EP1301226A2 - Kits et compositions pour la realisation d'injections intracraniennes - Google Patents

Kits et compositions pour la realisation d'injections intracraniennes

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Publication number
EP1301226A2
EP1301226A2 EP01954737A EP01954737A EP1301226A2 EP 1301226 A2 EP1301226 A2 EP 1301226A2 EP 01954737 A EP01954737 A EP 01954737A EP 01954737 A EP01954737 A EP 01954737A EP 1301226 A2 EP1301226 A2 EP 1301226A2
Authority
EP
European Patent Office
Prior art keywords
kit
nutrient
solution
constituent
emulsion
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Withdrawn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
EP01954737A
Other languages
German (de)
English (en)
Other versions
EP1301226A4 (fr
Inventor
David P. Hesson
Glenn David Frazer
Timothy J. Pelura
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.)
Neuron Therapeutics Inc
Original Assignee
Neuron Therapeutics Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Neuron Therapeutics Inc filed Critical Neuron Therapeutics Inc
Publication of EP1301226A2 publication Critical patent/EP1301226A2/fr
Publication of EP1301226A4 publication Critical patent/EP1301226A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • 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
    • A61K31/02—Halogenated hydrocarbons
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0468—Liquids non-physiological
    • A61M2202/0476—Oxygenated solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0693—Brain, cerebrum

Definitions

  • the present invention relates to compositions and kits for providing nutrients and oxygen to tissue, including cerebral tissue, and to associated methods.
  • Focal cerebral ischemia or stroke, is the reduction or loss of blood flow to an area of cerebral tissue, denying the tissue sufficient oxygen and other metabolic resources. Similarly, during Traumatic Brain Injury (TBI) and Spinal Cord Injury (SCI) the tissues are also denied sufficient oxygen and other metabolic resources to carry out normal function or survive.
  • TBI Traumatic Brain Injury
  • SCI Spinal Cord Injury
  • Technology that has been explored by Osterholm has identified the cerebral spinal pathway, a connected system of cerebral ventricles and subarachnoid spaces of the brain and spinal cord, as an alternative pathway for delivering oxygen and nutrients to the tissue potentially affected by stroke. This stratagem has been shown in animal models for stroke to remarkably limit damage caused by focal cerebral ischemia.
  • the approach operates by placing a ventricular catheter into a lateral cerebral ventricle for use in administering an oxygenated fluorocarbon nutrient emulsion into the cerebral spinal pathway.
  • the oxygenated fluorocarbon nutrient emulsion typically is made up of an emulsified fluorocarbon composition, where the fluorocarbon efficiently binds oxygen, and preferably carbon dioxide as well.
  • the composition typically further contains additional nutrients.
  • a second catheter is placed to allow drainage of fluid in the cerebral spinal pathway as needed in view of the injected fluorocarbon composition.
  • nutrient compositions for use in the brain favorably contain no more than very limited amounts of all of glutamic acid, glutamine and glycine.
  • compositions contain nutritionally useful amounts of arginine, histidine, leucine, lysine, methionine, phenylalanine, threonine and valine.
  • Applicants have noted that a number of combinations of components lack the stability needed for use as a commercial process.
  • compounding from more basic components at or near the site and time of actual use increases the risk of error and microbial contamination.
  • constituent compositions that are adapted for use with automated compounding equipment that uses metered pumps to dispense the appropriate component amounts for making a fluorocarbon nutrient emulsion.
  • These constituent compositions have sufficient stability to allow kits of the constituent compositions to be prepared under pharmaceutical Current Good Manufacturing Practices (as defined under title 21 of the Code of Federal Regulations, 2000 publication) and remain stable for months or years until final compounding.
  • the vehicle kit is preferably matched in most constituent compositions, helping to facilitate standardized preparation, but further includes constituent compositions designed to equalize salts that would be provided by the missing fluorocarbon-containing composition.
  • the vehicle composition is favorably used during initial setup of the cerebral spinal perfusion, allowing a more convenient material to be used while seeking to establish a perfusion pathway.
  • kits providing pre-measured amounts of components to form a fluorocarbon nutrient emulsion capable of carrying oxygen to living tissue
  • the kit comprising: constituent solutions, emulsions or particle compositions, which are the constituent compositions, containing pre-measured amounts of components for making the fluorocarbon nutrient emulsion, the constituent compositions comprising: poly- fluorinated, oxygen-carrying compound; a physiologically acceptable emulsifying agent effective to emulsify the polymer; a nutrient-providing effective amount of carbohydrate; nutrient-providing effective amounts of amino acids or amino acid precursors; an oncotic agent in amount effective to provide, in conjunction with the other components of the solution, a physiologically acceptable oncotic pressure; and sufficient salts and buffering agents to provide a physiological osmotic pressure and physiologically appropriate concentrations of potassium and sodium ions; wherein constituent compositions are selected to allow for sufficient stability of the components to allow for commercial marketing of the kit.
  • kits providing pre-measured amounts of components to form a fluorocarbon nutrient emulsion capable of carrying oxygen to living tissue
  • the kit comprising: constituent solutions, emulsions or particle compositions, which are the constituent compositions, containing pre-measured amounts of components for making the fluorocarbon nutrient emulsion, the constituent compositions comprising: a first constituent composition comprising an emulsion of poly-fluorinated, oxygen-carrying compound; a second constituent composition comprising a solution of sodium and potassium salts; a third constituent composition comprising a solution of a nutrient-providing effective amount of glucose; a fourth constituent composition comprising a solution of an oncotic agent in amount effective to provide, in conjunction with the other components of the fluorocarbon nutrient emulsion, a physiologically acceptable oncotic pressure; a fifth constituent composition comprising solution of nutrient-providing effective amounts of amino acids; and a sixth constituent composition comprising a nutrient-providing effective amount
  • kits providing pre-measured amounts of components to form a fluorocarbon nutrient emulsion capable of carrying oxygen to living tissue
  • the kit comprising: constituent solutions, emulsions or particle compositions, which are the constituent compositions, containing pre-measured amounts of components for making the fluorocarbon nutrient emulsion, the constituent compositions comprising: a first constituent composition comprising an emulsion of poly-fluorinated, oxygen-carrying compound (and optionally a nutrient-providing effective amount of ⁇ -ketoglutaric acid); a second constituent composition comprising a solution of sodium, potassium, magnesium and calcium salts (and optionally a nutrient-providing effective amount of glucose); a third constituent composition comprising a solution of oncotic agent in an amount effective to provide, in conjunction with the other components of the fluorocarbon nutrient emulsion, a physiologically acceptable oncotic pressure; and a fourth constituent composition comprising solution of a nutrient-providing effective
  • either the second constituent composition comprises a nutrient-providing effective amount of glucose or the kit comprises a fifth constituent composition comprising a nutrient-providing effective amount of glucose.
  • the second, fourth or fifteh constituent composition can be dried, preferably by lyophilization, and adapted to be diluted in a pre-determined amount of water before use.
  • a vehicle kit providing pre-measured amounts of components to form a vehicle corresponding to a fluorocarbon nutrient emulsion formed from a corresponding fluorocarbon nutrient emulsion kit, the vehicle kit comprising the following separate vehicle kit compositions: all the first constituent compositions but the emulsified poly-fluorinated, oxygen-carrying compound composition; and supplement constituent compositions comprising one or more components effective to supply the sodium or potassium ions that would be provided by the emulsified poly-fluorinated, oxygen-carrying compound composition.
  • the corresponding fluorocarbon nutrient emulsion kit comprising constituent solutions, emulsions or particle compositions, which are the first constituent compositions, containing pre-measured amounts of components for making the fluorocarbon nutrient emulsion, the first constituent compositions made up of: (a) poly-fluorinated, oxygen-carrying compound; (b) a phospholipid emulsifying agent effective to emulsify the poly-fluorinated, oxygen-carrying compound, wherein the poly-fluorinated, oxygen-carrying compound and the phospholipid emulsifying agent are supplied in one first constituent composition wherein the poly-fluorinated, oxygen-carrying compound is emulsified by the phospholipid emulsifying agent, this emulsified poly-fluorinated, oxygen-carrying compound composition providing a portion of sodium or potassium ions of the fluorocarbon nutrient emulsion; (c) a nutrient-providing effective amount of carbohydrate
  • the vehicle kit compositions of the corresponding fluorocarbon nutrient emulsion kit comprise: (1) a first constituent composition comprising an emulsion of poly-fluorinated, oxygen-carrying compound; (2) a first constituent composition comprising a solution of sodium, potassium, magnesium and calcium salts; (3) a first constituent composition comprising a solution of a nutrient-providing effective amount of glucose; (4) a first constituent composition comprising a solution of an oncotic agent in amount effective to provide, in conjunction with the other components of the fluorocarbon nutrient emulsion, a physiologically acceptable oncotic pressure; (5) a first constituent composition comprising a solution of nutrient-providing effective amounts of amino acids; and (6) a first constituent composition comprising a nutrient-providing effective amount of ⁇ -ketoglutaric acid, whereby the vehicle kit compositions comprise first constituent compositions (b) through (f) and at least one supplement constituent composition.
  • the vehicle kit compositions of the corresponding fluorocarbon nutrient emulsion kit comprise: (1) a first constituent composition comprising an emulsion of poly-fluorinated, oxygen-carrying compound (and optionally a nutrient-providing effective amount of ⁇ -ketoglutaric acid); (2) a first constituent composition comprising a solution of sodium, potassium, magnesium and calcium salts (and optionally a nutrient-providing effective amount of glucose); (3) a first constituent composition comprising a solution of the oncotic agent in amount effective to provide, in conjunction with the other components of the fluorocarbon nutrient emulsion, a physiologically acceptable oncotic pressure; and (4) a first constituent composition comprising a solution of a nutrient-providing effective amounts of amino acids, whereby the vehicle kit compositions comprise first constituent compositions (2) through (4) and at least one supplement constituent composition.
  • the vehicle kit comprises a first vehicle kit composition comprising a solution of (i) sodium, potassium, magnesium and calcium salts, (ii) a nutrient-providing effective amount of ⁇ -ketoglutaric acid, and (iii) a nutrient-providing effective amounts of amino acids; a second vehicle kit composition comprising a solution of the oncotic agent in amount effective to provide, in conjunction with the other components of the fluorocarbon nutrient emulsion, a physiologically acceptable oncotic pressure; and_a third vehicle kit composition comprising a solution of a nutrient-providing effective amount of glucose.
  • a first vehicle kit composition comprising a solution of (i) sodium, potassium, magnesium and calcium salts, (ii) a nutrient-providing effective amount of ⁇ -ketoglutaric acid, and (iii) a nutrient-providing effective amounts of amino acids
  • a second vehicle kit composition comprising a solution of the oncotic agent in amount effective to provide,
  • a method of delivering a fluorocarbon nutrient emulsion to neural tissue of an animal having a cerebrospinal pathway comprising: (a) inserting a first catheter at a first point directed to deliver fluid to a cerebral ventricle; (b) inserting a second catheter at a second point lower in the cerebrospinal pathway, which point is adapted to drain excess fluid due to fluid insertion through the first catheter; (c) inserting through the first catheter a vehicle solution adapted to be physiologically compatible with the fluorocarbon nutrient emulsion, wherein the vehicle solution lacks sufficient oxygen carrying capacity to be capable of carrying a respiration-supporting amount of oxygen; (d) confirming with the vehicle solution the existence of a perfusion pathway from the first catheter to the second catheter; (e) if necessary, repositioning one or both of the catheters and repeating step (d) until a perfusion pathway is confirmed; and (f) once a perfusion pathway is confirmed, inserting an oxygenated fluorocarbon
  • a fluorocarbon nutrient emulsion capable of carrying a oxygen to living tissue or a kit of pre-measured components for such a solution
  • the solution or kit comprising: a poly-fluorinated, oxygen-carrying compound; a physiologically acceptable emulsifying agent effective to emulsify the poly-fluorinated, oxygen-carrying compound; and nutrient-providing effective amounts of amino acids or amino acid precursors, wherein the solution or kit is essentially lacking in glutamic acid, glutamine and glycine.
  • a nutrient solution or a kit of pre-measured components for such a solution comprising: a nutrient-providing effective amount of carbohydrate; an oncotic agent in amount effective to provide, in conjunction with the other components of the solution, a physiologically acceptable oncotic pressure; and nutrient-providing effective amounts of amino acids or amino acid precursors including arginine, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine and valine, wherein the solution or kit is essentially lacking in glutamic acid, glutamine and glycine.
  • a fluorocarbon nutrient emulsion capable of carrying a oxygen to living tissue or a kit of pre-measured components for such a solution
  • the solution or kit comprising: a poly-fluorinated, oxygen-carrying compound; a physiologically acceptable emulsifying agent effective to emulsify the poly-fluorinated, oxygen-carrying compound; and nutrient-providing effective amounts of amino acids or amino acid precursors, including at least one citric acid, cis-aconitic acid, isocitric acid, succinic acid, fumaric acid, malic acid or oxaloacetic acid or a pharmaceutically acceptable salt thereof, wherein the solution or kit is essentially lacking in glutamic acid and glutamine.
  • a nutrient solution or a kit of pre-measured components for such a solution comprising: a nutrient-providing effective amount of carbohydrate; an oncotic agent in amount effective to provide, in conjunction with the other components of the solution, a physiologically acceptable oncotic pressure; and nutrient-providing effective amounts of amino acids or amino acid precursors including arginine, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, valine, and at least one of citric acid, cis-aconitic acid, isocitric acid, succinic acid, fumaric acid, malic acid or oxaloacetic acid or a pharmaceutically acceptable salt thereof, wherein the solution or kit is essentially lacking in glutamic acid and glutamine.
  • a method of irrigating exposed cerebral-spinal tissue comprising irrigating with a solution comprising: a nutrient-providing effective amount of carbohydrate; an oncotic agent in amount effective to provide, in conjunction with the other components of the solution, a physiologically acceptable oncotic pressure; and nutrient-providing effective amounts of amino acids or amino acid precursors including arginine, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, valine, and at least one of citric acid, cis-aconitic acid, isocitric acid, ⁇ -ketoglutaric acid succinic acid, fumaric acid, malic acid or oxaloacetic acid or a pharmaceutically acceptable salt thereof, wherein the solution or kit is essentially lacking in glutamic acid and glutamine.
  • the surgery can comprise: opening an animal to provide access to cerebral spinal tissue; irrigating the accessed cerebral spinal tissue; and conducting the surgery. Or it can comprise: irrigating the exposed cerebral spinal tissue of an animal; conducting the surgery; and closing the animal to end the exposed state of the spinal tissue.
  • Still further provided is a method of delivering a fluorocarbon nutrient emulsion to neural tissue of an animal having a cerebrospinal pathway comprising: oxygenating an emulsion of a poly-fluorinated, oxygen-carrying compound at a temperature from within ⁇ 1 °C of the physiological intracranial temperature (To) of the animal; reducing the temperature of the oxygenated emulsion by at least 2 °C; and perfusing the reduced temperature emulsion through at least a portion of the cerebral spinal pathway.
  • a method of delivering a physiologically acceptable solution or suspension (such as an emulsion) to neural tissue of an animal having a cerebrospinal pathway, the method comprising: conditioning the solution or suspension at temperature from within ⁇ 1 °C of the physiological intracranial temperature (To) of the animal; reducing the temperature of the conditioned solution or suspension by at least 2 °C; and perfusing the reduced temperature solution or suspension through at least a portion of the cerebral spinal pathway.
  • the devices and methods of the invention can be used to treat stroke, TBI, SCI or any other condition likely to deprive cerebral spinal tissue of needed oxygen or nutrients.
  • Figure 1 displays the catheter placements for a venticulo-lumbar perfusion.
  • Figure 2 shows an exemplary perfusion device.
  • the suspensions of poly-fluorinated, oxygen-carrying compound used to deliver oxygen, and preferably remove carbon dioxide from cerebral-spinal tissue pursuant to various methods described herein have been found to be relatively unstable for storage. Even the non-emulsion components cannot be stored as a complete mixture for sufficient periods of time without precipitates and other undesirable components forming. Readily standardized, stable solutions or suspensions have now been discovered. These solutions or suspensions can be delivered to automated compounding equipment, such as an Automix compounding device from Clintec Nutrition Company, Deerfield, Illinois.
  • the fluorocarbon nutrient emulsions contain a protein-based oncotic agent, which is stored separately from the carbohydrate component.
  • the oncotic agent is preferably also stored separate from any keto-containing component.
  • the amino acid components are preferably stored separate from the carbohydrate component, and preferably separate from any keto-containing component.
  • constituents of the fluorocarbon nutrient emulsion of the invention are preferably in amounts as described in the table below:
  • the pH of the emulsion, or vehicle is in the physiological range, such as about 7.3.
  • the amino acids include tryptophan.
  • One exemplary kit for making fluorocarbon nutrient emulsion containing eight constituent compositions is as set forth in the table below for a 1200 mL unit of the emulsion. Though the constituent compositions are provided to the mixing process in somewhat greater volume than listed in the table below (e.g., 515 mL for 500 mL), the amounts listed below are normalized to the 1200 mL of the final unit.
  • supplement constituent compositions containing the sodium and potassium are provided to deliver the sodium and potassium ions otherwise provided by constituent composition #1.
  • the ⁇ -ketoglutaric acid component can be stored as a dry powder, which is dissolved in, for example, sterile water before use.
  • a second exemplary kit for making fluorocarbon nutrient emulsion containing four constituent compositions is as set forth in the table below normalized for a 3,000 mL unit of the emulsion.
  • a third exemplary kit for making fluorocarbon nutrient emulsion containing five constituent compositions is as set forth in the table below for a 1200 mL unit of the emulsion.
  • the lyophilized compositions described below are reconstituted with water, preferably USP sterile water for injection, prior to addition into composition 1.
  • the dilution amounts are 20 mL each for compositions 2 and 3, and 10 mL for composition 5
  • a forth exemplary kit for making fluorocarbon nutrient emulsion containing four constituent compositions is as set forth in the table below for a 1200 mL unit of the emulsion.
  • the lyophilized compositions described below are reconstituted with water, preferably USP sterile water for injection, prior to addition into composition 1.
  • the dilution amounts are 20 mL for composition 2 and 10 mL for composition 4.
  • a fifth exemplary kit for making fluorocarbon nutrient emulsion containing four constituent compositions is as set forth in the table below for a 1200 mL unit of the emulsion.
  • the lyophilized composition described below is reconstituted with water, preferably USP sterile water for injection, prior to addition into composition 1.
  • the dilution amount is 10 mL.
  • supplement constituent compositions containing the sodium and potassium are provided to deliver the sodium and potassium ions otherwise provided by constituent composition #1.
  • the supplement constituent components also provide the ⁇ -ketoglutaric acid provided by constituent composition #1.
  • fluorocarbon nutrient emulsion kit with three constituent compositions, for example, one can provide the amino acid annex with the emulsified fluorocarbon composition.
  • most of the constituent compositions are packaged in separate chambers of a multi-chambered bag, where the seams between the chambers can be broken by applying pressure to the chambers, thereby mixing the contents of the chambers.
  • multi-chambered bags are available, for example, as ComplevenTM multi-chambered bags, which are marketed by Fresenius Kabi, Uppsala, Sweden.
  • Such bags are preferably manufactured to provide reduced oxygen and carbon dioxide permeability.
  • Such bags can be constructed of, for example, ethylene vinyl acetate (EVA) or polyvinylchloride (PVC).
  • EVA ethylene vinyl acetate
  • PVC polyvinylchloride
  • An outer bag, or outer layer of polymer can be provided to reduce oxygen permeability.
  • the chamber used to house the oncotic agent is lined with a non-plasticized polymer such as polyester films, (including the polyester films and suitable multi-layered films based on a polyester support marketed by E.I. Dupont du Nemours and Company, Wilmington, Delaware as Mylar® film), polyester-based multilayer films having a metal foil layer (again marketed as a form of Mylar® film) polyolefin or a metal foil, such as an aluminum foil (itself not coated with a plasticized polymer).
  • the oncotic agent can be stored separately, for example in glass, and injected into the chambers at the time of use.
  • the multi-chambered bag is thus favorably provided with an injection port.
  • pressure can be used to break the barriers between chambers to allow the contents to mix, with the contents mixing to provide the appropriate concentrations.
  • the appropriate concentration is that of the final fluorocarbon nutrient emulsion adjusted for the dilutions or additions provided by any separate fourth constituent composition.
  • the kit when not using the multi-chambered bag, is provided in standardized packaging, with designated slots for each constituent composition.
  • each constituent composition can have highly visible unique markings, which markings can be keyed to markings provided for at the automated compounding equipment to assure that each constituent composition is applied to that equipment consistent with the instrument's programming for compounding the fluorocarbon nutrient emulsion.
  • markings can include color codes, color combinations, bar codes, and the like.
  • gas-impermeable refers to a sufficiently reduced transmission so as to allow storage for months or more without substantial deterioration in quality due to oxygen or carbon dioxide intrusion or water vapor loss.
  • the gas permeability of the bag, or the bag in combination with an outer bag enveloping the mult-chambered bag has an oxygen permeability (measured under ASTM D3985) or carbon dioxide permeability of 10 cc/m -day-atm or less, preferably 1.0, 0.5 or 0.2 cc/m 2 -dayatm or less.
  • the multi-compartment bags can be enclosed in Mylar ® MC2 film (DuPont), which is a polyester film with a vacuum deposited layer of aluminum on one side and overcoated on both sides with a heat sealable polyvinyl dichloride copolymer.
  • the film has excellent oxygen, moisture and light barrier properties (oxygen permeability of 0.15 cc/m 2 -day-atm), and is available in 50 gauge (34,900 in 2 /lb) and 100 gauge (19,700 in 2 /lb). Strong materials with low oxygen permeability can also be made with Kevlar® (DuPont).
  • Kevlar ® polymer materials consist of long molecular chains produced from poly-paraphenylene terephthalamide.
  • the chains are highly oriented with strong interchain bonding.
  • the emulsion (or the corresponding vehicle) preferably comprises nutrient-providing effective amounts of arginine, histidine, leucine, lysine, methionine, phenylalanine, threonine and valine.
  • the emulsion (or the corresponding vehicle) is essentially lacking in glutamic acid, glutamine and glycine.
  • the salts provided include physiologically suitable amounts of potassium and sodium salts, as well, preferably, as calcium or magnesium salts.
  • a precursor is provided in the form of at least one of citric acid, cis-aconitic acid, isocitric acid, ⁇ -ketoglutaric acid, succinic acid, fumaric acid, malic acid or oxaloacetic acid, or a pharmaceutically acceptable salt thereof.
  • the precursor is provided in the form of at least one of citric acid, cis- aconitic acid, isocitric acid, succinic acid, fumaric acid, malic acid or oxaloacetic acid, or a pharmaceutically acceptable salt thereof.
  • the precursor is provided in the form of ⁇ -ketoglutaric acid or a pharmaceutically acceptable salt thereof.
  • any component molecule such as an amino acid, used in the invention which has a salt form, can be utilized in such a salt form so long as the counterion does not disrupt the physiological or pharmacologic acceptability of a nutrient emulsion or vehicle solution.
  • Vehicle Solutions and Kits
  • the fluorocarbon nutrient emulsions can be matched to vehicle solutions, which preferably are matched in all physiologically significant ions, nutrients and oncotic agents.
  • vehicle solutions which preferably are matched in all physiologically significant ions, nutrients and oncotic agents.
  • kits for vehicle these preferably share most of the constituent compositions of kits for the corresponding emulsion, with one or more new constituent compositions provided to supply significant components absent due to the absence of the emulsion of poly-fluorinated oxygen-carrying compound.
  • One exemplary kit for making fluorocarbon nutrient emulsion vehicle containing nine constituent compositions is as set forth in the table below for a 1200 mL unit of the emulsion. This kit is substantially matched to the first exemplary fluorocarbon nutrient emulsion kit.
  • Constituent compositions nos. 8 and 9 provide the sodium and potassium ions that otherwise would be provided by the fluorocarbon nutrient emulsion.
  • a second exemplary kit for making fluorocarbon nutrient emulsion vehicle containing nine constituent compositions is as set forth in the table below for a 3,000 mL unit of the emulsion. This kit is substantially matched to the second exemplary fluorocarbon nutrient emulsion kit.
  • a third exemplary kit for making fluorocarbon nutrient emulsion vehicle containing three constituent compositions is as set forth in the table below for a 1069 mL unit of the solution.
  • Composition 3 is reconstituted with water, preferably USP sterile water for injection, prior to addition into composition 1.
  • the dilution amount is 20 mL.
  • the invention provides a kit which is a jointly packaged combination of a fluorocarbon nutrient emulsion and a corresponding vehicle kit.
  • the packaging places the components of the two kits in recognizably distinct locations, and used labeling that makes clear the constituent compositions of each sub-kit.
  • Poly-fluorinated, oxygen-carrying compounds are known in the art.
  • the basic requirements are effectiveness in carrying a physiologically useful amount of oxygen.
  • Factors involved in selecting preferred such compounds include oxygen capacity, tissue retention (preferably minimized), emulsion stability, toxicity, and the like.
  • Such compounds are described, for example, in: Riess et al., "Design Synthesis and Evaluation of Fluorocarbons and Surfactants for In vivo Applications New Perfluoroalkylated Polyhydroxylated Surfactants", Biomat. Artif. Cells Artif.
  • oxygen-carrying compounds are those of the formula
  • C m Fm+ ⁇ — CH CH— C n F n + 1 , where m + n equals 6 to 10.
  • the double bond is trans.
  • One preferred poly- fluorinated, oxygen-carrying compound is trar ⁇ -Bis-perfluorobutyl ethylene (m and n each equal 4).
  • m and n each equal 4 are also preferred.
  • One of the perfluoro alkyls can be substituted with a halo from Br (preferably), Cl or I. Further preferred are those of the formula
  • a flow pathway from the entry catheter e.g., a ventricular catheter into a lateral ventricle of the brain
  • an exit point at a different location in the cerebral spinal pathway (e.g., into the intrathecal space of the lumbar (L4-L5) region of the spine) without prematurely inserting the emulsion.
  • a ventricular catheter 1 is inserted into a lateral ventrical 2.
  • a flow pathway can be established to a lumbar outflow catheter 6.
  • vehicle can be used to establish the existence of a flow pathway (such as that illustrated) from the inflow catheter to the outflow catheter.
  • the vehicle is infused under gravity feed, with the pressure head designed to avoid excessive intracranial pressure.
  • the vehicle can be substituted with the emulsion of poly-fluorinated, oxygen-carrying compound.
  • An exemplary perfusion device illustrated in Fig. 2 is made up of a conditioning circuit 100 and a delivery circuit 200.
  • Oxygen is supplied by a wall oxygen supply 101A or an oxygen tank 101B, regulated by switching regulator 102.
  • Carbon dioxide is provided by tanks 106, regulated by switching regulator 105.
  • Gas supply can be monitored through indicia displayed on gas supply indicator 103.
  • Gas flow can be monitored at rotameter 104.
  • Gas is fed through filter 108 to hollow fiber oxygenator 108.
  • An examples of a suitable oxygenator includes, for example, the Spinal OXYTM oxygenator from Baxter (Irvine, CA).
  • the fluorocarbon nutrient emulsion is introduced through port 112 to reservoir
  • Circulation pump 111 delivers the fluorocarbon nutrient emulsion to the hollow fiber oxygenator 108 and an associated heating unit 110.
  • the temperature of the fluorocarbon nutrient emulsion at the hollow fiber oxygenator 108 is monitored by temperature monitor 300. Fluorocarbon nutrient emulsion either cycles between reservoir 113 and the hollow fiber oxygenator
  • Delivery pump 201 delivers the fluorocarbon nutrient emulsion to heat exchanger 202 which is provided with heat exchange fluid by heat exchange conditioner 203.
  • a pressure overlimit device 210 in this example a manometer-type device with fluid overflow at a pressure head that can be calibrated. Fluid overflow container 211 contains any overflow.
  • Outlet 220 is to the inflow catheter. The temperature of fluorocarbon nutrient emulsion delivered to outlet 220 is also monitored by temperature monitor 300.
  • the conditioning circuit operates at the accepted physiological intracranial temperature of the animal being operated upon ( ⁇ 1 °C), while the delivery circuit lowers the temperature of the fluorocarbon nutrient emulsion or physiologically acceptable solution or suspension by at least 2 °C, preferably by 2 to 27 °C, more preferably by 5 to 15 °C.
  • the conditioning can include temperature conditioning, providing the opportunity for the solution or suspension to outgas if needed, or, if bicarbonate-based buffer is used, conditioning with an appropriate concentration of carbon dioxide.
  • This aspect of the invention can be used, for example, with simple saline solutions, but is preferably used with more sophisticated solutions or suspensions containing for example appropriate oncotic agents, or nutrient carbohydrate, or nutrient amino acids or precursors, or more sophisticated mixes of salts.
  • amino acid precursors are compounds that are facilely converted by mammalian enzymes to a corresponding amino acid.
  • a fluorocarbon nutrient emulsion or kit is essentially lacking in an amino acid if the amount is less than that which would reasonably be expected to provide an effective amount of nutrient. Such a lack exists when the concentration of the amino acid is 0.01 mg L or 0.001 mg/L or less in the nutrient solution.
  • • exposed cerebral-spinal tissue Exposed cerebral-spinal tissue is any cerebral-spinal tissue which can be accessed by surgical equipment, including micro-scaled equipment such as endoscopes.
  • • nutrient-providing effective amount A nutrient-providing effective amount of a substance is a amount that can be expected, provided sufficient amounts of other nutrients, to increase metabolism or reproduction of mammalian cells compared with nutrient solutions lacking that substance.
  • • oncotic agent By oncotic agent is meant substances, generally macromolecules, that are of a size that is not readily able to leave the body cavity or other fluid containing body spaces (such as the cerebrospinal pathway, including the cerebral ventricles and subarachnoid spaces) into which they are inserted.
  • Such oncotic agents are exemplified by blood plasma expanders which are known in general as macromolecules having a size sufficient to inhibit their escape from the blood plasma through the circulatory capillary bed into .the interstitial spaces of the body.
  • Serum albumin preferably human serum albumin
  • Polysaccharide blood plasma expanders are often glucan polymers.
  • Hetastarch (a product of American Home Products) is an artificial colloid derived from a waxy starch composed almost entirely of amylopectin with hydroxyethyl ether groups introduced into the alpha (1-4) linked glucose units.
  • the colloid properties of a 6% solution (wt/wt) of hetastarch approximates that of human serum albumin.
  • Other polysaccharide derivatives may be suitable as oncotic agents in the blood substitute according to the invention.
  • such other polysaccharide derivatives are hydroxymethyl alpha (1-4) or (1-6) polymers and cyclodextrins.
  • the polysaccharide is one that is non-antigenic.
  • High molecular weight agents such as Dextran 70 having a molecular weight of about 70,000 Daltons are generally less preferred because they increase viscosity of the colloidal solution and impair the achievement of high flow rates.
  • the oncotic agent is in an amount effective to provide, in conjunction with other components of a fluorocarbon nutrient emulsion or a nutrient solution, an oncotic pressure of one to seven torr.
  • respiration Respiration is the physical and chemical processes by which an organism supplies its cells and tissues with the oxygen needed for metabolism and, preferably, relieves them of the carbon dioxide formed in energy-producing reactions.
  • respiration-supporting amount A respiration-supporting amount of oxygen is an amount that would, in model experiments, provide a statistically significant reduction in morbidity following a focal ischemic event.

Abstract

Cette invention se rapporte notamment à un kit fournissant des quantités prémesurées de composants, pour former une émulsion d'éléments nutritifs au fluorocarbone capable de transporter de l'oxygène dans des tissus vivants, ce kit comprenant: des solutions de constituants, des émulsions de constituants ou des compositions particulaires, qui sont les compositions de constituants contenant des quantités prémesurées de composants destinés à produire l'émulsion d'éléments nutritifs au fluorocarbone, ces compositions de constituants comprenant: un composé polyfluoré transporteur d'oxygène; un agent émulsifiant physiologiquement acceptable propre à émulsifier le polymère; une quantité d'hydrates de carbone propre à fournir des éléments nutritifs; des quantités d'acides aminés ou de précurseurs d'acide aminé propres à fournir des éléments nutritifs; un agent oncotique en quantité suffisante pour produire, associé aux autres composants de la solution, une pression oncotique physiologiquement acceptable; et des sels et des agents de tamponnage en suffisance pour produire une pression osmotique physiologique et des concentrations physiologiquement appropriées d'ions potassium et sodium; ces compositions de constituants étant choisies pour assurer une stabilité suffisante des composants, en vue de permettre la commercialisation du kit.
EP01954737A 2000-07-19 2001-07-18 Kits et compositions pour la realisation d'injections intracraniennes Withdrawn EP1301226A4 (fr)

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US61941400A 2000-07-19 2000-07-19
US619414 2000-07-19
PCT/US2001/022539 WO2002005870A2 (fr) 2000-07-19 2001-07-18 Kits et compositions pour la realisation d'injections intracraniennes

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WO2002069711A1 (fr) * 2001-03-02 2002-09-12 Neuron Therapeutics, Inc. Therapie genique pour tissus neurologiques
EP2543249B1 (fr) 2007-02-17 2018-05-23 President and Fellows of Harvard College Compositions et procédé de conservation de tissu
BRPI0908266A2 (pt) * 2008-02-15 2015-07-21 Harvard College Solução substituta do sangue

Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0220153A1 (fr) * 1985-10-25 1987-04-29 Kabi Pharmacia AB Emulsion nutritive capable de transporter de l'oxygène et son procédé de préparation
WO1988005261A1 (fr) * 1987-01-16 1988-07-28 Tops Systems, Inc. Systeme de perfusion totale pour organes
US4981691A (en) * 1980-04-14 1991-01-01 Thomas Jefferson University Oxygenated fluorocarbon nutrient solution
WO2001034225A2 (fr) * 1999-11-12 2001-05-17 Neuron Therapeutics, Inc. Liquide cephalo-rachidien artificiel hyperoncotique et procede pour le traitement d'oedemes cerebraux a l'aide de ce liquide

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US4686085A (en) * 1980-04-14 1987-08-11 Thomas Jefferson University Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
US6316403B1 (en) * 1996-09-27 2001-11-13 The Trustees Of Columbia University In The City Of New York Methods for treating an ischemic disorder and improving stroke outcome

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4981691A (en) * 1980-04-14 1991-01-01 Thomas Jefferson University Oxygenated fluorocarbon nutrient solution
EP0220153A1 (fr) * 1985-10-25 1987-04-29 Kabi Pharmacia AB Emulsion nutritive capable de transporter de l'oxygène et son procédé de préparation
WO1988005261A1 (fr) * 1987-01-16 1988-07-28 Tops Systems, Inc. Systeme de perfusion totale pour organes
WO2001034225A2 (fr) * 1999-11-12 2001-05-17 Neuron Therapeutics, Inc. Liquide cephalo-rachidien artificiel hyperoncotique et procede pour le traitement d'oedemes cerebraux a l'aide de ce liquide

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Title
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1991, BELL R D ET AL: "A NOVEL TREATMENT FOR ISCHEMIC INTRACRANIAL HYPERTENSION IN CATS" XP002265774 Database accession no. PREV199191087427 & STROKE, vol. 22, no. 1, 1991, pages 80-83, ISSN: 0039-2499 *
See also references of WO0205870A2 *

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AU2001276963A1 (en) 2002-01-30

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