Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-02-24
1996-04-02
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514869, A61K 3141
Patent
active
055040993
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns aqueous injection solutions that are ready for injection and contain an organic solvent and at least one water-soluble, physiologically well-tolerated salt of azosemide as the active substance and it concerns a process for the production of such injection solutions.
Azosemide (2-chloro-5-(1H-tetrazol-5-yl)-N.sup.4 -2-thenylsulfanilamide) and water-soluble and physiologically well-tolerated salts thereof are used in medicine as a diuretic. Azosemide can also be used advantageously in combination with other diuretics or with beta blockers. Such combinations are described for example in the patent DE 25 56 001.
The problem that aqueous solutions which contain a canrenoate or combinations of such a salt with other diuretics are not stable due to the occurrence of inexplicable turbidities after the usual heat sterilization at 120.degree. C. is solved in DE 25 56 001. As described in DE 25 56 001 the instability problem was previously circumvented by producing a lyophilisate of canrenoate or of a combination preparation containing it by dissolving the dry substance in an aqueous solvent. However, this preparation of an injection solution has disadvantages: the production of a lyophilisate is technically very time consuming. The lyophilisates have to be sterilized by a complicated sterilization by filtration, whereby it is not possible to avoid a proportion of unsterile lots containing pyrogens. Moreover, in addition to the really necessary solvent ampoule, a further handling is necessary to dissolve the lyophilisate.
According to DE 25 56 001 an improved stability is achieved by increasing the pH value of the solutions from a maximum of 10.2 to a value in the range between 10.2 and 11.2. Although the injection solutions stabilized in this manner have a usable venous tolerance, their high pH value is not physiologically acceptable.
The venous tolerance of an injection solution mainly depends on the following factors: pH value, buffer capacity and titration basicity or titration acidity.
The buffer capacity is generally defined as that equivalent amount (val of acid or lye) which is necessary to change the pH value of a solution with a volume of one liter by one pH unit. If monobasic acids or bases are used, the specification val/l of the acid or base used corresponds to the molar amount mol/l of this acid. Since in the present case the solutions used preferably have a pH value in the alkaline range, the buffer capacity can also be alternatively defined as that amount of for example a 0.1 normal HCl solution which is required to reduce the pH value of a solution of 1 l by one pH unit. The determination of the buffer capacity in therapeutic agents is based on the ready-to-use infusion solutions which, in addition to the active substance, contain auxiliary substances or additives which are usually used in pharmaceutical practice.
The titration basicity is generally defined as that amount of an acid which is necessary to adjust the pH value of a solution with a volume of one liter to the pH value of blood (about 7.2-7.4). In the present case the titration basicity can be alternatively defined as that amount of, for example, a 0.1 normal HCl solution which is necessary to reduce the pH of 1 l of a solution to that of blood. The titration basicity can be influenced by a change of the pH value and an appropriate selection of the buffer.
Injection solutions with a pH value in the range of the pH value of blood, i.e. between 7.2 and 7.4, or which have a higher pH value but a lower buffer capacity and a lower titration basicity, are very well tolerated by the veins. In the case of the solutions claimed in DE 25 56 001 the solubility among others of the active substance is increased by the increase in the pH value.
The solubility--for example--of the sodium salt of azosemide in water is actually good in particular at higher pH values (165 mg/100 ml at pH 8.0 and 201 mg/100 ml at pH 10.0). However, it was not possible to produce clear, stable injection solutions without recrystallisates in a pu
REFERENCES:
patent: 3665002 (1972-05-01), Popelak et al.
Martindale The Extra Pharmacopoeia, 30 ed (1992).
Gruber Werner
Woog Heinrich
Boehringer Mannheim GmbH
Burn Brian M.
Raymond Richard L.
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