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WO2004112630A2 - Formulation et procede limitant lors du stockage la deterioration du sang pondant son stockage, et particulierement la baisse du niveau de 2,3 diphcisphoglycerate - Google Patents

Formulation et procede limitant lors du stockage la deterioration du sang pondant son stockage, et particulierement la baisse du niveau de 2,3 diphcisphoglycerate Download PDF

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Publication number
WO2004112630A2
WO2004112630A2 PCT/IN2003/000225 IN0300225W WO2004112630A2 WO 2004112630 A2 WO2004112630 A2 WO 2004112630A2 IN 0300225 W IN0300225 W IN 0300225W WO 2004112630 A2 WO2004112630 A2 WO 2004112630A2
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WO
WIPO (PCT)
Prior art keywords
blood
solution
formulation
level
diphosphoglycerate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2003/000225
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English (en)
Other versions
WO2004112630A3 (fr
Inventor
Achutha Kurup Parameswara
Arun Peethambaran
Balagopal Chandrasekhar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TERUMO PENPOL Ltd
Original Assignee
TERUMO PENPOL Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by TERUMO PENPOL Ltd filed Critical TERUMO PENPOL Ltd
Priority to AU2003253248A priority Critical patent/AU2003253248A1/en
Priority to PCT/IN2003/000225 priority patent/WO2004112630A2/fr
Publication of WO2004112630A2 publication Critical patent/WO2004112630A2/fr
Publication of WO2004112630A3 publication Critical patent/WO2004112630A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/02—Blood transfusion apparatus
    • A61M1/0272—Apparatus for treatment of blood or blood constituents prior to or for conservation, e.g. freezing, drying or centrifuging

Definitions

  • TITLE - A FORMULATION AUD A PROCESS FOR REDUCING THE DETERIORATION OF BLOOD WITH PARTICULAR REFERENCE TO DECREASE IN THE LEVEL OF 2,3 DIPHOSPHOGLYCERATE DURING STORAGE
  • This invention relates to a formulation and a process for redudng the deterioration of blood particularly the decrease in the level of 2 f 3 Diphosphoglycerate during storage.
  • Blood is usually collected and stored in certain anticoagulant preservative solutions like ACD (acid-citrate-dextrose), CPD (dtrate-phosphate-dextrose) and CPDA (dtrate-phosphate-dextrose-adenine).
  • ACD acid-citrate-dextrose
  • CPD dtrate-phosphate-dextrose
  • CPDA dtrate-phosphate-dextrose-adenine
  • An ACD solution may contain- Trisodium citrate (dihydrate) 22.0g Citric acid (anhydrous) S.Og Dextrose (monohydrate) 24.6g Distilled Water to make up to 1 litre
  • a CPD solution may contain-
  • a CPDA solution may contain-
  • the plastic Bags normally used for the collection and storage of blood may be P ⁇ /C Bags which use di-(2- ⁇ thyi hexyl) phthalate (D&iP), tri-(2-ethyl hexyl) trimellitate (TBfTM) or butyl-n-tri-hexyi citrate (BTHC) as the plasticizer or non-PVC Bags like, polyolefin.
  • D&iP di-(2- ⁇ thyi hexyl) phthalate
  • TBfTM tri-(2-ethyl hexyl) trimellitate
  • BTHC butyl-n-tri-hexyi citrate
  • Any increase in plasma hemoglobin may cause renal failure and other complications when blood containing high levels of plasma hemoglobin Is transfused. Increased plasma potassium may cause hyperkalemia which may result in cardiac complications.
  • D&IP plasticiz ⁇ d PVC Bags Another deleterious effect of storage when D&IP plasticiz ⁇ d PVC Bags are used, is an increase in the amount of D&1P solubilized in the blood, which may cause toxic problems in recipients of blood transfusion.
  • D&1 has been reported to be toxic particularly to the liver and reproductive organs and is also carcinogenic.
  • DB P at low levels causes decrease In Insulin and cortispl, depletion of fat soluble vitamins (A D & E), increase in T 3 & T 4 and more important inhibition of membrane bound Na + - K ATPase.
  • a D & E fat soluble vitamins
  • T 3 & T 4 and more important inhibition of membrane bound Na + - K ATPase.
  • the last observation is significant since it is now known that there is inhibition of this enzyme activity in a variety of pathologic conditions like neurodegenerative disorders, cardiovascular disease, diabetes, cancer etc.
  • the decrease in the level of ATP is not very drastic, but the level of 2, 3 DPG fells to a very low level during storage.
  • the invivo restoration of 2, 3 DPG depends on the level of 2, 3 DPG in the blood transfused. If the level is very low, then it may take a long time, some time over 20hrs to restore the original level.
  • a major purpose of blood transfusion is to restore oxygen supply to the tissues. This is particularly so in transfusions with compromised circulation in the heart or brain, or in massive loss of blood. This is also more particulariy important in infants, since inadequate delivery of oxygen can result in development of hypoxy/ischemic encephalopathy, the major cause of long term rr ⁇ uro developmental problem in children.
  • 2, 3 DPG has a regulatory effect on the oxygen affinity of hemoglobin and on oxygen transport invivo.
  • Hemoglobin binds to oxygen to form oxyhemoglobin which does not release oxygen to the tissues.
  • 2,3 DPG binds strongly to oxyhemoglobin and this binding decreases the affinity of hemoglobin to oxygen with consequent release of oxygen to the tissues. Therefore an adequate level of 2,3DPG in the blood is essential particularly in critical situations like cardiac surger , brain surgery or in case of massive hemorrhage.
  • ATP level is a measure of the metabolic activity of the cells, particularly RBCs. Maintaining of red cell viability is relatively closely associated to the cellular concentration of ATP. Since ATP level does not fell to a level below 50% of the original level, post transfusion restoration of ATP does not take much time, as is the case with the situation in 2, 3 DPG
  • ATP is produced by RBCs during glycolysis, which also produces 2,3DPG from 1,3- diphosphoglycerate by the drphospho glycerate shunt
  • 1, 3-df phospho glycerate produced during glycolysis has two metabolic hurdles, one, it is converted directly to 3-ph ⁇ spho glycerate and continues in the glycolytic pathway to lactate.
  • the second one is the shunt pathway where it is converted to 2, 3-diphospho glycerate by the action of the enzyme 2, 3-diph ⁇ spho glycerate mutase.
  • 2, 3-diphospho glycerate is then acted on by 2,-diphospho glycerate phosphatase to form 3- phospho glycerate which continues in the glycolytic pathyway.
  • Nicotinic acid may be replaced by nicotinamide.
  • This invention provides a Double Blood System comprising of 2 Bags - Primary Bag and Satellite Bag.
  • the Primary Bag contains solution A and Satellite Bag solution B.
  • This invention relates to a anti-coagulant preservative formulation solution used in the process of collection and preservation of blood.
  • This Invention relates to an apparatus and a process for preparing a formulation for reducing the deterioration of blood with particular reference to decrease in the level 2, 3 diphosphoglycerate during storage using the Double Blood Bag system herein above mentioned along with the anti-coagulant preservative formulation solution herein mentioned.
  • the solution B contained in Satellite Bag B is transferred to Primary Bag A containing the solution A and mixed.
  • the blood is collected in the mixed solution in the Primary Bag A
  • This formulation Is effective in minimizing the deleterious effects which occur during storage of blood in Wood Bags.
  • a formulation for better storage and preservation of blood characterized in that it has a PH above 7.Q, it contain nicotinic add and ascorbic add at optimum levels.
  • None of the anticoagulant preservative solutions hitherto known contains nicotinic add and ascorbic acid or has PH above 7.0, and as stated herein above it was an important finding for us to see that the incorporation of nicotinic add and ascorbic acid and maintaining PH above 7.0 of the anticoagulant preservative solution considerably reduces the deterioration of blood during storage.
  • an apparatus and a process for preparing a formulation for reducing the deterioration of blood during storage characterized in that the anticoagulant preservative solution used for the preservation of blood is modified by the incorporation of nicotinic acid, ascorbic acid and keeping PH above 7.0.
  • the concentration of nicotinic add used in the anticoagulant solution may vary, and it may preferably be in the range of 5 to 8 mg/dl blood to be collected. However the optimum concentration was found to be 6.8 m ⁇ /dl of blood collected.
  • the nicotinic acid may be replaced by nicotinamide for same results.
  • the concentration of ascorbic add used in the anticoagulant solution also may vary, and it may preferably be in the range of 3 to 5 mg/dl blood to be collected. However the optimum concentration with minimum hemolytfc effect and maximum beneficial effects was found to be 4.0 mg/dl blood collected.
  • the PH of the preservative solution can vary from 7,0 to 8.0, but the optimum PH was found to be optimum at 7.6.
  • Double Blood Bag which had a Primary Bag A and Satellite Bag B.
  • the Bag system containing the respective solution in A and B is autoclaved at a temperature of 1170C at 15lbs pressures for 15 minutes.
  • solution from the Satellite Bag (B) is transferred to the solution in the Primary Bag (A) and the contents thoroughly mixed. Blood is collected in the mixed solution.
  • Blood is collected from the donor as per usual procedure, mixed with the anticoagulant preservative solution, in one case the modified formulation was used and in the other, normal CPDA solution.
  • Various biochemical parameters are studied in an aliquot immediately after collection of blood (O day ) and the Bags are kept at 4 ⁇ 1° C. These parameters are again measured after 28 days in another aliquot
  • 2,3 DPG is essential for maintaining oxygen delivery to the tissues.
  • Plasma Hb and plasma K* ana measures of hemolysis. The extent of hemolysis should be low.
  • ATP is a measure of metabolic activity of red cells.
  • Malondialdehyde is a measure of lipid peroxidation and its higher concentration indicates higher lipid peroxidation, which is harmful.
  • Reduced glutathione is an antiox ⁇ dant, which protects against the harmful effects of lipid peroxidation.
  • concentration the higher is the protective effect
  • D&IP is harmful and a lower level in the blood is desirable.
  • the concentration of nicotinic acid is varied for 3 to 6 mg/dl blood collected. Similarly the concentration of ascorbic acid is kept constant while that of nicotinic acid was varied from 5 - 8 mg/dl blood collected. Optimum beneficial effects are obtained when the concentration of nicotinic a id is 68 mg/dl blood collected and that of ascorbic acid 4.0 mg/dl blood collected.
  • the modified solution is thus effective in preventing the drastic fell in 2,3 DPG that take place during storage of whole blood.
  • the level of 2,3 DPG improved over 1100%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

Une solution de CPDA (citrate-phosphate-dextrose-adénine) est l'agent conservateur anticoagulant le plus largement utilisé pour la collecte et le stockage de sang entier dans des poches à sang. Même si la période autorisée de stockage de sang dans une solution de CPDA est de 35 jours, on constate une détérioration régulière et progressive de la qualité du sang avec la durée de stockage. Les changements les plus néfastes sont: une décroissance importante du niveau de 2,3 diphosphoglycérate (essentiel pour assurer l'apport d'oxygène aux tissus), une hémolyse accrue (qui libère dans le plasma du Hb et du K+, provenant des globules rouges, tous deux nocifs), et une solubilisation progressive du di-(2-éthyl héxyl) phthalate (DEHP), le plastifiant généralement utilisé pour la fabrication des poches de sang, qui est également nocif. L'invention porte donc sur un procédé réduisant la détérioration du sang, et en particulier celle due à la baisse du 2,3 diphosphoglycérate, pendant le stockage du sang, au moyen d'une formulation d'agent conservateur anticoagulant qui limite l'étendue de ces altérations, en particulier la diminution importante du 2,3 DPG.
PCT/IN2003/000225 2003-06-20 2003-06-20 Formulation et procede limitant lors du stockage la deterioration du sang pondant son stockage, et particulierement la baisse du niveau de 2,3 diphcisphoglycerate Ceased WO2004112630A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003253248A AU2003253248A1 (en) 2003-06-20 2003-06-20 A formulation and a process for reducing the deterioration of blood with particular reference to decrease in the level of 2,3 diphosphoglycerate during storage
PCT/IN2003/000225 WO2004112630A2 (fr) 2003-06-20 2003-06-20 Formulation et procede limitant lors du stockage la deterioration du sang pondant son stockage, et particulierement la baisse du niveau de 2,3 diphcisphoglycerate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000225 WO2004112630A2 (fr) 2003-06-20 2003-06-20 Formulation et procede limitant lors du stockage la deterioration du sang pondant son stockage, et particulierement la baisse du niveau de 2,3 diphcisphoglycerate

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WO2004112630A2 true WO2004112630A2 (fr) 2004-12-29
WO2004112630A3 WO2004112630A3 (fr) 2005-02-24

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PCT/IN2003/000225 Ceased WO2004112630A2 (fr) 2003-06-20 2003-06-20 Formulation et procede limitant lors du stockage la deterioration du sang pondant son stockage, et particulierement la baisse du niveau de 2,3 diphcisphoglycerate

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AU (1) AU2003253248A1 (fr)
WO (1) WO2004112630A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6447987B1 (en) * 1978-09-09 2002-09-10 The United States Of America As Represented By The Secretary Of The Army Prolonged storage of red blood cells

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Publication number Publication date
WO2004112630A3 (fr) 2005-02-24
AU2003253248A1 (en) 2005-01-04

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