Patient oxygenation using stabilized fluorocarbon emulsions

Details Patient oxygenation using stabilized fluorocarbon emulsions Patient oxygenation using stabilized fluorocarbon emulsions

1999-03-05

2001-03-20

Lovering, Richard D. (Department: 1712)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Halogenated hydrocarbon doai

C514S743000, C514S759000, C514S772000, C514S832000

Reexamination Certificate

active

06204296

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to emulsions comprising highly fluorinated or perfluorinated compounds. More particularly, it relates to fluorocarbon emulsions having superior particle size stability during storage.
Fluorocarbon emulsions find uses as therapeutic and diagnostic agents. Most therapeutic uses of fluorocarbons are related to the remarkable oxygen-carrying capacity of these compounds. One commercial biomedical fluorocarbon emulsion, Fluosol (Green Cross Corp., Osaka, Japan), is presently used as a gas carrier to oxygenate the myocardium during percutaneous transluminal coronary angioplasty (R. Naito, K. Yokoyama, Technical Information Series No. 5 and 7, 1981). Fluorocarbon emulsions have also been used in diagnostic applications such as imaging. Radiopaque fluorocarbons such as perflubron (perfluorooctyl bromide or C
8
F
17
Br) are particularly useful for this purpose.
It is important that fluorocarbon emulsions intended for medical use exhibit particle size stability. Emulsions lacking substantial particle size stability are not suitable for long term storage, or they require storage in the frozen state. Emulsions with a short-shelf life are undesirable. Storage of frozen emulsions is inconvenient. Further, frozen emulsions must be carefully thawed, reconstituted by admixing several preparations, then warmed prior to use, which is also inconvenient.
Davis et al., U.S. Pat. No. 4,859,363, disclose stabilization of perfiuorodecalin emulsion compositions by mixing a minor amount of a higher boiling perfluorocarbon with the perfluorodecalin. Preferred higher boiling fluorocarbons were perfluorinated saturated polycyclic compounds, such as perfluoroperhydrofluoranthene. Others have also utilized minor amounts of higher boiling fluorocarbons to stabilize emulsions. See, e.g., Meinert, U.S. Pat. No. 5,120,731 (fluorinated morpholine and piperidine derivatives), and Kabalnov, et al., Kolloidn Zh. 48: 27-32 (1986) (F-N-methylcyclohexylpiperidine).
Davis, et al. suggested that the primary phenomenon responsible for instability of small particle size fluorocarbon emulsions was Ostwald ripening. During Ostwald ripening, an emulsion coarsens through migration of molecules of the discontinuous phase from smaller to larger droplets. See generally, Kabalnov, et al., Adv. Colloid Interface Sci. 38: 62-97 (1992). The force driving Ostwald ripening appears to be related to differences in vapor pressures that exist between separate droplets. Such a difference in vapor pressure arises because smaller droplets have higher vapor pressures than do larger droplets. However, Ostwald ripening may only proceed where the perfluorocarbon molecules are capable of migrating through the continuous phase between droplets of the. discontinuous phase. The Lifshits-Slezov equation relates Ostwald ripening directly to water solubility of the discontinuous phase. See Lifshits, et al., Sov. Phys. JETP 35: 331 (1959).
It is known that addition of higher molecular weight compounds, having lower vapor pressures and lower solubility in the continuous phase, reduces such interparticle migration. This, in turn, reduces Ostwald ripening and improves particle size stability. Thus, the conventional prior art solution to the particle size stability problem is to add a certain amount (e.g., 10-30% of the fluorocarbon content) of a higher molecular weight fluorocarbon to the discontinuous phase.
Fluorocarbon emulsion particles are taken up and temporarily retained by cells of the reticuloendothelial system (RES). It is desirable to minimize this retention time. Unfortunately, when the prior art included higher molecular weight fluorocarbons in fluorocarbon emulsions, organ retention times were also increased considerably. Organ retention time for most fluorocarbons bears an exponential relationship to the molecular weight of the fluorocarbon. See J. G. Riess, Artificial organs 8: 44, 49-51; J. G. Riess, International Symposium on Blood Substitutes, Bari, Italy: Jun. 19-20, 1987, Proceedings pp. 135-166.
There is a need for perfluorocarbon emulsions that exhibit both storage stability in the nonfrozen state and a rapid rate of elimination from the body. Accordingly, it is an object of the invention to provide fluorocarbon emulsions having these characteristics.
SUMMARY OF THE INVENTION
The present invention involves stabilization of fluorocarbon emulsions with higher molecular weight fluorocarbons that include a lipophilic moiety. Alternatively, any fluorocarbon having a critical solution temperature that is 10° C. or more below that which is predicted by its molecular weight can be used to stabilize fluorocarbon emulsions in accordance with this invention.
A major advantage of the present invention is the surprisingly short organ retention times of the stabilized emulsion. Perfluorodecyl bromide, for example, has a calculated half life in vivo in organs of the reticuloendothelial system (RES) of approximately 18 days, while those of nonlipophilic perf luorocarbons having about the same molecular weight vary from about 50 to 300 days. (See Table IV.) This distinction is critical; it spells the difference between formulations which are physiologically acceptable and those which are not. Note that none of the prior art stabilizers are lipophilic; thus, none share the advantageous properties of the present invention. For example, with reference to Table IV and
FIG. 5
, the stabilizers of the present invention all have critical solution temperatures (CSTs) and projected organ retention times much lower than those of the prior art stabilizers of Davis, et al., Kabalnov, and Meinert. Aside from the stabilizers of the present invention, conventional fluorocarbons exhibit a direct correlation between retention time in RES organs and molecular weight. Also, aside from the lipophilic fluorocarbons used in the present invention, the perf luorochemical structure has little effect on the strong retention time/molecular weight relationship. Thus, the presence of heteroatoms or cyclic structure has little effect on organ retention time.
Another major advantage of the present invention over the prior art is that the emulsions are remarkably stable. This is particularly true when both the major (first) fluorocarbon and the stabilizing (second) fluorocarbon include lipophilic moieties.
Thus, in accordance with one aspect of the present invention, there is provided a storage stable fluorocarbon emulsion, comprising a continuous aqueous phase, an effective amount of an emulsifying agent, and a discontinuous fluorocarbon phase, comprising from about 50% to about 99.9% of a one or more first fluorocarbons, and from about 0.1% to about 50% of one or more second fluorocarbons having a molecular weight greater than each such first fluorocarbon, wherein each such second fluorocarbon includes at least one lipophilic moiety. The first fluorocarbon can be selected from a variety of materials, including bis (F-alkyl) ethenes, perfluoroethers having the general structure C
n
F
2n+1
—O—C
n′
F
2n′+1
, wherein the sum of n and n′ equals 6 to 8, perfluoromethylbicyclo [3.3.1]-nonane, perfluoro-2,2,4,4-tetramethylpentane, perfluorotripropylamine, bis(F-butyl)ethene, (F-isopropyl) (F-hexyl) ethene, perfluoromethyladamantane, perfluorodimethyladamantane, F-N-methyldecahydroisoquioline, F-4-methyloctahydroquinolidizine, perfluorodecalin, or most preferably, perfluorooctyl bromide. In one embodiment, each first fluorocarbon has a molecular weight from about 460 Daltons to about 550 Daltons, and also preferably has a half life in vivo of less than about 4 weeks, preferably less than 2 or 3 weeks, and most preferably 7 days or less. In the second fluorocarbon, the lipophilic moiety or moities are advantageously Br, Cl, I, H, CH
3
, or a saturated or unsaturated hydrocarbon chain of 2 or 3 carbon atoms. In one preferred embodiment, the second fluorocarbon is an aliphatic perfluorocarbon having the general formula C
n
F
2n+1
R or C
n
F
2n
R
2
, wherein n is an integer from 9 to 12 and R

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