U.S. patent application number 09/270562 was filed with the patent office on 2002-01-03 for low-oxygen fluorocarbon as an agent for ophthalmology.
Invention is credited to DRESP, JOACHIM, GABEL, VIET-PETER, KOBUCH, KARIN, MENZ, DIRK-HENNING.
Application Number | 20020001607 09/270562 |
Document ID | / |
Family ID | 7861270 |
Filed Date | 2002-01-03 |
United States Patent
Application |
20020001607 |
Kind Code |
A1 |
KOBUCH, KARIN ; et
al. |
January 3, 2002 |
LOW-OXYGEN FLUOROCARBON AS AN AGENT FOR OPHTHALMOLOGY
Abstract
The present invention concerns fluorocarbons for use in
ophthalmology. Fluorocarbons disclosed in the prior art can only be
left in the eye for a limited period of time because they cause
damage to the retina or intraocular structure. The present
invention provides an oxygen-fluorocarbon mixture having a
dissolved oxygen content of less than 6% by volume, which can be
used as an ophthalmological agent for longer periods of time than
conventional fluorocarbons, with little or no damage to the retina
or intraocular structures. The invention also provides a process
for preparing the oxygen-fluorocarbon mixture. In one embodiment,
up to 20% by volume of a second gas, such as carbon dioxide or
nitric oxide, is combined with the oxygen-fluorocarbon
mixtures.
Inventors: |
KOBUCH, KARIN; (PENTLING,
DE) ; GABEL, VIET-PETER; (REGENSBURG, DE) ;
DRESP, JOACHIM; (MUNCHEN, DE) ; MENZ,
DIRK-HENNING; (DIEDORF, DE) |
Correspondence
Address: |
THOMAS P. SARRO
LARSON & TAYLOR
SUITE 900
1199 NORTH FAIRFAX STREET
ALEXANDRIA
VA
22314
|
Family ID: |
7861270 |
Appl. No.: |
09/270562 |
Filed: |
March 16, 1999 |
Current U.S.
Class: |
424/423 |
Current CPC
Class: |
A61P 27/02 20180101;
A61K 31/025 20130101; A61K 9/0048 20130101 |
Class at
Publication: |
424/423 |
International
Class: |
A61F 013/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 18, 1998 |
DE |
198 11 683.7 |
Claims
We claim:
1. An oxygen-physiologically acceptable fluorocarbon mixture having
a dissolved oxygen content of less than 6% by volume, wherein the
fluorocarbon is selected from the class of saturated,
perfluorinated hydrocarbons in which all of the hydrogen atoms are
replaced by fluorinated atoms, or partially fluorinated alkanes
having the general formula R.sub.FR.sub.H or R.sub.FR.sub.HR.sub.F
that can be present in a liquid or gel-like state, and wherein
R.sub.F is a perfluorinated alkyl group and R.sub.H is an alkyl
group.
2. An oxygen-fluorocarbon mixture according to claim 1, having a
dissolved oxygen content of less than 4% by volume.
3. An oxygen-fluorocarbon mixture according to claim 1, having a
dissolved oxygen content of less than 1% by volume.
4. A process for preparing an oxygen-physiologically acceptable
fluorocarbon mixture having a dissolved oxygen content of less than
6% by volume, wherein the fluorocarbon is selected from the class
of saturated, perfluorinated hydrocarbons in which all of the
hydrogen atoms are replaced by fluorinated atoms, or partially
fluorinated alkanes having the general formula R.sub.FR.sub.H or
R.sub.FR.sub.HR.sub.F that can be present in a liquid or gel-like
state, wherein R.sub.F is a perfluorinated alkyl group and R.sub.H
is an alkyl group; and wherein the fluorocarbon is deoxygenated
using a heterogeneous oxygen getter, and stored in an
oxygen-lacking state until use.
5. A process according to claim 4 wherein said heterogeneous oxygen
getter comprises a low-valence metal oxide.
6. A process according to claim 5, wherein said low-valence metal
oxide is reduced Cu.sub.2O.
7. A process according to claim 4, wherein said oxygen-lacking
state is achieved by hermetic sealing.
8. A process according to claim 4, wherein said oxygen-fluorocarbon
mixture is stored in a sealed container with said heterogeneous
oxygen getter; and filtered through a sterile filter prior to
use.
9. A process according to claim 4, wherein said fluorocarbon is
stored in a projecting gas chamber with said heterogeneous oxygen
getter, until use.
10. A process according to claim 4, wherein said fluorocarbon is
filtered through an absorber cartridge containing said
heterogeneous oxygen getter and then filtered through a sterile
filter.
11. A process for making an oxygen-physiologically acceptable
fluorocarbon mixture having a dissolved oxygen content of less than
6% by volume, wherein the fluorocarbon is selected from the class
of saturated, perfluorinated hydrocarbons in which all of the
hydrogen atoms are replaced by fluorinated atoms, or partially
fluorinated alkanes having the general formula R.sub.FR.sub.H or
R.sub.FR.sub.HR.sub.F that can be present in a liquid or gel-like
state, and wherein R.sub.F is a perfluorinated alkyl group and
R.sub.H is an alkyl group; wherein said fluorocarbon is
deoxygenated using a heterogeneous oxygen getter; and
proportionately mixed with an oxygen-containing fluorocarbon to
obtain a desired oxygen concentration within a range of 0% to 6% by
volume; and stored in an oxygen-lacking state until use.
12. An oxygen-fluorocarbon mixture according to claim 1, combined
with a second gas, wherein said second gas constitutes between 0
and 20% by volume of the mixture.
13. An oxygen-fluorocarbon mixture according to claim 12 wherein
said second gas is selected from the group consisting of carbon
dioxide and nitric 0oxide.
14. Use of a physiologically acceptable fluorocarbon having a
dissolved oxygen content of less than 6% by volume as an agent for
ophthalmology, wherein the fluorocarbon is selected from the class
of saturated, perfluorinated hydrocarbons in which all of the
hydrogen atoms are replaced by fluorinated atoms, or partially
fluorinated alkanes having the general formula R.sub.FR.sub.H or
R.sub.FR.sub.HR.sub.F that can be present in a liquid or gel-like
state, and wherein R.sub.F is a perfluorinated alkyl group and
R.sub.H is an alkyl group.
15. Use according to claim 14, wherein the dissolved oxygen content
is less than 4% by volume.
16. Use according to claim 14, wherein the dissolved oxygen content
is less than 1% by volume.
17. Use according to claim 14, wherein the dissolved oxygen content
is greater than 0% by volume.
18. Use according to claim 14, wherein said fluorocarbon is
combined with a second gas to create a mixture, and wherein said
second gas constitutes between 1 and 20% by volume of the
mixture.
19. Use of a fluorocarbon according to claim 14, as an intraocular
agent.
20. Use of a fluorocarbon according to claim 17, as an intraocular
agent.
21. Use of a fluorocarbon according to claim 14, as a retina
tampon.
22. Use of a fluorocarbon according to claim 17, as a retina
tampon.
23. Use of a fluorocarbon according to claim 14, as an agent for
treating ischemic retinal disorders.
24. Use of a fluorocarbon according to claim 17, as an agent for
treating ischemic retinal disorders.
25. Use of a fluorocarbon according to claim 14, as a vitreous body
replacement.
26. Use of a fluorocarbon according to claim 17, as a vitreous body
replacement.
Description
FIELD OF THE INVENTION
[0001] The invention concerns the use of a fluorocarbon as an agent
for ophthalmology.
BACKGROUND OF THE INVENTION
[0002] Within the meaning of this description, the term
"fluorocarbon" either refers to compounds from the class of
saturated, perfluorinated hydrocarbons in which all of the hydrogen
atoms are replaced by fluorinated atoms, or partially fluorinated
alkanes having the general formula R.sub.FR.sub.H or
R.sub.FR.sub.HR.sub.F that can be present in a liquid or gel-like
state. In this case, R.sub.F is a perfluorinated alkyl group and
R.sub.H an alkyl group. Substances of this type, as well as their
possible applications in medicine and technology are, for example,
described in DE 42 05 341 A1, U.S. Pat. Nos. 5,275,669, 4,490,351,
EP 493 677 A2 and DE 195 36 504 A1.
[0003] These fluorocarbons are almost always saturated with oxygen
in a highly concentrated manner, whereby the oxygen is present in a
physical solution. When increasing the partial pressure of the
oxygen, fluorocarbons can store up to 50% by volume of oxygen. This
compound-typical property was the basis for the development of
numerous technical applications of these compounds (see the article
by B. Cornils "Fluorous biphasic systems" in Angew. Chemie [Applied
chemistry] 1997, 109, 2147), as well as medical applications, e.g.
as blood substitutes, as means for liquid artificial respiration,
as oxygen carriers in ointments, etc. Fluorocarbons having a low
content of dissolved oxygen spontaneously and very quickly absorb
oxygen in contact with air until a balance between dissolved oxygen
and the oxygen content of the ambient atmosphere is reached. These
medical applications of fluorocarbons as oxygen carriers were
described, for example, in the aforementioned publications and in
the paper by K. C. Lowe "Properties and Biomedical Applications of
PFC and their Emulsions", in Org. Fluorine Chem.: Principles and
Commercial Appl., Plenum Press, N.Y. 1994.
[0004] Moreover, the application of fluorocarbons as an agent in
ophthalmology has been described, for example, in the European
Patent Application 563 446 A1. In particular, fluorocarbons are
used as retina tampons when treating retinal detachments, where
their density and their surface properties are of special
significance.
[0005] So that it can be used as an ophthalmological agent via an
intraoperative treatment, the fluorocarbons have to be left in the
eye socket for a longer time instead of the vitreous body
previously removed, e.g. in order to exert a constant, permanent
pressure on the retina.
[0006] However, it has been shown that the known fluorocarbons can
only be left in the eye for a limited period of time, see U.S. Pat.
No. 5,037,384. That is, damage to the retina and the vessel system
occur after only a short duration in the eye, the cause of which is
to a great extent unknown and is, inter alia, attributed to the
high density of the compounds. Due to the strong binding energy
between carbon and fluorine, the fluorocarbons are chemically inert
and are therefore not broken down by metabolical reactions.
[0007] To date, no importance has been ascribed to the quantity of
oxygen usually dissolved in the fluorocarbons when the retina and
adjacent intraocular structures are damaged. To the extent that
this subject has been discussed at all in the literature, e.g. in
the paper by A. J. Augustin, M. Spitznas, F. H. J. Koch, T. Boker,
J. Lutz in Graefes Arch. Clin. Exp. Ophthalm. 1995, 233, 45-27,
"Local Effects of Different Perfluorochemical Agents", the
conclusion was that the damage to the retina and the intraocular
system observed in animal experiments had to be caused by other
factors, e.g. by the tensides contained in the emulsions. This was
reinforced in the paper which indicated that toxic effects could
not be observed when using pure fluorocarbons (that nevertheless
contained oxygen).
[0008] In other studies also, damage caused by fluorocarbons was
ascribed to other properties of these substances and not to their
dissolving power for oxygen. On the contrary, the oxygen solvency
of these substances was repeatedly described as an advantage for
ophthalmological applications.
SUMMARY OF THE INVENTION
[0009] Accordingly, this invention seeks to provide an agent for
ophthalmology which can be used for a longer period of time than
conventional fluorocarbons, with little or no damage to the retina
and adjacent intraocular structures.
[0010] Thus, this invention provides an oxygen-physiologically
acceptable fluorocarbon composition wherein the content of
dissolved oxygen is less than 6%; and the fluorocarbon is chosen
from compounds from the class of saturated, perfluorinated
hydrocarbons in which all of the hydrogen atoms are replaced by
fluorinated atoms, or partially fluorinated alkanes having the
general formula R.sub.FR.sub.H or R.sub.FR.sub.HR.sub.F that can be
present in a liquid or gel-like state. In this case, R.sub.F is a
perfluorinated alkyl group and R.sub.H an alkyl group. In one
embodiment, the mixture also contains 0 to 20% by volume of a
second gas, such as carbon dioxide or nitric oxide.
[0011] This invention also provides a process of creating an
oxygen-physiologically acceptable fluorocarbon composition, wherein
the content of dissolved oxygen is less than 6%.
[0012] In another aspect, this invention provides the use of a
physiologically acceptable fluorocarbon having a dissolved oxygen
content of less than 6% by volume as an agent for ophthalmology. In
particular, said fluorocarbon may be used as an intraocular agent,
a retina tampon, an agent for treating ischemic retinal disorders,
or as a vitreous body replacement.
[0013] An advantage of fluorocarbons having a dissolved oxygen
content of less than 6% by volume is that it appears that they can
be used as an ophthalmological agent for longer periods of time
than conventional fluorocarbons, with little or no damage to the
retina or intraocular structures.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The inventors recognized that the toxic effect during
long-term applications can be ascribed to a considerable content of
the physically dissolved oxygen (with a simultaneously low content
of dissolved carbon dioxide) in the fluorocarbons. This is in
contradiction to the teachings of the prior art.
[0015] Our studies have shown that fluorocarbons whose oxygen
contents were not carefully reduced resulted in damage to the
retinal blood vessels after having been inserted into the vitreous
area of the eye of a rabbit. In fluorescence angiography, a
narrowing of the vessels appears from the second post-operative
day. As time passes, vessel occlusions, a rarefaction of the
capillary bed and the development of microaneurisms appear.
Histologically, flat preparations of the retinal blood vessels
exhibit caliber fluctuations in the area of the vascular walls and
a loss of pericytes and endothelial cells from the vascular walls.
On the other hand, control tests with deoxygenated fluorocarbons
according to the present invention showed normal retinal blood
vessels.
[0016] Under normal conditions and in a pure oxygen atmosphere,
fluorocarbons exhibit a high constituent of physically dissolved
oxygen. This is up to 50% by volume. In ordinary ambient air, the
oxygen content is still at about 8% by volume. To produce
fluorocarbons with a relatively low oxygen content required
according to the present invention, the fluorocarbons must first be
deoxygenated. It should then be ensured that the low oxygen content
obtained during deoxygenation is maintained until the fluorocarbons
are used.
[0017] Known rinsing processes with gases other than oxygen can be
used as suitable processes for the deoxygenation, whereby rinsing
can be improved by gentle heating and/or successive evacuating and
gas rinsing.
[0018] Especially effective are processes for deoxygenation using
oxygen getters in a heterogeneous phase. Low-valence metal oxides,
in particular reduced Cu.sub.2O, which have previously been
primarily used for oxygen separation from gases, are especially
suitable as heterogeneous oxygen getters. The heterogeneous oxygen
getters can thereby be used as a filling for absorber cartridges
through which the fluorocarbons are led. If these absorber
cartridges are combined with sterile filters, then the fluorocarbon
can be deoxygenated immediately prior to being used as an
ophthalmological agent.
[0019] Due to the very strong solvency of the fluorocarbons for
oxygen, it should be ensured that, once the fluorocarbons have been
deoxygenated, they remain in an oxygen-lacking state until their
use, which is usually only possible by hermetic sealing.
[0020] To ensure that fluorocarbons that are otherwise packaged,
e.g. in bottles, also remain low-in-oxygen until their use, the
aforementioned heterogeneous oxygen getters can also be added to
the fluorocarbons. In this case, however, the oxygen getters should
be separated immediately prior to use of the fluorocarbons as an
agent in ophthalmology which can, for example, be accomplished by
filtration.
[0021] Alternatively thereto, the heterogeneous oxygen getters can
be placed in the projecting gas chamber, whereby its action of
maintaining the deoxygenated condition can unfold by means of
diffusion processes via a gas phase. A further advantage of using
heterogeneous oxygen getters is that partial pressure of other
dissolved gases can be set extremely well, which cannot be
accomplished in deoxygenation by means of flowing gases without
special additional processes. Thus, the content of other physically
dissolved gases such as nitrogen, carbon dioxide, or nitric oxide
can be easily set to the value that is most advantageous for the
respective application.
[0022] If, after complete deoxygenation of the fluorocarbons, one
wishes a specific, defined oxygen concentration, then this can be
obtained by proportionately mixing with the same substance that
has, however, been stored in air and thus enriched with oxygen,
since the equilibrium concentration of the oxygen in the
fluorocarbon stored under atmospheric conditions is a very stable
and reproducible value, and is 8% by volume.
[0023] A value that differs from zero of the oxygen content of the
fluorocarbons is recommended e.g. in an ischemic retina to which
oxygen should deliberately be supplied, however, not so much that a
toxic injury to the retina occurs.
[0024] Furthermore, the oxygen-lacking fluorocarbon can also be
mixed with other gases, for example, with nitrogen, carbon dioxide,
or nitric oxide (NO). Enrichment with carbon dioxide/nitric oxide
is medically of particular significance because an autoregulation
system acts in cerebral blood vessels, including the retinal
vessels, which reacts to an increased carbon dioxide or nitric
oxide content with a vessel dilatation and an increased blood flow.
For example, a partial pressure of carbon dioxide corresponding to
the air concentration sets in in fluorocarbons. However, in
contrast to oxygen, this is below physiological values. While
carbon dioxide has partial pressures of 40 mmHg in arterial blood
and 45 mmHg in venous blood, fluorocarbons have a carbon dioxide
partial pressure of less than 1 mmHg in room air.
[0025] An increased carbon dioxide content is always coupled with a
low oxygen content in blood. This fixed ratio can be easily offset
in an agent by setting increased carbon dioxide contents that
result in a vessel dilatation. At the same time, otherwise
physiologically optimal oxygen values can be set. An agent
containing a nitric oxide can only unfold its action when the
partial pressure of oxygen is set such that the competitive
reaction of the free radical NO can be sufficiently suppressed with
oxygen.
[0026] The oxygen-lacking fluorocarbon of the invention can then be
used in a known manner in ophthalmology and as described in the
aforementioned publications, e.g. as a vitreous body replacement or
retina tampon.
[0027] In one embodiment, the entire physically dissolved oxygen
was first desorped from highly purified perfluorodecalin by rinsing
with nitrogen. This process was monitored by oxygen measurements.
Based on an oxygen concentration of 8% by volume, a value of 1% by
volume was obtained after 30 minutes.
[0028] This oxygen-lacking perfluorodecalin was then sterile
filtered and injected into one eye each of two rabbits, whereby,
prior to the injection, the vitreous body was gas compressed in a
known manner. After the gas compression, the gas was intravenously
exchanged for 1.2 ml of the deoxygenated perfluorodecalin, so that
about two thirds of the vitreous body area, including the area of
the retinal blood vessels, was filled with perfluorodecalin.
[0029] After durations of between two days and six weeks, the eyes
were examined for vessel damage. It was shown that, in comparison
to each of the untreated eyes, there was a completely normal
condition.
[0030] Studies have shown that the substances of the invention are
also suitable as an agent in ophthalmology-related fields, in
particular as an agent in brain surgery in ischemic-related
disorders.
* * * * *