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
  • A61K35/16—Blood plasma; Blood serum
• • 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
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
• • 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
• • 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

Definitions

• the invention relates to a method of preparing a plasma-protein-containing medicament from citrated plasma or from a citrate-containing plasma fraction, the medicament being substantially free from undesired metals.
• albumin is the main component in plasma. Its therapeutic use has been known for a long time, an administration of albumin being indicated, e.g., in case of an acute loss of blood or plasma or in case of failure of the vasomotoric regulation. Since the osmotic pressure of a 20% (25%) albumin solution is approximately 4 times (5 times) that of normal human serum, the effect of albumin is mainly based on its ability to maintain the osmotic pressure.
• Human albumin preparations are prepared from human plasma by multiple fractionation, e.g. by a fractionation according to Cohn, or they are prepared by means of recombinant methods. On account of various materials used during its preparation or when the albumin solution is stored in glass containers, aluminum gets into the albumin preparation so that the final content of aluminum in the respective preparations may be quite substantial.
• Aluminum which constitutes one of the most frequently occurring elements in nature, has recently been increasingly associated with various diseases of the human body, primarily with diseases of the nervous and bone systems. Although the lungs and the gastro-intestinal tract form an efficient barrier for the uptake of aluminum, this barrier is no longer effective in patients receiving intravenous preparations, and the aluminum possibly present in the administered preparations may be taken up without hindrance. Thus, e.g., D. S. Milliner et al. (N. Engl. J. Med. (1985), 312, pp. 165-167) report that some albumin products comprising large amounts of aluminum have lead to diseases of the bones or to encephalitis. Aluminum is also increasingly associated with Alzheimer's disease.
• the present invention has as its object to provide a novel and simple method of avoiding or reducing, respectively, undesired metals in plasma-protein-containing medicaments, in which both, the undesired metals are removed in the course of the preparation method and a contamination of the finished preparations during storage in metal-containing containers is prevented or reduced, respectively.
• citrate ion-containing preparations are precipitated and subsequently taken up in a citrate ion free buffer, the new solution may still contain considerable portions of citrate ions. Since most of the fractionation methods in the recovery of pharmaceutical preparations from plasma—to which nearly always citrate is added during the extraction—comprise one or several precipiation steps, the inventive exchange method for citrate ions thus constitutes an interesting possibility for a simple, low-cost and efficient removal of citrate ions which can easily be incorporated into already established procedures.
• the plasma fraction e.g. a fraction obtained according to the Cohn fractionation
• albumin e.g., an albumin-containing precipitate from the Cohn fractionation is used.
• the exchange step thus must be carried out under non-precipitating conditions, since otherwise—as has been mentioned—there will be a risk that the citrate can be removed only insufficiently because of its high affinity to the precipitated protein.
• the exchange of the citrate will take place at an early time in the preparation method.
• a medicament comprising one or several factors of coagulation and fibrinolysis, immunoglobulins, glycoproteins and/or albumin, is prepared.
• fibrinogen, prothrombin, the factors V, VII, VIII, IX, X, XI, XII and XIII optionally in their activated form, von Willebrand factor, but also anticoagulants, such as heparin, heparinoids or cumarin derivatives, or fibrinolytic agents, such as streptokinase, urokinase, pro-urokinase, t-PA or plasmin, can be considered as the coagulation and fibrinolysis factors.
• the immunoglobulins various preparations comprising immunoglobulins of the classes IgG, IgA, IgM and mixtures thereof, optionally in high titers, may be prepared.
• glycoprotein orosomucoid may, e.g., be used.
• a salt of an organic carboxylic acid having 2 to 20 carbon atoms is used for the exchange of the citrate, a caprylate or a tartrate or mixtures thereof being particularly preferred.
• an organic mono- or dicarboxylic acid is to be understood as a mono- or dicarboxylate, since in any case the exchange of the citrate in solution will always be for the anion of the acid.
• an organic mono- or dicarboxylic acid having 2 to 4 carbon atoms is used for exchanging the citrate.
• the method according to the invention has proved particularly suitable for the preparation of plasma-protein-containing medicaments that exhibit excellent properties particularly in respect of their aluminum contamination by being substantially free from any detectable aluminum.
• exchanging of the citrate must be effected under non-precipitating conditions.
• the exchange step is effected during a diafiltration, ultrafiltration or during a chromatographic process, since these steps have proved particularly suitable for a simple, low-cost and effecient exchange.
• the conditions during the exchange step depend on the method used and in particular will be chosen such that the exchange of the citrate and optionally also of citrate-bound metals will be as complete as possible. Therefore, the respective parameter which determine the method, in particular the temperature, the duration of the exchange step and the concentration of the respective mono- or dicarboxylate or mono- or dicarboxylic acid, respectively, have to be optimized.
• the temperature will preferably be in a range of between 0 and 50° C., more preferred in a range of between 10 and 30° C., most preferred approximately at room temperature.
• the respective period of time for the exchange is particularly dependent on the ratio of the volume to be exchanged to the membrane surface and on the temperature and preferably is at least 30 minutes, in particular the period of time will be in a range of between 30 minutes and several hours.
• a parameter like the period of time will just as well depend on the respective exchange volume of the material in question.
• the exchange volume will be at least 5 times, most preferred at least 30 times that of the starting solution, and the period of time for the exchange will be chosen accordingly.
• the concentration of mono- or dicarboxylate or of mono- or dicarboxylic acid preferably is in a range of between 0.001 and 10 mol/l, most preferred in a range of between 0.001 and 1 mol/l.
• Sodium caprylate e.g., is added at a concentration of between 1.0 mmol/l and 1.5 mol/l, preferably in a range of between 1.0 mmol/l and 25 mmol/l.
• Sodium acetate e.g., is added at a concentration of between 1 mmol/l and 5.5 mol/l, preferably between 50 mmol/l and 1.0 mol/l.
• the sodium salt of the hexanoic acid e.g., is added at a concentration of between 1.0 mmol/l and 1.0 mol/l, preferably in a range of between 5.0 mmol/l and 0.1 mol/l.
• Sodium tartrate may be added at a concentration of between 1.0 mmol/l and 1.2 mol/l, preferably between 10.0 mmol/l and 0.2 mol/l.
• salts of higher acids thus the efficient amounts can already be found in a range of from 0.001 to 0.1 mol/l, while salts of lower acids preferably are added at somewhat higher concentrations.
• a further parameter which is decisive for the method is the pH of the solution.
• it is at pH 6 to 8, most preferred at pH 6.5 to 7.5.
• Beside carboxylate or carboxylic acid may be contained in the solution for increasing the ionic strength thereof.
• inorganic salts such as, e.g., sodium or potassium salts
• an at least 4% sodium chloride solution is contained.
• various buffer salts may be contained.
• materials for the respective exchange method in particular commercially available materials, such as, e.g., diafiltration membranes, ultrafiltration units, various chromatographic gels, molecular sieves and others may be used. All these materials may be based on organic or inorganic materials; they may be of synthetic of biological origin.
• a preferred embodiment of the method according to the invention thus relates to a method in which the plasma-protein-containing solution is treated, preferably heat-treated, before and/or after the exchange so as to inactivate possibly present viruses.
• Common virus inactivation treatments which may be used within the scope of the present method have been described in EP-0 159 311, EP-0 519 901 or in EP-0 674 531.
• the plasma protein recovered is further subjected to a dialyses against a medium with a low salt content, e.g. water. This may provide an additional stabilizing effect for the plasma protein because of the presence of the mono- or dicarboxylate.
• the recovery of the plama protein or plasma proteins and the finishing of the medicament preferably should be effected exclusively with citrate-free components so as to avoid the renewed contamination of the preparation with citrate ions which are responsible for a renewed contamination with metal ions in case of longer storage.
• the method according to the invention has proved quite particularly suitable for removing aluminum ions or for preventing a renewed contamination with aluminum ions, respectively, during storage of the medicament.
• metal ions from which it is known that they may contaminate plasma-protein-containing medicaments, such as aluminum-like metals, cadmium, zink, lead, iron and others, may efficiently be reduced.
• an object of the present invention is also a plasma-protein-containing medicament which is obtainable according to the method of the invention and has a content of undesired metal of less than 100 ⁇ g/l, preferably less than 10 ⁇ g/l, in particular less than 200 ng/l, determined, e.g., by atomic absorption spectroscopy, this maximum content not being exceeded even after extended storage, even when stored for more than 5 years.
• the plasma-protein-containing medicament of the invention may be stored in the most varying containers of the prior art.
• Such containers may consist of glass, synthetic material, metals or combinations thereof.
• the containers may also be specially pre-treated; thus, the surface may have been siliconized, e.g.
• As the glasses both hard glasses and soft glasses (cf. e.g. glasses of the classification USP 23, p. 1781) may be used.
• the plasma-protein-containing medicament of the invention has a low content of undesired metals when stored in hard glasses; particularly preferred the latter is less than 100 ⁇ g/l, more preferred less than 10 ⁇ g/l, most preferred less than 200 ng/l.
• a precipitate of Cohn fractionation comprising albumin in a purity of >95% is dissolved 1+2 (w/v; 1kg in 2) in 50 g/l NaCl solution at a neutral pH.
• the solution is continuously diafiltered with a regenerated cellulose membrane at +4° C. against water. At this, 0.1 mmol caprylate is added per g of protein.
• Table 1 b) shows the aluminum decrease and the citrate decrease after diafiltration with the addition of 0.1 mmol caprylate. 1 b) with the addition of caprylate Aluminum content Citrate content ⁇ g/g ⁇ mol/g Sample Protein in % Protein in % Before 2.999 100.0 139.5 100.0 diafiltration Diaconcentrate 0.096 3.2 1.1 0.8
• a precipitate of Cohn fractionation comprising albumin in a purity of >95% is dissolved 1+2 (w/v; 1 kg in 2 l) in 50 g/l NaCl solution at a neutral pH.
• the solution is continuously diafiltered with a regenerated cellulose membrane at +4° C. against water. At this, 5 mmol acetate is added per g of protein.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
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• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
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• Molecular Biology (AREA)
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• Animal Behavior & Ethology (AREA)
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• Pharmacology & Pharmacy (AREA)
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• Bioinformatics & Cheminformatics (AREA)
• Developmental Biology & Embryology (AREA)
• Biotechnology (AREA)
• Biomedical Technology (AREA)
• Virology (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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