Abstrict The present invention discloses a blood bag system that avoids
the requirements of a plasticizer that is extractable by blood or
blood components. The blood bag is made of a certain plastic material
having particular properties including sufficient oxygen and carbon
dioxide permeabilities. The blood bag also contains an effective
amount of vitamin E.
Claims We claim:
1. A blood storage system essentially free of blood extractables
that are harmful to the human body comprising: a plastic container
characterized as being flexible, hemocompatible, sterilizable, having
an oxygen permeability of at least 100 PU and a carbon dioxide permeability
of at least about 800 PU; and an amount of vitamin E to stabilize
blood stored therein, said amount being at least 5 mg per dl blood,
wherein said plastic container has sufficient oxygen and carbon
dioxide permeabilities to be effective in blood storage in combination
with said vitamin E.
2. The blood storage system of claim 1 wherein said vitamin E is
selected from d-alpha-tocopherol, d-alpha-tocopheryl acetate, d-alpha-tocopheryl
succinate and mixtures thereof and said amount of vitamin E is that
amount sufficient to cause blood stored in said blood bag to exhibit
an improvement in at least one of the following properties when
compared to blood stored in a comparable blood container free of
vitamin E; reduced plasma hemoglobin content, reduced osmotic fragility,
and reduced hemolysis due to H.sub.2 O.sub.2 challenge.
3. The blood storage system of claim 2 wherein said plastic container
is made of a plastic material that has a modulus in the film of
no more than 30000 psi is inert, smooth, translucent or transparent
and is selected from the group consisting of at least one of copolyesters,
polyesters, and polyolefins.
4. The blood storage system of claim 3 wherein said vitamin E is
d-alpha-tocopherol present in an amount of about 5 to 100 mg per
dl blood and said plastic material is between about 3 and 15 mil
thick and has an oxygen permeability of at least 250 PU and a carbon
dioxide permeability of at least 2500 PU.
5. The blood storage system of claim 4 wherein said amount of vitamin
E is about 10 to about 50 mil per dl blood, and said plastic material
is an elastomeric copolyester and is between about 5 and 10 mg thick.
6. The blood storage system of claim 1 wherein said plastic material
is a copolyesterether having an inherent viscosity of about 0.8
to 1.5 comprising:
A a dicarboxylic acid component consisting essentially of 14-cyclohexanedicarboxylic
acid having a trans isomer content of at least about 70%,
B. a glycol component consisting essentially of
(1) 14-cyclohexanedimethanol, and
(2) about 15 to about 50 weight percent, based on the weight of
the polyesterether, of polytetramethylene ether glycol having a
molecular weight of about 500 to about 1100 and
C. about 0.1 to about 1.5 mole percent, based on the mole percent
of the acid or glycol component, of a branching agent having at
least three COOH or OH functional groups and from 3 to 60 carbon
atoms,
said copolyesterether being characterized by having a die swell
between about -90% and about +100% and a minimum crystallization
time of less than about 2.5 minutes.
7. A blood storage system comprising: a plastic container essentially
free of blood extractables harmful to the human body comprised of
a flexible, hemocompatible, sterilizable, smooth, inert, translucent
or transparent elastomeric copolyester between about 2 and 60 mils
thick having a modulus in the film of no more than 30000 psi, an
oxygen permeability of at least about 250 PU, and a carbon dioxide
permeability of at least about 2500 PU and contained therein about
5 to 100 mg per dl volume of vitamin E.
8. The blood storage system of claim 7 wherein said amount of vitamin
E is 10 to 50 mg per dl volume of d-alpha-tocopherol and said elastomeric
copolyester is between about 3 and 15 mil thick and is a copolyesterether
having an inherent viscosity of about 0.8 to about 1.5 comprising:
A. a dicarboxylic acid component consisting essentially of 14-cyclohexanedicarboxylic
acid having a trans isomer content of at least about 80%,
B. a glycol component consisting essentially of
(1) 14-cyclohexanedimethanol having a trans isomer content of
at least about 60%, and
(2) from about 20 to about 35 weight percent, based on the weight
of the polyesterether, of polytetramethylene ether glycol having
a molecular weight of about 500 to about 1000 and
C. from about 0.1 to about 1.5 mole percent, based on the mole
percent of the acid or glycol component, of trimellitic anhydride,
said copolyesterether being characterized by having a die swell
of between about -50% and about +50% and a minimum crystallization
time of less than about one minute.
9. The blood storage system of claim 8 wherein said blood stored
system additionally contains a beneficial amount of at least one
of the following: vitamin C, anticoagulants, nutrients, salts, minerals,
antibiotics, or mixtures thereof and said copolyesterether forming
said plastic container is about 5 mil thick and additionally contains
an effective amount of a phenolic antioxidant.
10. A method for storing blood comprising placing at least one
blood fraction in contact with an effective blood stabilizing amount
of vitamin E in a blood bag essentially free of blood extractables
that are harmful to the human body comprised of a flexible, hemocompatible,
sterilizable plastic material having an oxygen permeablity of at
least about 100 pu and a carbon dioxide permeability of at least
about 800 pu wherein said amount of vitamin E is at least 5 mg per
dl blood.
11. The method of claim 10 wherein said plastic material has a
modulus in the film of no more than 30000 psi is also smooth, inert,
translucent or transparent, and is selected from copolyesterethers,
polyesters, and polyolefins; and said vitamin E is present in an
amount of about 5 to 100 mg per dl blood and is selected from d-alpha-tocopherol,
d-alpha-toco-pheryl acetate, d-alpha-tocopherol succinate and mixtures
thereof.
12. The method of claim 11 wherein said vitamin E is present in
a concentration at about 10 to 50 mg per dl blood and said plastic
material has an oxygen permeability of at least 250 PU and a carbon
dioxide permeability of at least about 2500 PU, is between about
5 and 40 mils thick and is a copolyesterether having an inherent
viscosity of about 0.8 to about 1.5 comprising:
A. a dicarboxylic acid component consisting essentially of 14-cyclohexanedicarboxylic
acid having a trans isomer content of at least about 70%,
B. a glycol component consisting essentially of
(1) 14-cyclohexanedimethanol, and
(2) from about 15 to about 50 weight percent, based on the weight
of the polyesterether, of polytetramethylene ether glycol having
a molecular weight of about 500 to about 1100 and
C. from about 0.1 to about 1.5 mole percent, based on the mole
percent of the acid or glycol component, of a branching agent having
at least three COOH or OH functional groups and from 3 to 60 carbon
atoms,
said copolyesterethers being characterized by having a die swell
between about -90% and about +100% and a minimum crystallization
time of less than about 2.5 minutes.
13. The method of claim 12 wherein said vitamin E is d-alpha-tocopherol
and said plastic material is about 5 mil thick.
14. A composition suitable for preparing blood bags comprising:
an effective blood stabilizing amount of vitamin E and a flexible,
sterilizable, hemocompatible copolyesterether material essentially
free of blood extractables that are harmful to the human body having
a modulus in the film of no more than about 30000 psi and an oxygen
permeability of at least about 250 PU, and a carbon dioxide permeability
of at least about 2500 PU wherein said amount of vitamin E is at
least 5 mg per dl blood.
15. The composition according to claim 14 wherein said copolyesterether
has an inherent viscosity of about 0.8 to 1.5 and comprises:
A. a dicarboxylic acid component consisting essentially of 14-cyclohexanedicarboxylic
acid having a trans isomer content of at least about 70%,
B. a glycol component consisting essentially of
(1) 14-cyclohexanedimethanol, and
(2) from about 15 to about 50 weight percent, based on the weight
of the polyesterether, of polytetramethylene ether glycol having
a molecular weight of about 500 to about 1100 and
C. from about 0.1 to about 1.5 mole percent, based on the mole
percent of the acid or glycol component, of a branching agent having
at least three COOH or OH functional groups and from 3 to 60 carbon
atoms,
said copolyesterethers being characterized by having a die swell
between about -90% and about +100% and a minimum crystallization
time of less than about 2.5 minutes.
16. The method according to claim 10 wherein said blood fraction
is a blood product that contains blood cells.
17. A blood storage system essentially free of blood extractables
that are harmful to the human body comprising: a plastic container
made of a plastic material selected from copolyesters, polyesters,
and polyolefins between about 3 and 15 mils thick characterized
as being inert, smooth, translucent or transparent, flexible, hemocompatible,
sterilizable, having an oxygen permeability of at least 250 pu,
and a carbon dioxide permeability of at least 2500 pu; and about
5 to 100 mg per dl blood of d-alpha-tocopherol.
18. The blood storage system of claim 17 wherein said plastic material
is a copolyester material about 5 mil thick.
19. A blood storage system essentially free of blood extractables
that are harmful to the human body comprising: a plastic container
comprised of a plastic material characterized as being flexible,
hemocompatible, and sterilizable, having an oxygen permeability
of at least 100 PU and a carbon dioxide permeability of at least
about 800 PU; and an amount of vitamin E to stabilize blood stored
therein, said amount being at least 5 mg per dl blood, wherein said
plastic container has the proportional oxygen and carbon dioxide
permeabilities as a 5 ml thickness of said plastic material, said
permeabilities being sufficient for said container to be effective
in blood storage in combination with said vitamin E.
20. The blood storage system of claim 19 wherein said plastic material
has an oxygen permeability of at least 250 PU and a carbon dioxide
permeability of at least 2500 PU.
Description This invention relates to blood bag systems and blood storage.
BACKGROUND OF THE INVENTION
Single and multiple blood bags are currently commercially available
for storing whole blood and fractions thereof. Most of these blood
bags are made of polyvinylchloride (PVC) plasticized with di-2-ethylhexylphthalate
(DEHP, also known as dioctyl phthalate or DOP). Plasticizers such
as DOP are an essential component of these and other blood bags.
(See U.S. Pat. Nos. 4451259; 4286597; 4300559 4301800;
4507387; 4222379). The use of a plasticizer in the plastic material
was needed in order to make the PVC material sufficiently flexible
to be made into bags; it was later found, however, that DOP was
also needed to increase the storage life of blood to acceptable
levels and somehow interacted with the blood. Containers made of
a plastic material without a plasticizer caused blood stored in
such containers, under the usual blood storage conditions, to exhibit
an undesirably high plasma hemoglobin content, indicating that the
rate of red blood cell lysis was high.
Many physicians and other interested parties have expressed concern
over inclusion of a plasticizer in blood bags (see, for example,
Report to the U.S. Consumer Product Safety Commission by the Chronic
Hazard Advisory Panel on di(2-ethylhexyl) phthalate (DEHP). U.S.
Consumer Product Safety Commission Directorate for Health Sciences,
Washington, September 1985 and Journal of The American Association
of Blood Banks, May, 1989 Vol. 29 No. 4 pp 287-297). The plasticizer
in blood bags is blood extractable, i.e. extractable from the plastic
material into the blood. The extracted plasticizer enters the human
body along with the blood during infusion and could be significantly
detrimental to the health of the body, particularly if there is
an allergic reaction or if the plasticizer is built up over numerous
infusions.
Attempts have been made to prepare blood bag materials without
the use of a plasticizer. (See U.S. Pat. No. 4301800). These attempts
were generally unsuccessful and resulted in an unacceptably high
level of blood cell lysis when used for blood storage materials.
Therefore, it would be desirable to have an acceptable blood bag
system which does not require the presence of a plasticizer but
yet is compatible with stored blood and its components, i.e., does
not result in an undesirably high red blood cell lysis when storing
red blood cells. Vitamin E has been shown in some instances to have
beneficial effects on blood. (See, for example, S. Luczek and F.
Wolf, German Medical Monthly, Vol. VIII, No. 5 Stuttgart, May 1963
pp. 182-185; I. Kurokawa et al., Vitamins (Japan) 39 (2), 1969
pp. 86-90; I. Kurokawa et al., Vitamins (Japan) 40 (3), 1969 pp.
206-209; and I. Kurokawa et al., The Journal of Vitaminology, 16
1970 pp. 180-189).
SUMMARY OF THE INVENTION
It has been unexpectedly found that a suitable blood bag system
can be made using vitamin E in combination with a flexible plastic
material essentially free of blood extractables such as plasticizers.
In accordance with the present invention there is provided a blood
bag comprising: an effective blood stabilizing amount of vitamin
E; and a flexible, transparent, hemocompatible, sterilizable, smooth,
inert plastic material having sufficient oxygen and carbon dioxide
permeabilities to be effective as a blood storage bag and maintain
the useful life of stored blood and its components.
There is also provided a method for storing blood or at least one
blood fraction which comprises placing said blood or blood fraction
in the blood bag of this invention.
We have discovered that the effects of vitamin E on the stability
of blood subjected to long term storage varies considerably depending
upon the type and thickness of material which is used to make the
container for storing the blood. We have also found differences
in activity among the various forms of vitamin E on the stability
of blood in storage which have heretofore been unknown.
Based on our findings, we have developed a novel blood bag system
that is acceptable and meets the long-felt need in the art of a
system substantially free of harmful extractables such as plasticizers.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that acceptable stability of blood stored in
blood bags can be achieved with an effective amount of vitamin E
if the plastic material forming the blood bag is essentially free
of harmful blood extractables, flexible, hemocompatible, sterilizable
and has sufficient oxygen and carbon dioxide permeabilities.
It is preferred that this plastic material have an oxygen permeability
of at least about 100 PU; and a carbon dioxide permeability of at
least about 800 PU. It is more preferred that this plastic material
have an oxygen permeability of at least about 250 PU and a carbon
dioxide permeability of at least about 2500 PU. PU means permeability
units in cc(STP).multidot.mil/100 square inches.multidot.day.multidot.atm.
STP=standard temperature and pressure; mil=0.001 inches; and atm=pressure
of 1.0 atmosphere.
The oxygen and carbon dioxide permeabilities of a given plastic
material depend greatly upon the chemical nature of the material.
In addition, the oxygen and carbon dioxide permeabilities of these
materials generally vary proportionally with the thickness of the
material i.e. the thicker the material the lower the permeability.
At present there are no real upperlimits to the oxygen and carbon
dioxide permeabilities and thus it is preferred that the plastic
material be as thin as possible but yet sufficiently thick so as
to maintain its integrity and not fail during use. Therefore, while
having sufficient oxygen and carbon dioxide permeabilities it is
also preferred that the plastic material forming the blood bag have
a plastic thickness between about 2 and 60 mils, preferably between
about 5 and 40 mils. Blood cells need good dissolved gas exchange
and thus need to be stored in blood bags with higher oxygen and
carbon dioxide permeabilities. Therefore, when storing blood products
that contain red blood cells, or platelets, the preferred thickness
of the plastic material is between about 3 and 15 mils. More preferably,
the thickness of the plastic material is between about 5 and 10
mils with about 5 mil being most preferred.
The plastic material of the present invention should also have
other characteristics if it is to be a commercially acceptable blood
bag. The blood bag must then be flexible, hemocompatible, and sterilizable.
In addition, it is desirable that the blood bag be smooth, translucent
or transparent, and inert.
By "flexible" it is meant that the blood bag system is
sufficiently pliable to collapse and allow the entire bag contents
to empty. It is preferred that the blood bag be as flexible as possible
but yet retain sufficient strength and temperature resistance to
be functional. Modulus is an indicator of flexibility and it is
preferred that the plastic material have a modulus in the film of
no more than about 25000 or 30000 psi as determined by ASTM method
D882 (tensile properties of film and sheeting). The plastic material
more preferably has a modulus in the film of no more than about
20000 psi with a modulus of no more than about 15000 psi being
most preferred.
Another factor related to flexibility, that is an important feature
of a blood bag, is its "hand". Those in the health care
industry are used to IV bags, or blood bags, that have a certain
feel or "hand". This property can be related to the materials'
stiffness or modulus. A bag that is too flexible is generally considered
unsuitable due to a concern that the bag may not be strong or tough
enough to avoid being ruptured during handling. However, if the
bag is too rigid damage to the contents and proper drainage of the
contents become a concern. This feature is not easily quantifiable
and is simply a factor that needs to be considered when producing
the final blood bag product.
By "hemocompatible" it is meant that the blood bag system
(containing vitamin E, etc.) has the characteristic that it will
not interact with the stored blood or other biological materials
during storage and usage conditions in a way that will significantly
lower the safety, purity or potency (efficacy) of the stored blood
or its components or other biological materials. By "sterilizable"
it is meant that the blood bag system is capable of withstanding
autoclave (i.e. 121.degree. C. for 30 minutes), ethylene oxide gas
(ETO), radiation or other sterilization methods used to kill microorganisms
without suffering significant adverse effects on the physical and/or
chemical properties of the system or its biocompatibility. By "smooth"
it is meant that the surface of the material is sufficiently even
such that damage of blood components due to abrasion is minimized;
however, if blood cells are not present this is not of particular
importance. "Inert" refers generally to the same quality
as hemocompatibility but is meant that the plastic material itself
is essentially innocuous and does not, to any significant extent,
react chemically with the blood. The blood bag should be sufficiently
transparent or have sufficient contact clarity so that during typical
use, a technician, nurse, physician or other person will be able
to visibly identify the contents of the bag and identify pertinent
blood characteristics including quality (particularly color) and
quantity. This characteristic is, however, not absolutely required
for the present invention, since there may be other acceptable methods
of identifying the contents of the bag and its quality such as some
form of color and/or freshness coding or marking.
Several different plastic materials have sufficient characteristics
to be suitable for use in the present invention. It is envisioned
that any plastic material that meets the above requirements of flexibility,
hemocompatibility and sterilizability would be useful in the blood
bag system of the present invention. Suitable classes of plastic
materials include, for example, polyesters, copolyesters, polyolefins,
and the like. More preferred plastic materials, however, are elastomeric
copolyesters, more specifically copolyesterethers having a high
melt strength and a fast crystallization rate.
The copolyesterethers according to the more preferred aspect of
this invention are derived from a dicarboxylic acid component consisting
essentially of 14-cyclohexanedicarboxylic acid or an ester forming
derivative thereof such as dimethyl-14-cyclohexane-dicarboxylate.
The diol component consists essentially of 14-cyclohexanedimethanol
and polytetramethylene ether glycol. The copolyesterethers further
comprise from about 0.1 to about 1.5 mole %, based on the acid or
glycol component, of a polyfunctional branching agent having at
least 3 carboxyl or hydroxyl groups.
Such a copolyesterether is disclosed in U.S. Pat. No. 4349469
the disclosure of which is incorporated herein by reference in its
entirety. Such a preferred plastic material is comprised of copolyesterethers
having an inherent viscosity of about 0.8 to about 1.5 comprising
A. a dicarboxylic acid component consisting essentially of 14-cyclohexanedicarboxylic
acid (or an ester forming derivative thereof) having a trans isomer
content of at least about 70%,
B. a glycol component consisting essentially of
(1) 14-cyclohexanedimethanol, and
(2) from about 15 to about 50 weight percent, based on the weight
of the polyesterether, of poly(tetramethylene ether) glycol having
a molecular weight of about 500 to about 1100 and
C. from about 0.1 to about 1.5 mole percent, based on the mole
percent of the acid or glycol component, of a branching agent having
at least three COOH or OH functional groups and from 3 to 60 carbon
atoms, and said copolyester being characterized by having a die
swell of between about -90.degree. and about +100% and a minimum
crystallization time of less than 2.5 minutes.
The inherent viscosity (I.V.) is an indicator of processability
and is a number relatable to the composition and molecular weight
of the polyester and is in deciliters per gram. It is determined
by measuring the flow time of a solution of known polymer concentration
and the flow time of a solvent-blank in a capillary viscometer and
then calculating the I.V. by using the following equation: ##EQU1##
{.eta.} 25.degree. C.=Inherent viscosity at 25.degree. C. at a 0.50%
polymer concentration of 0.50 gm per 100 mil of solvent.
ln=Natural Logarithm
t.sub.s =Sample Flow Time
t.sub.o =Solvent minus blank flow time
C=Concentration of Polymer in Grams Per 100 ml of Solvent=0.50
The die swell is expressed as a percent and is calculated as follows
using a 0.1 inch diameter die. ##EQU2##
If the extrudate is less than 0.1 inch in diameter, the die swell
is then a negative number because there is no swell. If the extrudate
is larger than 0.1 inch in diameter, the die swell is a positive
number. A die swell of 0% therefore indicates no change in the size
of the extrudate.
To decrease processing time it is highly desirable to use rapidly
crystallizing polyesterethers. The rates of crystallization of copolyesterethers
can be measured by determining the times (t.sub.p) to reach the
peak crystallization exotherm during crystallization at various
temperatures. Typically, there exists a temperature at which t.sub.p
is less than for any other temperature. This minimum value of t.sub.p
can be used as a single parameter characterization of crystallization
rate. The shorter the minimum crystallization time the faster the
copolyesterether will crystallize.
In the above-described copolyesterether it is preferred that said
14-cyclohexanedicarboxylic acid have a trans isomer content of
at least about 80%, said 14-cyclohexanedimethanol have a trans
isomer content of at least about 60%, and the molecular weight of
the polytetramethylene ether glycol be about 500 to 1000.
It is also preferred that the polytetramethylene ether glycol of
said copolyesterether be present in an amount of about 20% to 35%
based on the total weight of copolyesterether, and that the branching
agent of said copolyesterethers be trimellitic anhydride. Other
preferred embodiments of said copolyesterether include a preferred
die swell between about -50% and +50%; and a preferred minimum crystallization
time less than about one minute, more preferably less than about
one-half minute. It is also preferred that said copolyesterether
additionally contain an effective amount of a phenolic antioxidant.
A preferred effective amount of said phenolic antioxidant is about
0.1% to 1.0% based on the weight of the copolyesterether.
A preferred phenolic antioxidant is available from Ciba-Geigy under
the trademark Irganox 1010. This additive is a tetrafunctional compound
that also aids in thermal stability and about 0.2% is preferably
present in the polymer.
An even more preferred plastic material is disclosed in U.S. Pat.
No. 4349469 and can be described as being comprised of copolyesterethers
having an inherent viscosity from about 0.8 to about 1.5 comprising
A. a dicarboxylic acid component consisting essentially of 14-cyclohexanedicarboxylic
acid (or an ester forming derivative thereof) having a trans isomer
content of at least about 80%,
B. a glycol component consisting essentially of
(1) 14-cyclohexanedimethanol having a trans isomer content of
at least about 60%, and
(2) from about 20 to about 35 weight percent, based on the weight
of the polyesterether, of poly(tetramethylene ether) glycol having
a molecular weight of about 500 to about 1000 and
C. from about 0.1 to about 1.5 mole percent, based on the mole
percent of the acid or glycol component, of a branching agent having
at least three COOH or OH functional groups and from 3 to 60 carbon
atoms,
said copolyesterether being characterized by having a die swell
of between about -90% and about +100% and a minimum crystallization
time of less than about 2.5 minutes.
A suitable, preferred copolyesterether within the description above
is available from Eastman Chemical Products, Inc., Kingsport, Tennessee,
and is known by the trademark ECDEL.
Another preferred plastic material suitable for use in the present
invention is a polyester of 14-cyclohexanedicarboxylic acid and
14-cyclohexanedimethanol modified with 10 to 30 mole percent dimer
acid. Such a polyester is disclosed in U.S. Pat. No. 4045431
the disclosure of which is incorporated herein by reference in its
entirety. Such a suitable plastic material disclosed in said patent
can be described as being comprised of a polyester having an inherent
viscosity of at least about 0.6 preferably at least about 0.7
a flexural modulus of about 30000 psi or less and a melting point
of at least about 140.degree. C., the polyester being comprised
of:
A. a dicarboxylic acid component which is
(1) from about 90 to about 70 mole percent, preferably about 85
to about 75 mole percent, 14-cyclohexanedimethanol acid having
a trans isomer content of at least about 90%, and
(2) from about 10 to about 30 mole percent, preferably from about
15 to about 25 mole percent dimer acid, and
B. 14-cyclohexanedimethanol having a trans isomer content of at
least about 60%.
It is presently contemplated, though not preferred, that the plastic
materials described above can have incorporated therein non toxic
plasticizers such as acetyl tributyl citrate.
It is also presently contemplated, though not preferred, that the
plastic material suitable for use in the blood bag of the present
invention can be laminated (i.e., have two or more layers) wherein
the individual plastic layers are of the same or different material.
The presently preferred method of forming this layered material
is by coextrusion, however, any conventional method of coextrusion
or extrusion lamination is believed to be useful to make these materials.
Suitable coextruded structures include for example but are not
limited to one or more layers of at least one polyolefin and/or
polyolefin copolymer, one or more layers of at least one polyester
such as an elastomeric copolyester and one or more layers of at
least one adhesive such as one produced from a copolyester. A preferred
coextruded layered structure would be copolyesterether/adhesive/polyolefin.
These coextruded materials are less permeable than the single layer
material but preferably have oxygen carbon dioxide permeabilities
as described above.
The effective blood-stabilizing amount of vitamin E is that amount
that produces an increase in blood or blood component stability
in stored blood as compared to blood stored under identical conditions
without vitamin E. An increase in blood stability means that the
stored blood or blood component is better suited for clinical use
(i.e. for infusing into patients) which for whole blood or red blood
cells usually means that following storage they have less cell lysis
and higher cell viability when compared with storage in a comparable
blood container free of vitamin E. This improvement is generally
manifest by reduced plasma hemoglobin content, reduced osmotic fragility
and/or reduced hemolysis due to H.sub.2 O.sub.2 challenge. Generally,
a certain time period passes before the improved stability becomes
manifest, typically at least about 14 days under normal storage
conditions. Normal storage conditions are typically about atmospheric
pressure and about 4.degree. C.
A typical preferred effective amount of vitamin E is about 5 to
about 100 mg per deciliter (dl=100 ml) of whole blood; a more preferred
effective amount is about 10 to about 50 mg per dl. Of course, when
the vitamin E is added to the blood bag prior to introducing the
blood, the effective amount of vitamin E is based upon the volume
of blood that will later be introduced into the blood bag.
The vitamin E can be incorporated in concentrated form or added
as solution in a suitable solvent, e.g. alcohol, at the desired
concentration to the blood bag or at least one compartment thereof.
It is also contemplated that the vitamin E can be incorporated into
the plastic material directly, using conventional techniques, so
that an effective amount of vitamin E will be in contact with the
blood during storage.
It is believed that any method of incorporating the vitamin E into
the blood bag system so as to increase the blood stability is suitable
for the present invention. For example, the vitamin E can be present
in the blood-containing compartment or can be stored in a second
sealed compartment attached to the main body of the bag or the tubing
and then added to the blood after blood collection.
Vitamin E is known to include several forms of alpha tocopherol.
As used herein the term "vitamin E" refers to any form
of vitamin E that exists (which includes esterified forms) or any
combination thereof. One form of vitamin E is the d-alpha-tocopherol
which is isolated from natural sources and consists solely of the
naturally occurring stereoisomer RRR-alpha-tocopherol. Another form
is the d,l-alpha-tocopherol also known as all racemic-alpha-tocopherol
which is a mixture of 8 stereoisomers produced during its synthesis.
In general, the naturally occurring d-alpha form and its esters
are preferred over the synthetic forms due to the higher biological
potency and the absence of synthetic stereoisomers which may impose
stress upon the human body receiving the infusion of blood. It is
preferred that the purity of the vitamin E exceed 97% and be essentially
free of synthetic stereoisomers. Typical esters include alkyl esters
such as C.sub.1 -C.sub.4 alkyl esters (e.g., d-alpha-tocopheryl
acetate, and succinate) and polyethylene glycol succinate.
We have also found that d-alpha-tocopherol (RRR-alpha-tocopherol)
is surprisingly more effective in maintaining the integrity of the
blood cells than are related forms of vitamin E, such as its acetate
ester (depending upon the plastic material and its thickness). The
blood bag of the present invention can be made using conventional
techniques known in the art. The blood bag of the present invention
can also be of any physical design known in the art. Examples of
suitable blood bag designs are disclosed in U.S. Pat. Nos. 4451259;
4286597; 4300559; 4301800; 4507387; and 4222379 the disclosures
of which are incorporated herein by reference in their entirety.
A typical blood bag is equipped with access tubing and sealed access
ports. If desired, the blood bag of this invention can be a multi-compartment
system wherein a first compartment for holding blood or at least
one blood fraction, and other compartments can contain other beneficial
substances.
In addition to vitamin E, other beneficial substances can be added
to the blood or be in the first or second compartments described
above, or can be in one or more other compartments. The individual
compartments can have one or more common walls or can be separate
bags connected by tubing. It is important that the portion of the
blood bag that is in contact with the blood during storage is made
of the plastic material that is flexible, hemocompatible, and sterilizable
and is substantially free of harmful blood extractables. The other
parts of the blood bag, e.g., tubing and/or other compartments,
can be made of the same material or of some other material suitable
for that purpose.
The "other beneficial substances" described above can
be anticoagulants/preservatives, nutrient additives, salts, minerals,
antibiotics, or any other substance or a mixture thereof commonly
used by medical or research personnel for use in conjunction with
stored blood, fractions thereof, or stored biological materials.
Examples of anticoagulants/preservatives commonly used in the trade
are: CPD(citrate phosphate dextrose) and CPDA-1 (citrate phosphate
dextrose adenine). An example of a nutrient additive is ADSOL which
contains adenine, dextrose, mannitol and saline (available from
Fenwal Laboratories). Ascorbic acid and its salts (vitamin C) have
a sparing effect on the antioxidant activity of vitamin E in red
blood cells. It is, therefore, envisioned that a combination of
vitamins E and C can be used in the system. Similarly, other compounds
with antioxidant activity such as beta-carotene, (vitamin A), etc.
can also be included.
Blood to be stored in accordance with the present invention can
be placed into the blood bag by any conventional means known in
the art. The blood in the blood bag is then typically stored at
about 4.degree. C. for a desired period of time. Typically, blood
is stored over 21 days up to 35 days at this temperature; however,
it is possible to have suitable blood when stored up to 49 days
when using the blood bag of this invention. Blood or suitable blood
components can also be stored in these bags for extended periods
in the freezer at temperatures of -20.degree. to -196.degree. C.;
however, the blood bags of the present invention are particularly
useful when storing blood and blood components that must be kept
above freezing temperatures.
The present invention is contemplated as being useful for the storage
of many biological solutions particularly blood and blood products.
Suitable biological solutions include but are not limited to whole
blood, red blood cells, platelets, plasma, cell cultures, and nutritional
and medicinal biological solutions. The stored biological solutions
that are benefited the most by the blood bags of the present invention
are those that contain red blood cells and platelets. Red blood
cells and platelets are known to require good oxygen and CO.sub.2
exchange and are delicate and very susceptible to damage.
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