Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-09-14
2001-05-22
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S040000, C424S438000, C424S437000, C424S442000
Reexamination Certificate
active
06235315
ABSTRACT:
Stable, pulverulent lycopene formulations, comprising lycopene having a degree of crystallinity of greater than 20%.
The invention relates to stable, pulverulent lycopene formulations, comprising lycopene having a degree of crystallinity of greater than 20%, processes for their preparation and their use as an additive to foodstuffs, cosmetics, pharmaceuticals and animal feedstuffs.
Lycopene, which belongs to the carotenoids class of substances, occurs widely in nature. Thus tomatoes having a lycopene content of about 20 mg/kg of tomato form the most important natural source of this red pigment.
Epidemiological studies have shown that a more frequent and regular consumption of tomatoes or tomato products decreases the risk of chronic disorders, inter alia cardiac and circulatory disorders, and exerts a positive effect on the prevention of cancer. This protective function of lycopene is seen in its action as a very effective antioxidant.
Both for the foodstuffs and feedstuffs industry and for pharmaceutical technology, lycopene, for example as a substitute for artificial colorants, represents an important coloring material and is moreover of interest for the reasons mentioned at the outset as a foodstuff additive for healthcare.
The synthesis of lycopene is described, inter alia, in EP-A-382067 and EP-A-000140. WO 97/48287 describes the extraction of lycopene as a natural carotenoid from tomatoes.
Like all carotenoids, lycopene is also insoluble in water, while in fats and oils a solubility which, however, is only slight is found. This limited solubility and the high sensitivity to oxidation stand in the way of direct use of the relatively coarse-grain crystalline lycopene in the coloration of foodstuffs and feedstuffs, since the pure substance is too unstable in coarse-crystalline form, is only inadequately absorbed and thus yields only poor coloring results.
Only by means of specifically prepared formulations in which the active compounds are present in finely divided form, and if appropriate protected against oxidation by protective colloids, can improved color yields be achieved in the direct coloring of foodstuffs.
In view of the particularly low stability to oxidation, in comparison with other carotenoids, and the low color stability and storage stability of lycopene also connected therewith, particularly high demands are placed on these formulations.
For carotenoids generally, a large number of formulations and processes for their preparation are described.
Thus lycopene, for example, is obtainable under the name Lyc-O-Mato® (LycoRed, Israel) as a 6% strength oily dispersion. It is extracted from tomatoes as a natural carotenoid according to WO 97/48287. On account of the high phospholipid content in the Lyco-O-Mato®, combined with a high viscosity of the oily dispersion, the application properties of this formulation, inter alia the water dispersibility, are not satisfactory.
EP-A-0 410 236 describes a process for the preparation of carotenoid dry powders, in which a suspension of a carotenoid is briefly heated in a high-boiling oil, this mixture of molten carotenoid and oil is emulsified in an aqueous solution of a colloid and this emulsion is then spray dried.
DE-A-1 211 911, describes carotenoid products for whose preparation firstly the carotenoids are dissolved in a water-insoluble solvent, and then this solution is emulsified into an aqueous protective colloid solution and spray dried.
EP-A-0 065 193 describes a process for the preparation of pulverulent carotenoid products, which comprises briefly dissolving a carotenoid in a water-miscible, organic solvent at elevated temperatures, immediately precipitating the carotenoid in colloidally disperse form from the resulting solution by rapid mixing with an aqueous solution of a protective colloid and converting the resulting dispersion into a dry powder.
According to EP-A-0 832 569, a carotenoid dry powder in which the active compound particles are largely present in X-ray amorphous form is obtained by heat treatment of the dispersion prepared according to EP-A-0 065 193 at a temperature between 40° C. and 90° C. and subsequent spray drying.
WO 98/16204 describes a process for the preparation of pulverulent carotenoid products, which comprises dissolving a carotenoid in dimethyl ether in an autoclave at elevated pressure and temperature and removing the solvent again by very rapid depressurization.
Numerous methods, described, inter alia, in Chimia 21, 329 (1967), WO 91/06292 and in WO 94/19411, make use of the grinding of carotenoids, e.g. &bgr;-carotene, by means of a colloid mill, and thus achieve particle sizes of 2 to 10 &mgr;m.
Despite the large number of publications in this area, information for solving the stability problem of lycopene going beyond general statements about carotenoid formulations is found in none of the texts mentioned in the prior art.
It is therefore an object of the present invention to make available pulverulent lycopene formulations in which the lycopene is particularly stable to oxidation and light and which do not have the above mentioned disadvantage of the prior art.
We have found that this object is achieved according to the invention by stable, pulverulent lycopene formulations comprising lycopene having a degree of crystallinity of greater than 20%.
The degree of crystallinity of lycopene in the formulations according to the invention can be determined, for example, by X-ray diffraction measurements and in general lies in the range greater than 20%, preferably in the range from 25 to 100%, particularly preferably in the range from 30 to 95%, very particularly preferably in the range from 40 to 80%.
With respect to double bond isomerism, the lycopene contained in the pulverulent formulations can be present without restriction in all isomeric forms, for example in the all-trans, 5-cis or 9,13-di-cis form. Preferred pulverulent formulations are those comprising lycopene having an all-trans content of at least 50%, particularly preferably lycopene having an all-trans content of 52 to 100%, very particularly preferably lycopene having an all-trans content of 55 to 90%.
The content of lycopene in the formulations according to the invention lies in the range from 0.5 to 25% by weight, preferably in the range from 2 to 21% by weight, particularly preferably in the range from 5 to 16% by weight, very particularly preferably in the range from 8 to 12% by weight, based on the dry mass of the formulations.
The mean particle size of lycopene in the dry powders lies in the range below 10 &mgr;m, preferably in the range below 5.0 &mgr;m, particularly preferably in the range from 0.05 to 1 &mgr;m.
To increase the stability of the pulverulent lycopene formulations, it is advantageous to incorporate into the formulation protective colloids, plasticizers and/or stabilizers, additionally to the active compound.
Protective colloids used are, for example, gelatin, fish gelatin, starch, dextrin, plant proteins, pectin, gum arabic, casein, caseinate or mixtures thereof. However, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose and alginates can also be employed. For more details, reference is made to R. A. Morton, Fat Soluble Vitamins, Intern. Encyclopedia of Food and Nutrition, Vol. 9, Pergamon Press 1970, pp. 128-131. To increase the mechanical stability of the final product, it is expedient to add a plasticizer, such as sugars or sugar alcohols, e.g. sucrose, glucose, lactose, invert sugar, sorbitol, mannitol or glycerol, to the colloid.
The ratio of protective colloid and plasticizer to carotenoid solution is in general selected such that a final product is obtained which contains between 0.5 and 25% by weight of lycopene, 10 to 50% by weight, preferably 15 to 35% by weight, of a protective colloid, 20 to 70% by weight, preferably 30 to 60% by weight, of a plasticizer, all percentage data based on the dry mass of the powder, and, if appropriate, minor amounts of a stabilizer.
To increase the stability of the active compound against oxidative de
Auweter Helmut
Haberkorn Herbert
Musaeus-Jensen Nina
Rieger Jens
Runge Frank
BASF - Aktiengesellschaft
Keil & Weinkauf
Page Thurman K.
Pulliam Amy
LandOfFree
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