PROCESS FOR MANUFACTURING IRON DEXTRAN USING ULTRAFILTRATION

PROCEDE DE FABRICATION DE FER-DEXTRAN PAR ULTRAFILTRATION

English Abstract

A process for manufacturing Iron Dextran comprising, forming a direct complex of dextran with ferric chloride, and using an ultrafiltration membrane having a molecular weight cut off between 5,000 to 50,000 to purify the product.

French Abstract

Procédé permettant de fabriquer du dextrane de fer, consistant à former un complexe direct de dextrane avec du chlorure ferrique, et à utiliser une membrane d'ultrafiltration de masse moléculaire se situant entre 5 000 et 50 000 pour purifier le produit.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for manufacturing Iron Dextran comprising,
forming a direct complex of dextran with ferric chloride,
and using an ultrafiltration membrane to purify the product.
2. The process of claim 1 wherein the ultrafiltration
membrane has a molecular weight cutoff between 5,000 to
50,000.
3. The process of claim 1 wherein the Fe content of the
product is between 5 to 20%.
4. The process of claim 2 wherein the Fe content of the
product is between 5 to 20%.
5. An Iron Dextran product made by the process of claim 1,
2, 3 or 4 which is substantially free of impurities.
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Description

2195283
90030-23 RDF:bw
PROCESS FOR MANUFACTURING IRON DEXTRAN
USING ULTRAFILTRATION
It is well known that the so called "IRON DEXTRAN"
preparation has been developed and utilized as a satisfactory
product for therapeutic use, as intramuscular injection in
animals and intravenous injection in humans for correcting
iron deficiencies.
A wide variety of preparations have been utilised for the
above purpose. Most preparations of iron dextran are made,
using degraded dextran complex with ferric hydroxide and
purified alcohol, e.g. isopropyl alcohol, ethyl alcohol,
methyl alcohol etc.
The raw dextran is obtained according to known methods by
growing organisms, especially leuconostoc mesenteroldes, under
carefully controlled conditions in a suitable nutrient medium
with high concentration of sugar. Crude dextran is partially
hydrolysed by dilute mineral acid. Fractions of different
average molecular weight can be precipitated with organic
liquid such as isopropyl alcohol, methyl alcohol, ethyl
alcohol. This degraded product consists of polymerized
glucose in which the anhydroglucose units are linked
predominantly by oo-1:6 and to a lesser extent by o0-1:4
linkage.
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CA 02195283 2004-12-13
The dextrans used for most Iron Dextran preparations have
molecular weight less than 10,000. After fractionation,
dextran is converted to heptonic acid with an alkali metal such
as cyanide, or hydrogenated with sodium borohydride as
described in US Patent No. 3,234,209.
Further, experience with manufacturing Iron Dextran
complex using the above method has indicated loss of dextran
and Iron Dextran during precipitation with alcohol and
consequent loss of stability of final product. Again due to
purification with alcohol. The product from this standard
method has pronounced variation such as pH, Dextran content,
colour and chemical variation from batch to batch.
We have now discovered a process for manufacturing Iron
Dextran, using dextran produced with a known process, which by
a direct complex with ferric chloride and, with modified
purification method, produces a stable complex with minimum
variation from batch to batch.
Purification is done using tightly controlled molecular
weight ultrafiltration membranes instead of alcohol
precipitation. Ultrafiltration membranes remove all other
impurities e.g. chloride, heavy metal, free acid etc. without
loss of dextran or Iron Dextran. Using such ultrafiltration
membranes also reduces free ferric ions and free ferrous ions
in the final product. This increases the stability, reduces
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CA 02195283 2004-12-13
the toxicity, and increase the yield of Iron Dextran.
In addition to the above advantages, the new process,
reduces the chances of explosion or environmental risk due to
lack of alcohol in the process.
Accordingly, we have discovered a process for
manufacturing Iron Dextran comprising, forming a direct complex
of dextran with ferric chloride, and using an ultrafiltration
membrane to purify the product. The ultrafiltration membrane
may have a molecular weight cut off between 5,000-50,000. The
Fe content of the final product may be between 5-20%. The
invention extends to Iron Dextran made by the novel processes
described herein which is substantially free of impurities.
Example: 1
A solution of ferric chloride having Fe content of 8.0% is
added into a plastic tank.
Separately a 20.0% solution of sodium carbonate is made,
and with agitation added to the ferric chloride solution, until
the pH of the solution is 1.6.
A solution of dextran having a concentration of about
16.0% is added to the above mixture in a ratio of 1:1.4
(Fe:Dextran), continuously adding the solution of sodium
carbonate until the pH of the mixture is 5.5.
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2195283
Transfer the resulting solution into a glass lined
reactor and heat at 80 C until the concentration of Fe in the
solution is 4.0%. Cool and purify with ult raf ilt rat ion
membrane, having the Molecular Weight cutoff 5,000-50,000.
Purification is continued until the Fe concentration is
raised to 10.0%, and other impurities are removed, pH:of
solution adJusted to 6.5, adding required amount of phenol as
preservative. The solution is then filtered and stabilized by
heating the solution at 105 C for 3 hours.
Example: 2
A solution of ferric chloride having Fe content of 8.0%
is added into a plastic tank.
Separately a 20.0% of sodium carbonate is made, and with
agitation added to the ferric chloride solution, unt i l the pH
of the solution is 1.6.
A solution of dextran having a concentration of about
16.0% is added to the above mixture in a ratio of 1:4
(Fe : Dext ran ), with continuous adding of the so lut ion of sodium
carbonate until the pH of the mixture is 6Ø
Transfer the resulting solution into a glass lined
reactor and heat at 80 C until the concentration of Fe in the
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2195283
solution is 4.0%. Cool and purify with ultrafiltration
membrane (Molecular Weight cutoff 5,000-50,000).
Purif icat ion is continued unt i 1 the Fe concent rat ion is
raised to 5.0%, and other impurities are removed. The pH of
the solution is adJusted to 6.5, adding the required amount of
phenol. The solution is filtered and stabilized by heating
the solution at 105 C for 3 hours.
Example: 3
A solution of ferric chloride having Fe content of 8.0%
is added into a plastic tank.
Separately 20.0% solution of sodium carbonate is made,
and with agitation added to the ferric chloride solution,
until the pH of the solution is 1.6.
A solution of dextran having a concentration of about
16.0% is added to the above mixture in a ratio of 1:1.1
( Fe : Dext ran ), with cont inuous adding of the solut ion of sodium
carbonate until the pH of the mixture is 5.5.
Transfer the resulting solution into a glass lined
reactor and heat at 80 C until the concentration of Fe in the
solution is 4.0%. cool and purify with ult raf ilt rat ion
membrane.
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Purification is continued until the Fe concentration is
raised to 20.0%, and other impurities are removed. The pH of
the solution is adJusted to 6.5, adding the required amount of
phenol as preservative. The solution is filtered and
stabilized by heating solution at 105 C for 3 hours.
The aforesaid examples are for i llust rat ive purposes and
do not limit the scope of the invention. Those skilled in the
art will appreciate modifications which may be made to the
aforedescribed processes which fall within the scope of the
invention.
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