EP0605690A1 - Conservation de sang, de tissus et de fluides biologiques dans du peroxyde d'hydrogene et du povidone - Google Patents

Conservation de sang, de tissus et de fluides biologiques dans du peroxyde d'hydrogene et du povidone

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Publication number
EP0605690A1
EP0605690A1 EP93915475A EP93915475A EP0605690A1 EP 0605690 A1 EP0605690 A1 EP 0605690A1 EP 93915475 A EP93915475 A EP 93915475A EP 93915475 A EP93915475 A EP 93915475A EP 0605690 A1 EP0605690 A1 EP 0605690A1
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EP
European Patent Office
Prior art keywords
pnp
iodine
hydrogen peroxide
biological material
derivative
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Withdrawn
Application number
EP93915475A
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German (de)
English (en)
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EP0605690A4 (fr
Inventor
Edward Shanbrom
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Individual
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Individual
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Publication of EP0605690A1 publication Critical patent/EP0605690A1/fr
Publication of EP0605690A4 publication Critical patent/EP0605690A4/fr
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Classifications

    • 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
    • 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
    • A61K35/16—Blood plasma; Blood serum
    • 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
    • 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
    • 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
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
    • 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.
  • povidone hydrogen peroxide PVP-H-,0, is used in the treatment of treating biological materials.
  • a physiologically compatible reducing agent such as an ascorbate salt, as an additive or on a solid support, e.g. in a bed or filter of solid povidone, may be used to remove the last traces of oxidizing iodine.
  • This invention may, thus, be used to kill or inactivate virus, bacteria, chlamydia, rickettsia, mycoplasmaand other potentially pathogenic microorganisms and to remove all oxidizing iodine.
  • 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.
  • Protozoa give rise to many diseases, some of great medical and economic importance. Examples of such protozoa are the genus Plasmo ⁇ um, e.g. P. falciparum, P. malariae, P. ovale and P. vivax, which causes malaria,
  • the method of this invention is effective in eliminating these causative organisms in blood and blood products.
  • Many 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. (Kupferschmied, H. U., ⁇ t al
  • 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.
  • pathogens to which this invention is applicable is cytomegalovirus (CMV).
  • Herpesviruses of which CMV is a member, 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 present invention is also useful in preventing the transmission of human immunodeficiency virus (HIV). While testing has made blood products safer than it was a decade ago, the complete elimination of HIV contaminated blood and blood products has not been possible using present knowledge and technology.
  • 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.
  • 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.
  • blood 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.
  • 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, 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.
  • 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 and standards 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. 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.
  • tissue culture If a tissue is explanted into the culture media for the purpose 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.
  • Hydrogen peroxide (H 2 0 2 ), mol wt 34.016, is a weakly acidic, clear colorless liquid, miscible with water in all proportions. The four atoms are covalently bound in a nonpolar H--0--0— H structure. It is now prepared primarily by anthraquinone autoxidation processes. It is used widely to prepare other peroxygen compounds and as a nonpolluting oxidizing agent. The reactions of hydrogen peroxide are:
  • Hydrogen peroxide may react directly or after it has first ionized or dissociated into free radicals. In many cases, the reaction mechanism is extremely complex and may involve catalysis or be dependent upon the reaction environment. Hydrogen peroxide can form free radicals by homolytic cleavage of either an 0--H bond or the 0--0 bond.
  • HOOH ⁇ H. +.OOH 380 Kj/mol or 90 kcal/mol
  • HOOH ⁇ 2.0H 210 Kj/mol or 50 kcal/mol
  • Hydrogen peroxide is a strong oxidant and most of its uses and those of its derivatives depend on this property. It oxidizes a wide variety of organic and inorganic compounds, ranging from iodide ions to color bodies of unknown structure in cellulosic fibers. Hydrogen peroxide reduces stronger oxidizing agents such as chlorine.
  • Aqueous hydrogen peroxide is sold in grades ranging from 3 to 98%, mainly containing 35, 50, 70, or 90% H 2 0 2 .
  • the 3-6% H,0, solutions for cosmetic and medicinal use are obtained by diluting a more concentrated grade, usually with the addition of extra stabilizer.
  • Hydrogen peroxide is irritating to the skin, eyes, and mucous membranes. However, low concentrations (3-6%) are used in medicinal and cosmetic applications.
  • Hydrogen peroxide is used to treat wastewaters and sewage effluents, and to control hydrogen sulfide generated by the anaerobic reaction of raw sewage in sewer lines or collection points. It has been proposed as a supplemental oxygen source for overloaded activated sludge plants. It reportedly controls denitrification in secondary clarifiers and improves bulking conditions. It has been used as a flotation assistant. It has been generated in a wastewater reservoir by the cathodic reduction of oxygen.
  • Hydrogen peroxide has been used with povidone iodine in biocidal processes. A number of such methods are described in the following patents to Witkin, et al.
  • Simon, Gilbert I; Witkin, Roy T, US Patent 4997625 910305 describe the treatment of dental and medical instruments and appliances to be chemically sterilized by immersion in an admixture of an iodophor such as the povidone iodine complex or a quaternary ammonium compound such as cetyl pyridinium chloride and a peroxide such as H,0, the antimicrobial action of the iodine derived from the iodophor being enhanced or potentiated by oxygen released from the peroxide.
  • an iodophor such as the povidone iodine complex or a quaternary ammonium compound such as cetyl pyridinium chloride
  • a peroxide such as H,0
  • Witkin, Roy T, US Patent 4935248 900619 describes applying, spraying, or sponging antimicrobially effective amounts of aqueous iodophor peroxide solutions to the udder surfaces of cows, or other animals to be milked prior to milking.
  • the udders are shampooed with anonstaining shampoo containing iodine in a povidone-iodine complex and hydrogen peroxide as a nascent oxygen source.
  • iodophor constituting a source of iodine and a peroxide as a source of oxygen.
  • the iodophor is preferably a povidone iodine complex soluble in water and the peroxide is preferably hydrogen peroxide, the oxygen from the peroxide acting to enhance the antimicrobial activity of the iodine derived from the povidone iodine complex.
  • Witkin, Roy T, US Patent 5066497 911119 discloses an antimicrobial veterinary composition having enhanced antimicrobial activity against a broad spectrum of microorganisms afflicting small and large animals.
  • the composition is a solution or mixture povidone iodine complex and nascent oxygen obtained from a peroxide source.
  • Hydrogen peroxide has been combined directly with povidone to provide a dry powder source of H 2 0,.
  • Garelick Paul; Login, Robert B; Merianos, John J, US Patent 5066488 911119 describe a semi-anhydrous, suspension process for preparing substantially anhydrous complexes of PVP and H 2 0, containing about 18% to about 22% by weight H 2 O 2 .
  • the process comprises suspending substantially anhydrous PVP and an aqueous solution of 70 to 85% H 2 0 2 in an anhydrous ethyl acetate medium to precipitate a free-flowing, fine white powders of the complex, and filtering and drying under vacuum at about 40-50°C. to form the desired product.
  • Biss Russell B Cohen Jeffrey; Merianos John J; Taylor Paul D, US Patent 5077047 911231, also describe a process for the production of pvp-H 2 0 2 products in the form of free-flowing powders.
  • a fluidized bed maintained at a reaction temperature of about room temperature to 60°C. is contacted with finely divided droplets of a 30 to 85% by weight aqueous H,0 2 solution.
  • a 50-70% H,0, solution is used, and the feed rate of introduction of the H-0 2 solution is about 5-50 g/minute/kg PVP present.
  • the pvp-H 2 0 2 product preferably contains about 15-24%, preferably 18-22%, H,0 2 (1:1 molar ratio) and less than about 5% water.
  • Hydrogen peroxide has been reported in scientific literature as being used with "varying degrees of success" in the treatment of cardiovascular, pulmonary, and infectious diseases; immune disorders; and other illnesses such as Alzheimer's, cancers of the blood and lymph, and migraine headaches. Skeptics are , however, suspicious when a single remedy is claimed to cure many illnesses.
  • Hydrogen peroxide has also been evaluated as a bactericide in poultry chilling water to kill bacteria that reside on the carcasses of poultry prepared for use as a food, Lillard H S; Thomson J E, J Food Sci 48 (1), 1983, 125-126
  • Povidone is used generally to describe compounds described in the U.S. Pharmacopeia to identify polyvinyl pyrrolidone suitable for use in physiologically acceptable solutions and to include polyvinylpyrrolidone (PVP) compositions that have not yet been approved for use in the preparation of therapeutic compounds, and equivalents, as described hereinbefore.
  • PVP polyvinylpyrrolidone
  • percent concentrations are referred to in connection with povidone-hydrogen peroxide, the percentage refers to the percent of povidone-hydrogen peroxide by weight, based upon the weight of the solution or material to which the povidone-hydrogen peroxide is added.
  • a 1 weight percent (w/o) solution of povidone-hydrogen peroxide indicates that enough povidone-hydrogen peroxide has been dissolved to result in a concentration of lw/o povidone-hydrogen peroxide.
  • the ratio of polyvinyl pyrrolidone to hydrogen peroxide in the povidone-hydrogen peroxide product according to this invention is in the range of 1 part of hydrogen peroxide to 5-12 parts of povidone. Higher povidone to hydrogen peroxide are preferred in some instances, as described hereinafter.
  • Typical stock solutions are 10% PVP-H 2 0 2 (5,000 ppm to 20,000 ppm H,0 2 ), 5% (2,500 ppm to 10,000 ppm H 2 0,) and 1%
  • povidone-hydrogen peroxide in such compositions means the concentration of standard PVP-H 2 0, (calculated as having an 0.05 to 0.2 parts of
  • PVP-H 2 0 2 -PVP is used as an abbreviation for povidone enriched povidone hydrogen peroxide, i.e a composition in which the total povidone to hydrogen peroxide ratio is greater than 15 to 1.
  • PVP-H 2 0,-PVPLMW is used as an abbreviation for PVP-H 2 0 2 -PVP in which at least ten percent of the povidone has a molecular weight of no greater than approximately 12,000 daltons.
  • PVPXL-H,0 2 is used as an abbreviation for solid, e.g. cross-linked, povidone-hydrogen peroxide.
  • Polyvinylpyrrolidone (PVP, Povidone) is manufactured by BASF Aktiengesellschaft, Unternehemens Suite Feincheme, D-6700 Ludwigshaven. Germany and sold under the trademark KOLIDON®. Povidone-iodine products and the preparation of such products are described in U.S. Patents 2,707,701,
  • Patent No. 4,128,633, Lorenz et al, 1978 - preparation of PVP-I complex U.S. PatentNo. 4,139,688, Dixon, 1979 - cross-linked viny -pyrrolidone; U.S. PatentNo. 4,180,633, Dixon, 1979 ⁇ cross-linked vinylpyrrolidone; U.S. PatentNo. 4,190,718, Lorenz, et.al., 1980 -increasing molecular weight of polyvinylpyrrolidone.
  • povidone-iodine is described in my copending patent Application Nos.
  • Albumin-iodine is defined for purposes of this invention as a composition of matter consisting essentially of albumin and iodine, the iodine approximately saturating the binding sites on the albumin.
  • Albumin-iodine treatments and preparation are described in my copending patent Application No. 07/844,241, 03021992.
  • a significant portion of the iodine is available for contact and reaction with biological materials and in an amount such that when the ALB-I is dissolved in aqueous solution there exists an equilibrium condition ALB-I ⁇ ALB + I, wherein oxidizing iodine is in solution in an amount of at least about 0.0.01 wt percent.
  • the invention thus encompasses, a process of preparing ALB-I comprising reacting substantially pure albumin, preferrably unsterilized, unstabilized and delipidated albumin, with sufficient iodine-containing reagent to substantially saturate all binding sites thereon
  • Albumin iodine is useful in process in which povidone iodine is useful.
  • a liquid composition that contains bacteria, virus, or other pathogenic organisms can be sterilized by passing it in contact with ALB-I. Thereafter, if it is desired to assure total iodine removal, the solution can be passed into contact with albumin that is less than saturated with iodine, preferably having no more than a trace of iodine or another iodine absorbing material, such as cross- linked povidone to remove the excess iodine.
  • a reducing agent such as a reducing sugar, ascorbate, sodium sulfite, etc.
  • a reducing agent such as a reducing sugar, ascorbate, sodium sulfite, etc.
  • Reducing sugars, ascorbic acid (Vitamin C) and its salts, and sodium sulfite are well-known, readily available reducing agents that are physiologically acceptable. However, any physiologically acceptable reducing agents may be used.
  • Povidone polyvinyl pyrrolidone
  • PVP polyvinyl pyrrolidone
  • the cytophylactic benefit of povidone and the biocidal effect of hydrogen peroxide, H,O 2 are combined in the treatment of blood, plasma, serum, packed blood cells, and other blood products and fractions.
  • Povidone- hydrogen peroxide, PVP-H 2 O 2 is, of course, known and has been used in methods for sterilizing hard surfaces and in the topical treatment of tissues and membranes.
  • PVP-H 2 O 2 is useful in process in which povidone iodine is useful.
  • a liquid composition that contains bacteria, virus, or other pathogenic organisms can be sterilized by passing it in contact with PVP-H 2 O 2 . Thereafter, if it is desired to assure total peroxide removal, the solution can be passed into contact with PVP that is less than saturated with hydrogen peroxide, preferably having no more than a trace of hydrogen peroxide or another hydrogen peroxide absorbing material, such as cross-linked povidone to remove the excess hydrogen peroxide.
  • a reducing agent such as a reducing sugar, ascorbate, sodium sulfite, etc., may be added to eliminate the last traces of oxidizing hydrogen peroxide.
  • Reducing sugars, ascorbic acid (Vitamin C) and its salts, and sodium sulfite are well-known, readily available reducing agents that are physiologically acceptable. However, any physiologically acceptable reducing agents may be used.
  • This invention comprises the use of PVP-H,O 2 for the manufacture of a medicament consisting essentially of blood cells in plasma or another carrier liquid for the treatment of disorders wherein the patient requires the transfusion of blood cells, the PVP-H,O 2 being added in an amount in excess of that required to kill or inactivate all microbes therein comprising from 0.01 w/o to 5w/o of the medicament. Transfusion, transplantation and sperm-containing compositions are similarly prepared.
  • the invention is embodied in a method of disinfecting biological materials.
  • the steps of the method include treating biological material before separation of the components thereof with PVP-H 2 O 2 to provide from a concentration of 0.01 w/o to 5w/o PNP-H,O 2 in said material before separation of the components thereof.
  • a derivative of the material resulting from the preceding step is prepared and, optionally, also treated with PNP-H 2 O 2 to provide from 0.01 w/o to 5w/o PVP-H 2 O 2 in the derivative.
  • the derivative may be treated by addition of a physiologically acceptable reducing agent or contact with cross-linked PNP to reduce or remove residual hydrogen peroxide.
  • the invention also includes drug delivery material comprising blood cell concentrate wherein the cell walls of the cells have been opened by treatment with from 0.01 w/o to 5 w/o PNP-H 2 O 2 , a drug has been introduced into the cells through passages produced by the PNP-H 2 O 2 treatment, the cell walls have been sealed by heating the cells to from 42 to 48 oC. and the resulting material optionally having been treated by addition of a physiologically acceptable reducing agent or contact with cross-linked PNP to reduce or remove residual hydrogen peroxide.
  • drug delivery material comprising blood cell concentrate wherein the cell walls of the cells have been opened by treatment with from 0.01 w/o to 5 w/o PNP-H 2 O 2 , a drug has been introduced into the cells through passages produced by the PNP-H 2 O 2 treatment, the cell walls have been sealed by heating the cells to from 42 to 48 oC. and the resulting material optionally having been treated by addition of a physiologically acceptable reducing agent or contact with cross-linked PNP to reduce or remove residual hydrogen
  • Also included in the invention is the improved method of treating patients with plasma comprising the steps of collecting plasma from, a donor, and thereafter infusing the plasma into the patient to be treated, of mixing the plasma with PNP-H 2 O 2 sufficient to resulting a PVP-H 2 O 2 a concentration of from about 0.01 w/o to about 5 w/o, and allowing contact of said plasma with said PNP-H 2 O 2 for at least about one-half minute sufficient to inactivate or destroy infective pathogenic microbes in the plasma and optionally thereafter removing oxidizing hydrogen peroxide from the resulting mixture by passing said mixture into intimate contact with cross-linked PNP or adding a physiologically acceptable reducing agent.
  • the apparatus is in the form of a liquid container having, in use an upper reservoir portion for holding said liquid and a lower elutriation portion for recovering liquid and structure defining first and second beds of paniculate matter, the first bed comprising substantially insoluble PVP-H-,0, and the second bed consisting essentially of substantially insoluble PNP; the beds being so formed and configured as to permit the passage of the liquid therethrough in intimate contact with the surfaces of the particles forming the respective beds.
  • the first bed may be cross-linked PNP.
  • the apparatus may comprising a third layer between the first and second layers, the third layer comprising substantially insoluble PNP hydrogen peroxide particulate matter.
  • the apparatus may contain a layer of particulate matter comprising an hydrogen peroxide reducing agent.
  • a layer of soluble PNP-H 2 O 2 may be provided on the first layer in the liquid reservoir. All or only part of the layers, after the first and second layers, may be provided.
  • One method of sterilizing an implantable tissue in accordance with this invention comprises placing tissue that is physiologically acceptable for implantation into a human patient into a vacuum chamber, evacuating the chamber and maintaining a vacuum on the chamber for a period long enough to extract at least about one-half of the unbound water originally present in said tissue, and introducing into the vacuum chamber a solution of PVP-H 2 O 2 for thereby reconstituting into the tissue said solution in place of the water that was vacuum extracted.
  • hydrogen peroxide may be removed by washing or reconstituting the tissue with a reducing agent such as ascorbic acid or a salt thereof or sodium sulfite, for example.
  • the invention comprises a method of disinfecting biological materials comprising the steps of treating biological material before separation of the components thereof with PNP-H 2 O, and an iodine-containing complex selected from the group consisting of povidone- iodine or albumin-iodine or mixtures thereof to provide from a concentration of 0.01 w/o to lOw/o PVP-H 2 O 2 and from 0.01 w/o to 5w/o of iodine-containing complex in said material before separation of the components thereof and thereafter preparing a derivative of the material resulting from the preceding step.
  • an iodine-containing complex selected from the group consisting of povidone- iodine or albumin-iodine or mixtures thereof to provide from a concentration of 0.01 w/o to lOw/o PVP-H 2 O 2 and from 0.01 w/o to 5w/o of iodine-containing complex in said material before separation of the components thereof and thereafter preparing a derivative of the material
  • the derivative may be treated with PVP-H 2 O, and an iodine- containing complex selected from the group consisting of povidone-iodine or albumin-iodine or mixtures thereof to provide from a concentration of 0.01 w/o to lOw/o PNP-H 2 O 2 and from 0.01 w/o to 5w/o of iodine-containing complex in said derivative.
  • the derivative may be further treated by addition of a physiologically acceptable reducing agent or contact with cross- linked PNP to reduce or remove residual hydrogen peroxide and iodine, if iodine-containing complex is used.
  • Figure 1 depicts an apparatus for contacting a liquid material with PNP-
  • H,O 2 and with either or both of (a) an hydrogen peroxide absorbing material and/or (b) an hydrogen peroxide reducing material, and for providing other materials for processing biological liquids, in particular, according to this invention.
  • Figure 2 depicts, largely schematically, an apparatus for treating solid tissue samples.
  • Povidone-hydrogen peroxide abbreviated hereinafter as PNP-H 2 O 2 . is prepared beginning as described by Garelick et al, supra, or any other convenient method. It is considered most convenient to use solid povidone- hydrogen peroxide as the hydrogen peroxide source because this material provides a convenient source of hydrogen peroxide, has high hydrogen peroxide content and does not add other chemicals or constituents to the resulting PVP-
  • a bed of solid povidone-hydrogen peroxide, cross-linked povidone reacted with hydrogen peroxide or povidone that has been cross-linked by reaction with hydrogen peroxide that binds to the povidone during cross- linking, or any other solid povidone hydrogen peroxide may be used.
  • PNP-H 2 O 2 optionally followed by treatment with a physiologically acceptable reducing agent for the manufacture of a medicament is contemplated by this invention.
  • Such a medicament may, for example, consist essentially of blood cells in plasma or another carrier liquid. Such medicaments may be used for the treatment of disorders wherein the patient requires the transfusion of blood cells.
  • PVP-H 2 0 2 is added in an amount in excess of that required to kill or inactivate all microbes is added.
  • PNP-H,O 2 may comprise, for example, from about 0.01 to 10 weight percent, preferably from 0.01 w/o to 5 w/o of the blood.
  • the PNP-H-,0. is allowed to remain in contact with the blood cells or plasma, or other biological material being prepared to be a medicament, for a period of at least about a half a minute sufficient to kill the microbes, but under about 24 hours, at low concentrations, and 1 hour at higher concentrations, so as not to denature or otherwise injure the biological material. Usually, contact of under an hour is preferred.
  • the contact times will be referred to as from one-half minute to one hour with the caveat that longer contact is not necessary or beneficial and may result in injury to the biological, but would, nevertheless, be within the scope of the invention.
  • the reducing agent is then added in an amount to reduce substantially all hydrogen peroxide.
  • the maximum amount of reducing agent required is easily calculated.
  • the actual amount normally required, to which a safety margin amount will be added, is determined by an hydrogen peroxide assay on typical batches using known, routine procedures.
  • a second treatment as described may be performed to assure total sterilization, if desired. Likewise, a second similar treatment may be performed on a product or fraction of the initial biological material treated as described above.
  • PVP-H 2 O 2 and a physiologically acceptable hydrogen peroxide absorbent material e.g., solid povidone or cross-linked povidone
  • a medicament may, for example, consist essentially of blood cells in plasma or another carrier liquid.
  • Such medicaments may be used for the treatment of disorders wherein the patient requires the transfusion of blood cells.
  • PVP-H,O 2 in an amount in excess of that required to kill or inactivate all microbes is added.
  • PNP-H 2 O 2 may comprise, for example, from about 0.01 to 10 weight percent, preferably from
  • the PNP-H 2 O is allowed to remain in contact with the blood cells or plasma, or other biological material being prepared to be a medicament, for a period of at least about a half a minute sufficient to kill the microbes, but not long enough to denature or otherwise injure the biological material. Usually, contact of under an hour is preferred.
  • the contact times will be referred to as from one-half minute to one hour with the caveat that longer contact is not necessary or beneficial and may result in injury to the biological, but would, nevertheless, be within the scope of the invention.
  • the mixture resulting from the above is then contacted with an hydrogen peroxide absorbing reagent such as cross-linked PVP, or povidone, to remove the hydrogen peroxide.
  • an hydrogen peroxide absorbing reagent such as cross-linked PVP, or povidone
  • a reducing agent may thereafter be added in an amount to reduce any hydrogen peroxide that may not have been absorbed.
  • the contact with the hydrogen peroxide absorbing material is preferably accomplished by passing the material undergoing treatment through a layer, i.e. a bed or filter, of solid, substantially insoluble povidone.
  • a second treatment as described may be performed to assure total sterilization, if desired.
  • a second similar treatment may be performed on a product or fraction of the initial biological material treated as described above.
  • the "addition" of a reducing agent to the material undergoing treatment may be accomplished by passing the material through a layer of substantially insoluble material that has active reducing sites thereon or equilibrates with the liquid material undergoing treatment to partially dissolve into such liquid, or make readily available in said liquid (as by swelling, for example) reducing moieties.
  • a bed of beads or fibers, for example, that expose on the surface thereof reducing sugar moieties may be used very conveniently.
  • Figure 1 depicts an apparatus for contacting a liquid material with PVP-H 2 O 2 and with either or both of (a) an hydrogen peroxide absorbing material and/or (b) an hydrogen peroxide reducing material, and for providing other materials for processing biological liquids, in particular, according to this invention.
  • the apparatus being shown and described in a generally schematic fashion, may be in any of many configurations. The only significant structure, insofar as this invention relates is to the arrangement of the layers
  • the apparatus 10 may be viewed as a filter funnel or a column.
  • a filter may, indeed must, remove only part of the material.
  • the apparatus comprises cylindrical portion 12 that, in part, defines a reservoir portion.
  • the reservoir may be large or very small as desired.
  • the apparatus in the configuration depicted comprises a second, smaller cylindrical tube portion 14 and a conical transition zone 16 connecting the two cylindrical portions as is conventional in funnel manufacture. It is again emphasized, however, that it is immaterial whether the apparatus defines a reservoir and or funnel portion of any particular size or configuration.
  • the apparatus defines a first layer 20 and a second layer 22.
  • the first layer is made up of substantially insoluble PNP-H 2 O 2 .
  • This layer is described as being made up of particulate materials in that the use or particulates in one way or another is usually involved. Particles of solid, insoluble PVP-H 2 O 2 , e.g. cross-linked PNP-H 2 O 2 , in the form of a layer or bed of particles, either supported directly by a layer below or by way of another support, e.g. being bonded to or entrapped within a layer of fibers or particles, is contemplated.
  • the first layer may also contain some soluble PVP-H 2 O 2 .
  • a frit made of particles bound together adhesively, by heat or pressure would also be within the disclosure and invention.
  • the PNP-H 2 O may be formed in situ by reacting a layer of povidone with hydrogen peroxide or the layer may be made up of pre-synthesized PVP-H 2 0 2 .
  • the second layer is downstream of the first layer, i.e. the liquid to be treated flows through the first layer and then the second layer.
  • the second layer may comprise an insoluble hydrogen peroxide absorbent, e.g.
  • the layer may be a self-supporting frit or other structure or may be supported by a support or other layer.
  • the essential function of the apparatus is to cause a liquid that is to be treated to pass, with or without cells or other particles therein, first through a layer of PNP-H 2 O 2 and, thereafter, to contact such liquid with absorbent to remove the hydrogen peroxide and/or reductant to reduce the hydrogen peroxide.
  • the layers may be quite deep or quite thin, adjacent each other or spaced from each other, as is necessary or desirable to provide adequate contact of the liquid with each of the layers or beds.
  • the liquid container that is generally defined by the overall apparatus in the simplified, schematic example of Figure 1, and has an upper or liquid inflow reservoir portion for holding liquid to be treated. This may be a very small reservoir or quite large. The reservoir may displaced from the beds or layers by a very large distance, though this is not generally beneficial.
  • the apparatus has a lower or elutriation or recovery portion for recovering liquid that has been treated. Between these portions, first and second beds of particulate matter are defined by suitable structure.
  • the first bed or layer comprises substantially insoluble PVP-H 2 O 2 .
  • the second bed consists essentially of substantially insoluble povidone, or other hydrogen peroxide absorbent, and/or hydrogen peroxide reducing agent.
  • the beds are so formed and configured as to permit the passage of the liquid therethrough in intimate contact with the surfaces of the particles forming the respective beds.
  • the usual and most common hydrogen peroxide absorbent is cross-linked povidone.
  • the apparatus may desirably further comprise a third layer 24 between the first and second layers.
  • the third layer comprises substantially insoluble povidone hydrogen peroxide particulate matter. The presence of the third layer entraps and regenerates hydrogen peroxide and significantly increases the biocidal activity of hydrogen peroxide.
  • a fourth layer 26, which may be in the form of a sublayer within the second layer, comprising particulate hydrogen peroxide reducing agent may be provided downstream from the second layer to provide for the reduction of any residual hydrogen peroxide from 12 to iodide, or, if reduction is earlier provided, to add a safety step to assure that all oxidizing hydrogen peroxide has been reduced.
  • the fifth layer may also comprise soluble povidone, preferably low molecular weight (MW ⁇ 12,000 daltons) on the top of the first layer for being dissolved into the liquid to be treated to provide a cell protective milieu for the cells carried by the liquid.
  • the fifth layer may comprise soluble PNP-H 2 O, to provide both hydrogen peroxide and cell protection.
  • At least about one-fourth of all the PVP in solution is low molecular weight PNP, i.e., MW ⁇ ⁇ 15,000.
  • the first and second layers are essential to the full and proper functioning of the apparatus. After those layers or beds, however, any number of additional layers or additives may be provided, so long as they do not interfere with the combined function of the first and second beds or layers.
  • a layer 30 may be a frit, a filter paper or a porous layer.
  • the thickness of the beds may be the same or greatly different. It is a simple matter to calculate contact time in a column and to provide suitable beds of materials therein.
  • any of the beds may be made up the active material, e.g. PNP-H 2 O 2 , reducing sugar, etc., attached to carrier particles, such as ground glass, charcoal, ion exchange resin, cellulose derivatives, etc.
  • carrier particles such as ground glass, charcoal, ion exchange resin, cellulose derivatives, etc.
  • the particulate matter may, in a preferred form, consist essentially of particles having a diameter of from about 10 to about 100 microns, but any size that permits suitable flow rates and assures intimate contact may be used.
  • PVP-H 2 O and a physiologically acceptable reducing agent for the manufacture of transfusion biological material from one human or mammal for transfusion of such material to another human or mammal, or the transplant or transfusion biological material is a part of this invention.
  • the transfusion or transplant is disinfected with a PVP-H 2 O 2 solution having concentration of from about 0.01 to 10 weight percent, preferably O.Olw/o to 5w/o, and thereafter treated with the reducing agent to reduce the residual hydrogen peroxide.
  • Liquid materials may be treated in any suitable manner, such as has been described. Solid tissue samples may be treated simply be soaking, by infusing or by vacuum infusing.
  • Figure 2 depicts, largely schematically, an apparatus for treating solid tissue samples.
  • the apparatus comprises a chamber system 100 capable of withstanding the forces of a vacuum.
  • a cylinder 102 is closed at the respective ends by end covers 104 and 106, the end 106 being removable to gain access to the inside of the chamber.
  • a portion 108 of the end 106 may be slipped into the cylinder 102 and sealed using "O" rings, etc., to provide a vacuum tight seal.
  • a vacuum line 110 through valve 112 and line 114 permits evacuation of the chamber.
  • An input line 120, coupled to valve 122 and line 124 permits the introduction of liquid into the chamber.
  • a platform 126 secured to the end 106, supports a tissue sample 130. The tissue sample is placed in the chamber, the chamber evacuated and then liquid is introduced, thereby substantially replacing water in the sample with the liquid introduced.
  • Implantable tissues may be treated to kill microbes, i.e. "sterilized" by placing tissue that is physiologically acceptable for implantation into a human patient into a vacuum chamber, evacuating the chamber and maintaining a vacuum for a period long enough to extract at least about one-half of the unbound water originally present in said tissue and then introducing into said vacuum chamber a solution of PVP-H,O, for thereby reconstituting into the tissue said solution in place of the water that was vacuum extracted.
  • the thus treated tissue may then be soaked in a solution of an physiologically acceptable hydrogen peroxide reducing agent.
  • the chamber may again be evacuated to extract the PNP-H 2 O 2 solution from the tissue and a solution of physiologically acceptable hydrogen peroxide reducing agent introduced into the vacuum chamber for saturating the tissue for reducing any residual hydrogen peroxide.
  • the invention may comprise treating blood before separation of the components thereof with PVP- H 2 O 2 to provide from a concentration of from about 0.01 to 10 weight percent, preferably 0.01 w/o to 5 w/o, PNP-H,O : in the blood, preparing a derivative of the blood from step, treating the derivative with PVP-H 2 O 2 to provide from about 0.01 to 10 weight percent, preferably O.Olw/o to 5w/o, hydrogen peroxide in the derivative thereafter treating the derivative by addition of a physiologically acceptable reducing agent or contact with cross-linked PVP to reduce or remove residual hydrogen peroxide.
  • PNP-H 2 O 2 opens pathways through the cell wall which permits certain components of the cell, e.g. potassium salts, to "leak" from the cell.
  • certain components of the cell e.g. potassium salts
  • treatment of red blood cells with from one to about five percent hydrogen peroxide as PNP-H 2 O 2 opens the cells to "inward leaking".
  • compounds which have a virucidal or other effect in the cell can be introduced into the cell.
  • PVP-H 2 O can, for example, be used as described to increase the uptake of antiviral compounds, e.g. carbenoxolone, AZT, etc., which, in turn, may 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 PVP-H 2 O 2 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 hydrogen peroxide may be removed and the cell concentrate is heated to 42 - 48 oC 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.
  • Infective pathogenic microorganisms are believed to be inactivated when PVP-H 2 O 2 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 hydrogen peroxide compound in a concentration of from about 0.01 to 10 weight percent, preferably O.Olw/o to about 5w/o (10 to 5000 ppm 12), preferably from about 0.25 w /o to about 2 /o. After a period of time, most of the unreacted molecular hydrogen peroxide compound is washed away and any residual molecular hydrogen peroxide compound is absorbed into the protein or converted to inactive iodides, e.g.
  • Sperm-bearing solutions treated to be made freed of pathogenic microbes by washing and/or storing the sperm in a solution which contains a concentration of PVP-H,O 2 in a concentration is from about 0.01 to 10 weight percent, preferably O.Olw/o to about 5w/o, (100 to 5000 ppm 12) and, preferably, sufficient to inactivate bacteria, viruses and other pathogenic organisms, and washing the sperm cells in the solution, optionally with a solution of a reducing agent compound.
  • PVP-H 2 O 2 is considered to be effective in protecting the sperm cells from the spermicidal activity of hydrogen peroxide 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 PNP-H 2 O 2 solution.
  • Other reagents such as are conventionally used in sperm treatment, storage and preparation, or for particular purposes may, of course, also be included in the infusion solution.
  • residual hydrogen peroxide may be washed out and or removed using ascorbate or other reducing agent and any suitable storage fluid, including solutions of polyvinyl pyrrolidone, may be used to store and handle the sperm cells.
  • the material to be purified is a liquid or cells carried in a liquid
  • a bed e.g. the conventional filter structure of solid particles on a porous or foraminous support
  • solid particles of PNP-H 2 O 2 of suitable size
  • the particles must be large enough to permit intimate contact without entrapping or binding the cells.
  • the liquid may then be passed through a layer or in contact with solid phase PVP-H 2 O 2 to assure complete biocidal effect. Thereafter, the liquid is passed through or into intimate contact with cross-linked PNP to absorb the molecular hydrogen peroxide from the liquid.
  • a reducing agent such as ascorbate may be added if considered necessary as a precaution.
  • the liquid or cell-bearing liquid is contacted with the solid PNP-H 2 O 2 .
  • This may be done most efficiently, in most cases, by passing the liquid through a settled or fluidized or packed bed of PVP-H 2 O 2 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 PNP-H 2 O 2 material, e.g. over a multiple-plate array of sheets of such material.
  • the PNP-H 2 O 2 may be washed and the hydrogen peroxide content therein regenerated between uses.
  • reducing agent e.g. a reducing sugar (or mixtures of reducing sugars), ascorbic acid or ascorbate, a sulfite, e.g. sodium sulfite, etc. in which the agent is in a concentration of 0.01 to 1 percent is suitable and such is implicit unless otherwise noted.
  • the invention may be carried using PNP- H 2 O 2 as described, alone, or in combination with PVP-I or ALB-I, or combinations of PVP-I and ALB-I, the latter being in concentrations of from 0.001 to 5w/o.
  • This invention finds application in medicine and veterinary science.

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Abstract

L'invention se rapporte au traitement et à la conservation de sang, de dérivés sanguins et d'autres fluides, cellules et tissus organiques à l'aide de PVP-H2O2, après quoi le potentiel d'oxydation du peroxyde d'hydrogène dans le PVP-H2-O2 est supprimé afin de détruire les microbes patogènes sans nuire à l'utilité des tissus, des fluides et des cellules. La figure (1) représente un appareil (2) permettant de mettre une substance liquide en contact avec du PVP-H2O2 et avec (a) une substance d'absorption de peroxyde d'hydrogène et/ou (b) une substance réductrice de peroxyde d'hydrogène. L'appareil permet également d'utiliser d'autres substances afin de traiter en particulier des liquides biologiques selon cette invention.
EP19930915475 1992-06-29 1993-06-25 Conservation de sang, de tissus et de fluides biologiques dans du peroxyde d'hydrogene et du povidone. Withdrawn EP0605690A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US90534492A 1992-06-29 1992-06-29
US905344 1992-06-29
PCT/US1993/006096 WO1994000161A1 (fr) 1992-06-29 1993-06-25 Conservation de sang, de tissus et de fluides biologiques dans du peroxyde d'hydrogene et du povidone

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EP0605690A1 true EP0605690A1 (fr) 1994-07-13
EP0605690A4 EP0605690A4 (fr) 1994-12-07

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DE4343226A1 (de) * 1993-12-17 1995-06-22 Schenk Filterbau Gmbh Tiefenfilter zur Abtötung von Mikroorganismen und Inaktivierung von Viren und dessen Anwendung
US5591350A (en) * 1994-04-15 1997-01-07 Pall Corporation Iodine disinfection method using a gaseous iodine treated porous medium
FR3072246B1 (fr) * 2017-10-13 2020-06-12 Biodesiv Efnium Polymere antimicrobien pour semences animales

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0127605A2 (fr) * 1983-05-31 1984-12-05 IMMUNO Aktiengesellschaft für chemisch-medizinische Produkte Procédé d'obtention de préparations du plasma sanguin humain
WO1991007184A1 (fr) * 1989-11-08 1991-05-30 Gaf Chemicals Corporation Complexes sensiblement anhydres de pvp et h2o¿2?
WO1992004031A1 (fr) * 1990-09-04 1992-03-19 Edward Shanbrom Preservation de sang, de tissus et de fluides biologiques
WO1992004061A1 (fr) * 1990-09-04 1992-03-19 Edward Shanbrom Preservation antimicrobienne de plasma
WO1993004678A1 (fr) * 1991-09-03 1993-03-18 Edward Shanbrom Conservation antimicrobienne de plaquettes et de facteurs sanguins
WO1993006911A1 (fr) * 1991-10-08 1993-04-15 Isp Investments Inc. Procede de traitement du sang

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Publication number Priority date Publication date Assignee Title
US3065139A (en) * 1953-11-12 1962-11-20 Astra Ab Anti-infectant topical preparations
JPS5749453A (en) * 1980-09-05 1982-03-23 Jujo Paper Co Ltd Method of removing hydrogen peroxide from food instrument material

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0127605A2 (fr) * 1983-05-31 1984-12-05 IMMUNO Aktiengesellschaft für chemisch-medizinische Produkte Procédé d'obtention de préparations du plasma sanguin humain
WO1991007184A1 (fr) * 1989-11-08 1991-05-30 Gaf Chemicals Corporation Complexes sensiblement anhydres de pvp et h2o¿2?
WO1992004031A1 (fr) * 1990-09-04 1992-03-19 Edward Shanbrom Preservation de sang, de tissus et de fluides biologiques
WO1992004061A1 (fr) * 1990-09-04 1992-03-19 Edward Shanbrom Preservation antimicrobienne de plasma
WO1993004678A1 (fr) * 1991-09-03 1993-03-18 Edward Shanbrom Conservation antimicrobienne de plaquettes et de facteurs sanguins
WO1993006911A1 (fr) * 1991-10-08 1993-04-15 Isp Investments Inc. Procede de traitement du sang

Non-Patent Citations (1)

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Title
See also references of WO9400161A1 *

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WO1994000161A1 (fr) 1994-01-06
JPH06510798A (ja) 1994-12-01

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