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WO1997010268A1 - Hemoglobine obtenue par pulverisation-dessiccation - Google Patents

Hemoglobine obtenue par pulverisation-dessiccation Download PDF

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Publication number
WO1997010268A1
WO1997010268A1 PCT/NL1996/000355 NL9600355W WO9710268A1 WO 1997010268 A1 WO1997010268 A1 WO 1997010268A1 NL 9600355 W NL9600355 W NL 9600355W WO 9710268 A1 WO9710268 A1 WO 9710268A1
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WO
WIPO (PCT)
Prior art keywords
haemoglobin
solution
dried
composition
foregoing
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/NL1996/000355
Other languages
English (en)
Inventor
Jeroen Joost Valentijn Tahey
Henri Joseph Hubert Hens
Joachim Cornelis Bakker
Petrus Theodurus Maria Biessels
Willem Karel Bleeker
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.)
Stichting Centraal Laboratorium Van de Bloedtransfusiedienst Van
Nederlanden Minister van Defensie Militair Geneeskundig Beleid
Original Assignee
Stichting Centraal Laboratorium Van de Bloedtransfusiedienst Van
Nederlanden Minister van Defensie Militair Geneeskundig Beleid
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 Stichting Centraal Laboratorium Van de Bloedtransfusiedienst Van, Nederlanden Minister van Defensie Militair Geneeskundig Beleid filed Critical Stichting Centraal Laboratorium Van de Bloedtransfusiedienst Van
Priority to AU70989/96A priority Critical patent/AU726684B2/en
Priority to JP9511855A priority patent/JP2000505049A/ja
Priority to EP96932079A priority patent/EP0862583A1/fr
Publication of WO1997010268A1 publication Critical patent/WO1997010268A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/795—Porphyrin- or corrin-ring-containing peptides
    • C07K14/805—Haemoglobins; Myoglobins

Definitions

  • This invention relates to methods for obtaining a dried haemoglobin product with a long shelf life, which can be reconstituted quickly and easily, having sufficient low levels ot methaemoglobin to effectively function as an oxygen carrying solution upon administration to a patient
  • the invention further relates to the dried compositions themselves and to the reconstituted product which has a physiologically acceptable formulation
  • the haemoglobin based composition includes all preparations of haemoglobin, modified haemoglobin, recombinant haemoglobin and/or encapsulated haemoglobin
  • haemoglobin solution must be carried out in such a way that characteristics, such as oxygen-carrying capacity, polymer- and ionic composition remain substantially unchanged
  • the haemoglobin can be stored either as a solution or as a dried product
  • a dried product can be achieved for instance by freeze-drying (ChaiHot 1981) spray-drvmg (Franks et al 1992, Labrude et al , 1989) or spray- granulation
  • freeze-drying ChaiHot 1981
  • spray-drvmg Frranks et al 1992, Labrude et al , 1989
  • spray- granulation The advantages of a dried product over a solution are clearly the storage life (shelf life) and the storage volumes
  • the advantages of spray-drying or spray-granulation over freeze-drying are shorter process times and less energy consumption
  • spray-dried/granulated materials generally take the form of homogeneous powders, which are less hygroscopic than those obtained
  • injectable preparations which are solutions when examined under suitable conditions of visibility, should be clear and practically free from particles. Additionally, where stated in individual monographs, solutions to be injected and which are supplied in containers of 100 ml or more should comply with the limit test for particulate matter In this test, the number of particles per 1 0 ml of the product is determined The average particle count, for the undiluted product, should not exceed 1000 per ml for particles greater than 2 0 ⁇ and should not exceed 100 per ml for particles greater than 5 0 ⁇ m.
  • haemoglobin based compositions should comply with a test for (large volume) parenteral injections
  • the use of the granulation technique, with or without a binding agent, in combination with the process conditions reduces the particulate contamination to an acceptable level
  • the invention thus provides a method for preparing a dried reconstitutable haemoglobin composition having a long shelf life, which composition can be reconstituted to a solution having a colloid-osmotic pressure of about 20-40 mbar and an osmolarity of about 250-350 rrtosm/1, whereby in said method a solution comprising haemoglobin is provided, which solution is divided into small droplets, which droplets are dried to a solid particle form by a stream of inert gas.
  • the haemoglobin may be in any form, it may also be chemically modified, recombinant or encapsulated It is however important to protect the haemoglobin in whatever form of degradation Therefore the haemoglobin solution further contains at least one stabilising additive.
  • the additive may be any one that protects the haemoglobin from said degradation and is compatible with administration to a patient
  • Preferred stabilising additives are sucrose, dextran-1 or human serum albumin or combinations thereof
  • the dried compositions must be easily reconstitutable to solutions having physiologically acceptable properties especially regarding the osmotic properties of the reconstituted solution.
  • the protective additives should be added in amounts that will lead to protection of the haemoglobin but also to physiologically acceptable properties upon reconstitution w th Water For Injection or aqueous solutions such as saline
  • the granulation step is included in the process of drying Granulation of the particles may be carried out by wetting the surface of the solid particles in a fluidised bed This causes the particles to fuse
  • a binding agent is used, the solid particles will agglomerate In this way the material of the binding agent forms bridges between the solid particles in the fluidised bed
  • the binding agent should be very soluble in aqueous solutions and capable to "glue" the solid haemoglobin based particles together
  • the binding agent should be compatible with administration to a patient and should be added in amounts that will lead to a functional and physiologically acceptable formulation
  • Preferred binding agents are sodium chloride, sucrose, dextran-1, sodium lactate or compositions thereof These amounts can be readily determined by a person skilled in the art and depend among others on the final
  • a carrier substance may be used in the granulation process to reduce particulate contamination
  • the carrier substance should be very soluble in aqueous solutions, compatible with administration to a patient and added in amounts that will lead to a functional and physiologically acceptable formulation
  • Preferred carrier substances are sodium chloride and human serum albumin These amounts can be readily determined by a person skilled in the art and depend among others on the final formulation of the composition.
  • the final composition should have a colloid osmotic activity 10-300 mbar, preferably an colloid osmotic pressure in a range between 20 and 40 mbar depending on the therapeutic use
  • the osmolarity should be in a range between 150 and 600 mosm/1 preferably in the range between 250 and 350 mosm/1 , more preferably between 280-300 mosm/1 (Henry et al (ed), 1974) also depending on the therapeutic use.
  • the maximum methaemoglobin concentration that can be allowed is 15% (w/w) of the total haemoglobin concentration
  • the methaemoglobin concentration should be below 5% of the total haemoglobin concentration
  • the spray-drying and -granulation process for instance operate as follows.
  • the first stage is to provide a solution of the haemoglobin based composition formulated in Water For Injection This may be done by ultrafiltration or dialysis or any other suitable method. To shorten the process time of the drying process, a concentrated solution, of up to 20% (w/w) haemoglobin is preferred.
  • the second step is the addition of the desired protective additives
  • the protective additive may be sucrose, dextran-1 or any other additive (e.g. sugars or amino acids) that protects the haemoglobin from degradation
  • the protective additives should be added in an amount to be able to protect the haemoglobin from degradation and to preserve the physiological acceptability of the reconstituted product
  • sucrose this amount will vary between approximately 50 mM and 300mM, preferably 130mM.
  • dextran 1 this amount will vary between approximately 30mM and lOOmM, preferably 70mM and for human serum albumin between approximately 15 ⁇ M and 1.5rr-M, preferably 0 15mM.
  • concentrations are all based on the final reconstituted formulation of approximately 6.4mM haemoglobin (16kD) and depend on the therapeutic use and the final formulation of the composition.
  • an electron quenching additive may be used to prevent oxidation of the haemoglobin caused by free radicals, e.g induced by (direct) light
  • the electron quenching additive should be soluble in aqueous solutions, compatible with administration to a patient, and added in amounts that lead to a functional and physiologically acceptable formulation These amounts can be readily determined by a person skilled in the art and depend among others on the final formulation of the composition.
  • Preferred electron quenching additives are ascorbic acid and human serum albumin, but may be any other additive that quenches free electrons (e.g. anti-oxidants) .
  • the solution is preferably stabilised by exclusion of oxygen.
  • the haemoglobin is deoxygenated by use of, for example, a hollow fibre system in combination with nitrogen, but any other inert gas may be used.
  • the haemoglobin may be stabilised by saturation with a specific binding compound such as carbon monoxide .
  • the next step is the drying operation
  • a spray-granulation process is performed to dry the product, preferably into granulates
  • Three methods to be used to start the granulate formation are exemplified
  • aqueous haemoglobin mixture is spray-dried into a drying chamber by using a high flow of a drying gas.
  • the spray-dried powder is for the largest part collected on a filter and no fluidised bed is formed
  • the drying gas throughput is lowered to form a fluidised bed and the granulation process starts In this way haemoglobin itself is used as the granulate starter
  • a separate starting material is used to create a fluidised bed
  • the product to be dried is directly sprayed into the fluidized bed and is granulated immediately
  • Apparatus to carry out spray-granulation on a fairly small scale are available from various manufacturers One is Heinen GmbH, Varel, Germany who manufactures a small scale batch-drier. Another manufacturer is Niro Aeromatics, Bubendorf, Switzerland who manufactures a small-scale spray-drier/granulator Process plants to carry out spray- granulation on a larger scale are also available
  • Figure 1 shows a schematic diagram of the spray-granulator In this apparatus the drying gas is drawn in by a blower (1) and passes over an electric heater (2) Then the gas is blown upwards into the drying chamber (3) passing a sieve (4)
  • the aqueous mixture to be sprayed is drawn up from a supply vessel (5) by means of a peristaltic metering pump (6) and delivered to a spray nozzle (7) which discharges the aqueous mixture as a fine spray (10) into the streams of hot drying gas coming from the heater (2)
  • the stream of hot drying gas and the product are counter current
  • the spray droplets are dried to a solid powder form as they pass down mside the drying chamber (3) Before the spray droplets are completely dried, they make contact with the material in the fluidised bed (9)
  • the granulation process takes place by wetting the surface of the particles in the fluidised bed This causes the particles to fuse or when a binding agent is used, the particles are "glued” together by agglomeration In this way, after multiple steps, a
  • a significant parameter in the operation of any spray- drying or -granulating apparatus is the temperature of the gas stream which is admitted to the drying chamber and into which the spray is delivered
  • this inlet temperature of the gas stream will generally exceed 80°C will usually be approximatel 100°C and mav veil lie _.n a range from 100°C up to 150°C
  • the drying gas will topically be nitrogen but could be some other gas
  • haemoglobin composition according to the invention comprises less than 15%, preferably less than 5% methaemoglobin
  • the composition should be stable for periods in the order of many months, preferably for at least a year, when kept at temperatures in the range of 0 - 30° For actual prolonged storage, refrigerator temperatures should of course be chosen
  • the dried product results in a solution containing less than 1000 particles per ml having a size greater than 2 ⁇ m and less than 100 particles per ml having a size of greater than 5 ⁇ m
  • Reconstitution, optionally after storage, from a composition produced by drying in accordance with this invention can be effected by adding the desired solution to a quantity of the composition
  • the solvent may be Water For Injection or an infusion liquid, but the result has to be a physiologicallv acceptable formulation
  • _.t is important that reconstitution of the material is an easy process, without the need of any (electronical) equipment.
  • the material has to dissolve almost instantaneously and completely.
  • the solution should not be shaken during reconstitution.
  • a wetting agent may be used.
  • the wetting agent may be lecithin (phosphatidylcholine), Tween (polyoxyethylene sorbitan monooleaat) , Triton (alpha [4-(l,l,3,3,- Tetramethylbutyl)phenyl] - ⁇ -hydroxypely (oxy-1, 2-ethanediyl) or any other additive (eg. surfactants) which improve the solubility.
  • lecithin phosphatidylcholine
  • Tween polyoxyethylene sorbitan monooleaat
  • Triton alpha [4-(l,l,3,3,- Tetramethylbutyl)phenyl] - ⁇ -hydroxypely (oxy-1, 2-ethanediyl) or any other additive (eg. surfactants) which improve the solubility.
  • the wetting agent should be compatible with administration to a patient and should be added in amounts that will lead to a physiologically acceptable formulation. These amounts can be readily determined by a person skilled in the art.
  • the reconstituted product according to the invention is an optically clear, dark red solution and has sufficient low levels of particulate contamination to be safe for use as a large volume parenteral injection. It has an osmolarity of between 150 and 600 mosm/1, preferably between about 250-350 mosm/1 , more preferably between about 280-300 mosm/1. Besides, it has a colloid osmotic pressure between 10 and 300 mbar, preferably between about 20-40mbar.
  • the solution reconstituted from the dried haemoglobin has sufficient low levels of methaemoglobin to effectively function as an oxygen carrying solution after reconstitution and upon parenteral administration to a patient.
  • the reconstituted product obtainable by a method according to this invention is of course also part of the invention.
  • Example 1 Preparation of anaerobically spray-granulated deoxyhaemoglobm A 0.22 ⁇ m filtered solution of modified haemoglobin (polyHbXl, CLB) in Water For Injection, containing 150 gram haemoglobin and 68 gram sucrose (Merck) per litre is spray- granulated by the use of a He en batch drier, type CWT 3,5 RFS The haemoglobin solution is deoxygenated before use
  • the mlet temperature of the drying gas is set to 100°C
  • the gas flow is set high, so no fluidised bed is formed yet
  • the haemoglobin solution is spray-dried into the drying chamber with a flow rate of approximately 50 ml/min
  • the temperature of the emerging gas is approximately 55°C.
  • the gas flow is lowered in order to obtain a fluidised bed
  • the temperature of the emerging gas is kept at approximately 55°C by lowering the flow of the haemoglobin solution to approximately 20 ml/min.
  • the spray-dried material becomes granulated by spraying on top of the fluidied bed.
  • the inlet temperature of the drying gas is set to 20°C to cool the haemoglobin granulates
  • the cooled powder is aseptically removed from the granulator and filled in 72.7 gram quantities (excl residual moisture) in sterilised glass bottles of 500 ml
  • the removal of the haemoglobin granulates and the filling of the glass bottles is performed under anaerobic conditions
  • the glass bottles are stoppered and capped.
  • one unit (72 7 gram) of the dried product is dissolved in a 500 ml solution of lactated Ringer (Fresenius) and Water For Injection (50/50 (v/v)) resulting in a 10% (w/w) haemoglobin solution with 133 mM sucrose
  • lactated Ringer Fresenius
  • Water For Injection 50/50 (v/v)
  • one unit (75 7 gram powder) of the dried product is solved in a 500 ml solution of lactated Ringer without sodium chloride and Water For Injection (50/50 (v/v)), resulting in a 10% (w/w) haemoglobin solution with 133 mM sucrose and 102 mM sodium chloride.
  • the final product so obtained has substantially not altered physical-chemical properties when compared with the raw material
  • the haemoglobin solution is deoxygenated before use (Capiox 350 oxygenator Terumo) and the drying gas is nitrogen (medical grade, Air Products)
  • the mlet temperature of the drying gas is set to 100°C
  • the solution is sprayed into the drying chamber ⁇ ith a flow rate of approximately 3 ml/min
  • the temperature of the emerging gas is approximately 70°C
  • the inlet temperature of the drying gas is set to 20°C to cool the haemoglobin product
  • the cooled powder is removed from the drier and filled in 1 0 gram quantities (excl residual moisture) into sterilised glass vials of 20 ml
  • the cooled powder
  • one unit 75 7 gram of the dried product is dissolved in a 500 ml solution of lactated Ringer without sodium chloride and Water For Injection (50/50 (v/v/)), resulting in a 10% (w/w) haemoglobin solution with 133 mM sucrose and 102 mM sodium chloride
  • the final product so obtained has substantially not altered physical-chemical properties when compared with the raw material
  • Withm minutes after addition of the solvent the granulated product is dissolved and the solution is ready to use
  • the let temperature of the drying gas is set to 20°C to cool the haemoglobin granulates
  • the cooled powder is aseptically removed from the granulator and filled in 100 0 gram quantities (excl residual moisture) into sterilised glass bottles of 1000 ml
  • the removal of the haemoglobin granulates and the filling of the glass bottles is performed under aerobic conditions
  • the glass bottles are stoppered and capped
  • the methaemoglobin content increased by approximately 5% of the total haemoglobin
  • the characteristics (oxygen affinity, molecular weight distribution) of the haemoglobin proved to be substantially not altered during 24 months of storage at 4°C and 20°C
  • the methaemoglobin content increased by less than 6% of the total haemoglobin over the total period and less than 2% of the total haemoglobin during the last 23 months
  • the methaemoglobin content increased by less than 15% of the total haemoglobin over the total period
  • the stability of the haemoglobin proved to be even better when the complete process and storage is performed under anaerobic conditions Based on these and other data, we expect the granulated haemoglobin product to be stable for a period of at least 5 years
  • haemoglobin is a pasteurised stroma free haemoglobin solution (sfHb, CLB)
  • sfHb pasteurised stroma free haemoglobin solution
  • CLB lactated Ringer and Water For Injection

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Saccharide Compounds (AREA)
  • Drying Of Solid Materials (AREA)
  • Vaporization, Distillation, Condensation, Sublimation, And Cold Traps (AREA)

Abstract

L'invention porte sur un procédé d'obtention d'un produit sec à base d'hémoglobine stable en cas de stockage prolongé (plusieurs années) à la température ambiante (4-30°C) rapidement soluble (dans les 10 minutes, ou mieux dans les 5 minutes, ou encore mieux dans la minute), facilement (sans installations spéciales), et totalement (en donnant une solution limpide d'un rouge sombre présentant un minimum de contamination par des particules). La solution reconstituée à partir d'hémoglobine desséchée présente un niveau suffisamment bas de méthémoglobine pour servir de vecteur d'oxygène après reconstitution, et administration parentérale. Le produit reconstitué présente par ailleurs une formule physiologiquement acceptable (osmolarité normalement comprise entre 250 et 350 mosm/1) et une activité osmotique du colloïde. Le procédé de dessiccation peut s'appliquer à de l'hémoglobine, à de l'hémoglobine modifiée, à de l'hémoglobine reconstituée ou à des préparations d'hémoglobine en capsules. Le produit sec est obtenu par granulation-pulvérisation, avec adjonction d'un ou deux additifs protecteurs et éventuellement d'un vecteur destiné à réduire la contamination par les particules. Pour empêcher l'oxydation de l'hémoglobine, le traitement et le stockage peuvent avoir lieu dans une atmosphère sans oxygène, d'azote ou d'autres gaz inertes.
PCT/NL1996/000355 1995-09-11 1996-09-10 Hemoglobine obtenue par pulverisation-dessiccation Ceased WO1997010268A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU70989/96A AU726684B2 (en) 1995-09-11 1996-09-10 Spray-drying haemoglobin
JP9511855A JP2000505049A (ja) 1995-09-11 1996-09-10 噴霧乾燥化ヘモグロビン
EP96932079A EP0862583A1 (fr) 1995-09-11 1996-09-10 Hemoglobine obtenue par pulverisation-dessiccation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP95202463 1995-09-11
EP95202463.6 1995-09-11

Publications (1)

Publication Number Publication Date
WO1997010268A1 true WO1997010268A1 (fr) 1997-03-20

Family

ID=8220626

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL1996/000355 Ceased WO1997010268A1 (fr) 1995-09-11 1996-09-10 Hemoglobine obtenue par pulverisation-dessiccation

Country Status (5)

Country Link
EP (1) EP0862583A1 (fr)
JP (1) JP2000505049A (fr)
AU (1) AU726684B2 (fr)
CA (1) CA2229408A1 (fr)
WO (1) WO1997010268A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60178822A (ja) * 1984-02-22 1985-09-12 Ajinomoto Co Inc 修飾ヘモグロビンのメト化防止剤
EP0290252A2 (fr) * 1987-05-05 1988-11-09 Majesty The Queen In Right Of Canada As Represented By The Minister Of National Defence Of Her Majesty's Canadian Gov. Her Substitut du sang pasteurisable, lyophilisable, à base d'hémoglobine
WO1990013780A1 (fr) * 1989-05-01 1990-11-15 Enzytech, Inc. Coulage a tres basse temperature de microspheres a liberation regulee
EP0520748A1 (fr) * 1991-06-26 1992-12-30 Pafra Limited Emmagasinage de matériaux

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60178822A (ja) * 1984-02-22 1985-09-12 Ajinomoto Co Inc 修飾ヘモグロビンのメト化防止剤
EP0290252A2 (fr) * 1987-05-05 1988-11-09 Majesty The Queen In Right Of Canada As Represented By The Minister Of National Defence Of Her Majesty's Canadian Gov. Her Substitut du sang pasteurisable, lyophilisable, à base d'hémoglobine
WO1990013780A1 (fr) * 1989-05-01 1990-11-15 Enzytech, Inc. Coulage a tres basse temperature de microspheres a liberation regulee
EP0520748A1 (fr) * 1991-06-26 1992-12-30 Pafra Limited Emmagasinage de matériaux

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LABRUDE, P. ET AL: "Protective effect of sucrose in spray drying of oxyhemoglobin", J. PHARM. SCI. (1989), 78(3), 223-9, XP002022148 *
PATENT ABSTRACTS OF JAPAN vol. 010, no. 023 (C - 325) 29 January 1986 (1986-01-29) *

Also Published As

Publication number Publication date
EP0862583A1 (fr) 1998-09-09
JP2000505049A (ja) 2000-04-25
AU726684B2 (en) 2000-11-16
AU7098996A (en) 1997-04-01
CA2229408A1 (fr) 1997-03-20

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