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WO1992004031A1 - Preservation de sang, de tissus et de fluides biologiques - Google Patents

Preservation de sang, de tissus et de fluides biologiques Download PDF

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Publication number
WO1992004031A1
WO1992004031A1 PCT/US1991/006240 US9106240W WO9204031A1 WO 1992004031 A1 WO1992004031 A1 WO 1992004031A1 US 9106240 W US9106240 W US 9106240W WO 9204031 A1 WO9204031 A1 WO 9204031A1
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Prior art keywords
iodine
povidone
blood
cells
cell
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Application number
PCT/US1991/006240
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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.)
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Publication date
Application filed by Edward Shanbrom filed Critical Edward Shanbrom
Publication of WO1992004031A1 publication Critical patent/WO1992004031A1/fr
Priority to NO92921756A priority Critical patent/NO921756L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • 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
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/12—Chemical aspects of preservation
    • A01N1/122—Preservation or perfusion media
    • A01N1/124—Disinfecting agents, e.g. antimicrobials
    • 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
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/14—Mechanical aspects of preservation; Apparatus or containers therefor
    • A01N1/146—Non-refrigerated containers specially adapted for transporting or storing living parts whilst preserving
    • 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
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/16—Physical preservation processes
    • A01N1/165—Pressure processes, e.g. following predefined pressure changes over time
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A61K31/79—Polymers of vinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • This invention relates to the treatment and preservation of blood and blood derivatives, the treatment and preparation of other body tissues and cells, the treatment and preparation of tissue cultures and tissue culture products, and the preparation of laboratory reagents, standards and samples.
  • the treatment of this invention is to kill or inactivate virus, bacteria, chlamydia, rickettsia, mycoplasma and other potentially pathogenic microorganisms.
  • the treatment and preparation of human blood, tissues, etc. and of the blood, tissues, etc. of other animals are contemplated.
  • the field of this invention lies in medicine and veterinary practice; most examples being related to the practice of medicine for the benefit of human patients, use in analogous fields of veterinary medicine to the extent applicable being within the scope of the invention.
  • Blood and blood derivatives means whole blood and blood fractions, components, and products of blood. Unless “whole blood” or a specific blood derivative, e.g. a blood fraction, component or product of blood is stated, the term “blood” may apply to whole blood at the time of collection or a blood derivative at any stage in processing, as indicated by context.
  • Blood derivatives mean blood components such as blood cell concentrates (red blood cells, platelets, etc.), plasma, and serum and products and factors prepared from blood such as albumin and the blood factors.
  • Body tissues and cells means any tissue(s), organ(s) or cells or fluids which contain tissue(s), organ(s) or cells of animal origin.
  • body tissues and cells include blood and the cellular components of blood; however, for the most part, simply for clarity in presentation, blood is treated as a separate application of the invention.
  • body tissues and cells include sperm, bone marrow, kidneys, cornea, heart valves, tendons, ligaments, skin, bone and homograft or xenograft implants and prosthesis generally.
  • Tissue and cell cultures means cells and tissues grown or enhanced in culture media and the culture media per se, but not including nutrients intended for use in cell cultures.
  • An examples of a cultured tissue is cultured skin tissue for use in burn victims.
  • Cells and cellular products prepared by standard biological and/or genetic engineering techniques are other examples of tissue cultures.
  • Laboratory reagents, standards and samples means reagents and standards produced from or comprising human or animal fluids, cells or tissues. Examples of such products are red blood cell panel utilized for typing blood, control sera and chemistry controls. Samples of tissues and fluids to be tested include samples of blood, urine, sputum, cell smears, etc. Donor. While the term “donor” is not usually applied to the individual from whom such samples are acquired, that term, “donor” will be used here in a more general sense to include the individual from whom any blood, tissue, cells or fluid is obtained for any purpose, and such term will be used to refer even to an unwilling donor. Povidone (USP) is used in the sense that it is used in the U.S.
  • molecular iodine compound is used in this patent to mean and include molecular iodine, I, diatomic iodine, I 2 , 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.
  • movidone-iodine is the principal example of such compounds.
  • Povidone-Iodine is a complex of molecular iodine with polyvinyl pyrrolidone. Povidone-iodine complexes of the type under consideration have been described in the literature and are marketed by The Purdue-Frederick Co. When percent concentrations are referred to in connection with povidone-iodine, the percentage refers to the percent of povidone-iodine by weight, based upon the weight of the solution or material to which the povidone-iodine is added.
  • povidone-iodine indicates that enough povidone-iodine has been dissolved to result in a concentration of P7o povidone-iodine.
  • povidone-iodine is added as a solution, e.g. 10% solution in water, pH about 1.5, but it can be added as a powder or otherwise.
  • 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)).
  • the ratio of polyvinyl pyrrolidone to iodine in the povidone- iodine product used in the experiments referred to hereinafter is 8.5 parts of povidone-iodine per 1 part of active iodine.
  • the product also contains about 0.5 parts of inactive iodine as iodide.
  • Typical stock solutions are 10% (10,000 ppm I 2 ), 5% (5,000 ppm I 2 ) and 1 % (100 ppm I,).
  • a dditional povidone polyvinyl pyrrolidone
  • concentration of povidone-iodine in such compositions means the concentration of povidone-iodine added as 8:5 to 1 PVP to I 2 povidone-iodine.
  • Those who deal with blood and other invasively obtained body fluid samples risk infection from the samples.
  • Those at risk include the doctor, nurse or clinical technician who takes the sample, the technicians who handle the sample and who use the sample in conducting analyses and tests, those who handle the sampling and testing equipment and apparatus, and the entire chain of individuals who attend to the disposal of sampling apparatus and the like, from the individuals who pick up the used apparatus through those who ultimately dispose of the apparatus, usually in specially designed high temperature furnaces.
  • EBV Epstein-Barr virus
  • CMV cytomegalovirus
  • Other pathogenic viruses to which health care workers, and those who handle blood and fluid sampling and handling apparatus, are exposed include hepatitis and human immunodeficiency virus (HIV) as well as a large number of less life-threatening viruses.
  • Yersinia enterocolitica Another organism which may contaminate blood and blood products or fractions and which presents a serious risk is the bacteria Yersinia enterocolitica. It su ⁇ asses Shigella and rivals Salmonella and Campylobacter /as a cause of acute bacterial gastroenteritis. A significant increase in transfusion related infections of Y. enterocolitica has been reported, Tipple, et al., Transfusion 30, 3, p.207 (1990). Y. enterocolitica and other bacteria which propagate at relatively low temperatures, e.g. Staphylococcus epidermis and Legionella pneumonophilia, present, potentially, a serious threat in blood products. Bacterial infections are a continuing concern to blood banking industry.
  • viruses e.g. hepatitis virus
  • Some viruses are detected in the urine of infected individuals. A risk of infection of technicians begins with the collection of the sample and continues until the sample is disposed of or treated to kill the virus. This risk is virtually eliminated by the present invention.
  • this invention is applicable to the treatment of donated blood and products produced from blood, tissues and fluids for inactivating virus, bacteria, chlamydia, rickettsia, mycoplasma and other potentially pathogenic microorganisms.
  • CMV cytomegalovirus
  • CMV infection is a serious limiting factor in the transplantation of organs, tissues and cells and the transfusion of blood and plasma from one individual to another.
  • the kidney transplant patient runs a high risk of contracting serious, and not infrequently fatal, CMV infection from CMV introduced by the transplant organ.
  • Recipients of whole blood, plasma, bone marrow, cornea, cardiac, and semen run a serious risk of CMV infectious disease, the risk being multiplied where the immune system of the recipient is suppressed to prevent rejection of the foreign organ or cells, or where immunosuppression is present from natural causes.
  • He ⁇ esviruses represent a very large group of viruses which are responsible for, or involved in, cold sores, shingles, a venereal disease, mononucleosis, eye infections, birth defects and probably several cancers.
  • the alpha subfamily includes HV 1 (he ⁇ es virus simplex 1) which causes cold sores, fever blisters, eye and brain infections, HV 2 (he ⁇ es virus simplex 2) which cause genital ulceration, and HV 3 (HV varicella zoster) which causes chicken pox, shingles and brain infections.
  • HV 1 he ⁇ es virus simplex 1
  • HV 2 he ⁇ es virus simplex 2
  • HV 3 HV varicella zoster
  • the gamma subfamily includes HV 4 (Epstein-Barr) which cause infectious mononucleosis and is involved in Burkitt's lymphoma and nasopharyngeal carcinoma.
  • My United States Patent 4,891 ,221 describes and ' claims a method for inactivating virus in blood samples using glycyrrhizic trite ⁇ enoid compounds. While the use of glycyrrhizic trite ⁇ enoid compounds in blood product treatment is a major step forward, there remains a need for a method of treatment which would kill or inactivate all or nearly all pathogenic organisms, including those in the cells of the blood or blood products.
  • tissue culture If a tissue is explanted into the culture media for the pu ⁇ ose of propagating its cells, the procedure is called tissue culture whereas the explanting of individual cells into culture media would be called cell culture; however, both procedures are often referred to by the term "tissue culture” procedures without differentiation, unless the distinction is critical for some ancillary reason. This general usage of the term is employed here. Tissue cultured cells are extremely fragile in many ways, having exacting requirements not only as to nutrients but also to the amount and type of resident organisms which can be tolerated, and culture media are highly susceptible to bacterial and/or viral infection.
  • viruses in both animals and humans, may be transmitted by artificial insemination using sperm from infected individuals.
  • Bovine leucosis (Mateva, V. et al, Monatsh. Veterinaermed. 1987, 42(9) 310) and bovine rhinotracheitis virus are transmitted by sperm of infected bulls. (Kupfer- schmied, H. U., et al Theriogenology 1986, 25(3) 439).
  • Singh, EX. ((10th Int. Cong, on Animal Repr. and Artificial Insemination, Cong. Proc. V. I - IV, 1984) concluded that some viruses, e.g.
  • BTV bluetongue virus
  • IBRV infectious bovine rhinotracheitis virus
  • BVDV bovine viral diarrhea virus
  • FMDV foot and mouth virus
  • AV akabane virus
  • BBV bovine parvovirus
  • HBV DNA was been found in spermatozoa by Hadchouel et al who concluded that hepatitis B virus could be transmitted by true vertical transmis ⁇ sion of HBV via the germ line (Hadchouel, M. et al J. Med. Virol. 1985, 16(1) 61) and Ayoola. E.A., et al (Int. J. Gynaecol. Obstet. 1980, 18(3) 185) concluded that the hepatitis B virus could be transmitted by sexual intercourse via HBV in semen or sperm of the male. Since cytomegalovirus (CMV) infections may alter host defense to a variety of pathogens (Miller, S.A. , et al, (Infect, lmmun 1985, 47(1) 605), it is doubly important to avoid introduction of CMV with a transplanted organ or tissue or with sperm cells as the result of artificial insemination.
  • CMV cytomegalovirus
  • sperm both human and animal
  • sperm is quarantined for several months and the donor's health is followed to assure that the donor is not infected with a pathogenic microbe.
  • the donor may carry the disease-causing organism for months or years without showing any symptoms of the disease. It would be an important step forward to be able to inactivate or destroy pathogenic microbes to prevent infection of the artificial insemination recipient. It is, generally, impossible to define with precision the exact materials required to propagate a given cell line and, therefore, it is common practice to use media based upon or containing serum and to add nutrient serum as needed during the cell propagation.
  • Bovine serum from adult animals may be suitable in some instances, but fetal bovine serum (FBS) (sometimes referred to as fetal calf serum (FCS)) is required for the safe propagation of many cell lines, and where high purity is critical. Even the use of FBS is not, however, a guarantee of freedom from infective agents. Indeed, every lot of commercially produced FBS is contaminated with infectious bovine viral diarrhea (BVD) virus and infections with infectious bovine rhinotracheitis (IBR), parainfluenza 3 (PI 3) are extremely common. At best, pools of raw serum probably contain at least 10 4 infectious BVD virus particles per milliliter.
  • FBS fetal bovine serum
  • FCS fetal calf serum
  • Serum filtration is a common step in reducing the load of infectious organisms in serum, but serum quality can be damaged by filtration if significant amounts of serum components are adsorbed to the filters or if macromolecules are sheared. Shearing of macromolecules during filtration occurs generally when tangential flow filtration is used and turbulence develops. It is currently very difficult to obtain reliable results on the removal of BVD viruses from serum using filtration.
  • Blood plasma is used in the production of many important blood fractions, components and products.
  • Transfusion plasma per se, is frequently prepared as a single blood bag product; however, many plasma fractions and products are produced from large pools of plasma.
  • Pyrogen production could be eliminated or substantially reduced if pyrogen producing organisms were killed early in the process, e.g. in the initial whole blood or in the pooled plasma.
  • Virus infections among the most serious being hepatitis, present a constant and serious risk to both handlers and recipients of blood and blood products. It has been shown that fractionation workers, particularly those engaged in the preparation of plasma pools, are at high risk of developing hepatitis B.
  • the high risk products are fibrinogen, AHF, and prothrombin complex.
  • the low risk products are ISG, PPF, and albumin. The lack of infectivity of PPF and albumin is attributable to heating the final products at 60°C. for 10 hours; however, such process steps tend to denature certain products and are unsuitable in the preparation of heat sensitive products.
  • Other diseases which can be transmitted from the donor(s) to the patient(s) include the numerous diseases in which the causative pathogen appears in viable form, at least during one stage of development, in the blood, fluids or tissues of the donor.
  • the risk can be reduced by screening potential donors and refusing to accept blood, tissue or fluids for transfer to patients; however, the availability of blood, blood fractions and products, tissues and fluids could be very greatly increased and the cost thereof greatly decreased if all potential donors could be accepted followed by killing all potential pathogens in the donated blood, fluid or tissue.
  • iodine iodophors
  • PVP poly(vinyl- pyrrolidone)
  • 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.
  • membranes e.g. vaginal membranes
  • the uses continue to be largely medicinal, though some iodophors are used in industrial sanitation and disinfection in hospitals, building maintenance, and food-processing operations.
  • iodine There has been some interest in the use of iodine for purification of potable water and swimming pools.
  • 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 adso ⁇ tion. 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 an ti -bacterial properties.
  • PVP polyvinyl pyrrolidone
  • povidone USP polyvinyl pyrrolidone
  • PVP-iodine polyvinyl pyrrolidone
  • BetadineTM and IsodineTM Such products are marketed as BetadineTM and IsodineTM.
  • 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 Co ⁇ oration and in a number of GAF Co ⁇ oration publications; see, e.g.
  • Povidone-iodine powder contains approximately 85% PVP, 10 % I 2 and 5%Iodide. A 10% solution of this powder contains 1 % free, available iodine. (Gershenfeld, Am. J. Surgery 94, 938 (1957)). Under ordinary conditions, PVP is stable as a solid and in solution.
  • PVP polystyrene-maleic anhydride
  • binding capability This property has permitted utilization in numerous commercial applications.
  • Small quantities of PVP stabilize aqueous emulsions (qv) and suspensions, apparently by its abso ⁇ tion 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.
  • 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 contami- nated with liquid substrata (e.g.
  • povidone-iodine was absorbed in serum albumin and it is known that povidone-iodine is bound to albumin but it has been discovered that the antimicrobial activity of povidone-iodine is not destroyed by albumin binding. Whether the activity remains because the albumin povidone-iodine is active or whether povidone- iodine and/or iodine are released from the albumin-povidone-iodine complex has not been determined.
  • povidone-iodine as a spermicide is known and one would not consider povidone-iodine as a candidate for killing pathogenic microbes in sperm-carrying liquids.
  • This invention is embodied in, inter alia, a method of testing body fluids wherein body fluids are collected from a donor human or animal into a container and thereafter subjected to testing to determine physical, chemical or biological characteristics of such fluids or constituents thereof.
  • This is an improvement in the collection of such fluids to prevent the transmission of disease.
  • the improvement comprises removing a sample of body fluid from the donor, mixing the body fluid sample substantially at the time the sample is taken with molecular iodine compound in a concentration of from about 0.1 to 5 w /o (100 to 5,000 ppm I 2 ) and allowing contact with said molecular iodine compound for at least two minutes sufficient to inactivate or destroy infective pathogenic microorganisms and thereafter subjecting the sample to testing.
  • the molecular iodine compound is preferably povidone-iodine.
  • the vacuum tube comprises a sampling tube, means for directing a sample of body fluid into the sampling tube, and molecular iodine compound in the sampling tube in sufficient amount to inactivate or destroy infective pathogenic microorganisms.
  • This invention is embodied in, inter alia, a method of treating patients with blood cell concentrates comprising the steps of collecting blood from a donor, concentrating selected blood cells, and thereafter infusing the blood cells into the patient to be treated.
  • the improvement of this invention comprises the additional steps of mixing the blood cells with molecular iodine compound in a concentration of from about 0. l w /o to about 2 w /o (100 to 2000 ppm I 2 ) and allowing contact of said blood with said molecular iodine compound for at least two minutes sufficient to inactivate or destroy infective pathogenic microbes.
  • the molecular iodine compound is preferably povidone- iodine and, preferably, the step of mixing of the blood with povidone-iodine may be carried out in sub-steps.
  • the sub-steps are, first, introducing povidone-iodine into the blood in a concentration of from about 0. l w /o to about 2 w /o (100 to 2000 ppm I 2 ); second, maintaining the blood in contact with the povidone-iodine for a period of about one to two minutes; and, third, again introducing povidone-iodine into the blood in a concentration of from about 0. r/o to about 2 * /o (100 to 2000 ppm I 2 ).
  • This invention is embodied in, inter alia, a method of treating patients with blood comprising the steps of collecting blood from a donor, and thereafter infusing the blood into the patient to be treated.
  • the improvement of this invention comprises the additional steps of mixing the blood with molecular iodine compound in a concentration of from about 0. l w /o to about 57o (100 to 5000 ppm I 2 ), preferably 0.57o to 27o (500 to 2000 ppm I 2 ), and allowing contact of said blood with said molecular iodine compound for at least two minutes sufficient to inactivate or destroy infective pathogenic microbes.
  • the mixing of the blood cells with povidone-iodine may be carried out in sub- steps, namely, first, introducing povidone-iodine into the blood cells in a concentration of from about O. PVo to about 57o (100 to 5000 ppm I 2 ) preferably 0.5 o to 27o (500 to 2000 ppm I 2 ); second, maintaining the blood cells in contact with the povidone-iodine for a period of about one to two minutes; and, third, again introducing povidone-iodine into the blood cells in a concentration of from about 0.1 w /o to about 27o (100 to 2000 ppm I 2 ).
  • This invention is embodied in, inter alia, in an improvement in the treatment of patients using transplant tissue wherein a tissue is collected from a donor, washed and thereafter implanted into the patient under treatment.
  • the improvement comprises infusing said transplant tissue with a solution comprising molecular iodine compound in a concentration of from about 0. l w /o to about 17o (100 to 1000 ppm I 2 ) and allowing contact of said tissue with said molecular iodine compound for at least two minutes sufficient to inactivate or destroy infective pathogenic microorganisms.
  • This invention is embodied in, inter alia, in a method for the induction of pregnancy into a female comprising the steps of collecting sperm cells from a donor, washing the sperm cells and thereafter inseminating the sperm cells into the uterus of the female.
  • the improvement comprises the steps of washing the sperm cells in a solution of povidone-iodine in aqueous solution, e.g. buffer, in a concentration of from about 0.17o to about 17o (100 to 1000 ppm I 2 ) sufficient to kill bacteria, viruses and other pathogenic micro ⁇ organisms but insufficient to inactivate the sperm cells.
  • This invention is embodied in, inter alia, a method of controlling a cell line comprising adding povidone-iodine to the cell line nutrient in a concentra- tion of from about O. PVo to about 17o (100 to 1000 ppm I 2 ) based on the nutrient sufficient to arrest or inhibit the propagation of the cell line but insufficient to kill the cells of the cell line and harvesting the composition of interest after such composition has been expressed by the cell line.
  • This invention may also be embodied in a method of preserving blood cells comprising adding povidone-iodine to the cell-containing milieu in a concentration of from about O. PVo to about 17o (100 to 1000 ppm I 2 ) sufficient to arrest or inhibit the principal metabolic functions of the blood cells but insufficient to kill the blood cells.
  • This invention is embodied in, inter alia, a method of purifying liquid or cell-bearing liquid comprising contacting the liquid to be purified into contact with solid povidone-iodine having sufficient surface area to expose the liquid to sufficient iodine on such surface to kill pathogenic organisms therein, and removing the liquid from contact with the solid povidone-iodine.
  • the method may further comprise reacting the surface of the solid povidone-iodine with iodine between uses to regenerate the iodine content thereof.
  • This invention is embodied in, inter alia, a method of treating a patient which comprises the step of collecting a transplant or transfusion biological material from another human or animal, preserving the biological material, thawing the biological material and transfusing or transplanting the biological material into the patient.
  • the step of preserving the biological material comprises disinfecting the transplant or transfusion biological material in a solution of from about O. P/o to about 17o povidone-iodine (100 to 1000 ppm I 2 ) and maintaining the biological material under refrigeration emersed in a solution of povidone.
  • the biological material may be frozen for preservation in a solution of povidone.
  • This invention is embodied in, inter alia, a method of disinfecting blood derivatives comprising treating blood (using the term in the broad sense to include blood derivatives) before separation of the components thereof with povidone-iodine to provide from about 0. P/o to about 27o povidone-iodine (100 to 2000 ppm I 2 ) in the blood, preparing a derivative of the blood from the preceding step and treating the derivative from the next preceding step to provide from about 0. P ' /o to about 27o (100 to 2000 ppm I 2 ) povidone-iodine in the derivative.
  • This invention is embodied in, inter alia, a drug delivery material comprising blood cell concentrate wherein the cell walls of the cells have been opened by treatment with from about 1 to about 57o povidone-iodine, a drug has been introduced into the cells through passages produced by the povidone- iodine treatment, and the cell walls have been sealed by heating the cells to from about 42 to about 48 °C.
  • Povidone has been found to possess a sufficient cytophylactic effect upon blood cells, e.g., red blood cells, and upon other cells and tissues to protect cells and tissues from the cytolytic effect of iodine when the ratio of PVP to I 2 is sufficiently high, e.g. about 12: 1 , preferably at least about 15: 1 ,
  • povidone to iodine ratios are from about 15: 1 to 30: 1 , but ratios as high as 60: 1 are considered suitable. Higher ratios may be used but are of no greater advantage.
  • Povidone has been found to possess a significant virucidal effect without iodine accomplishing a kill of virus of from 2 to 5 logs.
  • Povidone has been found to cause a more rapid sedimentation of cells from liquid and to result in a better separation and differentiation of the cells.
  • povidone-I 2 compounds can be used to protect and preserve blood and blood-derived products which are used in diagnostic tests without altering the test results, with the single exception of an increase in iodine.
  • Whole blood which is to be transfused as whole blood or from which transfusable blood products are produced are treated with molecular iodine, e.g. povidone-iodine, in one or plural povidone-iodine treatment steps to inactivate or destroy infective pathogenic microorganisms.
  • this invention relates to the treatment of blood cell concentrates to inactivate or destroy infective extracellular and intracellular pathogenic microorganisms with molecular iodine, preferably absorbed by or in complex with an organic stabilizer such as povidone.
  • Plasma in single bags or in pools, is treated to kill potential pathogenic organisms and organisms which, if not killed early in the chain of processing, introduce pyrogens into plasma and blood product.
  • the invention comprises the plural-step addition of molecular iodine, preferably in the form of povidone-iodine, to whole blood initially or specific blood derivatives.
  • the initial addition of povidone-iodine inactivates pathogens and pyrogen-causing organisms which are readily available in the serum and some cell-attached organisms.
  • a significant portion of the first step povidone-iodine addition becomes bound to albumin and cell membranes and is not fully efficacious in the instant kill of microbes.
  • the first povidone-iodine addition is, however, biostatic, i.e. it prevents the multiplica ⁇ tion of microbes.
  • the first povidone-iodine also renders the residual microbes more susceptible to the microbicidal effects of iodine. The integrity of the cellular components of blood is protected by the known cell-stabilizing effect of PVP.
  • povidone-iodine additions is very highly effective in killing microbes which survive the first step addition of povidone- iodine and has even less tendency to cell-attack, e.g. inducement of hemolysis, than would be the case if the entire load of povidone-iodine were added at one time. If, however, time is an important factor, povidone-iodine having a higher than the normal 2: 1 ratio of povidone to iodine may be added at a sufficiently high level, about one percent, to whole blood to effect a complete kill of microbes in both the sera and cellular components of blood with minimal hemolysis and without significant detrimental effect on the oxygen- carrying capacity of the red blood cells.
  • molecular iodine e.g. povidone-iodine
  • concentrations of above about 0.5 weight percent (7o) (500 ppm I, ) povidone-iodine, e.g. generally from about 0.87o to about 27o, (800 to 2,000 ppm I 2 ) are required to effect a complete kill of microbes in whole blood.
  • povidone-iodine (100 to 1000 ppm I 2 ) are sufficient to eliminate viable microbes from plasma, serum and other blood derivatives.
  • Two-step additions of povidone-iodine may be preferred, the ratio of the first step addition to the second step addition being from about 1 : 1 to 3: 1.
  • a first addition of 0.67o povidone- iodine (600 ppm I 2 ) followed by a second addition, a few minutes or more later, of 0.27o (200 ppm I 2 ) povidone-iodine is preferred over a single addition of 1 o povidone-iodine.
  • Cell concentrates may be washed with and/or stored in povidone-iodine solutions of from about 0. P/o to about 17o (100 to 1000 ppm I 2 ).
  • Body tissues and cells are washed with and/or stored, with or without freezing, with povidone-iodine. Renal, cardiac, cornea, and marrow tissue, and any other tissue intended for transplantation are washed to kill infective pathogenic microorganisms.
  • Povidone-iodine concentrations of from about 0.1 o to about 17o (100 to 1000 ppm I 2 ) generally are suitable for washing and/or for storage. Povidone to iodine ratios of 15: 1 or higher may be preferred.
  • Complete organs, e.g. kidneys, etc. may be treated according to this invention. Certain organs, e.g. ground bone, are sometimes comminuted used to promote healing and reconstruction in various surgical procedures.
  • Individual cells such as sperm cells may be treated to kill pathogenic microbes with tolerable or no impact upon the viability and motility of the cells.
  • Such tissues are prepared, by treatment with povidone-iodine solutions at one or more stages.
  • the organ may, for example, be placed, upon removal, in a solution of from about 0.17o to about 17o, or higher, povidone-iodine and/or treated at a later stage, e.g. during comminu ⁇ tion or other processing, or immediately before use with povidone-iodine.
  • an organic stabilizer e.g. povidone-iodine.
  • povidone-iodine solutions serve to preserve the tissue, organ or cells during storage above freezing, usually at about 4 °C, or during freezing, frozen storage and thawing.
  • the povidone- iodine treatment may be one-step or involve plural contact with povidone- iodine, such as immediately upon collection or acquisition, and/or during treatment and preparation, and/or just before use.
  • Biological cells, tissues and fluids from animal or human donors are used in a virtually infinite variety of laboratory tests as controls or standards or in reagents. It is important to protect the technicians who prepare and use these materials from infection from pathogenic microbes contained in these biological materials. It is, of course, of great importance that the biological and biochemical characteristics of importance in the ultimate product be protected during processing to maintain the integrity of the ultimate test. Povidone-iodine additions to the biological material at the time of collection, typically in a concentration of from about 0.17o to about 17o protects works through the entire chain of handling.
  • povidone-iodine added to blood or red blood cell concentrates in a concentration range of from about 0. l w /o to about 17o effectively kills all pathogenic organisms and not only protects the specific binding determinants on the red blood cells but actually enhances the antigenic reactivity of the cells.
  • FIG. 2 depicts an alternative form of the vacuum tube of this invention.
  • Samples of blood, tissue and body fluids are, preferably, treated with povidone-iodine at the time the sample is taken or shortly thereafter to inactivate or destroy infective pathogenic microorganisms.
  • Body fluids generally, e.g. Urine
  • the risk of contracting AIDS and other microbial infections from urine samples, serum, peritoneal fluid, etc., is virtually eliminated by collecting the liquid sample into a povidone-iodine- containing solution or adding povidone-iodine, in a concentration of from about O. P/o to about 17o, (100 to 1000 ppm I 2 ) at the time of collection.
  • Blood and blood derivatives - Samples for Testing Blood collection is conventionally carried out using a variety of containers and devices. Exemplary are the various types of devices known in the industry as "vacuum tubes" which comprise an invasive needle which is inserted into the vein, or other fluid containing body structure, a test tube for collecting the sample, and a syringe-like sealing device for causing a vacuum to form inside the test tube when the test tube is moved relative to the sealing device.
  • the interior of the test tube is in fluid communication, through the needle, with the vein or fluid containing body structure, thereby causing the blood or fluid to flow into the test tube for further handling and testing.
  • the test tube contains a predetermined amount of a molecular iodine compound.
  • FIG. 1 depicts a vacuum tube blood sampling apparatus modified to embody the present invention.
  • the vacuum tube 10 is provided with a sealing septum 12 which maintains a vacuum in the tube, as is conventional and well known.
  • a molecular iodine reagent is also included in the vacuum tube as indicated at 14.
  • the molecular iodine reagent is depicted as a crystal or powder which will dissolve in the blood sample; however, the compound may be a liquid or solution.
  • This invention is, thus embodied in a sampling vacuum tube which comprises a chamber for receiving the blood, a septum for receiving and sealing around a needle, the septum sealing the chamber and maintaining the chamber under a reduced pressure, i.e. vacuum, and a molecular iodine compound.
  • the vacuum tube modified to embody ' the invention as described is used in conventional manner.
  • the needle assembly 20 which is conventionally received in sleeves protecting ends of the needle 22 maintaining sterility and protecting the user from injury, is screwed into the holder cylinder 40, the threaded portion on sleeve 24 being threadably received in the internally threaded passage 26 in the holder 40.
  • the vacuum tube is moved, as shown by the arrow, such that the septum 12 receives, is punctured by and seals around the needle 22, pushing the resilient sleeve 30 off the end of the needle.
  • This operation which is conventional, is done after the distal end of the needle 22, shown at the left in the figures, is inserted in the patient's blood vessel.
  • the vacuum in the tube draws the sample of blood and the vacuum tube is removed, allowing the sleeve 30 to re cover the proximal end of needle 22. This may be repeated with as many vacuum tubes as desired for multiple sampling.
  • the vacuum tube comprises a gel plug 200 formed of a hydrophilic polymer such as hydroxyethylmethacrylate, methoxy- methylmethacrylate, carboxymethyl cellulose, agar, etc.
  • a hydrophilic polymer such as hydroxyethylmethacrylate, methoxy- methylmethacrylate, carboxymethyl cellulose, agar, etc.
  • This operation may be carried out using the vacuum tube of this invention in the conventional manner after which the blood sample is thoroughly mixed with the molecular iodine compound in the sampling tube.
  • molecular iodine compound e.g. PVP I 2
  • Infective pathogenic microorganisms are inactivated when molecular iodine compound is added to whole blood in a concentration of from about 0.5 w /o to about 57o (500 to 5000 ppm I 2 ). The preferred range is from about 0.57o to 27o (500 to 2000 ppm I 2 ).
  • Such blood can be used as whole transfusion blood or fractionated to produce an entire family of blood products which are free of pathogenic microorganisms.
  • the povidone-iodine may be in the blood collection bag at the time the blood is collected .but, preferably, is the preservative additive solution 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 povidone-iodine necessary to result in a concentration of iodine in the blood of about 0.5 w /o to about 57o is provided in the solution bag.
  • the povidone-iodine ratio differs very substantially from the standard ratio of about 8.5: 1 povidone to iodine and is preferably at least about 12: 1 and preferably from about 15: 1 to 60: 1 povidone to iodine.
  • Blood cell concentrates may, likewise, be treated with a molecular iodine compound to kill pathogenic microbes. Blood cells may, of course, be treated as part of whole blood in the manner described above.
  • povidone-iodine in a concentration range of from about 0. P/o to about 57o .
  • the application of from about 0.57o to about 27o iodine as povidone-iodine results in a total kill of bacteria and virus in packed cells and blood clots.
  • the cells may be washed and then treated with the molecular iodine compound or washed in a solution containing the molecular iodine compound.
  • 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.
  • a povidone to iodine ratio of from about 15: 1 to 60: 1 is preferred.
  • Red Blood Cell Concentrates It is advantageous to treat the red blood cells with a solution of povidone-iodine in which the povidone: iodine ratio is at least about 15: 1. It has been found that this povidone: iodine ratio there is negligible lysis.
  • the oxygen-carrying capacity of the red blood cells is preserved by treatment of the cells, alone or as part of blood, with the povidone-iodine solution. Following treatment, the cells may, if desired, be washed to remove excess molecular iodine compound from the cell milieu; however, residual iodine and povidone are well tolerated and, ordinarily, need not be removed.
  • Povidone-iodine is an effective preservative solution, used as described above, for red blood cell preparations used as laboratory standards or panels in blood banking. It has been discovered that treatment of red blood cells with povidone-iodine as described does not alter the red blood cell antigen specificity and actually increase the reactivity of these antigens which are on the red blood cell surface to antibody binding.
  • Tables I and II demonstrate that PVP, alone, has viricidal activity and that povidone-iodine is effective in killing virus in whole blood and in cell concentrates.
  • C-15 is polyvinyl pyrrolidone having a molecular weight of 12,500 produced by GAF Co ⁇ oration.
  • PVP-I povidone-iodine powder produced by Purdue-Frederick Company which contains approximately 85% PVP, 10 % I, and 5%Iodide.
  • C-30 is polyvinyl pyrrolidone produced by GAF Corporation having a molecular weight of 50,000.
  • K-26-28 is polyvinyl pyrrolidone produced by GAF Co ⁇ oration having a molecular weight of between 40,000 and 50,000. 1 % PVP K-26-28 + 0.10% PVP-I 4.5 6.5
  • red blood cells with from one to about five percent iodine as povidone-iodine opens the cells to "inward leaking".
  • compounds which have a virucidal or other effect in the cell can be introduced into the cell.
  • Povidone-iodine can, for example, be used as described to increase the uptake of GTPD compounds which, in turn, prevent the replication of virus in the cell. The net effect of this procedure is a biological synergism.
  • a new drug delivery system involves the use of povidone-iodine to open pathways through the cell wall of red blood cells.
  • Red blood cell concentrates are treated as described to open passageways into the cell.
  • the then permeable cell is emersed in or treated with a drug which is to be delivered to the patient.
  • the cell walls having passages therethrough permit the drug to enter into the cell.
  • the iodine may be removed and the cell concentrate is heated to 42 - 48 °C to seal the cell walls.
  • the concentrated cells are then infused into the patient where they carry out the normal function of such cells. These cells have a finite life. As the cells age, they lyse, thereby releasing the drug directly into the blood stream where the drug can become effective.
  • polyvinyl pyrrolidone alone, in the course of studying the present invention. It was discovered that polyvinyl pyrrolidone alone was capable of killing about 2 to 5 logs of virus in body fluids. Whether or not there is a synergism vis-a-vis this anti-viricidal activity and the activity of iodine has not yet been determined.
  • Povidone-iodine is cross-linked to the hemoglobin to produce a hemoglobin product which as a greatly increased life as an oxygen carrier when introduced into the blood circulation system.
  • Povidone-iodine- hemoglobin complex in water or saline solution thus, constitutes a blood substitute which can be stored with minimal risk of microbial contamination and used as a blood extender in emergency situations such as may be found on the battlefield or in remote areas.
  • Ratios of povidone-iodine to hemoglobin of from about 0.1 : 1.0 to about 1.0:0.1 are considered satisfactory, povidone- iodine in which the povidone: iodine ratio is at least as high as 4: 1 may be preferred.
  • povidone-iodine binds very strongly to hemoglobin allows for the development of a blood substitute.
  • the prior art teaches the binding of PVP to hemoglobin by a variety of reagents. According to this invention, however, it has been discovered that iodine produces the binding of PVP to hemoglobin and, additionally, sterilizes the blood substitute assuring the absence of viable pathogenic organisms.
  • Transplant Organs Infective pathogenic microorganisms are inactivated when molecular iodine compound is used in solution to perfuse tissues and organs after removal from the donor and before transplantation to the recipient.
  • the perfusion solution contains molecular iodine compound in a concentration of from about 0. P/o to about 57o (100 to 5000 ppm I 2 ), preferably from about 0.257o to about 27o. After a period of time, most of the unreacted molecular iodine compound is washed away and any residual molecular iodine compound is absorbed into the protein or converted to inactive iodides and does not significantly interfere with acceptance by the recipient.
  • Spermsperm-bearing solutions can be freed of pathogenic microbes by washing and/or storing the sperm in a solution which contains a concentra- tion of povidone-iodine in a concentration is from about 0. P/o to about 17o, (100 to 1000 ppm I 2 ) and, preferably, wherein polyvinyl pyrrolidone is added to give a polyvinyl pyrrolidone to iodine ratio is at least about 30 to about 1, the iodine concentration being sufficient to inactivate bacteria, viruses and other pathogenic organisms, and washing the sperm cells in the solution.
  • polyvinyl pyrrolidone protects the sperm cells from the spermicidal activity of iodine sufficient to permit the killing of pathogenic organisms while leaving viable, motile sperm cells suitable for artificial insemination.
  • the washing is continued or repeated to assure that substantially all of the seminal fluid is replaced with povidone-iodine solution.
  • Other reagents such as are conventionally used in sperm treatment, storage and preparation, or for particular pu ⁇ oses may, of course, also be included in the infusion solution. If desired, residual iodine may be washed out and any suitable storage fluid, including solutions of polyvinyl pyrrolidone, may be used to store and handle the sperm cells.
  • the invention also contemplates a composition of matter consisting essentially of povidone and iodine wherein the ratio of povidone to iodine is from 15 to 60 parts of povidone to 1 part of iodine.
  • Such compositions of matter may be powdered povidone-iodine with an increased amount of povidone or solutions of the same.
  • Solid Povidone-iodine Solid Povidone-iodine.
  • the above applications in which the material to be purified is a liquid or cells carried in a liquid can be carried out by flowing the liquid through a bed of solid particles of povidone-iodine of suitable size or by contacting the liquid and/or the cells in the liquid with particles or a membrane or surface of solid povidone-iodine.
  • a bed of particles is used with a cell-bearing liquid, 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 10 K daltons to 40
  • 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 iodine to form solid, substantially water insoluble povidone-iodine compositions that the present invention is directed.
  • the liquid or cell-bearing liquid is contacted with the solid povidone-iodine.
  • This may be done most efficiently, in most cases, by passing the liquid through a settled or fluidized or packed bed of povidone-iodine particles; however, such approaches will not, ordinarily, be suitable for treating cell-bearing liquids.
  • Cell-bearing liquids may be treated 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 iodine content therein regenerated between uses.
  • This invention finds application in medicine and veterinary science.

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Abstract

L'invention décrit le traitement et la préservation de sang, de dérivés sanguins et autres tissus, fluides ou cellules corporels au moyen de polyvidone iodé pour tuer les microbes pathogènes sans détruire l'efficacité des tissus, des fluides et des cellules.
PCT/US1991/006240 1990-09-04 1991-09-03 Preservation de sang, de tissus et de fluides biologiques WO1992004031A1 (fr)

Priority Applications (1)

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NO92921756A NO921756L (no) 1990-09-04 1992-05-04 Konservering av blod, vev og biologiske fluider

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US57720490A 1990-09-04 1990-09-04
US577,204 1990-09-04

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WO1992004031A1 true WO1992004031A1 (fr) 1992-03-19

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EP0559856A1 (fr) * 1991-09-03 1993-09-15 Edward Shanbrom Conservation antimicrobienne de plaquettes et de facteurs sanguins
EP0614368A4 (fr) * 1992-05-04 1994-04-12 Edward Shanbrom Sang de transfusion humain sans danger.
EP0605690A1 (fr) * 1992-06-29 1994-07-13 Edward Shanbrom Conservation de sang, de tissus et de fluides biologiques dans du peroxyde d'hydrogene et du povidone
EP0605704A1 (fr) * 1992-06-29 1994-07-13 Edward Shanbrom Conservation du sang, de tissus et de fluides biologiques au moyen de peroxyde de complexe amidon-iode
EP0619722A1 (fr) * 1991-12-31 1994-10-19 Osteotech, Inc., Preparation d'os destine a la transplantation
US5513662A (en) * 1991-12-31 1996-05-07 Osteotech, Inc. Preparation of bone for transplantation
US5591350A (en) * 1994-04-15 1997-01-07 Pall Corporation Iodine disinfection method using a gaseous iodine treated porous medium
US5741894A (en) * 1995-09-22 1998-04-21 Baxter International, Inc. Preparation of pharmaceutical grade hemoglobins by heat treatment in partially oxygenated form
EP0915648A4 (fr) * 1995-08-29 1999-05-19
US6083408A (en) * 1993-12-17 2000-07-04 Basf Aktiengesellschaft And Schenk Filterbau Gmbh Depth-type filter for killing microorganisms and inactivating viruses which comprises a fibrous material and crospovidone-iodine and its use
US6093564A (en) * 1997-10-03 2000-07-25 V.I. Technologies, Inc. Methods and compositions for the selective modification of nucleic acids
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
US6171583B1 (en) 1995-11-29 2001-01-09 Basf Aktiengesellschaft Powdery iodine complexes
US6352695B1 (en) 1997-10-03 2002-03-05 V.I. Technologies, Inc. Methods and compositions for the selective modification of nucleic acids
US6403359B1 (en) 1998-09-25 2002-06-11 V. I. TECHNOLOGIES, Inc. Solid phase quenching systems
WO2002034293A3 (fr) * 2000-10-23 2003-03-13 Shanbrom Tech Llc Activateurs de desinfection microbiologique et d'apoptose ciblee
US6617100B2 (en) 1998-09-25 2003-09-09 V.I. Technologies, Inc. Solid phase quenching systems
EP1856973A1 (fr) * 2005-03-04 2007-11-21 National Universiy Corporation Tokyo Medical and Dental University Solution destinee a maintenir et a ameliorer la fonction d un organe
WO2008125884A2 (fr) * 2007-04-16 2008-10-23 Safemed Limited Composition de conservation
WO2019073071A1 (fr) 2017-10-13 2019-04-18 Biodesiv Efnium Polymere antimicrobien pour semences animales
CN109938008A (zh) * 2019-03-20 2019-06-28 上海创宏生物科技有限公司 一种动物精液处理剂及其应用方法

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JP5379192B2 (ja) * 2011-07-01 2013-12-25 エヌディー パートナーズ，リミティド ライアビリティー カンパニー 殺生物剤ロック

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EP0559856A4 (en) * 1991-09-03 1993-11-10 Edward Shanbrom Antimicrobial preservation of platelets and blood factors
EP0559856A1 (fr) * 1991-09-03 1993-09-15 Edward Shanbrom Conservation antimicrobienne de plaquettes et de facteurs sanguins
EP0619722A1 (fr) * 1991-12-31 1994-10-19 Osteotech, Inc., Preparation d'os destine a la transplantation
US5513662A (en) * 1991-12-31 1996-05-07 Osteotech, Inc. Preparation of bone for transplantation
EP0619722A4 (fr) * 1991-12-31 1994-12-21 Cryolife Inc Preparation d'os destine a la transplantation.
EP0614368A1 (fr) * 1992-05-04 1994-09-14 Edward Shanbrom Sang de transfusion humain sans danger
EP0614368A4 (fr) * 1992-05-04 1994-04-12 Edward Shanbrom Sang de transfusion humain sans danger.
EP0605690A1 (fr) * 1992-06-29 1994-07-13 Edward Shanbrom Conservation de sang, de tissus et de fluides biologiques dans du peroxyde d'hydrogene et du povidone
EP0605690A4 (fr) * 1992-06-29 1994-12-07 Edward Shanbrom Conservation de sang, de tissus et de fluides biologiques dans du peroxyde d'hydrogene et du povidone.
EP0605704A1 (fr) * 1992-06-29 1994-07-13 Edward Shanbrom Conservation du sang, de tissus et de fluides biologiques au moyen de peroxyde de complexe amidon-iode
EP0605704A4 (fr) * 1992-06-29 1994-11-17 Edward Shanbrom Conservation du sang, de tissus et de fluides biologiques au moyen de peroxyde de complexe amidon-iode.
US6083408A (en) * 1993-12-17 2000-07-04 Basf Aktiengesellschaft And Schenk Filterbau Gmbh Depth-type filter for killing microorganisms and inactivating viruses which comprises a fibrous material and crospovidone-iodine and its use
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
EP0915648A1 (fr) * 1995-08-29 1999-05-19 Pentose Pharmaceuticals, Inc. Procedes et compositions de modification selective d'acides nucleiques
EP0915648A4 (fr) * 1995-08-29 1999-05-19
US6114108A (en) * 1995-08-29 2000-09-05 V.I. Technologies, Inc. Methods and compositions for the selective modification of viral nucleic acids
EP1129728A1 (fr) * 1995-08-29 2001-09-05 V.I. Technologies, Inc. Procédés et compositions de modification sélective d' acides nucléiques
US5741894A (en) * 1995-09-22 1998-04-21 Baxter International, Inc. Preparation of pharmaceutical grade hemoglobins by heat treatment in partially oxygenated form
US6171583B1 (en) 1995-11-29 2001-01-09 Basf Aktiengesellschaft Powdery iodine complexes
US6093564A (en) * 1997-10-03 2000-07-25 V.I. Technologies, Inc. Methods and compositions for the selective modification of nucleic acids
US6617157B1 (en) 1997-10-03 2003-09-09 V.I. Technologies, Inc. Methods and compositions for the selective modification of nucleic acids
US6352695B1 (en) 1997-10-03 2002-03-05 V.I. Technologies, Inc. Methods and compositions for the selective modification of nucleic acids
US6106773A (en) * 1998-09-24 2000-08-22 American National Red Cross Pathogen inactivating compositions for disinfecting biological fluids
US6617100B2 (en) 1998-09-25 2003-09-09 V.I. Technologies, Inc. Solid phase quenching systems
US6403359B1 (en) 1998-09-25 2002-06-11 V. I. TECHNOLOGIES, Inc. Solid phase quenching systems
US6720136B2 (en) 1998-09-25 2004-04-13 V. I Technologies, Inc. Solid phase quenching systems
WO2002034293A3 (fr) * 2000-10-23 2003-03-13 Shanbrom Tech Llc Activateurs de desinfection microbiologique et d'apoptose ciblee
EP1856973A1 (fr) * 2005-03-04 2007-11-21 National Universiy Corporation Tokyo Medical and Dental University Solution destinee a maintenir et a ameliorer la fonction d un organe
EP1856973A4 (fr) * 2005-03-04 2011-10-12 Nat Univ Corp Tokyo Med & Dent Solution destinee a maintenir et a ameliorer la fonction d un organe
WO2008125884A2 (fr) * 2007-04-16 2008-10-23 Safemed Limited Composition de conservation
WO2008125884A3 (fr) * 2007-04-16 2009-09-03 Safemed Limited Composition de conservation
WO2019073071A1 (fr) 2017-10-13 2019-04-18 Biodesiv Efnium Polymere antimicrobien pour semences animales
FR3072247A1 (fr) 2017-10-13 2019-04-19 Biodesiv Efnium Polymere antimicrobien pour semences animales
FR3072246A1 (fr) * 2017-10-13 2019-04-19 Biodesiv Efnium Polymere antimicrobien pour semences animales
CN109938008A (zh) * 2019-03-20 2019-06-28 上海创宏生物科技有限公司 一种动物精液处理剂及其应用方法

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AU644216B2 (en) 1993-12-02
EP0500893A1 (fr) 1992-09-02
CA2072871A1 (fr) 1992-03-05
AU8503791A (en) 1992-03-30
EP0500893A4 (en) 1993-03-10
JPH05502183A (ja) 1993-04-22

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