Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-05-28
2002-09-03
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C424S456000, C424S725000, C514S04400A, C514S055000, C514S169000, C514S170000, C514S182000
Reexamination Certificate
active
06444659
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the use of mixtures of phytostenols or phytostenol esters and selected potentiating agents for the production of preparations for reducing the serum cholesterol content of warm-blooded organisms.
Hypocholesterolemic agents are understood to be agents which lead to a reduction in the serum cholesterol level of warm-blooded organisms without either inhibiting or reducing the formation of cholesterol in the blood. Phytostenols, i.e. vegetable stenols, and esters thereof with fatty acids have already been proposed for this purpose by Peterson et al. in J. Nutrit. 50, 191 (1953). U.S. Pat. No. 3,089,939, U.S. Pat. No. 3,203,862 and DE-OS 2 035 069 (Procter & Gamble) also point in the same direction. The active substances are normally added to frying oils or edible oils and, accordingly, are absorbed through the food. However, the quantities used are generally minimal and, normally, amount to less than 0.5% by weight to prevent the edible oils from clouding or the stenols from precipitating on the addition of water. For use in food, in cosmetics, in pharmaceutical preparations and in the agricultural sector, storable emulsions of the stenol esters in sugar or polyglycerol esters are proposed in European patent application EP-A1 0 289 636 (Ashai). The incorporation of sitostanol esters in margarine, butter, mayonnaise, salad creams and the like for reducing the blood cholesterol level is proposed in European patent EP-B1 0 594 612 (Raision).
Unfortunately, a disadvantage of phytostenol esters is that, normally, they can only be added to foods in small quantities because otherwise they are in danger of affecting the taste and/or consistency of foods. However, if the blood cholesterol level is to be lastingly influenced, relatively large quantities of phytostenols or phytostenol esters would have to be absorbed. The rate at which the substances reduce serum cholesterol is also in need of improvement. Accordingly, the problem addressed by the present invention was to remedy these deficiencies.
DESCRIPTION OF THE INVENTION
The present invention relates to the use of mixtures of active substances for the production of hypocholesterolemic preparations, characterized in that
(a) phytostenols and/or phytostenol esters and
(b) potentiating agents selected from the group consisting of chitosans, phytostenol sulfates and/or (deoxy)ribonucleic acids are used.
It has surprisingly been found that chitosans, phytostenol sulfates and/or (deoxy)ribonucleic acids which, on their own, have very poor hypocholesterolemic properties, if any, act as potentiating agents for phytostenols and/or phytostenol esters, i.e. accelerate the reduction of the serum cholesterol level in the presence of phytostenols or phytostenol esters. In addition, when encapsulated in gelatine, both the phytostenols and/or phytostenol esters and the active-substance mixtures can readily be taken in by mouth.
Phytostenols and Phytostenol Esters
Phytostenols (also known as phytosterols) are vegetable steroids which only contain a hydroxyl group but no other functional groups at C-3. In general, phytostenols contain 27 to 30 carbon atoms and one double bond in the 5/6 position and occasionally in the 7/8, 8/9 or other positions. The corresponding saturated stanols, which are also encompassed by the present invention, can be obtained by hydrogenation from the unsaturated stenols. Typical examples of suitable phytostenols are ergostenols, campestenols, stigmastenols, brassicastenols and, preferably, sitostenols or sitostanols and, more particularly, &bgr;-sitostenols or &bgr;-sitostanols. Besides the phytostenols mentioned, their esters are preferably used. The acid component of the ester may go back to carboxylic acids corresponding to formula (I):
R
1
CO—OH (I)
in which R
1
CO is an aliphatic, linear or branched acyl group containing 2 to 22 carbon atoms and 0 and/or 1, 2 or 3 double bonds. Typical examples are acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid, 2-ethyl hexanoic acid, capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselic acid, linoleic acid, linolenic acid, elaeosteric acid, arachic acid, gadoleic acid, behenic acid and erucic acid and the technical mixtures thereof obtained, for example, in the pressure hydrolysis of natural fats and oils, in the reduction of aldehydes from Roelen's oxosynthesis or in the dimerization of unsaturated fatty acids. Technical fatty acids containing 12 to 18 carbon atoms, for example cocofatty acid, palm oil fatty acid, palm kernel oil fatty acid or tallow fatty acid, are preferred. It is particularly preferred to use esters of &bgr;-sitostenol or &bgr;-sitostanol with fatty acids containing 12 to 18 carbon atoms. These esters may be prepared both by direct esterification of the phytostenols with the fatty acids or by transesterification with fatty acid lower alkyl esters or triglycerides in the presence of suitable catalysts, for example sodium ethylate or, more particularly, enzymes [cf. EP-A2 0195311 (Yoshikawa)].
Chitosans
Chitosans are biopolymers which to the group of hydrocolloids. Chemically, they are partly deacetylated chitins differing in their molecular weights which contain the following—idealized—monomer unit (II):
In contrast to most hydrocolloids, which are negatively charged at biological pH values, chitosans are cationic biopolymers under these conditions. The positively charged chitosans are capable of interacting with oppositely charged surfaces and are therefore used in cosmetic hair care and body-care products and pharmaceutical preparations (cf. Ullmann's Encyclopedia of Industrial Chemistry, 5th Ed., Vol. A6, Weinheim, Verlag Chemie, 1986, pages 231-332). Overviews of this subject have also been published, for example, by B. Gesslein et al. in HAPPI 27, 57 (1990), by O. Skaugrud in Drug Cosm. Ind. 148, 24 (1991) and by E. Onsoyen et al. in Seifen-Öle-Fette-Wachse 117, 633 (1991). Chitosans are produced from chitin, preferably from the shell residues of crustaceans which are available in large quantities as inexpensive raw materials. In a process described for the first time by Hackmann et al., the chitin is normally first deproteinized by addition of bases, demineralized by addition of mineral acids and, finally, deacetylated by addition of strong bases, the molecular weights being distributed over a broad spectrum. Either low molecular weight chitosans with an average molecular weight of around 50,000 to around 250,000 dalton or high molecular weight chitosans with an average molecular weight of around 500,000 to around 2,000,000 are preferably used. Corresponding processes are known, for example, from Makromol. Chem. 177, 3589 (1976) or French patent application FR-A 2701266. Particularly preferred types are those which are disclosed in German patent applications DE-A1 4442987 and DE-A1 19537001 (Henkel) and which have an average molecular weight of 800,000 to 1,200,000 dalton, a Brookfield viscosity (1% by weight in glycolic acid) below 5,000 mPas, a degree of deacetylation of 80 to 88% and an ash content of less than 0.3% by weight. Besides the chitosans as typical cationic biopolymers, anionically or nonionically derivatized chitosans, such as for example the carboxylation, succinylation or alkoxylation products described, for example, in German patent DE-C2 3713099 (L'Oreal) and in German patent application DE-A1 19604180 (Henkel), may also be used for the purposes of the present invention.
Phytostenol Sulfates
Phytostenol sulfates are known substances which may be obtained, for example, by sulfation of phytostenols with a complex of sulfur trioxide and pyridine in benzene [cf. J. Am. chem. Soc. 63, 1259 (1941)]. Typical examples are the sulfates or ergostenols, campestenols, stigmastenols and sitostenols. The phyto-stenol sulfates may be used in the form of alkali metal and/or alkaline earth metal salts, ammonium, alk
Fabry Bernd
Weitkemper Norbert
Choi Frank
Cognis Deutschland GmbH
Dees Jose′ G.
Drach John E.
Murphy Glenn E.
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