EP2107904A2 - Compositions pour l'inversion et la détoxification des anesthétiques et d'autres composés et procédés d'utilisation de ces compositions - Google Patents

Compositions pour l'inversion et la détoxification des anesthétiques et d'autres composés et procédés d'utilisation de ces compositions

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Publication number
EP2107904A2
EP2107904A2 EP07873662A EP07873662A EP2107904A2 EP 2107904 A2 EP2107904 A2 EP 2107904A2 EP 07873662 A EP07873662 A EP 07873662A EP 07873662 A EP07873662 A EP 07873662A EP 2107904 A2 EP2107904 A2 EP 2107904A2
Authority
EP
European Patent Office
Prior art keywords
particles
composition
drug
toxin
reversed
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.)
Withdrawn
Application number
EP07873662A
Other languages
German (de)
English (en)
Other versions
EP2107904A4 (fr
Inventor
David M. Anderson
Vincent M. Conklin
Benjamin C. Cameransi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lyotropic Therapeutics Inc
Original Assignee
Lyotropic Therapeutics Inc
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Filing date
Publication date
Application filed by Lyotropic Therapeutics Inc filed Critical Lyotropic Therapeutics Inc
Publication of EP2107904A2 publication Critical patent/EP2107904A2/fr
Publication of EP2107904A4 publication Critical patent/EP2107904A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • This invention focuses on the administration of dispersions of certain lyotropic liquid crystal compositions to attenuate the toxic or medically undesirable effect of one or more compounds present in the body of a human or other mammal.
  • the particles in dispersion comprise reversed cubic phase and/or reversed hexagonal phase liquid crystalline material in which a toxin or a drug substance is soluble and partitions substantially.
  • the particle dispersions are suitable for administration to a human, and are given preferably by injection, most preferably intravenously, in an amount sufficient to be effective in attenuating the effects of a toxin or therapeutic drug in the body.
  • the attenuation of the effects of toxins or drug substances in the body may result from sequestering the toxin or therapeutic drug from the plasma, displacing the toxin from the site of action, inducing redistribution of the toxin, or by other mechanisms. Adjusting the composition by various means may increase or decrease the absorption or adsorption of a toxin or drug substance to the particles, the rate of uptake of the particles and associated toxins or drug substances by the liver, and otherwise impact attenuation of the effects of a toxin or drug substance.
  • the invention is especially applicable in reversing adverse effects of local anesthetics delivered systemically, and attenuating the therapeutic effects of general anesthetics in the course of treatment.
  • local anesthetics are typically injected or applied at or near a site intended to render an area or region of the body insensate to painful stimuli. Once applied or administered, systemic absorption of the local anesthetic occurs or, in some instances, a portion of the injectate may be inadvertently administered directly into the vascular system. In any case, local anesthetics may exert varying degrees of systemic toxicity. Toxicity is usually directly proportional to the potency of the local anesthetic administered.
  • the unintentional intravascular administration of local anesthetics, bupivacaine in particular, which can occur during procedures designed to effect regional anesthesia can result in severe cardiac complications. These reactions include marked hypotension, atrioventricular dissociative heart block, idioventricular dysrhythmias as well as ventricular tachycardia and ventricular fibrillation. It is widely accepted that the R+ isomer of bupivacaine has a strong affinity to binding cardiac sodium channels and that its dissociation from this site is very slow. At higher concentrations, calcium and potassium channels can also be blocked, further exacerbating the cardiotoxic effects.
  • Bupivacaine induced cardiac toxicity is a life-threatening emergency in which aggressive measures must be undertaken to preserve life. These measures frequently involve immediate and repeated administration of vasopressors to maintain normovascular tone as well as other agents to control the bradycardia, complete heart block and the various cardiac dysrhytmias which ensue. Cardiopulmonary resuscitation may be required to maintain oxygenation of vital organs while the myocardium is in arrest.
  • Intralipid® has been investigated for use in ropivacaine toxicity. [Litz et al. (2006) Anaesthesia 61:800]. Tebbutt et al. found increased survival in a rat model of verapamil toxicity. [Tebbutt et al., Acac. Emerg. Med. (2006) 13:134]. Bania, Chu and Stolbach looked at the use of Intralipid® to try to raise the LD50 in mice of an organophosphate compound, paraoxon. [Acad Emerg Med (2005) 12(5 Supplement 1):12]. The group of Bania and Chu has also looked at the use of Intralipid® to treat toxicities from propanolol, VER, and amitriptyline.
  • Intralipid® and related parenteral fatty emulsions have several disadvantages and limitations in the present context. Perhaps most importantly, they rely on triglycerides (soybean oil in Intralipid®, other fats for the other fatty emulsions) for the solubilization and partitioning of compounds into the emulsion droplets, and as such they are strongly limited. Triglycerides are many-fold higher in molecular weight (on the order of 900Da) than most compounds that are known to be effective solubilizers, as the favorable entropies of mixing associated with low-MW compounds is important for the functioning of most solvents. They are extremely hydrophobic, and thus very poor solvents for compounds that have one, or particularly more than one, polar group.
  • a method of attenuating the toxic effect of a toxin in a human or other mammal is achieved by administering to the human or other mammal in whom a toxin is or is suspected to be present an effective amount of a composition comprising particles which are formed from or include reversed cubic or reversed hexagonal phase material.
  • the particles are preferably present in a stable dispersion which includes a liquid comprising a polar solvent.
  • the particles may be ionically charged (anionic or cationic).
  • the administration is preferably by injection (preferably i.v.) and results in the attenuation of the toxic effects of the toxin by the particles adsorbing or absorbing or otherwise sequestering the toxin from the site of toxic action.
  • a method of attenuating the therapeutic effect of a drug substance present in a human or other mammal is achieved by administering to the human or mammal in whom a drug substance is or is suspected to be present an effective amount of a composition comprising particles which are formed from or include reversed cubic or reversed hexagonal phase material.
  • the particles are preferably present in a stable dispersion which includes a liquid comprising a polar solvent.
  • the particles may be ionically charged (anionic or cationic).
  • the administration is preferably by injection (preferably i.v.) and results in the attenuation of the therapeutic effects of the drug substance by the particles adsorbing or absorbing or otherwise sequestering the drug substance from the site of pharmacologic action.
  • a further exemplary embodiment of this invention is to provide a method of attenuating the effect of a chemical substance in a human comprising administering to the human a stabilized composition comprising lipid, tocopherol and a liquid comprising a polar solvent.
  • drugs are not always present at the most desired level in the body, and at times it may be necessary or beneficial to attenuate their effects.
  • Some drugs of medical use most notably the local anesthetics, can become life-threatening if they are inadvertently injected into a vein or artery, calling for removal or reduction to avoid or minimize neurotoxicity and cardiotoxicity.
  • drugs used in medical practice can call for removal or reduction in a number of circumstances: for example, after interruption or even completion of a surgical procedure, it may be desirable to attenuate the lingering effects of the general anesthetic or paralytic agent whose normal therapeutic effect has become, post-operatively, a nuisance, danger or impediment to optimum patient management.
  • a drug may have side effects on account of generating toxic metabolites in circulation, it may be debilitating to the patient, or it may be detrimental in terms of tolerance or addiction, and attenuation of the effects of the drug may be an important therapeutic need.
  • a toxin can be endogenous, such as an autoantibody or Cortisol.
  • the invention permits attenuating the therapeutic effects of drugs on a selective basis, as well as in the removal of exogenous drug substances and endogenous toxins from the site of action.
  • Therapeutic agents such as propofol and other general anesthetics are selected for use and used, in part, on the basis of the duration and intensity of their therapeutic effect.
  • therapeutic effects for example, by reducing the time to emergence from the effect of a general anesthetic, or the duration of effect of the neuromuscular blocking agent.
  • the invention provides the ability to attenuate those effects and would provide an additional tool for optimum management of, for example, a course of surgery, as well as for the safety, comfort and convenience of the patient.
  • Neuromuscular blocking agents are used to facilitate endotracheal intubation in securing and maintaining a patent airway, effecting relaxation of skeletal muscles to enable certain operative procedures and to ensure patient safety in certain clinical settings.
  • Depolarizing agents i.e. succinylcholine, act as acetylcholine (Ach) receptor agonists and quickly cause short lived muscle relaxation due to the rapid diffusion away from the neuromuscular junction and are hydrolyzed by nonspecific cholinesterases.
  • non-depolarizing agents i.e. vecuronium
  • non-depolarizers are neither metabolized by acetylcholinesterase nor eluted quickly from the Ach receptor predictably result in prolonged depolarization of the neuromuscular endplate, and yield longer duration of muscle relaxation.
  • the best clinical practice and safest approach in the care of those paralyzed with neuromuscular blocker agents is to reverse, as completely as possible, the relaxant effects of these agents, especially non-depolarizing agents once relaxation is no longer required.
  • cholinesterase inhibitors also known as anticholinesterases, i.e., neostigmine.
  • cholinesterase inhibitors also known as anticholinesterases, i.e., neostigmine.
  • These agents reversibly bind to the enzyme that degrades Ach thereby indirectly increasing the amount of Ach available to competitively displace non-depolarizing agents from the Ach receptor by reestablishing normal neuromuscular function at the neuromuscular endplate. Complications and other adverse reactions can occur with the administration cholinesterase inhibitors.
  • These agents may be metabolized or administered in lower doses causing ineffective displacement of non- depolarizers from the receptor, yielding latent and unexpected return of paralysis.
  • Achase inhibitors may paradoxically potentiate the effects of neuromuscular blockade.
  • Other well known effects of increases in Ach associated with the use of Achase inhibitors include vagal mediated bradycardia, bronchospasm initiated by smooth muscle contraction, central nervous system effects including diffuse excitation, intestinal spasms, increased bladder tone and papillary constriction. Therefore, any strategy to minimize, supplement or preferably avoid the use of cholinesterase inhibitors in the reversal of neuromuscular blockade offers multiple advantages in the clinical setting. In an exemplary embodiment of the invention, this invention provides such a strategy.
  • Cyclodextrins are known to bind a number of drug molecules, such as rocuronium and vecuronium, and as such are being used as reversal agents for compounds like rocuronium. It should be noted that bradycardia is sometimes associated with the intravenous use of cyclodextrins, which is a distinct problem for the use of such compounds in connection with rescue from local anesthetic toxicity, where bradycardia is already a serious life-threatening complication. In another exemplary embodiment of the invention, an alternative to the use of cyclodextrins is provided.
  • Another embodiment of the invention relates to the management of the use of anesthetics in the clinical setting (e.g., hospital, doctor's office, clinic, nurses station, etc.).
  • a patient will be provided with an anesthetic before, or after, or simultaneously with a composition containing particles that include reversed cubic phase or reverse hexagonal phase material.
  • the patient will be subject to a medical or surgical procedure or will be simply observed.
  • the anesthetizing effect of the anesthetic will be attenuated by the particles containing the reversed cubic phase or reverse hexagonal phase material. This allows control of the anesthetizing effect and may enhance a patient's recovery time.
  • anesthetics which may be managed in this way include both general anesthetics such as propofol, etomidate, ketamine, thiopental, a benzodiazepine, a barbiturate, an opioid, haloperidol, droperidol, and phencyclidine, and local anesthetics such as bupivacaine, lidocaine, ropivacaine, mepivacaine, and cocaine.
  • general anesthetics the invention can be used for decreasing a duration of sedation, reducing a time to emergence, reducing a duration of apnea, and reducing a time to full cognition.
  • pharmaceuticals in a wide range of drug classes can have their effects selectively attenuated by providing the patient with a composition including particles that have either reversed cubic phase or reversed hexagonal phase materials.
  • the methods of the invention can be used in conjunction with, for example, a patient that has or is suspected to have taken, or a patient that will be provided with a benzodiazepine, an opiate, a central venous system depressant, a respiratory depressant, a cardiovascular depressant, a psychomotor stimulant, a psychotropic, a sedative, a hypnotic, a muscle relaxant, and an organophosphate.
  • “Attenuation" of a drug effect or toxic effect of a toxin means that one or more of the following occur (as compared to in the absence of treatment with the invention): substantial reduction in intensity of the effect, substantial reduction in the duration of the effect, substantial reduction in physiological insult and damage, substantially accelerated clearance of the drug or toxin from active or otherwise critical sites in the body, substantial reduction in symptoms of adverse reaction to the drug or toxin, substantial reduction in the concentrations of one or more toxic metabolites of the drug or toxin from critical sites in the body, or substantial reduction in pathological binding of exogenous or endogenous substance(s).
  • an effect such as a reduction (e.g., in intensity) is considered substantial if it is clinically or medically useful or beneficial, or useful or beneficial in the management of a patient, to an extent that, in the view of one skilled in the art, it would warrant use of the invention in that situation.
  • the effect of attenuating the drug or toxin should be preferential over other effects or side effects that would otherwise negate or render insignificant the desirable attenuating effect.
  • Drug means a compound consisting of or comprising an Active Pharmaceutical Ingredient (API).
  • Toxin in the context of this disclosure, is much broader than the connotation usually implied in day to day speech.
  • toxin means any compound, or closely related group of compounds (such as different stereoisomers of a drug or different chain lengths of a particular lipid type), that pose a health risk or medical inconvenience to a mammal or human, and as such call for removal or reduction in the body, or for redistribution within the body (e.g., from tissues to blood, or from the blood to the liver, etc.).
  • a toxin could be endogenous, such as an autoantibody or Cortisol for example, though it will more often be an exogenous compound, and most typically an exogenous compound recognized to be toxic or antigenic at least under some circumstances (for purposes of this application, antigenic materials will be treated as toxins).
  • Certain compounds, such as cocaine or morphine, for example are of course used in medical practice, but also are used as drugs of abuse and as such may require removal or reduction in the course of detoxification and rehabilitation, and thus can be toxins in the context of this invention; furthermore, metabolites of such compounds, such as cocaethylene in the case of cocaine, have considerable toxicity and their removal by the present invention could be of importance in many settings.
  • drugs of medical use most notably the local anesthetics, can become life-threatening if they are inadvertently injected into a vein or artery, calling for removal or reduction, and in such cases become toxins in the context of this disclosure.
  • Other drugs used in medical practice such as those associated with anesthesia or pain control, including general anesthetics like propofol or paralytic agents like rocuronium or vecuronium, can call for removal or reduction in a number of circumstances, including overdosage, triggering of dangerous reactions such as malignant hyperthermia (MH) and respiratory depression.
  • MH malignant hyperthermia
  • the treating physician or clinician may wish to attenuate the anesthetic effect for clinical reasons, for example, to allow a patient to be safely discharged from a hospital or clinic without having to wait for the entire length of time required for normal metabolism/excretion of the drug.
  • Certain long-acting drugs of medical use such as reserpine, or sustained-release formulations such as DepoMorphine, may call for removal or reduction if the duration of action needs to be cut, in which case the drug can be deemed a toxin in the context of this invention.
  • “Pharmaceutically-acceptable” generally designates compounds or compositions in which each excipient is approved by the Food and Drug Administration, or a similar body in another country, for use in a pharmaceutical or vaccine formulation, or belongs to a succinct class of compounds for which a Drug Master File is on file with a government regulatory agency, usually the FDA, or, less preferably, is known from extensive toxicity studies to be safe for the intended route of administration (which in the context of this invention is typically, though not always, intravenous). This also includes compounds that are major components of approved excipients. Listings of approved excipients, each with the various routes of administration for which they are approved, are published from time to time by the Division of Drug Information Resources of the FDA, as in January, 1996 and entitled "Inactive Ingredient Guide”.
  • Site of action of a toxin or drug is defined herein to be a location, in molecular terms, where the toxin or drug manifests a clinically significant toxic or pharmacologic effect, which in the context of the invention is a harmful or otherwise undesirable effect motivating application of the invention.
  • To be at the site of action in some cases may include being in the tissue, organ, blood and/or other body fluids.
  • the drug or toxin is in such proximity, at the level of molecular binding, to a molecular target as to be capable of exerting a toxic or pharmacologic effect at that moment in time, such as acting as agonist or antagonist at a receptor protein, or otherwise binding and affecting an enzyme, lipid, saccharide, lectin, nucleic acid, vitamin, metal ion, neurotransmitter, hormone, or other target.
  • a toxin or drug could itself be exogenous, such as in the case of an antibiotic or antifungal compound where the site of action is on or in a microbe, existing at the time within the body of a human
  • Recovery of a toxin or drug by a multitude of particles means that the particles substantially (i.e., with clinically desirable effect) displace it from its site or sites of toxic or pharmacologic action, or prevent it from interacting with that site before it ever requires displacement through interactions between the particles and toxin or drug, including but not limited to adsorption or absorption of the toxin or drug by the particles.
  • An example of recovery that is broadly illustrative is where a toxin molecule, existing at or in the vicinity of a receptor, enzyme, or other molecular target by virtue of interactions with the molecular target, is sequestered by a particle by virtue of interaction(s) with the particle (such as hydrophobic interaction), said toxin molecule therefore becoming less prone to interact with the molecular target due to its sequestration by the particle and, in some cases, by movement of the particle away from the molecular target with subsequent clearance of the toxin and/or particle-toxin combination.
  • Reversed liquid crystalline phases in the context of this disclosure includes reversed hexagonal phase and reversed cubic phase, which itself includes both reversed bicontinuous cubic phase and reversed discrete cubic phase. These phases are known in the art of surfactant self-association. All are understood to be as described in detail elsewhere (e.g. in U.S. Patent 6,638,621, filed June 13, 2002, the complete contents of which is herein incorporated by reference).
  • Reversed cubic and reversed hexagonal phase material particles have quite a distinct morphology and therefore characteristics in comparison with oil in water emulsions and liposomes.
  • the following compares four different 200 nanometer diameter particles, each made of one of the four materials above. Particles are compared by morphology, phase, radius of monolayer curvature, specific surface area, hydrophobic volume fraction, farthest distance to polar or apolar domains, and loading capacity.
  • Reversed cubic phase material has an intricate long range nanometer-scale order, and may exist either in bulk material or particulate form.
  • the fluid lipid bilayer is arranged with precise curvature in repeating cubic space groups, creating interlaced polar and apolar microdomains. It has a very high interfacial surface area.
  • the radius of monolayer curvature of a typical cubic phase is on the order of 3 nanometers.
  • the specific surface area is approximately 40 m 2 /mL.
  • the hydrophobic volume fraction approximates 50-75%.
  • the farthest distance to a polar or apolar domain from any point in or on the particle is only 3 nanometers.
  • a reversed cubic phase particle can carry hydrophobic, hydrophilic and amphiphilic compounds in hydrophilic domains, in hydrophobic domains, and straddling both types of domains.
  • reversed hexagonal phase material also has an intricate long range nanometer- scale order, and may be bulk material or particulate form. It also consists of a fluid lipid layer arranged with precise curvature creating polar microdomains, but in contrast to reversed cubic phase material, the structural units are cylinders arranged in a repeating pattern conforming to a hexagonal space group. Reversed hexagonal phase material also has a high interfacial surface area, though not as high as the reversed cubic phase.
  • the radius of monolayer curvature of a reversed hexagonal phase is on the order of approximately 1.5 nanometers.
  • the specific surface area is about 25m /mL and the hydrophobic volume fraction is roughly 80%.
  • the farthest distance to a polar or apolar domain is approximately 3 nanometers from any point in or on the particle.
  • the reversed hexagonal phase particle like the reversed cubic phase particle, can carry hydrophobic, hydrophilic and amphiphilic compounds in hydrophilic domains, in hydrophobic domains, and straddling both types of domains.
  • an oil-in- water emulsion such as Intralipid®
  • Intralipid® has no long range nanometer- scale order. It consists of fat droplets of various sizes and shapes surrounded by a lipid-rich layer in an aqueous medium.
  • a 200 nanometer emulsion oil droplet has the lowest interfacial surface area of all particles compared here. It is comprised of an oil-rich liquid phase surrounded by lipid-rich phase. For such an emulsion particle, the radius of monolayer curvature is 100 nanometers. The specific surface area is only 6 ⁇ T/mL.
  • the hydrophobic volume fraction is 95%, but the farthest distance to polar or apolar domain is 98 nanometers.
  • Liposomes too, differ significantly in structure and characteristics from reversed cubic and reversed hexagonal phase material particles. As true of emulsions, liposomes have no long range nanometer scale order. They occur only in particulate form: the basic structure is one or more solid lipid (or less commonly, fluid) bilayers, generally spherical, encapsulating a large polar liquid phase (usually aqueous) compartment. Liposomes have a very low interfacial surface area. They are derived from lamellar phase material, with a liquid phase core. The radius of monolayer curvature of a 200 nanometer liposome is approximately 100 nanometers. The specific surface area is 12m7mL. The hydrophobic volume fraction is a very small, e.g. 5%, and the farthest distance to polar or apolar domains, like the emulsion droplet, is very large, 96 nanometers.
  • the reversal of toxin and drug effects by the invention can be at least partly, if not fully, understood as resulting directly from the action of the particles in absorbing toxin within the particle interior, or adsorbing toxin at the particle surface.
  • the former namely absorption, can occur by virtue of the ability of the liquid crystalline material to solubilize the toxin or drug (which is amply demonstrated by Example 7), whereas the latter, adsorption, can occur by virtue of particle surface charge, specific capture molecules (such as antibodies) at the surface, hydrophobic interaction, solubilization and partitioning of the toxin within a particle surface layer such as a PEG-rich layer, or a number of other interactions.
  • tissue-bound toxin molecules may diffuse out of tissue to fill the void left by the departed, particle-sequestered toxin molecules, where they can be ab/adsorbed, and the cycle continues.
  • a more complete description of the process would take into account particle uptake of protein-bound toxin, RES uptake of particles, and other effects, but in any case the key step in the process is absorption or adsorption of toxin by the particles. It is at that point that the particles provided to a human or other mammal patient according to the invention step in and manifest their effect on the pharmacokinetics of the toxin.
  • the preferred particle architecture is that of a charge-stabilized, uncoated particle, as specified in detail in U.S. Patent Application 10/889,313.
  • the uncoated particle has the distinct advantage that no occlusive layer interferes with the direct absorption or adsorption of toxins from medium.
  • lamellar coatings are advised against since they would interfere with the toxin- absorbing properties of the reversed liquid crystalline phase interior.
  • a bicontinuous reversed cubic phase in particular, when uncoated, has a microstructure that allows bilayer- impermeable toxins to migrate directly into its pore space, where the toxin can be effectively maintained there by some combination of permselectivity, hydrophobic interactions with the bilayer, electrostatic interactions with the bilayer, van der Waals forces, or interaction with interior components of the cubic phase.
  • Other particle architectures are possible as well provided that a substantial portion of the particle is a reversed cubic or reversed hexagonal phase.
  • Solid-coated particles are antithetical to the purpose of rapid toxin uptake and are thus inconsistent with the objects of the invention; this applies to both crystalline lamellar and solid (crystalline or amorphous) nonlamellar coatings.
  • most or nearly all of the particle is a reversed liquid crystalline phase, with reversed cubic being most preferred among these.
  • the reversed cubic or reversed hexagonal phase material in particulate form should be readily accessed by the diffusion of toxin molecules from a site in the body to the material when the particle is at the site.
  • the particle should not be occluded by an impermeable coating.
  • An impermeable coating would be one which is substantially crystalline (such as a lipid in the gel phase), or more generally in which the self-diffusion coefficient of the toxin within the coating is strongly reduced relative to the self-diffusion coefficient inside the liquid crystalline material; alternatively, the probe of permeability known as pyioPC (chemical name 1-palmitoyl- 2-[l'-pyrenedecanoyl] phosphatidylcholine) can be used, and we take impermeable to mean that the self-diffusion coefficient of pyioPC in the coating material as measured by the fluorescence photobleaching recovery method as used by Vaz et al. is less than about 1 micron /sec. [See Vaz, W. L. C, Z.
  • ionically-charged (electrostatically-charged), bilayer-bound components discussed above, and described in detail in U.S. Patent Application 10/889,313 which is herein incorporated by reference may bind toxin or pharmacological substances via electrostatic interactions, free of an impermeable coating, or coating of any sort.
  • uncoated particles particularly uncoated ionically charged particles
  • particles having reversed cubic or reversed hexagonal phase materials that are coated with solid coatings such as those described in U.S. Patent 6,482,517 and U.S. Patent 6,638,621 to Anderson.
  • any polar groups on the toxin can simultaneously localize in close proximity to such a surfactant polar group, and/or to water molecules (which hydrate the surfactant head groups), to experience energetically favorable polar interactions, without paying a large entropic price.
  • the surface area of accessible bilayer surface in a 200 nm particle of the bicontinuous cubic phase is an order of magnitude higher than that of an Intralipid® emulsion droplet of the same size.
  • This in itself makes the dispersions of the invention advantageous over emulsions in a number of cases: where the toxin adsorbs to the bilayer or binds to a bilayer component; where the toxin binds to a component (such as an antibody) which extends from the bilayer surface, perhaps with a spacer arm; where uptake of the toxin is limited by diffusion through a concentration gradient that extends the full particle radius in the case of an emulsion droplet (thus approximately 100 nm), but only half the bilayer thickness in a cubic phase particle (thus approximately 2 nm); where the toxin is a macromolecule that binds to the particle by inserting a hydrophobic moiety (such as an alpha-helix) into the bilayer; and where the toxin has a low partition
  • Particle size for intravenous embodiments of the invention will preferably have an average particle size between about 80 and 1,000 nm, most preferably between about 100 and 700 nm, and wherein 90% of the particle volume is in particles with size less than about 1,500 nm and most preferably less than about 1,000 nm.
  • the full particle size distribution can be adjusted by manipulating the processing conditions (in particular, homogenization time and temperature, and microfluidization if desired), in particular to adjust the fraction of particles that are below about 80 nm in size, since evidence indicates that such particles are cleared more slowly than particles above 80 nm, and it might be desirable in a particular application to have a longer-circulating fraction of particles, so that toxin removal continues for a longer period than in the absence of particles smaller than 80 nm.
  • Dispersions of uncoated particles of the preferred embodiment bind to plasma protein much less strongly than do emulsion droplets. This is important because where a large volume of emulsion droplets or particles of the invention are given for detoxification, it is disadvantageous, if not dangerous, for the particles or droplets to remove proteins and other components naturally present in the bloodstream. Moreover, in analogy with liposome- disrupting effects of protein opsonization well known in the art, overt uptake of proteins by lipid- based particles— particularly those such as emulsions which are already nonequilibrium structures — can rapidly destabilize particles. Because they are weakly attracted to plasma proteins, it is unlikely that a targeting or toxin-capturing compound associated with the particle will be interfered with by interaction of the particle and plasma protein.
  • Toxins that are especially amenable to sequestration by particles of the instant invention are those that contain at least one hydrophobic group, and are thus considered either hydrophobic or amphiphilic.
  • Compounds that are strictly hydrophilic, and contain no hydrophobic groups compounds such as inorganic salts, glycine, and methanol, generally are not amenable to the invention since they will not partition preferentially into the particles of the invention.
  • a compound is very likely to partition significantly into particles of the invention if one or more of the following criteria is met: a) it has a contiguous string, or ring, of at least 6 carbon atoms in the molecule; b) it has a solubility of at least 1% in alpha- tocopherol; c) it has an octanol- water partition coefficient equal to or greater than about 100; d) it lowers the surface tension of water to less than about 50 dynes/cm at low concentrations (e.g., less than 1%); or e) if a peptide or protein, it contains a contiguous sequence of at least 4 hydrophobic amino acids.
  • Bupivacaine and many other local anesthetics clearly fit one or more of these criteria.
  • the octanol- water coefficient of bupivacaine at pH 7.4 is greater than 1,000.
  • the reference to the traditional octanol-water partition coefficient (Kow) is made here because this measure is often tabulated or otherwise available for a wide range of compounds. Nevertheless, in the context of this invention, it is the partition coefficient of the toxin in particles of the invention, as opposed to octanol, that is the most relevant measure.
  • K QW the partition coefficient in a cubic (Q) phase over water (or aqueous buffer more generally); that is, the ratio of concentration of the toxin in the cubic phase to the concentration in water, taken after the toxin has had time to equilibrate between contacting water and cubic phase volumes.
  • this cubic phase-water partition coefficient referred to in this paragraph, should be measured in the absence of albumin (unless the cubic phase in a particular formulation of the invention is, in fact, formulated with albumin as one ingredient) or other proteins.
  • a measurement is performed of partitioning into the cubic phase in the presence of albumin, in order to more closely mimic the situation where the invention is applied in the body, and this method of measurement is to be distinguished from measurement of the cubic phase-water partition coefficient per se.
  • the term "effective partition coefficient" is used herein when the aqueous phase contains albumin,and typically this will be an albumin concentration of about 40 mg/mL..
  • propofol and other general anesthetics meet the above criteria.
  • the invention could be used to attenuate the effects of the following intravenous general anesthetics, all of which have octanol-water partition coefficients greater than one hundred (100): eltanolone, minaxolone, methohexital, thiamylal, thiopental, ketamine, chlormethiazole, alphaxalone, and pentobarbital.
  • attenuation of these anesthetics by the invention could be performed either in cases of overdose, or simply to reverse anesthesia when it is no longer needed.
  • Vecuronium bromide and other muscle relaxants also meet or more or these criteria (for example, by virtue of a steroidal backbone), and as shown in Example 15 below, although the octanol-water partition coefficient of vecuronium bromide is less than 100, its cubic phase-water partition coefficient is well above 100, and indeed above 1 ,000 for at least some cubic phases of use in the invention.
  • Lipopoly saccharide endotoxins such as Lipid A partition extremely strongly into lipid membranes such as those of the instant invention, and could be especially responsive to removal by the instant invention. The removal or attenuation of the effect of endotoxins in this manner could open up treatment to a variety of conditions, including, for example, sepsis.
  • the ability to adsorb, absorb, sequester or otherwise recover a pharmaceutical or toxin may be enhanced by choosing particles of specific constitutions. This may be accomplished by selection of a reversed liquid crystal composition that more favorably solubilizes the toxin or pharmaceutical of interest, and which is pharmaceutically-acceptable, and preferably which achieves a high partition coefficient over aqueous buffer at the relevant pH (typically about 7.4).
  • a reversed liquid crystal composition that more favorably solubilizes the toxin or pharmaceutical of interest, and which is pharmaceutically-acceptable, and preferably which achieves a high partition coefficient over aqueous buffer at the relevant pH (typically about 7.4).
  • Compositions for reversed liquid crystalline phases are discussed at length in U.S. Patent No. 6,482,517, filed September 8, 1998, U.S. Patent Application Ser. No. 09/994,937, filed November 28, 2001, and U.S. Patent Application Ser. No. 10/460,659, filed June 13, 2003, as well as U.S.
  • the liquid crystal composition should solubilize the toxin (or toxins), at a level that provides for clinically significant recovery of the toxin.
  • the toxin is soluble in the reversed cubic or hexagonal phase liquid crystal to a level of at least 0.01%, more preferably equal to or greater than about 0.1%, and most preferably equal to or greater than about 1% by weight.
  • the preferred solubility levels are reached by taking advantage of the inherent compound-solubilization properties of reversed liquid crystalline materials, discussed and demonstrated at length in the disclosures cited in the previous paragraph, and by further optimizing the liquid crystal composition through selection of the hydrophobe.
  • the reversed liquid crystal compositions typically are comprised of a lipid or surfactant, a hydrophobe and water.
  • hydrophobe means the third major [pseudo-]component of a surfactant/water/third component liquid crystal composition even if this third component is, strictly speaking, amphiphilic by virtue of, e.g., a hydroxyl group, as in the case of linalool.
  • Liquid crystal compositions in which the main structural lipid (which is a surfactant, in accordance with the definition of the term "surfactant”, see U.S. Patent No. 6,482,517) is phosphatidylcholine ("PC"), or a phosphatidylcholine-rich product such as a purified lecithin, are strongly preferred in the invention.
  • the current invention makes advantageous use of naturally- occurring phospholipids, particularly phosphatidylcholine, and most preferably phosphatidylcholine that have a transition temperature below body temperature, or preferably below ambient temperature — that is, the compositions employed are above the so-called Krafft line, temperatures below which crystalline phases appear and above which liquid crystalline and/or liquid phases appear.
  • Phosphatidylcholine is put forth as uniquely well suited as the structural basis of injectable particles for toxin removal due to a constellation of favorable features, most importantly low toxicity, but including also the fact that it is endogenous, biocompatible, biodegradable, non-antigenic, cost-effective, and has a decades-long history of safe use in intravenous products at levels of 5 -25 grams per day. While other surfactants and lipids, such as poloxamers (e.g., Pluronics), Tweens, cremophors, mono- and di-glycerides for example, can be used in the invention, these compounds must be scrutinized for toxicities that, in the context of toxin reversal, could lead to dangerous and unpredictable effects. This is particularly true since in the practice of this invention, in the face of toxic challenges to the body, fairly high volumes of the dispersions may be used, typically on the order of 100-400 mL, which contain on the order of 5-20 grams of lipid.
  • poloxamers
  • the hydrophobe for an injectable product will be one or more of the following five hydrophobes: tocopherol, linalool, squalene, benzyl benzoate, and long-chain diacetylated monoglycerides.
  • the solubility of the toxin is first determined, using methods well known in the art, in each of the five preferred hydrophobes identified above. If desired, pairwise combinations of these five solvents (numbering ten) can also be tested, preferably at a 50:50 cosolvent ratio, still keeping the number of solubility tests to a manageable number (viz., 15). Generally speaking, for the purposes of this invention, the hydrophobe mixture that best solubilizes the toxin will also yield the liquid crystalline particle that exhibits the greatest partition coefficient (measured between the liquid crystal and water). Partitioning experiments can easily be performed by methods well known in the art, and as described in the Examples below.
  • Tocopherol has the most extensive history of safe use particularly in intravenous products, as it has been used in parenteral nutrition for many decades, even in neonates, and thus it is the most preferred of the five hydrophobes from that perspective. Indeed, tocopherol is widely known to be of very low toxicity, with intravenous doses as high as 30 mg/Kg/day being essentially free from any adverse effects, and the excipient has a long history of safe use in intravenous products, both parenteral nutrition and in liposomal products.
  • Diacetylated monoglycerides in particular the brand Myvacet®, which has been used as an excipient in regulatory-approved intravenous products.
  • Benzyl benzoate has been used in marketed injectable formulations, though not yet in intravenous formulations.
  • Squalene has been used in vaccines as an adjuvant. Care should be taken to avoid inclusion of squalene in products intended for use in indications where adjuvant stimulation of the immune system may be contraindicated.
  • Linalool has been found to be safe in a battery of toxicity studies and nonmutagenic [U.S. National Institute of Environmental Health Sciences report, Technical Resources International, Contract No. NO2-CB-50511, June 1997], but has not been used in marketed injectable formulations, and could be a candidate for formal approval in an appropriate product.
  • Tocopherol can be included as part of the hydrophobe mixture in most cases, for a number of reasons: it helps protect phospholipids from rancidification; it helps with the formation and stability of reversed cubic phases; it is a surprisingly effective solvent for a wide range of hydrophobic and amphiphilic compounds; and its cleansing effect as a vitamin is well known and can serve a helpful role in the detoxification applications of the invention.
  • wax-like components such as ethyl butyrate have been investigated for use in injectable products
  • neither ethyl butyrate nor any of the waxes are on the FDA Inactive Ingredient Guide as injectable excipients nor, of course, has any ever been used as a parenteral active or component, and the present invention avoids the use of these waxes.
  • the composition of the reversed liquid crystalline phase is then found by a simple phase behavior mapping, as described in, e.g., U.S. Patent 6,638,821. Quantitative guidelines for determining the composition of a reversed cubic phase are given in U.S. Patent Application 10/460,659. An examination of viscosity and appearance under polarizing optical microscopy are indicative of the phases of lyotropic liquid and liquid crystal material.
  • a dispersant is typically, though not necessarily, incorporated in order to maintain the particles dispersed, and stable as such over time, preferably at least two years without detrimental increase in effective particle size, and in particular without an increase in the fraction of particles larger than about 1.5 micron (and more preferably 1 micron), as this fraction should preferably remain less than 10% preferably, and more preferably less than 1%, by volume.
  • DMPG dimyristoylphosphatidylglycerol
  • the bile salts discussed herein are the preferred dispersants, with glycocholate being most preferred except possibly in situations where the danger posed by the toxin is low enough that a product with a high cost of materials, due to the high cost of glycocholate, is not justifiable.
  • Bile salts are preferred for another reason, namely they promote uptake of particles by the liver, probably through binding of apolipoprotein E and/or related proteins, resulting in removal of the toxin from circulation; alternatively, cholesterol can be incorporated into the particles, and generally particles of the invention for intravenous use will contain either a bile salt or cholesterol, or both.
  • dispersants are sodium oleate (preferably at 0.03% or less of the dispersion by weight), and other acidic diacyl phospholipids including phosphatidylglycerols, diphosphatidylinositol, and phosphatidic acid.
  • other preferred dispersants are sodium docusate, and others given in US Patent Application 10/889,313.
  • salts of fatty acids, including sodium oleate should be avoided since they are not FDA approved as intravenous excipients, or in the case of caprylic acid, are approved only at extremely low levels, too low to be effective.
  • Preferred tonicity adjusters are neutral amino acids such as glycine or valine, and other standard, nonionic tonicity adjusters such as mannitol, glycerol, dextrose and xylitol.
  • an effective amount of the composition intravenously to a patient who is suffering neurotoxicity or cardiotoxicity due to the administration of a local anesthetic would attenuate the severe neurological and cardiological toxicity caused by the local anesthetic.
  • Administration of an effective amount of the composition under these circumstances would partially or entirely attenuate the toxicity, and mitigate or altogether end the toxic crisis for the patient.
  • the administration of an effective amount of the composition to a patient under the influence of a recently administered therapeutic dose of the general anesthetic propofol would attenuate the effects of that drug, allowing the patient to emerge from anesthesia and return to clear headedness more quickly than without the administration of the composition.
  • the ability to shorten the duration of effect can be of important medical value and become part of a standard of care from a point of view of safety and convenience.
  • the administration of an effective amount of the composition to a patient who has been treated with and is experiencing the therapeutic effects of a skeletal muscle relaxant such as vecuronium can attenuate the paralytic effects of that drug more quickly than in the absence of the administration of the composition.
  • Prophylactic use of the invention is also possible.
  • the effect of the toxin or drug can be attenuated from the beginning, and either mitigated in severity or duration or indeed attenuated to such an extent that clinical indications never appear. This is demonstrated in Example 16 below.
  • the dispersion in order to successfully attenuate the effect of the toxin (since the definition of "attenuate" requires substantial reduction in the effect of the insult), the dispersion must be administered fairly close in proximity to the time of the insult, preferably less than about 15 minutes before the ingestion or administration of the toxin, and more preferably less than about 5 minutes.
  • the invention encompasses embodiments that can circulate for considerably longer time periods than minutes.
  • circulation times may be greatly increased.
  • lipids which are readily incorporated into particles of focus in the invention as demonstrated in Example 9 below, include PEGylated lipids such as polyethyleneglycol-2000-phosphatidylethanolamine, Vitamin E TPGS, and other lipids created by covalent attachment of hydrophilic polymer chains to hydrophobic lipids.
  • the attenuation of a toxin by adsorbing or absorbing the toxin from the site of toxic action stands in contrast with other methods that rely on administering an antidote, provided that one is even available. While a competitive agonist or antagonist might preferentially displace a toxin from binding to a receptor or enzyme, the toxin can nonetheless remain at the site and continue to compete with the antidote for receptor binding, and in the case where the toxin and antidote bind to a common enzyme the competition continues as long as toxin remains in the organ of toxic insult, or in some cases as long as it remains in circulation.
  • the current invention provides for liver uptake and detoxification by virtue of liver uptake of the particles, which can easily be one, or two, or more, orders of magnitude faster than liver uptake of individual molecules; lipidic particles in the 80-1000 nm range can be substantially taken up by the liver in under 10 minutes.
  • the invention could, in fact, be used to detoxify the body of a mammal thought, but not known, to be suffering the effects of a toxin or toxins, such as in cases in man where the patient might be unconscious, delusional, or unwilling to admit the ingestion of toxic substances such as drugs of abuse.
  • Targeting compounds such as antibodies, lectins, ligands, bacterial adhesion receptors, complementary nucleic acids, bile salts, biotin derivatives, etc.
  • Targeting compounds can be incorporated (as described in U.S. Patent Application 10/889,313) so as to target particles of the invention to sites where toxins may accumulate and/or where they may do the most physiological damage, or to bind toxins directly, and/or to direct particles to elimination sites after toxin recovery.
  • a cholesterol- and/or bile salt-laden particle of the invention could be directed to, e.g., the liver by the ApoE mechanism discussed herein, where it could bring recovered toxin for detoxification, or where it could sequester toxin from the liver so as to, e.g., decrease the local concentration of free, unbound toxin.
  • glycolipid bacterial adhesion receptors such as Forssman's antigen, are readily incorporated into the liquid crystalline particles of this invention, and such tagged particles could well bind bacteria with considerable specificity, so as to remove infectious bacteria, or to remove a bacterial by-product such as an endotoxin.
  • biospecific capture compounds again including antibodies, lectins, ligands, complementary nucleic acids, bile salts, biotin derivatives, and also chelating agents, cyclodextrins, etc., can be incorporated into particles of the invention so as to amplify their ability to recover toxin.
  • the instant invention includes provisions for adjusting the rate of clearance, by the liver, of the particles, via a simple adjustment of the composition.
  • the uptake of these toxin or drug-laden particles by the liver constitutes a dominant mechanism for the removal of toxin or drug away from tissues in the body where it exerts its pharmacological effect.
  • Changing the dispersant from a bile salt, such as deoxycholate, to a charged phospholipid which is not recognized by Apolipoprotein E can have a large effect on the circulation time of particles.
  • the rate of clearance of the liquid crystalline particles can be increased by raising the concentration of cholesterol and/or bile salt in the particles, or decreased by lowering the concentration of these compounds.
  • a bile salt If used for this adjustment, it must satisfy two structural requirements: first, it must have a hydroxyl (-OH) group at the 3-position, and second, it must have an alkyl side chain at the C 17 position of the steroidal ring system.
  • Some of the preferred compounds for use in the instant invention, which satisfy these requirements, are the acid and salt (e.g., sodium salt) forms of cholic, glycocholic, deoxycholic, and chenodeoxycholic acids most preferably, and less preferably glycochenodeoxycholic, glycodeoxycholic, lithocholic, and ursodeoxycholic acids.
  • Glycocholate and deoxycholate salts are especially preferred, as they are more hydrophobic, less toxic, and more reliably charged than others in the series.
  • Deoxycholate has the additional advantage that it is inexpensive relative to glycocholate, although it is less reliably charged than glycocholate and the pH must remain above 7.2 to avoid precipitation.
  • lipid emulsions such as Intralipid® are poorly suited for addition of bile salt or cholesterol without undue experimentation.
  • Addition of bile salt to a fat emulsion tends to create mixed micelles, as is well known in the art.
  • a small amount of cholesterol could, at least in principle, be incorporated in a fat emulsion, this would be difficult to prepare due to the extremely low aqueous solubility of cholesterol in water, precluding the possibility of mixing the fat emulsion with an aqueous cholesterol solution.
  • the natural instability of fat emulsion makes them extraordinarily sensitive to changes in composition.
  • ROS reactive oxygen species
  • particles of the invention can reasonably be expected to perform better at detoxifying reactive oxygen species than solution formulations of vitamin E, for example, because the ability of the particles to sequester ROS compounds through the solubilization and partitioning effects discussed herein will translate into a longer residence time of proximity between the toxic compound and tocopherol (and phosphatidylcholine as well).
  • the sequestering effect of particles of the invention can be used to amplify the effect of detoxifying agents when those agents are embedded in the particles.
  • the toxin-attenuating aspect of the invention can be combined with other measures known in the medical arts to be of value in the treatment of the particular toxic insult.
  • particles of the invention deliberately selected to attenuate the effects of a toxin A, could also be loaded with an Active Pharmaceutical Ingredient B, so as to deliver the agent B while at the same time substantially recovering toxin A.
  • an Active Pharmaceutical Ingredient B for measures that involve delivery of a pharmaceutical agent that is hydrophobic or amphiphilic in accordance with the discussions above, it must be borne in mind that this pharmaceutical agent may itself be significantly sequestered by particles of the invention if co-administered close in time. Thus it may be necessary to adjust dosages and dosing schedules of anesthetic agents, antibiotics, paralytic agents, and other agents used in the course of treatment when combined with treatment as per the instant invention.
  • anesthetics may be attenuated after performing a surgical procedure (e.g., elective or non-elective) or after an observation of a patient (e.g., simply observing a patients response to an anesthetic, etc.) by administration of a particles which include a reversed cubic phase or reversed cubic phase material.
  • a surgical procedure e.g., elective or non-elective
  • an observation of a patient e.g., simply observing a patients response to an anesthetic, etc.
  • a particles which include a reversed cubic phase or reversed cubic phase material.
  • Decompression sickness is a condition in which nitrogen bubbles appear in the bloodstream and occurs in diving operations, pressurized mines, aircraft and spacecraft.
  • Administration of dispersions of the invention, particularly embodiments in which fluorocarbons are incorporated, could substantially increase the solubility of nitrogen in the bloodstream by solubilizing diatomic nitrogen within the particle interior (that is, by absorbing nitrogen gas), and attenuate the noxious effects of nitrogen in decompression. This is an example of where a normally innocuous substance (N 2 ) can, under certain circumstances, become a toxin in the sense of this disclosure.
  • a number of drugs are associated with QTc prolongation and/or torsade de pointes (TdP) including several that have been pulled off the market due to this toxicity problem, and the availability of a reversal agent such as provided by the instant invention could enable the safe use of these drugs.
  • TdP torsade de pointes
  • Some such drugs, potential toxins because of these effects, include disopyramide, procainamide, quinidine, amiodarone, bretylium, dofetilide, sotalol, astemizole, terfenadine, fluoroquinolone antibiotics such as grepafloxacin, levofloxacin, and sparfloxacin, macrolide antibiotics such as clarithromycin and erythromycin, imidazoline antifungals such as ketoconazole, antimalarials such as chloroquine, halofantrine and quinine, other antimicrobials such as cotrimoxazole, pentamidine and spiramycin, calcium antagonists such as prenylamine and terodiline, cisapride, and probucol, tricyclic and related antidepressant drugs such as amitriptyline, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline
  • High atomic weight earth metals in particular strontium and barium, bind to phospholipid head groups, and have been found in the course of this work to bind rapidly and strongly to particles of the invention containing phospholipids (See Example 12).
  • the invention could be useful in removing such toxins from the body, pointing out yet another mechanism by which toxins can be bound by the invention.
  • the invention might be useful in removing leftover radioactive radionuclides following cancer therapy.
  • Bile salt accumulation in the blood causes jaundice, and since bile salts partition strongly into particles of the invention, another possible use for the invention is in the treatment of jaundice.
  • a number of compounds used in the operating room and emergency room are known to cause, in some people, allergic reactions such as anaphylaxis. Examples of such compounds, where the current invention could be used to remove such toxins, are salicylates, sulfonamides, cremophor, and penicillins, and to a lesser extent benzyl alcohol.
  • tocopherols Due to the inclusion of significant levels of tocopherols in preferred embodiments of the invention, it is likely that the damaging effects of reactive oxygen species from a number of sources could be ameliorated with the invention.
  • Iniralipid® has been tested against reactive oxygen species from produced by phorbol myristate acetate, but only a weak effect was found, which is not surprising since Intralipid® does not contain significant levels of any strongly antioxidant compounds.
  • many preferred embodiments of the instant invention comprise both high levels of tocopherols and hydrophobic domains into which such species may preferentially partition, such domains typically being tocopherol-rich.
  • Ischemia and reperfusion are areas where the invention could be useful in a number of ways.
  • the ability of tocopherol-containing embodiments of the invention to not only sequester, but also detoxify (by quenching radicals) reactive oxygen species is of course important in this potential application.
  • the cardioplegia solution used to bring the heart to standstill (which typically includes local anesthetic among other toxins) can be mopped up with the methods and compositions of the invention administered, e.g., via the cardiotomy infusion site to deactivate the cardioplegia solution before attempting to restart the heart.
  • the reversed liquid crystalline phase material will contain, in its interior, a droplet of a hydrophobe-rich phase that is distinct from the reversed liquid crystalline phase; this is not to be confused with hydrophobic domains that are structural elements of the reversed liquid crystalline phase itself.
  • This hydrophobe-rich droplet will be of a size between about 20 nm and 100 microns, that will contain as a major component a hydrophobe, thus a component of low solubility in water (less than about 3%), and/or of high octanol-water partition coefficient (Kow greater than or equal to about 10, more preferably greater than about 100), in which are solubilized the toxin and some fraction (perhaps very small) of each of the components of the second volume.
  • solubility of a given toxin in a mixture of hydrophobe and lipid is typically a very strongly increasing function of an increasing hydrophobe: lipid ratio, because the hydrophobe can generally be chosen specifically for its ability to solubilize the particular toxin whereas the choice of lipid has much more to do with its ability to form the desired liquid crystal (in the presence of the hydrophobe, in particular).
  • Such "oil-core" reversed liquid crystalline particles are described in detail in U.S. Patent No. 6,991,809, filed June 21, 2002, the complete contents of which are incorporated herein by way of reference.
  • the instant invention can be administered by a number of routes depending on the source and nature of the toxic challenge.
  • Intraarticular injections could be particularly useful for insults within one or more joints of a mammal.
  • Intramuscular, subcutaneous, and intraperitoneal administration may be used for insults that may be more local in nature. For example, if an intramuscular or subcutaneous administration of a drug has undesired consequences, local injection of dispersions of the invention could reverse, or at least attenuate, the undesirable effect.
  • removal of the dispersed particles laden with toxin could possibly be effected, by, e.g., removing the particle-containing fluid from the site with a syringe, or by applying local pressure or suction, or by using the dispersion of particles more along the lines of an irrigation solution in the first place.
  • the preferred route might be oral, e.g., via pills, tablets, lozenges, capsules, troches, syrups and suspensions, but most preferably as a simple dispersion in most cases.
  • Intrarectal administration might also be useful for toxins within the GI tract.
  • particles and particularly dispersions of this invention can be applied through a wide range of ophthalmic routes: periocular, intraocular, conjunctival, subconjunctival, transconjunctival, peribulbar, retrobulbar, subtenons, transscleral, topical eye drop, topical gel, topical dispersion, intraorbital, intrascleral, intravitreal, subretinal, transretinal, choroidal, uveal, intracameral, transcorneal, intracorneal, and intralenticular.
  • the invention can be applied through an appropriately chosen non-oral route including but not limited to intrathecal, intramuscular, subcutaneous, intraarterial, rectal, intravaginal, intranasal, via inhalation, and topical.
  • most, in fact nearly all, of the preferred hydrophobes in the instant invention are at least partially miscible with phosphatidylcholine (the overwhelmingly preferred surfactant), and thus form water-saturated reversed liquid crystalline phases when combined with PC and water — in sharp contrast with long-chain triglycerides, which due to near-complete immiscibility with PC form emulsions, rather than liquid crystals, at high water content.
  • phosphatidylcholine the overwhelmingly preferred surfactant
  • Example 1 An 800 niL batch of a dispersion of reversed cubic phase was prepared consisting of 862.83 mg/mL sterile water, 6.68 mg/mL sodium deoxycholate, 36.34 mg/mL alpha-tocopherol, 71.17 mg/mL PC-90G (Phospholipon 90G, from Phospholipid GmbH), and 22.98 mg/mL glycine.
  • a 14% sodium deoxycholate solution was prepared by sonicating 5.6 g of sodium deoxycholate in 34.4 g of deionized water.
  • the dispersion was homogenized for another 2 hours followed by addition of 0.6016 g of sodium deoxycholate and homogenization for 1 hour.
  • the resulting dispersion consisted of submicron particles of reversed cubic phase material, at a volume concentration of approximately 5%, with a strongly negative zeta potential to the bilayer surface (both internal and external surfaces within the particle), making it well suited for uptake of bupivacaine, or other positively-charged toxins such as vecuronium and morphine.
  • Example 2 Two dispersions per the instant invention were first prepared, varying in the composition of the hydrophobe, and then tested in the next Example for their ability to sequester bupivacaine, as compared to Intralipid® 20%.
  • a 770 mL batch of a dispersion, hereafter called "RA5E" was prepared consisting of 937.38 mg/niL sterile water, 1.30 mg/mL sodium deoxycholate, 18.67 mg/mL alpha-tocopherol, 21.85 mg/mL Phospholipon PC-90G, and 20.80 mg/mL glycine.
  • RA5EL the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and linalool.
  • a 3OmL beaker added 0.3236 grams of sodium deoxycholate, 2.6621 grams of a 50:50 mixture of alpha-tocopherol and linalool, 2.3052 grams of deionized water, and 2.6682 grams of the phosphatidylcholine-rich product Phospholipon 90 (from Phospholipid GmbH). This mixture was stirred until well-mixed.
  • Example 3 In this Example the dispersions of Example 2 were tested for bupivacaine partitioning, as compared to Intralipid® 20%.
  • a 50 mL solution of Krebbs-Ringer buffer was prepared with 4% albumin and approximately 0.1 mg/niL bupivacaine.
  • 2.0081 g bovine albumin was stirred until dissolved in 49.998g Krebbs-Ringer buffer.
  • 50.0252g of this Krebbs-Ringer Buffer with albumin was added to 0.0054 g of bupivacaine.
  • 1 N HCl solution was added to the beaker until pH reached 2.0 and allowed to stir until bupivacaine dissolved. The pH was readjusted to 7.4 with 1 N NaOH solution.
  • One mL of formulation (RA5E, RA5EL, as prepared above, or Intralipid® 20%) was volumetrically added to a 15 cm length of 1,000 MW dialysis tubing wherein one end was tied shut. The bag was tied on the opposite ends and soaked in deionized water. The bag was then placed in a 10 mL graduated cylinders and 10 mL of Krebbs-Ringer buffer with 4% albumin and approximately 0.1 mg/mL bupivacaine was added volumetrically. The sample was allowed to sit without agitation until HPLC analysis was performed on the dialysis bath water.
  • the first number gives the percentage of total bupivacaine that was sequestered from the reservoir of spiked buffer; the second number gives the approximate amount sequestered per gram of lipid; this is a far more important measure; and the third number is the approximate effective partition coefficient between the lipid phase and the buffer:
  • the effective partition coefficient of bupivacaine (in the presence of albumin, hence "effective" partition coefficient) into particles of the instant invention was measured to be an order of magnitude higher than that into Intralipid® emulsion droplets.
  • Example 4 the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and a diacetylated monoglyceride product marketed under the name Myvacet.
  • a reversed cubic phase was prepared in a 12mL test tube by combining 0.944gm of Phospholipon 90 (Phospholipid GmbH, Cologne, Germany) along with 0.733gm distilled water, and stirring until a homogenous consistency was reached.
  • Phospholipon 90 Phospholipid GmbH, Cologne, Germany
  • the Myvacet diacetylated monoglyceride behaves qualitatively very differently from long-chain triglycerides such as soybean oil when mixed with phosphatidylcholine and water: long-chain triglycerides are well known to form emulsions (Intralipid® being an instance), whereas this Example shows that diacetylated monoglycerides, with the right compositions, forms reversed liquid crystalline phases. Furthermore, diacetylated monoglycerides are far better solvents in general that long-chain triglycerides.
  • Example 5 the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and benzyl benzoate.
  • a reversed cubic phase was prepared in a 12mL test tube by combining 0.950gm of Phospholipon 90, along with 0.750gm distilled water, and stirring until a homogenous consistency was reached. Then 0.276gm benzyl benzoate (Sigma Chemical Company) and 0.285gm of alpha-tocopherol were added, and after thorough mixing the material was optically isotropic and of high viscosity.
  • This reversed cubic phase was then dispersed in a solution of sodium glycocholate, with the glycocholate being approximately 3.5% of the cubic phase by weight.
  • Example 6 the partition coefficient of the compound methylene blue, an antimethemoglobinemic drug which is strongly colored, into particles of the invention was estimated using UV-Vis spectrometry.
  • 1 mL of an "RA5E" dispersion of the invention prepared as in Example 2 was spiked with 5 mL water and 250 microliters of a methylene blue solution. A small portion of this dispersion was passed through a 0.1 micron filter every 30 seconds until 6 minutes, then every minute until 12 minutes, and then every 2 minutes until 24 minutes.
  • UV/Vis spectrophotometry was used to determine the concentration of methylene blue in samples collected at 1 minute and 22 minutes.
  • the one-minute sample gave an absorbance of 1.15 and the 22-minute sample gave an absorbance of 1.26, these being equal to within the error of the experiment due to idiosyncrasies of the filtration step.
  • UV/Vis analysis of the methylene blue stock solution compared with the methylene blue concentration in test tubes yielded a log K QW >12 for the dispersion, and no significant difference of concentration or K QW at 1 minute and 22 minutes, where K QW stands for the partition coefficient measured between the cubic phase and water (or aqueous buffer).
  • Example 7 selected drugs of considerable potency, and thus potential toxins, that are each of very low solubility in water and in soybean oil triglycerides (and thus in pharmaceutical emulsions such as Intralipid®) were tested for their solubilities in the preferred phosphatidylcholine / tocopherol / water cubic phase of the invention.
  • solubility in soy oil, and in tocopherol was first determined as follows. Volatile organic solvents were first screened for the ability to dissolve both compound X and soy oil, or tocopherol. Methanol and dichloromethane were particularly effective for this purpose. After solubilizing the compound and soy oil or tocopherol together with the common solvent, the common solvent was then evaporated using a rotovap. At the resulting concentration of the compound in soy oil or tocopherol, the sample was monitored over approximately 4 weeks for any sign of precipitation, using centrifugation and microscopy; the microscopy was performed using a combination of Differential Interference Contrast (DIC), transmitted dark field, and polarizing modes.
  • DIC Differential Interference Contrast
  • the solution of compound X in tocopherol was split into two parts, and phosphatidylcholine plus water added at the proper ratios to create a cubic phase (this composition is approximately 34% phosphatidylcholine, 31% tocopherol plus compound, and 35% water.
  • This cubic phase was monitored for signs of crystallization of the compound.
  • the approximate solubility of the compound was determined to sufficient accuracy for the present purpose, in soy oil, tocopherol, and PC-tocopherol-water cubic phase.
  • the solubility was determined in both the PC-tocopherol-water cubic phase, and in another cubic phase with spearmint oil replacing tocopherol.
  • the following table gives the final results of the work.
  • Example 8 Reversed cubic phase material was prepared in a 25OmL beaker by combining 2.00gm sodium deoxycholate (Marcor Development), 44.15gm distilled water, 56.57gm phosphatidylcholine 9OG (Phospholipid GmbH), 15.70gm linalool (Aldrich Chemical) and 20.39gm vitamin E (Archer Daniels Midland). The mixture was stirred thoroughly after the addition of each component and the resulting material was optically isotropic and of high viscosity. Of this, 128.5gm of cubic phase was added to a 3 L stainless steel beaker into which had previously been added 631.Ogm of distilled water.
  • the cubic phase/aqueous solution was dispersed with a standard homogenizer (Silverson AX-60) at 5174 rpm for approximately two hours, then 40.0gm mannitol (Sigma Chemical) was slowly added to the dispersion and homogenization continued for 15 minutes.
  • the pH was measured at 7.6 (Hanna Instruments).
  • a portion was filtered through a 5-micron Nylon® syringe filter and poured into 1OmL sterile Hollister-Stier glass vials. The vials were capped and autoclaved at 121°C and 15 psi pressure for 20 minutes. After cooling, the zeta potential was measured at -58mV (Beckman Coulter Delsa 440SX) and the particles were substantially submicron in size.
  • the particle density in this formulation of the invention is approximately 16 vol%.
  • Example 9 This Example shows that particles of the instant invention can be produced which exhibit dramatically less plasma protein binding than emulsion droplets of the Intralipid® type.
  • a dispersion of particles loaded with the drug propofol was first prepared as described in US 10/889,313. Diprivan emulsion was obtained from the manufacturer. While these particles contain on the order of 10% propofol, the effect of the drug on protein binding is small compared to the effects of bile salts, surfactants, and cholesterol, as will be seen in the results below, so that the experiment is by and large a reasonable model of dispersions of the invention at least as far as plasma protein binding.
  • Nanosep Centrifugal devices with 300K MWCO 200 microliters of dilute human plasma solution was incubated with 200 microliters of either a dispersion of the instant invention, or a marketed, Intralipid®-based propofol formulation. Centrifugal devices were spun down on a microcentrifuge for 20 minutes to separate unbound plasma proteins from particle-bound plasma proteins. SDS solution was added to particle-bound plasma proteins and heated in a boiling water bath for 1 hour.
  • Lane 1 Long Range Protein Standard (control, i.e., no dispersion or emulsion involved);
  • Lane 2 Plasma proteins bound to Diprivan (marketed propofol emulsion, a 1% propofol in Intralipid® emulsion);
  • Lane 3 Plasma proteins bound to a dispersion of uncoated, reversed cubic phase particles containing propofol and stabilized with a bile salt
  • Lane 5 Plasma proteins bound to a dispersion as in lane 3 but with 5% cholesterol incorporated in the particles;
  • Lane 6 Plasma proteins bound to a dispersion of phosphatidylcholine / tocopherol / propofol / water reversed cubic phase particles with 5% cholesterol in the cubic phase and Pluronic F-68 as dispersant;
  • Lane 7 Plasma proteins bound to a dispersion of phosphatidylcholine / tocopherol / propofol / water reversed cubic phase particles with Pluronic F-68 as dispersant (no cholesterol);
  • Lane 8 Plasma proteins bound to a dispersion of phosphatidylcholine / tocopherol / propofol / water reversed cubic phase particles with sodium oleate as dispersant, where the oleate concentration is quite low (0.03%); Lane 9: Plasma proteins bound to Baxter's marketed 1% Propofol emulsion based on a fat emulsion;
  • Lane 10 Plasma proteins (control, i.e., no dispersion or emulsion involved).
  • Example 10 The uptake of 3 toxins — paraoxon, etomidate, and clomipramine — into particles of the invention, in the presence of albumin, was measured in this Example.
  • Phospholipon 9OG from Phospholipid GmbH
  • the other half of the dispersion was placed in a round bottom flask and on a rotovap, whereupon the dispersion weight was reduced from 344.3 gm to 119.9 gm; 2.604 gm of glycine and sufficient NaOH were added to yield a final pH of 7.7.
  • Twenty-milliliter vials were filled, sparged and autoclaved at 121° for 20 minutes, yielding two sterile dispersions, which will be referred to as "RA5-5E" and "RA5-15E” for the 5.6% and 15% particle concentrations, respectively.
  • the zeta potentials were recorded as -46 mV and -32 mV, respectively.
  • Three toxin solutions were prepared. These were: 18 mg of etomidate in 9 mL of Krebbs-Ringer buffer with 40 mg/mL albumin, 20 microliters of paraoxon in 10 mL deionized water, and 15.1 mg of clomipramine in 30 mL of Krebbs-Ringer buffer with albumin.
  • Nanosep Omega centrifuge filters at 300,000 MWCO from Pall Filtron were used to separate particles from exterior phase.
  • RA5-5E or RA5-15E also called LT-728(5E) and LT-728(15E) respectively
  • 100 microliters of toxin solution 100 microliters of toxin solution
  • 150 microliters of distilled water 150 microliters of distilled water.
  • the loaded tubes were incubated at 40 0 C for 45 minutes, then centrifuged at 10,800 RPM in a Jouan high-speed centrifuge for approximately 1 hour.
  • the bottom phase liquid (filtrate) was injected directly, and the top phase (retentate) dissolved in 500 microliters of methanol, then injected.
  • the mobile phase in the HPLC was 30% pH 8.1 phosphate buffer, 35% acetonitrile and 35% methanol. Standards were run for each of the toxins, and toxin concentrations determined in the exterior (bottom) phase and in the top phase retentate.
  • the following three tables show the data (assay values are in mg/mL) and the analysis thereof, for the three toxins.
  • the analysis proceeded as follows.
  • the top phase dilution factor was first computed by noting that either 5.6 or 14% liquid crystal was diluted into 500 microliters of methanol. From this and the top phase assay value, the concentration of toxin in the particles was back-calculated. This was then divided by the aqueous phase (bottom phase) concentration, since this was undiluted, in order to arrive at an effective partition coefficient.
  • Example 11 Using the same dispersions and methods as in Example 10, the effective partition coefficients of lidocaine, benzocaine, and bupivacaine in the presence of albumin were measured. Lidocaine yielded a value of 57 (with the mass balance being within 3% of theoretical), benzocaine a value of 148 (with the mass balance being 84 whereas 95 was theoretical), in the case of the RA5-15E dispersion, and the value for bupivacaine was 62 (mass balance within 3% of theoretical).
  • Example 12 strontium ions (Sr 2+ ), which are known in the art to bind to phosphatidylcholine head groups, were shown to exhibit strong binding to the bilayer-rich cubic phase particles of the invention.
  • strontium ions Sr 2+
  • RA5-15E strontium ions
  • this Example illustrates how the effect of large bilayer surface areas in cubic phase particles can result in effective uptake of toxins that bind to bilayer components.
  • Example 13 A 15% particle concentration dispersion of the invention was made in the Example without requiring rotovapping (as was used in Example 10). An amount 1.9093 gm of sodium deoxycholate was dissolved in 24.761 gm of sterile water for injection, to which were added 15.94 gm of alpha-tocopherol and 24.06 gm of phosphatidylcholine (Phospholipon 9OG from Phospholipid GmbH), and the mixture was stirred vigorously.
  • phosphatidylcholine Phospholipon 9OG from Phospholipid GmbH
  • Vials were loaded, sparged with nitrogen, capped and autoclaved at 121 0 C and 15 psi for 15 minutes.
  • the final dispersion had a mean particle size, using unimodal analysis, of 193 nm, and a pH of 8.0.
  • Example 14 In this Example a fluorocarbon was incorporated into the particles, making the particles well suited for uptake of diatomic nitrogen, for potential treatment or prophylaxis of decompression sickness ("the bends" and related conditions).
  • the specific fluorocarbon used was hexafluoropropanol.
  • 0.318 gm of sodium deoxycholate was dissolved in 4.127 gm of water.
  • Example 15 the partitioning of the quaternary ammonium skeletal muscle relaxant vecuronium bromide, a water-soluble compound with a low octanol-water partition coefficient, between a phosphatidylcholine / tocopherol / water reversed cubic phase and water is measured, and found to be very high, sufficiently high as to enable the use of the invention in attenuating the effect of the drug in the body of a mammal.
  • Example 16 The RA5-5E and RA5-15E dispersions prepared in Example 10 were tested in vivo as prophylaxis, in a rat model incorporating a normally-lethal intravenous injection of bupivacaine. Sixteen adult male rats were randomly arranged into four groups of four animals each.
  • Each group of animals were pre-treated with intravenous doses of either 4 ml/Kg normal physiologic saline (Group A), 4ml/Kg of dispersion RA5-15E of the instant invention with a 15 percent particle concentration (Group B), 6ml/Kg of dispersion RA5-5E of the instant invention with a 5.6 percent particle concentration (Group C) or 4ml/Kg Intralipid®, a commercially available fat emulsion useful for parenteral nutrition. Animals in all four groups were then given intravenously a known lethal dose (12 mg/Kg) of the amide local anesthetic bupivacaine.
  • Example 17 The RA5-5E and RA5-15E dispersions prepared in Example 10 were subsequently tested in vivo as a rescue agent in a rat model incorporating a normally-lethal intravenous injection of bupivacaine. Twelve adult male rats were randomly arranged into three groups of four animals each. Animals in each group were given a known lethal dose (12 mg/Kg) of the amide local anesthetic bupivacaine intravenously. Each animal was monitored for signs of acute cardiotoxicity. All animals became pulseless within 10 seconds of the injection of bupivacaine.
  • Example 18 Ten adult rats with previously inserted in-dwelling intra-jugular (IJ) venous cannulae were given 10 mg/kg of the intravenous anesthetic induction agent, propofol, via the indwelling IJ catheter. This constitutes a therapeutic dose.
  • the Time to Emergence from anesthesia (defined as the elapsed time from the start of the propofol injection until the time of eye-closure and the loss of palpebral or eyelash reflex) was recorded for each of the animals.
  • Amphotericin B provides an example of an API with high toxicity which has a site of action in the interior of a fungal lipid biomembrane.
  • the partition coefficient of amphotericin B between the preferred cubic phase of the invention composition approximately 30% phosphatidylcholine, 30% alpha-tocopherol and 40% water
  • water both phases containing residual DMSO from the experiment
  • amphotericin B partitions much more strongly into fungal cell membranes, the site of pharmacologic action, than into cell membranes of the human kidney, the site of toxic action. It is therefore possible that the application of the instant invention, using for example a phospholipid / tocopherol / water composition, could recover amphotericin B from the site of toxic action preferentially over the site of desirable pharmacologic action, thus increasing the therapeutic index, or relieving a patient of toxic effects while maintaining antifungal activity.

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Abstract

La présente invention concerne des procédés d'atténuation des effets toxiques ou médicalement indésirables des médicaments et des toxines chez un être humain par l'administration chez l'humain d'un formulation injectable comprise d'une dispersion de particules comprenant un matériel liquide cristallin lyotrope cubique inversé ou hexagonal inversé. Les particules absorbent ou adsorbent ou autrement séquestrent et atténuent l'effet des médicaments et des toxines et peuvent être utilisées comme un agent de sauvetage ou d'inversion, ou à titre prophylactique. L'invention est applicable en particulier à l'inversion des effets contraires des anesthétiques locaux délivrés systémiquement par inadvertance et à l'atténuation des effets thérapeutiques des anesthétiques généraux au cours du traitement.
EP07873662A 2006-12-07 2007-12-06 Compositions pour l'inversion et la détoxification des anesthétiques et d'autres composés et procédés d'utilisation de ces compositions Withdrawn EP2107904A4 (fr)

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