WO1989006538A1 - Procede de preparation d'une substance therapeutiquement active en particulier pour la cicatrisation et en geriatrie et composition therapeutique contenant une telle substance - Google Patents

Procede de preparation d'une substance therapeutiquement active en particulier pour la cicatrisation et en geriatrie et composition therapeutique contenant une telle substance Download PDF

Info

Publication number
WO1989006538A1
WO1989006538A1 PCT/AT1989/000003 AT8900003W WO8906538A1 WO 1989006538 A1 WO1989006538 A1 WO 1989006538A1 AT 8900003 W AT8900003 W AT 8900003W WO 8906538 A1 WO8906538 A1 WO 8906538A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
blood
papain
alcohol
carried out
Prior art date
Application number
PCT/AT1989/000003
Other languages
German (de)
English (en)
Inventor
Gerhard Hantich
Johanna Krenauer
Volker Eisenreich
Ernst Hesse
Original Assignee
Gebro Broschek Kg Pharmazeutische Fabrik
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gebro Broschek Kg Pharmazeutische Fabrik filed Critical Gebro Broschek Kg Pharmazeutische Fabrik
Publication of WO1989006538A1 publication Critical patent/WO1989006538A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the invention relates to a method for producing a therapeutically active substance, particularly for healing or for treatment in geriatrics, in which defined blood from warm-blooded mammals, in particular from young cattle or calves, undergoes enzymatic hydrolysis with papain subjected, filtered, the permeate concentrated and treated with alcohol, preferably ethanol.
  • Preparations usually consist of defibrinated, often also hemolyzed, blood from usually young slaughter animals, especially calves, young cattle or horses, in the usual way to free cell substances, minerals and / or protein and to concentrate the extracts as a whole or fractions thereof and to formulate as active ingredient preparations.
  • deproteinization or deproteinization takes place by heating or centrifuging or filtering, or else by the action of acids or alcohols and subsequent centrifugation and / or filtration of the precipitated proteins.
  • a deproteinization by heating and subsequent filtration with the aid of a membrane separation process is described in EP-A 95 170, the continuous membrane multi-stage ultrafiltration using membranes with a molecular exclusion limit of more than about 8000 daltons being used as part of the membrane separation process - Wise separation of the inorganic salts is carried out by electrodialysis with membranes with a permeability of up to about 300 daltons.
  • EP-A 140 134 describes a similar process for the production of a biologically active extract from organs of mammals and from cell cultures, in which the starting material is comminuted with digestion of the cells, rapidly heated to a temperature of 70 to 90 °, cooled, centrifuged, from the solution obtained by ultrafiltration, the substances with a molecular weight of more than 10,000 D are removed and the remaining solution is removed by electrodialysis, the salt ions.
  • Thymus, spleen, liver and other organs, as well as, are examples of the starting material for this * method
  • High-voltage electrophoresis, high-voltage dialysis, gel filtration, thin-layer chromatography or counter-current distribution can be separated into fractions, of which those with a UV maximum at 245 to 246 m ⁇ are used to isolate the active substance.
  • N of ## ## N of ##tren ⁇ ung made concentration or drying can occur for example by ultrafiltration or by spray drying.
  • Organs or body fluids from mammals are obtained in order
  • 25 r Glykosphi ⁇ golipide is of the following formula:
  • 1-5 animals are broken down by fermentation and / or subjected to a dialysis with water or alcohols after a fractional deprotection with aliphatic alcohols or acids to remove the higher molecular weight components. If necessary, the dialysate is freed from the organic solvents and gently concentrated.
  • DE-OS 2 349 186 proposes to add a physiologically usable acid addition salt of heptaminol- (6-amino-2-methylheptan-2-ol) to the preparation obtained according to DE-PS 1 076 888 above to potentiate the effect of the preparation.
  • the object of the invention is to avoid these disadvantages of the known methods, to eliminate the tendency to turbidity and to increase the yield and the effectiveness of the active ingredient with improved procedural economy.
  • papain hydrolysis be carried out on u-hemolyzed blood with activated papain at a pH of 6.5 to 7.4, that the reaction is then stopped by cooling, that up to 10,000 D for deproteinization and removal of papain is ultrafiltered, and then the essentially protein-free permeate is concentrated to 1/25 to 1/35, based on the blood used, and left to cool for at least 24 hours, mixed with alcohol, and ⁇ is finally filtered off.
  • the simplified process procedure is also advantageous since a hemolysis step is saved. This is to be understood in this way that in the course of the enzymatic hydrolysis with papain
  • I-CD hemolysis takes place, so that the two steps of hydrolysis and hemolysis take place in one.
  • a later addition of water to facilitate ultrafiltration or to thermally stop the reaction no longer results in significant hemolysis.
  • C5 known preparations has an increased wound healing effect.
  • a comparatively improved oxygen utilization is achieved.
  • cerebral blood flow and peripheral arterial blood flow are increased in comparison to known preparations.
  • the method according to the invention provides surprisingly high
  • ZLX booties based on the amount of blood used and is extremely economical in terms of process technology.
  • Another important advantage of the method according to the invention is that it is possible to standardize the clear-filtered mixture to the desired concentration, preferably by
  • defibrinated blood from slaughter animals in particular from calves or young cattle (Ms maximum 3 years) is preferably used as the starting material.
  • This blood is pre-digested with an activated papain solution. Hiebei becomes a preparatory
  • 3S Papai ⁇ get into the final active ingredient concentrate, the aqueous suspension is ultrafiltered. The concentrate is then mixed with cysteine solution, which activates the papain and uses it as an incubation solution. is applied.
  • the blood which may have been stored in frozen form and in this case is thawed beforehand, is heated to 35-42 ° C in the incubation kettle, the pH is adjusted to 6.5-7.4 with 1N HC1 and preferably approximately with the incubation solution Incubated for 14 to 18 h.
  • the completely incubated blood is mixed with fresh aqua dest.ad inject at a temperature of 0-10 ° C., whereby the enzymatic hydrolysis or pre-digestion is interrupted and the mass is diluted for the ultrafiltration.
  • the ultrafilter is usually prefiltered to protect it, in order to separate particles with a size of - 50 ⁇ m.
  • the - filtered concentrate is then mixed with about 2 1/2 times the volume of pre-cooled 96% ethanol and left in the cold, preferably at: cold room temperature (4-6 ° C). Instead of ethanol, methanol, propanol or butanol can also be used. After a standing time of at least 24 h, preferably about 48 h, X is filtered clear, which can be done with the help of a black band filter. The alcohol added for the precipitation is then distilled off in a Rotavapor. This usually leads to precipitation again, which is clear-filtered using black tape and glass fiber pre-filters.
  • SCI * at 50 ° C or by storing the solution in the refrigerator at 5 ° C can be reduced to a few days. If the ultrafiltration is only carried out after the alcohol precipitation, the positive effect on the shelf life can no longer be determined without clouding the active ingredient, despite the concentration mentioned above.
  • Comparative Product I A commercially available, protein and pyrogen-free product which is obtained from the blood of calves ready for slaughter.
  • Comparative Product II Another, commercially available product, 15 produced essentially by the process according to DE-PS 1076888.
  • Comparative Product III A product produced by the process according to DE-OS 1949 195. Method: Z ⁇ column: TSK 2000 SW , 0.75 x 60 cm.
  • FIG. 1 The results are shown in FIG. 1 in comparison to the measurement results of the product (IV) according to the invention.
  • the diagrams show the full absorption AFS (absorptio ⁇ fill scale) as a function of the retention time RT.
  • the comparative products I and II each show only a single main maximum with a retention time of 47.8 and 48.2 minutes, respectively. This corresponds to an approximate molecular weight of 350-400. 1 * same product I has one shoulder each with a retention time of
  • the preparation (IV) according to the invention differs significantly from UCC from the substances mentioned hitherto. It has three distinct maxi a, the first maximum being in a lower molecular weight range than in the previously mentioned preparations, namely approximately at MG 200. This is probably achieved by the additional ethanol precipitation. The other two maxima are 115 at MG ⁇ 150 and MG ⁇ 100. In addition, the preparation according to the invention shows no shoulders in the low-molecular range, but two in the higher-molecular range at MG 500 and MG 300.
  • Comparative preparation I covering preparation II comparative preparation m preparation IV according to the invention 3.blekula__ weight of the total substances detectable in the experiment
  • the product produced according to the invention was also tested in various test and examination series for its effectiveness in therapeutic terms. The exact test conditions will be given later.
  • the preparation When examining the effect of the preparation on the incorporation of 3 H-thymidine in DNA from human fibroblasts and liver cells, it was found that the preparation has a significantly stronger (5 to 10-fold) effect on the growth of both fibroblasts and compared to known products of liver cells.
  • the regenerating effect of the preparation produced according to the invention on human foreskin fibroblasts was examined, which were damaged by the withdrawal of fetal calf serum.
  • the preparation according to the invention while increasing the DNA synthesis, clearly has a regenerating effect on damaged human fibroblast cells and that the concentration ranges and the inhibition range are similar to known products.
  • human foreskin fibroblasts were mixed in the 8th 5 ' to 10th passage with variable amounts of the product according to the invention or the known comparative preparation I and the 3 H-thymidine incorporation in DNA was measured.
  • they were first allowed to grow to 1/2 to 2/3 confluence and then in artificial medium without the addition of fetal calf serum. an essential medium component, incubated for 6 to 9 hours. The medium was then changed to one which contained only small amounts of fetal calf serum and increasing amounts of the preparation according to the invention and 3 H-labeled thymidine or of the comparative preparation I. 5- This approach was incubated for 12 to 24 hours and the radioactivity vity in the DNA fraction determined after appropriate processing of the cells.
  • Fig. 2 of the accompanying drawing shows the results in diagram form, where the measurement curve for a product according to the invention is shown with full lines, that for the known comparative preparation I is shown with dashed lines.
  • the preparation additions are indicated • in microliters, on the ordinate the radioactive count. 5
  • the examination methodology corresponded to that of the fibroblast
  • SEGD heights eg partial activity of damaged fibroblasts or increase in cellular, mitochondrial oxygen consumption. These cell-activating effects can, for example, be regarded as desirable in the context of wound healing. On the other hand, the activation of neoplastic cells would be undesirable. Investigations showed that, in contrast to the known comparative preparation I, the preparation according to the invention reduced oxygen. 1 - need of tumor cells (mouse ascites tumor cells) not activated.
  • Comparative preparation I ampoules, commercial preparation (0.2 ml / chamber)
  • the new preparation is therefore also excellently suited for the symptomatic treatment of psychopathological side effects - cerebral vascular insufficiency.
  • the concentrate produced according to the invention can be processed for use in therapy according to methods known per se for injection solutions, tablets, dragees, wound ointments or gels.
  • Therapeutic preparations according to the invention which can be wound healing or geriatric preparations in particular, contain a concentrate, optionally after it has been dried, which was produced by the previously described method.
  • Papai pretreatment and activation Pretreatment of the papain is advisable in order to separate insoluble substances and to 1. To avoid that low molecular weight substances (MW - 10,000) from the Pa ⁇ pai ⁇ get into the active ingredient concentrate.
  • papayotin from Extract-Chemie / activity: 80 U / mg
  • centrifuged centrifuge: Sorvell 5 RC-3, rotor: HG-4L: 3,000 rpm. 20 min).
  • Prefiltration for ultrafiltration (the solution should be free of particles> 10 ⁇ m) via: black filter or round filter 595, glass fiber pre-filter (from Sartorius), 8 ⁇ m membrane filter (from Sartorius) Ultrafiltration: device Pellicon cassette system from M- llip ⁇ re N> EG: 10,000 0- sample volume after centrifugation and prefiltration - * 0.77 1 concentrate volume: 0.38 1 flow rate: 60 ml / min
  • Prefiltration particle size - 50 ⁇ m; device: Seitz plate filter 0: for 7 filter layers Seitz Supra 300.
  • the concentrate is diluted at - ⁇ 60 1 with 30 1 and filtered - 5: again down to - * -> - 20 - 25 1 retentate.
  • Total filtration volume 205 ⁇ - 2101. After 30, 100 and 2001 permeate, samples are taken to check the filter tightness using TCA precipitation (must be negative!).
  • Concentration in the evaporator The ultrafiltrate is concentrated as quickly as possible in the evaporator at 60 - 80 ° C to 3 - 4 1 final volume under vacuum.
  • the finished active ingredient concentrate is passed through a sterile filter (0.2 ⁇ m membrane filter, from Sartorius) and again through an ultrafilter (NMGG:
  • This active ingredient concentrate is the basis for the production of ampoules, infusion solutions, tablets, dragées, capsules, ointments, gels etc.
  • Preferred galenical forms are powders or granules which are filled into hard or soft gelatin capsules.
  • the mixture is filtered to a concentration of 50 ml and then to 1 Activation of the Papai ⁇ s with Cystei ⁇ solution (300 mg Cystei ⁇ in 151 ml ad) diluted to a total of 200 ml.
  • the ultrafiltrate is discarded.
  • the incubated blood is stirred in 10 l of pre-cooled distilled water.
  • the diluted blood is prefiltered for ultratiltration through a plate filter system for 7 filter layers and then filtered through an ultrafilter with a molecular weight limit of 10,000 daltons and immediately concentrated to 360 ml.
  • the substances which have precipitated out due to the concentration are separated off by filtration through a black band filter.
  • the protein-free filtrate is stirred into 900 ml of 10% pre-cooled ethanol 96% and left in the refrigerator at 7 ° C.
  • the protein-free test is carried out in a rapid test with trichloroacetic acid. After standing for at least 48 hours, the precipitates are filtered off and the alcohol is removed in a Rotavapor. 15
  • the product obtained in this way is diluted with sterile, pyrogen-free water to a dry substance content of 200 mg / ml and filled aseptically into sterile bottles. Analysis: pH 6.1
  • Example 2 50 l of calf blood are defibrinated at the slaughterhouse by stirring. The fibri flakes are filtered off through a sieve. The blood is processed immediately as in Example 1. -.-.- A ⁇ alyse ⁇ date ⁇ : pH 6.0
  • Example 10 '1 defibrinated fresh bovine blood is adjusted to pH 6.5 with HC1, incubated with 20 g of activated papain pretreated according to Example 1 at room temperature for 18 hours and then filtered undiluted ultra-5.
  • the protein-free ultrafiltrate is concentrated to 300 ml in a vacuum evaporator, mixed with 0.75 l of ethanol and then stored in the refrigerator for 24 hours.
  • the precipitate is separated off by centrifugation or filtration and the alcohol is evaporated off in a rotary evaporator.
  • the concentrate is adjusted with sterile, pyrogen-free water at 0 '200 mg dry matter / ml and dispensed into sterile bottles.
  • Example 5 The concentrate produced according to Examples 1 to 4 is injected with Aqua ad.
  • Example 6 The concentrate produced according to Examples 1 to 4 is injected with Aqua ad 0. adjusted to a dry matter content of 50-70 mg / ml and lyophilized. Tablets are made by 500.0 glyophilisier. Concentrate 1,987.5 g of methyl cellulose, 12.5 g of Mg stearate 25. Are mixed and compressed to 250 mg tablets. Since the lyophilized concentrate is extremely hygroscopic, the tableting must take place under dry: room air ( ⁇ 20% relative humidity). The cores are coated with a saliva-resistant, white film by 30U g spray solution consisting of: 30: 12.0 g Eudragit E 100 for 750 g cores
  • Example 7 1.25 1 of the concentrate prepared according to Examples 1 to 4 are made on 1 kg of granules consisting of 98% methyl cellulose and 2% gelatin, very long • sprayed on. The granules obtained in this way are subsequently dried at 60 ° C. in a drying cabinet with circulating air for at least 18 hours. After reaching a residual moisture of max. 0.5%, the granules are mixed with 0.5% Mg stearate and compressed to 250 mg tablets. & The tablets are coated as in Example 6.
  • Example 8 For the production of a wound gel with a dry substance content of the active ingredient concentrate of 8 mg / g gel prepared according to Examples 1 to 4, 1-0 1.75.0 g methyl cellulose 4,000 cps are used

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Le procédé de préparation d'une substance thérapeutiquement active, utilisable en particulier pour la cicatrisation ou le traitement de l'insuffisance cérébro-vasculaire utilise le sang défibriné de jeunes boeufs ou veaux, soumis à une hydrolyse enzymatique à la papaïne, à un pH compris entre 6, 5 et 7, 4. La réaction est stoppée par addition d'eau froide et est suivie d'une ultrafiltration à 10000 D. Ensuite, le filtrat est concentré et additionné d'alcool, soumis à un refroidissement pendant au moins 24 h puis filtré jusqu'à clarification. Les préparations obtenues ont une activité notablement améliorée pour la guérison des plaies et en gériatrie.
PCT/AT1989/000003 1988-01-13 1989-01-13 Procede de preparation d'une substance therapeutiquement active en particulier pour la cicatrisation et en geriatrie et composition therapeutique contenant une telle substance WO1989006538A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATA61/88 1988-01-13
AT0006188A AT392003B (de) 1988-01-13 1988-01-13 Verfahren zur herstellung eines insbesondere zur wundheilung oder zur behandlung in der geriatrie verwendbaren wirkstoffes aus saeugetierblut durch papainhydrolyse und ein einen solchen wirkstoff enthaltendes praeparat

Publications (1)

Publication Number Publication Date
WO1989006538A1 true WO1989006538A1 (fr) 1989-07-27

Family

ID=3480490

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AT1989/000003 WO1989006538A1 (fr) 1988-01-13 1989-01-13 Procede de preparation d'une substance therapeutiquement active en particulier pour la cicatrisation et en geriatrie et composition therapeutique contenant une telle substance

Country Status (4)

Country Link
EP (1) EP0396597A1 (fr)
JP (1) JPH03505200A (fr)
AT (1) AT392003B (fr)
WO (1) WO1989006538A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002067957A1 (fr) * 2001-02-28 2002-09-06 Biopure Corporation Utilisation de sang defibrine pour fabriquer un substitut sanguin a base d'hemoglobine
US7001715B2 (en) 2002-02-28 2006-02-21 Biopure Corporation Purification of red blood cells by separation and diafiltration
EP1640012A1 (fr) * 2004-09-24 2006-03-29 Salama, Zoser B. nat.rer.Dr. Agents pharmaceutiques comprenant des constituants du sang 10 kDa et l'utilisation dans la prophylaxe et dans le traitement des troubles du système immunitaire
WO2006032268A1 (fr) * 2004-09-24 2006-03-30 Salama Zoser B Produit pharmaceutique comprenant des produits sanguins et son utilisation comme produit a injecter ou a perfuser pour la prevention et le traitement de defauts du systeme immunitaire chez l'homme

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE553356A (fr) *
US2912359A (en) * 1955-05-04 1959-11-10 Developments Inc Wound healing agent obtained from blood and method of preparation
GB1288242A (fr) * 1968-11-02 1972-09-06
EP0038511A2 (fr) * 1980-04-17 1981-10-28 Rolf Dr. Schäfer Compositions pour guérir des blessures
EP0095170A2 (fr) * 1982-05-21 1983-11-30 Solco Basel AG Procédé d'obtention de substances actives stimulant la respiration cellulaire, à partir du sang de veaux
EP0140134A2 (fr) * 1983-10-05 1985-05-08 Solco Basel AG Procédé de préparation d'un extrait biologiquement actif

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1459501A (fr) * 1965-12-03 1966-11-18 Procédé d'élimination de la cytotoxicité d'un sérum thérapeutique
IT1135153B (it) * 1981-01-23 1986-08-20 Consiglio Nazionale Ricerche Processo per rendere incoagulabile il sangue mediante enzimi proteolitici e uso del sangue incoagulabile per produrre un concentrato proteico da sangue intero
US4511557A (en) * 1981-08-24 1985-04-16 Gauri Kailash Kumar Pharmaceutical composition

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE553356A (fr) *
US2912359A (en) * 1955-05-04 1959-11-10 Developments Inc Wound healing agent obtained from blood and method of preparation
GB1288242A (fr) * 1968-11-02 1972-09-06
EP0038511A2 (fr) * 1980-04-17 1981-10-28 Rolf Dr. Schäfer Compositions pour guérir des blessures
EP0095170A2 (fr) * 1982-05-21 1983-11-30 Solco Basel AG Procédé d'obtention de substances actives stimulant la respiration cellulaire, à partir du sang de veaux
EP0140134A2 (fr) * 1983-10-05 1985-05-08 Solco Basel AG Procédé de préparation d'un extrait biologiquement actif

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002067957A1 (fr) * 2001-02-28 2002-09-06 Biopure Corporation Utilisation de sang defibrine pour fabriquer un substitut sanguin a base d'hemoglobine
US6518010B2 (en) 2001-02-28 2003-02-11 Biopure Corporation Use of defibrinated blood for manufacture of a hemoglobin-based oxygen carrier
US6986984B2 (en) 2001-02-28 2006-01-17 Biopure Corporation Use of defibrinated blood for manufacture of a hemoglobin-based oxygen carrier
US7553613B2 (en) 2001-02-28 2009-06-30 Biopure Corporation Use of defibrinated blood for manufacture of hemoglobin-based oxygen carrier
US7001715B2 (en) 2002-02-28 2006-02-21 Biopure Corporation Purification of red blood cells by separation and diafiltration
EP1640012A1 (fr) * 2004-09-24 2006-03-29 Salama, Zoser B. nat.rer.Dr. Agents pharmaceutiques comprenant des constituants du sang 10 kDa et l'utilisation dans la prophylaxe et dans le traitement des troubles du système immunitaire
WO2006032268A1 (fr) * 2004-09-24 2006-03-30 Salama Zoser B Produit pharmaceutique comprenant des produits sanguins et son utilisation comme produit a injecter ou a perfuser pour la prevention et le traitement de defauts du systeme immunitaire chez l'homme

Also Published As

Publication number Publication date
JPH03505200A (ja) 1991-11-14
EP0396597A1 (fr) 1990-11-14
ATA6188A (de) 1990-07-15
AT392003B (de) 1991-01-10

Similar Documents

Publication Publication Date Title
DE3027105C2 (fr)
EP0140134B1 (fr) Procédé de préparation d'un extrait biologiquement actif
DE3402647A1 (de) Verfahren zur gewinnung von koloniestimulierendem faktor und kallikrein aus menschlichem urin
DE1949195A1 (de) Verfahren zur Herstellung deproteinisierter Bluextrakte mit Heilwirkung
EP0101063B1 (fr) Polypeptide ayant une activité sur le système immunitaire, procédé pour son isolement et sa purification, son application et composition le contenant
DE2645993C2 (fr)
CH702736B1 (de) Phospholipid-Emulsion, die Dihydroquerzetin beinhaltet.
EP0894094A1 (fr) Procede pour l'obtention d'um complexe de facteurs de croissance
DE3421789C2 (fr)
DE2459915B2 (de) Aktive Verbindung des Plasminogen-Typs, Verfahren zu ihrer Reinigung und ihre Verwendung
EP0145005A2 (fr) Tensio-actif pulmonaire, procédé de préparation et utilisation pharmaceutique
DE3306944C2 (fr)
AT392003B (de) Verfahren zur herstellung eines insbesondere zur wundheilung oder zur behandlung in der geriatrie verwendbaren wirkstoffes aus saeugetierblut durch papainhydrolyse und ein einen solchen wirkstoff enthaltendes praeparat
DE60311595T2 (de) Zusammensetzung zur behandlung von gastrointestinalen beschwerden
DE2732587C2 (fr)
DE2558537C2 (de) Verfahren zum Isolieren von Substanzen mit insulinähnlicher Wirksamkeit aus Blut oder Blutbestandteilen von Kälbern oder Schweinen
CN111920827B (zh) 促组织愈合的复方缓释纳米粒的制备方法
DE19726626C1 (de) Verfahren zur Herstellung eines eine Hyaluronidase enthaltenden Präparats
DE1617279C3 (de) Verfahren zur Herstellung eines die Aspergillopeptidase ARL 1 enthaltenden Präparates aus Aspergillus oryzae und sie enthaltendes Arzneimittel
CH640865A5 (de) Glykoproteid des menschlichen urins, verfahren zu seiner herstellung und mittel zur bekaempfung von leukozytopenie.
CH640244A5 (en) Biologically active substance
DE2246969C2 (de) Urokinase-Heparinat und dieses enthaltende Arzneimittel
EP0273121B1 (fr) Oligopeptides à partir du sang de boeuf
DE1802386C2 (de) Verfahren zur Gewinnung von cytobiotischen Globulinen
DE1095464B (de) Verfahren zur Herstellung eines Heilmittels zur Behandlung von Schizophrenie und anderen Geisteskrankheiten

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): DK FI JP NO US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1989901246

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1989901246

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1989901246

Country of ref document: EP