Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Patent
1995-08-08
1997-10-28
Hulina, Amy
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
424489, A61K 919
Patent
active
056815735
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for preparing a pharmaceutical preparation having neuromuscular blocking activity. The invention particularly relates to a process for preparing such a preparation containing as neuromuscular blocking agent a 16beta-monoquaternary ammonium derivative of a 2beta, 16beta-bis-piperidino-3alfa, 17beta-dihydroxy-5alfa-androstane-3alfa, 17beta-diacylate.
From British Patent Nr. 1 138 605 it is known that the 2beta, 16beta-bisquaternary ammonium derivatives of 2beta, 16beta-bis-piperidino-3alfa. 17beta-dihydroxy-5alfa-androstane-3alfa, 17beta-diacylates are highly active neuro-muscular blocking agents. An example of such a compound is pancurontumbromide (2beta, 16beta-bis-piperidino-5alfa-androstane-3alfa, 17beta-diol 3alfa, 17beta-diacetate 2beta, 16beta-dimethobromide).
In J. Med. Chem. 16, 1116 (1978) it is disclosed that not only such bisquaternary derivatives, but also the corresponding 16-mono-quaternary derivatives are interesting neuromuscular blocking agents. These mono-quaternary derivatives are even more interesting than the corresponding bis-quaternary compounds because of their quicker onset and shorter duration of action, thus offering under most surgical conditions pronounced advantages, and because of their lack of cardiovascular side-effects. A well-known example of a mono-quaternary compound is vecuroniumbromide (2beta, 16beta-bis-piperidino-5alfa-androstane-3alfa, 17beta-diol 3alfa, 17beta-diacetate 16beta-methobromide), hereinafter referred to as "VB".
Generally, the quaternarizing group in the above-mentioned androstane compounds is an alkyl, alkenyl or alkynyl group of up to 4 carbon atom, of which the methyl group is preferred. The counterion for the positive quaternary group may be any pharmaceutically acceptable organic or inorganic anion, such as methylsulphate, p-toluene-sulphonate and especially the halides such as chloride, bromide and iodide, of which bromide is preferred. The acyl group in 3alfa- and 17beta-position is derived from a lower aliphatic carboxylic acid having 1-6 carbon atom and is preferably the acetyl group.
The present invention is described herein with respect to VB. However, it should be noted that in the following disclosure any of the abovementioned 16-mono-quaternary analogues of VB may be substitited for VB without departing from the scope of the present invention.
According to the disclosure of EP-A-008824 VB decomposes almost immediately when dissolved in water and hence cannot be used in aqueous injection preparations. Neuromuscular blocking agents are mainly used in surgical treatments and are administered through injection of their aqueous solution. For making stable injection preparations of VB it is suggested in EP-A-008824 to convert VB into a pharmaceutically acceptable acid addition salt thereof by reacting VB with a pharmaceutically acceptable organic or inorganic acid, preferably a water soluble acid, e.g. hydrochloric acid, acetic acid, fumaric acid, citric acid.
According to the "Repertorium" (a review of information texts of pharmaceutical specialite's registered in the Netherlands, edited by Nefarma, the Dutch Phamaceutical Manufactures Association) the preparation of VB (Norcuron.RTM.) consists of a vial containing a lyophilized mixture of the acid addition salt of VB (4 mg or 10 NaCl (0.15 mmol), mannitol (24.5 mg) and a citrate or phosphate buffer. For obtaining an injectable solution the contents of the vial should be dissolved in water for injection purposes (1 ml or 5 ml) giving an isotonic injection solution having a pH of 4. The injection solution is stable for 24 hours at room temperature in the light.
It is an object of the present invention to provide a new method for preparing stable pharmaceutical preparations of VB for injection purposes.
The present invention comprises a method for preparing a stable pharmaceutical preparation containing VB characterized by the steps of solvent, provide in each container the required unit dosage form of VB, container by lyophilization or evaporation, and
The spe
REFERENCES:
patent: 3553212 (1971-01-01), Hewett et al.
patent: 5030633 (1991-07-01), Williams
Buckett et al., "Pancuronium Bromide and Other Steriodal Neuromuscular Blocking Agents Containing Acetylcholine Fragments", Journal of Medicinal Chemistry, vol. 16, No. 10 (1973) pp. 1116-1124.
Hulina Amy
N.V. Inpharm
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