Title: Lipid emulsions in the
treatment of systemic poisoning
United States Patent: 7,261,903
Issued: August 28, 2007
Inventors: Weinberg; Guy
(Skokie, IL), Hertz; Paul (Skokie, IL)
Appl. No.: 09/622,816
Filed: February 22, 1999
PCT Filed: February 22,
PCT No.: PCT/US99/03805
July 17, 2001
PCT Pub. No.: WO99/43301
PCT Pub. Date: September
Executive MBA in Pharmaceutical Management, U. Colorado
Lipid emulsion compositions and methods
of using such composition via intravenous infusion to reduce the
bioavailability and toxicity of poisonous agents in the bloodstream.
Description of the Invention
FIELD OF THE
This invention relates to lipid emulsion
compositions and to methods of reducing the bioavailability and toxicity
of poisons and other noxious agents present in the circulation by the
intravenous infusion of a lipid emulsion composition.
BACKGROUND OF THE
An emulsion is a collective of lipid or
oil microparticles dispersed in water usually by the action of an
emulsifying agent. Historically, emulsions have been widely used in the
cosmetic and drug industries in connection with creams, depilatories,
antiperspirants, deodorants, antiseptics and the like. Emulsion systems
which include sugars, amino acids, vitamins, and electrolytes have also
been utilized as a means of providing intravenous nutrition in order to
maintain a patient's life when oral or nasal feeding is impossible or
insufficient (see U.S. Pat. No. 5,674,527 to Inoue et al.). Another common
use of emulsions is in parenteral drug delivery systems (see U.S. Pat. No.
3,538,216 to Polin et al.). These drug delivery systems feature
hydrophobic medicinals suspended in an emulsion to be delivered to the
patient in a sustained release manner. The lipid emulsion in this system
consists of a thixotropic agent, a gelatinous-oil composition containing
an ion-exchange agent, and water.
Also, edible but non-digestible emulsions have been used as traps for
toxins present in the gastrointestinal (GI) tract as described in U.S.
Pat. No. 4,183,918 to Asher et al. In this trap system, the emulsion is
fed to a symptomatic patient wherein the toxins are removed by the action
of the absorbent-containing emulsion passing through the GI tract. Key
features of this system include the use of non-digestible oils as the
exterior phase of the emulsion and the use of a reactant or adsorbent in
the interior aqueous phase of the emulsion. Examples of exterior phase
oils used in this system include highly refined hydrocarbon oils, mineral
oils, and silicone oils, while preferred interior phase reactants and
adsorbents include silica gel and carbon.
Other means of detoxifying the body include the delivery of liposomes
containing active reagents to a patient. For example, an aqueous solution
of the chelating agent EDTA was encapsulated by liposomes (synthetic
membrane vesicles) and given to a patient undergoing chemotherapy in order
to remove the radioactive metal plutonium from the patient's body. (Rahman
et al., Science (1973) 180:300). Liposomes, in most cases, act by
rupturing their membranes to release their inner contents. As such,
liposomes have also been used to deliver drugs in a controlled-release
manner as described in U.S. Pat. No. 4,837,028 to Allen. However,
liposomes are not readily permeable to extraneous toxic agents present in
Despite the foregoing, a need remains for materials and methods to
effectively decrease the bioavailability and toxic substances in the
bloodstream, especially those lipophilic or amphilic agents such as
antidepressants, anesthetics, alcohol, or others which require immediate
intervention when present in dangerous amounts.
SUMMARY OF THE
The invention is directed to lipid
emulsion compositions and methods for reducing the bioavailability and
toxicity of poisonous agents in the circulation by the intravenous
infusion of a lipid emulsion. Preferred lipid emulsion compositions
comprise an oil, an emulsifier, a tonicity modifier, and water. In a
preferred method of the invention, a patient having toxic levels of a drug
or other toxic substances is intravenously infused with a composition of
the lipid emulsion wherein the toxic substance permeates the emulsion and
is redistributed according to its lipid:aqueous partition coefficient into
the non-aqueous (lipid) phase of the emulsion, thereby decreasing the
bioavailability of the toxic substance. Such lipid sinks have wide
applicability to the treatment of toxicity associated with lipophilic and
amphiphilic substances. In a preferred embodiment, the invention is
directed to the treatment of toxicity due to lipophilic and amphiphilic
In another preferred embodiment, the invention is useful in the treatment
of cardiotoxicity, including those instances of cardiac arrest due to
unknown toxic agents and, in particular, when the toxic agents are
lipophilic and amphiphilic substances.
Yet another embodiment of the present invention comprises materials and
methods for treating toxicity associated with anesthetic agents, including
but not limited to, bupivacaine, lidocaine, and other anesthetic agents.
A preferred lipid emulsion composition comprises about 20 percent by
weight soybean oil, about 2 weight percent glycerin, about 1 weight
percent egg yolk phospholipid, and about 80 weight percent water; however,
the composition can vary depending upon the nature and lipid partition
coefficient of the toxic substance in the bloodstream.
In a preferred embodiment, a 20 percent by weight solution of the emulsion
in water is infused intravenously at an initial rate of about 7.5
milliliters per kilogram for a time period of about 30 seconds followed by
a steady-state rate of about 3 milliliters per kilogram per minute for a
time period of about 2 minutes.
Other lipid-emulsions according to the present invention include emulsions
comprising one or more of the following substances: glycerophospholipids
such as phosphatidylcholine; cholesterol, stearylamine; phosphatidylserine;
phosphotidylglycerol and other lipids. Also included within the scope of
the invention are microemulsions which include oil, water, and an
amphiphile system that is macroscopically mono-phasic, optically
isotropic, thermodynamically stable and characterized by ultra-low
interfacial tension values.
The invention is also directed to a device for the convenient
administration of the emulsions of the present invention to a patient. The
device is also useful for administering other therapeutic substances by
way of a regimen comprising the administration of a bolus of the agent and
the subsequent infusion of the agent over a period of time.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph depicting the probit analysis of the mortality fraction
versus the bupivacaine dose for animals treated according to protocol 2
(lipid resuscitation) for intravenous infusions of either saline or a
lipid emulsion composition.
FIG. 2 depicts a device for administering to a patient the emulsions of
the present invention.
The present invention relates to lipid emulsion compositions and to
methods and apparatus for reducing the bioavailability and toxicity of
poisonous or noxious agents present in the circulation, by intravenous
administration of a lipid emulsion. A preferred method for the treatment
of systemic toxicity includes making a patient in need of such therapy,
rapidly lipemic by the intravenous infusion of an initial large bolus dose
of an emulsion followed by a slower steady-state rate infusion of the
emulsion. Although the rate of infusion can vary with respect to the
particular emulsion utilized with the toxic agent involved and with the
particular patient, by way of example, an initial rate of the infusion may
be in the range of about 0.5 ml/kg/min to about 10 ml/kg/min for a time
period of about 0.5 min followed by a steady-state rate in the range of
about 0.1 ml/kg/min to about 3 ml/kg/min for a time period of about 2
The lipid emulsion composition used to detoxify the blood comprises an
oil, an emulsifier, a tonicity modifier, and water. Additional ingredients
can include a surfactant, a co-solvent, a bacteriostat, a preservative, an
active ingredient, and an adsorbent.
Preferably the oil in the emulsion composition is one or more oils
selected from the group consisting of monoglycerides, diglycerides,
triglycerides, and mixtures thereof. More preferably, the oil is a
naturally occurring plant oil selected from the group consisting of
soybean oil, cottonseed oil, safflower oil, corn oil, coconut oil, sesame
oil, peanut oil, olive oil, and mixtures thereof. Most preferably the oil
is soybean oil. In addition, the oil can be an animal oil or a fish oil
such as cod liver oil. The oil can also can be a mineral oil or a
chemically-synthesized oil such as 2-linoleoyl-1,3-dioctanoyl glycerol.
Semisynthetic mono-, di- or triglycerides may also be used and include
rac-glyceryl-1-monopalmitic, acyl glyceryl-1-monoolein, 1,2-dipalmitic,
1,3-dipalmitic, trimyristin, tripalmitin, tristearin, triolein, trilaiden
and the like.
The emulsifier in the lipid emulsion composition preferably is a
naturally-occurring phospholipid. Preferred phospholipids can be derived
from egg or soy sources. Exemplary phospholipids include but are not
limited to, egg yolk phospholipids, hydrogenated egg yolk phospholipids,
soybean phospholipids, hydrogenated soybean phospholipids, and mixtures
thereof. Preferably, the phospholipid is egg yolk phospholipid. The
emulsifier also can be a synthetic lecithin such as dihexanoyl-L-.varies.-lecithin.
Among the other emulsifiers useful in the practice of the present
invention are other glycerophospholipids such phosphatidylcholine lipids
such as cholesterol, stearylamine, phosphatidylserine,
phosphatidylglycerol and other lipids.
The tonicity modifier preferably is a member of the group consisting of
glycerin, sorbital, polyoxyethylated hydrocarbons, and C.sub.6 C.sub.20
saturated or unsaturated aliphatic acids. The optional co-solvent
preferably is an alcohol such as isopropanol or benzyl alcohol or the
like. The bacteriostat or preservative can be any of those commercially
available which are non-toxic. The active ingredient can be a desired drug
or reactant which can render the toxic agent non-toxic or which may act to
counter the physiological effects of the toxic agent, while the adsorbent
can be, for example, charcoal, silica gel, or the like.
In formulating the emulsion, the oil is preferably present in an amount in
the range of about 10 to about 30 percent by weight of the composition.
The surfactant in the emulsion composition is present in an amount in the
range of about 1 to about 5 percent by weight of the composition. Water is
present in the emulsion composition in an amount in the range of about 70
to about 90 percent by weight.
A preferred lipid emulsion composition comprises about 20 weight percent
soybean oil, about 2 weight percent glycerin, about 1 weight percent egg
yolk phospholipid, and about 80 weight percent water.
In the following examples, the commercially available (Healthcare,
Deerfield, Ill.) lipid emulsion composition, Intralipid.RTM. was used.
Intralipid.RTM. (Baxter) was introduced into the U.S. marketplace in 1975
for intravenous use. Intralipid.RTM. contains 10% w/v soybean oil as a
source of polyunsaturated fatty acids, and 1.2% w/v of purified egg
phospholipids which act as an emulsifying agent. The remainder of the
composition is water added to achieve final lipid concentration in the
range of about 10% w/v to about 30% w/v as is desired. Glycerol is added
to make the lipid emulsion isotonic, with about 2.25% w/v present in
Intralipid.RTM.. The pH range of the Intralipid.RTM. emulsion is from
about 5.5 to 8.
The lipid emulsion can be prepared by any convenient means, such as
sonication and the like. The components of the emulsion can be mixed or
premixed in any order prior to the sonication process. The emulsion
preferably comprises particles in the range of about 0.25 microns to about
0.75 microns in diameter.
While the invention is exemplified by way of reducing or eliminating the
toxic effects of the anaesthetic, bupivacaine, it is readily apparent to
one of skill in the art that lipid emulsions may also be used to treat
toxicity associated with other lipophilic or amphiphilic agents including
tricyclic antidepressants (e.g., amitryptiline), adriamycin, organic
solvents, other anesthetic agents such as tetracaine, etidocaine and
The methods and compositions of the present invention are applicable to
several clinical scenarios in addition to treatment of acute toxicity such
as is exemplified below. For example, in the situation where a patient
will be receiving a known amount of toxin (e.g., a lipophilic
chemotherapeutic agent such as adriamycin), an emulsion according to the
invention may be administered to the patient to reduce toxicity of the
agent thereby increasing its safe dose.
In another scenario, when an acutely ill patient presents with apparent
toxicity or a possible overdose of a known or unknown drug, e.g.,
presenting with cardiac arrhythmias in a young, otherwise healthy person,
or a person with a history of depression being treated with tricyclic
antidepressants, the patient may be treated with an emulsion according to
the present invention.
Other exemplary lipophilic toxic agents which may be sequestered using the
emulsions of the present invention include gasoline, inhaled propellants,
The amount of toxin might be known precisely, or entirely unknown. In the
latter case, the patient's clinical status (mildly or severely ill) will
guide treatment. The length of treatment following an initial dose will be
determined by clinical response against a predetermined maximum safe dose
for a patient's weight, which is readily determined by routine methods.
The spent emulsion will be metabolized slowly (over hours) probably by
lipoprotein lipase which releases the fatty acids from the triglycerides.
The toxin is then released from the emulsion droplets, but this slow
release allows the patient's normal metabolism to chemically modify,
excrete, or otherwise detoxify the toxin. The emulsion can be delivered
via any peripheral or central vein.
Claim 1 of 9 Claims
1. A method for treating cardiotoxicity
caused by a lipophilic or amphiphilic anesthetic agent, which comprises
infusing a lipid emulsion composition intravenously whereby the anesthetic
agent permeates the lipid emulsion composition and is withdrawn from the
bloodstream, said lipid emulsion comprising soybean oil, an emulsifier, a
tonicity modifier, and water, wherein the soybean oil is present in an
amount in the range of about 10 to about 30 percent by weight, the water
is present in an amount in the range of about 70 to about 90 percent by
weight, and the emulsifier is present in an amount in the range of about 1
percent to about 5 percent by weight, wherein said anesthetic agent is
selected from the group consisting of bupivacaine, lidocaine, tetracaine,
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