WO1993004731A1 - Traitement a l'iode-iodure de cellules sanguines rouges - Google Patents

Traitement a l'iode-iodure de cellules sanguines rouges Download PDF

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Publication number
WO1993004731A1
WO1993004731A1 PCT/US1992/007233 US9207233W WO9304731A1 WO 1993004731 A1 WO1993004731 A1 WO 1993004731A1 US 9207233 W US9207233 W US 9207233W WO 9304731 A1 WO9304731 A1 WO 9304731A1
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WIPO (PCT)
Prior art keywords
iodine
red blood
povidone
iodide
blood
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Application number
PCT/US1992/007233
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English (en)
Inventor
Edward Shanbrom
Original Assignee
Edward Shanbrom
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 Edward Shanbrom filed Critical Edward Shanbrom
Publication of WO1993004731A1 publication Critical patent/WO1993004731A1/fr

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    • 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
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A61L2/0088—Liquid substances

Definitions

  • Red blood cells are transfused into patients as a component of whole blood and in various red blood cell concentrates.
  • the risk of transmitting pathogenic microorganisms to the recipient remains serious in spite of efforts to provide a safe blood supply.
  • a new method of treating red blood cells to inactivate microorganisms which may be present in red blood cell transfusion preparations is disclosed and claimed herein.
  • Povidone USP is used in the sense that it is used in the U.S. Pharmacopeia to describe grades of polyvinyl pyrrolidone (PVP) suitable for introduction into the human body.
  • PVP polyvinyl pyrrolidone
  • molecular iodine compound is used in this patent to mean and include molecular iodine, I, diatomic iodine, I,, or a compound or a mixture of compounds which either comprises iodine available in molecular form, typically as diatomic I 2 , or which reacts with or in the presence of the sample to produce such iodine.
  • molecular iodine I, diatomic iodine, I, or a compound or a mixture of compounds which either comprises iodine available in molecular form, typically as diatomic I 2 , or which reacts with or in the presence of the sample to produce such iodine.
  • Povidone-iodine is the principal example of such compounds.
  • Iodide is used to describe a compound which disassociates in aqueous solution to produce iodide ions.
  • Potassium iodide and sodium iodide are considered to be the optimum iodides suitable for use in this invention.
  • the antimicrobial effect iodine in red blood cell containing preparations is greatly enhanced by pre-treating the red blood cells with iodide or treating the red blood cells with iodide and iodine contemporaneously.
  • the cytophylactic effect of povidone in protecting whole blood and packed or clotted red blood cells from the cytolitic effect of iodine is enhanced by the generally contemporaneous treatment of the cells with certain salts when the ratio of PVP to I, is sufficiently high, at least about 4:1 (by weight).
  • This invention relates to the treatment of whole blood to inactivate or destroy infective pathogenic microorganisms found in animal fluids and cells.
  • inactivate as applied to the inactivation of virus in accordance with the present invention means that the pathogenic microorganisms are rendered non-infectious to the patient.
  • Whole blood and red blood cell transfusions exemplify generally one application of this invention.
  • This invention is generally applicable to the transfer of red blood cells and other cells which bind iodine from one species to the same species and, to the extent immunological incompatibility problems can be overcome, to inter species transfer.
  • Epste n-Barr virus (EBV) and/or cytomegalovirus (CMV) are commonly found pathogenic viruses.
  • Other pathogenic viruses frequently found in red blood cell containing preparations include hepatitis and human immunodeficiency virus (HIV). Many other less life-threatening viruses are also found in red blood cell containing preparations.
  • Y. enterocolitica and other bacteria which propagate at relatively low temperatures e.g. Staphylococcus epidermidis and Legionella pneumophila, present, potentially, a serious threat in blood products.
  • Bacterial infections generally, are a continuing concern to blood bankers and those who produce transfusion products from blood. Indeed, a national surveillance system for transfusion-associated bacterial infections has been called for, Editorial, Transfusion 30, 3, p. 193 (1990).
  • Protozoa give rise to many diseases, some of great medical and economic importance. Examples of such protozoa are the genus Plasmodium, e.g. P. falcipamm, P. malariae, P. ovale and P. vivax, which causes malaria, Trypanosoma, which causes Chagas' disease, and Leishmania, which cause a variety of leishmaniasis.
  • the method of this invention is effective in eliminating these causative organisms in blood and blood products.
  • this invention is applicable to the treatment of donated blood and other red blood cell containing preparations for inactivating virus, bacteria, chlamydia, rickettsia, mycoplasma and other potentially pathogenic microorganisms.
  • iodine as an antiseptic dates back to 1839. It is used today for various medicinal purposes.
  • iodine complexes with either nonionic surfactants, eg, polyethylene glycol mono(nonylphenyl) ether, or poly(vinylpyrrolidone) (PVP).
  • nonionic surfactants eg, polyethylene glycol mono(nonylphenyl) ether, or poly(vinylpyrrolidone) (PVP).
  • PVP poly(vinylpyrrolidone)
  • Medicinal povidone-iodine preparations include aerosol sprays, gauze pads, lubricating gels, creams, solutions, douche preparations, suppositories, gargles, perineal wash solutions, shampoos, and skin cleansers and scrubs.
  • Povidone-iodine preparation are applied topically to the skin and to membranes, e.g. vaginal membranes, and in infected wounds and surgical incisions.
  • Iodine and iodine-containing compounds and preparations are employed extensively in medicine, eg, as antiseptics, as drugs administered in different combinations in the prophylaxis and treatment of certain diseases, and as therapeutic agents in various thyroid dyscrasias and other abnormalities.
  • Iodine is a highly reactive substance combining with proteins partly by chemical reaction and partly by adsorption. Therefore its antimicrobial action is subject to substantial impairment in the presence of organic matter such as serum, blood., urine, milk, etc. However, where there is no such interference, non-selective microbicidal action is intense and rapid. A saturated aqueous solution of iodine exhibits anti-bacterial properties.
  • PVP polyvinyl pyrrolidone
  • PVP-iodine polyvinyl pyrrolidone
  • BetadineTM and IsodineTM are marketed as BetadineTM and IsodineTM by The Purdue-Frederick Co.
  • Povidone-iodine products and the preparation of such products are described in U.S. Patents 2,707,701, 2,826,532, and 2,900,305 to Hosmer and Siggia, assigned to GAF Corporation and in a number of GAF Corporation publications; see, e.g.
  • Povidone-iodine powder contains approximately 85% PVP, 10 %* I, and 5%Iodide. A 10% solution of this powder contains 1% free, available iodine. (Gershenfeld, Am. J. Surgery 94, 938 (1957)).
  • PVP polyvinyl urethane
  • the single most attractive property of PVP is its binding capability. This property has permitted utilization in numerous commercial applications. Small quantities of PVP stabilize aqueous emulsions and suspensions, apparently by its absorption as a thin layer on the surface of individual colloidal particles.
  • the single most widely studied and best characterized PVP complex is that of PVP-iodine. For example, hydrogen triiodide forms a complex with PVP that is so stable that there is no appreciable vapor pressure. It is superior to tincture of iodine as a germicide.
  • iodine is less likely to be consumed by proteinaceous substrates than bromine and chlorine, its efficacy as a disinfectant is still reduced at certain antiseptic applications. This is due to a reducing effect of the material to be disinfected which leads to the conversion of iodine into non-bactericidal iodide. Thus, not only the reservoir of available iodine is diminished but also the equilibrium of triiodide is influenced as well. Both of these effects cause a decrease in the proportion of free molecular iodine, the actual anti-microbial agent.
  • povidone-iodine preparations are contaminated with liquid substrata (e.g.
  • povidone-iodine was absorbed in serum albumin and it is know that povidone-iodine is bound to albumin but it has been discovered that the antibiotic activity of povidone-iodine is not destroyed by albumin bounding. Whether the activity remains because the albumin povidone-iodine is active or whether povidone-iodine and/or I 2 are released from the albumin- povidone-iodine complex.
  • This invention relates to the treatment of red blood cell containing preparations, i.e. blood which is to be transfused as whole blood or tranfusable red blood cell containing products to inactivate or destroy infective pathogenic microorganisms with molecular iodine in the presence of iodide.
  • the iodine is preferably absorbed by or in complex with an organic stabilizer.
  • infective pathogenic microorganisms are inactivated when molecular iodine compound is added to whole blood in a concentration of from 0.5 wt % to about 1.5 wt %.
  • the preferred range is from 0.5 to 1.0 wt %.
  • Such blood can be used as whole transfusion blood used to produce red blood cell containing preparations which are free of pathogenic microorganisms. It has now been discovered that the antimicrobial effect of iodine in such preparations is greatly enhanced if the red blood cell containing preparation has been pretreated with iodide or, to a lesser extent, the iodine treatment is carried out in the presence of iodide.
  • the iodide and the iodine compound may be in the blood collection bag at the time the blood is collected.
  • the iodide is added first, e.g. is in the collection bag, followed by the addition of iodine, which may be in the
  • additive bag which, commonly, is a separate bag containing an additive solution of a number of reagents which tend to stabilize the blood or prepare the blood for further processing.
  • the capacity of the blood bag being known, e.g. one pint, the quantity of iodide, e.g. KI or Nal, and iodine, e.g. povidone-I 2 necessary to result in a concentration of I, in the blood of about 1 ⁇ 0.5 wt % is provided in the solution bag.
  • the synergistic enhancement of the antimicrobial effect of iodine is not dependent upon the presence of povidone; however, povidone-iodine compositions protect the red blood cells from the cytolytic effect of iodine and is thus preferred as a source of iodine.
  • the povidone:!, ratio differs very substantially from the standard ratio of about 2:1 povidone to I, and is preferably at least about 4:1 povidone to I,.
  • the invention is also embodied in the method of treating packed red blood cells with a molecular iodine compound in the presence of iodide or after treatment with iodide. Red blood cells may, of course, be treated as part of whole blood in the manner described above.
  • iodide may be added substantially contemporaneously with the iodine, though somewhat greater antimicrobial enhancement is achieved by pre-treatment of the red blood cell containing preparation with iodide.
  • Iodide preferably in the form of potassium iodide or sodium iodide, is added in approximately the same concentration range as the concentration of iodine, i.e. in the range of from 0.001 to 0.5 wt percent, the preferred range being from 0.01 to 0.25 wt %.
  • a concentration of 0.1 wt % I, added as povidone- 1, to red blood cell containing preparations which are previously or contemporaneously treated with iodide results in a total kill of bacteria and virus.
  • the cells may, for example, be washed with an iodide containing solution and then treated with the molecular iodine compound or washed in a solution containing the molecular iodine compound and iodide.
  • iodide enhances the antimicrobial effect of iodine in red blood cell containing preparation
  • iodine can be used alone, as I 3 or as povidone iodine if suitable substances are included in the red blood cell containing preparation to provide an osmotic balance between the interior and the exterior of the red blood cells; i.e. to prevent undue dehydration or swelling of the red blood cells as a result of a differential in osmotic pressure between the interior of the cell and the liquid surrounding the cell.
  • povidone it is believed, performs this function directly, i.e.
  • Calcium or magnesium salts, sulfate salts, and/or water soluble poylmers, e.g. hydroxyethyl starch, for example, may be used in red blood cell containing preparation treatment solutions.
  • iodine Upon entry into the cell and reaction with a microbe or a constituent of the cell, iodine becomes iodide ion, thereby changing the osmotic balance between the interior and exterior of the cell. Addition of molecules which are too large to enter into the cell, but increase the effective concentration of the fluid outside the cell may be used to restore the proper osmotic balance.
  • the iodine treatment of red blood cells may be conducted immediately after separation or immediately before transfusion into the patient, or at any intermediate stage.
  • the oxygen-pickup and carrying ability of the red blood cells is preserved by treatment of the cells, alone or as part of blood, with the povidone-I 2 solution described. Following treatment, the cells may then be washed to remove excess molecular iodine compound from the cell milieux.
  • Povidone-I is an effective preservative solution, used as described above, for red blood cell preparations used as laboratory standards or panels in blood banking.
  • the red blood cell containing preparations to be purified can be treated with iodide and then caused to contact or flow through a solid which exposes the preparations to molecular iodine.
  • whole blood to which potassium iodide has been added may be contacted with particles, a membrane or surface of solid povidone-iodine. Where a bed of particles is used, the particles must be large enough to permit intimate contact without acting as a filter, i.e. entrapping or binding the cells.
  • Polyvinyl pyrrolidone used in the preparation of soluble povidone- iodine preparations is polymerized to a molecular weight of from about 10 Kdaltons to 40 Kdaltons, 30 Kdaltons being a typical molecular weight.
  • povidone-iodine preparations can be prepared using very much higher molecular weight polymers which only tend to swell rather than to dissolve in aqueous solutions. It is the use of these higher molecular weight Polyvinyl pyrrolidone polymers reacted with I 2 to form solid, substantially water insoluble povidone-iodine compositions that the present invention is directed.
  • the red blood cell containing preparation is contacted with the solid povidone-iodine.
  • This may be done most efficiently, in most cases, b passing the liquid through a settled or fluidized or packed bed of povidone-iodine particles or by mixing the particles in a container of the liquid or passing the liquid over a surface of the povidone-iodine material, e.g. over a multiple-plate array of sheets of such material.
  • the povidone-iodine may be washed and the I, content therein regenerated between uses.
  • iodide enhances the antimicrobial activity of iodine not known.
  • a possible mechanism is, however, postulated without any intention to be bound by the postulate. It is believed that iodine and iodide are bound to the cell surface membrane of red blood cells. Once bound, the iodine is less possibly less available and/or reacts with components of the cell to become iodide, which has little or no antimicrobial activity. Thus, if this postulate is correct, little iodine enters the cell and much of the iodine is not available for reaction with pathogenic microbes. According to the present postulate, iodide binds to the sites on the cell surface membrane, blocking those sites * and thereby leaving iodine available as an antimicrobial agent.
  • This invention finds application in medicine and veterinary science.

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Abstract

Des préparations contenant des cellules sanguines rouges sont traités avec du iodure et de l'iode, le iodure servant à augmenter l'effet antimicrobien de l'iode, afin d'obtenir des préparations contenant des cellules sanguines rouges sans pathogène.
PCT/US1992/007233 1991-09-03 1992-08-26 Traitement a l'iode-iodure de cellules sanguines rouges WO1993004731A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75373491A 1991-09-03 1991-09-03
US07/753,734 1991-09-03

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WO1993004731A1 true WO1993004731A1 (fr) 1993-03-18

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0614368A4 (fr) * 1992-05-04 1994-04-12 Edward Shanbrom Sang de transfusion humain sans danger.
US5591350A (en) * 1994-04-15 1997-01-07 Pall Corporation Iodine disinfection method using a gaseous iodine treated porous medium
WO1998022151A1 (fr) * 1996-11-20 1998-05-28 Edward Shanbrom Prelevement de traces dans des fluides biologiques
US6096216A (en) * 1994-06-09 2000-08-01 American National Red Cross Iodinated matrices for disinfecting biological fluids
US6106773A (en) * 1998-09-24 2000-08-22 American National Red Cross Pathogen inactivating compositions for disinfecting biological fluids
WO2024023572A1 (fr) * 2022-07-29 2024-02-01 Romano Laboratory Srls Sang enrichi en iode moléculaire, son procédé de préparation et ses utilisations

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2621823A (en) * 1951-04-19 1952-12-16 Nashua Corp Method of labeling containers
US4898572A (en) * 1986-06-24 1990-02-06 Futur-Quotidien S.A. Autotransfuser
US4959319A (en) * 1985-08-01 1990-09-25 Skelnik Debra L Process of corneal enhancement
US5071648A (en) * 1989-04-06 1991-12-10 Merocel Corporation Polymeric broad-spectrum antimicrobial materials

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2621823A (en) * 1951-04-19 1952-12-16 Nashua Corp Method of labeling containers
US4959319A (en) * 1985-08-01 1990-09-25 Skelnik Debra L Process of corneal enhancement
US4898572A (en) * 1986-06-24 1990-02-06 Futur-Quotidien S.A. Autotransfuser
US5071648A (en) * 1989-04-06 1991-12-10 Merocel Corporation Polymeric broad-spectrum antimicrobial materials

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CA 110(1): 320U; GOTTARDI et al., "The Decrease of Efficiency of Povidone-Iodine Preparations by Blood by Bloods Model Experiments on the Reaction of Iodine-Containing Disinfectants with Protein Constituents, 1987", pp. 357-377. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0614368A4 (fr) * 1992-05-04 1994-04-12 Edward Shanbrom Sang de transfusion humain sans danger.
EP0614368A1 (fr) * 1992-05-04 1994-09-14 Edward Shanbrom Sang de transfusion humain sans danger
US5591350A (en) * 1994-04-15 1997-01-07 Pall Corporation Iodine disinfection method using a gaseous iodine treated porous medium
US6096216A (en) * 1994-06-09 2000-08-01 American National Red Cross Iodinated matrices for disinfecting biological fluids
WO1998022151A1 (fr) * 1996-11-20 1998-05-28 Edward Shanbrom Prelevement de traces dans des fluides biologiques
US6106773A (en) * 1998-09-24 2000-08-22 American National Red Cross Pathogen inactivating compositions for disinfecting biological fluids
WO2024023572A1 (fr) * 2022-07-29 2024-02-01 Romano Laboratory Srls Sang enrichi en iode moléculaire, son procédé de préparation et ses utilisations

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