EP0855917A1 - Stable pharmaceutical forms of administration containing parathormone - Google Patents
Stable pharmaceutical forms of administration containing parathormoneInfo
- Publication number
- EP0855917A1 EP0855917A1 EP96934715A EP96934715A EP0855917A1 EP 0855917 A1 EP0855917 A1 EP 0855917A1 EP 96934715 A EP96934715 A EP 96934715A EP 96934715 A EP96934715 A EP 96934715A EP 0855917 A1 EP0855917 A1 EP 0855917A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- pharmaceutical preparation
- preparation according
- amino acids
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 102000003982 Parathyroid hormone Human genes 0.000 title claims abstract description 15
- 108090000445 Parathyroid hormone Proteins 0.000 title claims abstract description 15
- 239000000199 parathyroid hormone Substances 0.000 title claims abstract description 15
- 150000001413 amino acids Chemical class 0.000 claims abstract description 33
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 35
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 30
- 235000001014 amino acid Nutrition 0.000 claims description 30
- 229940024606 amino acid Drugs 0.000 claims description 30
- 239000002552 dosage form Substances 0.000 claims description 24
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 15
- 239000004475 Arginine Substances 0.000 claims description 12
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 12
- 239000012634 fragment Substances 0.000 claims description 12
- 150000007522 mineralic acids Chemical class 0.000 claims description 10
- 150000007524 organic acids Chemical class 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 7
- 235000003704 aspartic acid Nutrition 0.000 claims description 7
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 229960001319 parathyroid hormone Drugs 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 5
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 5
- 229960000310 isoleucine Drugs 0.000 claims description 5
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 3
- 238000001802 infusion Methods 0.000 claims description 3
- 239000008297 liquid dosage form Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000003978 infusion fluid Substances 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 208000015202 calcium metabolic disease Diseases 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- 238000003860 storage Methods 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 5
- 235000009697 arginine Nutrition 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000008215 water for injection Substances 0.000 description 10
- 239000011521 glass Substances 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
- 239000000539 dimer Substances 0.000 description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 4
- 229930064664 L-arginine Natural products 0.000 description 4
- 235000014852 L-arginine Nutrition 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000014705 isoleucine Nutrition 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 235000006109 methionine Nutrition 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 238000003958 fumigation Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000004898 n-terminal fragment Anatomy 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- OHDBPOYAFZHWQO-FOIRCHMTSA-N [(1S)-1-carboxy-4-(diaminomethylideneamino)butyl]azanium phosphate Chemical compound [O-]P([O-])([O-])=O.NC(N)=NCCC[C@H]([NH3+])C(O)=O.NC(N)=NCCC[C@H]([NH3+])C(O)=O.NC(N)=NCCC[C@H]([NH3+])C(O)=O OHDBPOYAFZHWQO-FOIRCHMTSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
Classifications
-
- 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
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
Definitions
- the invention relates to pharmaceutical preparations which contain parathyroid hormone or its fragments as an active ingredient, and to corresponding pharmaceutical dosage forms in the form of lyophilisates or injection solutions
- Parathomone is an eighty-four amino acid protein that is involved in regulating the calcium and phosphate levels in blood and tissue. From the literature (see also WO 90/10067; WO 91/06564; EP 0 301 484, WO 93/15109) it is known that N-terminal fragments of this hormone, but also peptides with corresponding modifications in the amino acid sequence via an analog have biological activity like PTH (1-84).
- dimers can lead to a loss of activity of the protein in the dosage form, in particular if the dosage forms are stored for a longer period of time or at suboptimal temperatures.
- lyophilization is problematic in the context of the production of appropriately dried pharmaceutical dosage forms.
- Parathormone fragments in the sense of the invention are in particular the human N-terminal fragments of the intact protein, for example fragments (1-34), (1-35), (1-36), (1-37) or ( 1-38)
- fragments of the parathyroid hormone which are shortened at the N- and C-terminal for example fragments which are shortened at the N-terminal by one or two amino acids.
- corresponding variants or modifications of this hormone can also be used , in which one or more amino acids are replaced by other amino acids in the amino acid sequence of PTH (1-84). This also applies to the fragments shortened correspondingly at the N- and / or C-terminal produce pharmaceutical preparations containing the parathormone fragment hPTH 1-37.
- the active substance content of parathyroid hormone or parathyroid hormone fragments in the liquid dosage forms is up to 10 mg / ml, in particular up to 5 mg / ml or up to 2 mg / ml.
- the active substance content is preferably at least 0.01 mg / ml, 0.04 mg / ml or 0.1 mg / ml.
- the active substance content is preferably, for example, 0.01-5 mg / ml, in particular 0.04-2 mg / ml.
- the lyophilized dosage forms contain the active ingredient in such amounts that by adding a certain volume of a physiologically contractual reconstitution solution, corresponding infusion or injection solutions of the active ingredient are obtained with the concentration ranges mentioned.
- the pharmaceutical dosage forms within the meaning of the present invention are essentially free from surfactants and customary physiologically compatible antioxidants, in particular from reagents containing sulfhydryl groups, such as methionine or cysteine, or ascorbic acid. Furthermore, they are preferably essentially free of chloride ions, since chloride ions are the Favor formation of dimers
- the dosage forms according to the invention otherwise contain no further pharmaceutical additives or auxiliaries, such as, for example, sugar or physiologically compatible polymers.
- the dosage forms within the meaning of the invention are distinguished in particular by the fact that they consist essentially only of amino acids and organic or inorganic acids exist, but at least one basic amino acid is contained
- basic amino acids are all physiological, contractual amino acids with at least one basic side group.
- Basic side groups are in particular amino groups, which may be replaced by other radicals, such as e.g. Ci-C ⁇ - alkyl groups, may be substituted.
- Preferred basic amino acids are in particular histidine, lysine, arginine or ornithine.
- the physiologically acceptable amino acids with side groups which have no sulfhydryl groups are suitable as neutral amino acids
- the amino acids can in principle be used in the form of their racemates or the optically active forms (D- or L-amino acids).
- the concentration of the amino acids in the liquid dosage form is in the range of up to 100 mg / ml. Concentrations of up to are particularly advantageous 80 mg / ml, in particular up to 60 mg / ml, or up to 50 mg / ml or 40 mg / ml.
- the concentration of the amino acids is advantageously at least 1 mg / ml, in particular at least 5 mg / ml
- organic acids which are physiologically acceptable are carboxylic acids, hydroxycarboxylic acids or amino acids, and their salts, in particular alkali salts.
- carboxylic acids hydroxycarboxylic acids or amino acids
- salts in particular alkali salts.
- Advantageous in the context of the invention are, for example, lactic acid, acetic acid, citric acid or aspartic acid. the racemates or the optically active derivatives can be used
- Suitable inorganic acids are physiologically acceptable acids, for example phosphoric acid or sulfuric acid, or their salts, which can also be used as a buffer in aqueous solution, such as sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogen sulfate, etc.
- the organic or inorganic acids can also be used in combination with one another.
- the amount of acid is chosen such that the aqueous solution has a pH of 4-8, preferably 6-8.
- the concentration of the acid in the solution is up to 100 mg / ml, in particular up to 50 mg / ml or up to 40 mg / ml.
- the concentration of the acid is at least 1 mg / ml, preferably at least 5 mg / ml or 10 mg / ml
- the following combinations of additives are used as physiologically contractual auxiliaries in particular: a) arginine and phosphoric acid (argininium phosphate), b) arginine, phosphoric acid and aspartic acid or c) arginine, phosphoric acid, aspartic acid and isoleucine
- arginine and phosphoric acid argininium phosphate
- arginine, phosphoric acid and aspartic acid or c) arginine, phosphoric acid, aspartic acid and isoleucine
- the pharmaceutical dosage forms can be made available as ready-to-use injection or infusion solutions in corresponding ampoules.
- it is also possible to provide appropriate lyophilisates which are converted into the aqueous form shortly before application to the patient by adding isotonic solvents can be
- the dosage forms are expediently prepared by preparing an aqueous solution of all the ingredients and transferring them to corresponding ampoules or glass vials.
- the drying is preferably carried out directly from the glass containers into which the solution was filled
- PTH (1-37), 15 mg, arginine 3.0 g, aspartic acid 1.0 g and isoleucine 1.0 g were dissolved in 100 ml of water for injections and the pH was adjusted to pH with 85% phosphoric acid 7.4 set. This solution was sterile filtered and each with N 2 gassing
- Example 2 the formulation from Example 2 is produced with different pH values.
- the amount of arginine is varied at the same time
- PTH and arginine were dissolved in 100 ml of water for injections and the pH was adjusted to the respective pH with 85% phosphoric acid.
- the solutions were sterile filtered and 1 ml of the solution was filled into vials with N2 gassing. These vials were lyophilized, sealed and bound
- Example 9 The recipes in Example 9 were prepared analogously to the recipe in Example 2. 10 mg of methionine were used in formulation 9 a). 10 mg of ascorbic acid were added in formulation 9 b). Both solutions were adjusted to pH 7.4. The solutions were sterile filtered and 1 ml of this solution was poured into vials each under N2 gassing, and these vials were lyophilized, sealed and sealed
- Example 10 In Example 10, the recipe from Example 2 was used with the addition of 10 mg of Tween 20. PTH (1-84), arginine and Tween 20 were dissolved in water for injection purposes and the pH was raised to 85% phosphoric acid pH 7.4 set. This solution was sterile filtered and filled with 1 ml of the solution in vials each with N2 gassing. These vials were lyophilized, sealed and sealed
- PTH 1-3-7
- 15 mg and 3.5 g of histidine were dissolved in 100 ml of water for injections and the pH was adjusted to 7.4 with 85% phosphoric acid.
- This solution was sterile filtered and under N2 Fumigation filled with 1 ml of the solution in vials. This vial was lyophilized, sealed and sealed
- PTH (1-84) (manufacturer Sigma Corporation), 15 mg and 5.5 g of L-arginine were dissolved in 100 ml of water for injections and the pH was adjusted to pH 7.4 with 85% phosphoric acid The solution was filtered st ⁇ l and filled with 1 ml of the solution in vials under gassing with N2. These vials were lyophilized, sealed and sealed
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Endocrinology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Diabetes (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention concerns pharmaceutical preparations of parathormone. The preparations are stable during storage and contain a basic amino acid and optionally an organic or inorganic physiologically tolerated acid.
Description
Stabile pharmazeutische Darreichungsformen enthaltend ParathormonStable pharmaceutical dosage forms containing parathyroid hormone
Die Erfindung betrifft pharmazeutische Präparate, die als Wirkstoff Parathormon oder dessen Fragmente enthalten sowie entsprechende pharmazeutische Darreichungsformen in Form von Lyophilisaten oder InjektionslösungenThe invention relates to pharmaceutical preparations which contain parathyroid hormone or its fragments as an active ingredient, and to corresponding pharmaceutical dosage forms in the form of lyophilisates or injection solutions
Parathomon (PTH) ist ein aus vierundachtzig Aminosäuren aufgebautes Protein, das an der Regulierung des Calcium- und Phosphatgehaltes von Blut und Gewebe beteiligt ist. Aus der Literatur (vgl. auch WO 90/10067; WO 91/06564; EP 0 301 484, WO 93/15109) ist bekannt, daß N-terminale Fragmente dieses Hormons, aber auch Peptide mit entsprechenden Modifiationen in der Aminosauresequenz über eine analoge bio¬ logische Aktivität wie PTH(l-84) verfugen.Parathomone (PTH) is an eighty-four amino acid protein that is involved in regulating the calcium and phosphate levels in blood and tissue. From the literature (see also WO 90/10067; WO 91/06564; EP 0 301 484, WO 93/15109) it is known that N-terminal fragments of this hormone, but also peptides with corresponding modifications in the amino acid sequence via an analog have biological activity like PTH (1-84).
Aufgrund von Oxidationsprozessen an den freien Methioningruppen im Molekül ist die Stabilisierung des PTH in einer pharmazeutischen Darreichungsform jedoch problema- tisch. Ein Zusatz von Antioxidantien, wie z. B. Methionin oder Ascorbinsäure. fuhrt nicht zu Darreichungsformen mit einer für pharmazeutische Zwecke ausreichenden Stabilität. Aus EP 0 619 119 ist bekannt, daß eine Stabilisierung durch Gefriertrocknung einer Kombination von Zuckern und Natriumchlorid erzielt werden kann. Es hat sich jedoch gezeigt, daß diese Art der Stabilisierung die Bildung von Dimeren begünstigt. Dimere in pharmazeutischen Darreichungsformen sind jedoch problematisch, da sie aufgrund von immunologischen Reaktionen bei der Verabreichung am Patienten zu unerwünschten Nebenwirkungen fuhren können. Außerdem können Dimeren zu einem Aktivitätsverlust des Proteins in der Darreichungsform fuhren, insbesondere wenn die Darreichungsformen über einen längeren Zeitraum oder bei nicht optimalen Tempera- turen gelagert werden. Darüber hinaus ist die Lyophilisation im Rahmen der Herstellung von entsprechend getrockneten pharmazeutischen Darreichungsformen problematisch.However, due to oxidation processes on the free methionine groups in the molecule, the stabilization of the PTH in a pharmaceutical dosage form is problematic. An addition of antioxidants, such as. B. methionine or ascorbic acid. does not lead to dosage forms with a sufficient stability for pharmaceutical purposes. It is known from EP 0 619 119 that stabilization can be achieved by freeze-drying a combination of sugars and sodium chloride. However, it has been shown that this type of stabilization favors the formation of dimers. However, dimers in pharmaceutical dosage forms are problematic because they can lead to undesirable side effects due to immunological reactions when administered to the patient. In addition, dimers can lead to a loss of activity of the protein in the dosage form, in particular if the dosage forms are stored for a longer period of time or at suboptimal temperatures. In addition, lyophilization is problematic in the context of the production of appropriately dried pharmaceutical dosage forms.
ORIGINAL UNTERLAGEN
Überraschenderweise wurde gefunden, daß pharmazeutisch stabile Darreichungsformen von PTH bzw dessen Fragmente erhalten werden, wenn als pharmazeutische Hilfsstoffe eine oder mehrer basische Aminosäuren, insbesondere Arginin. Lysin oder Ornithin in der Darreichungsform enthalten sind Dadurch ist es möglich, auf den Zusatz von Anti¬ oxidantien oder Tensiden zu verzichten Außerdem fuhrt der Zusatz von basischen Aminosäuren zu Darreichungsformen, die über einen längeren Zeitraum hinweg lager¬ stabil sind Insbesondere kann die unerwünschte Bildung von Aggregaten reduziert bzw weitgehend vermieden werden Weiterhin wurde gefunden, daß durch den weiteren Zusatz einer sauren Aminosäure und/oder einer neutralen Aminosäure sich die Lyophi¬ lisation verbessern laßt Stabile wässrige Darreichungsformen sind insbesondere solche, die eine anorganische oder organische Saure enthalten und deren pH-Wert von 4 bis 8, insbesondere 6 bis 8 aufweisenORIGINAL DOCUMENTS Surprisingly, it has been found that pharmaceutically stable dosage forms of PTH or its fragments are obtained if one or more basic amino acids, in particular arginine, are used as pharmaceutical auxiliaries. Lysine or ornithine are contained in the dosage form. This makes it possible to dispense with the addition of anti-oxidants or surfactants. In addition, the addition of basic amino acids leads to dosage forms that are stable over a longer period of time. In particular, the undesired formation of Aggregates are reduced or largely avoided. It has also been found that the further addition of an acidic amino acid and / or a neutral amino acid can improve the lyophilization. Stable aqueous dosage forms are in particular those which contain an inorganic or organic acid and their pH have from 4 to 8, in particular 6 to 8
Als Parathormon-Fragmente im Sinne der Erfindung kommen insbesondere die humanen N-terminalen Fragmente des intakten Proteins in Frage, beispielsweise die Fragmente (1- 34), (1-35), (1-36), (1-37) oder (1-38) Ebenso können jedoch auch solche Fragmente des Parathormons eingesetzt werden, die N- und C-terminal verkürzt sind, beispielsweise Fragmente, die N-terminal um eine oder zwei Aminosäuren verkürzt sind Außerdem können auch entsprechende Varianten oder Modifikationen dieses Hormons eingesetzt werden, bei denen in der Aminosauresequenz des PTH(l-84) eine oder mehrere Amino¬ säuren gegen andere Aminosäuren ausgetauscht sind Dies trifft auch für die ent¬ sprechend N- und/oder C-terminal verkürzten Fragmente zu Insbesondere lassen sich im Sinne der Erfindung solche pharmazeutische Zubereitungen herstellen, die das Parat- hormon-Fragment hPTH 1-37 enthalten Dieses Fragment ist aufgrund seiner Struktur und Konformation sehr labil Die Herstellung von pharamazeutischen Zubereitungen mit üblichen pharmazeutischen Hilfsstoffen führte daher oft zu Instabilitäten der Produkte, da sich der Wirkstoffgehalt durch Agglomeration oder Zersetzung des Peptides bei längerer Lagerung stetig verringerte
Der Wirkstoffgehalt an Parathormon bzw Parathormonfragmenten in den flussigen Darreichungsformen betragt bis zu 10 mg/ml, insbesondere bis zu 5 mg/ml oder bis zu 2 mg/ml Der Wirkstoffgehalt betragt vorzugsweise mindestens 0,01 mg/ml, 0,04 mg/ml oder 0, 1 mg/ml Bevorzugte liegt liegt der Wirkstoffgehalt beispielsweise bei 0,01 - 5 mg/ml, insbesondere bei 0,04 - 2 mg/ml. Die lyophilisierten Darreichungsformen ent¬ halten den Wirkstoff in solchen Mengen, daß durch den Zusatz eines bestimmten Volumens einer physiologisch vertraglichen Rekonstitutionslosung entsprechende Infusions- oder Injektionslosungen des Wirkstoffes mit den genannten Konzentrations¬ bereichen erhalten werden. Die pharmazeutischen Darreichungsformen im Sinne der vorliegenden Erfindung sind im wesentlichen frei von Tensiden und üblichen physio¬ logisch vertraglichen Antioxidantien, insbesondere von sulfhydrylgruppen-haltigen Reagentien, wie beispielsweise Methionin oder Cystein, oder Ascorbinsaure Ferner sind sie vorzugsweise im wesentlichen frei von Chloridionen, da Chloridionen die Bildung von Dimeren begünstigen Insbesondere enthalten die erfindungsgemaßen Darreichungs- formen sonst keine weiteren pharmazeutische Zusatz- oder HilfsstofFe, wie z B Zucker oder physiologisch verträgliche Polymere Die Darreichungsformen im Sinne der Erfindung zeichnen sich insbesondere dadurch aus, daß sie im wesentlichen nur aus Aminosäuren und organischen oder anorganischen Sauren bestehen, wobei jedoch mindestens eine basische Aminosäure enthalten istParathormone fragments in the sense of the invention are in particular the human N-terminal fragments of the intact protein, for example fragments (1-34), (1-35), (1-36), (1-37) or ( 1-38) However, it is also possible to use fragments of the parathyroid hormone which are shortened at the N- and C-terminal, for example fragments which are shortened at the N-terminal by one or two amino acids. In addition, corresponding variants or modifications of this hormone can also be used , in which one or more amino acids are replaced by other amino acids in the amino acid sequence of PTH (1-84). This also applies to the fragments shortened correspondingly at the N- and / or C-terminal produce pharmaceutical preparations containing the parathormone fragment hPTH 1-37. This fragment is very unstable due to its structure and conformation. The preparation of pharmaceutical preparations Therefore, the use of conventional pharmaceutical excipients often led to instabilities in the products, since the active substance content steadily decreased due to agglomeration or decomposition of the peptide during longer storage The active substance content of parathyroid hormone or parathyroid hormone fragments in the liquid dosage forms is up to 10 mg / ml, in particular up to 5 mg / ml or up to 2 mg / ml. The active substance content is preferably at least 0.01 mg / ml, 0.04 mg / ml or 0.1 mg / ml. The active substance content is preferably, for example, 0.01-5 mg / ml, in particular 0.04-2 mg / ml. The lyophilized dosage forms contain the active ingredient in such amounts that by adding a certain volume of a physiologically contractual reconstitution solution, corresponding infusion or injection solutions of the active ingredient are obtained with the concentration ranges mentioned. The pharmaceutical dosage forms within the meaning of the present invention are essentially free from surfactants and customary physiologically compatible antioxidants, in particular from reagents containing sulfhydryl groups, such as methionine or cysteine, or ascorbic acid. Furthermore, they are preferably essentially free of chloride ions, since chloride ions are the Favor formation of dimers In particular, the dosage forms according to the invention otherwise contain no further pharmaceutical additives or auxiliaries, such as, for example, sugar or physiologically compatible polymers. The dosage forms within the meaning of the invention are distinguished in particular by the fact that they consist essentially only of amino acids and organic or inorganic acids exist, but at least one basic amino acid is contained
Als basische Aminosäuren kommen im Sinne der vorliegenden Erfindung alle physio¬ logische vertraglichen Aminosäuren mit mindestens einer basischen Seitengruppe in Frage. Basische Seitengruppen sind insbesondere Aminogruppen, die gegebenenfalls durch andere Reste, wie z.B. Ci-Cβ- Alkylgruppen, substituiert sein können. Als basische Aminosäuren kommen vorzugsweise insbesondere Histidin, Lysin, Arginin oder Ornithin in Frage.For the purposes of the present invention, basic amino acids are all physiological, contractual amino acids with at least one basic side group. Basic side groups are in particular amino groups, which may be replaced by other radicals, such as e.g. Ci-Cβ- alkyl groups, may be substituted. Preferred basic amino acids are in particular histidine, lysine, arginine or ornithine.
Als neutrale Aminosäuren kommen entsprechend die physiologisch vertraglichen Amino¬ säuren mit Seitengruppen in Frage, die über keine Sulfhydrylgruppen (Cystein, Methionin) verfügen, beispielsweise Phenylalanin, Glycin oder Isoleucin
Die Aminosäuren können prinzipiell in Form ihrer Racemate oder der optisch aktiven Formen (D- oder L-Aminosauren) eingesetzt werden Die Konzentration der Amino¬ säuren in der flussigen Darreichungsform liegt im Bereich von bis zu 100 mg/ml Besonders vorteilhaft sind Konzentrationen von bis zu 80 mg/ml, insbesondere bis zu 60 mg/ml, bzw bis zu 50 mg/ml oder 40 mg/ml Die Konzentration der Aminosäuren betragt vorteilhaft mindestens 1 mg/ml, insbesondere mindestens 5 mg/mlAccordingly, the physiologically acceptable amino acids with side groups which have no sulfhydryl groups (cysteine, methionine), for example phenylalanine, glycine or isoleucine, are suitable as neutral amino acids The amino acids can in principle be used in the form of their racemates or the optically active forms (D- or L-amino acids). The concentration of the amino acids in the liquid dosage form is in the range of up to 100 mg / ml. Concentrations of up to are particularly advantageous 80 mg / ml, in particular up to 60 mg / ml, or up to 50 mg / ml or 40 mg / ml. The concentration of the amino acids is advantageously at least 1 mg / ml, in particular at least 5 mg / ml
Als organische Sauren kommen im Sinne der vorliegenden Erfindung physiologisch vertragliche Carbonsauren, Hydroxycarbonsäuren oder Aminosäuren in Frage, sowie deren Salze, insbesondere Alkalisalze Vorteilhaft im Sinne der Erfindung sind beispiels¬ weise Milchsaure, Essigsaure, Zitronensaure oder Asparaginsäure Sofern diese Sauren über ein chirales Zentrum verfügen, können die Racemate oder auch die optisch aktiven Deπvate eingesetzt werdenAccording to the present invention, organic acids which are physiologically acceptable are carboxylic acids, hydroxycarboxylic acids or amino acids, and their salts, in particular alkali salts. Advantageous in the context of the invention are, for example, lactic acid, acetic acid, citric acid or aspartic acid. the racemates or the optically active derivatives can be used
Als anorganische Sauren kommen physiologisch vertragliche Sauren in Frage, beispiels¬ weise Phosphorsaure oder Schwefelsaure, bzw deren Salze, die in wassriger Losung auch als Puffer eingesetzt werden können, wie z B Natriumdihydrogenphosphat, Kaliumdihydrogenphosphat, Dinatriumhydrogenphosphat, Natriumhydrogensulfat, etc Die organischen oder anorganischen Sauren können auch in Kombination miteinander eingesetzt werden Die Menge der Saure wird derart gewählt, daß die wässrige Losung einen pH- Wert von 4 - 8, bevorzugt 6 - 8 aufweist In der Regel betragt die Konzentra¬ tion der Saure in der Losung bis zu 100 mg/ml, insbesondere bis zu 50 mg/ml oder bis zu 40 mg/ml Die Konzentration der Saure betragt mindestens 1 mg/ml, bevorzugt mindestens 5 mg/ml oder 10 mg/mlSuitable inorganic acids are physiologically acceptable acids, for example phosphoric acid or sulfuric acid, or their salts, which can also be used as a buffer in aqueous solution, such as sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogen sulfate, etc. The organic or inorganic acids can also be used in combination with one another. The amount of acid is chosen such that the aqueous solution has a pH of 4-8, preferably 6-8. As a rule, the concentration of the acid in the solution is up to 100 mg / ml, in particular up to 50 mg / ml or up to 40 mg / ml. The concentration of the acid is at least 1 mg / ml, preferably at least 5 mg / ml or 10 mg / ml
Als physiologisch vertragliche HilfsstofFe werden im Sinne der vorliegenden Erfindung insbesondere folgende Kombinationen an Zusatzstoffen eingesetzt a) Arginin und Phosphorsaure (Argininiumphosphat), b) Arginin, Phosphorsaure und Asparaginsäure oder c) Arginin, Phosphorsaure, Asparaginsäure und Isoleucin
Die pharmazeutischen Darreichungsformen können als spπtzfertige Injektions- oder In¬ fusionslosungen in entsprechenden Ampullen zur Verfugung gestellt werden Alternativ ist es ebenfalls möglich, auch entsprechende Lyophilisate zur Verfugung zu stellen, die durch Zusatz von isotonischen Lösungsmitteln kurz vor der Applikation am Patienten in die wässrige Form überführt werden könnenIn the context of the present invention, the following combinations of additives are used as physiologically contractual auxiliaries in particular: a) arginine and phosphoric acid (argininium phosphate), b) arginine, phosphoric acid and aspartic acid or c) arginine, phosphoric acid, aspartic acid and isoleucine The pharmaceutical dosage forms can be made available as ready-to-use injection or infusion solutions in corresponding ampoules. Alternatively, it is also possible to provide appropriate lyophilisates which are converted into the aqueous form shortly before application to the patient by adding isotonic solvents can be
Die Herstellung der Darreichungsformen erfolgt zweckmaßigerweise dadurch, daß man eine wässrige Losung aller Inhaltsstoffe herstellt und in entsprechende Ampullen oder Glasvials überfuhrt Im Falle der Herstellung der Lyophilisate erfolgt die Trocknung vorzugsweise direkt aus den Glasbehaltnissen, in die die Losung abgefüllt wurdeThe dosage forms are expediently prepared by preparing an aqueous solution of all the ingredients and transferring them to corresponding ampoules or glass vials. In the case of the production of the lyophilisates, the drying is preferably carried out directly from the glass containers into which the solution was filled
Anhand der folgenden Ausführungsbeispiele wird die Erfindung naher erläutertThe invention is explained in more detail with reference to the following exemplary embodiments
Beispiel 1example 1
15 mg PTH (1-37) und 2,5 g L-Arginin wurden in 100 ml Wasser für Injektionszwecke gelöst und der pH- Wert mit 99%-iger Essigsaure auf pH 6,5 eingestellt Diese Losung wurde steril filtriert und unter N2-Begasung je 1 ml der Losung in Glasvials abgefüllt15 mg PTH (1-37) and 2.5 g L-arginine were dissolved in 100 ml water for injections and the pH was adjusted to pH 6.5 with 99% acetic acid. This solution was sterile filtered and under N 2 -Fumigation filled 1 ml of the solution in glass vials
Beispiel 2Example 2
15 mg PTH (1-37) und 5,5 g Arginin wurden in 100 ml Wasser für Injektionszwecke gelöst und der pH-Wert mit 85%-iger Phosphorsaure auf pH 7,4 eingestellt Diese Lösung wurde steril filtriert und unter N2-Begasung je 1 ml der Losung in Glasvials ab¬ gefüllt Diese Vials wurden lyophilisiert, verschlossen und verbordelt15 mg of PTH (1-37) and 5.5 g of arginine were dissolved in 100 ml of water for injections and the pH was adjusted to pH 7.4 with 85% phosphoric acid. This solution was filtered sterile and with N 2 gassing 1 ml each of the solution is filled into glass vials. These vials were lyophilized, sealed and sealed
Beispiel 3Example 3
150 mg PTH (1-37) und 5,5 g Arginin wurden in 100 ml Wasser für Injektionszwecke gelöst und der pH-Wert mit 85%-iger Phosphorsaure auf pH 7,4 eingestellt Diese
Losung wurde steril filtriert und unter N2-Begasung je 1 ml der Losung in Glasvials ab¬ gefüllt Diese Vials wurden lyophilisiert, verschlossen und verbordelt150 mg of PTH (1-37) and 5.5 g of arginine were dissolved in 100 ml of water for injections and the pH was adjusted to pH 7.4 with 85% phosphoric acid The solution was sterile filtered and 1 ml of the solution was poured into glass vials under N 2 gassing. These vials were lyophilized, sealed and sealed
Beispiel 4Example 4
15 mg PTH (1-37), 3 g L-Arginin und 2 g Asparaginsäure wurden in 100 ml Wasser für Injektionszwecke gelöst und der pH- Wert mit 85%-iger Phosphorsaure auf pH 7,4 ein¬ gestellt Diese Lösung wurde steril filtriert und unter N2-Begasung je 1 ml der Losung in15 mg of PTH (1-37), 3 g of L-arginine and 2 g of aspartic acid were dissolved in 100 ml of water for injection purposes and the pH was adjusted to 7.4 with 85% phosphoric acid. This solution was sterile filtered and with N 2 gassing 1 ml of the solution in
Glasvials abgefüllt Diese Vials wurden lyophilisiert, verschlossen und verbordeltFilled glass vials These vials were lyophilized, sealed and sealed
Beispiel 5Example 5
15 mg PTH (1-37), L-Arginin 3,0 g und Isoleucin 2,0 g wurden in 100 ml Wasser für15 mg of PTH (1-37), L-arginine 3.0 g and isoleucine 2.0 g were in 100 ml of water for
Injektionszwecke gelöst und der pH-Wert mit 85%-iger Phosphorsäure auf pH 7,4 ein- gestellt Diese Lösung wurde steril filtriert und unter N2-Begasung je 1 ml der Losung inInjection purposes solved and the pH adjusted to pH 7.4 with 85% phosphoric acid. This solution was sterile filtered and 1 ml of the solution in with N 2 gassing
Glasvials abgefüllt Diese Vials wurden lyophilisiert, verschlossen und verbordelt.Filled glass vials These vials were lyophilized, sealed and sealed.
Beispiel 6Example 6
PTH (1-37), 15 mg, Arginin 3,0 g, Asparaginsäure 1,0 g und Isoleucin 1,0 g wurden in 100 ml Wasser für Injektionszwecke gelöst und der pH-Wert mit 85%-iger Phosphor¬ säure auf pH 7,4 eingestellt. Diese Lösung wurde steril filtriert und unter N2-Begasung jePTH (1-37), 15 mg, arginine 3.0 g, aspartic acid 1.0 g and isoleucine 1.0 g were dissolved in 100 ml of water for injections and the pH was adjusted to pH with 85% phosphoric acid 7.4 set. This solution was sterile filtered and each with N 2 gassing
1 ml der Lösung in Vials abgefüllt. Diese Vials wurden lyophilisiert, verschlossen und verbördelt.1 ml of the solution is filled into vials. These vials were lyophilized, sealed and crimped.
Beispiel 7Example 7
PTH (1-37), 15 mg Saccharose 2,0 mg und 100 mg Natriumchlorid wurden in 100 ml Wasser für Injektionszwecke gelöst Diese Lösung wurde steril filtriert und unter N2- Begasung je 1 ml der Lösung in Vials abgefüllt. Diese Vials wurden lyophilisiert, ver¬ schlossen und verbördelt.
Beispiel 8PTH (1-37), 15 mg sucrose, 2.0 mg and 100 mg sodium chloride were dissolved in 100 ml of water for injections. This solution was sterile filtered and 1 ml of the solution was filled into vials with N2 gassing. These vials were lyophilized, closed and crimped. Example 8
In diesem Beispiel wird die Rezeptur aus Beispiel 2 mit verschiedenen pH- Werten herge¬ stellt Dazu wird gleichzeitig die Menge an Arginin variiertIn this example, the formulation from Example 2 is produced with different pH values. The amount of arginine is varied at the same time
PTH und Arginin wurden in 100 ml Wasser für Injektionszwecke gelost und der pH- Wert mit 85%-iger Phosphorsaure auf den jeweiligen pH- Wert eingestellt Die Losungen wurden steril filtriert und unter N2-Begasung je 1 ml der Losung in Vials abgefüllt Diese Vials wurden lyophilisiert, verschlossen und verbordeltPTH and arginine were dissolved in 100 ml of water for injections and the pH was adjusted to the respective pH with 85% phosphoric acid. The solutions were sterile filtered and 1 ml of the solution was filled into vials with N2 gassing. These vials were lyophilized, sealed and bound
Beispiel 9Example 9
Die Rezepturen in Beispiel 9 wurden analog der Rezeptur in Beispiel 2 hergestellt In Rezeptur 9 a) wurden 10 mg Methionin eingesetzt In Rezeptur 9 b) wurden 10 mg Ascorbinsaure zugesetzt Beide Losungen wurden auf pH-Wert 7,4 eingestellt Die Losungen wurden steril filtriert und unter N2-Begasung je 1 ml dieser Losung in Vials abgefüllt, und diese Vials wurden lyophilisiert, verschlossen und verbordeltThe recipes in Example 9 were prepared analogously to the recipe in Example 2. 10 mg of methionine were used in formulation 9 a). 10 mg of ascorbic acid were added in formulation 9 b). Both solutions were adjusted to pH 7.4. The solutions were sterile filtered and 1 ml of this solution was poured into vials each under N2 gassing, and these vials were lyophilized, sealed and sealed
Beispiel 10
In Beispiel 10 wurde die Rezeptur aus Beispiel 2 mit einem Zusatz von 10 mg Tween 20 eingesetzt Dabei wurden PTH(l-84), Arginin und Tween 20 in Wasser für Injektions¬ zwecke gelost und der pH-Wert mit 85%-iger Phosphorsaure auf pH- Wert 7,4 einge¬ stellt Diese Losung wurde steril filtriert und unter N2-Begasung je 1 ml der Losung in Vials abgefüllt Diese Vials wurden lyophilisiert, verschlossen und verbordeltExample 10 In Example 10, the recipe from Example 2 was used with the addition of 10 mg of Tween 20. PTH (1-84), arginine and Tween 20 were dissolved in water for injection purposes and the pH was raised to 85% phosphoric acid pH 7.4 set. This solution was sterile filtered and filled with 1 ml of the solution in vials each with N2 gassing. These vials were lyophilized, sealed and sealed
Beispiel 1 1Example 1 1
PTH (1-37), 15 mg und 3,5 g Histidin wurden in 100 ml Wasser für Injektionszwecke gelost und der pH-Wert mit 85%-iger Phosphorsaure auf pH-Wert 7,4 eingestellt Diese Losung wurde steril filtriert und unter N2-Begasung je 1 ml der Losung in Vials abge¬ füllt Diese Vials wurde lyophilisiert, verschlossen und verbordeltPTH (1-37), 15 mg and 3.5 g of histidine were dissolved in 100 ml of water for injections and the pH was adjusted to 7.4 with 85% phosphoric acid. This solution was sterile filtered and under N2 Fumigation filled with 1 ml of the solution in vials. This vial was lyophilized, sealed and sealed
Beispiel 12Example 12
PTH (1 -84) (Hersteller Sigma Corporation), 15 mg und 5,5 g L-Arginin wurden in 100 ml Wasser für Injektionszwecke gelost und der pH-Wert mit 85%-iger Phosphorsaure auf pH-Wert 7,4 eingestellt Diese Losung wurde steπl filtriert und unter N2-Begasung je 1 ml der Losung in Vials abgefüllt Diese Vials wurden lyophilisiert, verschlossen und verbordeltPTH (1-84) (manufacturer Sigma Corporation), 15 mg and 5.5 g of L-arginine were dissolved in 100 ml of water for injections and the pH was adjusted to pH 7.4 with 85% phosphoric acid The solution was filtered stπl and filled with 1 ml of the solution in vials under gassing with N2. These vials were lyophilized, sealed and sealed
Anmerkungen zur TabelleNotes on the table
Die Ergebnisse der Stabilitatsuberprufüng nach einer Lagerzeit von einem oder drei Monaten bei Kuhlschranktemperatur (KS) und bei 50 °C sind für die oben genannten Ausführungsbeispiele in Tabelle 1 zusammengefaßt
Im Rahmen der erfindungsgemaßen Darreichungsformen konnten keine Dimere bei der Bestimmung nach der SDS-PAGE-Methode festgestellt werden Außerdem zeigte sich, daß der PTH-Gehalt nach einer Lagerzeit von einem bzw drei Monaten bei ca 4 °C mindestens 98 % betragt Auch bei höheren Temperaturen (50 °C) konnte kein signifikanter Verlust im PTH-Gehalt festgestellt werdenThe results of the stability test after a storage period of one or three months at refrigerator temperature (KS) and at 50 ° C. are summarized in Table 1 for the above-mentioned exemplary embodiments In the dosage forms according to the invention, no dimers could be determined when determined by the SDS-PAGE method. It was also found that the PTH content after a storage period of one or three months at about 4 ° C. was at least 98%, even at higher temperatures (50 ° C) no significant loss in the PTH content was found
Die in Beispiel 7, 9 und 10 beschriebenen Darreichungsformen hingegen begünstigen die Entstehung von Dimeren, bzw. zeigen einen geringeren PTH-Gehalt nach einer Lagerzeit von einem oder drei Monaten und können somit in bezug auf die Lagerstabilitat als weniger geeignete pharmazeutische Darreichungsformen eingestuft werden Prinzipiell hat sich gezeigt, daß sich ein Gehalt von Chloridionen negativ hinsichtlich der Lager¬ stabilitat auswirkt, so daß bei den erfindungsgemaßen Darreichungsformen chloridfreie Formen bevorzugt in Frage kommen.
The dosage forms described in Examples 7, 9 and 10, on the other hand, favor the formation of dimers or show a lower PTH content after a storage period of one or three months and can therefore in principle be classified as less suitable pharmaceutical dosage forms in terms of storage stability It has been shown that a content of chloride ions has a negative effect on the storage stability, so that chloride-free forms are preferred in the dosage forms according to the invention.
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Claims
Patentansprüche claims
1 Lagerstabile pharmazeutische Zubereitung enthaltend als Wirkstoff Parathomon oder ein Parathormon-Fragment sowie eine oder mehrere basische Arminosauren1 Storage-stable pharmaceutical preparation containing the active ingredient parathomone or a parathyroid hormone fragment and one or more basic amino acids
2 Pharmazeutische Zubereitung nach Anspruch 1, enthaltend ferner eine orgamsche oder anorganische Saure, die zur Einstellung des pH-Werte auf 3,0 bis 8,0 geeignet ist2 Pharmaceutical preparation according to claim 1, further comprising an organic or inorganic acid which is suitable for adjusting the pH to 3.0 to 8.0
3 Pharmazeutische Zubereitung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß zusatzlich eine oder mehrere neutrale Aminosäuren enthalten sind3 Pharmaceutical preparation according to claim 1 or 2, characterized in that one or more neutral amino acids are additionally contained
4 Pharmazeutische Zubereitung nach einem der Ansprüche 1 -3, dadurch gekenn- * zeichnet, daß die basischen Aminosäuren Histidin, Lysin oder Arginin sind4 Pharmaceutical preparation according to one of claims 1 -3, characterized- * characterized in that the basic amino acids are histidine, lysine or arginine
5 Pharmazeutische Zubereitung nach einem der Ansprüche 1 - 4, dadurch gekenn¬ zeichnet, daß die organische Saure aus der Gruppe der Carbonsauren oder der Aminosäuren ausgewählt wird, insbesondere Milchsäure, Essigsaure, Zitronensaure oder Asparaginsäure5 Pharmaceutical preparation according to one of claims 1-4, characterized gekenn¬ characterized in that the organic acid is selected from the group of carboxylic acids or amino acids, especially lactic acid, acetic acid, citric acid or aspartic acid
6 Pharmazeutische Zubereitung nach einem der Ansprüche 1 - 4, dadurch gekenn¬ zeichnet, daß die anorganische Saure Phosphorsaure oder Schwefelsaure ist6 Pharmaceutical preparation according to one of claims 1-4, characterized gekenn¬ characterized in that the inorganic acid is phosphoric acid or sulfuric acid
7 Pharmazeutische Zubereitung nach einem der Ansprüche 1- 6, dadurch gekenn¬ zeichnet, daß Kombinationen von organischen und anorganischen Sauren enthalten sind, insbesondere Phosphorsaure und Asparaginsäure bzw deren physiologisch vertraglichen Salze
8 Pharmazeutische Zubereitung nach einem der Ansprüche 3 - 7, dadurch gekenn¬ zeichnet, daß als neutrale Aminosäuren sulfhydrylgruppen-freie Aminosäuren enthalten sind, insbesondere Phenylalanin. Glycin oder Isoleucin7 Pharmaceutical preparation according to one of claims 1- 6, characterized gekenn¬ characterized in that combinations of organic and inorganic acids are contained, in particular phosphoric acid and aspartic acid or their physiologically acceptable salts 8 Pharmaceutical preparation according to one of claims 3 - 7, characterized gekenn¬ characterized in that sulfhydryl group-free amino acids are contained as neutral amino acids, especially phenylalanine. Glycine or isoleucine
9 Pharmazeutische Zubereitung nach einem der Ansprüche 1 - 8 in Form einer flussigen Darreichungsform für Injektions- oder Infusionszwecke, dadurch gekenn¬ zeichnet, daß der pH-Wert des Losung im Bereich von 4 bis 8 liegt9 Pharmaceutical preparation according to one of claims 1-8 in the form of a liquid dosage form for injection or infusion purposes, characterized gekenn¬ characterized in that the pH of the solution is in the range of 4 to 8
10 Pharmazeutische Zubereitung nach einem der Ansprüche 1 - 8 in Form eines Lyophilisates zur Herstellung einer Infusions- oder Injektionslosung mit einem pH- Wert von 4 bis 8, insbesondere mit einem pH-Wert von 6 bis 810 Pharmaceutical preparation according to one of claims 1-8 in the form of a lyophilisate for the preparation of an infusion or injection solution with a pH of 4 to 8, in particular with a pH of 6 to 8
1 1 Pharmazeutische Zubereitung nach einem der Ansprüche 1 - 10, dadurch gekenn¬ zeichnet, daß der Wirkstoff in einer Konzentration Menge von 0,01 bis 10 mg/ml, bevorzugt von 0,04 bis 2 mg/ml enthalten ist1 1 Pharmaceutical preparation according to one of claims 1-10, characterized gekenn¬ characterized in that the active ingredient is contained in a concentration amount of 0.01 to 10 mg / ml, preferably 0.04 to 2 mg / ml
12 Pharmazeutische Zubereitung nach einem der Ansprüche 1 -1 1, dadurch gekenn¬ zeichnet, daß die basische Aminosäure in einer Konzentration von 1 - 100 mg/ml, bevorzugt von 5 - 60 mg/ml enthalten ist12 Pharmaceutical preparation according to one of claims 1 -1 1, characterized gekenn¬ characterized in that the basic amino acid is contained in a concentration of 1-100 mg / ml, preferably 5-60 mg / ml
13 Pharmazeutische Zubereitung nach einem der Ansprüche 1 - 12, dadurch gekenn¬ zeichnet, daß die organische oder anorganische Saure in einer Konzentration von 1 - 50 mg/ml, bevorzugt von 5 - 40 mg/ml enthalten ist13 Pharmaceutical preparation according to one of claims 1-12, characterized gekenn¬ characterized in that the organic or inorganic acid is contained in a concentration of 1-50 mg / ml, preferably 5-40 mg / ml
14 Pharmazeutische Zubereitung nach einem der Ansprüche 1 - 13 bestehend im wesentlichen aus Aminosäuren und einer organischen oder anorganischen Saure, wobei mindestens eine basische Aminosäure enthalten ist14 Pharmaceutical preparation according to one of claims 1-13 consisting essentially of amino acids and an organic or inorganic acid, at least one basic amino acid being contained
15 Verfahren zur Herstellung von pharmazeutischen Zubereitungen nach einem der Ansprüche 1 - 13, dadurch gekennzeichnet, daß man eine Losung oder Suspension des Wirkstoffes in einem physiologisch vertraglichen Losungsmittel herstellt und
eine oder mehrere basische Aminosäuren und eine oder mehrere organische oder anorganische Sauren hinzufügt und anschließend die Losung zu spritzfertigen Injektions- oder Infusionslosungen verarbeitet oder die Losung lyophilisiert15 A process for the preparation of pharmaceutical preparations according to any one of claims 1-13, characterized in that a solution or suspension of the active ingredient is prepared in a physiologically acceptable solvent and adding one or more basic amino acids and one or more organic or inorganic acids and then processing the solution into ready-to-use injection or infusion solutions or lyophilizing the solution
Verwendung von pharmazeutischen Darreichungsformen nach einem der Ansprüche 1 - 13 zur Behandlung von Calciumstoffwechselerkrankungen, insbesondere von OsteoporoseUse of pharmaceutical dosage forms according to one of claims 1-13 for the treatment of calcium metabolic diseases, in particular of osteoporosis
Verwendung einer basischen Aminosäure zur Herstellung von lagerstabilen pharmazeutischen Darreichungformen enthaltend Parathormon oder ein Parat¬ hormon-Fragment
Use of a basic amino acid for the production of storage-stable pharmaceutical dosage forms containing parathyroid hormone or a paratormone fragment
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19538687 | 1995-10-17 | ||
DE19538687A DE19538687A1 (en) | 1995-10-17 | 1995-10-17 | Stable pharmaceutical dosage forms containing parathyroid hormone |
PCT/EP1996/004503 WO1997014429A1 (en) | 1995-10-17 | 1996-10-17 | Stable pharmaceutical forms of administration containing parathormone |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0855917A1 true EP0855917A1 (en) | 1998-08-05 |
Family
ID=7775105
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96934715A Withdrawn EP0855917A1 (en) | 1995-10-17 | 1996-10-17 | Stable pharmaceutical forms of administration containing parathormone |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0855917A1 (en) |
JP (1) | JPH11515002A (en) |
KR (1) | KR19990064322A (en) |
AU (1) | AU7294196A (en) |
BR (1) | BR9610983A (en) |
CA (1) | CA2234724A1 (en) |
CZ (1) | CZ108398A3 (en) |
DE (1) | DE19538687A1 (en) |
HU (1) | HUP9900751A3 (en) |
NZ (1) | NZ320237A (en) |
SK (1) | SK47298A3 (en) |
TR (1) | TR199800690T1 (en) |
WO (1) | WO1997014429A1 (en) |
ZA (1) | ZA968715B (en) |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19539574A1 (en) | 1995-10-25 | 1997-04-30 | Boehringer Mannheim Gmbh | Preparations and processes for stabilizing biological materials by means of drying processes without freezing |
DE19716154A1 (en) * | 1997-04-18 | 1998-10-22 | Boehringer Mannheim Gmbh | Stable pharmaceutical dosage form for peptides, proteins and nucleic acids |
MY120063A (en) † | 1997-12-09 | 2005-08-30 | Lilly Co Eli | Stabilized teriparatide solutions |
US6770623B1 (en) | 1997-12-09 | 2004-08-03 | Eli Lilly And Company | Stabilized teriparatide solutions |
SE9801495D0 (en) * | 1998-04-28 | 1998-04-28 | Astra Ab | Protein formulation |
WO2001032201A2 (en) * | 1999-10-29 | 2001-05-10 | Eli Lilly And Company | A pharmaceutical composition having high cell membrane permeability |
DE60125986T3 (en) * | 2000-02-08 | 2011-07-28 | Allergan, Inc., 92612, Calif. | Pharmaceutical compositions with botulinum toxin |
MY136546A (en) * | 2000-06-30 | 2008-10-31 | Asubio Pharma Co Ltd | A pharmaceutical component based on human parathyroid harmone and a pharmaceutical composition for intranasal administration comprising the component |
US8765124B2 (en) | 2003-02-28 | 2014-07-01 | Chugai Seiyaku Kabushiki Kaisha | Stabilized preparation containing protein |
WO2005014034A1 (en) * | 2003-07-14 | 2005-02-17 | Nps Allelix Corp. | Stabilized formulation of parathyroid hormone |
KR100700869B1 (en) * | 2005-06-03 | 2007-03-29 | 재단법인 목암생명공학연구소 | The stabilized parathyroid hormone composition comprising parathyroid hormone buffer and stabilizing agent |
USRE49444E1 (en) | 2006-10-03 | 2023-03-07 | Radius Health, Inc. | Method of treating osteoporosis comprising administration of PTHrP analog |
FR2947181B1 (en) * | 2009-06-26 | 2012-05-04 | Lfb Biotechnologies | FACTOR VII COMPOSITION |
CN108195965B (en) | 2011-06-07 | 2021-02-23 | 旭化成制药株式会社 | Method for testing PTH peptide-containing lyophilized preparation, and method for producing pharmaceutical product containing PTH peptide-containing lyophilized preparation |
BR112017023269A2 (en) | 2015-04-29 | 2018-11-06 | Radius Pharmaceuticals Inc | methods for cancer treatment |
JP6634758B2 (en) * | 2015-09-25 | 2020-01-22 | ニプロ株式会社 | Liquid composition and freeze-dried preparation |
US10385008B2 (en) | 2017-01-05 | 2019-08-20 | Radius Pharmaceuticals, Inc. | Polymorphic forms of RAD1901-2HCL |
US10996208B2 (en) | 2017-04-28 | 2021-05-04 | Radius Health, Inc. | Abaloparatide formulations and methods of testing, storing, modifying, and using same |
CA3075977A1 (en) * | 2017-09-22 | 2019-03-28 | Asahi Kasei Pharma Corporation | Teriparatide-containing liquid pharmaceutical composition having excellent stability |
CN112423844A (en) | 2018-07-04 | 2021-02-26 | 雷迪厄斯制药公司 | Polymorphic forms of RAD1901-2HCL |
JP6947946B1 (en) * | 2020-05-11 | 2021-10-13 | 旭化成ファーマ株式会社 | Stable liquid pharmaceutical product containing teriparatide or a salt thereof |
WO2021229835A1 (en) * | 2020-05-11 | 2021-11-18 | 旭化成ファーマ株式会社 | Stable liquid pharmaceutical preparation containing teriparatide or salt thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816568A (en) * | 1986-05-16 | 1989-03-28 | International Minerals & Chemical Corp. | Stabilization of growth hormones |
JP2739482B2 (en) * | 1988-08-11 | 1998-04-15 | バイオ・チバ株式会社 | Method for producing stable calcitonin injection |
JPH0341033A (en) * | 1989-07-07 | 1991-02-21 | Kyowa Hakko Kogyo Co Ltd | Stable preparation containing motilins |
US5563122A (en) * | 1991-12-09 | 1996-10-08 | Asahi Kasei Kogyo Kabushiki Kaisha | Stabilized parathyroid hormone composition |
DE4203040A1 (en) * | 1992-02-04 | 1993-08-05 | Boehringer Mannheim Gmbh | NEW PARATHORMON FRAGMENTS, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM |
-
1995
- 1995-10-17 DE DE19538687A patent/DE19538687A1/en not_active Withdrawn
-
1996
- 1996-10-16 ZA ZA9608715A patent/ZA968715B/en unknown
- 1996-10-17 CA CA002234724A patent/CA2234724A1/en not_active Abandoned
- 1996-10-17 JP JP9515527A patent/JPH11515002A/en active Pending
- 1996-10-17 KR KR1019980702819A patent/KR19990064322A/en not_active Application Discontinuation
- 1996-10-17 NZ NZ320237A patent/NZ320237A/en unknown
- 1996-10-17 HU HU9900751A patent/HUP9900751A3/en unknown
- 1996-10-17 BR BR9610983A patent/BR9610983A/en not_active Application Discontinuation
- 1996-10-17 WO PCT/EP1996/004503 patent/WO1997014429A1/en not_active Application Discontinuation
- 1996-10-17 CZ CZ981083A patent/CZ108398A3/en unknown
- 1996-10-17 AU AU72941/96A patent/AU7294196A/en not_active Abandoned
- 1996-10-17 TR TR1998/00690T patent/TR199800690T1/en unknown
- 1996-10-17 SK SK472-98A patent/SK47298A3/en unknown
- 1996-10-17 EP EP96934715A patent/EP0855917A1/en not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO9714429A1 * |
Also Published As
Publication number | Publication date |
---|---|
SK47298A3 (en) | 1998-11-04 |
ZA968715B (en) | 1998-04-16 |
JPH11515002A (en) | 1999-12-21 |
KR19990064322A (en) | 1999-07-26 |
WO1997014429A1 (en) | 1997-04-24 |
NZ320237A (en) | 1999-11-29 |
HUP9900751A2 (en) | 1999-07-28 |
AU7294196A (en) | 1997-05-07 |
DE19538687A1 (en) | 1997-04-24 |
BR9610983A (en) | 1999-03-02 |
CZ108398A3 (en) | 1998-09-16 |
TR199800690T1 (en) | 1998-06-22 |
CA2234724A1 (en) | 1997-04-24 |
HUP9900751A3 (en) | 2000-07-28 |
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