Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1997-09-17
2002-06-04
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S195110, C424S489000, C514S772300, C514S784000
Reexamination Certificate
active
06399099
ABSTRACT:
It has been proved by a great number of clinical trials that the active agent of ginkgo biloba leaves, extracted with acetone-water is effective in a number of diseases in the field of peripheral and cerebral circulatory disturbances. These results have caused the commission E at the German Federal Health Office [Kommission E beim Deutschen Bundesgesundheitsamt] to pass a monography (Federal Gazette [Bundesanzeiger] No. 133 of Jul. 19, 1994) stating of the following indications:
for the symptomatic treatment of cerebro-organic induced vitality deficiences in connection with a whole therapeutic concept in demential syndroms with the principle symptoms: dismnesia, lack of concentration, depressive mood, dizziness, susurrus aurium, headache;
improvement of the painfree walking range in peripheral, arterial occlusive disease at stage II according to Fontaine (Claudicatio intermittens) in connection with physical-therapeutical measures, particularly walking training;
dizziness, tinnitus (noise in the ears) of vascular and involutional origin.
The effect of the dry extracts of ginkgo biloba leaves may be caused by one therapeutically effective component or by a combination of many effective components. The most important therapeutically effective components are flavonoids, such as ginkgo flavone glycosides and terpenoids, e.g. ginkgolides and bilobalides. Accordingly pharmaceutical preparations are standardized on said components. One of these dry extracts, EGb 761, contains about 24% ginkgo flavone glycosides and about 6% terpenes; see Jos Kleijnen, Paul Knipschild, The Lancet Nov. 7, 1992, Vol. 340, 1136. Further dry extracts and processes for their preparation and their use are described in German patents DE 39 40 091 and DE 39 40 092.
The active agent is usually administered in the form of tablets or as a solution, in which nonaqueous solvents, such as ethanol or propylene glycol must be used. Purely aqueous solutions are not available because on the one hand certain components show a very poor solubility in water, like ginkgolides of less than 0.02%. On the other hand, some components, like bilobalide are not stable in neutral or slightly basic aqueous medium. Precipitations as well as chemical degradation processes of extract components occur in aqueous solutions. For these reasons it is not obvious to prepare effervescent preparations. Additionally the extract has hygroscopic, sticky characteristics which impair the processing to effervescent tablets.
However, there is a frequent need for purely aqueous preparations of a dry extract of ginkgo biloba leaves. Thus, the problem underlying the present invention is to provide a preparation of dry extracts of ginkgo biloba leaves in the form of an effervescent composition for which only water may be used as solvent for dissolving the effervescent composition, in which no notable degradation processes occur during the period of use, and which have a stability of the solution resulting after adding water of at least one hour.
This problem is solved by the development of an effervescent composition which comprises a ginkgo biloba dry extract and an effervescent mixture which contains a physiologically acceptable acid or sodium salt thereof and a physiologically acceptable carbonate or hydrogen carbonate in such a ratio that the resulting solution after adding water to the effervescent composition has a pH value of about 6 to 8 and is stable for at least one hour.
The weight ratio of acid to carbonate or hydrogen carbonate is preferably about 1:1 to 1:3.
By the addition of auxiliary agents and by determining the components of the effervescent mixture and thus of the conditions of the medium of the resulting solution after adding water a virtually clear solution can be obtained which is stable during the period of use. After dissolving the effervescent composition in water the resulting solution has a pH value of about 6 to 8.
The term “effervescent composition” when used herein means e.g. powder, granulate and tablets, preferably tablets.
Effervescent mixtures contain physiologically acceptable acids and carbonate or hydrogen carbonate for releasing C0
2
. Specific examples for carbonates and hydrogen carbonates are sodium salts. These effervescent mixtures develop CO
2
along with their decomposition upon contact with water. To optimize the CO
2
development an excess of acid is usually added. This means for the resulting solutions slightly acidic pH values of 3 to 5. However, this medium is disadvantageous for the solution of the dry extracts of ginkgo biloba leaves. The use of a shortage of acid was surprisingly suitable for the preparation of the solutions according to this invention. Although the CO
2
development was reduced under these conditions, the resulting pH value of about 6 to 8 was suitable for dissolving the dry extracts.
By the addition of minor amounts of a physiologically acceptable water soluble surfactant the solubility of the dry extract is additionally positively influenced. Specific examples for preferred surfactants are polysorbates, i.e. non-ionic surfactants of the type of ethoxylated sorbitan esters, polyoxyethylene fatty acid esters, ethoxylated glycerol esters and sodium dioctylsulfosuccinate. The surfactant is preferably used in an amount of about 0.01 to 0.5% by weight, preferably 0.05% by weight.
An acceptable taste of the resulting solution of the dry extracts which have a bitter taste can be achieved by adding suitable taste improvement agents, e.g. flavouring agents, sugar or sugar surrogates. Sugar or sugar surrogates may be present in an amount of up to about 50% by weight. Suitable taste improvement agents for the preparation of the solutions according to this invention are artificial or natural sweetening agents, preferably saccharin-Na, sorbite, aspartame or mannite, preferably in an amount of about 0.5 to 5% by weight or artificial or natural flavouring agents, preferably lemon flavour or grapefruit flavour and mixtures thereof. The flavours are preferably used in an amount of about 0.5 to 3% weight, preferably 1% by weight.
The dosage of the dry extract per form of administration, e.g. tablet, is about 30 to 240 mg.
REFERENCES:
patent: 5082666 (1992-01-01), Rene et al.
patent: 3723735 (1988-02-01), None
patent: 3832277 (1988-09-01), None
patent: 0 431 536 (1991-06-01), None
Dr. W. A. Ritschell, Die Tablette, Grundlagen and Praxis des Tablettierens, Granulierens and Dragierens, Edition Cantor KG/Aulendorf i. Wurtt, pp. 48 and 49, 108, 115, 117, 118, 119 and 137-142.
Rudof Voigt, Pharmazeutische Technologic, 7 uberarbeitete Auflage, Berlin, Ullstein Mosby (1993), pp. 238-239.
P. C. Schmidt and I. Christin, Brausetabletten-eine fast vergessene Arzneiform, Pharmazie45(1990), H.2, pp. 89-101.
JP 07069862-A (cited in the ISR).
Bundesanzeiger No. 133, p. 7362, Jul. 19, 1994.
Dr. Willmar Schwabe GmbH & Co.
McDonnell & Boehnen Hulbert & Berghoff
Spear James M.
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