EP1858529A2 - Acide hyaluronique soluble dans le sang et destine a reduire la resistance a l'ecoulement - Google Patents

Acide hyaluronique soluble dans le sang et destine a reduire la resistance a l'ecoulement

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Publication number
EP1858529A2
EP1858529A2 EP06736388A EP06736388A EP1858529A2 EP 1858529 A2 EP1858529 A2 EP 1858529A2 EP 06736388 A EP06736388 A EP 06736388A EP 06736388 A EP06736388 A EP 06736388A EP 1858529 A2 EP1858529 A2 EP 1858529A2
Authority
EP
European Patent Office
Prior art keywords
hyaluronic acid
ppm
physiologically acceptable
acceptable salt
increase
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Withdrawn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
EP06736388A
Other languages
German (de)
English (en)
Inventor
Kipling Thacker
Marina Kameneva
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.)
Lifecore Biomedical Inc
University of Pittsburgh
Original Assignee
Lifecore Biomedical Inc
University of Pittsburgh
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
Priority claimed from US11/364,577 external-priority patent/US20070032452A1/en
Priority claimed from US11/364,566 external-priority patent/US20070032451A1/en
Application filed by Lifecore Biomedical Inc, University of Pittsburgh filed Critical Lifecore Biomedical Inc
Publication of EP1858529A2 publication Critical patent/EP1858529A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to improved microflow drag reducing polymers for use in blood as well as the restoration and/or enhancement of microcirculation and tissue oxygenation.
  • the invention is further directed to methods for the restoration and/or enhancement of microcirculation and perfusion and oxygenation of mammalian tissues due to changes in fluid properties of blood induced by drag reducing polymers provided herein.
  • Drag reducing polymers provide positive hemodynamic effects in various acute and chronic animal models. Nanomolar concentrations of various DRPs that are injected intravenously have been shown to increase aortic and arterial blood flow and decrease blood pressure and peripheral vascular resistance. Intravenous injections of DRPs have also been shown to diminish the development of atherosclerosis in atherogenic animal models. [004] The DRPs that have been studied thus far have been polyacrylamides, polyethylene oxides, polyethylene glycols, a polysaccharide extracted from okra and calf thymus DNA.
  • the present invention provides an endogenously derived DRP that can be used to increase aortic blood flow, arterial blood flow, increase capillary blood flow, increase venous blood blow, decrease blood pressure, decrease peripheral vascular resistance, diminish the development of atherosclerosis, and/or prevent lethality of hemorrhagic shock.
  • Suitable DRPs of the present invention include hyaluronic acid and hyaluronic acid derivatives, such as pharmaceutically acceptable salts of hyaluronic acid.
  • the present invention further provides suitable pharmaceutical compositions of the DRPs of the invention.
  • the present invention also provide packaged pharmaceutical formulations that contain the DRPs of the invention and instructions how to use the DRP(s).
  • the DRPs of the invention generally have molecular weights of from about 500 kD to about 7,000 kD, more particularly between about 500 kD and about 2000 kD, e.g., between about 680 kD to about 1500 kD.
  • Useful concentrations of the DRPs are between about 0.1 ppm and about 1000 ppm.
  • Figure 1 demonstrates that suitable concentrations of low molecular weight sodium hyaluronate are effective in reducing the flow resistance in an aqueous solution simulating behavior in blood.
  • Figure 2 shows a higher drag-reducing efficiency of HLA. with MW of -1500 kD compared to that of PEO with MW 2000 kD, and an incredibly low rate of mechanical degradation of this HLA. which was circulating in the in vitro flow system at a flow rate of 4.5 L/min at the concentration in the solution of 100 ppm.
  • Figure 3 shows a higher drag-reducing efficiency of HA with MW of -1500 kD compared to that of PEO with MW 2000 kD, and an incredibly low rate of mechanical degradation of this HA which was circulating in the in vitro flow system at a flow rate of 4.5 L/min at the concentration in the solution of 100 ppm.
  • Figure 4 shows viscosity results for the HA-1500 and PEO-2000 solutions at the concentrations of 2500, 1000 and 500 ppm @ 24.5°C presented as the mean and standard deviations of three measurements.
  • Figure 6 depicts data on elasticity of PEO-2000 solutions.
  • Figure 7 shows data from Figure 6 in a larger scale.
  • Figure 8 shows the results of several tests with turbulent flow of the HA-1500 and PEO-2000 in a pipe.
  • Figure 9 depicts data represented in Tables 2 and 3.
  • Figure 10 shows results of microchannel studies.
  • Figure 12 depicts an image of a 10 ppm HA 1481 kDa sample in bovine RBC suspension in a microchannel.
  • Figure 13 depicts an image of a 50 ppm HA 1481 kDa sample in a bovine RBC suspension in a microchannel.
  • Figure 14 depicts an image of a 10 ppm PEO-2000 sample in a bovine RBC suspension in a microchannel.
  • Figure 15 depicts an image of a 50 ppm PEO-2000 sample in a bovine RBC suspension in a microchannel.
  • HA-990 and PEO-1000 at the concentrations of 2500, 1000, and 500 ppm measured @ 24.3 0 C.
  • Figure 17 shows the results of Figure 16 excluding the 2500 ppm
  • Figure 18 shows viscosity results for the HA and PEO solutions at the concentrations of 2500, 1000 and 500 ppm @ 24.5°C presented as the mean and standard deviations of three measurements.
  • Figure 19 provides the results as in Figure 18 excluding the 2500 ppm HA preparation.
  • Figure 20 provides elasticity of HA-990 2500 ppm solution.
  • Figure 21 shows the results of several tests with turbulent flow of the HA-990 and PEO-1000 in a pipe.
  • Figure 22 depicts data represented in Tables 5 and 6.
  • Figure 23 depicts data represented in Tables 5 and 6.
  • Figure 25 depicts an image of a 10 ppm PEO-1000 sample in bovine RBC suspension in a microchannel.
  • Figure 26 depicts an image of a 10 ppm 9863 kDA HA sample in bovine RBC suspension in a microchannel.
  • Figure 27 depicts an image of a 10 ppm PEO WSR-301 sample in bovine RBC Suspension in a microchannel.
  • the present invention provides a unique and unexpected advantage that increased concentrations of an endogenously occurring material, relative to the naturally occurring level of such an endogenous material, can be used as a drag reducing polymer (DRP).
  • an endogenous material is hyaluronic acid (or physiologically acceptable salts thereof), hereinafter referred to as "HA".
  • HA provides the unique advantage that the physiology of the mammal that requires treatment can more readily accept an endogenous substance rather than a foreign material, such as a polyethylene oxide.
  • hyaluronic acid is known in the art and it should be understood, that the term “hyaluronic acid” includes hyaluronan.
  • Hyaluronic acid under physiological conditions, is converted into various forms, based on electrolytes and other physiological medium. Therefore, it should be understood that once the hyaluronic acid is placed in an electrolytic solution, it is more correctly known as hyaluronan.
  • HA is a carboxyl containing polysaccharide.
  • Carboxyl containing polysaccharides useful to treat the various diseases or conditions identified throughout the application are considered within the scope fo the present invention.
  • a carboxyl-containing polysaccharide is intended to mean a polysaccharide containing at least one carboxyl group.
  • the polysaccharide chosen may initially contain carboxyl groups or it may be derivatized to contain carboxyl groups.
  • Examples of carboxyl-containing polysaccharides include, but are not limited to, carboxymethyl cellulose, carboxymethyl chitin, carboxymethyl chitosan, carboxymethyl starch, alginic acid, pectin, carboxymethyl dextran, and glucosaminoglycans such as heparin, heparin sulfate, chondroitin sulfate and hyaluronic acid (HA).
  • the most preferred carboxyl-containing polysaccharides are carboxymethyl cellulose, carboxymethyl chitin and HA.
  • the most preferred carboxyl-containing polysaccharide is HA.
  • the compositions of the invention include a carboxyl-containing polysaccharide, or alternatively, a pharmacologically acceptable salt of the polysaccharide can be used, e.g., hyaluronan. Suitable pharmacologically acceptable salts are alkali or alkaline earth metal salts. Therefore, in one embodiment, the composition contains sodium hyaluronate.
  • Carboxyl-containing polysaccharides that can be used to prepare useful compositions of the invention are known compounds that are described, for example, in U.S. Pat. No. 4,517,295 and U.S. Pat. No. 4,141,973; and Handbook of Water Soluble Gums and Resins, Chapter 4, by Stelzer & Klug, published by McGraw-Hill, 1980. Processes for preparing the carboxyl-containing polysaccharide, HA, are illustrated in the Balazs patent, which details a procedure for extracting HA from rooster combs, and in U.S. Pat. No. 4,517,295 that describes fermentation process for making HA.
  • the HA used to make the DRP should be highly purified (medical grade quality) for in vivo applications.
  • physiologically acceptable salts thereof (of hyaluronic acid) is intended to include those derivatives wherein one or more of the acidic protons of the carboxylic acid groups of the hyaluronic acid moiety is substituted by a counterion. Suitable counterions include groups I, II, III and IV metals, ammonium complexes, amino acid complexes, etc.
  • the physiologically acceptable salt can include sodium, lithium, magnesium, potassium, ammonium ion and various amino acids as counterions.
  • the HA generally has a molecular weight of from low molecular weight oligosaccharides of HA to about 7,000 kD, in particular between about 500 kD and about 2000 kD, more particularly between about 600 kD and 1700 kD and in one embodiment about 1100 kD.
  • the HA is a sodium salt.
  • HA can be provided in the form of a pharmaceutical composition.
  • the pharmaceutical composition can be in the form of an injectable intravenous preparation, hi another aspect, the composition can be placed into an intravenous solution that is administered over a period of time, e.g., an iv drip.
  • the pharmaceutical composition can be an aqueous solution that includes sodium salt(s), i.e., sodium chloride, potassium salt(s), i.e., potassium chloride, calcium salt(s), i.e., calcium chloride, magnesium salt(s), such as magnesium chloride, sodium acetate, sodium citrate and/or sodium phosphate.
  • the solution can be a saline solution or PBS.
  • Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
  • Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles.
  • the compositions may also contain formulating agents, such as suspending, stabilizing and/or dispersing agent.
  • the formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.
  • the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use.
  • a suitable vehicle including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc.
  • the HA may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • the HA can be formulated as a depot preparation for administration by implantation, intravenous or intraperitoneal injection.
  • the HA may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
  • transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the HA for percutaneous absorption may be used.
  • permeation enhancers may be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described in for example, U.S. Patent No. 5,407,713.; U.S. Patent No.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the HA.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the HA and pharmaceutical compositions described herein can be administered to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated.
  • the compound(s) may be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • administration of HA to a patient suffering from bleeding due to wound, trauma or surgery ameliorates the effect of the loss of blood, possibly by improved peripheral tissue oxygenation and better waste removal from peripheral tissue.
  • Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized
  • the HA may be administered to a patient at risk of developing one of the previously described diseases. Alternatively, prophylactic administration may be applied to avoid the onset of symptoms in a patient diagnosed with the underlying disorder.
  • the amount of HA administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art. [055] Effective dosages may be estimated initially from in vitro assays.
  • an initial dosage for use in animals may be formulated to achieve a circulating blood or serum concentration of HA that is at or above an IC 50 of the HA as measured in as in vitro assay, such as those described in Kameneva, cited herein below, and those references cited therein.
  • Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the HA is well within the capabilities of skilled artisans.
  • the reader is referred to Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pagamonon Press, and the references cited therein.
  • Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well-known in the art.
  • Dosage amounts of the HA will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval may be adjusted individually to provide plasma levels of the HA which are sufficient to maintain therapeutic or prophylactic effect.
  • the HA may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician.
  • the HA will provide therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the HA may be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index.
  • the DRPs of the present invention can be used to increase aortic blood flow, increase arterial blood flow, increase venous blood flow, decrease blood pressure, decrease peripheral vascular resistance, diminish the development of atherosclerosis, and/or prevent lethality of hemorrhagic shock.
  • the DRPs are provided in therapeutically effective amounts.
  • the DRPs of the invention can be evaluated using standard methods in the art to determine the efficacy in the increase of aortic blood flow, increase arterial blood flow, increase capillary blood flow, increase venous blow flow, decrease blood pressure, decrease peripheral vascular resistance, diminish the development of atherosclerosis, and/or prevent lethality of hemorrhagic shock.
  • Suitable animal models are known as described by Kameneva et al. "Blood soluble drag-reducing polymers prevent lethality from hemorrhagic shock in acute animal experiments", Biorheology 41 (2004), 53-64, the contents of which are incorporated herein in their entirety, including the teachings of those references cited therein.
  • Figure 1 provides evidence that hyaluronate reduces hydrodynamic resistance to turbulent flow of an aqueous solution.
  • Hyaluronate (NaHy) with MW of 1,481,000 Da (HA-1500), compared to polyethylene oxide with molecular weight 2,000,000 Da (PEO-2000) [064]
  • Viscotek GPC analysis For all of the GPC tests the solvent was 0.1M NaNC ⁇ with 0.01% NaN3. The flow rate was 0.5 ml/min and the temperature was 30°C. [067] Viscosity Average Molecular Weight, Mv: 1 ,262,000 Da
  • HA-1500 and PEO-2000 solution viscosity was evaluated using several types of rheometers/viscometers.
  • Original HA-1500 solution (0.97% concentration) was diluted with saline to achieve the polymer concentrations of 2500, 1000, 500, 100 and 10 parts per million (ppm).
  • Commercial PEO with MW of 2000 IdD (Aldrich Chemical Co, #37,280-3) was used for this study.
  • the stock PEO-2000 solution was prepared at the concentration of 2500 ppm.
  • Figure 4 shows viscosity results for the HA-1500 and PEO-2000 solutions at the concentrations of 2500, 1000 and 500 ppm @ 24.5 0 C presented as the mean and standard deviations of three measurements.
  • Figure 5 enlarges Figure 4 excluding the 2500 ppm HA-1500 preparation to increase the scale.
  • Figure 8 shows the results of several tests with turbulent flow of the HA-1500 and PEO-2000 in a pipe.
  • the plot shows friction factor (Lambda) versus Reynolds number.
  • RBCs in a straight microchannel in laminar flow was studied using a circulating system consisting of a syringe pump, a pressure transducer, and a capillary tube with a diameter of 410 mm and length of 12.7 cm.
  • the RBC suspension in the syringe was kept well mixed using a small magnetic stirring bar placed inside the syringe and agitated by a magnet from outside, and the capillary was oriented in a vertical position in order to prevent RBC sedimentation on the walls.
  • Flow rates were varied from 0.5 to 2 ml/min. Pressure vs.
  • Table 2 shows the percentage of changes in the driving pressure for each flow rate after addition of HA- 1500 and PEO-2000 to the RBC suspension. Both polymers produced an increase in driving pressure at both concentrations.
  • Table 3 presents p-values for all of the experiments to test statistical significance of the difference with controls. Both polymers at both tested concentrations produced a statistically significant increase in the driving pressure after addition of the polymer to the flowing suspension of RBCs. Table 3 tTEST
  • Figure 10 shows the actual results of the microchannel studies.
  • Figures 11 through 15 show images obtained in these tests with a
  • both polymers showed a statistically significant increase in driving pressure which signified that even in this size of microchannels where a near-wall plasma layer was not well developed, these two polymers, HA-1500 and PEO-2000, changed distribution of RBCs across the tube at the studied concentrations. Both polymers showed the ability to affect flow of RBC suspension in a smaller microchannel (200 ⁇ m diameter) and thus the ability to change RBC distribution in microvessels.
  • HA-1500 demonstrated a slightly higher effect on the RBC flow behavior in this microchannel than PEO-2000. Based on in vitro studies, HAO has the potential to be efficient in improvement of microcirculation in animal models of hypoperfusion and other blood flow pathologies.
  • Hyaluronate (NaHy) with MW of 986,300 Da (HA-990), compared to polyethylene oxide with molecular weight 1,000,000 Da
  • Viscotek GPC analysis For all of the GPC tests the solvent was 0.1M NaNO3 with 0.01% NaN3. The flow rate was 0.5 ml/min and the temperature was 3O 0 C. [0116] Viscosity Average Molecular Weight, Mv: 922,000 Da
  • HA-990 and PEO-1000 solution viscosity was evaluated using several types of rheometers/viscometers.
  • Original HA-990 solution (0.95% concentration) was diluted with saline to achieve the polymer concentrations of 2500, 1000, 500, 100 and 10 parts per million (ppm).
  • Commercial PEO with MW of 1000 kD (Aldrich Chemical Co, #37,278-1) was used for this study.
  • the stock PEO-1000 solution was prepared at the concentration of 2500 ppm.
  • PEO-1000 at the concentrations of 2500, 1000, and 500 ppm measured @ 24.3 0 C are shown in Figure 16. Data represent mean and standard deviations of three measurements. The Brookfield rheometer did not allow for measuring HA-990 solution viscosity at the concentration of 2500 ppm at shear rates above 120 s "1 . [0135] At the same concentration of 2500 ppm, viscosity of the HA-990 solution is more than six times higher than viscosity of the PEO-1000 solution (both measured at the same shear rate of 99.99 s-1). Figure 17 shows the same results excluding the 2500 ppm HA preparation to reduce the scale. [0136] 3. Viscoelasticity.
  • Viscosity data obtained using the Vilastic rheometer are presented in Figure 18.
  • Figure 18 shows viscosity results for the HA and PEO solutions at the concentrations of 2500, 1000 and 500 ppm @ 24.5°C presented as the mean and standard deviations of three measurements. Once again, as was shown using a Brookfield rheometer, viscosity of HA-990 solution at the concentration of 2500 ppm is much higher than viscosity of the PEO-1000 solution (6.7 times at the shear rate -100 s "1 ).
  • Figure 19 shows the same results as in Figure 18 excluding the
  • the RBC suspension in the syringe was kept well mixed using a small magnetic stirring bar agitated by a magnet from outside, and the capillary was oriented in a vertical position in order to prevent RBC sedimentation on the walls.
  • Flow rates were varied from 0.5 to 2 ml/min.
  • Pressure vs. flow relationships were measured for each polymer at each concentration (10 ppm and 50 ppm), normalized to account for pressure change due to viscosity alone, and compared to the control RBC suspension in PBS with no polymer added. In such settings, an increase in pressure compared to control would indicate that the RBCs moved closer to the channel walls and near wall viscosity increased.
  • Table 5 shows the percentage of changes in the driving pressure for each flow rate after addition of HA-990 to the RBC suspension. HA produced a slight increase in pressure at both concentrations.
  • Table 6 shows pressure changes due to an addition of 10 and 50 ppm of PEO-1000 to a RBC suspension. The typical increase in driving pressure caused by effective drag- reducers at the studied flow conditions and concentrations was 20 — 30%.
  • Figures 22 and 23 show the actual results of the microchannel studies. There is no significant difference between flow of RBC suspensions with and without addition of HA-990 or PEO-1000at the all studied flow rates.
  • Figures 24 through 27 show images obtained in these test with a 10 ppm concentration of the additives specified. [0156] Only the positive control, obtained with an additive of the PEO
  • WSR-301 polymer that has much higher MW demonstrated a significant increase in the near-wall concentration of RBCs.
  • Control and PEO-1000 samples did not show any RBCs in the near- wall plasma layer.
  • a small amount of RBCs are present in the near-wall space in the RBC suspension with HA-990 added.
  • the data obtained in this study demonstrated that the HA-990 additive had much better drag-reduction efficiency at concentrations of 250 and 500 ppm than PEO-1000 at the same concentrations. It was found that HA-990 was very stable against mechanical stress. No mechanical degradation was observed after 5 hours of exposure to high flow shear stress which caused very fast total degradation of PEO-1000 (within 30 min).
  • Viscosity and elasticity of HA-990 were found to be much higher that those of PEO-1000 at the same concentrations, hi the capillary tube with diameter of 410 ⁇ m neither of the polymers shows a significant increase in driving pressure which signified that in this size of microchannels where a near-wall plasma layer was not well developed, these two polymers, HA-990 and PEO-1000, did not change distribution of RBCs across the tube at the studied concentrations, hi spite of notable drag-reducing activity at relatively high concentrations in solution, PEO- 1000 did not show the ability to affect flow of RBC suspension in a smaller microchannel (200 ⁇ m diameter) and thus the ability to change RBC distribution in microvessels.

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Abstract

L'invention concerne l'utilisation de l'acide hyaluronique et des sels physiologiquement acceptables de celui-ci comme agents destinés à réduire la résistance à l'écoulement. Les compositions de l'invention peuvent servir à accroître le flux sanguin aortique, à accroître le flux sanguin artériel, à accroître le flux sanguin veineux, à réduire la pression sanguine, à réduire la résistance vasculaire périphérique, à restreindre le développement de l'athérosclérose et/ou à prévenir la létalité du choc hémorragique.
EP06736388A 2005-02-28 2006-02-28 Acide hyaluronique soluble dans le sang et destine a reduire la resistance a l'ecoulement Withdrawn EP1858529A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US65711905P 2005-02-28 2005-02-28
US11/364,577 US20070032452A1 (en) 2005-02-28 2006-02-27 Blood soluble drag reducing hyaluronic acid
US11/364,566 US20070032451A1 (en) 2005-02-28 2006-02-27 Blood soluble drag reducing hyaluronic acid
PCT/US2006/007066 WO2006093957A2 (fr) 2005-02-28 2006-02-28 Acide hyaluronique soluble dans le sang et destine a reduire la resistance a l'ecoulement

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CN112972490B (zh) 2021-03-04 2022-02-18 中国人民解放军军事科学院军事医学研究院 透明质酸在用于制备预防或治疗铁死亡相关疾病的药物中的应用

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US5817642A (en) * 1991-07-03 1998-10-06 Hyal Pharmaceutical Corporation Clearing of atherosclerosis
US5585361A (en) * 1994-06-07 1996-12-17 Genzyme Corporation Methods for the inhibition of platelet adherence and aggregation
US5576072A (en) * 1995-02-01 1996-11-19 Schneider (Usa), Inc. Process for producing slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with at least one other, dissimilar polymer hydrogel

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