[go: up one dir, main page]

WO1993006881A1 - Agent therapeutique incorpore dans une matrice hydrophile - Google Patents

Agent therapeutique incorpore dans une matrice hydrophile Download PDF

Info

Publication number
WO1993006881A1
WO1993006881A1 PCT/US1992/008528 US9208528W WO9306881A1 WO 1993006881 A1 WO1993006881 A1 WO 1993006881A1 US 9208528 W US9208528 W US 9208528W WO 9306881 A1 WO9306881 A1 WO 9306881A1
Authority
WO
WIPO (PCT)
Prior art keywords
matrix
set forth
tubing
medicament
solution
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/US1992/008528
Other languages
English (en)
Inventor
Joseph R. Thomas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ethicon Inc
Original Assignee
Menlo Care Inc
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 Menlo Care Inc filed Critical Menlo Care Inc
Priority to JP5507158A priority Critical patent/JPH07500263A/ja
Priority to EP92921607A priority patent/EP0607284A4/fr
Publication of WO1993006881A1 publication Critical patent/WO1993006881A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • 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
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A61L2300/206—Biguanides, e.g. chlorohexidine
    • 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
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Definitions

  • the invention relates to the provision of chemicals such as therapeutic agents dispersed in hydrophilic media. Such media are useful for time release of the chemicals.
  • various coatings or layers are often applied- to the article and these coatings can then be treated to contain an active medicament. It is desired that these incorporated medicaments accumulate on or migrate to the surface to provide their effect.
  • One use is for drug delivery whereby the medicament on the surface can leach into the surrounding organism and provide a clinically useful effect.
  • Another use is to provide an implanted device (such as a catheter) with sufficient antibacterial medicament on the surface to inhibit bacterial colonization of the implant and prolong its useful life.
  • an anticoagulant medication can be used to avoid blood clotting, fibrin accumulation or blood activation.
  • medicaments can create unwanted systemic side effects, and to be able to control the rate of release of the medicament so that an effective amount is present over the entire period of implantation. If the device is to be implanted for a longer period of time, e.g., for a year or more, a higher amount of medicament could be provided and the rate of leaching could be controlled so that an effective amount of the medicament would be present for the longer period of time. It would also be desirable to be able to do this with medicaments which, like many medicaments, are only stable under relatively mild conditions and which would, therefore, be deleteriously affected if subjected to harsh
  • implantable medical devices such as urinary, venous, drainage, perfusion and dialysis catheters which can be protected from harboring
  • infectious organisms such as those already present on the patient's skin or in the blood or urine.
  • Kahn, et al in U.S. Patent 4,925,668 discloses a method of incorporating chlorhexidine in the bulk of slightly hydrophilic polymers by melt processing during formation of the article followed by extrusion and then by dip coating with a solution of chlorhexidine and silicone. This method has very limited applicability because very few desirable active ingredients are able to survive the aggressive temperatures, pressures and shear conditions in the extrusion melt process.
  • Kohn, et al in U.S. Patent 4,806,621 discloses a method similar to that of Kahn, et al for providing medicaments and the like dispersed in a hydrophobic poly (iminocarbonate) polymeric matrix.
  • Kahn, et al procedure very few desirable active ingredients are able to survive the aggressive temperatures, pressures and shear conditions in processing.
  • the resulting product biodegrades which can be a detriment when one desires a long term implant which is to eventually be removed.
  • the polymer is hydrophobic it cannot, in at least most instances, soften and/or swell as may be desirable if it is used as, for example, a cannula.
  • Mochizuki, et al in U.S. Patent 4,675,347 discloses the incorporation of cationic antimicrobial agents such as chlorhexidine into cationic natural rubbers to provide long term drug delivery from the resulting hydrophobic polymers. As with the Kahn, et al procedure, very few desirable active ingredients are able to survive the aggressive temperatures, pressures and shear conditions in processing.
  • the polymer is hydrophobic it cannot, in at least most instances, soften and/or swell as may be desirable if it is used as, for example, a cannula.
  • Japanese patent publication JP 6036064 discusses formation of nearly insoluble chlorhexidine derivatives by soaking hydrophobic rubber
  • the present invention is directed to overcoming one or more of the problems set forth above.
  • a method is set forth of incorporating a chemical in a swellable hydrophilic matrix.
  • the method comprises contacting the matrix with a solution having the chemical or a precursor of the chemical dissolved therein, the solution including a solvent which is selected to swell the matrix by at least 10% in volume and sufficient of the precursor or of the chemical to provide a desired level of the precursor or of the chemical dispersed throughout the matrix. Thereafter the chemical is deposited in the matrix in a form in which it exhibits a selectable aqueous solution solubility.
  • a method is set forth of incorporating a medicament in a preformed medical device comprising a swellable hydrophilic matrix.
  • the method comprises contacting the matrix with a solution having the medicament or a precursor of the medicament dissolved therein, the solution including a solvent which is selected to swell the matrix by at least 10% in volume and sufficient of the precursor or of the medicament to provide a desired level of the precursor or of the medicament dispersed throughout the matrix.
  • the medicament is deposited into the matrix in a form in which it exhibits a selectable aqueous solution solubility in such a manner that it has therapeutic effectiveness only in a narrow zone around the matrix but the effectiveness lasts for an extended period of time.
  • the method comprises contacting the matrix with a solution having the medicament dissolved therein, the solution including a solvent which includes a non-aqueous component and is selected to swell the matrix by at least 10% in volume, the solution further including sufficient of the
  • Another embodiment yet of the invention is a method of providing a preformed medical device which comprises a swellable hydrophilic matrix with long lasting antibiotic effectiveness. The method
  • Still another embodiment of the invention is a medical device comprising a swellable hydrophilic matrix which swells at least 10% in volume on
  • Articles and devices of the invention have applications in many fields including gradual diffusion of substances to inhibit surface corrosion or biofouling on surfaces such as polymer liners for boiler tubes or the membranes in oxygenators, slow medicament release to deliver therapeutic medicament doses locally (in a narrow zone about the articles or devices) and continued delivery of antibiotics from the bulk to the surface to prevent or retard bacterial growth and infection on medical devices for long periods of time.
  • Hydrophilic matrixes loaded in accordance with the present invention can release chemicals over very long periods of time due to the bulk dispersion of the chemical throughout the matrix and due to the fact that the substantially insoluble (really very slightly soluble in aqueous media, i.e., in the intended use environment, e.g., in blood, urine or other body fluids) or second form of the chemical can be selected to have very low solubility.
  • the chemical may be selected so that it is dispersed within a selectable time period by selection of a second form for the chemical which is sufficiently soluble so that it will be
  • Figure 1 is a graphical representation of the experimental data of Examples 19A, 19B, 19C and 19D and demonstrates the bactericidal effectiveness of relatively insoluble silver compounds over extended testing periods;
  • Figure 2 is a graphical representation of the testing of the catheter tubing of Examples 6B, 6E, 6F and 6H as tested in accordance with Example 22 and demonstrating that the duration of bactericidal effectiveness may be varied by the choice of the hydrophilic swelling substrate or by the form of the drug which is selected;
  • Figure 3 is a graphical representation of the testing of the catheter tubing of Example 4.
  • Figure 4 is a graphical representation of the testing of the catheter tubing of Example 4.
  • Figure 5 is a graphical representation of the testing of the catheter tubing of Example 7 as tested according to Example 23 and demonstrating long term bactericidal effectiveness.
  • This invention relates primarily to methods for incorporation of chemicals such as medicaments inside (as well as on the surface) of hydrophilic water swellable materials. Specifically various chemical techniques are disclosed whereby sparingly soluble (i.e. nearly insoluble) drugs can be
  • hydrophilic is well understood in the art but is generally used in a relative sense. This term is used in a more rigorously defined sense when used in describing the present invention.
  • swellable and hydrophilic in accordance with the present invention must have the property of being capable of absorbing water and swelling at least 10%, more preferably at least 20% and still more preferably at least 50% in volume when soaked in an aqueous solution. While being water swellable, the matrix is not water soluble, at least at use temperature (about 37oC. in the case of medical devices).
  • hydrophilic matrixes or materials useful in the practice of the invention, when used for pharmaceutical purposes, can be of any material suitable for introduction into a living subject.
  • these materials are polymeric in nature and, when used as cannulae, are selected to be
  • compositions which soften or exhibit a decreased 2.5% Secant Modulus upon, for example, exposure to liquids, insertion of the distal end portion of the cannula into the body of a living subject and its maintenance therein.
  • preferred compositions absorb liquid (i.e., hydrate) and thereafter soften to a 2.5% Secant Modulus of less than 7,000 N/cm 2 which reduces the trauma to the surrounding tissues of the subject.
  • softening ratio is used herein to refer to the ratio of the 2.5% Secant Modulus values of the composition selected in the form of a tubular cannula initially to the 2.5% Secant Modulus of the composition when softened (from dry matrix at 20oC. to wet matrix at 37oC).
  • the overall matrix must have the ability to hydrate sufficiently to absorb sufficient water to swell at least 10% in volume, as previously stated. It is preferred that the composition soften with a softening ratio of at least about 5:1, more preferably at least about 10:1 and still more preferably at least about 20:1, when it is to be used as a cannula.
  • softening polymers useful in the practice of the invention are those described in U. S. Patents Nos.4, 883, 699, issued November 28, 1987 and 4,911,691, issued March 27, 1990, both of which are incorporated herein by reference.
  • the preferred composition for the matrix comprises:
  • hydrophilic polymeric component
  • the material (i) being capable of absorbing water to an extent that its softens with a softening ratio of at least about 5 : 1 and/or swells with a swelling ratio of at least about 1.1:1; and (ii) when substantially completely hydrated, having an energy to break of at least about 700 N-cm/ ⁇ m a and a 2.5% Secant Modulus of less than about 7,000 N/cm 2 .
  • HPU hydrophilic polyurethane
  • PAN block hydrolyzed polyacrylonitrile
  • hydrophilic swellable polymers which can be formulated into devices, which are compatible with the specific medicament or chemical which is to be dispersed in them and which are compatible with their use
  • the present invention relates to depositing sparingly soluble substances inside the bulk material by in situ chemical
  • the desired chemical or a precursor of that chemical in a soluble form is absorbed or imbibed inside the bulk of the hydrophilic water swellable polymeric material. Once the precursor or the chemical is absorbed or imbibed the chemical is deposited within the material. In many instances this can be done by converting the precursor into the chemical which is usually much less soluble, but is efficacious for its intended purpose. Such a
  • transformation can be accomplished by any of many well known methods. Examples of some of these types of processes are precipitation with metal salts;
  • soluble acidic or basic medicaments can be changed in situ to less soluble (or more soluble, if desired) derivatives by reaction with metal ions or acid salts.
  • acidic drugs include sulfonamides
  • cephalosporins and various penicillins can be precipitated out of solution in situ by calcium, zinc, silver or other metal ions.
  • an acidic medicament e.g., RCOOH
  • fatty cations alkyl quaternary amines, amidines and guanidines
  • myristyltrimethylammonium bromide, stearyltrimethylammonium chloride and the like can be used to make salts of medicaments with carboxylic acid functions.
  • polar organic solvents with or without water may be desirable.
  • Examples of basic medicaments include antiseptics (chlorhexidine, benzalkonium chloride) and polypeptides (polymyxin). These can be precipitated out of solution in situ, for example, by reaction with fatty acids. For example, such compounds as sodium dodecylsulfate, sodium stearyl sulfate and the like can be used to make salts of medicaments having amine functionality. This technique can also be used with fatty alcohol mono sulfate esters which form strong salts with amines. Phospho-diglycerides can be used as the precipitating acid with the aid of organic solvents. Many
  • medicaments are amphoteri ⁇ in that they have groups which can exhibit acidic or basic functionality and their solubilities can be altered by suitable acidic or basic reagents. In some cases it is possible by changing pH to alter the solubility of various ingredients.
  • Tetracyclines (doxycy ⁇ line, chlorteracycline), sulfonamides (sulfaguanidine, sulfapyridine), nitrofurantoins and other medicaments can be precipitated in situ by use of an appropriate acid or base.
  • Nearly insoluble derivatives can be selected to diffuse out at different rates depending on the eluting environment.
  • pH values for vascular or urinary applications, with pH values of about 7.4 and 5.5 respectively, it is an advantage to be able to design the in situ deposited medicament to elute out at a desired rate at the specific pH of use of the device.
  • the substances formed inside the material by this "in situ" process can be selected to have desired solubility and activity. More soluble materials will diffuse out more quickly and in larger quantities.
  • Insoluble (really very slightly soluble) materials will remain effectively permanently dispersed in the material. This could be useful for certain
  • the formed substance if slightly soluble, can elute at a designated rate sufficient to provide antibiotic activity at the surface for long periods of time.
  • the formed medicament can be chosen for activity against various types of organisms and/or for duration of effect.
  • the form of the substance can often be controlled so that it will have a desired solubility. If the substance is, for example, silver, it can be deposited as the chloride, the bromide, the iodide, the sulfadiazine, etc., salt, all of which have different solubilities.
  • any medicament which is compatible with a human or animal body and which can be changed in solubility and/or formed in situ in a hydrophilic water swellable matrix can be used in the method of the present invention.
  • Representative antimicrobial agents include norfloxacin, oxacillin, nafcillin, sulfadiazine, pefloxacin, tobramycin, piromidic acid, pipemidic acid, enoxacin, AM-833, and cephalosporins, such as cefmenoxime, moxalactam, cefazolin,
  • agents which are not antimicrobial but which have other desirable properties are also useful medicaments and fall within the scope of the term medicament as used herein.
  • Such other medicaments include anticoagulants, such as heparin, urokinase, antifouling agents, etc.
  • Another method of depositing a substantially water insoluble substance in a hydrophilic water swellable matrix is by swelling the matrix with a solution of the substance in a non-aqueous or mixed aqueous/non-aqueous solvent system with the non- aqueous component being readily removable, for example readily volatilizable, and being, for example, methanol, ethanol, formamide, acetone,
  • the solvent system must be chosen so as to provide a desired level of the medicament and so that the matrix will absorb or imbibe sufficient of the solvent system so as to provide the desired amount of the medicament.
  • the matrix and solvent system must be such that the matrix absorbs or imbibes sufficient of the solvent system so that the matrix swells by at least 10%, more preferably at least 20% and still more preferably at least 50% in volume.
  • volatilizable is meant that the solvent system can be volatilized at a temperature and in a manner that will not deleteriously affect the medicament being
  • Certain medicaments can be selected that are soluble in these solvent systems and are nearly insoluble in water.
  • the polymeric materials are water or aqueous solution swellable. If the polymer is not water swellable, then effective rates of incorporated (by whichever method) and of medicament release will only be obtained in special circumstances.
  • This in situ method can also be applied to pure soft formless hydrogels but the products can just as easily be mixed into such hydrogels under mild conditions with few complications.
  • the preferred polymeric materials are water swellable compositions which are formed into useful articles and medical devices. Products from these polymeric materials can be made to have long lasting antibiotic activity by using the described in situ drug formation process.
  • a nerve sheath would preferably be swelled and
  • a relatively low concentration of a low solubility medicament can be provided throughout the bulk of the article and, due to the low concentration and low solubility, this effect will be local and will endure for a long period of time.
  • effectiveness can be provided for an extended period of time, for example, 5 days or more, preferably 10 days or more and still more preferably 30 days or more, in a narrow region, for example, within 50 mm, preferably within 25 mm, of a medicament containing medical device.
  • tubular articles which include a medicament impervious layer along with a hydrophilic layer from which the medicament can elute.
  • the medicament impervious layer in such articles prevents the medicament from diffusing past it away from the hydrophilic layer. In this manner diffusion can de controlled so as to occur only in a desired direction.
  • Coextruded layered tubing such as that described in U.S. Patent 4,994,047, which is incorporated herein by reference, with the hydrophilic layer having an in situ deposited medicament as described herein, are the preferred articles.
  • the impervious layer can be a middle layer between two different hydrophilic layers each of which has a different medicament dispersed in it whereby different medicaments will diffuse in different directions.
  • An inner hydrophilic layer can provide a selected medicament to the blood or other fluid passing through the cannula while an outer hydrophilic layer, separated from the inner hydrophilic layer by a medicament impervious layer, can provide a different selected medicament to the tissue, for example, to minimize irritation.
  • a hydrophilic medicament containing matrix may be coated, by solution or other process, to provide a medicament impervious coating on one or more selected areas where introduction of the medicament is not desired.
  • In situ chemical or physical incorporation of, for example, medicaments, in accordance with the invention can take place in a finished article or device. This is an advantage because the number of useful medicaments, etc. that can survive the high temperatures, shear and other processing conditions required to form polymeric articles is severely limited.
  • the present invention can also be performed on complex shaped articles or on selected portions of finished articles. See, for example, U.S. Patent 4,925,668 which is incorporated herein by reference. As the examples below show, the present invention avoids the problems associated with incorporating medicaments during polymer processing, provides a method of incorporating "insoluble" medicaments throughout the bulk of the material, and produces long lasting slow release of the incorporated medicaments.
  • composition contained 1.5 wt% gentamicin sulfate (Sigma Chemical Co. 565 ⁇ q/mg, 8.2% H 2 O) and was melt extruded into catheter tubing.
  • gentamicin sulfate has a melting point (218-237oC.) significantly higher (about 50oC.) than the melt and extrusion temperatures used, the melt
  • crosslinked elastomer hydrogel AQ tubing made as in Example 1A but without the
  • gentamicin sulfate were immersed in 50 mg/ml gentamicin sulfate solution (Sigma Chemical Co.). After 5 hours fresh solution was added for 14 additional hours. The tubing segments were rinsed with water, blotted on paper towels, then air dried. The tubing was exposed to an additional 2.5 megarads of radiation. This ⁇ rosslinked elastomer hydrogel material showed a volume swell or expansion of about 120% after immersion in aqueous solutions for several hours. These samples were calculated to contain about 5 wt.% gentamicin sulfate. The calculation was made by noting the volume of swelling, which was equated to the amount of solution absorbed. It was assumed that after evaporation of the solution all of the
  • Example 2A before the addition of the NaSZ solution. It was handled in a similar way as the tubing described in 2A, except water was used in place of medicament solution. Similar control tubing samples were used in all antibiotic testing described in the examples herein. In each instance
  • control tubing samples were run along side all various medicament samples. Control tubing, extracted for various times, was used as part of each microbiological assay sample set. The control samples invariably showed no
  • Crosslinked elastomer hydrogel AQ tubing was prehydrated for one day at body temperature.
  • Several stands were placed in a blackened polyethylene tube, as described in Example 2A above, and the strands were immersed in cold 1.5 wt% silver nitrate (Aldrich Chemical Co.) solution and allowed to soak in the dark at 4oC. After about 2% hours, fresh silver nitrate solution was added. After six additional hours, the solution was decanted and a cold (when the term cold is used herein it refers to a temperature of about 4oC.) 2.4 wt% solution of NaSZ was added. One half hour later, the NaSZ solution was exchanged for fresh NaSZ solution and left for 15 hours.
  • the resulting white tubing was calculated to contain about 1 wt% Ag (as AgSZ) and about 2.4 wt% NaSZ.
  • Crosslinked AQ tubing samples were coiled in an amber bottle and cold 1.6 wt% silver nitrate solution was added. After four hours the nitrate solution was replaced with fresh solution. Twelve hours later, the tubing was rinsed with cold water and cold 2.5% NaSZ added and then replaced after five hours.
  • Example 3 Two strands of non- swelling hydrophobic polyurethane tubing (PU) (made from Thermedics, 100A resin) were immersed in a 30 micromolar solution of NaSZ for one hour. The tubing was blotted dry and immersed in an equimolar silver nitrate solution for 10 minutes, rinsed in water, blotted dry, air dried for an hour in the dark and stored in a desiccator at 4oC. As the polyurethane was of the non-swelling variety it was impossible to calculate the amount of medicament adsorbed on the surface of the tubing. 2F. AgSZ on PU. This example is similar to example 2E above except the concentrations of the reagents were increased by over three thousand fold to use a silver nitrate
  • polydimethylsiloxane tubing (Dow Corning Silastic Rx50 medical grade) was coiled into a two ounce amber bottle and filled with cold 1.6 wt% AgNOg and kept in the dark at 4oC. for about five hours. Then the solution was discarded and fresh silver nitrate solution added, the tubing was kept immersed at 4oC. for another 19 hours. The tubing was washed gently with water and a cold 21 ⁇ 2 wt% solution of NaSZ added. After four hours the NaSZ was replaced with fresh solution. Six hours later the NaSZ solution was decanted and the tubing was rinsed inside and out with pH 7 buffer and soaked in buffer for five hours.
  • the tubing was rinsed inside and out with water, gently blown dry inside with air, blotted dry and stored cold in a desiccator in the dark. Later some of the tubing was cut into 2 to 21 ⁇ 2 cm segments and stored as above. As the material was of the non- swelling variety it was impossible to calculate the amount of medicament adsorbed on the surface of the tubing. Thus, although the concentrations of reagents used in this example are the same as that of most of the tubings described in Example 2 the actual amount of AgSZ and NaSZ incorporated on (or just inside) the tubing surface is unknown.
  • HPU water swellable hydrophilic polyurethane
  • crosslinked AQ tubing were coiled into a two ounce amber vial and immersed in a cold solution of 1.10g silver nitrate and 68.89g water and held for ten hours at 4°C.
  • the silver nitrate solution was decanted; the tubing was rinsed then immersed in water for twenty minutes, blotted dry, and stored in an open vial in a
  • Dry tubing was soaked in 1.6 wt% cold silver nitrate solution for just over four hours, rinsed with water and a 3% solution of sodium chloride (J.T. Baker, Inc.; 99.6%) added and left overnight.
  • the tubing was rinsed with water and soaked in PBS for five hours at room temperature, rinsed again with water, air dried in the dark and stored in a desiccator in the dark. This tubing was calculated to contain approximately 1 wt% Ag as AgCl.
  • Example 3A were followed, except 5.3% sodium bromide (J.T. Baker, Inc.; 99.3%) solution was added (instead of sodium chloride) and the finished product was allowed to
  • the tubing was white in color and was calculated to contain 1 wt% Ag as Agl
  • DHC doxycycline hydrochloride
  • Doxycycline hydrochloride is amphoteric; it is least soluble at pH's around 5 to 6 and more soluble at higher or lower pH's.
  • Formation of doxycycline free base (DFB) inside the tubing matrix was accomplished by adding sufficient sodium hydroxide to a pH 5.7 hydroxide-phosphate buffer to react with the measured amount of DHC.
  • This buffer/base solution was composed of 2.44g potassium dihydrogen phosphate, 30.70g water, and 1.45g sodium hydroxide.
  • the DHC solution was decanted and the tubing strands were rinsed with dilute (9:1) buffer solution.
  • the tubing was immersed in the above buffer/base solution for about five hours with intermittent agitation.
  • the pH of the solution was about 5.7.
  • the tubing was rinsed and immersed in water.
  • the pH measured about 5.4.
  • the tubing was blotted dry and cut into roughly 3 cm long segments and stored in a desiccator at 4oC. This procedure resulted in about two percent free doxycycline base being deposited throughout the elastomer hydrogel matrix.
  • the tubing was very light yellow. At the pH values used DFB was expected to be much less soluble than DHC.
  • tubing strands were looped into a glass vial as described above and immersed in a 10% DHC
  • This example illustrates the process of salinification by the reaction of polymyxin B sulfate (Pmyx) with organic acids forming a polymyxin salt complex.
  • Pmyx polymyxin B sulfate
  • Various n-alkyl carboxylic acids were separately reacted with polymyxin B sulfate by adding Pmyx solution to a slight excess (over the 5 times molar ratio required) of the dissolved sodium acid salt.
  • Acid derivatives investigated in glassware included acetic, caproic, caprylic, capric and myristic.
  • Sodium caprylate was chosen since it was of low solubility but was not completely insoluble.
  • Thermedics 100A grade. Swelling did not occur and it was not possible to calculate the amount of CAc on the surface of the tubing.
  • Chlorhexidine Dichloride made in situ from CDG impregnated AO. AQ tubing strands from Example 6A were taken before the drying step, coiled into a 2 ounce bottle and immersed in 0.1N HCl for almost 3 hours with the ends protruding. The HCl solution was then decanted and fresh HCl solution replaced it for an additional 21 ⁇ 4 hours. The tubing was removed from the HCl solution and was then soaked in pH 7 phosphate buffer
  • segments of non-swelling non-hydrophilic PU tubing with CAc from example 6C were immersed in 0.1 N HCl for four hours, rinsed with water, then pH 7 buffer and immersed in buffer for three hours with the ends
  • silicone tubing described in Example 2G coiled in an amber vial was immersed in saturated ( ⁇ 1.5 wt%) CAc solution at room temperature for five hours. The solution was replaced with fresh saturated CAc solution and left for 19 hours. The tubing was rinsed gently inside and out with water, blown dry inside, blotted dry and placed in a saturated ( ⁇ 1.5 wt%) CAc solution at room temperature for five hours. The solution was replaced with fresh saturated CAc solution and left for 19 hours. The tubing was rinsed gently inside and out with water, blown dry inside, blotted dry and placed in a
  • the tubing was gently re-coiled into an amber vial and immersed in 0.1N HCl for one half hour, after which the tubing was washed as above with water and kept damp at 100% RH for two hours.
  • the tubing was recoiled and reimmersed in fresh 0.1 N HCl for five additional hours. Again the acid was
  • polyurethane tubing described in Example 2H was used in this example.
  • the CCl was made in situ by reacting HCl with CAc using the identical procedures described in Example 6G above.
  • the tubing is calculated as
  • Example 7 Non Aqueous Impregnation of Medicament.
  • This example demonstrates the use of non-aqueous impregnation of a hydrophilic matrix by a medicament which is soluble in a non-aqueous solvent system and is substantially insoluble in water.
  • Oxytetracycline has a solubility in methanol of 18.5 mg/ml and in water of 0.6 mg/ml (Weiss et al, Solubility of Antibiotics, Antibiotics and
  • Example 7B Methanol Control. Segments of tubing were treated as in Example 7A above except only pure methanol was used. The dry tubing showed only very slight initial antibacterial activity ( ⁇ 0.1 mm zones, see below) with no antibacterial activity at all after 1 day extraction. This example was carried out to show that the antibacterial effectiveness of the tubing of Example 7A was not due to the presence of residual methanol used in the process.
  • Example 8 Activity of AQ with soaked in gentamicin
  • Table II summarizes the results from PBS extraction for the time indicated for various reasons
  • Example 9 shows that neither the virgin untreated tubing, the PBS solution, not the procedures used had any inhibiting effect against the Bacillus.
  • Example 10 with tubing containing about 1.5 wt% gentamicin sulfate (565/ ⁇ g/mg) incorporated into the tubing during melt processing, demonstrates that this material was completely extracted out of the tubing in 7-10 days. This is typical of water soluble substances, whether incorporated during processing as in this example or incorporated by soaking in as in Example 1 (results shown in Example 8).
  • Example 11 shows that 2.2 wt% sodium sulfadiazine in the tubing has virtually no activity against the organism even when dry and before any leaching has taken place. This proves that the activity of AgSZ impregnated tubing is not due to residual NaSZ left by the in situ AgSZ forming
  • Example 12 shows AgSZ containing swellable hydrophilic tubing maintains effective activity for over 291 hours.
  • the elastomer hydrogel AQ tubing acts as a reservoir for the relatively insoluble silver sulfadiazine resulting in a fairly constant slow release.
  • Various examples below prove the "insoluble" medicaments can be effective for much longer periods of time when incorporated by this in situ process.
  • Examples 2C and 3A The one inch tubing samples were extracted in small (8ml) vials by PBS, which was changed every 48 or 72 hours. This is an extension to longer time periods of Examples 12 and 13 above.
  • Tubing described in Example 2I was tested to demonstrate that the prolonged activity of the material containing the silver salts described in examples 15 and 16 was not an artifact of specimen preparation during the silver nitrate impregnation step. No residual silver nitrate is expected as it should be completely reacted (or diffused out) by the procedures used.
  • Example 2I were cut into one inch pieces, placed into 8ml amber vials and continuously flushed by pumping distilled water continuously at approximately 0.4 ml/min through the vial. At periodic intervals tubing specimens were removed, stored in water in sealed vials for 1 day then analyzed for microbiological activity as described for Example 9. Extraction times/zone sizes are as follows: dry/6.6 mm.; 1 day/6.6 mm.; 3 (and more) days/0 mm. This experiment demonstrates that the activity of any insoluble silver salt used in these examples cannot be due to residual silver nitrate or any unexpected silver-tubing
  • NaSZ is not present in effective antibacterial concentrations.
  • tubing from Example 2A (NaSZ only) was soaked for 4 hours in PBS. This tubing was immersed in the Staph Epi solution. No growth of the bacteria was observed after 20 hours
  • Example 2C is not due to the NaSZ also present.
  • the dry gentamicin sulfate loaded tubing (Example 1A) elutes sufficient
  • Example 2C has excellent antibiotic activity; even samples pre-extracted for 267 hours maintain sufficient activity to kill the Staph Epi present and the solution remains clear.
  • Tubing samples in this example (except Example 19C) contained in 8 ml amber vials were continuously washed with BNS (buffered normal saline) at about 0.4 ml/min, removed at stated time intervals, then analyzed as described in Examples 17 and 9. There is some
  • This control disc is a Kirby Bower pellet containing 10 micrograms of gentamicin.
  • the discs are about 6 millimeters in diameter and net zone sizes ranged from about 51 ⁇ 2 to 6 mm from the edge of the disc to the edge of the bacteria clear circle.
  • Tubing from Example 2D was used for this Example.
  • Figure 1 shows that tubing containing silver sulfadiazine formed in situ in the elastomer hydrogel AQ tubing retains activity for about 160-180 days of constant saline flush ( ⁇ 2 ml/min for the first 50 days in buffered tap water then ⁇ 0.4 ml/min in BNS).
  • Example 2H was continuously extracted in BNS at ⁇ 0.4 ml/min and was then tested -for activity against bacillus subtilis as
  • Example 2E non-extracted tubing from Example 2E was tested for activity against bacillus subtilis as described in Example 9. This dry tubing possessed no antibiotic activity even when tested dry.
  • This tubing was made following the teaching of U.S. Patent 4,581,028 using hydrophobic (contains about 1 wt% moisture) aliphatic polyurethane tubing. This
  • example is the same as 19E above, except the concentration of reagents was increased to the levels of other silver containing
  • Examples 19 E, F, G are examples of prior art on polyurethane or silicone tubing and have
  • Examples 19 A-D of the present invention have significant antimicrobial activity for several weeks to months and longer, even when continuously flushed with saline solution.
  • Tubing segments from Examples 5A and 5B were soaked in PBS, with periodic replenishment with fresh PBS solution. Segments which had been extracted for various time periods were tested against bacillus subtilus as described in Example 19C above.
  • the tubing with the less soluble polymyxin-caprylic acid complex maintained measurable antibiotic activity for approximately twice as long as the more soluble polymyxin B sulfate impregnated tubing.
  • Example 22 Antibiotic Activity of Chlorhexidine
  • the CCl containing AQ tubing made from the CDG tubing, showed zone sizes in the 5-9 mm range throughout the same time period. For this time period its behavior tracked the longer time performance of the CCl AQ tubing of Example 6E discussed immediately below and shown in Figure 2.
  • non-swelling silicone tubing of Example 6G had no activity at any time and does not appear in Figure 2.
  • the hydrophobic polyurethane of Example 6F showed some activity but all activity disappeared after about one day of extraction. It was very surprising to note that while CAc has higher solubility ( 1.9g/100ml) than does CCl (0.06g/100ml) it exhibited higher activity for much longer periods of time ( more than 200 days).
  • Example 7A shows how the technique illustrated in Example 7A allows preparation of AQ tubing possessing long lasting antibiotic protection. This tubing was extracted and tested using the same procedures as described in Example 19C. This tubing maintains antibiotic activity against bacillus
  • subtilis equivalent to 10/tg gentamicin for over 200 days see Figure 5.
  • the present invention provides a method of incorporating chemicals, particularly medicaments, in hydrophobic matrixes in controllably soluble form whereby the medicaments can be delivered over a selectively long period of time.
  • Articles having these properties can be used as slow time releases for medicaments and are particularly useful for forming cannulae, particularly water swellable cannulae.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un produit chimique est incorporé dans une matrice hydrophile susceptible de gonfler. Le produit chimique, ou un précurseur de celui-ci, peut être dissous dans une solution contenant un solvant qui fait gonfler la matrice d'au moins 10 %. Le produit chimique est alors déposé dans la matrice sous une forme présentant une solubilité relativement faible dans une solution aqueuse. Le produit obtenu permet une libération de longue durée du produit chimique dans la région environnante, à des fins médicales ou autres. Le produit peut être, notamment, une canule.
PCT/US1992/008528 1991-10-10 1992-10-07 Agent therapeutique incorpore dans une matrice hydrophile Ceased WO1993006881A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5507158A JPH07500263A (ja) 1991-10-10 1992-10-07 親水性マトリックス中の治療薬
EP92921607A EP0607284A4 (fr) 1991-10-10 1992-10-07 Agent therapeutique incorpore dans une matrice hydrophile.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US77456191A 1991-10-10 1991-10-10
US774,561 1991-10-10

Publications (1)

Publication Number Publication Date
WO1993006881A1 true WO1993006881A1 (fr) 1993-04-15

Family

ID=25101619

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/008528 Ceased WO1993006881A1 (fr) 1991-10-10 1992-10-07 Agent therapeutique incorpore dans une matrice hydrophile

Country Status (4)

Country Link
EP (1) EP0607284A4 (fr)
JP (1) JPH07500263A (fr)
CA (1) CA2120497A1 (fr)
WO (1) WO1993006881A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997004819A1 (fr) * 1995-07-31 1997-02-13 Caphco, Inc. Compositions et dispositifs nouveaux de liberation lente de principes actifs
EP1273313A3 (fr) * 1996-01-05 2003-02-05 The Trustees of Columbia University in the City of New York Dispositifs à usage médical contenant du triclosan
US7329412B2 (en) 2000-12-22 2008-02-12 The Trustees Of Columbia University In The City Of New York Antimicrobial medical devices containing chlorhexidine free base and salt
US8679571B2 (en) 2008-04-09 2014-03-25 Alexander Rübben Method for producing a bioactive surface on an endoprosthesis or on the balloon of a balloon catheter
US9981069B2 (en) 2007-06-20 2018-05-29 The Trustees Of Columbia University In The City Of New York Bio-film resistant surfaces

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5624704A (en) * 1995-04-24 1997-04-29 Baylor College Of Medicine Antimicrobial impregnated catheters and other medical implants and method for impregnating catheters and other medical implants with an antimicrobial agent

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4439583A (en) * 1980-11-12 1984-03-27 Tyndale Plains-Hunter, Ltd. Polyurethane diacrylate compositions useful in forming canulae
US4581028A (en) * 1984-04-30 1986-04-08 The Trustees Of Columbia University In The City Of New York Infection-resistant materials and method of making same through use of sulfonamides
US4917686A (en) * 1985-12-16 1990-04-17 Colorado Biomedical, Inc. Antimicrobial device and method

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3896813A (en) * 1967-06-23 1975-07-29 Sutures Inc Sutures having long-lasting biocidal properties
DK260782A (da) * 1981-06-12 1982-12-13 Nat Res Dev Hydrogeler

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4439583A (en) * 1980-11-12 1984-03-27 Tyndale Plains-Hunter, Ltd. Polyurethane diacrylate compositions useful in forming canulae
US4581028A (en) * 1984-04-30 1986-04-08 The Trustees Of Columbia University In The City Of New York Infection-resistant materials and method of making same through use of sulfonamides
US4917686A (en) * 1985-12-16 1990-04-17 Colorado Biomedical, Inc. Antimicrobial device and method

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0607284A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6706024B2 (en) 1995-06-07 2004-03-16 The Trustees Of Columbia University In The City Of New York Triclosan-containing medical devices
WO1997004819A1 (fr) * 1995-07-31 1997-02-13 Caphco, Inc. Compositions et dispositifs nouveaux de liberation lente de principes actifs
EP1273313A3 (fr) * 1996-01-05 2003-02-05 The Trustees of Columbia University in the City of New York Dispositifs à usage médical contenant du triclosan
US6626873B1 (en) 1996-01-05 2003-09-30 Trustees Of Columbia University Tricolosan-containing medical devices
US6872195B2 (en) 1996-01-05 2005-03-29 The Trustees Of Columbia University In The City Of New York Chlorhexidine-containing medical devices
US7329412B2 (en) 2000-12-22 2008-02-12 The Trustees Of Columbia University In The City Of New York Antimicrobial medical devices containing chlorhexidine free base and salt
US7537779B2 (en) 2000-12-22 2009-05-26 The Trustees Of Columbia University In The City Of New York Antimicrobial medical devices
US8906401B2 (en) 2000-12-22 2014-12-09 The Trustees Of Columbia University In The City Of New York Antimicrobial medical devices containing chlorhexidine free base and salt
US9981069B2 (en) 2007-06-20 2018-05-29 The Trustees Of Columbia University In The City Of New York Bio-film resistant surfaces
US8679571B2 (en) 2008-04-09 2014-03-25 Alexander Rübben Method for producing a bioactive surface on an endoprosthesis or on the balloon of a balloon catheter

Also Published As

Publication number Publication date
EP0607284A1 (fr) 1994-07-27
EP0607284A4 (fr) 1997-06-04
CA2120497A1 (fr) 1993-04-15
JPH07500263A (ja) 1995-01-12

Similar Documents

Publication Publication Date Title
US5554147A (en) Compositions and devices for controlled release of active ingredients
AU773655B2 (en) Triclosan and silver compound containing medical devices
US5788687A (en) Compositions and devices for controlled release of active ingredients
US5328954A (en) Encrusting and bacterial resistant coatings for medical applications
US5217493A (en) Antibacterial coated medical implants
AU730158B2 (en) Triclosan-containing medical devices
US5344411A (en) Method and device for inhibiting HIV, hepatitis B and other viruses and germs when using a catheter in a medical environment
US10022476B2 (en) Drug releasing medical catheters, tubes, and devices
US20130022651A1 (en) Hydrogel materials incorporating eluting ceragenin compound
BRPI0706622A2 (pt) composição de formação de filme antimicrobiano curável, dispositivo médico para a introdução em um corpo humano ou animal , composição de revestimento curável, e, revestimento de superficìe sólida antimicrobiano não-lixiviante
US7597903B2 (en) Method and composition for producing catheters with antibacterial property
WO1993006881A1 (fr) Agent therapeutique incorpore dans une matrice hydrophile
AU767489B2 (en) Triclosan-containing medical devices
Shintani Modification of polymer surfaces of medical devices to prevent infections
Szycher -Antimicrobial Polyurethanes
IE911473A1 (en) Anti-thrombogenic and/or anti-microbial composition

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2120497

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1992921607

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1992921607

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1992921607

Country of ref document: EP