WO2000013501A1 - Improved artificial blood fluids - Google Patents
Improved artificial blood fluids Download PDFInfo
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- WO2000013501A1 WO2000013501A1 PCT/US1999/020704 US9920704W WO0013501A1 WO 2000013501 A1 WO2000013501 A1 WO 2000013501A1 US 9920704 W US9920704 W US 9920704W WO 0013501 A1 WO0013501 A1 WO 0013501A1
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- artificial blood
- fluid
- blood fluid
- drag reducing
- blood
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/41—Porphyrin- or corrin-ring-containing peptides
- A61K38/42—Haemoglobins; Myoglobins
Definitions
- the present invention is directed to improved fluids for use as artificial blood as well as to fluids which are useful for the further preparation of artificial blood.
- the invention is also directed to methods for the improvement and maintenance of perfusion and oxygenation of mammalian tissues through contacting such tissues with artificial blood fluids provided herein.
- Hemoglobin-based blood substitutes are known to use hemoglobin obtained from outdated human or animal blood as an oxygen and carbon dioxide carrier. These include certain crosslinked hemoglobin materials, known as HemAssistTM, PolyHemeTM, and HemolinkTM, proposed, respectively, by the Baxter, Northf ⁇ eld Labs and Hemosol companies. Recombinant hemoglobin has also formed an active part of artificial blood substitutes offered by the Baxter, Biopure and DNX companies.
- Encapsulated hemoglobin which is believed to be bovine hemoglobin located internally to small, elongated sheaths, has been suggested for this use by the Enzon Company while polymerized bovine hemoglobin has been offered by the Biopure and Upjohn companies.
- hemoglobin- based artificial bloods have been proposed heretofore, each of which relies upon modified hemoglobin suspended or dissolved in a pharmacologically acceptable medium.
- U.S. Patent 4,301,144 - Iwashita, et al. discloses blood substitutes comprising hemoglobin attached to a polymer, wherein the oxygen-carrying ability of the modified hemoglobin is nearly equal to that of the original hemoglobin and the residence time in the circulation is satisfactorily long.
- U.S. Patent 4,336,248 - Bonhard, et al. discloses a blood replacement having a capacity to transport oxygen corresponding approximately to that of free hemoglobin and a blood residence time which is at least about twice that of free hemoglobin, comprising hemoglobin molecules coupled to one another or to another protein by a coupling reagent comprising an aliphatic dialdehyde.
- Walder discloses a blood substitute comprising a cross- linked, stroma-free hemoglobin with cross links between alpha chain subunits, soluble in aqueous and physiological fluids and capable of reversibly binding oxygen, and a pharmaceutically acceptable carrier.
- Walder U.S. Patent 4,600,531 , discloses a method of producing a cross-linked hemoglobin derivative suitable for use as a blood substitute.
- U.S. Patent 4,670,417 - Iwasaki, et al. discloses hemoglobin modified in that a poly (alkylene oxide) is bonded thereto by a bond between a terminal group of poly(alkylene oxide) and an amino group of hemoglobin.
- This modified hemoglobin is an effective oxygen carrier and can be used in blood substitutes.
- Schmidt, et al. in U.S. Patent 4,698,387, disclose a blood substitute with increased intravasal half-life comprising at least one tetramer of hemoglobin and at least one adduct of a physiologically acceptable macromolecular agent bound to the allosteric binding site of the hemoglobin.
- a preferred embodiment of the macromolecular agent has a molecular weight of about 400 D to about 500,000 D.
- Cerny, inU.S.4,900,780 discloses ablood substitute comprising the reaction product of a modified starch having a molecular weight of from 60,000 to 450,000 D or a tetronic polyol having a molecular weight of from 1 ,650 to 27,000 daltons which is ablock copolymer formed by the addition of ethylene and propylene oxide units to ethylene diamine, with a stabilized stroma-free hemoglobin which has been converted to an oxy-acid or diketone.
- U.S. Patent 5,438,041, Zheng, et al. discloses a high hemoglobin content water-in- oil-in-water multiple emulsion for use as a blood substitute having high oxygen exchange activity.
- Hoffman, et al., U.S. Patent 5,661,124 show a blood substitute comprising a recombinantly produced mutant hemoglobin oxygen carrier and a physiologically acceptable molecule that is less diffusible than dextrose including disaccharide.
- U.S. Patent4,439,424 (EcanowC. and EcanowB.) relates to whole blood substitutes comprising sodium chloride, urea, phospholipid, distilled water and albumin, said components forming a system which may include stroma free hemoglobin, an appropriate sterol, electrolytes and proteins.
- U. S. Patent 4,439,357 (Bunhard, et al. discloses a method for preparing highly purified, stroma-free, non-hepatitic hemoglobin solution.
- U.S. Patent 4,529,719 in the name of Tye depicts a stroma-free tense state tetrameric mammalian hemoglobin covalently crosslinked with a diamide bond-forming moieties.
- Bucci, etal., in U.S. Patent 4,584, 130 discloses stroma-free hemoglobin cross-linked with reagents that mimic 2, 3 diphosphoglycerate and transform stroma-free hemoglobin into a physiologically competent oxygen carrier.
- U.S. Patent 4,777,244 to Bonhard, et al. discloses a method for preparing a crosslinked hemoglobin of extended shelf life and high oxygen transport capacity.
- U.S. Patent 4,920,194 discloses a blood substitute consisting essentially of an aqueous medium wherein fragments of sulfated glycosaminoglycans are covalently linked with hemoglobin to form products with oxygen binding property.
- European Patent Application 140,640 in the name of Wong discloses a blood substitute comprising chemically coupling hemoglobin with dextran or hydroxyethyl starch.
- the blood substitute comprises the formula (PS)-X-(HB)-Z, where PS is a polysaccharide; where X is a covalently bonded chemical bridging group; where HB is a hemoglobin residue; and where Z is an oxygen affinity reducing ligand, containing 2 or more phosphate groups.
- Certain non-hemoglobin based materials are used as the oxygen transport - active component of proposed artificial blood fluids. Silicone liquids and fluorocarbons are known for their ability to carry oxygen. In the 1960's, Clark and Gollan demonstrated that mice immersed in oxygenated silicone oil (it was found to be extremely toxic) or liquid fluorocarbon could "breathe" in the liquid.
- Perfluorocarbons showed a particularly high gas solubility (40-50 ml of oxygen and 100-150 ml of carbon dioxide dissolve in 100 ml of PFCs), and the high stability of the carbon fluorine bond makes them inert.
- the combination of their excellent gas carrying capacity and their metabolic inertness supported their use as in vivo gas carriers.
- Fluosol-DA is a 20% (w/v) mixture of 7 parts of perfluorodecalin and 3 parts perfluoro-tripropylamine, with 2.7% pluronic F-68 as an emulsifier and 0.4% of egg yolk phospholipids to form membrane coating on the emulsion.
- perfluorodecalin cannot be used to form stable emulsion and perfluorotripropylamine, with aT 1/2 of 64.7 days, has to be combined to form the stable emulsion.
- the much shorter retention time of the fluosol-DA 20 than certain other fluorocarbons allowed its use for clinical trial and testing. Because of the high viscosity of the fluorocarbon emulsion at high concentrations, the maximum amount used is generally only about 20%.
- a further type of fluorochemical oxygen carrier is based on perfluoroctyl bromide and perfluorodichoroctane. Both types allow the use of higher concentrations of perfluorocarbon.
- OxygentTM developed by the Alliance Pharmaceutical Corp., San Diego, is prepared from perfluoroctyl bromide (C g F 17 Br) with egg yolk lecithin as the surfactant.
- OxyfluorTM developed by HemoGen, St. Louis, is based on the perfluoro- dichloroctane with triglyceride and egg yolk lecithin.
- perfluorochemicals for use as oxygen carriers are synthetic materials, which can be chemically produced in large amounts without dependence on donor blood or other biological sources. At present such oxygen carriers are limited by toxicity concerns to a relatively low dosage of 0.9 g/kg for human use. This low dosage is partly because of side effects observed in humans at dosage of 1.8 g/kg. The patients still must breathe 100% oxygen.
- the Russian pharmaceutical firm, Perftoran manufactures an artificial blood substitute with gas-transporting function, which is bas ed on aperfluorocarbon emulsion called PerftoranTM.
- Patents 5,502,094 and 5,567,765 disclose physiologically acceptable aqueous emulsions of perfluorocarbon ether hydrides having 8 to 12 carbon atoms for use as contrast media for various biological imaging modalities such as nuclear magnetic resonance, 19 F imaging, ultrasound, x-ray, and computed tomography, and as oxygen transport agents or "artificial bloods" in the treatment of heart attack, stroke, and other vascular obstructions, as adjuvants to coronary angioplasty and in cancer radiation treatment and chemotherapy.
- U.S. Patent 5,262,442 - Heldebrant et al disclose aprocess for final preparation, prior to administration to apatient, of a frozen oxygen transporting fluorocarbon emulsion, without degrading pharmacologic properties thereof, comprising rapidly thawing a frozen oxygen transporting fluorocarbon emulsion at a temperature above 40°C and thereafter storing said thawed emulsion in a liquid state for from over eight hours up to 15 days prior to its administration.
- U.S. Patent 4,931,472 discloses an artificial blood comprising a formulation of a highly fluorinated triethylenediamine including perfluorotriethylenediamine, undecafluorotri ethylenediamine or decafluorotri ethylenediamine, or any combination thereof, dispersed in water, and an emulsifying agent, wherein emulsifying agent is a copolymer of propylene oxide and ethylene oxide.
- U.S. Patent 4,917,930 - McCormick discloses a gas transfer agent comprising an aqueous dispersion of a perfluoro compound and a surfactant.
- An object of the invention is to use higher amounts of perfluoro compounds and lower amounts of surfactant, with proportionately improved capacity for gas transfer and therapeutic effect, andproportionately diminished toxicity attributable to the surfactant.
- U.S. Patent 4,613,708 discloses oxygen-carrying blood substitutes comprising oil-in-water emulsions of branched perfluoroalkylated ethenes.
- U.S. Patent 3,962,439, Yokoyama, et al disclosed a blood substitute comprising oxygen-transferable perfluorocarbon compounds emulsified in a physiologically acceptable aqueous solution such as Ringer's solution.
- U.S. Patent 4,423,061 discloses a perfluorocycloamine emulsion preparation having oxygen carrying ability. Also disclosed is the use of apolymeric nonionic surfactant and a phospholipid as an emulsifying agent, and an isotonizing agent.
- U.S. Patent 4,425,347 also to Yokoyama, et al. discloses a perfluorobicyclo compound emulsion preparation having oxygen carrying ability. Also disclosed is the use of a polymeric nonionic surfactant and a phospholipid as an emulsifying agent, a plasma extender, and an isotonizing agent.
- U.S. Patents 4,866,096 , 4,956,390, and 4,895,876 to Schweighardt disclose stable aqueous emulsions comprising perfluorochemicals, and in varying embodiments, phospholipid, triglyceride of fatty acids, and aqueous media.
- Segall et al in U.S. Patents 5,733,894, 5,747,071, disclose an artificial plasma-like substance having at least one water soluble polysaccharide oncotic agent selected from the group consisting of high molecular weight hydroxyethyl starch, low molecular weight hydroxyethyl starch, dextran 40 and dextran 70, and albumin which is buffered by lactate. Also disclosed is the supplementation of the plasma-like solution with sodium chloride and certain ions, including calcium, magnesium and potassium.
- U.S. Patent 5,114,932 discloses a blood substitute comprising a physiologically acceptable fluid electrolyte solution, a physiologically acceptable agent capable of increasing the osmolality of the blood substitute to a value greater than normal blood, an oxygen carrying substance, and a sufficient amount of water to achieve the desired osmolality. Also disclosed is the above blood substitute wherein the agent capable of increasing osmolality is a disaccharide and the oxygen carrying agent is perfluorocarbon, synthetic hemoglobin or recombinant hemoglobin.
- U.S. Patent 4,987,154, Long, Jr. discloses an emulsion comprising an emulsifying agent, a fluorocarbon and an osmotic agent for adjusting and maintaining the osmolality of the solution. Also disclosed is the above emulsion wherein the osmotic agent is a sugar selected from the group consisting of glucose, mannose, fructose, or combinations thereof. Visca, et al., in U.S. Patent 4,990,283 disclosed a microemulsion comprising an aqueous medium, a perfluoropolyether, and a fluorinated surfactant.
- U.S. Patent 5,330,681, Brunetta et al. discloses stable diphase emulsions consisting of perfluoropolyethers having perfluoroalkyl end groups and a conventional surfactant dispersed in a continuous dispersing phase.
- perflurochemical oxygen carriers for artificial blood fluid has progressed, their toxicity continues to present a significant problem.
- Adverse effects were reported from infusion of perfluorocompound, including fever, thrombocytopenia and undesirable immune responses.
- Hemoglobin-based products also possess toxicity concerns. They have been linked to hypertension, thrombocytopenia, activation of the complement and coagulation cascades, renal damage, reticuloendothelial cell blockage and even lethal toxicity. While these adverse effects may usually be diminished through reduction in the concentration of the oxygen carriers in the artificial blood fluids and in the total amount of such materials ultimately employed, this greatly diminishes the benefit from use of the materials in oxygenation of tissues. Accordingly, it is greatly desired to provide artificial blood fluids which are, at once, highly effective in transporting oxygen to tissues in mammals treated with the fluids, while exhibiting no or diminished toxicity when compared with similar, existing artificial blood fluids of comparable oxygen carrying capacity. It is also desired to provide artificial blood fluids which have improved shelf stability, which are cost effective, which are easy to use, which are safe from transmission of infectious disease and which are acceptable to persons of all social and religious viewpoints.
- Yet another object of the invention is to provide blood fluid components or precursor concentrates, which can be reconstituted into an artificial blood for application to patients in need of the same.
- Microflow drag reducing agents belong to the group of drag reducing agents, which are known er se and are generally of the class of polymers with mechanical properties which enable them to reduce the flow resistance of their solvents.
- artificial blood fluids which comprise oxygen carrying fluorocarbon, hemoglobin-based or other oxygenating species can enjoy unparalleled effectiveness in use, while greatly diminishing the toxic effects of the oxygen carrier, through inco ⁇ oration of a water soluble microflow drag reducing agent at the concentration of from about 0.1 part per million (ppm) to about 10,000 ppm, by weight of the artificial blood fluid.
- such artificial blood fluids preferably comprise a physiologically acceptable carrier, a colloidal-crystalloid containing a polyethylene glycol, at least one perfluorocarbon - based oxygen carrying compound, and at least one microflow drag reducing factor.
- a physiologically acceptable carrier preferably comprise a physiologically acceptable carrier, a colloidal-crystalloid containing a polyethylene glycol, at least one perfluorocarbon - based oxygen carrying compound, and at least one microflow drag reducing factor.
- Such fluids are easily made sterile, are non- pyrogenic and are shelf stable.
- the amount of perfluorocarbon can be from about 1 to about 20 grams per deciliter of the fluid. It is preferred that amount of perfluorocarbon be present of from about 2.5 to about 15 grams per deciliter, with from about 5 to about 10 grams per deciliter being more preferred.
- Amounts of microflow drag reducing factor present in the artificial blood fluids of the invention are preferably from about 0.1 to 10,000 parts per million by weight, based upon the weight of the fluid. Amounts of from about 1 to about 100 ppm are preferred with amounts of from about 5 to about 50 ppm being more preferred.
- the fluids of the invention preferably further comprise at least one emulsifier.
- emulsifiers are preferably present in amounts between 0.05 and 5 grams per deciliter. Emulsifier concentrations are from about 0.1 and 3 grams per deciliter with 0.5 to about 2 grams per deciliter being preferred.
- a class of emulsifiers has been identified as being preferred for use in connection with the formulation of artificial blood fluids in accordance with this invention, especially those based upon perfluorocarbons.
- Such emulsifiers are the class of dendritic polymers, especially those based upon polylysine linked to polyethylene glycol (PEG).
- PEG polyethylene glycol
- Such dendrimers, terminated with perfluorocarbon termini are thus, preferred for emulsifying perfluorocarbon-containing artificial blood fluids of this invention.
- Preferred species are the third and fourth generation dendrimers of the foregoing class.
- the present invention also provides concentrates useful in the formulation of artificial blood fluids.
- These concentrates are designed for long-term storage and are, accordingly, considered to be shelf stable. They comprise concentrates of perfluorocarbon-based oxygen carrying compound together with microflow drag reducing factor and surfactant in ratios such that, when diluted for use, they are in correct proportion for the final product.
- Such concentrates generally comprise from about 50 to about 99.9% by weight of perfluorocarbon together with an amount of microflow drag reducing factor which will be effective in improving the flow properties of the resulting, diluted, artificial blood fluid.
- the concentrates further preferably comprise a physiologically acceptable colloidal-crystalloid carrier containing a polyethylene glycol.
- the invention also provides artificial blood fluids having hemoglobin - based oxygen carriers.
- Such artificial blood fluids preferably comprise a physiologically acceptable carrier, a colloidal-crystalloid containing a polyethylene glycol, at least one hemoglobin-based oxygen carrying compound, and at least one microflow drag reducing factor.
- hemoglobin - based oxygen carriers are present in an amount of from about 0.1 to about 5 grams per deciliter of the fluid.
- the fluid further comprises from about 1 to about 10,000 ppm, by weight, of microflow drag reducing agent.
- amounts of hemoglobin derivatives present in the fluids for application to patients is preferably from 2 to about 4 grams per deciliter with from about 2.5 to about 3.5 grams per deciliter being still more preferred.
- Other oxygen - carrying moieties may also be used and may substitute for all or part of the hemoglobin derivatives.
- FIG. la is a composite graphic representation , which demonstrates the effect of the injection into a rat of a very small amount of a microflow drag reducing factor (plant-derived polysaccharide) on the hemodynamic parameters (blood pressure and tissue perfusion).
- a microflow drag reducing factor plant-derived polysaccharide
- FIG. lb is a composite graphic representation of a control experiment. It demonstrates the effect of Sodium Nitroprusside injected into vascular system of an experimental animal at the same hemodynamic parameters as Figure la. A notable decrease in the tissue perfusion along with a decrease in blood pressure can be seen.
- FIG. 2 is a composite graphic representation which illustrates the effect of an injection of a small concentration ( 10' 6 g/ml or 1 ppm) of a microflow drag reducing factor dissolved in blood on capillary blood flow in normal and diabetic rats.
- Alloxan-induced diabetic microangiopathies represent a generalized disturbance of the microcirculation accompanied by a reduction in blood flow, vascular lesions, decrease in erythrocyte deformability, and a significant decrease in the number of functioning capillaries.
- FIG. 2 the administration of the microflow drag reducing factor to the blood of diabetic rats caused a dramatic increase in blood flow.
- the microflow drag reducing factors of the present invention can be used to treat a variety of circulatory disorders, including hypertension, high blood pressure, and microcirculatory disorders.
- Fig. 3 is a composite graphic representation of the distribution of blood pressure in the vascular system in the cases of normotension, hypertension and presence of microflow drag reducing factor in the blood. As seen, the microflow drag reducing factor increases precapillary pressure level through the decrease of pressure drop in the resistive vessels (small arteries and aterioles).
- FIG. 4 displays data recorded during an experimental study of the effect of microflow drag reducing factors on outcome in ras with severe hemorrhage.
- This experimental model of hemorrhagic shock causes a 100% mortality in control animals.
- Restoration of the lost blood volume with PlasaLite containing a microflow drag reducing factor at the concentration of about 2 ppm led to recovery of animal hemodynamics . No signs of acidosis were observed after three hours following the hemorrhage.
- FIG. 5 is a composite graphic representation on flow of blood mixed with a 5% perfluorocarbon emulsion (Fluosol ® ) in a circulating loop with a centrifugal (Bio-Medicus) pump, measured before and after addition of a plant-derived microflow drag reducing agent.
- FIG. 6 is a composite graphic representation of the flow of blood mixed with a 5% perfluorocarbon emulsion (Fluosol ® ) in the same mock circulation loop of Figure 5, measured before and after addition of a plant-derived microflow drag reducing factor.
- FIG. 7a is a third generation PEG-dendritic-poly(lysine) hybrid useful as an emulsifying agent in connection with the present invention.
- FIG. 7b is a fourth generation PEG-dendritic-poly(lysine) hybrid useful as an emulsifying agent with the present invention.
- the present invention provides enhancement in the treatment of patients in need of blood replacement through the provision of improved artificial blood fluids.
- the discovery that small amounts of microflow drag reducing moieties, chiefly certain polymers and biopolymers, can greatly improve the efficacy of perfluorocarbon or hemoglobin - based artificial blood fluids has given rise to the ability to employ such fluids effectively, while mmirnizing or removing the problems with toxicity shown in prior systems.
- the ability to employ smaller amounts of the oxygen carrying compounds, surfactants, emulsifiers and other components in artificial blood fluids without losing their effectiveness permits both economy and improved therapeutics.
- the artificial blood fluids of this invention provide improved therapeutic modalities over prior artificial bloods and offer new clinical opportunities.
- tissue unde ⁇ erfusion associated with diseases such as atherosclerosis or impairedmicrocirculation
- diabetes acute my ocardial infarction
- acute transient cerebral ischemic attack ischemic heart disease
- sickle cell anemia and similar conditions.
- the overall improvement of circulation which attends employment of the artificial blood fluids of this invention with a very small or zero concentration of oxygen carrier and emulsifier, gives rise to diverse useful therapies employing such fluids.
- the artificial blood fluids of this invention can provide superior perfusion for preservation and maintenance of the functionality of isolated organs intended for transplantation.
- the artificial blood fluids of the present invention preferably include a polyethylene glycol added for protecting natural blood cells from mechanical damage, also are beneficial for use with artificial organs and therapeutic devices such as artificial hearts, cardiac assist devices, heart-lung machines, dialyzers, perfusion devices and the like. It is an ideal fluid for "priming" extraco ⁇ oreal blood flow devices.
- Other benefits from the present invention will be apparent to persons of ordinary skill in the art.
- the artificial blood fluids of the present invention are preferably based upon emulsions of oxygen-carrying perfluorocarbons. Any of the fluorocarbons known to persons of ordinary skill in the art, including all of those discussed supra, may be employed in connection with one or more embodiments of this invention.
- fluorocarbon derivatives and modifications thereof as may be developed hereafter may also find utility in the present invention so long as they function to carry oxygen in a way which can benefit cells in a living mammal or in mammalian tissue.
- Emulsifiers are present in amounts of from about 0.05 to about 5 grams per deciliter of blood fluid. It is preferred that emulsifiers be present in amounts from about 0.1 to about 3 g/dl with 0.5 to 2 g/dl being more preferred.
- fluorocarbon-based oxygen carrying compositions are best defined by what they do. Such compositions include a fluorocarbon compound or compounds in a form such that the same can be added to the blood in the circulatory system of a patient in need of artificial blood.
- compositions include pharmaceutically acceptable carriers, emulsifiers, salts, and other adjuvants as may be deemed necessary or desirable.
- materials are in a form effective for introduction into the circulatory system.
- exemplary fluorocarbon - based oxygen carrying moieties include, without limitation, perflurodecalin and/or perfluorotri-n-propylamine.
- Other oxygen carriers, such as hemoglobin-based, perfluoroalkanes, perfluoro ethers, etc. can also be employed within the spirit of this invention.
- fluorocarbon derivatives are generally emulsified for use and that persons skilled in the art are well-versed in attaining such emulsions.
- emulsifiers include lethicin, polyethylene glycol (PEG) - fatty acids, Pluronic type emulsifier, oleate salts, PEG perfluorcarbons ethers and the like. Other emulsifiers will likely be useful as well.
- the artificial blood fluids of the invention in addition to the fluorocarbon or hemoglobin-based oxygen carrier, and if desired, emulsifier also contain a microflow drag reducing factor.
- the amount of perfluorocarbon can be from as low as below one to about 20 grams per deciliter of the fluid. This amount of fluorocarbon compound is much lower than is conventionally employed due to the presence of the microflow drag reducing factor. This is believed to be made possible by the ability of the microflow drag reducing factor to facilitate circulation of the blood fluid through the body of a patient receiving it. While not being bound by theory, it is believed that hydrodynamic resistance to blood flow in the cardiovascular system of patients is significantly diminished through inclusion of the microflow drag reducing factor, such that circulation at a given pressure is significantly improved.
- the class of molecules which are microflow drag reducing factors are preferred for use in the context of this invention. A number of such factors can be employed with the present invention.
- the microflow drag reducing agent may be, for example, selected from the class of water soluble synthetic high-molecular weight polymers, polysaccharides, and polypeptides derived from plants such as okra and others, algae, gums,-; polypeptides and polysaccharides derived from bacteria;-; synthetic polypeptides and polysaccharide, biopolymers derived from fish slimes, sea-water and fresh-water biological growths; ovomucin of egg-whites; biopolymers derived from human or animal blood, blood plasma and blood cells.
- Certain non-naturally occurring synthetic polymers are useful such as high-molecular weight polyethylene oxides, polyacrylamides, and the like.
- products with the following tradenames and available from the following companies may be useful in one or more embodiments of the present invention as microflow drag reducing factors .
- Polyethylene oxides Polyox water soluble resins WSR-301 , 309, N-60K, N-750 and others, Union Carbide Co., USA
- polyacrilamides Polyacril 2515TR, 2540TR and others, Stockhausen, Inc., Sweden
- Carboxymethyl cellulose Gum Technology Co.
- gums such as Gum Guar (Sigma Chemical Co.), Tragacanth (Gum Technology Co.), Gum Karaya (Sigma Chemical Co.), Gum Xanthan (Sigma Chemical Co.).
- the microflow drag reducing factors useful in the present invention are best defined by what they do rather than by what they are.
- such materials are polymers or biopolymers which are water soluble under conditions suitable for the pu ⁇ oses of this invention.
- Such polymers must be non-pyrogenic, capable of acceptable shelf stability and consistent with use as a component in the circulation of a mammal.
- a major requirement is that compound be capable of reducing microcirculatory blood flow resistance vessel bifurcations, constrictions, expansions, and other local changes in the vessel geometry as well as with chaotic motion of blood cells.
- Persons of skill in the art will readily be able to identify subclasses and individual compounds belonging to the class of microflow drag reducing factors. The ability of certain water soluble linear macromolecules to increase fluidity of blood has been studied since 1970.
- U. S. Patent 4,154,822 discloses the administration of a polys accharide derivative from okra plants, which causes hemodynamic and rheological effects which enhance cardiac output.
- the mechanism was said to be a reduction in blood viscosity at relatively low shear rates, due to administration of the polysaccharide to the blood.
- the effect of drag reducing polymers on blood circulation in vivo cannot be explained solely by the Toms effect, however, since blood flow in the cardiovascular system is not turbulent. Neither can it be explained by reduction in blood viscosity as suggested by Polimeni, et al. in the U. S . Patent 4, 154,822, since the reduction in low shear blood viscosity can only be due to a decrease in the red blood cell aggregation .
- microflow drag reduction occurs at very low flow conditions and may be attributed to the diminishing of local disturbances of flow produced by the geometrical peculiarities of vascular bed and micro-vortices caused by chaotic motion of blood cells. Therefore the polymers which produce a very strong drag reduction at the turbulent flow conditions do not necessarily have the same effect under microflow conditions and vice versa.
- a simple can be applied for condition of turbulent flow. See FIGURES 4 and 5.
- further animal or special hydrodynamic testing may be employed.
- microflow drag reducing factors allows the concentration of the oxygen carrier in certain artificial blood fluids to be reduced to levels which previously would have been ineffective, but which provide acceptable oxygen levels of patients consistent with acceptable levels of toxicity to the patients .
- perfluorochemical oxygen carriers previously employed for example, in quantities as high as 20-40 g/dl (20-40% emulsions) or higher, may now be reduced for example, to 1-10 g/dl or even lower, when used with microflow drag reducing factors, while achieving acceptable rates of oxygen delivery.
- the similar reduction of hemoglobin-based oxygen carriers can be also achieved.
- the artificial blood fluids of this invention with a very small or zero concentration of oxygen carrier and/or emulsifier gives rise to different useful therapies employing such fluids .
- these fluids can be used for increasing the effectiveness of drug delivery to target organs and tissues utilizing a much lower concentration of the drug.
- artificial blood fluids of this invention for a much wider range of clinical interventions than possible with prior materials.
- Such fluids may be used in elective surgery, traumatic injury involving disturbance of microcirculation as well as in cases of significant blood loss, hemorrhagic shock, circulatory shock, medical conditions such a sickle cell anemia, diabetes, acute myocardial infarction, acute transient cerebral ischemic attack, ischemic heart disease and similar conditions.
- the overall microcirculatory improvement which attends employment of the artificial blood fluids of this invention gives rise to diverse, useful therapies employing such fluids.
- emulsifiers While all effective, pharmaceutically acceptable emulsifiers are contemplated for use within the spirit of this invention, the employment of certain emulsifiers has been found to be particularly useful, with fluorocarbon - based systems.
- the class of dendritic polymers has been found to be particularly useful. Such polymers are known, per se.
- PEG polyethylene glycol
- These emulsifiers have the configuration set forth in Figures 7a (third generation) and Figure 7a (fourth generation).
- the emulsifier is preferably present in a concentration of about 0.05 to 5 g/dl of the composition.
- Third and fourth generation amphiphilic PEG-co-dendritic-polylysines are preferred.
- Another preferred embodiment of the invention inco ⁇ orates an emulsifier comprising a third or fourth generation amphiphilic PEG-co-dendrimeric-polylysine with perfluorocarbon-containing termini.
- perfluorocarbon-containingtermini includes not only the generally understood moiety, having carbon chains wherein every hydrogen is replaced with fluorine, (i.e. all C-F an no C-H bonds) but also includes carbon chains wherein some hydrogen have not been replaced with fluorine (i.e., combinations of both C-F and C-H bonds).
- U.S. Patent 3,590,124 - Hoyt discloses a composition for injection into the blood system comprising a blood transfusion fluid, and 5 to 100 parts per million by weight of high molecular weight, water soluble polyethylene oxide, poly aery 1 amide, and linear polysaccharides.
- Partially hydrolyzed dextran in an isotonic sodium chloride solution, normal physiological saline, and normal liquid human plasma are disclosed as transfusion fluids suitable for use in the invention.
- An object of the invention is reduction of the turbulent friction properties of the transfusion fluid, and thus reduction of the body pumping requirements for the person receiving the transfusion, however, no efficacy was established for this suggestion.
- Patents 4,001,401 and 4,061,736 to Bonsen, Morris and Lover disclose a pharmaceutical composition useful as a blood substitute and blood plasma expander comprising a therapeutically effective amount of cross-linked, stromal-free hemoglobin, soluble in aqueous and physiological fluids, capable of reversibly binding a ligand and having a molecular weight of 64,000 to 1,000,000 D mixed with a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier is a member selected from the group consisting of poly(ethylene oxide), polyacrylamide, polyvinyl pyrrolidone, polyvinyl alcohol, ethylene oxide-polypropylene glycol condensates and polysaccharides, dextran, gum arabic, plasma proteins, albumin, pectin, fluid gelatin and hydroxyethyl starch as crystalloids and colloid polymeric solutions.
- concentration or molecular weight of the poly(ethylene oxide), polyacrylamide andpolysaccharides They are believed to be used as colloids or crystalloids and not to confer drag reducing effects.
- U.S. Patent 4,105,798 in the name of Moore et al. discloses an artificial blood comprising an emulsion of a non-aromatizable perfluorinated material in water, the amount of water being greater than 40% by volume, said emulsion containing anon-toxic emulsifier and aperfluorinated C 9 - C 18 poly cyclic hydrocarbon containing at least two bridgehead carbon atoms linked through a bridge containing at least one carbon atom.
- the present invention provides artificial blood fluids having relatively low amounts of perfluorochemical-based, hemoglobin-based or other natural or synthetic oxygen carriers.
- shelf stable fluids have oxygen carriers present along with microflow drag reducing factors, suspension agents, salts and other components, and may advantageously be included in ratios such that dilution to working blood substitute fluids can easily be accomplished.
- fluid concentrates may be diluted significantly, such as from about 2: 1 to about 10: 1 or more with sterile carrier, conveniently Ringers' lactate, saline or the like, to form a large volume of artificial blood fluid.
- the concentrated fluids are shelf stable.
- working artificial blood fluids are prepared in accordance with this invention comprising from about 1 (or below) to about 5 grams per deciliter of a hemoglobin - based oxygen carrying compound together with from about 0.1 to about 10,000 parts per million, by weight, of microflow drag reducing factor or factors.
- a hemoglobin - based oxygen carrying compound comprising from about 1 (or below) to about 5 grams per deciliter of a hemoglobin - based oxygen carrying compound together with from about 0.1 to about 10,000 parts per million, by weight, of microflow drag reducing factor or factors.
- the amount of hemoglobin - based oxygen carrier comprise from 2 to about 4 grams per deciliter of the artificial blood fluid, with from 2.5 to about 3.5 grams being more preferred. It is preferred that the microflow drag reducing factor be present in an amount of from about 1 to 1000 ppm, with about 5 to about 500 ppm being more preferred.
- the concentrates from which working artificial blood fluids may be reconstituted preferably comprise from about 50 to 99.9% by weight of hemoglobin - based oxygen carrier with a drag reducing agent in an appropriate amount such that when diluted, it is effective for reducing drag in artificial blood fluids.
- the concentrated fluids may also comprise physiologically acceptable carriers and the like.
- PraestolTM (Stockhausen, Inc., Greensboro, NC), believed to be a cationically modified polyproplylene material, was added to circulating artificial blood fluid, 10% perfluorochemical emulsion, Fluosol ® (Alpha Therapeutic Co ⁇ oration, Los Angeles, CA).
- FIGURE 5 demonstrates in a model blood vessel system that the addition of only trace amounts of PraestolTM (concentration of 10" 5 g/ml) significantly increased (by up to 50%) the flow rate at the same driving pressure. Further the required driving pressure was reduced up to 100% at constant flow rate.
- FIGURE 6 demonstrates in a model blood vessel system under turbulent flow conditions that the addition of this polysaccharide significantly increased (by more than 40%) the blood-Fluosol mixture flow rate at the same driving pressure and reduced driving pressure up to 80% at constant flow rate.
- Biopolymers derived from human or animal blood plasma and erythrocytes such as those disclosed in Grigorian, S.S., Kameneva, MN. et al., Proceedings of the Academy of Sciences of the USSR., Biophysics Section, July-December 1987, 178-179, which are purified, can be added to artificial blood fluids in accordance with this invention. An effect similar to that described in the EXAMPLES 1 and 2 can be achieved.
- FIG. la A plant-derived polysaccharide which meets the definitions of microflow drag reducing factor, was intravenously injected into normal rats.
- FIG. la The major baseline hemodynamic parameters changed significantly after injection. Tissue perfusion increased from 7.5 tissue perfusion units (TPU) to 33 TPU, systolic blood pressure decreased from 105 mm Hg to 90 mm Hg. Thus the tissue vascular resistance was decreased as much as 5 times.
- TPU tissue perfusion units
- systolic blood pressure decreased from 105 mm Hg to 90 mm Hg.
- Sodium ⁇ itroprusside a powerful clinically-used vasodilator
- Red blood cells separated from plasma were suspended in a solution of Polyethylene glycol (PEG, Sigma Chemical Co., Molecular weight of about 15,000-20,000 D) or in solution of dextran (Dextran-40, Sigma Chemical Co., Molecular weight of about 40,000 D). Then, the suspensions were both exposed to similar mechanical stress. Damage to red blood cells suspended in dextran was as much as three times higher than damage to red blood cells suspended in polyethylene glycol solution. The presence of polyethylene glycol in the suspension medium reduced mechanical damage to the red blood cells . Therefore, the polyethylene glycol can be used in the compositions of the present invention for the protection of blood cells from mechanical damage, as occurs clinically in extraco ⁇ oreal and implanted heart and lung assist devices, dialysis machines and other blood-wetted artificial organs.
- compositions of the present invention can also be used in powerful methods for treating impaired microcirculation in patients having severe blood circulatory disorders.
- administering the composition of the present invention to such a patient, generally intravenously the composition increases the fluidity of the patient's blood, thereby improving microcirculatory flow and tissue perfusion in the patient.
- This improved microcirculation can be achieved by administering a composition including the MDRF by itself, or the MDRF with the oxygen carrying compound, or with both the oxygen carrying compound and an emulsifier as disclosed herein.
- Such methods may treat, for example, impaired microcirculation in sickle cell disease, atherosclerosis, and other known blood circulatory disorders.
- the present invention also improves the extraco ⁇ oreal survivability of organs for transplantation. Perfusion of such organs with artificial blood fluids of this invention improves oxygenation with minimal damage to the tissues involved.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99968600A EP1111992A4 (en) | 1998-09-09 | 1999-09-09 | Improved artificial blood fluids |
CA002345895A CA2345895A1 (en) | 1998-09-09 | 1999-09-09 | Improved artificial blood fluids |
AU60315/99A AU6031599A (en) | 1998-09-09 | 1999-09-09 | Improved artificial blood fluids |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15013898A | 1998-09-09 | 1998-09-09 | |
US09/150,138 | 1998-09-09 | ||
US33964799A | 1999-06-24 | 1999-06-24 | |
US09/339,647 | 1999-06-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000013501A1 true WO2000013501A1 (en) | 2000-03-16 |
WO2000013501A9 WO2000013501A9 (en) | 2000-07-13 |
Family
ID=26847348
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/020704 WO2000013501A1 (en) | 1998-09-09 | 1999-09-09 | Improved artificial blood fluids |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1111992A4 (en) |
AU (1) | AU6031599A (en) |
CA (1) | CA2345895A1 (en) |
WO (1) | WO2000013501A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111420068A (en) * | 2019-11-13 | 2020-07-17 | 浙江大学 | Polyethylene glycol-dendritic polylysine/anhydride-cisplatin compound and preparation method and application thereof |
KR20210157189A (en) * | 2020-06-19 | 2021-12-28 | 대한민국(관리부서: 행정안전부 국립과학수사연구원장) | Artificial blood for bloodstain pattern analysis |
WO2021260558A1 (en) * | 2020-06-23 | 2021-12-30 | Biomodex, S.A.S. | Aqueous medium-soluble powder for blood flow simulation |
Citations (6)
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US3590124A (en) * | 1967-06-27 | 1971-06-29 | Us Navy | Blood transfusion fluids having reduced turbulent friction properties |
US4105798A (en) * | 1976-07-19 | 1978-08-08 | Sun Ventures, Inc. | Perfluoro polycyclic compounds for use as synthetic blood and perfusion media |
US4154822A (en) * | 1976-08-02 | 1979-05-15 | The University Of Chicago | Polysaccharide for enhancement of cardiac output |
US4186253A (en) * | 1978-10-10 | 1980-01-29 | The Green Cross Corporation | Perfusate for preserving organ to be transplanted and preserving method |
US5702881A (en) * | 1993-03-16 | 1997-12-30 | Alliance Pharmaceutical Corp. | Method and solution for organ preservation comprising retinal-derived growth factor, cyclodextrin, mucopolysaccharide and fluorocarbon |
US5753616A (en) * | 1986-11-10 | 1998-05-19 | Biopure Corporation | Method for producing a stable polymerized hemoglobin blood-substitute |
-
1999
- 1999-09-09 EP EP99968600A patent/EP1111992A4/en not_active Withdrawn
- 1999-09-09 WO PCT/US1999/020704 patent/WO2000013501A1/en not_active Application Discontinuation
- 1999-09-09 AU AU60315/99A patent/AU6031599A/en not_active Abandoned
- 1999-09-09 CA CA002345895A patent/CA2345895A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US3590124A (en) * | 1967-06-27 | 1971-06-29 | Us Navy | Blood transfusion fluids having reduced turbulent friction properties |
US4105798A (en) * | 1976-07-19 | 1978-08-08 | Sun Ventures, Inc. | Perfluoro polycyclic compounds for use as synthetic blood and perfusion media |
US4154822A (en) * | 1976-08-02 | 1979-05-15 | The University Of Chicago | Polysaccharide for enhancement of cardiac output |
US4186253A (en) * | 1978-10-10 | 1980-01-29 | The Green Cross Corporation | Perfusate for preserving organ to be transplanted and preserving method |
US5753616A (en) * | 1986-11-10 | 1998-05-19 | Biopure Corporation | Method for producing a stable polymerized hemoglobin blood-substitute |
US5702881A (en) * | 1993-03-16 | 1997-12-30 | Alliance Pharmaceutical Corp. | Method and solution for organ preservation comprising retinal-derived growth factor, cyclodextrin, mucopolysaccharide and fluorocarbon |
Non-Patent Citations (4)
Title |
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CHAPMAN ET AL.: "Fluorinated hydraamphiphiles: Poly(ethyleneoxide)-polylysine dendrimer hybrids with multiple terminal perfluorooctanoyl groups", POLYMERIC MATERIALS SCIENCE AND ENGINEERING,, vol. 73, 1995, pages 275 - 276, XP002926601 * |
KAMENEVA ET AL.: "Effect of perfluorochemical emulsion on blood trauma and hemorheology", ASAIO JOURNAL,, vol. 40, no. 3, 1994, pages M576 - M579, XP002926603 * |
MOFFITT.: "Blood Substitutes", CANADIAN ANAESTHOLOGIST SOCIETY JOURNAL,, vol. 22, no. 1, January 1975 (1975-01-01), pages 12 - 19, XP002926602 * |
See also references of EP1111992A4 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111420068A (en) * | 2019-11-13 | 2020-07-17 | 浙江大学 | Polyethylene glycol-dendritic polylysine/anhydride-cisplatin compound and preparation method and application thereof |
CN111420068B (en) * | 2019-11-13 | 2021-11-09 | 浙江大学 | Polyethylene glycol-dendritic polylysine/anhydride-cisplatin compound and preparation method and application thereof |
KR20210157189A (en) * | 2020-06-19 | 2021-12-28 | 대한민국(관리부서: 행정안전부 국립과학수사연구원장) | Artificial blood for bloodstain pattern analysis |
KR102384708B1 (en) | 2020-06-19 | 2022-04-11 | 대한민국 | Artificial blood for bloodstain pattern analysis |
WO2021260558A1 (en) * | 2020-06-23 | 2021-12-30 | Biomodex, S.A.S. | Aqueous medium-soluble powder for blood flow simulation |
Also Published As
Publication number | Publication date |
---|---|
CA2345895A1 (en) | 2000-03-16 |
WO2000013501A9 (en) | 2000-07-13 |
EP1111992A1 (en) | 2001-07-04 |
AU6031599A (en) | 2000-03-27 |
EP1111992A4 (en) | 2003-01-15 |
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