US20060088518A1 - Stable thrombin composition - Google Patents
Stable thrombin composition Download PDFInfo
- Publication number
- US20060088518A1 US20060088518A1 US11/251,566 US25156605A US2006088518A1 US 20060088518 A1 US20060088518 A1 US 20060088518A1 US 25156605 A US25156605 A US 25156605A US 2006088518 A1 US2006088518 A1 US 2006088518A1
- Authority
- US
- United States
- Prior art keywords
- thrombin
- composition according
- solution
- thrombin composition
- nanofiltration
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
-
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4833—Thrombin (3.4.21.5)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6429—Thrombin (3.4.21.5)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
Definitions
- This invention relates to a thrombin composition which is stable in solution for therapeutic use as a component of fibrin adhesives or for other haemostatic uses, which may be subjected to double nanofiltration in order to retain viruses, and which may be preserved in the lyophilised or frozen condition.
- Thrombin is a serine protease generated in circulating blood through the activation of its inactive precursor, prothrombin. It has a fundamental role in the coagulation process, splitting the fibrinogen molecule into fibrin monomers in order to form the fibrin coagulate, in order to maintain haemostasis. Thus thrombin has therapeutic applications as a local haemostatic agent and as a component of fibrin adhesives (compounds comprising mainly fibrinogen and thrombin as active ingredients).
- the thrombin in conventional use has been of animal origin (bovine or equine). These preparations have in many cases given rise to immunological reactions due to a heterologous protein overload.
- human thrombin has been purified from human plasma with significant degrees of purification, and more recently it has been possible to obtain human thrombin of recombinant origin on an industrial scale having an activity identical to that of thrombin of plasma origin [Biochem. (Tokyo) May 2004; 135(5):577-582] or of transgenic origin.
- Purified thrombin solutions of whatever origin give rise to stability problems both during the final stages of the production process and during storage for marketing (stability of the final product), and may suffer a significant loss of activity if not adequately stabilised.
- thrombin As a product of biological origin, thrombin must be subjected to specific stages to eliminate pathogenic agents associated with the starting material where it has its origin in plasma, or associated with the culture media in the case of recombinant products or the producing organisms in the case of transgenic products.
- the current trend is to include at least two supplementary virus elimination stages.
- the filtration of solutions through filters of a pore size capable of holding back viral particles is one method which has become widely used in recent years because it is a physical process which in principle has no potential capability to change the structure of the proteins and has an effective ability in eliminating viral load, depending upon the pore size used.
- This pore size is especially chosen for the spatial dimensions of the protein molecule which has to be filtered (which must pass through the filter).
- Filtration through 15 nm filters can guarantee a significant reduction in small naked viruses such as Hepatitis A virus and Parvovirus, which lie between 20 and 30 nm.
- the possibility of carrying out filtration in series using two 15 nm filters would increase the level of reduction in viral load and thus the level of safety with regard to these viruses. If this nanofiltration is carried out in a final stage, which avoids subsequent concentration operations and adjustment in the composition of the solution, it cancels out the possibility of accidental contamination of the nanofilter product.
- Patent ES 2108738 (Michalski), which describes a process for the preparation of thrombin, establishes a formulation combining gluconate buffer with 2 g/l of albumin, 5 g/l of saccharose and 60 mM of CaCl 2 , indicating that the albumin, saccharose and calcium are essential for stabilisation during handling in solution (24 hours stability), freezing and subsequent lyophilisation.
- the inventors have developed a thrombin formulation which is highly purified in the presence of human albumin and a neutral salt and possibly a solubilising agent and pH buffer.
- This formulation is nanofilterable, in series, through two filters of nominal pore size of up to 35 nm, and preferably 15 nanometers (nm), having a high filtration capacity and without any fall in product recovery or deterioration of the nanofiltered material, such that even the smallest viruses such as monodispersed porcine parvovirus (as a model of human B19) are retained to a level of more than log 4 (base 10).
- the nanofiltered material does not require subsequent treatment for adjustment of the formula or final composition, avoiding any risk of cross-contamination, the product obtained being sufficiently stable for subsequent processing, and is stored stably in a lyophilised or frozen state.
- the albumin acts as a stabiliser and preserves the activity of the thrombin during manipulation in the liquid state, in the process of nanofiltration, and during lyophilisation or freezing.
- the albumin has an effect as a pH buffer and imparts compactness to the lyophilised pellet.
- the neutral salt such as sodium chloride, is concerned, this acts to dissolve the thrombin and maintain the isotonicity of the solution, given that thrombin is very insoluble and precipitates out at a low ionic strength.
- pH damping effect and also the compacting and solubilisation of the lyophilisate can be complemented through the addition of a solubilising agent and/or pH buffer such as glycine, or sodium citrate or acetate.
- a solubilising agent and/or pH buffer such as glycine, or sodium citrate or acetate.
- the inventors have established that albumin concentrations in excess of 0.05% and the presence of sodium chloride are necessary.
- the sodium chloride concentration must be at least 0.05 molar, and better still if it is approximately isotonic or 0.15 molar.
- the thrombin solution can be doubly nanofiltered through filters of nominal pore size of up to 35 nm, and preferably 15 nm, with good productivity (up to 15 million IU of thrombin per m 2 of nanofiltration area, or even higher loading) without observing any significant loss of activity (thrombin recovery >90%).
- the nanofiltered material is sterilised using a 0.2 ⁇ m membrane and is aseptically metered into an appropriate container (vial, bottle, syringe, etc.) and frozen at ⁇ 18° C. for subsequent lyophilisation, or stored in the frozen state. In the latter case it is possible to adjust the formula through adding calcium chloride solution to the thrombin before freezing, without this affecting its stability.
- the thrombin solution purified by a method which gives rise to a product having specific activity characteristics equal to 1500 IU of thrombin/mg of protein or more and a potential of 500 IU of thrombin/ml or more is stabilised by adding and mixing with human albumin at a concentration of over 0.05% (w/v), and preferably between 0.1% and 1% (w/v) and sodium chloride at a concentration of 0.05 molar or higher and at a pH of between 5.0 and 8.5.
- This thrombin solution is treated using a double nanofiltration system up to a nominal pore size of up to 35 nm, and preferably 15 nm.
- the type of nanofilter used is marketed under the name Planova 15N® (from Asahi-Kasei) and has the configuration of a hollow fibre cartridge of regenerated cellulose with different filtration areas.
- Planova 15N® from Asahi-Kasei
- the nanofiltration capacity per filter may be greater than 30 l/m 2 , although in order to achieve efficient reduction of the smallest viruses (parvovirus) preferably not more than 30 litres of solution are applied per m 2 , more preferably between 5 and 30 l/m 2 .
- the nanofiltered liquid may have a nominal strength of approximately 500 IU/ml without additional handling given that it is already adjusted to the final formula, for either lyophilisation or subsequent freezing.
- amino acids such as glycine in a concentration of between 0.01 and 0.1 Molar
- salts of carboxylic acids such as sodium citrate or acetate at a concentration of, for example, 10 mM and calcium chloride or equivalent salts (normally between 20 and 60 mM).
- the resulting formulation continues to be nanofilterable and stable during this process.
- the product obtained is stable for a long period of time, both when lyophilised and when frozen.
- the lyophilised product may also be optionally subjected to viral inactivation through heat at high temperature with a short exposure time, for example between 90 and 115° C. for 0.5-8 hours, and preferably 1-2 hours at approximately 100° C.
- a purified thrombin composition whose formula comprises human albumin and a neutral salt such as sodium chloride, the resulting product being stable when stored either frozen or lyophilised.
- the thrombin is adjusted to a nominal strength of 500 IU of thrombin per ml of solution or more, and the human albumin is adjusted to a concentration of over 0.05% (w/v) and preferably between 0.1% and 1% (w/v).
- the sodium chloride concentration should be at least 0.05 molar, and better still if approximately isotonic or 0.15 molar.
- This thrombin composition can be filtered by double nanofiltration in series up to a nominal pore size of up to 35 nm and preferably 15 nm, it being possible to filter up to 30 litres of solution per m 2 of filtration area in each nanofilter.
- This lyophilised thrombin composition may be treated by dry heat for between a 1 ⁇ 2 hour and 8 hours at 90-115° C., and preferably for 1-2 hours at 100° C.
- a purified thrombin (lot T-1006) having a specific activity >1500 IU/mg of total protein was dialysed using 10 kDa ultrafiltration membranes against 5 volumes of a solution containing 75 mM of NaCl, 50 mM of glycine and 10 mM of sodium acetate at pH 6.5, finally being concentrated to 654 IU of thrombin/ml of solution. This was subsequently stabilised through the addition of up to 0.25% of human albumin (Albumina Grifols 20%)
- the solution stabilised in this way was frozen at ⁇ 20° C. to begin the nanofiltration tests.
- the effect of prior prefiltration (clarification) on double nanofiltration up to a 15 nm nominal pore size was investigated using regenerated cuprammonium cellulose nanofilters (Planova 15N®, from Asahi-Kasei).
- Plant 15N® regenerated cuprammonium cellulose nanofilters
- three aliquots of the stabilised solution were thawed in a water bath at 20 ⁇ 2° C. so that the final temperature of the product was between 2 and 8° C., the thrombin activity was between 591.0 and 614.5 IU/ml, and the total protein was between 2.54 and 2.80 mg/ml.
- the solutions were independently prefiltered using 3 types of filter of different pore size: 0.22 ⁇ m (PVDF, from Millipore), 0.1 ⁇ m (PVDF, from Pall Corp.) and 35 nm (regenerated cuprammonium cellulose, Planova 35N® from Asahi-Kasei); and subsequently by double 15 nm nanofiltration (2 ⁇ Planova 15N® from 0.001 m 2 ) simultaneously, performing a final post-wash with the equivalent of 20-28% of the initial volume of product.
- the viability of the process and the effect of prefiltration was tested with regard to the application ratio obtained (kg/m 2 ), the change or increase in the transmembrane pressure (TMP) during nanofiltration, total protein, thrombin activity and thrombin recovery.
- Formula A approximately 500 IU/ml of protein thrombin, 1% albumin, 10 mM sodium acetate and 75 mM sodium chloride
- Formula B approx. 500 IU/mL of thrombin, 2% mannitol, 10 mM histidine, 0.03% of PEG-3350 and 175 mM of sodium chloride.
- compositions were nanofiltered at 15 nm and the nanofiltered product was lyophilised in 10 ml vials, performing a final 24 hour drying at 37° C. under the maximum vacuum conditions of the equipment ( ⁇ 0.1 mbar), leaving a residual moisture content of less than 1%.
- the vials obtained were subjected to heat treatment at temperatures of 100° C., 105° C., 110° C. and 115° C., for periods of 1 ⁇ 2 h, 1 h, 2 h, 4 h and 8 h, with subsequent determination of the thrombin activity.
- results shown in the table above indicate the heat-protective effect of the albumin and show that it is possible to apply heat for up to approximately a maximum of 4 hours at a temperature of 100-105° C., 2 hours at 110° C. and 1 hour at 115° C. with a recovery of activity of 90 ⁇ 5% or higher.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/327,686 US9376674B2 (en) | 2004-10-22 | 2014-07-10 | Process to prepare a stable thrombin composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200402523 | 2004-10-22 | ||
ES200402523A ES2226587B1 (es) | 2004-10-22 | 2004-10-22 | Composicion de trombina estable. |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/327,686 Division US9376674B2 (en) | 2004-10-22 | 2014-07-10 | Process to prepare a stable thrombin composition |
Publications (1)
Publication Number | Publication Date |
---|---|
US20060088518A1 true US20060088518A1 (en) | 2006-04-27 |
Family
ID=34384852
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/251,566 Abandoned US20060088518A1 (en) | 2004-10-22 | 2005-10-13 | Stable thrombin composition |
US14/327,686 Active US9376674B2 (en) | 2004-10-22 | 2014-07-10 | Process to prepare a stable thrombin composition |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/327,686 Active US9376674B2 (en) | 2004-10-22 | 2014-07-10 | Process to prepare a stable thrombin composition |
Country Status (14)
Country | Link |
---|---|
US (2) | US20060088518A1 (es) |
EP (1) | EP1649867B8 (es) |
JP (1) | JP5105734B2 (es) |
AR (1) | AR051396A1 (es) |
AU (1) | AU2005225085B2 (es) |
BR (1) | BRPI0504445A (es) |
CA (1) | CA2523844C (es) |
ES (2) | ES2226587B1 (es) |
HU (1) | HUE052760T2 (es) |
MX (1) | MXPA05011283A (es) |
NZ (1) | NZ543084A (es) |
PL (1) | PL1649867T3 (es) |
PT (1) | PT1649867T (es) |
UY (1) | UY29172A1 (es) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090186395A1 (en) * | 2006-06-26 | 2009-07-23 | Israel Nur | Virus Removal by Nanofiltration |
US20140112901A1 (en) * | 2012-10-24 | 2014-04-24 | Orthovita, Inc. | Stable compositions containing thrombin and methods for preparation and use thereof |
US8940335B2 (en) | 2010-06-01 | 2015-01-27 | Baxter International Inc. | Process for making dry and stable hemostatic compositions |
US9084728B2 (en) | 2010-06-01 | 2015-07-21 | Baxter International Inc. | Process for making dry and stable hemostatic compositions |
US9408945B2 (en) | 2010-06-01 | 2016-08-09 | Baxter International Inc. | Process for making dry and stable hemostatic compositions |
US20160264954A1 (en) * | 2015-03-13 | 2016-09-15 | Vitrum Biologies Inc. | Method of stabilizing thrombin and composition thereof |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102014973A (zh) | 2008-02-29 | 2011-04-13 | 弗罗桑医疗设备公司 | 用于促进止血和/或伤口愈合的装置 |
CA2721335A1 (en) | 2008-04-16 | 2009-10-22 | Ryoichi Kawamura | Process for preparing bioabsorbable sheet preparation holding thrombin |
EP2822474B1 (en) | 2012-03-06 | 2018-05-02 | Ferrosan Medical Devices A/S | Pressurized container containing haemostatic paste |
BR112014030962A2 (pt) | 2012-06-12 | 2017-06-27 | Ferrosan Medical Devices As | métodos para preparação e para reconstituição de uma composição seca adequada para uso em hemostase e cicatrização de feridas, e, kit hemostático |
NZ708737A (en) * | 2012-12-03 | 2019-06-28 | Omrix Biopharmaceuticals Ltd | Thrombin solution and methods of use thereof |
US9212357B2 (en) | 2012-12-03 | 2015-12-15 | Omrix Biopharmaceuticals Ltd. | Thrombin solution and methods of use thereof |
US9724078B2 (en) | 2013-06-21 | 2017-08-08 | Ferrosan Medical Devices A/S | Vacuum expanded dry composition and syringe for retaining same |
EP3470094B1 (en) | 2013-12-11 | 2020-07-22 | Ferrosan Medical Devices A/S | Dry composition comprising an extrusion enhancer |
WO2016058612A1 (en) | 2014-10-13 | 2016-04-21 | Ferrosan Medical Devices A/S | Dry composition for use in haemostasis and wound healing |
WO2016102446A1 (en) | 2014-12-24 | 2016-06-30 | Ferrosan Medical Devices A/S | Syringe for retaining and mixing first and second substances |
WO2017005590A1 (en) | 2015-07-03 | 2017-01-12 | Ferrosan Medical Devices A/S | Syringe for mixing two components and for retaining a vacuum in a storage condition |
EP4321182A2 (en) | 2018-05-09 | 2024-02-14 | Ferrosan Medical Devices A/S | Method for preparing a haemostatic composition |
WO2023115427A1 (en) | 2021-12-23 | 2023-06-29 | Guangzhou Bioseal Biotech Co., Ltd. | Spray dried thrombin |
US20230210958A1 (en) | 2021-12-30 | 2023-07-06 | Baxter International Inc. | Fibrinogen and thrombin solutions for a fibrin sealant and fibrin sealant kit |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4696812A (en) * | 1985-10-28 | 1987-09-29 | Warner-Lambert Company | Thrombin preparations |
US4923815A (en) * | 1987-03-27 | 1990-05-08 | Green Cross Corporation | Process for heat treating thrombin |
US5304372A (en) * | 1991-07-18 | 1994-04-19 | Association Pour L'essor De La Transfusion Sanguine Dans La Region Du Nord | Process for preparing a human thrombin concentrate intended for therapeutic use |
US5476777A (en) * | 1991-12-31 | 1995-12-19 | Zymogenetics, Inc. | Methods for producing thrombin |
US5506127A (en) * | 1994-09-21 | 1996-04-09 | Proba; Zbigniew | Therapeutic grade thrombin produced by chromatography |
US5981254A (en) * | 1997-10-30 | 1999-11-09 | Haemacure Corporation | Process for producing thrombin from plasma |
US20010051154A1 (en) * | 2000-05-08 | 2001-12-13 | Aventis Behring Gmbh | Stabilized protein preparation and process for its preparation |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS5639782A (en) * | 1979-09-04 | 1981-04-15 | Dai Ichi Pure Chem Co Ltd | Stabilization of thrombin |
JPH0813750B2 (ja) | 1990-03-01 | 1996-02-14 | 持田製薬株式会社 | 経口用トロンビン製剤 |
GB9503750D0 (en) * | 1995-02-24 | 1995-04-12 | Common Services Agency | Thrombin preparation |
JPH10215875A (ja) * | 1997-02-06 | 1998-08-18 | Mitsubishi Chem Corp | 蛋白質の精製方法 |
EP1221479B1 (en) * | 1999-09-27 | 2006-11-22 | Sysmex Corporation | Method for stabilizing thrombin |
-
2004
- 2004-10-22 ES ES200402523A patent/ES2226587B1/es active Active
-
2005
- 2005-10-13 US US11/251,566 patent/US20060088518A1/en not_active Abandoned
- 2005-10-17 EP EP05380229.4A patent/EP1649867B8/en active Active
- 2005-10-17 HU HUE05380229A patent/HUE052760T2/hu unknown
- 2005-10-17 ES ES05380229T patent/ES2845143T3/es active Active
- 2005-10-17 PT PT53802294T patent/PT1649867T/pt unknown
- 2005-10-17 PL PL05380229T patent/PL1649867T3/pl unknown
- 2005-10-18 UY UY29172A patent/UY29172A1/es not_active Application Discontinuation
- 2005-10-19 CA CA2523844A patent/CA2523844C/en active Active
- 2005-10-19 AR ARP050104362A patent/AR051396A1/es not_active Application Discontinuation
- 2005-10-19 NZ NZ543084A patent/NZ543084A/en unknown
- 2005-10-20 MX MXPA05011283A patent/MXPA05011283A/es active IP Right Grant
- 2005-10-20 AU AU2005225085A patent/AU2005225085B2/en active Active
- 2005-10-21 BR BRPI0504445-6A patent/BRPI0504445A/pt not_active Application Discontinuation
- 2005-10-24 JP JP2005308548A patent/JP5105734B2/ja active Active
-
2014
- 2014-07-10 US US14/327,686 patent/US9376674B2/en active Active
Patent Citations (7)
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US4696812A (en) * | 1985-10-28 | 1987-09-29 | Warner-Lambert Company | Thrombin preparations |
US4923815A (en) * | 1987-03-27 | 1990-05-08 | Green Cross Corporation | Process for heat treating thrombin |
US5304372A (en) * | 1991-07-18 | 1994-04-19 | Association Pour L'essor De La Transfusion Sanguine Dans La Region Du Nord | Process for preparing a human thrombin concentrate intended for therapeutic use |
US5476777A (en) * | 1991-12-31 | 1995-12-19 | Zymogenetics, Inc. | Methods for producing thrombin |
US5506127A (en) * | 1994-09-21 | 1996-04-09 | Proba; Zbigniew | Therapeutic grade thrombin produced by chromatography |
US5981254A (en) * | 1997-10-30 | 1999-11-09 | Haemacure Corporation | Process for producing thrombin from plasma |
US20010051154A1 (en) * | 2000-05-08 | 2001-12-13 | Aventis Behring Gmbh | Stabilized protein preparation and process for its preparation |
Non-Patent Citations (1)
Title |
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Burnouf et al., "Nanofiltration of plasma-derived biopharmaceutical products". Haemophilia 9 :24-37 (2003). * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090186395A1 (en) * | 2006-06-26 | 2009-07-23 | Israel Nur | Virus Removal by Nanofiltration |
US8940335B2 (en) | 2010-06-01 | 2015-01-27 | Baxter International Inc. | Process for making dry and stable hemostatic compositions |
US9084728B2 (en) | 2010-06-01 | 2015-07-21 | Baxter International Inc. | Process for making dry and stable hemostatic compositions |
US9408945B2 (en) | 2010-06-01 | 2016-08-09 | Baxter International Inc. | Process for making dry and stable hemostatic compositions |
US10245348B2 (en) | 2010-06-01 | 2019-04-02 | Baxter International Inc. | Process for making dry and stable hemostatic compositions |
US10994045B2 (en) | 2010-06-01 | 2021-05-04 | Baxter International Inc. | Process for making dry and stable hemostatic compositions |
US20140112901A1 (en) * | 2012-10-24 | 2014-04-24 | Orthovita, Inc. | Stable compositions containing thrombin and methods for preparation and use thereof |
US9149529B2 (en) * | 2012-10-24 | 2015-10-06 | Orthovita, Inc. | Stable compositions containing thrombin and methods for preparation and use thereof |
US10124063B2 (en) | 2012-10-24 | 2018-11-13 | Orthovita, Inc. | Stable compositions containing thrombin and methods for preparation and use thereof |
US20160264954A1 (en) * | 2015-03-13 | 2016-09-15 | Vitrum Biologies Inc. | Method of stabilizing thrombin and composition thereof |
Also Published As
Publication number | Publication date |
---|---|
MXPA05011283A (es) | 2006-05-25 |
AU2005225085A1 (en) | 2006-05-11 |
AU2005225085B2 (en) | 2007-05-31 |
US20140322791A1 (en) | 2014-10-30 |
ES2845143T8 (es) | 2021-11-17 |
EP1649867A1 (en) | 2006-04-26 |
CA2523844C (en) | 2012-06-19 |
CA2523844A1 (en) | 2006-04-22 |
JP2006117678A (ja) | 2006-05-11 |
ES2845143T3 (es) | 2021-07-26 |
ES2226587A1 (es) | 2005-03-16 |
EP1649867B8 (en) | 2021-09-08 |
HUE052760T2 (hu) | 2021-05-28 |
JP5105734B2 (ja) | 2012-12-26 |
EP1649867B1 (en) | 2020-11-25 |
PL1649867T3 (pl) | 2021-06-14 |
BRPI0504445A (pt) | 2006-06-27 |
AR051396A1 (es) | 2007-01-10 |
ES2226587B1 (es) | 2005-12-16 |
UY29172A1 (es) | 2006-04-28 |
US9376674B2 (en) | 2016-06-28 |
NZ543084A (en) | 2007-03-30 |
PT1649867T (pt) | 2021-02-03 |
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