Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-01-02
1995-04-04
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
536 46, 544138, 424488, C07D27104, C06B 3716, A61K 3141
Patent
active
054038405
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Phase of PCT/HU91/00012 filed 28 Mar. 1991 and based upon Hungarian national application 1868/90 filed 28 Mar. 1990 and amended 27 Jun. 1990.
FIELD OF THE INVENTION
The invention relates to the inclusion complexes of N-ethoxycarbonyl-3-morpholino-sydnonimine (Molsidomin) or its salts formed with heptakis-2,6-O-dimethyl-.beta.-cyclodextrin (Dimeb), hydroxypropyl-.beta.-cyclodextrin or with .beta.-or .gamma.-cyclodextrin, to the preparation thereof and to the pharmaceutical compositions containing the same.
BACKGROUND OF THE INVENTION
Molsidomin is an antianginic and antiischemic compound which is widely used for the prevention and treatment of angina pectoris. Its advantage compared to the organic nitrates is that its effect is more lasting and it has less side-effects, thus it does not become habit forming and it rarely induces headaches which are also less severe. Its antiarrithmic and the fibrinolysis, the blood-platelet aggregation and blood-pressure decreasing effect are distinguished too.
The Molsidomin is on the market in the form of tablets containing 2, 4 (traditional) and 8 mg (delayed-action) of the active ingredient name Corvaton (Casella, Riedel), Morial (Takeda Ltd.). The delayed-action composition contains the active ingredient in a microencapsulated form applying a special wax in a ratio of 1:4, which ensures an effective plasma concentration for 12 hours.
The Molsidomin is relatively fairly soluble in water (18 mg/ml at 25.degree. C.), it is stable at a pH value of 5-7 in water. The rate determining step of the resorption from the stomach and of the intestinal tract is apparently not the solubility. The oral preparation containing 2 mg of the active ingredient is effective for 3-5 hours. The maximal blood level can be achieved within 1/2-1 hour. It is fairly absorbed along the whole Gi-tract, its bioavailability is satisfactory. Antianginal preparations for preventive purposes are formulated most advantageously with controlled release of the active ingredient. It ensures the extended and controlled resorption of the medicament and the long lasting therapeutically effective plasma level. The side effects can be decreased significantly by the elimination of the too high toxic plasma level. The transdermal formulation with a controlled release of the active agent is especially advantageous.
The resorption of the active ingredient through the skin depends on its physico-chemical properties and lipoid solubility, and mainly on the formulation applied.
Molsidomin itself is resorbed slowly and to a small extent through the skin; its bioavailability is only 4%. For this reason agents enhancing the resorption are used. The European Patent Specification No. 127468 of the Takeda Company describes a percutaneous fairly resorbing Molsidomin preparation, which contains a special penetration enchancer agent of 2 components--a propyleneglycol mixture containing 10% of oleic acid.
The mechanism of the outstanding bioavailability of 95% may be the following: the oleic acid component modifies the permeability of the skin's protective layer (the stratum corneum) by dissolving the barrier lipoid components of the same. Thus the Molsidomin is fairly resorbed through the modified stratum corneum.
It was stated that the resorption of Molsidomin and of propylene-glycol is of similar extent, and of similar quantity respectively, which means, that only the Molsidomin dissolved in the propylene-glycol will be resorbed.
DESCRIPTION OF THE INVENTION
It has been found, that the effect of Molsidomin or its salts can be retarded by complexation with heptakis-2,6-O-dimethyl-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, or with .beta.-cyclodextrin or .gamma.-cyclodextrin.
The present invention relates to the inclusion complexes of N-ethoxycarbonyl-3-morpholino-sydnonimine or its salts formed with heptakis-2,6-O-dimethyl-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin or with .beta.-or .gamma.-cyclodextrin. The inclusion complexe
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patent: 4834985 (1989-05-01), Elger et al.
patent: 4869904 (1989-06-01), Uekama et al.
patent: 5120546 (1992-06-01), Hansen et al.
patent: 5120732 (1992-06-01), Schonafinger
Sigma Chemical Co. pp. 1439 & 1550 1994.
Donilova, Dokl. Akad Nauk SSR 303, 1512 (1988).
Merck Index, 11th ed, G143 (1988).
Gaal Jozsef
Hermecz Istvan
Horvath Agnes
Horvath Gabor
Marmarosi Katalin
Chinoin Gyogyszer-Es Vegyeszeti Termekek Gyar Rt.
Dubno Herbert
Gerstl Robert
Myers Jonathan
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