BE898082A - SOLUTION FOR INJECTION AND PROCESS FOR ITS PREPARATION. - Google Patents
SOLUTION FOR INJECTION AND PROCESS FOR ITS PREPARATION. Download PDFInfo
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- BE898082A BE898082A BE0/211771A BE211771A BE898082A BE 898082 A BE898082 A BE 898082A BE 0/211771 A BE0/211771 A BE 0/211771A BE 211771 A BE211771 A BE 211771A BE 898082 A BE898082 A BE 898082A
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- Belgium
- Prior art keywords
- injection
- solution
- antirheumatic
- substances
- preparation
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- 238000002347 injection Methods 0.000 title claims abstract description 13
- 239000007924 injection Substances 0.000 title claims abstract description 13
- 239000000243 solution Substances 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 6
- 239000003435 antirheumatic agent Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 230000003356 anti-rheumatic effect Effects 0.000 claims abstract description 11
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 238000007918 intramuscular administration Methods 0.000 claims abstract description 4
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000003246 corticosteroid Substances 0.000 claims abstract description 3
- 229960000581 salicylamide Drugs 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract 4
- 239000013543 active substance Substances 0.000 claims description 11
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 239000003589 local anesthetic agent Substances 0.000 claims description 3
- 150000003218 pyrazolidines Chemical class 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000011782 vitamin Substances 0.000 description 6
- 229940010007 cobalamins Drugs 0.000 description 5
- 150000001867 cobalamins Chemical class 0.000 description 5
- 235000000639 cyanocobalamin Nutrition 0.000 description 5
- 239000011666 cyanocobalamin Substances 0.000 description 5
- 229960002104 cyanocobalamin Drugs 0.000 description 5
- 239000012154 double-distilled water Substances 0.000 description 5
- 229940088594 vitamin Drugs 0.000 description 5
- 229930003231 vitamin Natural products 0.000 description 5
- 235000013343 vitamin Nutrition 0.000 description 5
- 150000003722 vitamin derivatives Chemical class 0.000 description 5
- 229960003957 dexamethasone Drugs 0.000 description 4
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 4
- LGYTZKPVOAIUKX-UHFFFAOYSA-N kebuzone Chemical compound O=C1C(CCC(=O)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 LGYTZKPVOAIUKX-UHFFFAOYSA-N 0.000 description 4
- 229960000194 kebuzone Drugs 0.000 description 4
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 3
- 229930003779 Vitamin B12 Natural products 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 229960004194 lidocaine Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000011715 vitamin B12 Substances 0.000 description 3
- 235000019163 vitamin B12 Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960002442 glucosamine Drugs 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- -1 N-methylpyrrolidone Chemical class 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 210000005221 acidic domain Anatomy 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002301 glucosamine derivatives Chemical class 0.000 description 1
- 244000000053 intestinal parasite Species 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- RLISWLLILOTWGG-UHFFFAOYSA-N salamidacetic acid Chemical compound NC(=O)C1=CC=CC=C1OCC(O)=O RLISWLLILOTWGG-UHFFFAOYSA-N 0.000 description 1
- 229950000417 salamidacetic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- OEQSACUVTKYXIR-UHFFFAOYSA-M sodium;2-(2-carbamoylphenoxy)acetate Chemical compound [Na+].NC(=O)C1=CC=CC=C1OCC([O-])=O OEQSACUVTKYXIR-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
L'invention concerne une solution aqueuse pour injection contenant des substances antirhumatismales et une cobalamine, particulièrement bien tolérée enadministration intramusculaire, et qui est stable en présence d'agents solubilisants par ajustement du pH entre 5 et 8. Les substances antirhumatismales peuvent entre autres etre des dérivés de la pyrazolidine, du salicylamide ou d'un corticostéroide.The invention relates to an aqueous solution for injection containing antirheumatic substances and a cobalamin, particularly well tolerated in intramuscular administration, and which is stable in the presence of solubilizing agents by adjusting the pH between 5 and 8. The antirheumatic substances can inter alia be derived from pyrazolidine, salicylamide or a corticosteroid.
Description
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déposée par la société dite : GEROT-PHARMAZEUTIKA
GESELLSCHAFT mbH ayant pour objet : Solution pour injection et procédé pour sa préparation Qualification proposée : BREVET D'INVENTION
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La présente invention concerne une solution aqueuse pour injection qui contient à la fois des substances actives antirhumatismales et de la vitamine Bzw et un procédé pour sa préparation.
Les substances actives antirhumatismales, telles que les dérivés de la pyrazolidine, du salicylamide et des corticostéroïdes, sont peu solubles dans l'eau.
Mais, pour réduire au minimum le volume d'injection, il est nécessaire d'avoir une concentration relativement élevée en substance active, et par conséquent une bonne solubilité, laquelle, en l'absence d'addition d'agents solubilisants, n'est obtenue qu'en milieu alcalin.
La vitamine B,-, qui est utilisée dans les préparations antirhumatismales pour injection pour renforcer l'action antinévralgique et analgésique, est cependant instable en milieu alcalin. Comme l'indique la littérature, l'optimum de stabilité des Cobalamines se situe dans le domaine faiblement acide.
En raison des exigences de pH divergentes des agents antirhumatismaux d'une part, et des cobalamines d'autre part, on avait l'habitude jusqu'à présent de présenter les deux solutions actives séparées l'une de l'autre, soit en deux ampoules, soit dans deux chambres disposées l'une derrière l'autre d'une seringue prête à l'emploi.
L'utilisation de deux ampoules par injection est cependant compliquée pour le médecin traitant et exige des emballages plus grands, l'utilisation de la seringue à deux chambres occasionne une dépense technique accompagnée d'un supplément de coût correspondant.
La possibilité, déjà mise en pratique d'utiliser la vitamine B12 en solution faiblement alcaline à dose augmentée, est désavantagée elle-aussi du point de vue du prix de revient, par le prix relativement élevé des cobalamines.
On peut il est vrai stabiliser jusqu'à un pH de 7,0 à 7,5 les solutions de cyanocobalamines, qui sans cela
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ne sont stables qu'à un pH de 4 à 6, par addition de taurine (JP-Abstr. 56-7538 (A)) et on connaît aussi une série d'autres stabilisants pour les cobalamines (auxquels il est fait référence dans le brevet US-A-4 337 246, voir le brevet britannique GB-A-1 076 670), mais ceux-ci ne conviennent pas simultanément comme agents solubilisants pour les agents antirhumatismaux.
L'utilisation connue de préparations de vitamine B-. dans le cas de lésions cutanées (brevet britannique GB-A-1 264 509) et d'arthrite (EP-A-55 118) s'effectue à chaque fois en association avec d'autres substances actives comme agents antirhumatismaux.
Dans le cas d'une administration simultanée d'agents antirhumatismaux et de glucosamine. HC1 (demande de brevet DE-A 21 03 387), le sel de glucosamine sert conformément à la description comme substance active potentialisante, et non comme agent solubilisant.
EMI3.1
La N-méthylglucamine, qui se distingue fondamentalement de la glucosamine par sa structure l-amino-l-dés- oxy, est il est vrai connue comme agent solubilisant mais par exemple pour des salicylanilides halogénés sur le noyau utilisé contre des parasites intestinaux (AU-A 485 607).
La N-méthylpyrrolidone a déjà été décrit elle aussi comme agent solubilisant pour des substances thérapeutiquement actives (demande de brevet de DE-B 10 S 736).
On ne trouve cependant dans les exemples de cette demande de brevet, aucune substance active antirhumatismale en dehors de la cortisone, et surtout pas de cobalamine. Bien que la N-méthyl-pyrrolidone ne présente qu'une très faible
EMI3.2
toxicité (DL50 v 7 ml/kg sur le rat, par voie orale), on 't a ne connaît jusqu'à présent aucune préparation pour injec- tion contenant cet adjuvant en médecine humaine.
Comme il existe diverses indications selon lesquelles les cobalamines sont instables en solution en présence d'autres substances actives ou adjuvants (Chem. Abstr. 61,7273b ; 69,99367 J ; Ammon, Dirscherl"Fermente, Hormo-
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ne, Vitamine"111/2, 151/152, Thieme éditeur, 1975), il ne pouvait être prévu d'après l'état de la technique que l'on obtiendrait des solutions stables, et avec quels agents solubilisants.
On a trouvé à présent, de manière surprenante, que l'on pouvait préparer des solutions aqueuses des sub stances actives antirhumatismales ordinaires ou de leurs mélanges particulièrement bien tolérées par voie intramus- culaire, dans lesquelles la vitamine Bl2 est stable et n'exige donc aucun surdosage en ajustant le pH à une va- leur de 5 à 8 avec addition d'agents solubilisants.
Si par exemple on dissout un mélange de quanti- tés thérapeutiques de cétophénylbutazone, d'acide salicylamide-0-acétique et de dexaméthasone par simple addi- tion de NaOH dans de l'eau, un pH d'au moins 8 est néces- saire pour la dissolution complète, et une addition de vitamine Bl2 ne présente dans cette solution qu'une fai- ble durée de conservation. Par contre, si l'on remplace une partie de la sonde utilisée par de la N-méthylgluca- mine, on obtient alors une solution limpide dès un pH in- férieur à 8, la cyanocobalamine ajoutée s'y révèle possé- der une durée de conservation satisfaisante, et la tolé- rance en injection intramusculaire est améliorée.
Si l'on utilise à la place de la N-méthylgluca- mine un amide, tel que la N-méthylpyrrolidone, comme a- gent solubilisant, on obtient une solution limpide dès un pH de 5, donc à l'optimum de solubilité de la vitamine
EMI4.1
B12'Les solutions aqueuses pour injection des substances actives antirhumatismales contenant de la vitamine Bl2 pouvant être préparées conformément à l'invention peuvent être stérilisées par filtration et être introdui- tes dans des conditions stériles, le cas échéant en atmosphère d'azote, soit dans des seringues prêtes à l'emploi, soit dans des flacons à bouchon perforable. Les deux formes d'utilisation présentent l'avantage d'une manipulation simple pour un faible volume de chargement et d'une
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bonne stabilité de la vitamine ajoutée.
Pour soulager les malades, ces solutions peuvent contenir aussi un anesthésique local tel que la lidocaine.
Lors de l'essai comparatif de la tolérance locale d'injections intramusculaires selon G. Kienel (Arzneimittelforschung 23,263 (1973)), les solutions décrites dans les exemples ci-après se sont révélées mieux tolérées que deux préparations injectables du commerce ayant les mêmes indications. Alors que ces dernières présentaient des degrés de lésion de 75 à 78, on a observé pour la solution conforme à l'exemple 1 un degré de lésion de 70 la solution conforme à l'exemple 2 un degré de lésion de 40.
Les exemples non limitatifs suivants sont donnés à titre d'illustration de l'invention.
Exemple 1
On met en suspension dans 40 ml d'eau bidistillée un mélange de 15g de cétophénylbutazone, 5g de sel de sodium de l'acide salicylamide-O-acétique, 4g de N-méthylglucamine, 167 mg de lidocaine et 117 mg de déxaméthasone, et on l'agite en faisant passer de l'azote, tout en ajoutant goutte à goutte une solution de 1,0494 g de NaOH pure pour analyse dans 30 ml d'eau bidistillée. La solution limpide obtenue a un pH de 7,67. On y dissout 83,3 mg de cyanocobalamine et on complète à 100 ml avec de l'eau bidistillée. On stérilise la solution par filtration et on la transvase dans des conditions stériles et sous injection d'azote dans des seringues prêtes à l'emploi de 3 ml.
Chaque seringue prête à l'emploi contient alors :
450 mg de cétophénylbutazone
150 mg de salicylamide-O-acétate de sodium
5 mg de lidocalne-base
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3, 5 mg de dexaméthasone
31, 5 mg de NaOH p. p. a
120 mg de N-méthylglucamine 2 500 pg de cyanocobalamine.
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Exemple 2
On agite en refroidissant à 15 OC et sous barbotage d'azote un mélange de 15 g de cétophénylbutazone, 5 g de sel de sodium de l'acide salicylamide-0-acétique, 167 mg de lidocaine et 117 mg de dexaméthasone dans 53,3ml de N-méthylpyrrolidone et 17 ml d'eau bidistillée, tout en ajoutant goutte à goutte une solution de l 667 g de NaOH pure pour analyse dans 5 ml d'eau distillée. A la solution limpide ainsi préparée, on ajoute encore 83,3 mg de cyanocobalamine et on complète à 100 ml avec de l'eau bidistillée. On transvase la solution obtenue, qui a un pH de 5,95, dans des conditions stériles conformément à l'exemple 1.
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registered by the so-called company: GEROT-PHARMAZEUTIKA
GESELLSCHAFT mbH having for object: Solution for injection and process for its preparation Qualification proposed: PATENT OF INVENTION
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The present invention relates to an aqueous solution for injection which contains both anti-rheumatic active substances and vitamin Bzw and a process for its preparation.
Anti-rheumatic active substances, such as derivatives of pyrazolidine, salicylamide and corticosteroids, are poorly soluble in water.
However, to minimize the injection volume, it is necessary to have a relatively high concentration of active substance, and therefore good solubility, which, in the absence of addition of solubilizing agents, is not obtained only in an alkaline medium.
Vitamin B, -, which is used in antirheumatic preparations for injection to reinforce the antineuralgic and analgesic action, is however unstable in alkaline medium. As the literature indicates, the optimum stability for Cobalamins is in the weakly acidic domain.
Due to the divergent pH requirements of antirheumatic agents on the one hand, and cobalamins on the other hand, it has hitherto been the practice until now to present the two active solutions separated from each other, ie in two ampoules, either in two chambers arranged one behind the other of a ready-to-use syringe.
The use of two ampoules per injection is however complicated for the attending physician and requires larger packages, the use of the two-chamber syringe causes a technical expense accompanied by a corresponding additional cost.
The possibility, already put into practice of using vitamin B12 in weakly alkaline solution at increased dose, is also disadvantaged from the point of view of cost price, by the relatively high price of cobalamins.
It is true that it is possible to stabilize cyanocobalamin solutions up to a pH of 7.0 to 7.5, which otherwise
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are only stable at a pH of 4 to 6, by addition of taurine (JP-Abstr. 56-7538 (A)) and a series of other stabilizers are also known for cobalamins (to which reference is made in the US Pat. No. 4,337,246, see British Patent GB-A-1,076,670), but these are not simultaneously suitable as solubilizers for anti-rheumatic agents.
The known use of vitamin B- preparations. in the case of skin lesions (British patent GB-A-1,264,509) and arthritis (EP-A-55,118) is performed each time in combination with other active substances as anti-rheumatic agents.
In the case of simultaneous administration of antirheumatic agents and glucosamine. HC1 (patent application DE-A 21 03 387), the glucosamine salt is used according to the description as a potentiating active substance, and not as a solubilizing agent.
EMI3.1
N-methylglucamine, which differs fundamentally from glucosamine by its l-amino-l-de-oxy structure, is it is true known as a solubilizing agent but for example for salicylanilides halogenated on the nucleus used against intestinal parasites (AU -A 485 607).
N-methylpyrrolidone has also already been described as a solubilizing agent for therapeutically active substances (patent application DE-B 10 S 736).
However, in the examples of this patent application, there is no anti-rheumatic active substance apart from cortisone, and especially no cobalamin. Although N-methyl-pyrrolidone has very little
EMI3.2
toxicity (LD50 v 7 ml / kg in rats, orally), no preparation for injection containing this adjuvant in human medicine has yet been known.
As there are various indications that cobalamins are unstable in solution in the presence of other active substances or adjuvants (Chem. Abstr. 61,7273b; 69.99367 J; Ammon, Dirscherl "Fermente, Hormo-
<Desc / Clms Page number 4>
ne, Vitamine "111/2, 151/152, Thieme éditeur, 1975), it could not have been foreseen from the state of the art that stable solutions would be obtained, and with which solubilizing agents.
It has now surprisingly been found that it is possible to prepare aqueous solutions of the ordinary anti-rheumatic active substances or of their mixtures which are particularly well tolerated by the intramuscular route, in which vitamin B12 is stable and therefore does not require no overdose by adjusting the pH to a value of 5 to 8 with the addition of solubilizing agents.
If, for example, a mixture of therapeutic amounts of ketophenylbutazone, salicylamide-0-acetic acid and dexamethasone is dissolved by simple addition of NaOH in water, a pH of at least 8 is required for complete dissolution, and an addition of vitamin Bl2 only has a short shelf life in this solution. On the other hand, if one replaces part of the probe used by N-methylglucamine, one then obtains a clear solution from a pH lower than 8, the cyanocobalamin added appears to have a duration of satisfactory conservation, and the tolerance for intramuscular injection is improved.
If an amide, such as N-methylpyrrolidone, is used instead of N-methylglucamine as a solubilizing agent, a clear solution is obtained from a pH of 5, therefore at the optimum solubility of vitamin
EMI4.1
B12 'The aqueous solutions for injection of the antirheumatic active substances containing vitamin B12 which can be prepared in accordance with the invention can be sterilized by filtration and can be introduced under sterile conditions, if necessary in a nitrogen atmosphere, either in ready-to-use syringes, either in vials with puncture-resistant caps. The two forms of use have the advantage of simple handling for a small load volume and a
<Desc / Clms Page number 5>
good stability of the added vitamin.
To relieve the sick, these solutions may also contain a local anesthetic such as lidocaine.
During the comparative test of the local tolerance of intramuscular injections according to G. Kienel (Arzneimittelforschung 23,263 (1973)), the solutions described in the examples below have been found to be better tolerated than two commercial injectable preparations having the same indications . While the latter presented degrees of lesion from 75 to 78, a degree of lesion of 70 was observed for the solution according to example 1, the solution according to example 2 a degree of lesion of 40.
The following nonlimiting examples are given by way of illustration of the invention.
Example 1
A mixture of 15g of ketophenylbutazone, 5g of sodium salt of salicylamide-O-acetic acid, 4g of N-methylglucamine, 167 mg of lidocaine and 117 mg of dexamethasone is suspended in 40 ml of double-distilled water. it is stirred by passing nitrogen, while adding dropwise a solution of 1.0494 g of pure NaOH for analysis in 30 ml of double-distilled water. The clear solution obtained has a pH of 7.67. 83.3 mg of cyanocobalamin are dissolved therein and the mixture is made up to 100 ml with double-distilled water. The solution is sterilized by filtration and transferred under sterile conditions and under injection of nitrogen into 3 ml ready-to-use syringes.
Each ready-to-use syringe then contains:
450 mg ketophenylbutazone
150 mg sodium salicylamide-O-acetate
5 mg lidocalne-base
EMI5.1
3.5 mg dexamethasone
31.5 mg NaOH p. p. at
120 mg of N-methylglucamine 2,500 pg of cyanocobalamin.
<Desc / Clms Page number 6>
Example 2
Stirred with cooling to 15 ° C. and with nitrogen bubbling a mixture of 15 g of ketophenylbutazone, 5 g of sodium salt of salicylamide-0-acetic acid, 167 mg of lidocaine and 117 mg of dexamethasone in 53.3 ml of N-methylpyrrolidone and 17 ml of double-distilled water, while adding dropwise a solution of 1667 g of pure NaOH for analysis in 5 ml of distilled water. To the clear solution thus prepared, a further 83.3 mg of cyanocobalamin is added and the mixture is made up to 100 ml with double distilled water. The solution obtained, which has a pH of 5.95, is transferred under sterile conditions in accordance with Example 1.
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT392982A AT376879B (en) | 1982-10-27 | 1982-10-27 | METHOD FOR PRODUCING AN INJECTION SOLUTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BE898082A true BE898082A (en) | 1984-02-15 |
Family
ID=3557346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BE0/211771A BE898082A (en) | 1982-10-27 | 1983-10-26 | SOLUTION FOR INJECTION AND PROCESS FOR ITS PREPARATION. |
Country Status (7)
| Country | Link |
|---|---|
| AT (1) | AT376879B (en) |
| BE (1) | BE898082A (en) |
| CH (1) | CH657525A5 (en) |
| DE (1) | DE3337304A1 (en) |
| FR (1) | FR2535205B1 (en) |
| LU (1) | LU85040A1 (en) |
| NL (1) | NL8303549A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3437232A1 (en) * | 1984-10-10 | 1986-04-17 | Mack Chem Pharm | STABILIZED INJECTION SOLUTIONS FROM PIROXICAM |
| US5962536A (en) * | 1998-07-31 | 1999-10-05 | Komer; Gene | Injectable propofol formulations |
| DE102007012644A1 (en) | 2007-03-16 | 2008-09-18 | Bayer Healthcare Ag | Stabilization of vitamin B12 |
| JP5843873B2 (en) * | 2010-10-29 | 2016-01-13 | トロイカ ファーマスーティカルズ リミテッド | Intranasal composition of vitamin B12 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1053736B (en) * | 1956-03-02 | 1959-03-26 | Konink Nl Gist & Spiritusfabri | Process to increase the solubility of therapeutically active substances in water |
| DE1249453B (en) * | 1963-10-14 | |||
| GB1076670A (en) * | 1964-11-02 | 1967-07-19 | Chugai Pharmaceutical Co Ltd | A stabilised aqueous hydroxo cobalamin solution |
| DE2103387C3 (en) * | 1971-01-26 | 1982-05-06 | Johann G.W. Opfermann & Sohn, 5070 Bergisch-Gladbach | Use of the hydrochloride of glucosamine for the manufacture of pharmaceutical preparations |
| AU485607B2 (en) * | 1972-12-04 | 1975-04-24 | Ici Australia Limited | Compositions |
| DE2522187C2 (en) * | 1975-05-17 | 1977-10-28 | Byk Gulden Lomberg Chem Fab | Use of cysteine or its acid addition salt and sodium disulphite to stabilize injectable drugs with a pH between 7 and 9, vitamin B low 12 and non-steroidal anti-inflammatory drugs |
| JPS54151668A (en) * | 1978-05-22 | 1979-11-29 | Teijin Ltd | Production of fluffed fabric |
| LU80432A1 (en) * | 1978-10-26 | 1979-03-19 | Hoffmann K | PROCESS FOR PREPARING AN INJECTION SOLUTION CONTAINING MONOPHENYLBUTAZONE AND INJECTION SOLUTION PREPARED BY THIS PROCESS |
| JPS5675438A (en) * | 1979-11-22 | 1981-06-22 | Senjiyu Seiyaku Kk | Method for stabilizing aqueous solution of cyanocobalamin |
| JPS5675436A (en) * | 1979-11-22 | 1981-06-22 | Eisai Co Ltd | Solid pharmaceutical containing cobamamide or mecobalamin |
| NZ195881A (en) * | 1980-12-19 | 1984-08-24 | W Lysaght | Pharmaceutical compositions containing cobalt compounds |
-
1982
- 1982-10-27 AT AT392982A patent/AT376879B/en not_active IP Right Cessation
-
1983
- 1983-10-07 LU LU85040A patent/LU85040A1/xx unknown
- 1983-10-13 DE DE19833337304 patent/DE3337304A1/en not_active Withdrawn
- 1983-10-14 NL NL8303549A patent/NL8303549A/en not_active Application Discontinuation
- 1983-10-21 FR FR8316819A patent/FR2535205B1/en not_active Expired
- 1983-10-26 CH CH580983A patent/CH657525A5/en not_active IP Right Cessation
- 1983-10-26 BE BE0/211771A patent/BE898082A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH657525A5 (en) | 1986-09-15 |
| LU85040A1 (en) | 1984-03-22 |
| NL8303549A (en) | 1984-05-16 |
| ATA392982A (en) | 1984-06-15 |
| FR2535205B1 (en) | 1987-02-06 |
| FR2535205A1 (en) | 1984-05-04 |
| AT376879B (en) | 1985-01-10 |
| DE3337304A1 (en) | 1984-05-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RE | Patent lapsed |
Owner name: GEROT-PHARMAZEUTIKA G.M.B.H. Effective date: 19921031 |