WO1995034318A1 - Solution comprenant un facteur de croissance de type i proche de l'insuline ou tout autre analogue fonctionnel et methode de preparation - Google Patents
Solution comprenant un facteur de croissance de type i proche de l'insuline ou tout autre analogue fonctionnel et methode de preparation Download PDFInfo
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- WO1995034318A1 WO1995034318A1 PCT/SE1995/000685 SE9500685W WO9534318A1 WO 1995034318 A1 WO1995034318 A1 WO 1995034318A1 SE 9500685 W SE9500685 W SE 9500685W WO 9534318 A1 WO9534318 A1 WO 9534318A1
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- igf
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- drug product
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims description 7
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims abstract description 83
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims abstract description 82
- 239000000243 solution Substances 0.000 claims abstract description 47
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000001301 oxygen Substances 0.000 claims abstract description 29
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 29
- 239000007864 aqueous solution Substances 0.000 claims abstract description 22
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 22
- 229940126534 drug product Drugs 0.000 claims abstract description 20
- 238000003860 storage Methods 0.000 claims abstract description 20
- 230000002829 reductive effect Effects 0.000 claims abstract description 16
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 15
- 239000011261 inert gas Substances 0.000 claims abstract description 14
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 229930182817 methionine Natural products 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
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- 239000007924 injection Substances 0.000 claims description 4
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- 239000008363 phosphate buffer Substances 0.000 claims description 4
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
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- 235000010355 mannitol Nutrition 0.000 claims description 3
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- 239000004471 Glycine Substances 0.000 claims description 2
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- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 239000007951 isotonicity adjuster Substances 0.000 claims 2
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- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims 1
- 230000000717 retained effect Effects 0.000 abstract description 4
- 230000002035 prolonged effect Effects 0.000 abstract description 3
- 102000004169 proteins and genes Human genes 0.000 description 18
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- 235000006708 antioxidants Nutrition 0.000 description 12
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- 238000007254 oxidation reaction Methods 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
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- 229940079593 drug Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 239000000122 growth hormone Substances 0.000 description 4
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- -1 3 disulphide bonds Chemical class 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 108010024636 Glutathione Proteins 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
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- 239000008215 water for injection Substances 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
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- 229920005862 polyol Polymers 0.000 description 2
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 229960004799 tryptophan Drugs 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 1
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- 108010088751 Albumins Proteins 0.000 description 1
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- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 description 1
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- 108010074605 gamma-Globulins Proteins 0.000 description 1
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- SKEFKEOTNIPLCQ-LWIQTABASA-N mating hormone Chemical compound C([C@@H](C(=O)NC(CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCS(C)=O)C(=O)NC(CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CN=CN1 SKEFKEOTNIPLCQ-LWIQTABASA-N 0.000 description 1
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- 210000000107 myocyte Anatomy 0.000 description 1
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- 230000003076 paracrine Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
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Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K38/22—Hormones
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
Definitions
- the present invention relates to a final drug product comprising IGF-I or any functional analogue thereof in an aqueous solution with a reduced concentration of oxygen.
- the IGF-I purity can be retained during storage to a surprisingly high degree.
- the IGF-I purity can be retained for a prolonged period of time, if the final drug product further comprises an inert gas and/or an antioxidant.
- the present invention also relates to processes for reducing the oxygen concentration of the aqueous solution, and a method for improving the stability of IGF-I in an aqueous solution by storing the solution under an inert gas atmosphere.
- IGF-I Insulin-like Growth Factor I
- IGF-I Insulin-like Growth Factor I
- Human IGF-I has been purified from plasma and its complete amino acid sequence is established. (Rinderknecht E et al. "The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin” J. Biol. Chem 253; 2769-76, 1978) Sequences with extensive homologies to human IGF-I are present in IGF-I purified from plasma of other species.
- IGF-I Because of the scarcity of purified plasma IGF-I there was a great necessity to develop methodology for the commercial scale production of IGF-I. Recently, such large scale production can readily be achieved by using recombinant DNA techniques. As a result of studies with preparations of recombinant DNA IGF-I it has been demonstrated that it promotes skeletal growth and skeletal muscle protein synthesis. IGF-I has been shown to act both as an endocrine factor as well as a paracrine/autocrine factor. (Skottner et al, Endocrinology, Vol.
- IGF-I is also effective for the treatment or prevention of catabolic states in patients (Swedish patent application SE 9002731-9) and improves the regeneration of transected peripheral nerves (EP 0308386). It has previously been demonstrated in vitro that IGF-I also can promote actin synthesis in myocytes in culture (Florini, J R, Muscle and Nerve 10 (1987) 577-598 and contractility of neonatal rat cardiocytes in vitro (Vetter, U et al, Basic Res. Cardiol. 83 (1988)647-654).
- the stability of proteins is generally a problem in the pharmaceutical industry.
- a formulation with a low amount of protein will generally lose activity during purification, sterile manufacturing, storage and during the administration.
- freeze-drying process is also a costly and time consuming process step, and it would be of great advantage if this step could be avoided, when preparing a commercial product of a protein.
- Proteins are different with regard to physiological properties. When preparing a pharmaceutical preparation which should be physiologically acceptable, and stable for a long time, consideration can not only be taken to the physiological properties of the protein but also other aspects must be considered such as the industrial manufacture, easy handling for the patient and safety for the patient. The results of these aspects are not predictable when testing different formulations and each protein has often a unique solution regarding stability.
- EP 35204 discloses a method for imparting thermal stability to a protein composition in the presence of a polyol.
- EP 381345 discloses an aqueous liquid of a peptide, desmopressin, in the presence of carboxymethylcellulose.
- WO 89/09614 Genentech
- a stabilized formulation of human growth hormone containing glycine, mannitol, optionally a non-ionic surfactant and a buffer at pH 4-8 is disclosed.
- the non-ionic surfactant is added for reduced aggregation and denaturation.
- the formulation has an increased stability in lyophilized form and as a solution obtained after reconstitution.
- EP 303 746 International Minerals and Chemical corporation discloses growth hormone (GH) stabilized in aqueous environment by mixing the growth hormone with polyol, amino acid, polymer of amino acid or choline derivative.
- US 4165370 discloses a gamma globulin solution and a process for the preparation thereof.
- the solutions contains polyethylene glycol (PEG).
- EP 440989 discloses a method for preparing a dried composition of IGF-I, which comprises drying a solution containing IGF-I together with a strong acid.
- IGF-I in a citrate buffer at pH 6 is known from WO 91/18621, Genentech. None is mentioned regarding stability of IGF-I.
- the patent application PCT /SE94/00010 relates to a stable solution containing Insulin-like Growth factor I (IGF-1) in a phosphate buffer in an amount of 50 mmol or less, giving a pH of 5.5 to 6.5, which is isotonic and suitable for injection.
- IGF-1 Insulin-like Growth factor I
- US 5272135 discloses a method for inhibiting oxidation by adding methionine to a polypeptide.
- the oxidation process is reduced by the addition of a chemical compound.
- the concentration of oxygen in the solution is thereby not reduced.
- US 4727027, Diamond Scientific is directed to a method for photochemical decontamination of aqueous compositions containing biologically active proteins derived from blood or blood components, for minimizing loss in activity.
- the method comprises adding at least one furocoumarin to the composition and irradiating the obtained composition with ultraviolet (UV) light.
- UV ultraviolet
- the oxygen concentration of the aqueaous composition can be reduced to inhibit denaturatione.g.
- Aqueous solutions containing oxygen-sensitive chemical compounds including drugs other than proteins is normally deoxygenated as follows: Water for injection is bubbled with nitrogen to reduce the concentration of oxygen. The components are dissolved and the solution is bubbled with nitrogen and there-after kept under a nitrogen blanket. During filling, the bottles are flushed with nitrogen gas and the bottles are closed under a stream of nitrogen.
- Figure 1 shows % of oxidized IGF-I during 18 months' storage at 7°C.
- Figure 2 shows % of oxidized IGF-I during two months' storage at 25°C.
- Figure 1 shows % of oxidized IGF-I during two months' storage at 50°C. Description of the invention
- IGF-I can be deoxygenated without protein denaturation.
- IGF-I can be in a stable solution, and that such an aqueous solution with a low oxygen content is very stable when stored even at e.g. 25°C.
- the present invention relates to a final drug product comprising IGF-I or any functional analogue thereof in an aqueous solution with a reduced concentration of oxygen, for essentially retaining the IGF-I purity and activity during storage.
- the oxygen content in the solution can be below 150 mmol/L, suitably below 100 mmol/L and preferably 50 mmol/L or below.
- the final product can comprise an inert gas and the solution is suitably stored under the inert gas such as nitrogen, argon or helium, to essentially maintain the low content of oxygen.
- inert gas such as nitrogen, argon or helium
- the aqueous solution can also contain an antioxidant such as methionine. No concentration or amount can generally be given. It is, however, important that the amount of antioxidant, if used, is in a pharmaceutically acceptable amount For methionine the amount could be e.g. 2 - 50 mmol/L.
- the concentration of IGF-I is only dependent of its solubility in the used buffer and the desired therapeutically amount for the given dose.
- concentration of IGF-I is 1-100 mg/ml and more preferably 1-20 mg/ml.
- the aqueous solution may contain a phosphate buffer, such as sodium phosphate buffer, in an amount of 50 mmol/L or less, e.g.5-20 mmol/L, preferably around 10 mmol/L, giving a pH of 5.5 to 6.5 , preferably 5.7 - 6.2.
- the solution should be isotonic, which could easily be made by any of several excipients known for a person skilled in the art. E.g. NaCl, glycin, mannitol, glycerol and/or other carbohydrates can be added.
- Benzyl alcohol could be chosen as preservative.
- the final drug product has less than 2 % increase in oxidized IGF-I after 18 months 'storage at +7 ⁇ 1°C.
- Example 2 we have shown that it is not enough to reduce oxygen content in the head space in order to retain purity of IGF-I when stored. Also the oxygen concentration in the solution should be reduced.
- the invention also refers to a process for preparation of the claimed solution characterised by mixing IGF-I with an aqueous solution, and reducing the oxygen concentration in the solution by subjecting the aqueous solution to an inert gas atmosphere. It can first be done by reducing the pressure and thereafter introducing the inert gas. The latter process is preferably repeated in several cycles.
- the invention also refers to a method for improving the stability of IGF-I or any functional analogue thereof in an aqueous solution characterised in that the solution is subjected to a process so that the solution has a reduced concentration of oxygen.
- the IGF-I solution at a pH of 5.5 to 6.5. shows less than 2 % increase in oxidized IGF-I after storage for at least 18 months at a temperature of 7 ⁇ l °C
- Final drug product relates to the formulated drug in its final container.
- Suitable containers in the present invention are e.g. vials, syringes and injection devices.
- the low content of oxygen can be essentially maintained by adding an antioxidant to the aqueous solution.
- the antioxidant must, however, be specifically chosen, as there are few of the known and normally used antioxidants which will function and give the wanted result.
- Methionine is the preferred antioxidant. It has been found that glutathione, acetylcysteine, sodium bisulfite and ascorbic acid give a decreased stability and EDTA and tocopherol give no effect on stability for IGF-I, see Example 3.
- IGF-I Insulin-like Growth Factor
- rIGF-I recombinant IGF-I
- rhIGF-I human
- rbIGF-I bovine
- rpIGF-I rpIGF-I
- functional analogues compounds having the same therapeutic effect as IGF-I in animals and humans.
- rhIGF-I The recombinant human IGF-I (rhIGF-I) used in the experiments was produced in yeast. rhIGF-I was initially synthesised as a hybrid protein fused to the yeast a mating factor pre-pro leader peptide. After expression the primary translation product was secreted out of the cell. During this process the pre-pro-leader was cleaved off. Correctly processed and secreted rhIGF-I could then be isolated from the fermentation media in its native form.
- the media with rhIGF-I was then micro filtered and impurities were removed by several chromatographic techniques known within the field.
- IGF-I pools from the final step in the purification process were dissolved in the formulation buffer and chromatographed on a Sephadex G-50 column.
- This example presents the results from a stability study of a solution which has been stored at +7, +25 and +50°C, respectively.
- Nitrogen protection of the solutions was performed by deoxygenation in a vacuum chamber and replacing the evaporated oxygen by nitrogen.
- the oxygen content was 50 mmol/L.
- This example presents the results from a stability study of solutions filled in glass vials with or without head space and then stored at +5°C ⁇ 3°C and +25°C ⁇ 3°C.
- the head space contained 1.5 mL of sterile air.
- composition as in example 1.
- Table 1 Purity and percentage of oxidized IGF-I. 2 mg/mL IGF-I with or without head space stored at +5°C ⁇ 3°C.
- Reducing the head space in the vials is not sufficient to improve the stability of IGF-I or to reduce oxidation.
- This example presents the results from a stability study of solutions to which have been added different antioxidants.
- This composition gives a concentration of 1 mg/mL IGF-I in 50 mmol/L sodium phosphate buffer, and a pH 6, with 110 mmol/L sodium chloride as tonicity adjuster.
- To these solutions were added the following common antioxidants: Ascorbic acid, sodium bisulphite, reduced glutathione, acetylcyteine, methionine, tocopherol, EDTA, 1,4-dithiothreitol, sodium tiosulphate, n- propylgallat and L-tryptophan.
- the oxidants sodium bisulphite, reduced glutathione, acetylcysteine, 1,4- dithiothreitol, sodium tiosulphate, n-propylgallat and L-tryptophan were all incompatible with IGF-I. as precipitates of IGF-I were formed after some hours of storage. Ascorbic acid and sodium tiosulphate did in fact increase oxidation rates. EDTA and tocopherol did not enhance the stability towards oxidation. The antioxidant methionine did reduce the oxidation rate during storage. The results after storage are shown in table 3.
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Abstract
L'invention concerne un produit médicamenteux final comprenant un facteur de croissance de type I proche de l'insuline (IGF-I) ou tout autre analogue fonctionnel contenu dans une solution aqueuse à concentration réduite en oxygène. On peut ainsi maintenir la pureté de l'IGF-I pendant le stockage à un degré étonnament élevé. La pureté de l'IGF-I peut être maintenue pendant une période prolongée si le produit médicamenteux final comprend également un gaz inerte et/ou un antioxydant. L'invention concerne également des procédés de réduction de la concentration en oxygène de la solution aqueuse, ainsi qu'une méthode permettant d'améliorer la stabilité de l'IGF-I dans une solution aqueuse en stockant cette dernière dans une atmosphère de gaz inerte.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU27576/95A AU2757695A (en) | 1994-06-16 | 1995-06-08 | Solution comprising igf-i or any functional analogue thereof and method for its preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9402119-3 | 1994-06-16 | ||
SE9402119A SE9402119D0 (sv) | 1994-06-16 | 1994-06-16 | Solution |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995034318A1 true WO1995034318A1 (fr) | 1995-12-21 |
Family
ID=20394415
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1995/000685 WO1995034318A1 (fr) | 1994-06-16 | 1995-06-08 | Solution comprenant un facteur de croissance de type i proche de l'insuline ou tout autre analogue fonctionnel et methode de preparation |
Country Status (4)
Country | Link |
---|---|
AU (1) | AU2757695A (fr) |
IL (1) | IL114063A0 (fr) |
SE (1) | SE9402119D0 (fr) |
WO (1) | WO1995034318A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5783556A (en) * | 1996-08-13 | 1998-07-21 | Genentech, Inc. | Formulated insulin-containing composition |
US6559122B1 (en) | 1999-04-08 | 2003-05-06 | Genentech, Inc. | Formulated composition |
US6884083B2 (en) | 2001-04-20 | 2005-04-26 | Kettle Solutions Limited | Electrical connector |
EP2952203B1 (fr) * | 2014-05-29 | 2016-10-26 | Grifols, S.A. | Méthode pour la préparation de albumine humaine avec niveau réduit d'oxygène dissous |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4727027A (en) * | 1983-05-02 | 1988-02-23 | Diamond Scientific Co. | Photochemical decontamination treatment of whole blood or blood components |
US5272135A (en) * | 1991-03-01 | 1993-12-21 | Chiron Ophthalmics, Inc. | Method for the stabilization of methionine-containing polypeptides |
-
1994
- 1994-06-16 SE SE9402119A patent/SE9402119D0/xx unknown
-
1995
- 1995-06-08 WO PCT/SE1995/000685 patent/WO1995034318A1/fr active Application Filing
- 1995-06-08 AU AU27576/95A patent/AU2757695A/en not_active Abandoned
- 1995-06-08 IL IL11406395A patent/IL114063A0/xx unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4727027A (en) * | 1983-05-02 | 1988-02-23 | Diamond Scientific Co. | Photochemical decontamination treatment of whole blood or blood components |
US5272135A (en) * | 1991-03-01 | 1993-12-21 | Chiron Ophthalmics, Inc. | Method for the stabilization of methionine-containing polypeptides |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5783556A (en) * | 1996-08-13 | 1998-07-21 | Genentech, Inc. | Formulated insulin-containing composition |
US6559122B1 (en) | 1999-04-08 | 2003-05-06 | Genentech, Inc. | Formulated composition |
US7186686B2 (en) | 1999-04-08 | 2007-03-06 | Genentech, Inc. | Formulated composition |
US6884083B2 (en) | 2001-04-20 | 2005-04-26 | Kettle Solutions Limited | Electrical connector |
EP2952203B1 (fr) * | 2014-05-29 | 2016-10-26 | Grifols, S.A. | Méthode pour la préparation de albumine humaine avec niveau réduit d'oxygène dissous |
Also Published As
Publication number | Publication date |
---|---|
SE9402119D0 (sv) | 1994-06-16 |
AU2757695A (en) | 1996-01-05 |
IL114063A0 (en) | 1995-11-27 |
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