JPH06509118A - safe biofluids - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] safe biofluids Technical field The present invention relates to blood for human transfusion and derivatives.

Background technology Iodine was officially recognized by the United States Pharmacopeia in 1930 and is available in iodine tinctures and It is also approved as an iodine glue agent. Clinicians and microbiologists A large amount of experimental data and clinical drugs are described. Despite the results obtained with iodine It is known that, in the early stages, it has properties that are not suitable for practical use.

Killing of living cells by iodine molecules (or one of the reaction products produced in aqueous solution) Although the exact details of iodine are not known, iodine is basic N-H functional group, which is part of N-, histidine, arginine) and N- of nucleotides (adenine, cytosine and guanine) to produce iodo derivatives It is thought to react with bases. This reaction blocks important positions for hydrogen bonding. This results in fatal damage to the protein structure. Iodine is derived from the amino acid cysteine. oxidizes S-H groups, thereby forming disulfides ( -3-S-) The bonding of protein chains by cross-linking is thus lost. Iodine is an amino It reacts with the phenolic group of acid tyrosine to produce mono- or di-iodo derivatives.

In this case, most of the iodine atoms at the ortho position are unattached to the hydrogen bond of the phenol-OH group. Saturated fatty acids, together with carbon-carbon double bonds (C-C), provide a form of steric hindrance. child This results in changes in the physical properties of the lipids and membrane immobilization.

Iodine-polymer complexes, such as poly(vinylpyrrolidone) (PVP) and iodine Complexes of surfactants and nonionic surfactants, such as polyethylene glycol mono(nonionic) luphenyl) ether has been used with considerable success. But inert Its use in direct contact with biological materials may dissipate the killing power of iodine or damage inert biological materials. It is limited because it causes damage.

Povidone-iodine is a gram of all classes of pathogens encountered in nosocomial infections in a given setting. positive and gram-negative bacteria, mycobacteria, fungi, yeasts, viruses and protozoa can kill animals. Most bacteria are killed within 15-30 seconds of contact.

In general, if the severe restrictions on its use are removed, iodine will improve the intestinal bacteria and intestinal bacteria. important health-related microorganisms such as endoviruses, bacterial viruses, and protozoan infections. It is an excellent fast and effective fungicide with a broad spectrum of action, including almost all living organisms. . Mycobacteria and Bacillus and Clostridium spores are also iodine-resistant. Can kill. Additionally, iodine also exhibits bactericidal and trichomonal activity.

As expected, different classes or amounts of iodine are required to completely kill different classes or microorganisms. Uron is required. However, within the same class, regarding the bactericidal effect of iodine, There is very little published data. In particular, the sterilization time for spores and viruses is very different.

However, iodine is consumed by protein substances, and its efficacy as a disinfectant is It is reduced in certain antiseptic applications. This is mainly due to the reducing action of the obtained substance. The iodine is then converted to non-sterilizing iodide. Therefore, effective iodine resin Not only is the triiodide balance reduced, but the triiodide balance is also affected. both of these The effect is to reduce the proportion of free molecular iodine, which is the actual antimicrobial agent.

In whole blood, a significant decrease in free molecular iodine concentration occurs in the presence of plasma. It changes little (Durmaz, et al, Mikrobiyol, B ul, 22(3), 1988 (abstract); Gottardi W.

Hyg, Med, 12 (4), 1987, 150-154. ), nutritional broth and plasma have little inactivating activity, but 1 g hemoglobin contains free iodine. 50 mg of urin was inactivated: The experiment with I resulted in rapid absorption by red blood cells. It was shown that Optimal bactericidal action in clinical use is achieved in a relatively blood-free manner. Obtained in a state. Povidone-iodine is resistant to bacteria on healthy skin and can be persistent in some cases (Lacey, R.W., J., Appl., Bacterio f 46 (3), 1979. 443-450. ). dilute povidone iodine Bactericidal action is best with blood, followed by pus, fat and glove powder. (Zamora J, L; Surgery (St Lous) 9 8(1), 1985.25-29; Zamora, Am, J. Surgery .

151, p. 400 (1986); Waheed 5heikh, Curre nt Therapeutic Re5earch 40. No, 6.1096 (1986). 77 Van Den Broek et al. l, Antimicrobia! Agents and Chemother apL 1982, 593-597) binds to cell wall proteins and enters the liquid phase. (Abdulla). h, etal, Arzneim, -Forsch, /Drug Res.

31 (1), Nr, 5.828). -Ninneman et al. al, J. of Immunal, 81.1.265 (1981), povid Iodine is absorbed by and binds to serum albumin. reported.

Iodine is widely used in human medicine and for skin disinfection (e.g. Preoperative preparation, surgical disinfection of the hands, disinfection of the entire genital area before childbirth, infection and blood transfusion prior disinfection, etc.). Iodine preparations are also used therapeutically, e.g. in the treatment of infected and burned skin. It is used for this purpose, but it is a strong irritant. Iodophors largely eliminate the irritation. . Iodine is used in medical devices such as catheters, knife blades, samples, plastic products, rubber products, black, multi-throw vials and thermometers. Also used for disinfection.

"Compounds incorporating oxidizing iodine molecules", such as adsorption on purified vegetable carbon or use the grafted compound as a blood-contacting reagent with bactericidal and bacteriostatic properties. Surnguenee La 5nier) in U.S. Patent No. 4.898.572, but what No explanation was given.

A number of authors have summarized the literature and analyzed existing data to Attempts are being made to summarize the bactericidal effects of halogens and other halogens. The most important conclusion is that street (1) Standard eradication of enteric bacteria, amoebic cysts and enteric viruses (i.e. 99.999% sterilization in 10 minutes at 25℃), T2 is 0.2 and 3, respectively. ．． 5 and 14.6 ppm must remain.

(2) On a weight basis, iodine is more completely distributed over a wide range of water types than other halogens. can make the virus inactive.

(3) *In the presence of organic and inorganic substances, iodine is a particularly good cystocide, such as This is because iodine does not cause side reactions that impair its bactericidal properties.

(4) Iodine disinfects water and provides free residue compared to chlorine and bromine. This is the lowest dose (mg/L).

(5) Compared to HOI, I2 has 3 times more power as a cystocide and 6 times more power as a sporicidal agent. However, Hot is at least 40 times more effective as a virucidal agent than 12. This event The movement is due to the high diffusivity of molecular iodine through the cell wall of cysts and spores on the one hand, and on the other hand This is explained by the high oxidizing power of HOI.

Regarding these, Gottardi (Gottardi, W., “Iodinean d Iodine Compounds in DisnfectionSte rlzaton and Preservation”, Th1rd Edit on, Block, Seymour S,, Ed,, Lea & Febiger , Ph1ladelphia, 1983) and cited references are The technical background is described in more detail.

Polyvinylpyrrolidone (pvp, povidone) is manufactured by BASF (Aktienge). sel1schaft, UnternehemensbereichFei ncheme, D-6700 Ludwigshaven, Germany) It is manufactured and sold under the commercial name [rKOL ID0N1]. povidone-iodine The product and its manufacturing method are manufactured by GAF Hosmer and Hosmer. 51gg1a)l: U.S. Patent No. 2.707. ．． No. 701, No. 2. 826. No. 532 and No. 2.900, 305 and GAF Publication Number; Examples For example, Tabletting with Povidone USP (1981 ) and PVP Polyvinylpyrro1idone (1982). It's listed.

There is extensive patent literature on the preparation and use of various iodine-polymer complexes, e.g. For example, U.S. Pat. No. 3,294,76 to Ort et al. No. 5 (1966, title of invention: production of povidone-iodine complex); Paravas et al. U.S. Pat. No. 3,468,831 (1969) to Barabas et al. Year.

Title of the invention (graft copolymer of N-vinylpyrrolidone): US patent of Barabas et al. No. 3,488.31.2 (1970, title of invention, water-insoluble graft polymerization) U.S. Pat. No. 3, Field et al. No. 689.438 (1972 9 Title of invention: Cross-linked polymer - Production of iodine); Field U.S. Patent No. 3,907.720 (1975 1 Title: Bridge Polymer-iodine production); Cantor et al. No. 4,017,407 (1977 9 Title of invention: Solid N-vinyl for iodine -2-Pyrrolidone polymeric carrier: Dixon US Pat. No. 4. 1 No. 39゜688 (name of invention of 1979, cross-linked vinylpyrrolidone) Dixo U.S. Patent No. 4,180,633 (1979) Title: Cross-linked Vinyl pyrrolidone); Lorenz et al., US Pat. No. 4. No. 190゜718 (19809 Name of the invention/Molecular weight of polyvinylpyrrolidone increase).

Under normal conditions PVP is stable as a solid and in solution. The most attractive part of PVP Its only property is its ability to combine. This property allows for many simplified applications. Ta. Small amounts of PVP can be absorbed as a thin layer on the surface of individual colloidal particles Stabilizes aqueous emulsions and suspensions by. The most widely researched and only the best A distinctive PVP complex is PVP-iodine. For example, hydrogen triiodide is PVP It forms a complex with , but it has no significant vapor pressure and is stable. it is a disinfectant It is better than tincture of iodine.

Various polyoxamers (i.e., polyether alcohols) also have effective iodine Carriers (i.e. Prepodyne, Sep povidone-iodine) and exhibits the same bactericidal activity as povidone-iodine. iodofo A is available in various forms, e.g. 10% applicator solution, 2% cleaning solution, aerosol. Spray, aerosol foam, vaginal gel for Trichomospinus and Candida infections Available in ointment powder, mouthwash, perineal cleanser and vortex concentrate (all 2%).

All iodophors can be used in this invention and are generally equivalent to povidone iodine it is conceivable that.

In addition to the risk of transmitting infectious diseases through blood and blood products, various manufacturing and processing steps The growth of bacteria in the blood and blood products in introduced, they must be removed before use. Molecular iodine, e.g. For example, if povidone = I2 is introduced at the initial processing stage of blood products, the final product or both components pyrogen load is significantly reduced or eliminated.

Generally, the invention relates to donated blood, preparations made from blood, and therapeutic biological fluids. Viruses, bacteria, Chlamydia spp. Inactivates Ketchia, Mycoplasma and other pathogenic microorganisms.

Hereinafter, various medical and blood processing methods will be cited, all of which are well known. As such, the steps in these methods are fully described in the literature. The following documents are Provides sources for general technical background and specific method literature: “Tec hnical Manual” of the American As5oci ation of Blood Bankers, 9th Ed, (1985) ;”H1+Δ Techniques for Blood Bankers, ”.

American Δ5 socaton of [31ood Bankers (1984): “Developments in Biological” 5 tandarization”, Vals, 1-57.S, Karger, B a5el; “clincal immunity”, the American As5ocation for C11nical Che mistry;-Medicine"Vols, 1-2.5 scientific American, New York; “Care of the Sur” gical Patient-, Vals, 1-2.5 patientfc Amc rcan, New York: “Current I’rotocols i "Malecular Biology", Greene Publisher ng As5ociajes and Wiley-1interscience , John Wiley & 5ons, NewYark0 Disclosure of Inventions Safe blood for transport is made by removing a substantial portion of plasma from all sides and optionally clotting to serum. solidify and contact the plasma, or optionally serum, with an effective solid source of oxidizing iodine to It inactivates pathogenic microorganisms in the liquid and also contains an effective amount of 0.01 to 5% by weight of iodine. disease in plasma or optionally serum and blood cell concentrates. Inactivates pathogenic microorganisms and virtually all pathogenic microorganisms in blood cell concentrates iodinated plasma or optionally iodinated plasma in sufficient quantity to cause Plasma containing 0.01 to 5% by weight of available iodine or optionally serum Manufactured by reconstituting whole blood by mixing with bulb concentrate. Any adding a virucidal or biocide composition to said plasma or optionally to said serum; or Can be added to reconstituted blood to promote inactivation of viruses or microorganisms. Ru.

BEST MODE FOR CARRYING OUT THE INVENTION Examples of basic methods of carrying out the invention are described below. The present invention is useful for whole blood collection and be able to be incorporated into processing technology, add further steps, and It will be understood that many different modifications may be made within the scope of the invention.

Transfusion-quality blood units are separated into plasma and blood cell (blood cell) concentrate. serum For example, coagulation of plasma or coagulation of another unit of whole blood from the same donor. is generated by. Plasma is removed by compressing the blood through a filter. After squeezing out a substantial amount of plasma from the container, it leaves behind a blood cell concentrate and makes the blood lighter. This can be accomplished by centrifuging and decanting the plasma, or by another method. Ru. Serum is obtained from plasma or from separate units of the same blood by coagulation and centrifugation or other Generated using conventional methods. Separate a substantial amount of plasma or optionally serum from this blood The production of blood cell concentrates can be performed using conventional methods. All of Although it is not necessary to separate plasma or serum from the blood, it is not necessary to separate the plasma or serum from the blood; Best results are obtained when substantially all of the plasma that is not trapped in the interstices is removed.

Plasma or optionally serum from the blood then incorporates iodine into the plasma or optionally serum. contact with a solid source of oxidizable iodine that retains the iodine sufficiently loosely as possible.

A convenient method of carrying out the invention is to pass the polymer-iodine particles through a bed (filter) of polymer-iodine particles. Expression of plasma or optionally serum. This is a solid source of oxidizing iodine and plasma or optionally serum from the blood or from the cell concentrate. help. Some forms of solid povidone-iodine or other polymeric-iodine carriers is a suitable form of the iodine.

Plasma or serum from the blood and hemocyte concentrates are reconstituted into whole blood or serum. Forms retained blood cells. Residual iodine in the plasma or serum is caused by blood cells (blood cells). All extracellular viruses in the concentrate or intracellular viruses by entering the cell. 0° in an amount sufficient to kill or inactivate substantially all or all of the 0.001 to 5% by weight, typically 0.1 to 1% by weight. Uses the least amount of iodine To maximize the efficacy of biocides in blood reconstituted using It is important to reconstitute relatively quickly after adding iodine to plasma or optionally serum. Ru. Although there is no exact time limit and the length of the delay is not critical, Suitably the blood cell product is administered within 1 hour after adding iodine to plasma or optionally serum. or reconstitute within about 17'4 hours. High levels of iodization remove the blood from blood or hemocyte suspension from hemocyte concentrate and iodinated plasma or optionally serum. You can delay reconfiguring the version for a longer period of time. Whole blood or serum-blood cell composition A short reaction engine is required after reconstitution. A minimum of about 2 minutes is required, but at least It also takes about 15 minutes.

Other biological fluids are treated in a similar manner.

The water wash consists of 9 turbid blood cells in serum from essentially the same blood, making it safe and free of pathogens. Added chemical substances that do not contain living organisms and exclude iodine and iodide produced by the reduction of iodine produce whole blood or blood substitutes that do not contain Iodine is present in all blood components. It is reduced fairly quickly to iodide, and blood proteins, e.g. It is bound to Bumin and is therefore non-toxic.

Optionally, after a suitable period of time ranging from a few minutes to an hour or more, the blood is converted into plasma and and an iodine solvent that does not affect the hydrophilic components. Iodine from the blood A suitable extraction solvent for removing is a straight chain alkali, for example n-hebutane.

Of course, the iodine reduced to iodide remains primarily in the aqueous phase. Other extraction solvents Examples include similar congeners of heptane and soybean, cottonseed, and corn oils.

Biologically, it is essentially inert and has a density sufficiently different from that of water, and the water is in the aqueous phase. A hydrophobic solution for iodine that is thought to have a sufficiently high interfacial tension to clearly separate it from Any medium can be used as the solvent.

If iodine needs to be completely converted to iodide, a biologically compatible reducing agent can be used. Original substances, e.g. reducing sugars, ascorbic acid, ascorbates, sodium sulfate Add. The reconstituted blood is prepared using a solid iodine-absorbing material, e.g. contact with starch or starch. In this process, all free iodine is absorbed. removed from reconstituted blood. Of course, it is also possible to combine various methods. It is Noh.

However, it is widely known that iodine is tolerated in vivo by almost all humans. It is known and has been firmly confirmed. Therefore, the present invention is applicable to povidone and other polymers. removes obstacles to introducing quality into the masticator's bloodstream.

Pathogenic microorganisms that can be inactivated by the present invention include viruses, bacteria, and chlamydia. dia, rickettsiae, mycoplasma and other potentially pathogenic microorganisms.

Data from the above co-pending application demonstrate the bactericidal and virucidal efficacy of iodine. Ru.

Industrial applicability The present invention is useful for producing blood for transfusion that is safe for animal and human therapy.

Claims (8)

[Claims] 1. Whole blood is divided into hemocyte concentrate and serum, and at least the resulting iodinated serum is Also, 0.01% by weight of I2 was added to inactivate the microorganisms in the serum and blood cell concentrate. The hemocyte concentrate and thus treated serum were reconstituted to a concentration of at least 0.001 % of I2 and a hemocyte concentrate, the reconstituted A human transfusion process consisting of holding a blood cell composition for a period of 2 minutes or more before transfusion into a patient. Method of manufacturing blood for blood use. 2. A product of the method of claim 1. 3. The process of adding iodine to serum converts serum from blood into solid polymer iodine. 2. The method of claim 1, comprising contacting with a complex. 4. A product of the method of claim 3. 5. The whole blood is divided into a hemocyte concentrate and plasma, and the plasma is treated with at least 0.01% by weight of I2. is added to inactivate the microorganisms in the plasma and blood cell concentrate, and at least 0. Whole blood was reconstituted from the processed plasma containing 0.001% by weight I2 and hemocyte concentrate. , the step of holding the two-component blood for a period of at least 2 minutes before transfusion to the patient. A method for producing blood for human transfusion. 6. A product of the method of claim 5. 7. The process of adding iodine to plasma converts plasma from blood into a solid polymer-iodine complex. The product of claim 5, which comprises contacting with the body. 8. A product of the method of claim 7.