FR2535205A1 - Stable aq. solns. of antirheumatics and cobalamin(s) - Google Patents

Stable aq. solns. of antirheumatics and cobalamin(s) Download PDF

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FR2535205A1
FR2535205A1 FR8316819A FR8316819A FR2535205A1 FR 2535205 A1 FR2535205 A1 FR 2535205A1 FR 8316819 A FR8316819 A FR 8316819A FR 8316819 A FR8316819 A FR 8316819A FR 2535205 A1 FR2535205 A1 FR 2535205A1
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cobalamin
solution
stable
injection
antirheumatic
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FR2535205B1 (en
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Ludwig H Schlager
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Gerot Pharmazeutika GmbH
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    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Aqueous injection solution, which is stable and well tolerated when administered by intramuscular injection, contains an antirheumatic and a cobalamin, and opt. a local anaesthetic is characterised in that it has a pH of 5-8 and contains a solubilising agent. The solubilising agent is pref. N-methyl-pyrrolidone or N-methyl-glucamine. Antirheumatic composition, which allows relatively aqueous insoluble antirheumatics to be formulated in the same solution with cobalamus (used to reinforce the antineuralgia and analgesic activity) and avoids presently used costty two ampoule syringes and administration of two separate solutions

Description

La présente invention concerne une solution aqueuse pour injection qui contient à la fois des substances actives antirhumatismales et de la vitamine B12, et un procédé pour sa préparation. The present invention relates to an aqueous solution for injection which contains both anti-rheumatic active substances and vitamin B12, and a process for its preparation.

Les substances actives antirhumatismales, telles que les dérivés de la pyrazolidine, du salicylamide et des corticostéroides, sont peu solubles dans l'eau. Anti-rheumatic active substances, such as derivatives of pyrazolidine, salicylamide and corticosteroids, are not very soluble in water.

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.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.

La vitamine B12, 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. Vitamin B12, which is used in anti-rheumatic 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.

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.  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.

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. 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.

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. 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.

On peut il est vrai stabiliser jusqu'à un pH de 7,0 à 7,5 les solutions de cyanocobalamines, qui sans cela ne sont stables qu'â un pH de 4 à 6, par addition de taurine (JP-Abstr.56-7538 (A) ) et on connait 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. It is true that it is possible to stabilize cyanocobalamin solutions up to a pH of 7.0 to 7.5, which otherwise are only stable at a pH of 4 to 6, by adding taurine (JP-Abstr. 56 -7538 (A)) and we also know a series of other stabilizers for cobalamins (to which reference is made in patent US-A-4,337,246, see British patent GB-A-1,076,670), but these are not suitable simultaneously as solubilizing agents for anti-rheumatic agents.

L'utilisation connue de préparations de vitamine
B12 dans le cas d 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.Known use of vitamin preparations
B12 in the case of skin lesions (British patent
GB-A- 1 264 509) and arthritis (EP-A- 55 118) is carried out each time in combination with other active substances as anti-rheumatic agents.

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. 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.

La N-méthylglucamine, qui se distingue fondamentalement de la glucosamine par sa structure l-amino-l-désoxy, 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). N-methylglucamine, which differs fundamentally from glucosamine by its l-amino-l-deoxy structure, is it is true known as a solubilizing agent but for example for halogenated salicylanilides on the nucleus used against intestinal parasites (AU-A 485 607).

La N-methylpyrrolidone a déjà été décrit elle aussi comme agent solubilisant pour des substances thérapeutiquement actives (demande de brevet de DE-B 1G 53736).  N-methylpyrrolidone has already been described as a solubilizing agent for therapeutically active substances (patent application DE-B 1G 53736).

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 toxicité (DL50 ~ 7 ml/kg sur le rat, par voie orale), on ne connait jusqu'à présent aucune préparation pour injection contenant cet adjuvant en médecine humaine.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 only very low toxicity (LD50 ~ 7 ml / kg in rats, orally), no preparation for injection containing this adjuvant in human medicine has yet been known.

Comme il existe diverses indications selon lesquelles les cobalamines sont instables en solution en présence d'autres substances actives ou adjuvants (Chem.Abstr. 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 ne, Vitamine" III/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.61, 7273b; 69, 99367 J; Ammon, Dirscherl "Fermente, Hormo ne, Vitamine" III / 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.

On a trouvé à présent, de manière surprenante, que l'on pouvait préparer des solutions aqueuses des substances actives antirhumatismales ordinaires ou de leurs mélanges particulièrement bien tolérées par voie intramusculaire, dans lesquelles la vitamine B12 est stable et n'exige donc aucun surdosage en ajustant le pH à une valeur de 5 à 8 avec addition d'agents solubilisants. 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 any overdose. adjusting the pH to a value of 5 to 8 with the addition of solubilizing agents.

Si par exemple on dissout un mélange de quantités thérapeutiques de cétophénylbutazone, d'acide salicylamide-0-acétique et de dexaméthasone par simple addition de NaOH dans de l'eau, un pH d'au moins 8 est nécessaire pour la dissolution complète, et une addition de vitamine B12 ne présente dans cette solution qu' une faible durée de conservation. Par contre, si l'on remplace une partie de la sonde utilisée par de la N-méthylglucamine, on obtient alors une solution limpide dès un pH inférieur à 8, la cyanocobalamine ajoutée s'y révèle posséder une durée de conservation satisfaisante, et la tolérance en injection intramusculaire est améliorée. 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 necessary for complete dissolution, and an addition of vitamin B12 present in this solution only a short shelf life. 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 there proves to have a satisfactory shelf life, and the tolerance for intramuscular injection is improved.

Si l'on utilise à la place de la N-méthylglucamine un amide, tel que la N-méthylpyrrolidone, comme agent solubilisant, on obtient une solution limpide dès un pH de 5, donc à l'optimum de solubilité de la vitamine B12.  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 B12.

Les solutions aqueuses pour injection des substances actives antirhumatismales contenant de la vitamine
B12 pouvant être préparées conformément a' l'invention peuvent être stérilisées par filtration et être introduites dans des conditions stériles, le cas échéant en atmosphère d'azote, soit dans des seringues prêtes à l'em- ploi, 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 bonne stabilité de la vitamine ajoutée. Pour soulager les malades, ces solutions peuvent contenir aussi un anesthé situe local tel que la lidocaine.Aqueous solutions for injection of anti-rheumatic 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 or in stopper bottles perforable. The two forms of use have the advantage of simple handling for a small loading volume and good stability of the added vitamin. To relieve the sick, these solutions may also contain a local anesthetic such as 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 memes indications. Alors que ces derières 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.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 were found to be better tolerated than two commercial injectable preparations having the same indications. While these latter presented degrees of injury from 75 to 78, it was observed for
the solution according to example 1 a degree of lesion of 70
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.

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-0-acétique, 4g de N-méthylglucamine, 167 mg de lidocalne 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 pretes à l'emploi de 3 ml.Example 1
A mixture of 15g of ketophenylbutazone, 5g of sodium salt of salicylamide-0-acetic acid, 4g of N-methylglucamine, 167 mg of lidocalne and 117 mg of dexamethasone is suspended in 40 ml of bidistilled 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 with nitrogen injection into syringes ready to use 3 ml.

Chaque seringue prête à l'emploi contient alors
450 mg de cétophénylbutazone
150 mg de salicylamide-0-acétate de sodium
5 mg de lidocalne-base
3,5 mg de dexaméthasone
31,5 mg de NaOH p.p.a
120 mg de N-méthylglucamine
2 500 ,ug de cyanocobalamine. Each ready-to-use syringe then contains
450 mg ketophenylbutazone
150 mg salicylamide-0-sodium acetate
5 mg lidocalne-base
3.5 mg dexamethasone
31.5 mg NaOH ppa
120 mg N-methylglucamine
2,500 µg cyanocobalamin.

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-O-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 1 667 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. 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-O-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 a solution of 1667 g of dropwise
Pure NaOH for analysis in 5 ml of distilled water. To the clear solution thus prepared, a further 83.3 mg of cyanocobalamin are 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 (4)

R E V E N D I C A T I O N SR E V E N D I C A T I O N S 1 - Procédé de préparation d'une solution pour injection stable et particulièrement bien tolérée lors d'une application intramusculaire, contenant des substances antirhumatismales et une cobalamine, ainsi que le cas échéant un anesthésique local, caractérisé en ce qu'on ajuste le pH à une valeur de 5 à 8 en présence d'agents solubilisants. 1 - Process for preparing a solution for injection stable and particularly well tolerated during an intramuscular application, containing antirheumatic substances and a cobalamin, as well as if necessary a local anesthetic, characterized in that the pH is adjusted to a value of 5 to 8 in the presence of solubilizing agents. 2 - Procédé suivant la revendication 1, caractérisé en ce qu'on utilise comme agent solubilisant de la 2 - Process according to claim 1, characterized in that the solubilizing agent used is N-méthylpyrrolidone.N-methylpyrrolidone. 3 - Procédé suivant la revendication 1, caractérisé en ce qu'on utilise de la N-méthylglucamine. 3 - Process according to claim 1, characterized in that N-methylglucamine is used. 4 - Solution aqueuse pour injection contenant des substances actives antirhumatismales et une cobalamine, ainsi que le cas échéant un anesthésique local et qui est particulièrement bien tolérée lors d'une administration intramusculaire, caractérisée en ce que son pH est entre 5 et 8 et en ce qu'elle contient un agent solubilisant.  4 - Aqueous solution for injection containing anti-rheumatic active substances and a cobalamin, as well as if necessary a local anesthetic and which is particularly well tolerated during an intramuscular administration, characterized in that its pH is between 5 and 8 and in this that it contains a solubilizing agent.
FR8316819A 1982-10-27 1983-10-21 SOLUTION FOR INJECTION BASED ON ANTIRHUMATISMAL SUBSTANCES AND A COBALAMINE AND PROCESS FOR ITS PREPARATION Expired FR2535205B1 (en)

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Application Number Priority Date Filing Date Title
AT392982A AT376879B (en) 1982-10-27 1982-10-27 METHOD FOR PRODUCING AN INJECTION SOLUTION

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FR2535205A1 true FR2535205A1 (en) 1984-05-04
FR2535205B1 FR2535205B1 (en) 1987-02-06

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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)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0177870A2 (en) * 1984-10-10 1986-04-16 Heinrich Mack Nachf. Stabilized injection solutions of piroxicam
EP1131062A1 (en) * 1998-07-31 2001-09-12 Veterinary Research Associates, Inc. Injectable propofol formulations

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007012644A1 (en) 2007-03-16 2008-09-18 Bayer Healthcare Ag Stabilization of vitamin B12
ES2686299T3 (en) * 2010-10-29 2018-10-17 Troikaa Pharmaceuticals Ltd Vitamin B12 nasal compositions

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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
EP0055118A1 (en) * 1980-12-19 1982-06-30 Wallace Lysaght Arthritis treatment

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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
JPS5675436A (en) * 1979-11-22 1981-06-22 Eisai Co Ltd Solid pharmaceutical containing cobamamide or mecobalamin
JPS5675438A (en) * 1979-11-22 1981-06-22 Senjiyu Seiyaku Kk Method for stabilizing aqueous solution of cyanocobalamin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0055118A1 (en) * 1980-12-19 1982-06-30 Wallace Lysaght Arthritis treatment

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0177870A2 (en) * 1984-10-10 1986-04-16 Heinrich Mack Nachf. Stabilized injection solutions of piroxicam
EP0177870A3 (en) * 1984-10-10 1987-06-03 Heinrich Mack Nachf. Stabilized injection solutions of piroxicam
EP1131062A1 (en) * 1998-07-31 2001-09-12 Veterinary Research Associates, Inc. Injectable propofol formulations
EP1131062A4 (en) * 1998-07-31 2002-07-03 Veterinary Res Associates Inc Injectable propofol formulations

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BE898082A (en) 1984-02-15
ATA392982A (en) 1984-06-15
LU85040A1 (en) 1984-03-22
AT376879B (en) 1985-01-10
NL8303549A (en) 1984-05-16
DE3337304A1 (en) 1984-05-03
CH657525A5 (en) 1986-09-15
FR2535205B1 (en) 1987-02-06

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