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Description  |
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BACKGROUND OF THE INVENTION
1. Field of the Invention
Artificial blood compositions are prepared from certain perfluoro chemicals
in physiological saline using certain polyoxybutylene-polyoxyethylene
block copolymers. These clock copolymers provide stable emulsions.
2. Description of the Prior Art
In an article by Irving R. Schmolka entitled, "Introduction to Artificial
Blood Materials", from session 1 of a symposium on artificial blood
presented at the Blood Resource Branch for National Heart and Lung
Institute, NIH, Bethesda, Maryland, April 5-6, 1974,
polyoxypropylene-polyoxyethylene block polymers are disclosed as being
useful emulsifiers for perfluoro chemicals in synthetic blood
preparations.
The HS symposium, "Research in Perfluoro Chemicals in Medicine Biology",
Apr. 28-29, 1977 at Karolinska Institute Research Center, Huddinge
University Hospital in Huddinge, Sweden, was directed to fluoro chemicals,
in particular perfluorodecalin. A paper related to emulsions with
polyoxypropylene-polyoxyethylene block copolymer emulsifiers. Although it
is possible to emulsify perfluorodecalin in physiological saline, using a
block polymer of ethylene and propylene oxides, the resulting emulsion is
not stable. The reference relates to the use of a blend of
perfluorodecalin and perfluorotripropylamine (FTPA) in artificial blood
preparations to overcome the emulsion instability. Unfortunately, the FTPA
has a low vapor pressure and accumulates in the liver which is not
desirable.
U.S. Pat. No. 4,110,474 relates to perfluorinated
2,2,4,4-tetramethylpentane useful in synthetic blood substitute
compositions. The use of polyoxybutylene-polyoxyethylene block copolymers
as emulsifiers is not mentioned.
U.S. Pat. No. 4,105,798, Moore et al, Aug. 8, 1978, relates to
perfluorinated compounds useful in synthetic blood in perfusion media.
Polyoxybutylene-polyoxyethylene block copolymers are not mentioned as
emulsifiers.
Both patent reference U.S. Pat. Nos. 4,105,798 and 4,110,474 utilize a
polyoxypropylene-polyoxyethylene block copolymer known as PLURONIC F68.
Some of the problems utilizing this copolymer are enumerated above. This
invention is directed towards stable emulsions of perfluoro chemicals
devoid of the prior art problems.
SUMMARY OF THE INVENTION
The invention relates to an artificial blood composition comprising a
polyoxybutylene-polyoxyethylene block copolymer emulsifier, a perfluoro
chemical suitable for artificial blood preparation and physiological
saline, said emulsifier being a cogeneric mixture of conjugated
polyoxybutylene-polyoxyethylene compounds containing in their structure
oxybutylene groups, oxyethylene groups and an organic radical derived from
an organic compound containing a plurality of reactive hydrogen atoms,
preferably a water soluble organic compound containing a plurality of
reactive hydrogen atoms and 2 to 12 carbon atoms. The compounds are
characterized in that all the oxybutylene groups are present in
polyoxybutylene chains that are attached to the organic radical at the
site of a reactive hydrogen atom thereby principally constituting a
polyoxybutylene polymer. The oxyethylene groups are attached to the
polyoxybutylene polymer in polyoxyethylene chains. The average molecular
weight of the polyoxybutylene polymers in the mixture is from about 600 to
about 3000, as determined by hydroxyl number, and the oxyethylene groups
present constitute between about 60 percent and about 85 percent by weight
of the compound. These artificial blood products surprisingly provide a
stable emulsion of perfluoro chemical alone with the aqueous solution of a
polyoxybutylene-polyoxyethylene block copolymer.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The block copolymer of use in the invention is a cogeneric mixture of
conjugated polyoxybutylene-polyoxyethylene compounds having as a
hydrophobe, a polyoxybutylene polymer of at least 500 molecular weight.
The polyoxybutylene compounds are prepared by first condensing butylene
oxide with an organic compound containing a plurality of reactive hydrogen
atoms to prepare a polyoxybutylene polymer of at least 500 molecular
weight, and subsequently condensing ethylene oxide thereto. The compounds
used in this invention conform to the following generic formula:
Y[(C.sub.4 H.sub.8 O).sub.n -E-H].sub.x (A)
wherein Y is the residue of a water-soluble organic compound containing
therein x active hydrogen atoms; n is an integer; x is an integer greater
than 1; the values of n and x are such that the molecular weight of the
compound, exclusive of E, is at least 500, as determined by hydroxyl
number; E is a polyoxyalkylene chain wherein the oxygen/carbon atom ratio
is at least 0.5, and E constitutes 60 percent by weight to 85 percent by
weight of the compound.
The polyoxybutylene polymer, which is an intermediate in the preparation of
the compounds of use in this invention, has the following structure:
Y[(C.sub.4 H.sub.8 O).sub.n H].sub.x (B)
wherein Y, n and x are defined as in Formula A above.
The preferred compounds of use in this invention are prepared by condensing
ethylene oxide in an amount between 60 and 85 percent by weight of the
resultant compound, with the polyoxybutylene polymer. These compounds have
the following formula:
Y[(C.sub.4 H.sub.8 O).sub.n (C.sub.2 H.sub.4 O).sub.m H].sub.x (C)
wherein Y, n and x are defined as in Formula A and m has a value such that
the oxyethylene groups constitute 60 to 85 percent by weight of the
compound.
When ethylene oxide is condensed with a polyoxybutylene glycol of at least
500 molecular weight and derived from a butanediol initiator, the
resulting compounds have the following structure:
HO(C.sub.2 H.sub.4 O).sub.m (C.sub.4 H.sub.8 O).sub.n (C.sub.2 H.sub.4
O).sub.m,H (D)
where n is defined as previously set forth; and m'+m have a value such that
the oxyethylene groups constitute 60 percent by weight to 85 percent by
weight of the compound.
The hydrophilic portion of the polyoxyalkylene compounds may be supplied in
whole or in part by other polyoxyalkylene chains in lieu of the
polyoxyethylene chain set forth in Formula C. Any polyoxyalkylene chain
may be used provided that the oxygen/carbon ratio contained therein is at
least 0.5.
Examples of a water-soluble organic compound containing therein x active
hydrogen atoms, the residue of which is Y, are the initiators, which may
include water, diols such as propane diol, butane diol, triols such as
glycerol, tetrols such as pentaerythritol as well as initiators containing
more than four hydroxyl groups such as hexitol or sucrose. Also, amines
and other low molecular weight water-soluble compounds having two or more
active hydrogen atoms such as ethylene diamine or diethylene triamine may
be used as the initiator. Preferably used is butane diol. More perferably
used is 1,4-butanediol.
The butylene oxide used in making the hydrophilic polyoxybutylene polymer,
which is an intermediate in the preparation of the compounds used in this
invention, may be replaced with up to 10 percent by weight of propylene
oxide or ethylene oxide when added as a mixture with the butylene oxide.
Also, up to 10 percent by weight of propylene oxide or butylene oxide may
be used to replace ethylene oxide, when added as a mixture with ethylene
oxide, in preparing the block copolymers used in this invention. In lieu
of butylene oxide, other 4-carbon cyclic ethers such as methyloxetane,
tetrahydrofuran and isobutylene oxide may be used.
The preferred block copolymers conforming to structure D above of use in
this invention, are those block copolymers which contain a hydrophobe of
between about 500 and 3000, preferably 1200 and 1800, average molecular
weight and between about 60 percent by weight and about 85 percent by
weight, preferably about 80 percent by weight, ethylene oxide. The
emulsifier is used in an amount between 0.05 percent by weight to 10
percent by weight, preferably 2 percent by weight to 8 percent by weight,
more preferably 4 percent by weight to 6 percent by weight of the
artificial blood composition.
The perfluoro chemical found most suitable for artificial blood
preparations is perfluorodecalin (FDC). This material leaves the body
rapidly due to its high vapor pressure. It is excreted through the breath
and the skin. Emulsions of FDC, heretofore not stable with prior art
emulsifiers, have now been found unexpectedly to be stable when the
emulsifier is the polyoxybutylene-polyoxyethylene block copolymer of the
invention. Other perfluoro chemicals which may be used include
perfluoromethyldecalin, perfluorotributylamine and perfluoro
2,2,4,4-tetramethyl pentane. The perfuoro chemical is used in an amount
between 10 percent by weight and 40 percent by weight of the artificial
blood composition.
The saline solution of use in the artificial blood of this invention may be
any suitable physiological saline solution. The components may include
sodium chloride, magnesium chloride, potassium chloride, sodium lactate,
glucose and water. The saline solution is used as an electrolyte solution
in the artificial blood in an amount between 40 to 80 percent by weight of
the artificial blood composition.
Additional emulsifying agents may be used in a combination of emulsifiers
with polyoxybutylene-polyoxyethylene block copolymers of this invention.
Suitable additional emulsifying agents are the
polyoxypropylene-polyoxyethylene block copolymer designated as PLURONIC
Polyols and egg-yolk phospholipid.
The artificial blood compositions of this invention are prepared from 2 to
8 percent by weight of block copolymer emulsifier, 10 to 40 percent by
weight of perfluoro chemical and from 40 to 80 percent by weight of
physiological saline solution, preferably a 2 to 8 percent physiological
saline solution. An emulsion may be made as follows: the block copolymer
emulsifier is dissolved in water and then the perfluoro chemical is added.
The mixture is stirred by a suitable means such as sonication, under a
carbon dioxide atmosphere, for a suitable period of time, such as two
hours, to produce an optically clear stable emulsion of fine particles of
perfluoro chemical. The emulsions have a fine particle size of 0.3 microns
or less in diameter. The electrolyte solution is blended in any suitable
blender with perfluoro chemical in an amount of about 10 volume percent of
electrolyte solution and about 90 volume percent of emulsion.
The following examples will further illustrate the various aspects of the
invention. Where not otherwise specified throughout the specification and
claims, temperatures are in degrees Centigrade and parts, percentages and
proportions are by weight.
The following block copolymers are used in the examples:
______________________________________
Block Average MW of Percent by weight
Copolymer
Polyoxybutylene Hydrophobe
of Ethylene Oxide
______________________________________
A 600 80
B 1200 70
C 1200 80
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EXAMPLE 1
Peparation of an Artificial Blood Composition
The following aqueous solution is prepared:
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NaCl 6.0 grams
MgCl.sub.2 0.2 gram
KCl 0.3 gram
Sodium lactate 3.1 grams
Glucose 1.0 gram
Water to 100 ml
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The following perfluorocarbon emulsion is prepared:
______________________________________
Perfluorodecalin 18 grams
Block copolymer A 5 grams
Water to 100 ml.
______________________________________
The emulsion is made by dissolving the block copolymer A in the water, and
then adding the perfluorodecalin. The mixture is sonicated under a carbon
dioxide atmosphere for two hours to produce an optically clear stable
emulsion of fine particles of perfluorodecalin. For use as an artificial
blood, 10 ml of the electrolyte solution is blended with 90 ml of the
fluorocarbon emulsion.
EXAMPLES 2-6
An artificial blood composition is prepared by a procedure similar to
Example 1 from the following components:
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Percent by Weight Component
______________________________________
5 Block Copolymer A
19 Perfluorodecalin
76 5% Saline Solution
6 Block Copolymer B
18 Perfluoromethyldecalin
76 3% Saline Solution
4 Block Copolymer C
20 Perfluoro 2,2,4,4-tetra-
methylpentane
76 4% Saline Solution
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Amount Component
______________________________________
30 grams Perfluoromethyldecalin
7 grams Block copolymer C
to 100 ml Water
______________________________________
An artificial blood composition is prepared complete with no dilution.
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Amount Component
______________________________________
12 ml Perfluorotributylamine
2.5 grams Block copolymer A
3.0 grams Hydroxyethyl starch
54 mg NaCl
32 mg KCl
7 mg MgCl.sub.2
10 mg CaCl.sub.2
9.6 mg NaH.sub.2 PO.sub.4
to pH 7.45 Na.sub.2 CO.sub.3
to 100 ml Water
______________________________________
Stable emulsion are obtained which maintain their stability over long
periods of time.
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