Lipid emulsion compositions and methods of using such composition via intravenous infusion to reduce the bioavailability and toxicity of poisonous agents in the bloodstream.

FIELD OF THE INVENTION

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 INVENTION

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 the body.

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 INVENTION

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 substances.

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.

DETAILED DESCRIPTION

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 minutes.

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 alcohol.

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, N,N-diethyl-m-toluamide (DEET).

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, and etidocaine.
 

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