CA1058081A - Perfluoro polycyclic compounds for use as synthetic blood and perfusion media - Google Patents
Perfluoro polycyclic compounds for use as synthetic blood and perfusion mediaInfo
- Publication number
- CA1058081A CA1058081A CA241,138A CA241138A CA1058081A CA 1058081 A CA1058081 A CA 1058081A CA 241138 A CA241138 A CA 241138A CA 1058081 A CA1058081 A CA 1058081A
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- Prior art keywords
- perfluorinated
- emulsion
- water
- perfluorinated material
- composition according
- 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.)
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-
- 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
- A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/02—Halogenated hydrocarbons
- A61K31/025—Halogenated hydrocarbons carbocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Novel emulsions of perfluorinated compounds are useful as blood substitutes or as perfusion materials for the storage of organs such as kidneys prior to transplant.
The compounds employed are polycyclic compounds and emulsions prepared from the perfluorinated derivatives thereof possess extremely high stability, zero or extremely low ultimate residue in the body, and a vapor pressure which is just about right for use in the body without adverse effects thereon.
Novel emulsions of perfluorinated compounds are useful as blood substitutes or as perfusion materials for the storage of organs such as kidneys prior to transplant.
The compounds employed are polycyclic compounds and emulsions prepared from the perfluorinated derivatives thereof possess extremely high stability, zero or extremely low ultimate residue in the body, and a vapor pressure which is just about right for use in the body without adverse effects thereon.
Description
BACKGROUND OF THE I~ENTION
The need for synthet~c blood is ~ell kno~n. slood is becoming increasingly expensive, it is perishable, it must be matched to the blood type of the recipient and the transfusion itself can cause hepatitis if rigid procedures are not followed.
In addition, blood donations tend to be somewhat seasonal and they often do not coincide with the generally random demands therefor.
A synthetic blood must have several characteristics.
Initially, and quite obviously, it must have high oxygen and carbon dioxide solubility since its principal function is to transport oxygen and carbon dioxide. A synthetic blood also must be non-to~ic and in this respect ît is desirable that when :
the synthetic blood is replaced by natural blood there is no residue of the former left in vital bocly organs.
Another characteristic of blood substitutes is that they must have certain vapor pressure requirements. The blood substitutes leave the body by being exhaled and by vaporization through the skin. Preferably the substitute leaves the body at about the same rate that new natural blood is being generated by the body. If the vapor pressure of the substitute is too low it stays in the body too long, whereas if it is too high it :
d evaporates throughout the body's surface and creates problems i akin to the "bends".
^~ Blood substitutes must also be capable of forming very stable emulsions w~th this capability being even more . ,.,~
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important with perfusion materials. Blood substitutes are usually immiscible with blood and if used alone could cause embolisms. The problem is overcome by using it in an aqueous emulsion and obviously the emulsion should not separate in use or storage. In connection with perfusion materials this stability is even more strict because the oxygenators used to add oxygen to the perfusion material create very high shear and will break down all but the most stable emulsions.
Another reason aqueous emulsions are employed is that salts are added to the water in order to maintain the body salt balance.
.,. :.
- The Green Cross Corporation, Osaka, Japan, has published a phamphlet dated September 11, 1974 on perfluoro emulsions as oxygen and carbon dioxide carriers.
: `~
j~ Also Clark et al report on some of the compounds described -~
in the present invention in Microvascular Research Volume 8/3 1974, also presented at the Oxygen Transport to Tissue Symposium, Atlantic City, N.J. April 11, 1974. The blood substitute and perfusion material of choise so far has been ` 20 perfluorodecalin. It has a number of desirable properties `- but our compounds appear superior to perfluorodecalin in several respects.
SUMMARY OF THE INVENTION
The novel blood substitutes and perfusion com-pounds disclosed herein are perfluorinated polycyclic `--compounds having 9-18 carbon atoms and at least two bridgehead carbon atoms. They have extremely high oxygen solubility, very low body residue, form very stable emulsions, and have ;~ a very satisfactory vapor pressure for one or both uses.
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~ he present in~ention therefore provides an emulsion of a non-aromatizable perfluorinated material in water, the amount of water being greater than 40% by volume, said emulsion containing an emulsifier and said perfluorinated material being obtained ~y fluorination of a Cg-Cl8 polycyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom.
In another aspect the present invention provides an emulsion of a non-aromatizable perfluorinated Cg-Cl8 polycyclic hydrocarbon containing at least two bridgehead carbon a~oms linked through a bridge containing at least one carbon atom in water, the amount of water being greater than 40% by volume and said emulsion containing an emulsifier.
In a further aspect the invention provides an artificial blood or oxygen transport agent comprising an emulsion of a non-aromatizable perfluorinated material in water, the amaunt of water being greater than 40% by volume, said emulsion containing an emulsifier and said perfi-~orinated material being obtained by fluorination of a Cg~C18 poly-cyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom.
.: .
There is also disclosed a process for the ` preparation of such an emulsion comprising the step of ` emulsifying with water and a non-toxic emulsifier a perfluorinated material obtained by fluorination of a compound containing at least two carbon atoms common to three rings wherein the amount of water in the final ,: .
emulsion is greater than 40% by volume.
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DETAILED DESCRIPTION OF THE INVENTION
The polycyclic compounds suitable for the present purpose are those having two bridgehead carbon atoms, a bridge-head carbon atom being a carbon atom common to three rings. Our invention employs Cg-Cl8 polycyclics such as tricyclononanes (e.g., tricyclo~3,3,1]nonane), adamantane, methyl and dimethyl-adamantane, ethyl adamantane, tetrahydrodicyclopentadiene, methyl and dimethyl bicyclooctanes, ethylmethyladamantane, ethyldimethyladamantane, tetrahydrobinor-S, methyldiamantane, triethyladamantane, trimethyldiamantane, ethyldimethyldiamantane, and the like. They can be made by known means. Preferably the polycyclic contains 9-12 carbon atoms and it generally will have not more than four rings, usually 2-3 rings.
As synthetic blood C8 materials (in perfluorinated form) have too high a vapor pressure to be useful. The C10 and Cll materials are just about right whereas the Cgs are a little on the high side re vapor pressure and the C12s are a little on the low side. C10 and Cll materials have atmospheric boiling points between about 125-165C. and this is a satisfactory ~. . .:
:, criteria, with the preferred range between 125 and 145C. This ,. .
preferred range will be mostly C10 materials.
It should be noted that even though C12s are not `susitable as blood substitutes they and up to C18s can be used ;. . ~
~ as perfusion compounds as in this application vapor pressure is -;, .
; not as important. Above C18 the oxygen solubility of the ;, material is generally too low.
The polycyclic material is used in perfluorinated ~` form. For the present purpose the term perfluorinated includes :,"~"
. :, '''.' . .
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:;, -4-.~, . ................................................................. .
, ~, . . .
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C9-C18 polycyclics which are at least 95% by weight completely ~, fluorinated (i.e., perfluorinated in the strict sense), preferably '- at least 98% and more preferably 100%. In all cases of less ' than 100% the balance will of course be highly fluorinated.
,~ ~
The fluorination is carried out by known means. For example, the hydrocarbon is passed slowly over a bed of CoF3 containing 2-3 times the stoichiometric amount of fluorine at ,~ 250-275C. to effect complete fluorination. The procedure , is then repeated at 300-350C. to effect complete fluorination ,~ of all but a few percent impurities which are both saturated, ~' partially fluorinated compounds and olefinic fluorocarbons.
`'~ The former boil at least 10C hi~her than the desired perfluoro , compound and are removed by distillation. The latter boil at ~, 'essentially the same temperature so they are extracted with an ,' amine such as diethylamine (DEA). Residual amine is removed -' with concentrated H2SO4. Residual acicl is removed with 1%
~' NaHCO3 solution which is then extracted with acetone. Finally, residual acetone is distilled off.
.'' ~: The perfluoropolycyclic is employed as a water emulsion ;.i '~ containing more than 40% water by volume. Preferably the ~
,' emulsion contains 10-30 volume percent of the perfluoropolycyclic. ;, Normally the emulsion will contain 1-5 volume percent of an ~, emulsifier. The specific emulsifier employed is not critical -~ but it should itself be nontoxic and should form a stable ,- emulsion. The preferred emulsifier is yoke-phospholipid as ,~
~,, this is well known to be harmless in the body. Also suitable for perfusion purposes are the polyoxyethylenes and polyoxypro-; pylenes available commercially as "Pluronicl' . "Pluronic F-68"
'` has a molecular weight of 8350 and forms a very stable emulsion.
`~ :
'` *Trademark ' 5 js:
.,; . . . , :
~,, . , . , ~ , , However there is some unconfirmed reports that l'Pluronic"
type materials precipitate~ plasma protein and hence they are preferably limited to perfusion w~th the commercially available yoke phosp~olipids used for blood substitutes.
'~
~ The emulsion can be formed with conventional high - shear emulsifies such as the Manton-Gaulin homogenizer. Typi-cally, the particle size of the perfluoropolycyclic in the emulsion is .001-lO microns, frequently 0.01-lO micron, usually 0.05-.5 micron and preferably 50 weight percent of the particles have diameters of 0.05-.3 micron. As is well known the particle size can be adjusted by the amount of shear employed. The actual particle size of the emulsion is not as critical as the stability of the emulsion which is further discussed below.
.: :
As indicated above retention of the material in the body is important. The data below compare perfluorinated (PF) dimethyladamantane (DMA~ and methyl adamantane tMA) with PF
tributylamine (TBA), decalin (D), and methyldecalin (MD). These -~
.~:
materials are the best blood substitutes and perfusion candidates to date. Emulsions containing lO~ of the material to be tested, .. . .
surfactant and water are made up and tested in the manner spe-cified in Science, Vol. 181, August, 1973, page 681. Mice were injected with the various emulsions. The mice were killed at intervals thereafter, the liver analyzed, and the percentage of original amount of PF material injected and still in the liver was determined. The data below show these results.
Percent of Dose in Liver àfter Stated Weeks Mat`erial 2 6 1-2- 20 PFMD 30 l9 2 2 PFMA 7 l - -~' ~ ;
~ .
i", , ~ -6- ~
:, ;
. i . . . . . .
,,................................... . . :
.
It is apparent that the PFl~A (which had a small amount of higher boiling impuri*y which retards its release from the body) ls as good or better than PFD. Even the PFDMA gets down to the 2% level of the PFD but it does take longer.
The relative stability of a PFDMA emulsion and PFMA is excellent in that it is stable indefinitely, (e.g., over six months~ at 4-7~C whereas the PFD emulsion breaks down in several days at room temperature and in several weeks at 4-7C. PFTBA is also excellent. See for example the Journal of Microvascular Research, Au~ust, 1974. In addition to emulsion stability, emulsion prepared from PFDMA and PFD (in the same manner~ show optical densities of 0.1 and 0.4 respect-ively, which means that the particle size of the former is much smaller and therefore that it is much easier to emulsify. Even PFMA is 0.65, much lower than the 2.2 obtained with PFTBA.
It hàs also been found that our perfluorinated materials are very nontoxic. The LD50 after infusion (ml/kg) of our materials compared ~ith others is as follows:
LD50 :~
Emulsion 1 Hr3 Days 7 Days 10.9~ PFD 190 160 157 10~ PFDMA 200 175 175 5~ PFMA 200 200 200 10~ PFTBA 200 120 120 ~`;
- As noted above the perfluorinated materials of the invention have high ox~gen and carbon dioxide solubility. For : ' .
-;, example the perfluorinated materials can normally contain about 40-60 cc oxygen per 100 cc fluorocarbon and the carbon dioxide .~
'''; ': ' ' '~' '. .' ' ~ '' ,, ,. ' . ~, ~ s~
solubility is about twice this. Normal blood will absorb about 20 cc oxygen per 100 cc of blood with carbon dioxide solubility being twice that of oxygen. The compositions of my invention will normally contain 30-60 cc of oxygen per 100 cc of the perfluorinated material but ratios as low as 10 cc per 100 cc up to 100 cc per 100 cc can be used where available. All the foregoing solubilities are at 25C and 760 milliliters mercury. The compounds in the higher end (C12 C18) of the C9 C18 carbon atom range perform in the manner described above except that their oxygen solubility decreases. Above C18 the solubility is not high enough to make these compounds practical candidates.
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The need for synthet~c blood is ~ell kno~n. slood is becoming increasingly expensive, it is perishable, it must be matched to the blood type of the recipient and the transfusion itself can cause hepatitis if rigid procedures are not followed.
In addition, blood donations tend to be somewhat seasonal and they often do not coincide with the generally random demands therefor.
A synthetic blood must have several characteristics.
Initially, and quite obviously, it must have high oxygen and carbon dioxide solubility since its principal function is to transport oxygen and carbon dioxide. A synthetic blood also must be non-to~ic and in this respect ît is desirable that when :
the synthetic blood is replaced by natural blood there is no residue of the former left in vital bocly organs.
Another characteristic of blood substitutes is that they must have certain vapor pressure requirements. The blood substitutes leave the body by being exhaled and by vaporization through the skin. Preferably the substitute leaves the body at about the same rate that new natural blood is being generated by the body. If the vapor pressure of the substitute is too low it stays in the body too long, whereas if it is too high it :
d evaporates throughout the body's surface and creates problems i akin to the "bends".
^~ Blood substitutes must also be capable of forming very stable emulsions w~th this capability being even more . ,.,~
i , .
.'"~' ~ ~ ., "':;' :
. .
. . .
'. t ',. " :
important with perfusion materials. Blood substitutes are usually immiscible with blood and if used alone could cause embolisms. The problem is overcome by using it in an aqueous emulsion and obviously the emulsion should not separate in use or storage. In connection with perfusion materials this stability is even more strict because the oxygenators used to add oxygen to the perfusion material create very high shear and will break down all but the most stable emulsions.
Another reason aqueous emulsions are employed is that salts are added to the water in order to maintain the body salt balance.
.,. :.
- The Green Cross Corporation, Osaka, Japan, has published a phamphlet dated September 11, 1974 on perfluoro emulsions as oxygen and carbon dioxide carriers.
: `~
j~ Also Clark et al report on some of the compounds described -~
in the present invention in Microvascular Research Volume 8/3 1974, also presented at the Oxygen Transport to Tissue Symposium, Atlantic City, N.J. April 11, 1974. The blood substitute and perfusion material of choise so far has been ` 20 perfluorodecalin. It has a number of desirable properties `- but our compounds appear superior to perfluorodecalin in several respects.
SUMMARY OF THE INVENTION
The novel blood substitutes and perfusion com-pounds disclosed herein are perfluorinated polycyclic `--compounds having 9-18 carbon atoms and at least two bridgehead carbon atoms. They have extremely high oxygen solubility, very low body residue, form very stable emulsions, and have ;~ a very satisfactory vapor pressure for one or both uses.
:
~. .;
,'; ;,. ' _ .. ;
, ,~ :
. :
.i,, .
: ` ~
~ he present in~ention therefore provides an emulsion of a non-aromatizable perfluorinated material in water, the amount of water being greater than 40% by volume, said emulsion containing an emulsifier and said perfluorinated material being obtained ~y fluorination of a Cg-Cl8 polycyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom.
In another aspect the present invention provides an emulsion of a non-aromatizable perfluorinated Cg-Cl8 polycyclic hydrocarbon containing at least two bridgehead carbon a~oms linked through a bridge containing at least one carbon atom in water, the amount of water being greater than 40% by volume and said emulsion containing an emulsifier.
In a further aspect the invention provides an artificial blood or oxygen transport agent comprising an emulsion of a non-aromatizable perfluorinated material in water, the amaunt of water being greater than 40% by volume, said emulsion containing an emulsifier and said perfi-~orinated material being obtained by fluorination of a Cg~C18 poly-cyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom.
.: .
There is also disclosed a process for the ` preparation of such an emulsion comprising the step of ` emulsifying with water and a non-toxic emulsifier a perfluorinated material obtained by fluorination of a compound containing at least two carbon atoms common to three rings wherein the amount of water in the final ,: .
emulsion is greater than 40% by volume.
t .
.'-'~"
,,:; :, :.:
-3a-....
.. ;. , , . . .
DETAILED DESCRIPTION OF THE INVENTION
The polycyclic compounds suitable for the present purpose are those having two bridgehead carbon atoms, a bridge-head carbon atom being a carbon atom common to three rings. Our invention employs Cg-Cl8 polycyclics such as tricyclononanes (e.g., tricyclo~3,3,1]nonane), adamantane, methyl and dimethyl-adamantane, ethyl adamantane, tetrahydrodicyclopentadiene, methyl and dimethyl bicyclooctanes, ethylmethyladamantane, ethyldimethyladamantane, tetrahydrobinor-S, methyldiamantane, triethyladamantane, trimethyldiamantane, ethyldimethyldiamantane, and the like. They can be made by known means. Preferably the polycyclic contains 9-12 carbon atoms and it generally will have not more than four rings, usually 2-3 rings.
As synthetic blood C8 materials (in perfluorinated form) have too high a vapor pressure to be useful. The C10 and Cll materials are just about right whereas the Cgs are a little on the high side re vapor pressure and the C12s are a little on the low side. C10 and Cll materials have atmospheric boiling points between about 125-165C. and this is a satisfactory ~. . .:
:, criteria, with the preferred range between 125 and 145C. This ,. .
preferred range will be mostly C10 materials.
It should be noted that even though C12s are not `susitable as blood substitutes they and up to C18s can be used ;. . ~
~ as perfusion compounds as in this application vapor pressure is -;, .
; not as important. Above C18 the oxygen solubility of the ;, material is generally too low.
The polycyclic material is used in perfluorinated ~` form. For the present purpose the term perfluorinated includes :,"~"
. :, '''.' . .
,'': ~
:;, -4-.~, . ................................................................. .
, ~, . . .
, . '. . : ; i b;. ~ . .... ~ .
:
C9-C18 polycyclics which are at least 95% by weight completely ~, fluorinated (i.e., perfluorinated in the strict sense), preferably '- at least 98% and more preferably 100%. In all cases of less ' than 100% the balance will of course be highly fluorinated.
,~ ~
The fluorination is carried out by known means. For example, the hydrocarbon is passed slowly over a bed of CoF3 containing 2-3 times the stoichiometric amount of fluorine at ,~ 250-275C. to effect complete fluorination. The procedure , is then repeated at 300-350C. to effect complete fluorination ,~ of all but a few percent impurities which are both saturated, ~' partially fluorinated compounds and olefinic fluorocarbons.
`'~ The former boil at least 10C hi~her than the desired perfluoro , compound and are removed by distillation. The latter boil at ~, 'essentially the same temperature so they are extracted with an ,' amine such as diethylamine (DEA). Residual amine is removed -' with concentrated H2SO4. Residual acicl is removed with 1%
~' NaHCO3 solution which is then extracted with acetone. Finally, residual acetone is distilled off.
.'' ~: The perfluoropolycyclic is employed as a water emulsion ;.i '~ containing more than 40% water by volume. Preferably the ~
,' emulsion contains 10-30 volume percent of the perfluoropolycyclic. ;, Normally the emulsion will contain 1-5 volume percent of an ~, emulsifier. The specific emulsifier employed is not critical -~ but it should itself be nontoxic and should form a stable ,- emulsion. The preferred emulsifier is yoke-phospholipid as ,~
~,, this is well known to be harmless in the body. Also suitable for perfusion purposes are the polyoxyethylenes and polyoxypro-; pylenes available commercially as "Pluronicl' . "Pluronic F-68"
'` has a molecular weight of 8350 and forms a very stable emulsion.
`~ :
'` *Trademark ' 5 js:
.,; . . . , :
~,, . , . , ~ , , However there is some unconfirmed reports that l'Pluronic"
type materials precipitate~ plasma protein and hence they are preferably limited to perfusion w~th the commercially available yoke phosp~olipids used for blood substitutes.
'~
~ The emulsion can be formed with conventional high - shear emulsifies such as the Manton-Gaulin homogenizer. Typi-cally, the particle size of the perfluoropolycyclic in the emulsion is .001-lO microns, frequently 0.01-lO micron, usually 0.05-.5 micron and preferably 50 weight percent of the particles have diameters of 0.05-.3 micron. As is well known the particle size can be adjusted by the amount of shear employed. The actual particle size of the emulsion is not as critical as the stability of the emulsion which is further discussed below.
.: :
As indicated above retention of the material in the body is important. The data below compare perfluorinated (PF) dimethyladamantane (DMA~ and methyl adamantane tMA) with PF
tributylamine (TBA), decalin (D), and methyldecalin (MD). These -~
.~:
materials are the best blood substitutes and perfusion candidates to date. Emulsions containing lO~ of the material to be tested, .. . .
surfactant and water are made up and tested in the manner spe-cified in Science, Vol. 181, August, 1973, page 681. Mice were injected with the various emulsions. The mice were killed at intervals thereafter, the liver analyzed, and the percentage of original amount of PF material injected and still in the liver was determined. The data below show these results.
Percent of Dose in Liver àfter Stated Weeks Mat`erial 2 6 1-2- 20 PFMD 30 l9 2 2 PFMA 7 l - -~' ~ ;
~ .
i", , ~ -6- ~
:, ;
. i . . . . . .
,,................................... . . :
.
It is apparent that the PFl~A (which had a small amount of higher boiling impuri*y which retards its release from the body) ls as good or better than PFD. Even the PFDMA gets down to the 2% level of the PFD but it does take longer.
The relative stability of a PFDMA emulsion and PFMA is excellent in that it is stable indefinitely, (e.g., over six months~ at 4-7~C whereas the PFD emulsion breaks down in several days at room temperature and in several weeks at 4-7C. PFTBA is also excellent. See for example the Journal of Microvascular Research, Au~ust, 1974. In addition to emulsion stability, emulsion prepared from PFDMA and PFD (in the same manner~ show optical densities of 0.1 and 0.4 respect-ively, which means that the particle size of the former is much smaller and therefore that it is much easier to emulsify. Even PFMA is 0.65, much lower than the 2.2 obtained with PFTBA.
It hàs also been found that our perfluorinated materials are very nontoxic. The LD50 after infusion (ml/kg) of our materials compared ~ith others is as follows:
LD50 :~
Emulsion 1 Hr3 Days 7 Days 10.9~ PFD 190 160 157 10~ PFDMA 200 175 175 5~ PFMA 200 200 200 10~ PFTBA 200 120 120 ~`;
- As noted above the perfluorinated materials of the invention have high ox~gen and carbon dioxide solubility. For : ' .
-;, example the perfluorinated materials can normally contain about 40-60 cc oxygen per 100 cc fluorocarbon and the carbon dioxide .~
'''; ': ' ' '~' '. .' ' ~ '' ,, ,. ' . ~, ~ s~
solubility is about twice this. Normal blood will absorb about 20 cc oxygen per 100 cc of blood with carbon dioxide solubility being twice that of oxygen. The compositions of my invention will normally contain 30-60 cc of oxygen per 100 cc of the perfluorinated material but ratios as low as 10 cc per 100 cc up to 100 cc per 100 cc can be used where available. All the foregoing solubilities are at 25C and 760 milliliters mercury. The compounds in the higher end (C12 C18) of the C9 C18 carbon atom range perform in the manner described above except that their oxygen solubility decreases. Above C18 the solubility is not high enough to make these compounds practical candidates.
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Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An emulsion of a non-aromatizable perfluorinated material in water, the amount of water being greater than 40% by volume, said emulsion containing an emulsifier and said perfluorinated material being obtained by fluorination of a C9-C18 polycyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom.
2. Compostion according to Claim 1 wherein the amount of said perfluorinated material is 10-30%.
3. Composition according to Claim 1 wherein said perfluorinated material contains 10-11 carbon atoms.
4. Composition according to Claim 1 wherein said perfluorinated material is perfluorotetrahydrodicyclopentadiene.
5. Composition according to Claim 1 wherein said perfluorinated material is a perfluorinated adamantane hydrocarbon.
6. Composition according to Claim 1 additionally containing a yoke-phospholipid or poly(C2-C3 alkylene oxide) surfactant.
7. Composition according to Claim 1 wherein said perfluorinated material has a boiling point of 125-156°C.
8. Compositon according to Claim 1 additionally containing 10-100 cc O2 (25°C., 760 mm Hg) per 100 cc of the perfluorinated material.
9. Composition according to Claim 8 wherein said perfluorinated material is perfluorotetrahydrodicyclopentadiene.
10. Composition according to Claim 8 wherein said perfluorinated material is a perfluorinated adamantane hydrocarbon.
11. An emulsion of a non-aromatizable perfluorinated C9-C18 polycyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom in water, the amount of water being greater than 40% by volume and said emulsion containing an emulsifier.
12. An artificial blood or oxygen transport agent comprising an emulsion of a non-aromatizable perfluorinated material in water, the amount of water being greater than 40%
by volume, said emulsion containing an emulsifier and said perfluorinated material being obtained by fluorination of a C9-C18 polycyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom.
by volume, said emulsion containing an emulsifier and said perfluorinated material being obtained by fluorination of a C9-C18 polycyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53079174A | 1974-12-09 | 1974-12-09 | |
| US57976675A | 1975-05-22 | 1975-05-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1058081A true CA1058081A (en) | 1979-07-10 |
Family
ID=27063372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA241,138A Expired CA1058081A (en) | 1974-12-09 | 1975-12-05 | Perfluoro polycyclic compounds for use as synthetic blood and perfusion media |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS5753762B2 (en) |
| CA (1) | CA1058081A (en) |
| CH (1) | CH629938A5 (en) |
| DE (1) | DE2555408A1 (en) |
| DK (1) | DK154605C (en) |
| FI (1) | FI54560C (en) |
| FR (1) | FR2313024A1 (en) |
| GB (1) | GB1531418A (en) |
| IT (1) | IT1050731B (en) |
| NL (1) | NL184995C (en) |
| NO (1) | NO754103L (en) |
| SE (2) | SE7513814L (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2515198A1 (en) * | 1981-10-22 | 1983-04-29 | Centre Nat Rech Scient | AQUEOUS MICROEMULSIONS OF FLUOROCARBONS INDUFINIMENTALLY STABLE AT A DATA TEMPERATURE, PROCESS FOR OBTAINING AND APPLICATION AS OXYGEN TRANSPORTERS |
| US4569784A (en) * | 1980-11-17 | 1986-02-11 | Adamantech, Inc. | Preparation of a gel having gas transporting capability |
| GB8504916D0 (en) * | 1985-02-26 | 1985-03-27 | Isc Chemicals Ltd | Emulsions of perfluorocarbons in aqueous media |
| DE4100059C2 (en) * | 1991-01-03 | 1994-08-25 | Adatomed Pharma & Med | Treatment liquid for reapplication (detached) of detached retina to the choroid of the eye |
| WO2010077671A2 (en) * | 2008-12-08 | 2010-07-08 | University Of Utah Research Foundation | Stable perfluorocarbon emulsion for use as an artificial oxygen carrier |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH604490A5 (en) * | 1970-09-05 | 1978-09-15 | Green Cross Corp | |
| GB1343870A (en) * | 1971-05-19 | 1974-01-16 | Green Cross Corp | Emulsions and the preparation thereof |
| US3911138B1 (en) * | 1973-02-26 | 1996-10-29 | Childrens Hosp Medical Center | Artificial blood and method for supporting oxygen transport in animals |
| JPS5331209B2 (en) * | 1973-10-05 | 1978-09-01 |
-
1975
- 1975-11-28 IT IT29807/75A patent/IT1050731B/en active
- 1975-12-03 CH CH1572675A patent/CH629938A5/en not_active IP Right Cessation
- 1975-12-04 NO NO754103A patent/NO754103L/no unknown
- 1975-12-04 JP JP50143428A patent/JPS5753762B2/ja not_active Expired
- 1975-12-05 CA CA241,138A patent/CA1058081A/en not_active Expired
- 1975-12-05 NL NLAANVRAGE7514202,A patent/NL184995C/en not_active IP Right Cessation
- 1975-12-08 FI FI753442A patent/FI54560C/en not_active IP Right Cessation
- 1975-12-08 DK DK554675A patent/DK154605C/en not_active IP Right Cessation
- 1975-12-08 SE SE7513814A patent/SE7513814L/en unknown
- 1975-12-09 GB GB50472/75A patent/GB1531418A/en not_active Expired
- 1975-12-09 FR FR7537587A patent/FR2313024A1/en active Granted
- 1975-12-09 DE DE19752555408 patent/DE2555408A1/en active Granted
-
1983
- 1983-01-27 SE SE8300422A patent/SE8300422D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2313024A1 (en) | 1976-12-31 |
| JPS5198318A (en) | 1976-08-30 |
| FR2313024B1 (en) | 1980-05-23 |
| NL184995B (en) | 1989-08-01 |
| DK154605B (en) | 1988-12-05 |
| FI54560B (en) | 1978-09-29 |
| SE8300422L (en) | 1983-01-27 |
| GB1531418A (en) | 1978-11-08 |
| FI54560C (en) | 1979-01-10 |
| DK554675A (en) | 1976-06-10 |
| DE2555408A1 (en) | 1976-06-10 |
| CH629938A5 (en) | 1982-05-28 |
| DE2555408C2 (en) | 1988-06-23 |
| DK154605C (en) | 1989-06-05 |
| SE7513814L (en) | 1976-06-10 |
| SE8300422D0 (en) | 1983-01-27 |
| NO754103L (en) | 1976-06-10 |
| NL184995C (en) | 1990-01-02 |
| JPS5753762B2 (en) | 1982-11-15 |
| FI753442A (en) | 1976-06-10 |
| NL7514202A (en) | 1976-06-11 |
| IT1050731B (en) | 1981-03-20 |
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