about 8 ⁇ ⁇ ⁇ , and for the copolymer layer it was 0.12-0.19 mm.
  • Untreated parylene C, parylene C treated according to Example 1, and parylene C overexposed to oxygen plasma was tested by electrochemical impedance spectroscopy (EIS).
  • EIS electrochemical impedance spectroscopy
  • the tested sample (working electrode) was mounted into an electrolytic cell filled with 30 mL of electrolyte (synthetic physiological fluid). Additionally, a counter electrode (platinum grid) was mounted in the cell, and a saturated calomel electrode Ag/AgCl//KCl (SCE) was used as a reference electrode. All three electrodes were connected to a potentiostat, integrated with the analyser and PC. Measurements were taken at room temperature (25°C).
  • Example 3 Samples prepared using CVD, as in Example 1 and cleaned with ethanol, were treated with oxygen plasma under the following process parameters: pressure 0.2 mbar, time: 10 min, plasma generator power: 50 W.
  • a layer of drug-loaded copolymer was deposited on the samples, according to the description presented in Example 3. Because of insufficiently long treatment time the concentration of surface functional groups was too low, which resulted in unsatisfactory adherence between the layers of parylene C and drug-loaded copolymer.
  • Example 6 On the layer of parylene C coated using CVD and untreated with oxygen plasma, we deposited a solution of ibuprofen in ethanol, concentration 40 mg/mL, and after vaporisation the mass of the drug deposited on the surface was 1 mg. Next, we deposited a layer of copolymer comprising L-lactide and glycolide (85.15) obtained in ring-opening polymerisation using nontoxic Zr(acac) 4 as an initiator. We found that the layer of copolymer separated from the layer of the drug-loaded parylene.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Materials For Medical Uses (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un procédé permettant de fabriquer un revêtement protecteur polymère multicouche pour des matériaux d'implant avec fonction de libération pharmacologique contrôlée. Une couche de parylène d'une épaisseur de 6 à 20 μm est appliquée par dépôt chimique en phase vapeur sur la surface de l'implant, avant d'être traitée par oxygène plasma à une pression de 0,2 à 1 mbar pendant 15 à 60 minutes, en utilisant un générateur plasma d'une puissance de 10 à 60 W. La couche de parylène traitée est ensuite recouverte d'un mélange constitué de solutions de lactide et de glycolide en un rapport molaire lactide sur glycolide de 1:1 à 100:1, et avec la substance pharmacologique en une quantité de 5 à 10 % p/p du polymère et un initiateur de polymérisation. La polymérisation est ensuite effectuée et la couche obtenue est séchée.
PCT/PL2014/000145 2013-12-19 2014-12-18 Procédé de fabrication d'un revêtement protecteur polymère multicouche pour matériaux d'implant avec fonction de libération pharmacologique contrôlée WO2015093995A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE112014005909.9T DE112014005909B4 (de) 2013-12-19 2014-12-18 Verfahren zur Herstellung einer mehrschichtigen polymeren Schutzbeschichtung für Implantatmaterialien mit der Funktion der gesteuerten Freisetzung von Arzneimitteln

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP.406603 2013-12-19
PL406603A PL231176B1 (pl) 2013-12-19 2013-12-19 Sposób wytwarzania wielowarstwowej polimerowej powłoki ochronnej materiałów implantacyjnych z funkcją kontrolowanego uwalniania leków

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WO2015093995A1 true WO2015093995A1 (fr) 2015-06-25

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DE (1) DE112014005909B4 (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111317865A (zh) * 2018-12-17 2020-06-23 南京理工大学 双层抗菌复合薄膜的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100055145A1 (en) * 2008-08-29 2010-03-04 Biosensors International Group Stent coatings for reducing late stent thrombosis
US20100191324A1 (en) * 2008-07-23 2010-07-29 Bjoern Klocke Endoprosthesis and method for manufacturing same
US20110111367A1 (en) * 2009-11-10 2011-05-12 Dong Keun Han Nanocoupling for improvement of coating adhesion of polymer on metal substrates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100191324A1 (en) * 2008-07-23 2010-07-29 Bjoern Klocke Endoprosthesis and method for manufacturing same
US20100055145A1 (en) * 2008-08-29 2010-03-04 Biosensors International Group Stent coatings for reducing late stent thrombosis
US20110111367A1 (en) * 2009-11-10 2011-05-12 Dong Keun Han Nanocoupling for improvement of coating adhesion of polymer on metal substrates

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHRISTINE P. TAN ET AL: "Surface Engineering and Patterning Using Parylene for Biological Applications", MATERIALS, vol. 3, no. 3, 15 March 2010 (2010-03-15), pages 1803 - 1832, XP055126906, DOI: 10.3390/ma3031803 *
GOLDA M ET AL: "Oxygen plasma functionalization of parylene C coating for implants surface: Nanotopography and active sites for drug anchoring", MATERIALS SCIENCE AND ENGINEERING C, vol. 33, no. 7, 20 June 2013 (2013-06-20), pages 4221 - 4227, XP028686242, ISSN: 0928-4931, DOI: 10.1016/J.MSEC.2013.06.014 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111317865A (zh) * 2018-12-17 2020-06-23 南京理工大学 双层抗菌复合薄膜的制备方法

Also Published As

Publication number Publication date
PL231176B1 (pl) 2019-01-31
DE112014005909T5 (de) 2016-09-22
PL406603A1 (pl) 2015-06-22
DE112014005909B4 (de) 2017-06-29

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