EP0748161A1 - Desinfection et reparation de lesions - Google Patents

Desinfection et reparation de lesions

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Publication number
EP0748161A1
EP0748161A1 EP95913585A EP95913585A EP0748161A1 EP 0748161 A1 EP0748161 A1 EP 0748161A1 EP 95913585 A EP95913585 A EP 95913585A EP 95913585 A EP95913585 A EP 95913585A EP 0748161 A1 EP0748161 A1 EP 0748161A1
Authority
EP
European Patent Office
Prior art keywords
acid
chlorine dioxide
chlorite
ppm
wound
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.)
Withdrawn
Application number
EP95913585A
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German (de)
English (en)
Other versions
EP0748161A4 (fr
Inventor
Robert D. Kross
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.)
Alcide Corp
Original Assignee
Alcide Corp
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Filing date
Publication date
Application filed by Alcide Corp filed Critical Alcide Corp
Publication of EP0748161A1 publication Critical patent/EP0748161A1/fr
Publication of EP0748161A4 publication Critical patent/EP0748161A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine

Definitions

  • This invention relates generally to the disinfec ⁇ tion and repair of wounds, especially peritoneal cavity wounds and surgical sites.
  • tissues and organs of the body are capable of repairing injuries.
  • An injury may be broadly defined as an interruption in the continuity of tissues, and these are repaired by reestab ⁇ lishing that continuity.
  • Tissue repair is achieved pri ⁇ marily by proliferation, migration and differentiation of involved cells.
  • Epithelial tissue heals chiefly by cel ⁇ lular migration, presumably because epithelium is essen ⁇ tially two-dimensional.
  • mesodermal tissues, howev ⁇ er the three-dimensional configuration is correlated with a somewhat different mode of repair that takes the form of an aggregate of cells that migrate into the le- sion where they eventually redifferentiate into the tis ⁇ sue in question.
  • repair aggregates may take the form of granulation tissue in the case of dermis, frac ⁇ ture callus in the case of broken bones, or a comparable accumulation of cells between the cut ends of a severed tendon.
  • the physiological process of wound healing or tissue repair has been arbitrarily divided into three major phases: the inflammatory phase, the proliferative phase, and the remodeling phase.
  • a complex series of physiological and biochemical events can be correlated with macroscopic and microscopic changes in the wound as it heals.
  • the first, or inflammatory, phase of wound repair is initiated by a sequence of biochemical and cellular events that begins once the integrity and homeostasis of the tissue membranes are disrupted and involves both humoral and cellular components.
  • a commonly observed feature of inflammation is the release of various eicosa- noids and the appearance of polymophonuclear neutrophils, which migrate into both infected and noninfected wounds.
  • the neutrophils are followed by monocytic macrophages that remove wound debris and contribute soluble mediators including additional eicosanoids that promote wound re ⁇ pair.
  • collagen plays a pivotal structural role in the proliferative and remodelling phases of wound healing and tissue repair (id. , pages 146 to 147) .
  • the collagenous scaffold of the extracellular matrix compris ⁇ es at least 13 genetically distinct types of collagen (ijbid.), and the role the types play in the pathophysiol- ogy of tissue repair and their interplay with noncollage- nous matrix materials is incompletely understood, espe- cially the more recently described collagen types VI to
  • adhesion The overall union of the opposing surfaces of a wound results in an adhering or uniting process referred to as an adhesion.
  • the adhesion may involve tissue for- mation without differentiation of new elements, resulting in scarring and/or unnatural tissue associations.
  • foreign body reactions to lint and starch, sero- sal damage due to handling, ischemia and tension imposed by suturing and handling, and impaired fibrinolysis can contribute to adhesion formation.
  • Fibrovascular adhe ⁇ sions complicate gynecological, intestinal, tendon, and cardiac surgery (Cohen, et al . , cited above, page 576), and may result in ischemia.
  • Adhesion prevention after surgical procedures has been attempted by reducing fibrin deposition using heparin and fibrinolytic agents, inhib ⁇ iting fibroblast proliferation and collagen deposition using antihistamines or steroids, using careful surgical techniques and separating organs using various tech ⁇ niques, including separation with resorbable fabric. These methods have met with limited success due to the multiple and poorly understood etiology of adhesion for ⁇ mation (ibid. ) .
  • Perito ⁇ neal dialysis is the dialysis treatment of choice for diabetics and patients with peripheral vascular disease or congestive heart failure because the method provides less cardiovascular stress than hemodialysis, and for children, because they have relatively good peritoneal clearance. Peritoneal dialysis also allows for greater freedom and schedule flexibility and is thus often pre ⁇ ferred by working or disabled patients.
  • C.A.P.D. makes use of the fact that small molecular weight solutes reach complete equilibration with peritoneal fluid in 4 to 6 hours.
  • a patient on C.A.P.D. exchanges 1.5 to 3.0 liters of sterile dialysate containing hypertonic glucose and physiologic electrolytes three to five times a day, introduced and removed through a peritoneal dialysis catheter.
  • Disinfec ⁇ tants added to the solutions are potentially toxic; many disinfectants that can be employed on unbroken skin cause tissue damage and damage to tissue defenses when employed on wounds, especially surgical wounds (Cohen, et al . , cited above, pages 584-586) . Exposure of blood to either Hibiclens ® or Betadine ® surgical scrub solutions, for example, damage its cellular components. Some surgical irrigants employ a surfactant such as Poloxamer 188 which does not produce discernible toxic effects or allergic reactions in tissues, but this has the disadvantage of exhibiting no antibacterial activity. For wounds that are prone to infection, systemic antibiotic treatment must be employed (ibid. ) .
  • the present invention provides methods for using wound irrigants especially suitable for the peritoneal cavity which may be employed surgically or post-surgically or after physical trauma.
  • the irrigants exhibit broad-spec ⁇ trum antimicrobial activity, counter inflammation, and minimize scar and adhesion formation during the wound healing process.
  • the method involves irrigation or infusion of a wound, or catheter cleansing, with a solution containing dissolved chlorine dioxide.
  • the solutions typically com- prise from about 0.0005% (5 parts per million, ppm) to about 0.1000% (1000 ppm) of chlorine dioxide (C10 2 ) .
  • One embodiment efficacious in peritoneal dialysis solutions employs from about 5 to about 75 ppm C10 2 ; another effi ⁇ cacious as a post-surgical irrigant, from about 5 to about 250 ppm C10 2 ; and a third especially suitable as a surgical irrigant, from about 40 ppm to about 600 ppm C10 2 .
  • the chlorine dioxide solutions used in the inven ⁇ tion have a relative molar ratio of chlorine dioxide to residual chlorite of at least 5:1, typically at least 7.5:1, and preferably at least 10:1.
  • the chlorine dioxide solution may be provided in a number of ways. For example, it may be formed immedi ⁇ ately prior to infusion or irrigation by combination of a chlorine dioxide liberating compound (such as water-solu ⁇ ble alkali or alkaline earth metal chlorites or mixtures thereof) with a mineral acid such as sulfuric acid, hy- drochloric acid, and/or phosphoric acid, followed by adjustment of the pH to about 5 to 7.5.
  • a chlorine dioxide liberating compound such as water-solu ⁇ ble alkali or alkaline earth metal chlorites or mixtures thereof
  • a mineral acid such as sulfuric acid, hy- drochloric acid, and/or phosphoric acid
  • chlorine dioxide can be formed by reacting a chlorine dioxide liberating compound such as the chlorites mentioned above with an organic acid having a pK of from about 2.8 to about 4.2, such as malic acid, lactic acid, citric acid, mandelic acid, tartaric acid, and mixtures thereof. Lactic acid is employed in one embodiment; organic acids other than lactic acid are employed in other embodiments. Chloride ion can option ⁇ ally be used in these formulations, as can carbohydrate triggering substances that accelerate the formation of chlorine dioxide.
  • a chlorine dioxide liberating compound such as the chlorites mentioned above
  • an organic acid having a pK of from about 2.8 to about 4.2 such as malic acid, lactic acid, citric acid, mandelic acid, tartaric acid, and mixtures thereof. Lactic acid is employed in one embodiment; organic acids other than lactic acid are employed in other embodiments.
  • Chloride ion can option ⁇ ally be used in these formulations, as can carbohydrate triggering substances that accelerate the formation of chlorine dioxide.
  • chlorine dioxide can be formed by reacting a chlorine dioxide liberating compound, such as the chlorites mentioned above, with a saccharide which has been heat-activated by heating the saccharide to a temperature of from about 50 ⁇ c to about 150°c for at least about 1 minute, typically from about 5 to 240 min- utes and preferably from about 20 to 120 minutes, in a solution in the presence of an organic acid having a pK of about 2.8 to about 4.2 and at a pH below about 5.5.
  • Typical saccharides used in these formulations include glucose, galactose, mannose, ribose, rhamnose, lactose, sucrose, maltose, and mixtures thereof.
  • the volume of chlorine dioxide-containing solution used as a wound irrigant according to the method of the invention varies with the size of the wound and the mam- mal and the scope of the infection or potential infec ⁇ tion, and can range between about 10 milliliters to about 5 liters.
  • Solutions employed for wound irrigation according to the method of the invention typically contain a phar- maceutically acceptable carrier.
  • Pharmaceutically ac ⁇ ceptable carriers include any that do not irritate the wound or cavity, including dialysis solutions and iso ⁇ tonic solutions containing saline and other inorganic (e.g., phosphates and sulfates) and organic salts.
  • Typi- cal solutions have a pH of from about 5 to 7.5.
  • the solutions may optionally contain suitable wetting agents and emollients.
  • Figure 1 is a graphical plot of data obtained in lactate dehydrogenase assays of isolated polymorphonu- clear leukocytes in the presence of chlorine dioxide solutions used according to the method of the invention and antinflammatory ibuprofen controls.
  • the figure plots lactate dehydrogenase activity, expressed as % of a posi- tive control, versus dilutions of chlorine dioxide solu ⁇ tions (•) or ibuprofen (I) , and shows the effect of chlo ⁇ rine dioxide or ibuprofen on cell integrity with (solid lines) or without (dashed lines) incubating with 0.05% bovine serum albumin (BSA) prior to the assay.
  • a nega ⁇ tive control is denoted by 0.
  • Figure 2 is a graphical plot of data collected using chlorine dioxide and ibuprofen at various dilution levels run concurrently in a chemotaxis assay employing 10% bovine serum albumin with polymorphonuclear leukocyte cells.
  • •—• and •—• show the chlorine dioxide results
  • ⁇ — ⁇ and ⁇ — ⁇ show ibuprofen results
  • 0 is a negative control.
  • Figure 3 shows the results of a polymorphonuclear leukocyte chemotaxis assay that employs chlorine dioxide (•) and ibuprofen ( ⁇ ) at various dilution levels and bovine serum albumin levels of 0.05%.
  • the solid lines represent data obtained after incubation of the solutions with bovine serum albumin prior to addition of cells, and the dashed lines represent incubation of the cells with the solutions prior to addition of bovine serum albumin.
  • a negative control is shown as 0.
  • This invention is based upon the finding that a solution containing chlorine dioxide having defined chlo ⁇ rine dioxide-to-chlorite molar ratios that limit tissue irritation are efficacious as wound irrigants both pro- phylactically and therapeutically.
  • the present invention is di ⁇ rected to the use of effective amounts of chlorine diox ⁇ ide as a peritoneal cavity irrigant.
  • the enteric organ ⁇ isms which enter the peritoneal cavity through contamina ⁇ tion by gastrointestinal contact, whether by physical trauma or during surgery, are all susceptible to the cidal effects of chlorine dioxide, which is a broad-spec ⁇ trum antimicrobial.
  • Chlorine dioxide has demonstrated activity against all relevant organisms, both aerobic and anaerobic, including lactobacilli, streptococci, con ⁇ forms, Klebsiella species, Enterobacter species, Bacte- roide ⁇ species, clostridia and eubacteria.
  • addition of antibiotics to the irri ⁇ gating solution has not provided any additional benefit (Hau and Nishikawa, cited above) , and it is presumed that the peritoneal irrigation derives from its mechanical effect.
  • the ineffectivenss of local antibiotic solutions has been surprising to researchers, since the antibiotics that have been used were capable of in vitro inhibition of the bacterial species present in the peritoneal cavi ⁇ ty. It may be that the lack of effect was attributable to the brevity of contact of the antibiotic with the organisms, since usual flush times approximate five min ⁇ utes or less in duration, which would be too short for significant cidal action to occur.
  • This invention provides a quick-acting, broad- spectrum antimicrobial, that is not absorbed systemically because it is rapidly eliminated or degraded.
  • the inven ⁇ tive compositions have the requisite, extended range of antimicrobial action, rapidity of kill and degradability for this application.
  • 50 ppm C10 2 solutions have been shown to kill 6-logs/ml of a wide variety of organisms within one minute, including Pseudomonas aeru- ginosa , Staphylococcus species, Escherichia coli and other coliforms, Klebsiella pneumoniae , Streptococcus species, and Bacteroides species.
  • C10 2 reacts with oxi- dizable bonds of these organisms and other organic matter and, as a result, is reduced to lower oxidation states: initially chlorite and ultimately chloride.
  • the latter is present at high levels in the body (ca . 0.5% of cellu ⁇ lar fluids) , so that the small amount formed by C10 2 degradation (in the parts per million range) would disap ⁇ pear into that pool.
  • Compatability of these disinfecting peritoneal flush solutions is also appropriate, since the C10 2 is generated or dissolved in solutions which have osmotic pressures that are suitably isotonic with cellu ⁇ lar fluids.
  • C10 2 and related oxychlorine systems are their capability to inhibit the stimulation of fibro- plasia, the proliferation of fibroblast cells and expres- sion of collagen, which ordinarily ensues following wounding.
  • the oxychlorines resulting from acidification of chlorite to form chlorous acid significantly inhibits fibroblast proliferation and collagen formation.
  • a further study confirming the effect of C10 2 on wound healing combines an investigation of the immediate cellular re ⁇ sponse (chemotaxis) of the body to injury using isolated polymorphonuclear leukocytes, and another investigation assessing the interaction of C10 2 with free radicals which form during the course of tissue repair collagen synthe ⁇ sis.
  • C10 2 was found to control chemo ⁇ taxis by affecting the quality and morphology of the associated polymorphonuclear leukocytes.
  • the C10 2 which is a stable free radical containing one unpaired electron, was found to neutralize the super- oxide and related radicals involved in the process of collagen production.
  • this invention is directed to the use of oxychlorines as a prophylactic or therapeu ⁇ tic rinse for individuals on peritoneal dialysis.
  • Over 100,000 persons in the United States require dialysis treatments to supplement or replace the activity of fail ⁇ ing or failed kidneys.
  • the majority of these people rely on hemodialysis, which involves several hour sessions, three times per week, during which time their blood is passed through an external hemodialysis apparatus.
  • an alternative treatment is Continuous Ambulatory or Cycling Peritoneal Dialysis (C.A.P.D.
  • peritoneal cavities are filled with phosphate-buffered sugar solution
  • the peritoneal membrane acts as a dialyzing filter for waste products that have accumulated in the blood.
  • This technique frees the patient from thrice-weekly immobili ⁇ zation on a dialysis machine, but has a tendency to pro ⁇ mote peritoneal infections in the cavity by transfer of skin organisms into the peritoneum when the indwelling catheter that delivers the fluid is inserted. Other transfer of organisms takes place when connecting the daily dialysis fluid supply. Once an organism has reached the cavity, typically Staphylococcus epidermidis , it deposits on the catheter surface and grows a protec- tive glycocalyx structure around its colonies.
  • the average C.A.P.D. or C.C.P.D. patient has a peritonitis infection at least once a year, which dis ⁇ suades many people from this otherwise less-encumbering dialysis procedure.
  • This invention which is efficacious in the destruction of S. epidermidis encased in biofilms as illustrated below, provides a method to reduce this incidence.
  • the C10 2 -containing isotonic solutions of the invention can be used for C.A.P.D. patients ' in one of two ways. It can be included in the daily volume of the dialyzate infused into the patient, as a prophylactic means of destroying any incidental organisms that might be transferred during the daily exchange of fresh fluid for spent dialyzate. In this situation, a separate sat ⁇ ellite bag of C10 2 solution can be transferred to the main dialyzate volume prior to introduction into the peritone- urn.
  • the satellite bag itself can be a dual container of components which, when mixed, would release C10 2 at an appropriate level such that its dilution in the dialyzate fluid would approximate the desired final concentration (e. g. , 5 to 75 ppm) .
  • the method of the inven ⁇ tion is employed to treat peritonitis in C.A.P.D. pa ⁇ tients which arises from penetration of organisms into the peritoneum. While free-floating organisms are sus ⁇ ceptible to the cidal effects of C10 2 , S. epidermidis colonies on indwelling catheters can also be effectively destroyed. These colonies intermittently recontaminate the peritoneal cavity, which may be subsequently treated with an antibiotic without destroying the protected colo ⁇ ny on the catheter surface. As set out in the examples hereinafter, the cidal effectiveness of C10 2 was demon ⁇ strated using S. epidermidis biofilms that were grown on flat plates and exposed to a variety of disinfectants and antibiotics.
  • the method of the invention can also be used post- surgically. Following surgery, particularly abdominal surgery, it is generally necessary to flush the area of the operation with sterile saline solution to remove organic debris, including blood and serous fluids. When the surgery involves the gastrointestinal tract, there is generally the added presence of those organisms which inhabit that system. Even without such involvement, organisms in the surgical environment, although much reduced from normal levels, can deposit on the site, and must be removed. Without such removal, serious infec- tions can result after closure of the incision or wound. It is desirable therefore to incorporate an antimicrobial material in the flush, but broad use of antibiotics is discouraged and use of antiseptics such as hypochlorite or peroxide is discouraged because of tissue incompati ⁇ bility at levels that might be considered effective.
  • solutions containing fairly significant levels of C10 2 are particu ⁇ larly well tolerated by tissues.
  • solutions of 350 ppm in buffered saline have been shown to be safe ⁇ ly infusable into cows' udders without stimulation of any immune response by the animals.
  • C10 2 is capable of being reduced to lower oxidation states, such as chlorite and chloride, upon contact with organic materials, but is less reactive than, for example, hypochlorite, and a volume of C10 2 -containing saline is expected to retain significant antimicrobial activity when used to flush out organic debris from an incised area.
  • Appropriate use levels of C10 2 will vary, depending on the amount of organic detritus in the site, but generally concentra ⁇ tions of about 5 to 250 ppm in approximately isotonic solution can be used with good effect.
  • C10 2 is a broad-spectrum antimicrobial, capable of rapid destruction of aerobic and non-aerobic, gram-positive and gram-negative bacteria, as well as fungal organisms and viruses. It is particularly suitable for inclusion in a surgical irrigant or flush, since there is a diversity of microorganisms that could contact exposed areas during surgical procedures.
  • the unique benefit of C10 2 in addition to its high cidal capacity, is its ability to interfere with the biochemical processes that lead to augmented collagen production. As such, it can signifi ⁇ cantly suppress undesirable adhesions that often form between incised tissues during the course of post-surgi ⁇ cal healing.
  • the method of the invention employs the broad- spectrum antimicrobial, chlorine dioxide (C10 2 ) , typically provided from chlorine-dioxide generating compounds, in solution for body cavity, catheter, and wound disinfec ⁇ tion. Preformed chlorine dioxide is too unstable to be stored in neutral disinfectant solutions for any signifi ⁇ cant period of time.
  • the methods of the invention can be employed as a treatment for peritonitis, as a prophylac ⁇ tic or therapeutic rinse for people undergoing peritoneal dialysis, as a surgical irrigant, and as a disinfecting ear flush.
  • compositions of the invention are minimized in treat ⁇ ments using them because of the inorganic nature of chlo ⁇ rine dioxide, and its reductive degradation to chloride as a result of its interaction with organic matter (in ⁇ cluding bacteria, fungi, and viruses) .
  • materials may be non-inflammatory (i . e . , not provoke inflammation) but not anti-inflammatory (i.e., counter the effects of inflammation) .
  • Chlorine dioxide has been found to be non-inflammatory, by virtue of being infusible into the peritoneal cavity and other body cavi- ties without evoking the inflammatory response, as well as being anti-inflammatory; see the copending U.S.
  • techni ⁇ ques are employed which preferably either a) deliver the soluble chlorine dioxide gas in a solution relatively free of harmful chlorite, or b) employ a pre-infusion chemical reaction whereby the chlorite species has sub ⁇ stantially converted to chlorine dioxide leaving rela ⁇ tively little chlorite remaining.
  • the relative molar ratio of chlorine dioxide to residual chlorite is at least 5:1, typically at least 7.5:1, and preferably at least 10:1.
  • the concentration of chlorine dioxide in the infusate or irrigant typically varies from about 5 ppm ( g/liter) to about 1000 ppm in most embodi ⁇ ments, and is generally at least about 10 ppm.
  • One em- bodiment employs from about 5 to about 75 ppm C10 2 ; as mentioned above, this is especially efficacious in peri ⁇ toneal dialysis solutions.
  • Another employs from about 5 to about 250 ppm C10 2 ; this is especially suitable as a post-surgical irrigant.
  • a third particularly useful as a surgical irrigant employs from about 40 to about 600 ppm C10 2 .
  • the concentration requirement depends, to a significant degree, on the type of use for which the solution is employed, and the total volume used, since it is the total quantity of chlorine dioxide (i.e., concentration times volume) that is critical to the goal of overcoming the neutralizing effects of organ ⁇ ic matter in the wound in order to achieve the antimicro ⁇ bial and beneficial healing effects of chlorine dioxide.
  • a chlorine dioxide gen ⁇ erating compound is reacted with an acid in an aqueous solution.
  • exemplary chlorine dioxide generating com- pounds are water-soluble chlorites such as alkali metal chlorites, alkaline earth metal chlorites, and mixtures of these.
  • Sodium chlorite is employed in preferred em ⁇ bodiments.
  • a mineral acid is reacted with a chlorite such as sodium chlorite at such concentrations as to pro ⁇ vide rapid evolution of chlorine dioxide.
  • Typical miner ⁇ al acids include, but are not limited to, sulfuric acid, hydrochloric acid, phosphoric acid, and the like. Such admixture, however, results in a very acidic solution that requires neutralization before use.
  • Typical solu ⁇ tions are neutralized to a pH of from about 5 to about 7.5 prior to use.
  • a chlorine dioxide generating co - pound such as the chlorites mentioned above can be react ⁇ ed with a weaker acid, such as an organic acid having a pK of from about 2.8 to about 4.2.
  • Typical acids include lactic acid, citric acid, malic acid, glycolic acid, mandelic acid, tartaric acid, and mixtures thereof.
  • One embodiment employs lactic acid; the lactate so formed may enhance angiogenesis, collagen synthesis and deposi ⁇ tion, and modulate the response of fibroblasts to growth factors in the wound as summarized by Ninikowski, J., et al . , in Janssen, H. , et al . , eds., Wound Healing, Wright- son Biomedical Publishing Ltd, Petersfield, U.K., 1991, pages 169 to 170.
  • organic acids other than lactic acid are employed.
  • concentra ⁇ tions of sodium chlorite and activating acid are both below about 0.01- 0.02%, in isotonic saline.
  • solu- tions have been found to be appropriate for use in the uterine infusion treatment of the present invention for chlorine dioxide levels up to about 125 ppm.
  • the solu ⁇ tions may require pH adjustment, e. g. , to about 5 to about 7.5.
  • Typical solu ⁇ tions can contain up to about 1000 ppm chlorine dioxide, but higher concentrations, e. g. , up to about 5000 ppm chlorine dioxide are employed in some embodiments.
  • the composition may contain chloride ion, which is typically in the form of an alkali ' or alkaline earth metal salt.
  • chloride ion typically in the form of an alkali ' or alkaline earth metal salt.
  • concentra ⁇ tions can range between about 0.5% to 1.5% by weight; use of other salts requires an appropriate weight percent adjustment.
  • chloride ion causes chlorite ion to decompose in an accelerated man ⁇ ner, via the degradation of chlorous acid to form chlo ⁇ rine dioxide.
  • Preferred embodiments of the invention employ solutions that are approximately isotonic to the peritoneal cavity or peritoneal dialysis solutions.
  • chlorine dioxide formation in the reaction between chlorite and weaker acids is catalyzed by heat-activated saccharides.
  • Heat-activated saccharides are prepared by heating saccharides to a temperature of from about 50"C to about 150°C for at least about 1 minute, typically from about 5 to 240 min ⁇ utes. Some heat-activated saccharides are prepared by heating to about 75°C to about 110°C for about 20 to 120 minutes.
  • Exemplary saccharides include, but are not limited to, glucose, galactose, mannose, ribose, rham ⁇ nose, and disaccharides such as sucrose, lactose, and maltose, and mixtures thereof. Glucose is preferred in one embodiment. Heat-activated saccharides useful in these embodiments of the invention are described in grea- ter detail in U.S. Pat. No. 5,019,402 to Kross and
  • the chlorine dioxide solutions are generally buf ⁇ fered mixtures that maintain the irrigant at a pH compat- ible with the peritoneal or other cavity.
  • the pH typi ⁇ cally varies between about 4.5 or 5.0 and about 7.5.
  • the solutions can contain other ingredients typical in washes and irrigants such as, for example, wetting agents (such as nonylphenoxy polyoxyethylene (9)), soothing emol- lients, and the like.
  • Suitable carriers are chosen for their ability to dissolve or disperse chlorine dioxide as well as provide a composition conducive to infusion or irrigation. Many such compositions are known in the art, and can include thickening and emulsifying agents and the like, and such carriers are referred to herein as pharma ⁇ cologically acceptable carriers.
  • the solutions may be prepared immediately before infusion or irrigation in one embodiment.
  • the chlorine dioxide solution may be prepared and stored below a pH of about 5.5.
  • storage including storage of components and mixing of these prior to use, reference is made to U.S. Pat. Nos. 4,986,990 and 5,019,402, cited above, and references cited therein.
  • the following criteria should be met: 1) a storage pH below about 5.5 to mini ⁇ mize the degradation of chlorine dioxide to chlorite and other species; 2) a concentration of sodium chloride or equivalent material sufficient to render the solution approximately isotonic (e. g.
  • the volume of infusates varies with the size of the animal and the degree of infection or potential in ⁇ fection, and can range between about 10 milliliters to about 5 liters. Example volumes are given hereinafter.
  • solutions of the invention When solutions of the invention are infused into the peritoneal cavity, they are well tolerated, producing no noticeable irritation effects in the animals tested. Infusions with solutions of the invention are especially efficacious in the treatment of peritonitis.
  • compositions of the invention compares and contrasts the cidal effectiveness of compositions of the invention with other disinfectants and antibiotics against Staphylococcus epidermidis biofilms, which are frequently observed on the surface of C.A.P.D. peritoneal catheters even in the absence of peritonitis or exit site infections.
  • a strain of S. epidermidis with characteristic abundant slime production, and derived from a human source, is used to prepare the biofilms.
  • the isolate is fully sensitive in the fluid phase to all commonly used antibiotics as assayed using routine test methods. Ali- quots of the bacteria are frozen at -70°C in 10% glycerol broth or propagated on 5% defibrinated horse blood agar.
  • Standardized biofilms are formed on soda glass microscope slides or slides coated with Silastic ® (the basic materi- al of indwelling catheters; see Cecil 's, cited above, on page 542) , placed in Petri dishes containing 20 ml of tryptone soya broth (Oxoid Ltd. , England) , seeded with 10* cfu S. epidermidis and incubated for 18 hours at 37°C. Reproducible uniform and confluent S. epidermidis bio- films of minimal density are formed.
  • Antibiotic activity against S. epidermidis bio ⁇ films are determined using a supravital dye which acts as an electron acceptor in coupled oxidative systems in biofilm bacteria. The method allows the bacteria to be examined undisturbed within the biofilm matrix in situ .
  • the biofilms are exposed to antibiotic solutions and incubated at 37 ⁇ C for varying periods of time. Positive (viable, 1% peptone water) and negative (sterilized, 4% formol-peptone) controls are included in all experiments. After a designated exposure at 22°C for varying periods of time between 15 seconds to 6 hours, the biofilms are rinsed twice in sterile water and al ⁇ lowed to drain. They are then placed in a flat agar medium incorporating substantive dyes and incubated at 37'C for 4 hours, then 24 hours. Viability is assessed visually by a change in dye color and confirmed after 24 hours by mechanically scraping and subsequently culturing the biofilms. Sterilization is indicated by the absence of color changes and confirmed by culture of both intact and mechanically fragmented biofilms. Inhibition of growth is indicated by a lack of color change after a 4- hour incubation and confirmed by a positive color change by 24 hours.
  • antibiotics showed any activity against the bacteria after a 24 hour exposure to concen ⁇ trations shown in parenthesis: amikacin (60 ⁇ g/ml) , ampicillin (30 ⁇ g/ml) , bacitracin (20 ⁇ g/ml) , Bactrim ® (25 ⁇ g/ml) , cefadroxil (30 ⁇ g/ml) , cefamandole (60 ⁇ g/ml) , cefazolin (30 ⁇ g/ml) , cefoperazone (30 ⁇ g/ml) , cefotaxime (30 ⁇ g/ml) , cefsulodin (30 ⁇ g/ml) , ceftazidime (30 ⁇ g/ml) , cefuroxime (30 ⁇ g/ml) , cephalexin (30 ⁇ g/ml) , chloramphenicol (20 ⁇ g/ml), ciprofloxacin (12.5 ⁇ g
  • the materials in the table which are as effective as the 50 ppm Cl ⁇ 2 solution are ones that would be con ⁇ sidered to be too irritating and/or corrosive for use as an irrigant in a peritoneal cavity.
  • the 50 ppm C10 2 solution is well tolerated by mamma ⁇ lian tissue, as, for example, when used as an eye irri- gant, to treat bacterial infections induced in rabbits, to infuse into a cow's udder, or as a uterine douche for mares and cows in the prevention and treatment of endome- tritis.
  • hypochlorite will also be sub- ject to significant loss of activity as a result of its interaction with organic materials in peritoneal fluid.
  • Hydrogen peroxide at a concentration of 3%, requires a contact time 1200 times longer than the 50 ppm C10 2 to de ⁇ stroy the organisms in the biofilm, and also is likely to be too corrosive for infusion into the peritoneum.
  • isolated polymorphonu ⁇ clear leukocytes which are among the first cells to be found at a wound or a site of potential infection, are studied with respect to their response to chlorine diox- ide solutions and compared with a control containing ibuprofen, a known non-steroid anti-inflammatory com ⁇ pound.
  • the choice of in vitro assay is chemotaxis.
  • Isolated polymorphonuclear leukocytes are studied with respect to their response to a C10 2 solution varying in concentration from 3 to 300 ppm and an ibuprofen con ⁇ trol.
  • Cellular response and integrity is assayed in vitro after incubating with both compounds by measuring lactate dehydrogenase activity and/or release concurrently with observing morphology using scanning electron microscopy and/or transmission electron micros ⁇ copy.
  • Figure 1 shows the data obtained from the lactate dehydrogenase assays.
  • the figure plots lactate dehydro ⁇ genase activity, expressed as % of a positive control, versus dilutions of chlorine dioxide solutions or ibupro- fen, and shows the effect of chlorine dioxide or ibupro ⁇ fen on cell integrity with or without incubating with 0.05% bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • ⁇ — ⁇ shows ibuprofen incubated with BSA for 15 minutes, followed by adding cells, cen ⁇ trifuging and assaying, and ⁇ —I, incubation with cells for 15 minutes followed by adding BSA, centrifuging and assaying.
  • a negative control is denoted by 0.
  • Figure 2 shows chemotaxis when chlorine dioxide and ibuprofen are run concurrently in a chemotaxis assay.
  • the figure shows the effect of 0.10% bovine serum albumin on the cells. The albumin is added to the cells and incubated 15 minutes, and then cells are mixed in equal volumes with dilutions of chlorine dioxide or ibuprofen and incubated; 250 ⁇ l of each mixture is then applied to the top well of a modified Boyden chamber.
  • the y-axis plots percent of a positive control. In the figure, t—• and •—• show the chlorine dioxide results, ⁇ — ⁇ and ⁇ — ⁇ show ibuprofen results, and 0 is a negative control.
  • Figure 3 shows the results of the chemotaxis as ⁇ say. It demonstrates the effect of the difference in the sequence in which reagents are added and incubated.
  • reagents for each dilution, there is a known vol- ume of chlorine dioxide (•—•) or ibuprofen ( ⁇ — ⁇ ) to which bovine serum albumin is added to a final concentra ⁇ tion of 0.05%, the mixture is incubated for 15 minutes, and equal volumes of cells are added to each to a final concentration of 2.5 x 10 6 cells/ml.
  • a known volume of cells contain ⁇ ing approximately 6.0 x 10 6 cells/ml and an equal volume of chlorine dioxide (•—•) or ibuprofen ( ⁇ — ⁇ ) are incu ⁇ bated for 15 minutes and then bovine serum albumin is added to a final concentration of 0.05%.
  • 250 ⁇ l is applied to the top well of a modifed Boyden chamber. A negative control is shown as 0.
  • Free radicals are generated in vitro by the action of xanthine oxidase (XO) on xanthine.
  • XO xanthine oxidase
  • the generation of free radicals is monitored by the reduction of ferricyto- chrome C by the system.
  • the action of chlorine dioxide is compared with the scavenging action of the well known free radical scavengers superoxide dismutase (SOD) and catalase.
  • C10 2 (75 ppm) is generated by mixing 0.25% chlorite and 1.4% lactic acid. One hundred-fold dilutions are tested within one minute after mixing using electron paramagnetic spectroscopy (ESR) and a LKB luminometer. A strong free radical signal is generated using both meth- ods, and the signal is quenched using the free radical scavengers.
  • ESR electron paramagnetic spectroscopy
  • the chlorine dioxide solution is frozen in liquid nitrogen to -167°C and electron spin resonance analyzed using a Varian E3 instrument.
  • the luminometer assay utilizes a modified luminol assay for radical detection.
  • Luminol (LH 2 ) reacts with free radicals (R- ) as follows:
  • the pH optimum for the reaction is 10 to 12.
  • the assay is standardized with an enzymatic system in which the generation of free radicals could be quantified by mea ⁇ suring generation of -0 2 " , obtained with the following reaction, hypoxanthine + xanthine oxidase - urate + -0 2 " by the reduction of ferricytochro e C.
  • the experiments are divided into three groups.
  • 50 ⁇ moles of xanthine, 0.0217 units/mg XO, 0.1 mM EDTA are mixed in a total volume of 1.0 ml
  • HBSS Hank's Balanced Salt Solution
  • a lactic acid-activated chlorite solution is prepared by mixing 0.25% sodium chlorite with 1.5% lactic acid, which yields 150 to 600 ppm Cl ⁇ 2 .
  • the solution inhibits fibroblast proliferation in rat fetal lung fi- broblasts.

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Abstract

L'invention concerne des procédés destinés à prévenir et traiter les infections microbiennes dans des lésions, en particulier des lésions de la cavité péritonéale avec des sondes à demeure, et à accélérer simultanément la cicatrisation avec le moins d'adhérences possibles et une cicatrice minimale. Lesdits procédés consistent à envoyer dans la lésion, par perfusion ou irrigation, une solution contenant un excipient pharmaceutiquement acceptable et du dioxyde de chlore, en dose d'environ 5 ppm à 1000 ppm, selon un rapport de dioxyde de chlore et de chlorate de 5:1. Les solutions types contiennent du dioxyde de chlore en solution saline isotonique et présentent un pH d'environ 5 à 7,5. Du chlorate de sodium est utilisé dans les modes de réalisation préférés.
EP95913585A 1994-03-04 1995-03-01 Desinfection et reparation de lesions Withdrawn EP0748161A4 (fr)

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US20606294A 1994-03-04 1994-03-04
US206062 1994-03-04
PCT/US1995/002821 WO1995023511A1 (fr) 1994-03-04 1995-03-01 Desinfection et reparation de lesions

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003179A1 (fr) * 1987-10-13 1989-04-20 New Generation Products, Inc. Compose germicide au dioxyde de chlore
WO1993018781A1 (fr) * 1992-03-20 1993-09-30 Alcide Corporation Composition contenant du dioxyde de chlore pour la prevention et le traitement des infections bacteriennes

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US4986990A (en) * 1984-03-21 1991-01-22 Alcide Corporation Disinfection method and composition therefor
US4956184A (en) * 1988-05-06 1990-09-11 Alcide Corporation Topical treatment of genital herpes lesions
US5019402A (en) * 1988-08-10 1991-05-28 Alcide Corporation Composition and procedure for disinfecting blood and blood components
CA2045687A1 (fr) * 1989-01-27 1990-07-28 Francois Jooste Composition stabilisee, a base d'halogenures, pour la sterilisation ou la desinfection; methode et appareil pour l'utilisation de ladite methode

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003179A1 (fr) * 1987-10-13 1989-04-20 New Generation Products, Inc. Compose germicide au dioxyde de chlore
WO1993018781A1 (fr) * 1992-03-20 1993-09-30 Alcide Corporation Composition contenant du dioxyde de chlore pour la prevention et le traitement des infections bacteriennes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9523511A1 *

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CA2184813A1 (fr) 1995-09-08
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WO1995023511A1 (fr) 1995-09-08
CA2184813C (fr) 2000-01-04
AU2096795A (en) 1995-09-18

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