WO2012136172A1 - Método para la producción de formulaciones inyectables de productos proteicos hemoderivados y productos obtenidos utilizando dicho metodo - Google Patents
Método para la producción de formulaciones inyectables de productos proteicos hemoderivados y productos obtenidos utilizando dicho metodo Download PDFInfo
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- WO2012136172A1 WO2012136172A1 PCT/CR2011/000001 CR2011000001W WO2012136172A1 WO 2012136172 A1 WO2012136172 A1 WO 2012136172A1 CR 2011000001 W CR2011000001 W CR 2011000001W WO 2012136172 A1 WO2012136172 A1 WO 2012136172A1
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- albumin
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- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims abstract description 55
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 11
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- 231100000719 pollutant Toxicity 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
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- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
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- UQSHZBSQKMVQBS-YDALLXLXSA-M sodium;(2s)-2-acetamido-3-(1h-indol-3-yl)propanoate Chemical compound [Na+].C1=CC=C2C(C[C@H](NC(=O)C)C([O-])=O)=CNC2=C1 UQSHZBSQKMVQBS-YDALLXLXSA-M 0.000 description 1
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Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
- C07K16/065—Purification, fragmentation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0017—Filtration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0023—Heat
-
- 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
- C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
Definitions
- the present invention relates to the field of therapeutic protein purification, particularly with a method for the production of injectable formulations of blood products, such as immunoglobulins and / or albumin.
- Products derived from blood plasma such as human albumin, human immunoglobulins and heterologous antivenoms are important medications in the treatment of various diseases, accidents and injuries. Due to the increase in current demand for these products, it is important to improve the efficiency of their production methods, in order to adequately supply such demand, and thus prevent a global shortage of these medicines in the short term.
- Plasma fractionation by the Cohn technique is the most widespread and used method by the plasma derived biological products industry (see Cohn EJ, Strong LE, Hughes WL, Mulford DJ, Ashworth JN, Melin M., Taylor HL 1946. "Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissue and fluids", Journal of the American Chemical Society, 68: 459- 475).
- SDFA Plasma fractionation using two-phase aqueous systems
- SDFA two-phase aqueous systems
- the SDFAs are composed of polymer-polymer, polymer-salt or alcohol-salt mixtures, and have been used in the primary recovery and partial purification of biological products such as proteins, genetic material, cells or organelles thereof, organic compounds such as aromas and dyes, heavy metals and some drugs (see Benavides, J., Rito-Palomares, 2008. "Review: Practical experiences from the development of aqueous two-phase processes for the recovery of high value biological produc ⁇ s". J Chem Technol Biotechnol 3: 133-142; Huddleston, J., A. Veide, K. Kohler, J. Flanagan, S-0. Enfors and A. Lyddiat. 991. "The molecular basis of partitioning in aqueous two-phase systems". Tibtech 9: 381-388).
- US Patent 4,684,723 presents a method for separating the alpha-1-proteinase inhibitor from other proteins and nucleic acids present in the plasma or in culture medium through the use of SDFA.
- WO 2010 / 062244A1 proposes the recovery and partial purification of therapeutic proteins, specifically monoclonal antibodies, in two stages of extraction in SDFA. In the first stage, the antibodies are partitioned towards the upper phase, and in the second stage they precipitate in said phase. Subsequently, they are recovered and re-dissolved for subsequent purification by chromatography.
- the present invention overcomes the limitations of the state of the art, since it has a production line for obtaining injectable formulations of blood products with reduced viral load for human use, an aspect of great importance that has not been described in the state of the art. technique with respect to obtaining immunoglobulins and albumin using SDFA.
- An object of the present invention is a method for the production of injectable formulations of blood products with reduced viral load, the method of which comprises the steps of ( Figures 1 and 4): to fractionation of the starting material in a two-phase aqueous system by adding a polymer and at least one salt;
- the method of the invention can be carried out starting from a material that can be selected from the group consisting of blood plasma, blood serum, a fraction obtained by the Cohn method or any other material containing blood products, particularly albumin and / or immunoglobulins.
- fractionation of the starting material is carried out in a system consisting of two aqueous phases.
- a polymer and a salt are added, the polymer of choice being polyethylene glycol with molecular weight between 1000-6000 Da, and preferably polyethylene glycol of 3350 Da, which is used at a concentration in the range between 6 and 15% w / v, and preferably between 6 and 9% w / v.
- the salt used in the fractionation can be monobasic potassium phosphate, dibasic potassium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, ammonium sulfate and sodium citrate, preferably monobasic and dibasic potassium phosphate being used, at concentrations between 10 and 20% w / v, and preferably between 15 and 20% w / v.
- a salt that does not participate in the formation of the two phases, but which influences the partition of solutes in the system, preferably the sodium chloride, at a concentration between 5 and 20% w / v, preferably between 12 and 15% w / v.
- This fractionation step is performed at a pH between 5.5 and 7.5, and preferably at a pH of 6, and is performed at room temperature (between 20-25 ° C).
- the method of the invention employs phenol between 0.05 and 0.3% v / v, in a preferred embodiment it uses 0.25% v / v phenol.
- the upper and lower phases of the two aqueous phases system are separated by a combination of selected processes that can be: rest and separation, rest and filtration, rest and decantation or simply centrifugation.
- the next step is the purification of the products contained in the upper phase of the SDFA obtained.
- This phase is rich in immunoglobulins, and for its purification a precipitation with caprylic acid is carried out, the latter at a concentration between 1 and 6% v / v, and preferably at a concentration between 1.5 and 2% v / v.
- thermocoagulation is performed for the purification of the products that are in the lower phase of the system, which is rich in albumin. This process is carried out at a temperature between 60 and 70 ° C, and preferably at 65 ° C. This operation is carried out in the presence of 0.012 M sodium caprylate and 9% v / v ethanol.
- a chromatography step is used, which may comprise an ion exchange chromatography, affinity chromatography or hydrophobic exchange chromatography.
- the final stage of purification of the products obtained in the lower phase of the system is carried out using ion exchange chromatography.
- the removal of viral particles from the products obtained as a result of the process of the invention is carried out by nanofiltration, using a filter with exclusion for 20 nm.
- the products can be stabilized with agents such as sucrose and sodium caprylate for the solution of immunoglobulins and albumin, respectively.
- the immunoglobulin formulation can be kept in solution or lyophilized.
- a final pasteurization step is included for 10 hours at 60 ° C.
- the products obtained are sterilized through a membrane excluding 0.22 ⁇ .
- Both immunoglobulins and albumin obtained in Preferred embodiments of the invention are products that show quality of injectable solution, and have reduced viral load according to established specifications (WHO, 2010. Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins; WHO, 2004. Guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood plasma produc ⁇ s).
- FIG. 2 Gel filtration of samples of the method proposed in the invention for obtaining antivenom from hyperimmune equine plasma.
- a Superdex 200 10/300 GL column was used, elution was performed with a 150 mM NaCI buffer, 20 mM Tris-HCI, pH 7.5.
- FIG 3. Gel filtration of samples of the method proposed in the invention for obtaining equine albumin.
- a Superdex 200 10/300 GL column was used, elution was performed with a 150 mM NaCI buffer, 20 mM Tris-HCI, pH 7.5.
- FIG. 5 Gel filtration of samples of the method proposed in the invention for obtaining gamma globulins from human plasma.
- a Süperdex 200 10/300 GL column was used, elution was performed with a 150 mM NaCI buffer, 20 mM Tris-HCI, pH 7.5.
- FIG 6. Gel filtration of samples of the method proposed in the invention for obtaining human albumin.
- a Superdex 200 10/300 GL column was used, the elution was performed with a 150 mM NaCI buffer, 20 mM Tris-HCI, pH 7.5.
- the present invention deals with a method for the purification of blood products, and is particularly useful for the simultaneous obtaining of immunoglobulins and albumin with injectable quality, from mixtures that may contain these and other proteins.
- This method is characterized by being practical and economical, since it uses reagents of affordable cost, and unlike Cohn's method, it does not need specific equipment to meet strict temperature requirements.
- the products obtained (immunoglobulins and albumin), have high levels of purity (> 90%) and yield.
- the method can be used for the recovery of other blood products other than immunoglobulins and albumin, for example coagulation factors.
- immunoglobulin fragments F (ab ') 2 or Fab
- the process of obtaining each product includes 2 steps of inactivation and 1 of viral removal, which generate a reduction in the viral load of the product that guarantees its safety, as established in the regulations.
- this methodology can be used for the purification of antibodies from hyperimmune plasma, for example for the production of antivenoms or antitoxins.
- the starting material may consist of plasma or serum, digested or not with proteolytic enzymes, any fraction of the plasma or serum, or some mixture containing immunoglobulins and albumin of human origin or any other animal.
- the fractionation of the starting material is carried out in an SDFA ( Figures 1 and 4).
- the product of interest has an affinity towards one of the two aqueous phases that make up the system, different from the rest of the components of the mixture in which it is found.
- the phases are formed by mixing two or more hydrophilic substances that in certain concentrations become immiscible in water, based on thermodynamic forces related to their hydration.
- the water in the system corresponds to the water present in the starting material.
- the system comprises the use of a water soluble polymer, a water soluble salt and a water soluble salt that is involved in the partition of solutes, but which is not part of the formation of the two phases.
- the polymer is polyethylene glycol (PEG), with a molecular weight range of 1000-6000 Da, which is mostly separated in the upper phase;
- the salt is potassium phosphate, say y monobasic, which separates mostly in the lower phase, and the salt that does not participate in the formation of the phases is sodium chloride.
- the ratio between monobasic and dibasic potassium phosphate determines the pH of the system, as the monobasic potassium phosphate increases, the pH decreases.
- the desired partition of the proteins is carried out in a pH range of 5.5-7.5 and at room temperature (20-25 ° C).
- the addition of phenol is carried out with the aim of inactivating viral particles present in the starting material during fractionation.
- the antiviral capacity of phenol lies in its ability to produce physical disruption of proteins and lipid structures of viruses.
- the system components are added to the starting material under constant agitation conditions at the following concentrations: phenol between 0.05-0.3% v / v, PEG between 6-15 p / v%, potassium phosphate between 10-20 p / v % and sodium chloride between 5-20% w / v; preferably, 0.25% v / v phenol, between 6 and 9% w / v PEG, between 15 and 20% w / v potassium phosphate and 15% w / v NaCl.
- concentrations phenol between 0.05-0.3% v / v, PEG between 6-15 p / v%, potassium phosphate between 10-20 p / v % and sodium chloride between 5-20% w / v; preferably, 0.25% v / v phenol, between 6 and 9% w / v PEG, between 15 and 20% w / v potassium phosphate and 15% w / v NaCl.
- concentrations of the different components are expressed in terms of p / v (weight / volume), since as the starting material provides the water that makes up the SDFA, the addition of them is done in its solid form and not in solution. This fact results in an advantage when scaling the method, since it eliminates the need to handle several containers with the component solutions.
- phase separation is done by filtration, centrifugation or decantation. From this point on, each phase becomes a parallel purification line. Both lines will be described separately below ( Figures 1 and 4): Purification of immunoglobulins from the upper phase of SDFA.
- the precipitate recovered from the upper phase when separating the phases is resuspended in a volume of water that allows the total redisolution of the precipitate; preferably in a volume equal to or less than the starting volume, to favor the concentration of the product.
- the suspension is stirred until the total dissolution of the paste is achieved.
- a fatty acid is added, which precipitates and denatures the contaminating proteins, and leaves the immunoglobulins in suspension.
- the fatty acid works in a range of 1-6% v / v, preferably between 1.5 and 2% v / v.
- the fatty acid may be 6 to 8 carbons, preferably 8 carbons (caprylic or octanoic acid).
- Precipitation can be carried out in a pH range of 5 to 8 without affecting the result obtained. Stirring during precipitation should be vigorous and is performed in a range of 30 to 60 minutes. The precipitate is removed by microfiltration or centrifugation. In addition, this method works as a step of inactivating lipid-enveloped viruses.
- the non-ionized form of caprylic acid is lipophilic, and has the ability to penetrate and break the lipid bilayer of the virus and the proteins associated with it.
- the filtrate or supernatant in which the immunoglobulins are found is passed through a chromatographic column to increase its purity, which can be selected from the group consisting of anion exchange chromatography, affinity chromatography and hydrophobic exchange chromatography.
- the lower phase enriched in albumin ( Figures 1 and 4), is dialyzed or diafiltered to remove salts from SDFA. This process is carried out with a molecular cut membrane less than or equal to 30 KDa. Subsequently, the solution is subjected to the selective thermocoagulation process, in which it is heated in a temperature range of 60-70 ° C, preferably 65 ° C, for 0.5-2 hours. This step precipitates the rest of the proteins and leaves the albumin in solution, since at this temperature the other proteins in the plasma become denatured.
- Agents such as sodium caprylate and sodium N-acetyl tryptophanate are used to maintain the stability of albumin at said temperatures, preferably sodium caprylate in a range of 0.02-0.1, preferably 0.012 M.
- This heating is carried out in the presence of ethanol in a range of 5-15% v / v, preferably 9% v / v in order to promote precipitation of the rest of proteins.
- the solution is heated, it is brought to room temperature, and the pH is lowered to 5.
- the precipitate is separated by microfiltration or centrifugation, and the suspended albumin is recovered.
- this solution is passed through a chromatographic column, in a particular embodiment, through a cation exchange resin (sulfonic acid or carboxymethyl acid).
- both albumin and immunoglobulin solutions are nanofiltered, formulated, stabilized and packaged ( Figures 1 and 4).
- Nanofiltration is a viral removal step based on size exclusion, using a 20 nm filter. Viral particles can be removed as antibody-virus complexes, due to the presence of antiviral antibodies in immunoglobulin solutions, or as viral particles in the case of albumin formulation.
- the immunoglobulin formulation comprises the concentration of the product at 1.0 to 10.0 g / dL of protein by ultrafiltration with a membrane excluding 30 KD; pH adjustment in a range of 5 to 7, preferably 5; the addition of 5% sucrose as a stabilizer and 0.9% NaCI.
- the product is sterilized by filtration through a membrane excluding 0.22 ⁇ , and packaged.
- the product may be freeze dried or kept liquid.
- the product formulation comprises the concentration at 20 g / dL of protein by ultrafiltration with a membrane with exclusion for 10 KDa; pH adjustment in a range of 6.5 to 7.5, preferably 7; the addition of sodium caprylate as a stabilizer and 0.9% NaCl.
- the medicine is sterilized, packaged, and finally pasteurized at 60 ° C for 10 hours. Pasteurization inactivates enveloped and unwrapped viruses by exposure to high temperature. According to Kempf, C, Stucki, M., Boschetti, N. 2007.
- Example 1 Production of antivenoms and albumin from hyperimmune equine plasma
- 1 L of hyperimmune equine plasma that is, plasma rich in snake antivenom antibodies
- the plasma was obtained from horses immunized with venom from Bothrops asper, Lachesis stenophrys and Crotalus simus.
- the starting material contained 63% immunoglobulins and 27% albumin ( Figures 1 and 2).
- the system was vigorously stirred for 1 hour, and allowed to stand for 1 hour to favor the formation of the phases, an upper one in which the precipitated immunoglobulins are found, and a lower one in which the albumin is in suspension. Subsequently, the mixture was microlfiltered by gravity; This step can also be carried out by centrifugation or decantation. After filtration, the precipitate (immunoglobulins) and the filtrate (albumin) were further processed separately. As Figure 1 shows, once both phases were separated, 68% of the plasma antivenom immunoglobulins were recovered in the upper phase (Figure 2.B), and 100% of the plasma albumin in the lower phase ( Figure 3B). The purity value of each was estimated by gel filtration, and corresponds to 92% and 62% purity, respectively. The overall protein yield between the two phases was 88%, the other 12% corresponds to fibrin that is partitioned to the upper phase ( Figure 1).
- the precipitate was resuspended in 1400 ml_ of deionized water with constant stirring for 1 hour.
- caprylic acid was added. Normally, the amount of caprylic acid used for the production of antivenoms is 5-7% v / v. However, because in this case the immunoglobulin fraction comes from SDFA, it contains less pollutants. Consequently, less caprylic acid (1.75% v / v) is required.
- the mixture was vigorously stirred for 30 minutes to favor precipitation. This step has a dual purpose, since on the one hand it precipitates the contaminating proteins and on the other, it inactivates the enveloped viruses.
- the filtrate was dialyzed against deionized water with a 15 KDa exclusion membrane. Dialysis can be replaced by diafiltration in an ultrafilter.
- the antivenom was nanofiltered through a 20 nm exclusion filter. The product was concentrated by ultrafiltration with a 30 KDa exclusion membrane at the protein concentration required to reach the neutralizing activity specification (for example, 3 mg venom / mL antivenom for Bothrops asper, 3 mg venom / mL antivenom for Lachesis stenophrys , 2 mg venom / ml_ antivenom for Crotalus simus or 0.5 mg venom / mL antivenom for Micrurus nigrocinctus).
- the neutralizing activity specification for example, 3 mg venom / mL antivenom for Bothrops asper, 3 mg venom / mL antivenom for Lachesis stenophrys , 2 mg venom / ml_ antivenom for Crotal
- the product was formulated at pH 7 with 0.9% w / v NaCl and 0.25% v / v phenol, and sterilized by filtration with a membrane excluding 0.22 pm ( Figure 1). It was dispensed in sterile bottles with 10 mL each.
- the lower phase of the albumin-rich SDFA was dialyzed against water with a 15 KDa exclusion membrane to eliminate salts from the system. Dialysis can be replaced by diafiltration in an ultrafilter.
- the albumin suspension was subjected to thermocoagulation, for which 2.4 g (0.012 M) of sodium caprylate was added as stabilizer and 126 mL of 95% ethanol v / v (9% v / v ). Then, it was heated for 1 h at 65 ° C in a water bath with regulated temperature. Subsequently, it was brought to room temperature and the pH was adjusted to 5 with 0.5 M HCI. The precipitated proteins were removed by gravity microfiltration. As shown in Figures 1 and 3C, at this stage of the process, a yield of 94% was obtained, with a purity of 91%.
- the total protein concentration of the starting material and the samples from each purification stage was quantified, using a modification of the Biuret method (see Parvin, R., Pande, SV, Venkitasubramanian , A. 1965. "On the colorimetric Biuret Method of Protein Determination.” Analytical Biochemistry 12: 219-229). With the data obtained from the protein determination, the purity percentages per FPLC and the volume of each sample, the amount obtained of total immunoglobulins in terms of grams was expressed. Finally, the protein yield was calculated from the ratio of total immunoglobulins in the sample (g) and total immunoglobulins in the starting material (g).
- an ELISA of the starting material and samples from each stage of purification was performed for the quantification of specific antivenom antibodies of Bothrops asper.
- 96-hole plates were coated with 100 pL / hole of a solution of B. asper venom in phosphate solution (3 pg / hole), followed by overnight incubation at room temperature. Subsequently, 100 pL / hole of several sample dilutions were added in triplicate, and incubated for 1 hour at room temperature. After washing the plate, 100 pL / hole of a dilution of a horse anti-lgG conjugate bound to peroxidase was added, and one hour incubation was performed.
- the substrate hydrophilicity and o-phenylenediamine
- the absorbance was read in a microplate reader at 492 nm.
- the concentration of equine antivenom IgG was expressed in terms of g / L, using a standard calibration curve prepared with known concentrations of antivenom IgG. Said standard was obtained by affinity chromatography, by passing a partially purified hyperimmune equine plasma sample, through a Sepharose column attached to B. asper venom.
- the amount of antivenom immunoglobulins was expressed in terms of grams.
- the protein yield was calculated from the ratio of antivenom immunoglobulins in the sample (g) and the antivenom immunoglobulins in the starting material (g).
- the protein yield of the starting material and the samples from each purification step was determined in the manner described in example 3.
- IgG radial immunodiffusion kit
- IDR radial immunodiffusion kit
- the samples were applied in wells on an agarose gel and allowed to diffuse for 48 hours. Based on the concentration obtained and the volume of each sample, the amount of each type of antibody was expressed in grams.
- the purity of gamma globulins (IgG) in each sample was determined, based on the ratio of the amount of gamma globulins obtained by IDR and the total protein of the sample in question. Also, the yield of gamma globulins was calculated from the ratio of gamma globulins in the sample (g) and gamma globulins in the starting material (g).
- protein yield was determined as specified in the case of immunoglobulins, that is, based on the ratio of albumin in the sample (g) and albumin in the starting material (g).
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EP11863087.0A EP2719704B1 (en) | 2011-04-08 | 2011-04-08 | Method for producing injectable formulations of blood-derived protein materials, and materials obtained using said method |
CA2832665A CA2832665C (en) | 2011-04-08 | 2011-04-08 | Method for producing injectable formulations of blood-derived protein materials, and materials obtained using said method |
HUE11863087A HUE029232T2 (en) | 2011-04-08 | 2011-04-08 | A method for preparing injectable formulations of protein derived from blood, and materials obtained using said method |
PCT/CR2011/000001 WO2012136172A1 (es) | 2011-04-08 | 2011-04-08 | Método para la producción de formulaciones inyectables de productos proteicos hemoderivados y productos obtenidos utilizando dicho metodo |
ES11863087.0T ES2596407T3 (es) | 2011-04-08 | 2011-04-08 | Método para la producción de formulaciones inyectables de productos proteicos hemoderivados y productos obtenidos utilizando dicho método |
CN201180070045.0A CN103476786B (zh) | 2011-04-08 | 2011-04-08 | 一种生产血液来源蛋白质注射制剂的方法,以及使用上述方法获得的蛋白质物料 |
AU2011364724A AU2011364724B2 (en) | 2011-04-08 | 2011-04-08 | Method for producing injectable formulations of blood-derived protein materials, and materials obtained using said method |
MX2013011743A MX340349B (es) | 2011-04-08 | 2011-04-08 | Metodo para la produccion de formulaciones inyectables de productos proteicos hemoderivados y productos obtenidos utilizando dicho método. |
US14/110,594 US10562958B2 (en) | 2011-04-08 | 2011-04-08 | Method for producing injectable formulations of blood-derived protein materials, and materials obtained using said method |
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WO2016207353A1 (en) * | 2015-06-26 | 2016-12-29 | Ferring B.V. | Methods of purification and/or viral inactivation |
US20170233458A1 (en) * | 2015-09-29 | 2017-08-17 | Kieu Hoang | Method of manufacturing intravenous immunoglobulin from fraction iii |
CN110891664B (zh) * | 2017-06-01 | 2022-05-17 | 相达生物科技美国有限公司 | 用于多孔材料中双水相分离的相分离行为改性剂 |
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