Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Reexamination Certificate
2000-01-13
2001-10-23
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
C514S160000, C514S159000
Reexamination Certificate
active
06306843
ABSTRACT:
The invention relates to a method for producing stable acetylsalicylic acid solutions with pharmaceutically suitable non-aqueous organic solvents such as, e.g., dimethylisosorbide, propylene glycol or diethylene glycol monoethyl ether as well as stable solutions of acetylsalicylic acid and a preferred use of such solutions for the rapid dermal or sublingual absorption of the active substance.
The instability of acetylsalicylic acid in pharmaceutical preparations has already been known for long. The hydrolysis of acetylsalicylic acid in salicylic acid and acetic acid occurs relatively quickly as a function of a number of factors. Besides the known hydrolysis product salicylic acid, also acetylsalicylic anhydride and acetylsalicylosalicylic acid are known as impurities. The decomposition of aspirin results in a major loss of its pharmacological activity, in particular with the indication myocardial infarction prophylaxis, thus usually making acetylsalicylic acid be marketed only in the form of solid preparations. Solid preparations, in turn, as a rule can be administered only orally with rapid decomposition taking place primarily in the acidic environment of the stomach, during the absorption in the gastric mucuous membrane as well as through the first pass in the liver such that only approximately half of the acetylsalicylic acid will reach the blood stream in the decomposed form. The metabolite salicylic acid forming during absorption is made responsible for side effects such as, e.g., gastric hemorrhage and the overdosage required on account of the high degradation of the active substance during absorption constitutes a considerable additional burden on the organism.
In addition to the antiinflammatory, antipyretic and analgetic effects of aspirin, acetylsalicylic acid has been used also as an antirheumatic and for the prophylaxis of infarctions, wherein a number of tests have already been aimed to prevent the decomposition of the pharmaceutical preparation within the stomach in order to thereby avoid undesired side effects. It is advantageous, primarily in continuous therapy, to keep the concentration of salicylic acid in the organism as low as possible. For that reason, stable acetylsalicylic acid solutions have been developed, which upon dermal application are additionally able to transport the active substance rapidly into the skin and, further on, into the blood stream, so that a systemic action will take effect there without creating gastrointestinal side effects. Such solutions must exhibit a long-term stability for industrial exploitation.
The hydrolysis of aspirin to salicylic acid and acetic acid follows a kinetics of the first order and is catalyzed by both acids and bases. Due to the rapid hydrolysis of aspirin in aqueous media, attempts have so far been made to make liquid preparations of aspirin in non-aqueous solvents such as, e.g., propylene glycol, ethyl alcohol, glycerine or polyethylene glycol. Traces of moisture, deesterification or the like can, however, not be avoided with all those solvents such that only an insufficient stability will be obtained even in those cases. When using polyethylene glycol, deesterification into salicylic acid and acetylated polyethylene glycol has been observed upon extended storage. For that reason, esterified polyethylene glycols in liquid preparations have already been proposed.
A liquid preparation using dimethylisosorbide is to be taken from U.S. Pat. No. 4,228,162. Such a liquid solution may be characterized by a considerably enhanced stability as compared to a number of other solutions. Yet, even such solutions are not sufficiently stable for successful marketing and the long-term stability required. Moreover, dermal absorption proceeds only slowly upon application. The skin is wetted with liquid for a long time and it may, therefore, readily happen that the solution will be absorbed by clothes, thus preventing the active substance from being available for absorption by the body.
From EP 55 635 A1 a dermal preparation of acetylsalicylic acid has become known, which may be applied in the form of a gel. Dermal application, which sets particularly high demands on the stability of the solution, offers the advantage that the undesired first pass effect may be avoided and gastrointestinal irritations such as gastric hemorrhage do not occur. However, a prerequisite for an accordingly effective preparation is a high degree of stability, wherein EP 55 635 A1 inter alia proposes diethylene glycol monoethyl ether and propylene glycol. The preparation described there used a carboxyvinyl polymer for gel formation with ethylenediaminetetraacetic acid (EDTA) having been used for further stabilization.
Also that known preparation does not meet the required long-term stability and rapid absorption of the active substance. Departing from a solution of the initially defined kind, the present invention, therefore, aims to substantially enhance the stability and absorption of such solutions.
To solve this object, the method according to the invention for producing stable acetylsalicylic acid solutions with pharmaceutically safe non-aqueous organic solvents essentially consists in that 0.005-2% by weight of a cyclic acid imide and/or 0.005-2% by weight of a sulfaminic acid as well as, preferably, 1-40% by weight, based on the weight of the solution, of a compound of the general formula
wherein R
1
represents H, CH
3
or C
2
H
5
, n=0 or 1, and R
2
represents H or one or more lower alkyl, lower alkyloxy or lower alkenyl residues having 1 to 5 carbon atoms are added to the solution. The compounds of the general formula I indicated above frequently are components of essential oils or vegetable extracts. Thus, for instance, anise oil contains more than 90% anetholee, or fennel oil contains 50 to 60% anetholee, such that also these oils or extracts may be used depending on their concentrations of the compounds cited above.
Surprisingly, it has now been shown that the long-term stability of the solutions can be substantially enhanced by using the additives mentioned, wherein the admissible storage time could be raised by a factor of at least two. In doing so, it is essential to use the free acid rather than the Na salts as are found in sweetening agents, since the Na salts would destabilize the solutions. The range of concentration within which, for instance, saccharin may be used is at the lower limit of the concentrations used for stabilization, wherein it has been shown in a surprising manner that ethanol is not suitable as a solvent and ethanolic solutions of the active substance could not be stabilized with saccharin.
The highly fluid solutions are completely and irreversibly soaked into the skin within a few minutes without involving undesired external effects such as, e.g., clothes, distribution on other objects, and they are excellently suitable for dosing to precise acetylsalicylic acid contents by means of a dosing pump. Besides saccharin and/or cyclamic acid, compounds of the general formula I, to which anethole or benzyl alcohol belong in a preferred manner, have surprisingly proved to be of particular advantage. The exact mechanism by which long-term stability is substantially enhanced using the stabilizers proposed according to the invention could not be clarified for sure. The substitution of other organic acids such as sorbinic acid, benzoic acid or nicotinic acid for cyclamic acid or saccharin no longer resulted in an appropriate long-term stability. The values each determined in the long-term test in respect of the hydrolysis product salicylic acid formed over the time in any event were all far below half of the values observed with known solutions designated as stable.
Advantageously, the process according to the invention is carried out in a manner that cyclamic acid is used as said sulfamic acid. Like saccharin, which is preferably used as a cyclic acid imide, cyclamic acid in the concentrations mentioned has resulted in a storage quality at least twice as high.
The use of anethole and/or benzyl alcohol offers speci
Burghart Kurt
Burghart Walter
Jarvis William R. A.
Kim Vickie
Nixon & Vanderhye
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