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WO2002083154A1 - Utilisation de derives cationiques du dextrane pour proteger les organes a limitation de dose - Google Patents

Utilisation de derives cationiques du dextrane pour proteger les organes a limitation de dose Download PDF

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Publication number
WO2002083154A1
WO2002083154A1 PCT/FI2002/000305 FI0200305W WO02083154A1 WO 2002083154 A1 WO2002083154 A1 WO 2002083154A1 FI 0200305 W FI0200305 W FI 0200305W WO 02083154 A1 WO02083154 A1 WO 02083154A1
Authority
WO
WIPO (PCT)
Prior art keywords
dextran
mol
cationic
substituents
positively charged
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.)
Ceased
Application number
PCT/FI2002/000305
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English (en)
Inventor
Anders Holmberg
Jukka Hiltunen
Giovanni Paganelli
Marta Cremonesi
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.)
Map Medical Technologies Oy
Original Assignee
Map Medical Technologies Oy
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 to SK1273-2003A priority Critical patent/SK12732003A3/sk
Priority to EEP200300502A priority patent/EE200300502A/xx
Priority to EP02714245A priority patent/EP1383517A1/fr
Priority to BR0208860-6A priority patent/BR0208860A/pt
Priority to KR10-2003-7013284A priority patent/KR20040018350A/ko
Priority to JP2002580956A priority patent/JP2004525181A/ja
Priority to CA002443052A priority patent/CA2443052A1/fr
Priority to HU0401386A priority patent/HUP0401386A3/hu
Priority to IL15815302A priority patent/IL158153A0/xx
Application filed by Map Medical Technologies Oy filed Critical Map Medical Technologies Oy
Publication of WO2002083154A1 publication Critical patent/WO2002083154A1/fr
Priority to NO20034561A priority patent/NO20034561L/no
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/716—Glucans
    • A61K31/721—Dextrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran

Definitions

  • the present invention is related to the use of cationic dextran derivatives for protecting dose-limiting organs especially kidneys during systemic treatment of cancer or other diseases. Also disclosed is a method for protecting dose-limiting organs in patients subjected to systemic therapy by administrating cationic dextran derivatives.
  • the cationic dextran derivatives not only protect the dose-limiting organs, but are better tolerated and have less side effects than conventionally used protective agents.
  • Systemic therapy refers to the intravenous infusion of therapeutic drugs.
  • Drugs in this context can be cytostatic pharmaceuticals, compounds carrying cytostatic pharmaceuticals, antibiotics, radionuclides or compounds carrying radionuclides. These drugs, including other therapeutically active chemicals are known to have substantial side effects on certain vital organs including kidneys.
  • the intensity of the systemic treatment i.e. the infused dose and its frequency, is limited by said dose-limiting organs.
  • Two important dose-limiting organs are kidneys and bone marrow. This means that for each drug or drug combination there is a maximum dose that these organs can tolerate. Above this dose maximum the organs are seriously and permanently damaged by side effects caused by the drug. This restricts the drug dose that can be used and the frequency of its administration. If the dose can be increased without damaging the organs, the probability of successful treatment increases.
  • cationic dextran derivatives that is dextran substituted with positively charged substitutents, particularly amino acid residues from a group consisting of lysine, arginine, histidine, ornithine and mixtures thereof.
  • the present invention provides the use of such cationic dextran derivatives for manufacturing medical compositions, including infusion solutions and injectable formulations for the protection of dose-limiting organs particularly kidneys during systemic therapy in treatment of cancer as well as other diseases.
  • the cationic dextran derivatives not only protect the dose-limiting organs, but are better tolerated and have minimal side effects compared to conventional protective agents.
  • the present invention provides cationic dextran derivatives for manufacturing medical compositions for protecting dose-limiting organs, such as kidneys and bone marrow during systemic therapy of certain diseases, particularly cancer.
  • the cationic dextran derivatives comprise dextran the sugar monomers of which are substituted with substituents having positively charged cationic side groups, preferably amino groups.
  • the dextran moiety has a molecular weight of 50 kDa or less, preferably a molecular weight between 10-50 kD, more preferably 20-40 kD.
  • the positively charged cationic side groups are selected from a group consisting of the positively charged amino acids such as lysine, arginine, histidine, ornithine and mixtures thereof.
  • a particularly useful substituent is lysine.
  • a substantially sufficient substitution degree is 0.05 - 25 mol cationic residues / mol dextran, preferably 0.5 - 20 mol cationic residues / mol dextran, most preferably 5 - 10 mol cationic residues / mol dextran. 10-25 mol cationic substituents / mol dextran being a particularly suitable range.
  • the present invention provides a method for protecting a subject from damages in dose-limiting organs caused by effects of radioactive or cytotoxic agents during systemic treatment.
  • the method comprises the administration of an effective amount of a cationic dextran derivative that is dextran provided with substituents having positively charged cationic side groups, to a subject in association with or before the administration of a chemotherapeutic, radioactive or immunosuppressive agent.
  • the present invention particularly provides a method of protecting a subject from renal damage caused by nephrotoxic effects of radioactive or cytotoxic agents during systemic treatment of cancer.
  • Said method comprises the administration of a kidney protecting amount of a cationic dextran derivative provided with a substituent having positively charged cationic side groups to the subject in association with or before the administration of a chemotherapeutic, radioactive or immunosuppressive agent.
  • the cationic dextran derivative is provided in an intravenously administrable dosage form or they are intravenously co-administrated or co-infused with the drugs used in the systemic therapy.
  • Figure 1A depicts whole body images showing the anterior (front) and exterior (back) of a patient 3 hours after infusion without renal protection.
  • Figure IB depicts whole body images showing the anterior (front) and exterior (back) of a patient 3 hours after infusion with renal protection.
  • Figure 2A depicts blood clearance and kidney uptake as demonstrated by a curve indicating the percentage injected activity in blood as a function of time in the same patient without renal protection (basal), with prior art protection (amino acid) and with lysine substituted dextran (dextran + Lysine).
  • Figure 2B depicts blood clearance and kidney uptake as demonstrated by a curve indicating the percentage injected activity in kidneys as a function of time in the same patient without renal protection (basal), with prior art protection (amino acid) and with lysine substituted dextran (dextran + Lysine).
  • systemic therapy means the medication including cytostatic agents, radioactive substances and/or immunosuppressants pertaining to or affecting the body as a whole e.g. via blood circulatory system.
  • Systemic therapy in cancer treatment refers to the intravenous infusion of therapeutic drugs.
  • Drugs in this context can be cytostatic pharmaceuticals, compounds carrying cytostatic pharmaceuticals, radionuclides or compounds carrying radionuclides.
  • the intensity of the systemic treatment, i.e. the infused dose and its frequency, is limited by so called dose-limiting organs.
  • dose-limiting organs refers to those organs e.g. the kidneys and bone marrow that are seriously and permanently damaged when a systemically administered drug is administered above a certain dose. This means that for each drug or drug combination there is a maximum dose that these organs can tolerate. This dose limits the efficacy of the drug, since a higher dose, which would be useful for treating the cancer or other disease is detrimental and not be used because it has toxic side effects on the sensitive organs.
  • kidney (nephro) protection means the protection of the sensitive organ, specifically protection against renal damage in a patient receiving systemic cancer therapy with potentially nephrotoxic drugs.
  • the protection is achieved by infusion of cationic dextran derivatives which provides the negatively charged kidney with a layer, which allows a smooth and rapid passage of the drug preventing uptake in kidneys, thus preventing nephrotoxicity.
  • extract is applied to polysaccharides, i.e. high-molecular-weight polymers of D-glucose, produced by glycosyltransferase on the cell surface of certain lactic acid bacteria growing on a sucrose substrate.
  • polysaccharides i.e. high-molecular-weight polymers of D-glucose
  • glycosyltransferase glycosyltransferase on the cell surface of certain lactic acid bacteria growing on a sucrose substrate.
  • Several organisms produce dextrans, but only Leuconostoc mesentroides and L. dextranicum have been used commercially.
  • the chemical and physical properties of the dextrans vary with the method of production. Native dextrans usually have a high molecular weight; lower molecular weight clinical dextrans are usually prepared by depolymerization and subsequent fractionation of the native dextrans.
  • the dextrans used for kidney protection preferably have a molecular weight, which is below the kidney filtration threshold for clinical dextrans, i.e. 50 kD or less. Dextrans with a molecular weight above 50 kD are not filtrated through the kidneys.
  • the molecular weight of the invention preferably varies between 10-50 kD. The average molecular weight being 40 kD. This means that the cationic dextran derivatives for kidney protection comprises on average 222 glucose monomers, the mean range being +50 glucose monomers.
  • cationic dextran derivatives means dextrans having the structure, properties and functions defined above for "dextrans", but which dextrans are substituted with positively charged side groups, such as amino groups, preferably amino acid residues.
  • the positively charged groups which preferably are amino acid residues, are selected from a group of amino acids including lysine, arginine, histidine, ornithine an mixtures thereof, but also other positively charged substituents can be used. Diaminated alkyl chains are examples of other such substituents.
  • the degree of substitution should be such that the positive charge of the cationic dextran derivatives is sufficiently high to be attracted by the negatively charged kidney, but not so high that it is permanently attached to the kidney and cannot be removed from the kidney.
  • a sufficient substitution degree is 0.05 - 25 mol substituents / mol dextran, more preferably 0.5 - 20 mol substituents / mol dextran, most preferably 5 - 10 mol substituents / mol dextran.
  • An optimal substitution degree is obtained when 10 - 25 mol substituents / mol dextran are coupled.
  • the cationic dextran derivatives of the present invention can be chemically substituted forming dextran derivatives including for example, alkylated, esterified, etherified or amidized forms with a low substitution degree.
  • dextran derivatives including for example, alkylated, esterified, etherified or amidized forms with a low substitution degree.
  • small molecule substituents having aminated methyl or ethyl groups as substituents should not disturb the protective properties and functions of the cationic dextran derivatives.
  • a cationic dextran polymer to which lysine was covalently linked showed a high kidney protection capacity and had no side effects.
  • dextrans substituted with cationic side groups preferably amino acids carrying positively charged side groups, particularly lysine-dextran conjugates can be used to protect kidneys when administering potentially nephrotoxic drugs.
  • the dosage of the drug could be increased by 25-30% because of the effective inhibition of the nephrotoxicity. This means that a significantly higher dose of the drug could be used.
  • said increased dosage of drug may provide the additional efficacy necessary for curative treatment of the disease e.g. cancer.
  • the present invention is based on studies, in which it has been demonstrated for the first time that infused dextrans, substituted with lysine or another positively charged side group, including amino acid residues such as arginine, histidine, ornithine and mixtures, covalently linked to the dextran via an amine bond, protect the kidneys during systemic therapy more effectively than commonly used nephroprotective agents, such as amino acid mixtures and positively charged proteins. Additionally, the cationic dextran derivatives show no significant side effects.
  • the substituted cationic dextran derivative of the present invention comprises dextrans or dextran derivatives substituted with residues having positively charged side groups, preferably amino acids, which are covalently coupled to the activated hydroxyl groups of the glucose monomers in the dextran chains either by ether, ester or amine bonds.
  • the substituted cationic dextran derivatives substituted with animated alkyl groups, lysine, histidine, arginine, ornithine or mixtures thereof, are cationic polymers having an overall positive effective charge, whereas kidney is charged negatively leading to an effective blocking of the toxic effects of the drugs.
  • the nephroprotective effect is believed to be obtained by the fact that the positively charged cationic dextran derivatives of the present invention are attracted (attached) to the negatively charged tissues of kidney and other dose-limiting organs and thereby allow the cytotoxic and radioactive agents as well as immunosuppressives to pass the kidneys thus preventing uptake of the drug through the proximal tubuli of the kidneys.
  • the uptake by the kidneys of radioactive and/or cytotoxic drugs higher doses can be used thus increasing treatment efficacy.
  • the cationic dextran derivatives are macromolecules they seem to block the uptake of drugs more effectively than monomers, such as conventionally used amino acids or amino acid mixtures used as such.
  • the positively charged acromolecule, preferably the cationic dextran derivatives blocks the negative charges of the proximal tubules tissue more effectively than amino acids per se.
  • the time a macromolecule blocks the drug uptake in kidneys is longer than that of a monomer. Since a smaller amount can be used due to the good binding capacity of the dextran derivatives less, if any side effects occur.
  • Intravenous administration of the cationic dextran derivatives of the present invention to patients subject to cytostatic treatment counteracts toxic renal damage resulting from cytostatic drugs or that resulting from immunosuppressive agents.
  • the dose of the cationic dextran derivatives of the present invention as well as the time of administration is optimized in such a way that the accumulation kinetics in the tumor and the elimination of the drug produces an optimal radiation dose relation between the tumor and the rest of the organism.
  • the use of the present invention is preferably aimed at renally healthy patients who are at risk of being subjected to renal damage due to systemic treatment of another ailment with cytostatic pharmaceuticals, compounds carrying cytostatic pharmaceuticals, radionuclides or compounds carrying radionuclides.
  • the composition is specifically directed to block toxic effect of said cytostatic pharmaceutical compounds used in systemic therapy.
  • the charge of the polydisperse macromolecule is highly affected by the media in which the macromolecule of interest is situated. Said media dependent so called effective surface charge can deviate remarkably from the theoretical electric charge of the molecule based on the amount of dissociated groups. Said deviation is especially remarkable in a physiological medium, for example, in a human being, injected with said drug.
  • the evaluation of the effective surface charge is carried out with a multitude of different test systems, e.g. measuring of zeta-potentials. According to the generally accepted opinion, methods based on electrophoresis give the values, which best describe the actual situation.
  • the effective surface charge can be determined exactly with test system based on convective electrophoresis.
  • the cationic dextran derivatives of the present invention can be purified with conventional methods including chromatography and ultrafiltration.
  • the cationic dextran derivatives of the present invention comprise less than 20 % (w/w), preferably 5-15 % (w/w), more preferably 15-20 % (w/w), most preferably 20 % (w/w) of substituents or residues, preferably amino acid residues.
  • the charged substituents or residues are bound to 15-30 % of the glucose monomers of said dextran.
  • the compounds according to the invention in the basic form or in combination with pharmaceutically acceptable additives, carriers, adjuvants, etc. are valuable protective agents for dose-limiting organs and particularly valuable nephroprotective agents.
  • the cationic dextran derivatives of the present invention can be provided in free form or as salts.
  • Salts include salts formed from acid, e.g. organic acids, polymeric acids or inorganic acids, of which hydrochlorides and acetates are examples and forms of salts, which are formed from carboxylic groups or sulfonic acids.
  • kidney protective efficacy of the cationic dextran derivatives of the present invention can be demonstrated in patients with somatostatin receptor positive tumors.
  • the systemic therapy can be carried out by administering the cationic dextrans of the present invention before or simultaneously with the radioactive drug intravenously or by other suitable means of administration.
  • Kidney dose reduction after infusion of the protective agents can be evaluated by different means, including Medical Internal Radiation Dose (MIRD) formalism, followed by intrapatient analysis.
  • MIRD Medical Internal Radiation Dose
  • DxL dextran-lysine
  • LAL arginine-lysine
  • Mbq lHlndotatoc was administered intravenously (i.v).
  • Whole body images were acquired at 30 min, 3, 16, 24 and 48 h post injection.
  • Pharmacokinetics was determined by collecting blood and urine samples up to 50 h post injection.
  • Kidney dose reduction after infusion of the protective agents was evaluated by Medical Internal Radiation Dose (MIRD) formalism with an intrapatient analysis.
  • MIRD Medical Internal Radiation Dose
  • the mean kidney absorbed dose was reduced ca. 31 ⁇ 25% with the conventional lysine- arginine (LA) mixture, ca. 50+ 13 % with the positively charged protein (caP) more than 50 ⁇ 24% with dextran-lysine compound (DxL). No relevant differences were found in blood clearance with or without Cationic-Dextran. Urinary excretion curves were similar, except for a slight faster (10%) rate within the first few hours after injection with a cationic dextran derivative (DxL). Apart from kidney uptake, the biodistribution in other organs was not significantly modified. Time-activity curves for kidneys showed the same trend with and without protection, but with a lower uptake as demonstrated by percentage injected activity (%IA) at all time points.
  • %IA percentage injected activity
  • Figures 1A-1B and 2A-2B The results are also shown in Figures 1A-1B and 2A-2B.
  • Figure 1 whole body images in anterior (from the front) and posterior (from the back) views of the same patient 3 h after injection are shown.
  • 1A shows images without renal protection
  • IB shows images with renal protection using dextran-lysine (DxL).
  • Figure IB shows reduced doses of kidney absorption and higher activities in the bladder.
  • blood clearance and kidney uptake without renal protection (basal), with amino acids protection and with DxL protection are shown for the same patient.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne l'utilisation de dérivés cationiques du dextrane avec des substituants comprenant des groupes latéraux chargés positivement comme agents de protection destinés aux organes à limitation de dose dans le traitement systémique de maladies telles que le cancer. Ces dérivés cationiques du dextrane sont particulièrement utiles comme agents nephroprotecteurs chez un sujet soumis à un traitement systémique avec des agents pharmaceutiques cytostatiques, des composés renfermant des agents pharmaceutiques cytostatiques, des radionucléides ou des composés renfermant des radionucléides contre les lésions rénales. Ces dérivés cationiques du dextrane ne protègent pas uniquement les organes à limitation de dose, mais sont également mieux tolérés et entraînent moins d'effets secondaires que les agents de protection couramment utilisés.
PCT/FI2002/000305 2001-04-11 2002-04-11 Utilisation de derives cationiques du dextrane pour proteger les organes a limitation de dose Ceased WO2002083154A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
HU0401386A HUP0401386A3 (en) 2001-04-11 2002-04-11 Use of cationic dextran derivatives for preparation of pharmaceutical compositions protecting dose-limiting organs
EEP200300502A EE200300502A (et) 2001-04-11 2002-04-11 Katioonsete dekstraani derivaatide kasutamine annust piiravate elundite kaitsmiseks
EP02714245A EP1383517A1 (fr) 2001-04-11 2002-04-11 Utilisation de derives cationiques du dextrane pour proteger les organes a limitation de dose
BR0208860-6A BR0208860A (pt) 2001-04-11 2002-04-11 Uso de um derivado de dextrano catiÈnico, método para a proteção de um indivìduo contra o dano em órgãos com limitação de dose, e, método para a proteção de um indivìduo contra dano renal
KR10-2003-7013284A KR20040018350A (ko) 2001-04-11 2002-04-11 용량-제한 장기들의 보호를 위한 양이온성 덱스트란유도체의 용도
SK1273-2003A SK12732003A3 (sk) 2001-04-11 2002-04-11 Použitie katiónaktívnych derivátov dextránu ako protektívnych prostriedkov orgánov obmedzujúcich dávku
CA002443052A CA2443052A1 (fr) 2001-04-11 2002-04-11 Utilisation de derives cationiques du dextrane pour proteger les organes a limitation de dose
JP2002580956A JP2004525181A (ja) 2001-04-11 2002-04-11 用量制限臓器を保護するためのカチオン性デキストラン誘導体の使用方法。
IL15815302A IL158153A0 (en) 2001-04-11 2002-04-11 Use of cationic dextran derivatives for protecting dose-limiting organs
NO20034561A NO20034561L (no) 2001-04-11 2003-10-10 Anvendelse av kationiske dekstranderivater for beskyttelse av dosebegrensende organer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI20010764 2001-04-11
FI20010764A FI20010764A0 (fi) 2001-04-11 2001-04-11 Kationiset dekstraanijohdannaiset käytettäväksi munuaisten suojaamiseen

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WO2002083154A1 true WO2002083154A1 (fr) 2002-10-24

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PCT/FI2002/000305 Ceased WO2002083154A1 (fr) 2001-04-11 2002-04-11 Utilisation de derives cationiques du dextrane pour proteger les organes a limitation de dose

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EP (1) EP1383517A1 (fr)
JP (1) JP2004525181A (fr)
KR (1) KR20040018350A (fr)
BR (1) BR0208860A (fr)
CA (1) CA2443052A1 (fr)
EE (1) EE200300502A (fr)
FI (1) FI20010764A0 (fr)
HU (1) HUP0401386A3 (fr)
IL (1) IL158153A0 (fr)
NO (1) NO20034561L (fr)
PL (1) PL363024A1 (fr)
RU (1) RU2003132683A (fr)
WO (1) WO2002083154A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8685458B2 (en) 2009-03-05 2014-04-01 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
US9084944B2 (en) 2010-09-03 2015-07-21 Bend Research, Inc. Spray-drying apparatus and methods of using the same
US9084976B2 (en) 2010-09-03 2015-07-21 Bend Research, Inc. Spray-drying apparatus and methods of using the same
US9248584B2 (en) 2010-09-24 2016-02-02 Bend Research, Inc. High-temperature spray drying process and apparatus
DE102014016901A1 (de) * 2014-09-17 2016-03-17 Friedrich-Schiller-Universität Jena Neue Dextranderivate als Wirkstoffträgersystem
US9724664B2 (en) 2009-03-27 2017-08-08 Bend Research, Inc. Spray-drying process
CN110023755A (zh) * 2016-12-01 2019-07-16 诺伯特·格雷茨 用于组织结构的可视化的装置和方法
CN115003311A (zh) * 2019-12-14 2022-09-02 乔杜里·马努 降低多器官毒性的多元药物制剂

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DE3414491A1 (de) * 1984-04-17 1985-10-24 Hans Dr. 8202 Bad Aibling Dietl L-aminosaeurengemische fuer die parenterale und orale anwendung bei nierenerkrankungen
US5290538A (en) * 1988-12-22 1994-03-01 Skrezek Christian Nephro protective infusion solutions
WO2000021571A1 (fr) * 1998-10-13 2000-04-20 Map Ab Ciblage tumoral par echange d'ions
WO2001005383A2 (fr) * 1999-07-16 2001-01-25 Mallinckrodt, Inc. Inhibition de l'absorption renale de molecules pouvant potentiellement endommager les reins

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3414491A1 (de) * 1984-04-17 1985-10-24 Hans Dr. 8202 Bad Aibling Dietl L-aminosaeurengemische fuer die parenterale und orale anwendung bei nierenerkrankungen
US5290538A (en) * 1988-12-22 1994-03-01 Skrezek Christian Nephro protective infusion solutions
WO2000021571A1 (fr) * 1998-10-13 2000-04-20 Map Ab Ciblage tumoral par echange d'ions
WO2001005383A2 (fr) * 1999-07-16 2001-01-25 Mallinckrodt, Inc. Inhibition de l'absorption renale de molecules pouvant potentiellement endommager les reins

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9757464B2 (en) 2009-03-05 2017-09-12 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US8685458B2 (en) 2009-03-05 2014-04-01 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
US10675602B2 (en) 2009-03-27 2020-06-09 Bend Research, Inc. Spray-drying process
US10300443B2 (en) 2009-03-27 2019-05-28 Bend Research, Inc. Spray-drying process
US9724664B2 (en) 2009-03-27 2017-08-08 Bend Research, Inc. Spray-drying process
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
US9084944B2 (en) 2010-09-03 2015-07-21 Bend Research, Inc. Spray-drying apparatus and methods of using the same
US9084976B2 (en) 2010-09-03 2015-07-21 Bend Research, Inc. Spray-drying apparatus and methods of using the same
US9205345B2 (en) 2010-09-03 2015-12-08 Bend Research, Inc. Spray-drying apparatus and methods of using the same
US9358478B2 (en) 2010-09-03 2016-06-07 Bend Research, Inc. Spray-drying apparatus and methods of using the same
US9248584B2 (en) 2010-09-24 2016-02-02 Bend Research, Inc. High-temperature spray drying process and apparatus
US9084727B2 (en) 2011-05-10 2015-07-21 Bend Research, Inc. Methods and compositions for maintaining active agents in intra-articular spaces
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
DE102014016901A1 (de) * 2014-09-17 2016-03-17 Friedrich-Schiller-Universität Jena Neue Dextranderivate als Wirkstoffträgersystem
DE102014016901B4 (de) 2014-09-17 2021-08-12 Friedrich-Schiller-Universität Jena Verfahren zur Herstellung für neue Dextranderivate als Wirkstoffträgersystem und deren Verwendung
CN110023755A (zh) * 2016-12-01 2019-07-16 诺伯特·格雷茨 用于组织结构的可视化的装置和方法
CN115003311A (zh) * 2019-12-14 2022-09-02 乔杜里·马努 降低多器官毒性的多元药物制剂
EP4072563A4 (fr) * 2019-12-14 2024-01-24 Manu Chaudhary Formulations de médicaments polybasiques pour réduire la toxicité d'organes multiples
CN115003311B (zh) * 2019-12-14 2024-04-19 乔杜里·马努 降低多器官毒性的多元药物制剂

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HUP0401386A3 (en) 2005-06-28
FI20010764A0 (fi) 2001-04-11
EE200300502A (et) 2003-12-15
CA2443052A1 (fr) 2002-10-24
KR20040018350A (ko) 2004-03-03
NO20034561L (no) 2003-12-09
HUP0401386A2 (hu) 2004-12-28
JP2004525181A (ja) 2004-08-19
IL158153A0 (en) 2004-03-28
EP1383517A1 (fr) 2004-01-28
NO20034561D0 (no) 2003-10-10
BR0208860A (pt) 2004-10-19
PL363024A1 (en) 2004-11-15

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