US20070161122A1 - Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same - Google Patents
Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same Download PDFInfo
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- US20070161122A1 US20070161122A1 US10/589,825 US58982505A US2007161122A1 US 20070161122 A1 US20070161122 A1 US 20070161122A1 US 58982505 A US58982505 A US 58982505A US 2007161122 A1 US2007161122 A1 US 2007161122A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
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- 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
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/34—Extraction; Separation; Purification by filtration, ultrafiltration or reverse osmosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to an albumin purification method comprising a nanofiltration step, a solution and a composition for therapeutic use containing the same, obtainable by the method of the invention.
- Albumin is a major protein of human or animal blood plasma. Clinical use of albumin, as an active ingredient, requires its extraction and purification, which is traditionally carried out by known methods, such as those of Cohn et al. (J. Am. Chem. Soc., 68, 459, 1946) and Kistler et al. (Vox Sang., 7, 1962, 414-424) which are additionally applicable to an industrial scale.
- Albumin requirements amount to about 100-300 kg per million inhabitants according to country; for that reason, it is necessary, for clinical purposes, to provide an albumin free from pathogenic viruses and contaminants, which are sources of diseases.
- transfusion-transmissible viruses safety is ensured by viral inactivation methods such as liquid-state pasteurisation of an albumin composition at 60° C. for 10 hours in the presence of a biologically compatible stabiliser (sodium caprylate and/or tryptophanate) .
- a biologically compatible stabiliser sodium caprylate and/or tryptophanate
- recombinant albumin In order to avoid the risk of transmissible infectious agents being present, it has been suggested to produce a so-called “recombinant” albumin, according to U.S. Pat. No. 6,210,683: the gene of albumin is introduced s into a host cell, yeast or bacterium, having a high proliferation potential. In turn, this host cell produces albumin in the culture medium or its cytoplasm. This albumin is then separated from the cells by extraction and purified. However, the presence of host cell proteins is often detected and the purification methods must therefore have a very high resolution, which is generally detrimental to the yield. The production cost of a recombinant albumin may then prove to be too high in comparison to that of an albumin generated from plasma.
- a solution consists of adjusting the physicochemical parameters influencing the recovery yield of solutes, while avoiding the passage of contaminants through the filter. Varying these parameters—such as ionic strength, the nature of the solute to be filtered and the pH of the solution to be filtered—as well as the working conditions of the filtration—such as flow rate and pressure—has been the subject of many studies. For instance, the scientific publications by C. Wallis et al., Ann. Rev. Microbiol., 33, p. 413-437, 1979 and S. Jacob, Methods of Biochemical Analysis, 22, p. 307-350, 1974, show that the effect of each parameter can individually result in increased or decreased efficiency of virus retention and recovery yield of solutes, and that combining several parameters does not systematically favour a synergy of the effects of improvement of the filtration conditions.
- the object of the present invention is to provide a solution corresponding to a good compromise between two criteria, the retention efficiency of viruses and/or other macromolecules likely to induce diseases or side effects in patients, and the recovery yield of albumin, the relative importance of these two criteria depending on the desired application.
- the invention relates to a method for purifying albumin comprising a step of submitting an aqueous solution of albumin, with a concentration of 15 g/L to 80 g/L and a pH not lower than 7, to a nanofiltration in a temperature range of 15° C. to 55° C.
- the Applicant surprisingly found that using a judicious combination of pH, albumin concentration and temperature (and consequently viscosity) values, in the aqueous albumin solution submitted to the nanofiltration step, makes it possible to reach an efficient optimisation of the albumin recovery yield, and rates of reduction of viruses and other undesirable macromolecules higher than the limits set by the control authorities (4 log). It has been brought to light that a nanofiltration carried out under the conditions of the invention makes it possible to filter amounts higher than 5 kg albumin per m 2 filter, thus defining the protein load, while optimising the duration of the operation and the filtrate flow rate.
- the nanofiltered albumin solutions show a very high degree of safety in respect of particulate contaminants with a size of e.g.
- aqueous albumin solutions are also an intermediate product capable of being processed into pharmaceutical formulations for clinical use (see further on).
- the aqueous albumin solutions are solutions free from any reagent employed during various classical steps of albumin manufacture or purification, such as e.g. polyethyleneglycol (PEG), ethanol, organic salts (sodium caprylate, etc.) and inorganic salts.
- PEG polyethyleneglycol
- organic salts sodium caprylate, etc.
- inorganic salts such as sodium caprylate, etc.
- these various reagents are removed from the albumin solution by known processes, such as diafiltration, ultrafiltration, dialysis, etc.
- the presence of such reagents, or variations in their respective concentrations from one sample to another can result in unfavourable efficiencies in terms of virus retention and albumin recovery.
- the Applicant has further found that a decreasing ionic strength is correlated with a better viral reduction.
- the aqueous albumin solutions submitted to the nanofiltration may have an ionic strength lower than a maximum threshold connected, in this case, with the maximum allowable basic pH value. This value typically corresponds to about 11.5.
- the pH must be controlled in particular so that the variation in ionic strength caused by the addition of a pH control agent to the aqueous albumin solution is only very small, if not insignificant.
- pH controllers will preferably be selected among strong alkali metal bases such as NaOH and KOH, and among strong acids such as HCl, while respecting the above-mentioned criteria. Furthermore, it is preferable to avoid pH controllers based on organic compounds, such as organic bases.
- the method of the invention may be implemented with is all types of frontal or tangential nanofiltration devices, in particular frontal nanofiltration devices, known to those skilled in the art.
- frontal nanofiltration devices in particular frontal nanofiltration devices, known to those skilled in the art.
- filters have pore sizes smaller than 100 nm.
- the nanofiltration step according to the invention is preferably carried out on qualified filters having porosities of at least 13 nm, for example the nanometric filters with porosities of 15 ⁇ 2 or 20 ⁇ 2 nm which are commercially available as pleated membranes, flat membranes or hollow fibres.
- Regenerated cellulose nanofilters such as PLANOVA® having a porosities of 15 nm and surface areas of 0.01 m 2 (from Asahi, Japan), or PALL virus filters (U.S.A.) with porosities of 20 or 50 nm, may be mentioned by way of example.
- albumin starting material freeze-dried pure product, concentrate, etc.
- Any source of albumin starting material may be used, in particular those resulting from the fractionation of human or animal blood plasma according to the methods of Cohn et al. (J. Am. Chem. Soc., 68, 459, 1946) or Kistler et al. (Vox Sang., 7, 1962, 414-424).
- the pH of the aqueous albumin solution is preferably in the range from about 7.8 to about 11.5, and more preferably, from 9 to 10.5. Albumin is irreversibly altered by pH values higher than approximately 11.5.
- the method of the invention is preferably implemented with aqueous albumin solutions having concentrations in the range of 40 to 60 g/L and in a temperature range of 30 to 55° C.
- the method may further comprise a step of adding a pharmaceutically acceptable salt or salt mixture to the aqueous albumin solution to provide a solution with an ionic strength higher than 0.0032, and preferably, in the range of 0.01to 0.55, more preferably, of 0.01 to 0.3, even more preferably, of 0.05 to 0.15, and in particular, of 0.1 to 0.13.
- Alkali metal salts are preferably used, in particular sodium chloride present in an amount imparting to the albumin solution an ionic strength of 0.15.
- albumin may be suitably used as starting material, its origin may be a factor affecting the nanofiltration yield, depending on whether it contains thermal stabilisers or was heat-treated (thermal shock or pasteurisation).
- thermal stabilisers thermal stabilisers or was heat-treated (thermal shock or pasteurisation).
- using an albumin obtained by ethanol extraction according to Cohn et al. or Kistler et al. as mentioned above, and purified by ion-exchange or affinity chromatography can result in an increased albumin recovery and/or a reduced filtration duration.
- the nanofiltration of the aqueous albumin solution can be carried out in two successive steps on two filters with decreasing porosities, respectively.
- these two successive steps are carried out on filters with porosities of 23 to 50 nm and 15 or 20 nm, respectively.
- the method of the invention is implemented at pressures not exceeding 1 bar, preferably in the range of 0.2 to 0.8 bar.
- the method may comprise a subsequent step of known specific process intended to make the aqueous albumin solutions suitable to various therapeutic uses in accordance with the European Pharmacopoeia, such as their adjustment to the physiological pH if appropriate, to the isotonicity in the case of an intravenous injection and to a physiologically acceptable salt concentration, and/or conditioning, for example in freeze-dried or liquid form.
- European Pharmacopoeia such as their adjustment to the physiological pH if appropriate, to the isotonicity in the case of an intravenous injection and to a physiologically acceptable salt concentration, and/or conditioning, for example in freeze-dried or liquid form.
- the invention also relates to a virally safe aqueous albumin solution obtainable by implementing the method of the invention, in which the transport and binding sites of therapeutically active ingredients are available in the albumin.
- This albumin solution is further characterised in that it is free from macromolecules having a sedimentation constant, according to Svedberg Ph. et al. (“Ultracentri colg”, 7th edition, Ed. Steinkopff, Dresden, 1940) above 7 S (i.e. a molecular weight of about 160 kDa).
- this albumin solution contains at most 1% albumin polymers with a size smaller than 100 nm, preferably smaller than 20 nm.
- the invention further relates to an albumin composition for therapeutic use obtained by processing said albumin solution according to the invention to make it suitable to a clinical use.
- albumin compositions for therapeutic use makes it possible to suppress the pasteurisation step, a source of drawbacks as mentioned above, and therefore, to add usual protection stabilisers against thermal effects, which also bind on the albumin sites, thus preventing albumin from binding the relevant molecules.
- the albumin of these compositions according to the invention retains its binding and transport potential of various active ingredients, and through this binding, reduces their toxicity or increases the bioavailability by a depot effect.
- albumin compositions according to the invention may be used:
- FIG. 1 shows a device for implementing the method s of the invention
- FIGS. 2 to 6 are plots showing the variations of the instantaneous filtration flow rate (mL/min) versus the nanofiltration duration, obtained on the basis of various parameters.
- a filtration device 1 containing a PLANOVA® 15-nm filter with a surface area of 0.01 m 2 is equipped with tubes 10 , 11 at the retentate (pre-filtration solution) outlet and at the filtrate (post-filtration solution) inlet and outlet, made of pharmaceutically compatible materials, with diameters of about 5 mm, closed by clamps.
- the device is arranged on a stand (not shown) in vertical position with the help of graspers.
- the inlet of the 15-nm filter is connected, through the tube 10 , to a pressure vessel 12 the pressure of which is measured with a digital pressure gauge 13 connected to the upstream filter circuit.
- an integrity test is carried out on the 15-nm filter in accordance with the manufacturer's procedure: “Air leakage test during the integrity pre-and post-filtration test of PLANOVA® 15, 35, 75-nm filters”.
- the compressed air inlet 14 is connected to the pressure vessel 12 filled with a volume of about 100 mL NaCl at 9 g/L.
- the flask is pressurised progressively until a pressure of 0.5 bar is reached at the inlet of the 15-nm filter.
- the 15-nm filter is filled while air is released at the retentate outlet, without filling the outside of the filter fibres.
- the lower outlet is open and connected to an optical density measurement detection cell 15 connected to a recording device 16 , the top filtrate outlet remaining clamped.
- the rinse filtrate is collected in a container 17 on a weighing scale 18 connected to and controlled by a microcomputer 19 that records the filtrate weight increase, which makes it possible to is monitor the instantaneous filtration flow rate.
- the necessary time to filter a minimum volume of 40 mL at 0.5 bar is measured, and the average flow rate in mL/min is deduced.
- the system is progressively depressurised and all the outlets are clamped.
- the system can be at room temperature (about 20° C. ) or placed in an oven in which the working temperature is between 25 and 60° C.
- albumin starting material used is the one obtained by fractionation of human plasma according to Kistler et al. and having undergone alcohol elimination process, diafiltration and concentration by ultrafiltration. It should be noted that the above fractionation of various sources of plasma generally results in albumin with variable characteristics due to the biological nature of the starting material. This albumin may therefore influence the duration of the nanofiltration, the yield, etc.
- Albumin aqueous solutions to be filtered are prepared from the reference solutions above, by modification of characteristics thereof such as concentration, pH and ionic strength. Their volumes are adjusted so as to provide the desired protein loads. Depending on the particular example, the albumin concentrations vary from 15 g/L to 80 g/L. The pH is adjusted by adding 0.5 M NaOH or HCl and the ionic strength is adjusted by adding sodium chloride. Then, the albumin solutions are all prefiltered on commercially available 0.2- ⁇ m filters.
- the filter inlet is closed.
- one volume of purified water for injection (PWI) is introduced into the repressurised vessel 12 , and the filter is flushed out.
- the filtrate is collected until a perceptible reduction in optical density which is monitored on the recording device 16 .
- the downstream circuit is then flushed out to collect the finished filtrate.
- Samples are taken from the filtrate and submitted to subsequent analytic tests such as polymer assays, virus titrations, etc.
- the duration of filtration of one volume of albumin solution required to provide a fixed protein load is also measured, and the filtration yield is determined as the quotient between the albumin amount contained in the filtrate and in the retentate.
- an integrity test is carried out on the 15-nm filter in accordance with the manufacturer's procedure: “Air leakage test during the integrity pre-and post-filtration test of PLANOVA® 15, 35, 75-nm filters”.
- the dependence of the filtration durations and yields to the pH of the albumin solutions in a such a way as a protein load of 4 kg/m 2 is provided is determined using a batch of albumin A as starting material.
- Five solutions of albumin at 40 g/L, A1 to A5 are prepared in a solution of NaCl at 9 g/L, and adjusted to pH 5, 7, 9, 9.5 and 10 respectively, with 0.5 M solutions of HCl or NaOH, and submitted to a nanofiltration.
- the nanofiltration tests are carried out at 20° C. at a pressure of 0.5 bar.
- FIG. 2 shows the plots of filtration flow rate (mL/min) versus nanofiltration duration for each of the solutions considered.
- the shortest nanofiltration duration is that observed with A′1. However, the most optimal initial flow rate is observed with solution A4.
- the albumin used is obtained by fractionation according to the method of Kistler et al. and is made therapeutically active by heating at 60° C. for 10 hours in the presence of a suitable stabiliser, in accordance with the requirements of the European Pharmacopoeia.
- the albumin B thus obtained is then mixed with a buffer comprising: 0.01 M trisodium citrate, 0.12 M glycine, 0.016 M L-Lysine, 0.001 M calcium chloride and 0.17 M sodium chloride, pH 7-7.5.
- the final concentration of the albumin solutions is 20 g/L.
- Example 9 The same solutions B and working conditions as in Example 9 are used to measure the reduction in polymer content after nanofiltration (Table 8). TABLE 8 Polymer content Polymer content before filtration after filtration Solutions B (%) (%) Filter of 0.01 m 2 3.1 0.47 ⁇ 0.13 Filter of 1 m 2 4.3 ⁇ 0.7 0.38 ⁇ 0.05
- viruses are introduced into different solutions of albumin A (20 g/L) which are submitted to nanofiltration tests.
- the tests are carried out by infecting the albumin solutions with bacteriophage virus Phi-X 174, suspensions of which are obtained in accordance with AFNOR Standard NFT 72-181 (December 1989).
- This virus is a good marker for the 15-nm filter as its size is between 25 and 30 nm, which corresponds to the non-enveloped viruses that are transmissible to humans, such as parvovirus B19, the inactivation by pasteurisation of which is not satisfactory.
- albumin A nanofiltered without any stabiliser, in the transport and binding of medicines, are studied by comparing them with those obtained with two different albumin A batches pasteurised in the presence of sodium caprylate.
- three solutions A4 (Example 3) are provided, one of which has been nanofiltered under the conditions of the invention. These solutions are then processed into pharmaceutical formulations in a 0.07 M phosphate buffer, pH 7.4, to give albumin compositions, A′4, A′′′4 and A′′′4, with concentrations of 2.5 g/L.
- the albumin compositions A′′4 and A′′′4, not nanofiltered, are pasteurised in the presence of sodium caprylate, respectively.
- a sample of 1 mL is taken from each of the compositions, and a volume of between 10 ⁇ L and 1 000 ⁇ L of a parent alcohol-based solution of [ 14 C]warfarine and [ 14 C]diazepam at 0.1 M respectively, two active ingredients of the respective class of anticoagulants and neurotropes, is added to the albumin compositions considered in order to provide variable concentrations in these active ingredients.
- the mixture is then homogenised.
- a dialysis device including a cell with two compartments separated by a suitable dialysis membrane is obtained.
- One volume V of an albumin/active ingredient mixture is introduced into compartment 1 and the same volume V of dialysis buffer (phosphate buffer, as defined above) is introduced into compartment 2 .
- V of dialysis buffer phosphate buffer, as defined above
- compartment 1 contains albumin-bound and unbound active ingredient
- compartment 2 contains unbound active ingredient.
- Table 10 gives the percentages of albumin-bound [ 14 C]diazepam obtained with compositions A′4, A′′4 and A′′′4 respectively, in which increasing volumes of active ingredient have been added.
- Table 11 shows the results obtained with [ 14 C]warfarine instead of [ 14 C]diazepam. The results are shown as the average value of 5 tests.
- compositions A′′4 and A′′′4 Increasing the concentration in [ 14 C]diazepam in the albumin compositions A′′4 and A′′′4 results in appreciably constant percentages of albumin-bound [ 14 C]diazepam. Therefore, the binding site identified in the albumin A, nanofiltered without any stabiliser, in composition A′4 is no more functional since it is occupied by the stabiliser.
- vWf von Willebrand factor
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US14/611,460 US9611311B2 (en) | 2004-02-27 | 2015-02-02 | Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same |
US15/443,884 US10562957B2 (en) | 2004-02-27 | 2017-02-27 | Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same |
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FR0402001 | 2004-02-27 | ||
FR0402001A FR2866890B1 (fr) | 2004-02-27 | 2004-02-27 | Procede de purification d'albumine comprenant une etape de nanofiltration, solution et composition a usage therapeutique la contenant |
PCT/FR2005/000416 WO2005090402A1 (fr) | 2004-02-27 | 2005-02-23 | Procede de purificaton d’albumine comprenant une etape de nanofiltration, solution et composition a usage therapeutique la contenant |
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PCT/FR2005/000416 A-371-Of-International WO2005090402A1 (fr) | 2004-02-27 | 2005-02-23 | Procede de purificaton d’albumine comprenant une etape de nanofiltration, solution et composition a usage therapeutique la contenant |
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US14/611,460 Continuation US9611311B2 (en) | 2004-02-27 | 2015-02-02 | Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same |
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US10/589,825 Abandoned US20070161122A1 (en) | 2004-02-27 | 2005-02-23 | Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same |
US14/611,460 Active US9611311B2 (en) | 2004-02-27 | 2015-02-02 | Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same |
US15/443,884 Active 2025-08-20 US10562957B2 (en) | 2004-02-27 | 2017-02-27 | Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same |
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US15/443,884 Active 2025-08-20 US10562957B2 (en) | 2004-02-27 | 2017-02-27 | Albumin-purification method comprising a nanofiltration step, solution, and composition for therapeutic use containing the same |
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US (3) | US20070161122A1 (da) |
EP (1) | EP1718673B1 (da) |
JP (2) | JP4979571B2 (da) |
AT (1) | ATE373014T1 (da) |
AU (1) | AU2005223418B2 (da) |
BR (1) | BRPI0507886A (da) |
CA (1) | CA2557174C (da) |
CY (1) | CY1107082T1 (da) |
DE (1) | DE602005002461T2 (da) |
DK (1) | DK1718673T3 (da) |
ES (1) | ES2294696T3 (da) |
FR (1) | FR2866890B1 (da) |
IL (1) | IL177286A (da) |
PL (1) | PL1718673T3 (da) |
PT (1) | PT1718673E (da) |
WO (1) | WO2005090402A1 (da) |
Cited By (3)
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US20080207878A1 (en) * | 2005-06-29 | 2008-08-28 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Process for separating proteins fibrinogen, factor XIII and biological glue from a solubilized plasma fraction and for preparing lyophilised concentrates of said proteins |
WO2015140751A1 (en) * | 2014-03-21 | 2015-09-24 | Boreal Invest | Terminal nanofiltration of solubilized protein compositions for removal of immunogenic aggregates |
US11640846B2 (en) * | 2020-01-30 | 2023-05-02 | Fresenius Medical Care Holdings, Inc. | Techniques for modelling and optimizing dialysis toxin displacer compounds |
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Publication number | Priority date | Publication date | Assignee | Title |
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FR2866890B1 (fr) * | 2004-02-27 | 2008-04-04 | Lab Francais Du Fractionnement | Procede de purification d'albumine comprenant une etape de nanofiltration, solution et composition a usage therapeutique la contenant |
FR2894831B1 (fr) | 2005-12-16 | 2008-02-15 | Lab Francais Du Fractionnement | Colle biologique exempte de thrombine et son utilisation comme medicament. |
ES2294976B1 (es) * | 2007-11-12 | 2008-12-16 | Grifols, S.A. | "procedimiento de obtencion de albumina humana de alta eficacia para su uso en terapia de detoxificacion". |
SG191781A1 (en) | 2010-12-30 | 2013-08-30 | Lab Francais Du Fractionnement | Glycols as pathogen inactivating agents |
FR3004451B1 (fr) * | 2013-04-11 | 2015-12-11 | Lab Francais Du Fractionnement | Procede de preparation d'une solution de proteine c viralement securisee par une double etape de nanofiltration |
FR3040882A1 (fr) * | 2015-09-10 | 2017-03-17 | Lab Francais Du Fractionnement | Composition liquide d'albumine humaine a usage therapeutique |
US11739166B2 (en) | 2020-07-02 | 2023-08-29 | Davol Inc. | Reactive polysaccharide-based hemostatic agent |
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GB9019919D0 (en) | 1990-09-12 | 1990-10-24 | Delta Biotechnology Ltd | Purification of proteins |
US5440018A (en) | 1992-05-20 | 1995-08-08 | The Green Cross Corporation | Recombinant human serum albumin, process for producing the same and pharmaceutical preparation containing the same |
JPH06279296A (ja) * | 1993-03-25 | 1994-10-04 | Asahi Chem Ind Co Ltd | 血漿分画製剤中から蛋白質会合物の除去方法 |
JP4798832B2 (ja) * | 2000-10-24 | 2011-10-19 | 一般財団法人化学及血清療法研究所 | ヒト血清アルブミン多量体の除去方法 |
CN1275981C (zh) * | 2000-10-24 | 2006-09-20 | 财团法人化学及血清疗法研究所 | 人血清白蛋白多聚体的单体化方法 |
JPWO2004089402A1 (ja) | 2003-04-09 | 2006-07-06 | 財団法人化学及血清療法研究所 | アルブミン製剤の製造方法 |
FR2866890B1 (fr) * | 2004-02-27 | 2008-04-04 | Lab Francais Du Fractionnement | Procede de purification d'albumine comprenant une etape de nanofiltration, solution et composition a usage therapeutique la contenant |
-
2004
- 2004-02-27 FR FR0402001A patent/FR2866890B1/fr not_active Expired - Lifetime
-
2005
- 2005-02-23 DE DE602005002461T patent/DE602005002461T2/de active Active
- 2005-02-23 AU AU2005223418A patent/AU2005223418B2/en not_active Ceased
- 2005-02-23 JP JP2007500249A patent/JP4979571B2/ja not_active Expired - Fee Related
- 2005-02-23 BR BRPI0507886-5A patent/BRPI0507886A/pt active Search and Examination
- 2005-02-23 CA CA2557174A patent/CA2557174C/fr active Active
- 2005-02-23 AT AT05731028T patent/ATE373014T1/de active
- 2005-02-23 EP EP05731028A patent/EP1718673B1/fr active Active
- 2005-02-23 ES ES05731028T patent/ES2294696T3/es active Active
- 2005-02-23 US US10/589,825 patent/US20070161122A1/en not_active Abandoned
- 2005-02-23 WO PCT/FR2005/000416 patent/WO2005090402A1/fr active IP Right Grant
- 2005-02-23 PT PT05731028T patent/PT1718673E/pt unknown
- 2005-02-23 DK DK05731028T patent/DK1718673T3/da active
- 2005-02-23 PL PL05731028T patent/PL1718673T3/pl unknown
-
2006
- 2006-08-03 IL IL177286A patent/IL177286A/en not_active IP Right Cessation
-
2007
- 2007-12-12 CY CY20071101575T patent/CY1107082T1/el unknown
-
2011
- 2011-12-21 JP JP2011280288A patent/JP2012102115A/ja active Pending
-
2015
- 2015-02-02 US US14/611,460 patent/US9611311B2/en active Active
-
2017
- 2017-02-27 US US15/443,884 patent/US10562957B2/en active Active
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080207878A1 (en) * | 2005-06-29 | 2008-08-28 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Process for separating proteins fibrinogen, factor XIII and biological glue from a solubilized plasma fraction and for preparing lyophilised concentrates of said proteins |
US8598319B2 (en) | 2005-06-29 | 2013-12-03 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Process for separating proteins fibrinogen, factor XIII and biological glue from a solubilized plasma fraction and for preparing lyophilised concentrates of said proteins |
US9320779B2 (en) | 2005-06-29 | 2016-04-26 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Process for separating proteins fibrinogen, factor XIII and biological glue from a solubilized plasma fraction and for preparing lyophilised concentrates of said proteins |
US9339530B2 (en) | 2005-06-29 | 2016-05-17 | Laboratoire Francais Du Fractionnement Et Des Biotechnologies | Process for separating proteins fibrinogen, factor XIII and biological glue from a solubilized plasma fraction and for preparing lyophilised concentrates of said proteins |
WO2015140751A1 (en) * | 2014-03-21 | 2015-09-24 | Boreal Invest | Terminal nanofiltration of solubilized protein compositions for removal of immunogenic aggregates |
US11640846B2 (en) * | 2020-01-30 | 2023-05-02 | Fresenius Medical Care Holdings, Inc. | Techniques for modelling and optimizing dialysis toxin displacer compounds |
Also Published As
Publication number | Publication date |
---|---|
EP1718673A1 (fr) | 2006-11-08 |
JP2007535495A (ja) | 2007-12-06 |
ES2294696T3 (es) | 2008-04-01 |
IL177286A0 (en) | 2006-12-10 |
DK1718673T3 (da) | 2008-01-14 |
AU2005223418B2 (en) | 2008-12-18 |
JP2012102115A (ja) | 2012-05-31 |
US20170166626A1 (en) | 2017-06-15 |
CA2557174A1 (fr) | 2005-09-29 |
IL177286A (en) | 2012-08-30 |
FR2866890B1 (fr) | 2008-04-04 |
WO2005090402A1 (fr) | 2005-09-29 |
EP1718673B1 (fr) | 2007-09-12 |
US10562957B2 (en) | 2020-02-18 |
US20150152162A1 (en) | 2015-06-04 |
CA2557174C (fr) | 2013-04-30 |
US9611311B2 (en) | 2017-04-04 |
DE602005002461T2 (de) | 2008-06-12 |
AU2005223418A1 (en) | 2005-09-29 |
BRPI0507886A (pt) | 2007-08-07 |
PT1718673E (pt) | 2007-12-13 |
CY1107082T1 (el) | 2012-10-24 |
ATE373014T1 (de) | 2007-09-15 |
PL1718673T3 (pl) | 2008-03-31 |
FR2866890A1 (fr) | 2005-09-02 |
JP4979571B2 (ja) | 2012-07-18 |
DE602005002461D1 (de) | 2007-10-25 |
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