SI21783A - New water soluble form of coenzyme q10 in the form of inclusion complex with beta-cyclodextrine, procedure for its preparation and its application - Google Patents

Abstract

The essence of the invention is an inclusion complex of coenzyme Q10 with beta-cyclodextrine which can be surprisingly prepared by dissolving beta-cyclodextrine in water at a temperature higher than the room temperature, preferentially between 55 degrees Celsius and the boiling point temperature, adding coenzyme Q10 in the solid state or dissolved in a suitable solvent, preferentially in the solid form, and mixing further at an elevated temperature first, and then at the room temperature or temperature below the room temperature. After formation of this complex, solubility of coenzyme Q10 in water is essentially increased and thus also improved its dissolution properties, bioavailability and effectiveness in preventive and therapy. Thus the invention is solving in a simple and original manner the problem of poor water solubility of coenzyme Q10, which is making difficulties in preparation of effective preparations with this coenzyme on a non-lipophilic basis, as well as in addition to various products, especially the food, pharmaceutical and cosmetic ones. The invention therefore refers to the said inclusion complex, the procedure of its preparation and its application as additive to pharmaceutical, cosmetic and food products.

Description

A NEW WATER-SOLUBLE FORM OF COENZYM Q10 IN THE FORM OF INCLUSION COMPLEX WITH β-CYCLODESTRIN, PROCEDURE FOR ITS PREPARATION AND ITS USE

The subject of the invention is a new water-soluble form of coenzyme Q10, the process of its preparation and its use. The coenzyme Q10 of the invention is in the form of an inclusion complex with βcyclodextrin.

The invention relates to the inclusion complex of coenzyme Q10 with β-cyclodextrin. The invention also relates to processes for the preparation of this complex and use in the form of stand alone preparations or as supplements to pharmaceutical, cosmetic and food products.

The following equivalents will be used below:

- for coenzyme Q10: CoQ10,

- for the inclusion complex with coenzyme Q10 with β-cyclodextrin: CDQ10.

Coenzyme Q10 (CoQ10) is a lipophilic water-insoluble substance, essential for the functioning of the human body, since it participates as a coenzyme in many metabolic processes. Man provides sufficient amounts of CoQ10 in the body through synthesis and nutrition. The uptake of exogenous CoQ10 or. other coenzymes of Q (CoQ) in the human body also affect the synthesis of endogenous CoQ10. In particular, the intake of sufficient amounts of exogenous CoQ10 or. other coenzymes Q necessary in older years, when the synthesis of endogenous CoQ10 is pedestrian and the deficit needs to be compensated by food or. with additives in the form of various preparations. As there is often a significant reduction in the amount of CoQ contained in various food processing operations, replacing the deficit in the form of supplements is all the more important and it is important to add CoQ, especially CoQ10, to some key foods. However, due to its lipophilic character, the insolubility of CoQ, especially CoQ10 in water, makes the preparation of suitable preparations difficult, and therefore there is an ongoing need to prepare a water-soluble form of ubiquinone with better bioavailability, which would allow the preparation of preparations with improved biopharmaceutical or biopharmaceutical. nutritional properties of CoQ10 and which would also allow it to be added to foods and other products.

Commercially available preparations contain CoQ10 either in the form of oil suspensions, e.g. in soft gelatin capsules, or in powder forms with different fillers, e.g. in hard capsules.

Due to its lipophilic properties, the oil-based preparations of CoQ10 are partially solubilized so that they can be absorbed more quickly and reach relatively high blood concentrations after ingestion, but many authors have concluded that they are also rapidly excreted in the body with urine. Thus, the physiological effects are worse than expected.

On the other hand, dissolved CoQ10 is expected to be rapidly absorbed into cells in aqueous media such as e.g. muscle, and therefore excreted much more slowly from the body and therefore would have a longer effect. However, the solubility of CoQ10 in water is practically negligible and therefore its bioavailability is very poor. Therefore, it is necessary to use CoQ10 effectively as a dietary supplement. to develop a design in standalone formats that will allow for better water solubility and thus better bioavailability and efficiency. Research shows a direct correlation between dissolution rate and bioavailability! CoQ10. Water solubility is especially important in local applications, e.g. in the oral cavity, on the skin or. muscles, etc.

Therefore, many authors are trying to improve the water solubility of CoQ10 in various ways in order to increase its bioavailability and effectiveness.

Japanese company BioTakenaka Pharm. has developed a special CoQ10 solubility enhancement technology known as Bio-Coenzyme Q10 purum. The technology is based on an enzyme combination and provides good solubility and significantly increased bioavailability. The preparations on this basis are marketed by Kampoyaki Research SDN BHD (Malaysia) in the form of gels, tablets and capsules. Technology, however, is relatively complex, expensive and sensitive due to its combination with the enzyme.

From an article by A. Puppet, J. Pawlaczyk, Acta Poloniae Pharm. - Drug Res. 1995, 52, pp. 379-386 There are also known attempts to improve the water solubility of CoQ10 by incorporation into various cyclodextrins. From an article by J. Szeitli, J. Materials Chem. 1997, 7, pp. 575-587, it is known that the preparation of lipophilic complexes with cyclodextrins increases their solubility in water. The authors sought to prepare CoQ10 inclusion complexes with α-cyclodextrin, β-cyclodextrin, methyl-β-cyclodextrin (0.97 and 1.8), hydroxypropyl cyclodextrin and γcyclodextrin. It appears that they were able to prepare a complex between CoQ10 and γ-cyclodextrin, but probably also with substituted β-cyclodextrins, whereas with α-cyclodextrin, the complex was not formed. They have also failed to prepare a complex with β-cyclodextrin, which is otherwise commercially the most commercially viable due to its low cost, inherent and investigative nature. Namely, β-cyclodextrin itself has long been used in the diet except in the United States. Thus, it has been used in Japan without restriction since I 1983, and is also approved in many European countries. Recently, the Food and Agriculture Organization and the World Health Organization (WH0) jointly recommended a maximum daily dose for humans of 5 mg of β-cyclodextrin per kg of human body weight - article by Z. H. Qi, C. T. Sikorski, Pharm. Techol. Europe 1002, 13 (11), pp. 17-27. Thus, despite the use of relatively sophisticated equipment, the authors did not reach the goal of preparing a water-soluble form of CoQ10 with cheap and physiologically acceptable β-cyclodextrin.

The problem, which has not been adequately solved so far, is a suitable water-soluble form of coenzyme Q, in particular CoQ10, especially not one that could be easily prepared in an economical way. Therefore, despite numerous studies and results regarding the use of CoQ10, its use as a food additive and non-lipophilic cosmetics and pharmaceuticals, so far, are not known, nor are CoQ10 preparations known to be added to such products in such a way as to achieve appropriate concentrations. CoQ10 in them.

The object and object of the invention is the water-soluble form of coenzyme Q10 with β-cyclodextrin, the process of its preparation and its use in the form of stand alone preparations or as adjuvants to pharmaceutical, cosmetic and food products.

According to the invention, the problem is solved by the water-soluble form of the CoQ10 inclusion complex with β-cyclodextrin (CDQ10), the process of its preparation and its use according to independent claims.

Pictures show:

Figure 1: IR spectrum of CDQ10 and physical mixtures of β-cyclodextrin and CoQ10,

Figure 2: DSC curve of β-cyclodextrin,

Figure 3: CoSC10 DSC curve,

Figure 4: DSC physical mixtures of β-cyclodextrin and CoQ10 and CDQ10,

Figure 5: Powder X-ray diffractograms of CDQ10 and physical mixtures of βcyclodextrin and CoQ10,

The complexes are prepared in a surprising and original way so that, based on the properties of βcyclodextrin and CoQ10, the conditions under which the formation of the CDQ10 inclusion complex is possible are selected. The essence of the CDQ10 preparation process is to dissolve β-cyclodextrin in water at elevated temperature, i.e. above room temperature, preferably at a temperature between 55 ° C and boiling point, and then, under vigorous stirring, CoQ10 is added in solid form or dissolved in a minimum amount of a suitable solvent in which CoQ10 is dissolved, miscible with water and physiologically acceptable, such as ethanol, acetone and the like. The inclusion complex is formed in such a way that the CoQ10 molecule or. parts thereof, incorporate into one or more β-cyclodextrin molecules, due to their structure and especially because of the length of the CoQ10 molecule, they are incorporated into 1 to 10 β-cyclodextrin molecules. Therefore, the proportion and degree of ComQ10 complexation are affected by the ratio of CoQ10 to β-cyclodextrin. Partial improvement in the solubility of CoQ10 or its bioavailability is already achieved by subequimolar amounts of β-cyclodextrin relative to CoQ10 (eg at a ratio of 1:10), and the proportion of complexed CoQ10 and the degree of complexation (ie, the ratio of CoQ10 to β-cyclodextrin in the inclusion complex) increases with increasing the ratio in favor of β-cyclodextrin. . Therefore, any β-cyclodextrin to CoQ10 ratio of 1:10 to 10: 1, preferably 1: 5 to 5: 1, preferably at a ratio of about 1: 1, is achieved, in which the optimal effects on the inclusion complex properties and synthesis costs are achieved.

Preferably, CoQ10 is added in solid form and a 10-20% molar excess of βcyclodextrin relative to CoQ10 is used. Intensively stir until CoQ10 disappears or. until the inclusion complex of CDQ10 begins to emerge. The reaction mixture was cooled and CDQ10 was isolated by decanting, filtering or evaporating water. If necessary, it can be dried, but it can also be used dissolved or. non-drying CDQ10 complex, since the preparation process takes place in an aqueous medium so that the resulting mixture does not contain any harmful solvents. The formation of CDQ10 is practically quantitative, and CoQ10 dissolves significantly better in aqueous media in the form of CDQ10 obtained, so that it exceeds the solubility required for the administration of a daily dose of CoQ10 to an adult as a standalone preparation or as an admixture with food and other products.

Therefore, the invention also relates to preparations containing the CDQ10 complex and its use as a dietary supplement. independently for nutritional, preventive, therapeutic, cosmetic and other purposes.

The improved properties of CoQ10 in the form of CDQ10 make it technically simple and commercially viable to prepare preparations that are not lipid-based but exhibit appropriate dissolution and / or dissolution in aqueous media, thereby improving tissue absorption and enhancing physiological effects. In addition, their wider applicability for different purposes or applications is also possible. for different uses, such as oral, buccal and topical. The preparations may be solid, semi-solid, or liquid, e.g. in the form of capsules, tablets, powders, syrups, solutions, gels, drops, creams or other forms or forms. delivery systems. They are used to achieve a variety of systemic and local effects, including in the prevention and therapy of cardiovascular diseases, high cholesterol, diabetes, cancer, immune diseases, muscular dystrophy, oral cavity diseases, especially gums and the like.

Thus, it is easy to prepare an aqueous solution for flushing the gums, to which other ingredients can be added to increase user acceptance. CDQ10 can also be added to dental creams, which has a beneficial effect on the strengthening of the gums. The same applies to various creams and liquids for outdoor use.

In addition, the invention also relates to the use of the CDQ10 complex as a constituent of foodstuffs by mixing isolated or uninsulated foodstuffs. food products such as milk, yoghurts, cottage cheese, cheese, butter and other dairy products, jams and jams, fruit and vegetable juices and nectars, and various beverages, compotes, cereals, cereals, chocolate products, teas, honey products, meat products and the like. The inclusion complexes of the invention, in particular as e.g. CDQ10 can be incorporated into these products at one stage of the product preparation process, and in the case of liquid, semi-solid and semi-liquid products, even when the product is already in its final form. The ability to add e.g. The CDQ10 at the end of the process has the added benefit of allowing it to be easily organized and streamlined production into a core product, or a product with the addition of CDQ10, or both. In addition, e.g. CDQ10 should also be added to food and other products at the place of use or use. just before use by adding a complex to such a product in a suitable form for use, e.g. in the form of solution, syrup, drops, powder, capsules and the like.

For example, a sufficient amount of CDQ10 can be mixed into milk or yogurt so that an adult can consume a daily or even multiple daily dose of CoQ10 in one meal. The solubility of CoQ10 in the form of CDQ10 is e.g. namely, at room temperature, about 60 times as much as the solubility of CoQ10 itself, at which about 8.5 mg of CoQ10 in the form of CDQ10 are dissolved at 1 g of milk at room temperature. This can also increase the CoQ10 content of milk or yoghurt by 5000 times or more, since it contains e.g. natural milk ca 1.7.10 ^-3 mg CoQ10 / g milk, and many types of milk and dairy products are much smaller, even below the limit of detection by conventional methods. This makes the ability to add CoQ10 all the more important. Preferably, yoghurt or milk with the addition of CDQ10 is prepared by adding the desired amount of CDQ10 during mixing, e.g. from 30-150 mg CoQ10 in complex form in a suitable form. Preferably a non-drying complex or in the form of a reaction mixture is added, preferably in the form of a reaction mixture in a suitable form, such as e.g. solution, syrup, drops, etc. Then milk or milk. yoghurt with added CDQ10 is consumed, and if the process is in production, it is properly packed.

Similarly, we can add CDQ10 e.g. in oranges, berries, peaches and other juices, nectars and beverages in any quantity, made possible by solubility of CDQ10, preferably in amounts of the usual daily doses up to 150 mg of CoQ10 in the form of CDQ10, such that the CDQ10 complex is stirred at normal use temperature dissolve in juice, nectar or drink before ingestion or before packaging. In addition, an isolated, dried or non-dried complex or an uninsulated complex is used; preferably non-drying or uninsulated complex.

We add CDQ10 to semi-solid products in an analogous manner. This is how CDQ10 is mixed before use or before packing in toothpaste, liver pate, honey, jam, jam, etc. by adding the desired amount of isolated, dried or dried or uninsulated CDQ10 in a suitable form while mixing.

The invention also relates to the use of the CDQ10 complex and its products in relation to the functions of the human organism that are related to coenzyme Q10.

The invention is explained but not limited to the embodiments.

Β-Cyclodextrin Roquette, France and CoQ10 Vivati Pharma GmbH was used!

Germany.

EXAMPLE 1 Preparation of the CDQ10 Complex

a) Preparation process for β-cyclodextrin (1.575 g, 1.39 mmol) was dissolved in 13 mL of distilled water at 70 ° C. 1.00 g (1.16 mmol) of CoQ10 was added to the dissolved β-cyclodextrin and the mixture was stirred at 70 ° C for 20 minutes. After about 1 minute of stirring, the CDQ10 complex began to precipitate and the precipitation amount increased for about 20 minutes. The reaction mixture was stirred for a further 10 hours at 60-70 ° C and for several hours at room temperature until a homogeneous paste was formed. The resulting mixture was centrifuged, separated by phase, washed with a little water and dried at 30-35 ° C under reduced pressure. 1.9 g of a yellow-orange DCQ10 complex were obtained with decomposition at a temperature above 273 ° C. The product was identified by IR spectroscopy, thermal analysis (DSC) and X-ray powder analysis.

b) IR spectroscopy

A comparison of the IR spectra of Figure 1 and Table 1, which show bandwidths different in both spectra, shows differences between the physical mixture of β-cyclodextrin and CoQ10 and the inclusion complex of CDQ10. The spectra were recorded with a FT-IR spectrometer SPECTRUM 1000 (Perkin-Elmer).

Table T. Comparison of the wave numbers of selected bands in the CDQ10 IR spectrum and the physical mixtures of β-cyclodextrin and CoQ10 and the difference between the individual bands.

CDQ10 Tapes [cm · ¹ ] Physical mix tapes [cm ' ¹ ] Offset [cm ' ¹ ] 3390,46 3418,53 28.07 / 2944,11 2916,44 2913,28 2.16 1448,43 1446,53 1.9 / 1348,25 1334,00 1336,56 2.56 1289,78 1287,60 2.18 1230,76 1227,97 2.79 1057,34 / 1028,35 1026,07 2.28 1001,39 995,80 5.59 942,65 945,45 2.80 861,53 / / 780,41 703,52 707.40 3.88 598.60 601,37 2.77 575.05 579,42 4.37 444,75 / / 425.17 411,33 /

c) Thermal Analysis (DSC)

Figures 2, 3 and 4 show the DSC curves of β-cyclodextrin, CoQ10, the physical mixtures of both and the CDQ10 complex. The curves were obtained on an SDT 2960 thermal analysis system (TA Instruments Inc.). There are distinct differences in the displacements of the peaks and / or peaks. curve, in particular about 50 to 330 ° Cter, between 100 and 150 ° C.

d) X-ray powder analysis

Differences in the diffractograms of the CDQ10 complex and the physical mixture of CoQ10 and β-cyclodextrin according to Fig. 5, respectively. differences in the angles, grid distances, and intensities of the CoQ10, βcyclodextrin peaks, their equimolar physical mixtures, and CDQ10, which are shown in Tables 2 to 5, confirm the formation of the CDQ10 inclusion complex.

Table 2: Angles, distances and intensities in the X-ray powder diffractogram of β cyclodextrin.

Fall in as D Intensity Intensity I % Fall in as D Intensity Intensity % 2Θ [°] [Α] [Cps] [%] 2Θ [°] [Α] [Cps] [%] 4,478 th most common 19,717 th most common 1518 37,2 22,716 th most common 3,911 th most common 1076 26,4 6,232 th most common 14,170 th most common 414 10.1 23,440 3,792 th most common 364 8.9 8,993 th most common 9,826 th most common 1528 37,4 23,723 th most common 3,747 th most common 318 7.8 9,731 th most common 9,081 th most common 92 2.3 24,299 3,660 th most common 446 10.9 10,664 th most common 8,289 th most common 447 11,0 25,048 th most common 3,552 th most common 539 13.2 11,622 th most common 7,608 th most common 488 12,0 25,280 3,520 th most common 493 12,1 12,480 7,087 th most common 918 22.5 25,679 3,466 th most common 491 12,0 12,682 th most common 6,974 th most common 1098 26,9 26,657 th most common 3,341 th most common 679 16.6 13,540 th most common 6,534 th most common 285 7.0 27,064 3,292 th most common 869 21.3 14,756 th most common 5,998 th most common 967 23,7 27,600 3,229 th most common 318 7.8 15,376 th most common 5,758 th most common 420 10.3 28,576 th most common 3,121 th most common 336 8.2 16,072 th most common 5,510 th most common 258 6,3 29,500 3,025 th most common 336 8.2 16,909 th most common 5,239 th most common 450 11,0 30,222 th most common 2,955 th most common 365 8.9 17,111 th most common 5,178 th most common 790 19,4 30,848 th most common 2,896 th most common 320 7.8 17,675 th most common 5,014 th most common 1115 27.3 31,047 2,878 th most common 389 9.5 17,960 4,935 th most common 651 15.9 32,026 th most common 2,792 th most common 773 18.9 18,830 th most common 4,709 th most common 4082 100,0 32,858 th most common 2,723 th most common 352 8.6 19,572 th most common 4,532 th most common 716 17.5 34,066 th most common 2,630 th most common 382 9,4 20,729 th most common 4,281 th most common 879 21.5 34,560 2,593 th most common 560 1.3,7 20,911 th most common 4,245 th most common 800 19.6 34,833 th most common 2,573 th most common 845 20,7 21,227 th most common 4,182 th most common 612 15.0 35,329 th most common 2,538 th most common 478 11.7 21,520 4,126 th most common 347 8.5 35,801 th most common 2,506 th most common 383 9,4 22,064 th most common 4,025 th most common 177 4.3 36,637 th most common 2,451 th most common 457 11.2

Table 3: Angles, distances and intensities in CoQ10 X-ray powder diffractograms

Fall in as 2θ [°] D [Α] Intensity [Cps] Intensity % [%] Fall in as 2θ [°] D [Α] Intensity [Cps] Intensity % [%] 3,123 th most common 28,269 426 ^8.7 20,376 th most common 4,355 th most common 708 14.5 4,655 th most common 18,967 366 7.5 21,027 th most common 4,221 th most common 237 4.9 6,204 th most common 14,234 th most common 174 3.6 21,824 th most common 4,069 th most common 329 6,8 7,735 th most common 11,420 th most common 35 0.7 22,868 th most common 3,886 th most common 3600 73,9 9,152 th most common 9,654 th most common 58 1,2 23,369 th most common 3,803 th most common 651 13,4 10,893 th most common 8,116 th most common 130 2.7 24,652 3,608 th most common 578 11.9 11,361 th most common 7,782 th most common 416 8.5 25,714 th most common 3,462 th most common 253 5.2 11,729 th most common 7,539 th most common 224 4.6 26,949 3,306 th most common 243 5.0 12,210 th most common 7,243 th most common 129 2.6 27,322 th most common 3,261 th most common 633 13,0 12,444 th most common 7,107 th most common 166 3.4 28,584 3,120 602 12,4 12,902 th most common 6,856 th most common 77 1.6 29,694 3,006 th most common 593 12.2 13,840 6,393 th most common 152 3.1 30,401 th most common 2,938 th most common 555 11.4 14,003 6,319 th most common 213 4.4 30,849 th most common 2,896 th most common 327 6,7 14,431 th most common 6,133 th most common 173 3.6 31,353 2,851 th most common 237 4.9 14,725 th most common 6,011 th most common 241 4.9 32,286 th most common 2,770 th most common 462 9.5 15,599 th most common 5,676 th most common 262 5.4 32,756 th most common 2,732 th most common 235 4,8 17,144 th most common 5,168 th most common 334 6,9 33,080 2,706 th most common 304 6.2 18,176 th most common 4,877 th most common 280 5.7 33,680 2,659 th most common 193 4.0 18,698 4,742 th most common 4872 100,0 34,511 th most common 2,597 th most common 192 3.9 19,046 th most common 4,656 th most common 1890 38,8 35,844 th most common 2,503 th most common 189 3.9

Table 4: Angles, distances and intensities in the X-ray powder diffractogram of a physical mixture of β-cyclodextrin and CoQ10.

Fall in as 2Θ [°] D [Α] Intensity [Cps] Intensity % [%] Fall in as 2Θ [° j D [Α] Intensity [Cps] Intensity % [%] 3,045 th most common 28,992 83 3.5 21,956 th most common 4,045 th most common 191 8.0 4,463 th most common 19,782 th most common 351 14.7 22,860 th most common 3,887 th most common 1635 68,7 6,167 th most common 14,321 th most common 159 6,7 23,382 th most common 3,801 th most common 402 16.9 8,928 th most common 9,896 th most common 331 13,9 23,641 th most common 3,760 310 13,0 9,712 th most common 9,100 92 3.9 24,254 th most common 3,667 th most common 302 12.7 10,624 th most common 8,320 360 15.1 24,666 th most common 3,606 th most common 324 13.6 11,382 th most common 7,768 th most common 186 7.8 25,210 th most common 3,530 th most common 349 14.7 11,608 th most common 7,617 th most common 337 14.2 25,564 th most common 3,482 th most common 304 12,8 12,430 th most common 7,115 th most common 728 30.6 26,620 th most common 3,346 th most common 355 14.9 13,510 th most common 6,549 th most common 122 5.1 27,055 th most common 3,293 th most common 507 21.3 13,973 th most common 6,333 th most common 96 4.0 28,535 3,126 th most common 441 18.5 14,671 th most common 6,033 th most common 489 20.5 29,608 th most common 3,015 th most common 320 13,4 15,324 th most common 5,777 th most common 318 13,4 30,299 2,947 th most common 331 13,9 16,013 th most common 5,530 th most common 177 7.4 31,000 2,882 th most common 318 13,4 17,074 th most common 5,189 th most common 576 24.2 31,942 2,799 th most common 342 14,4 17,629 th most common 5,027 th most common 432 18,2 32,235 th most common 2,775 th most common 358 15.0 17,840 4,968 th most common 343 14,4 32,726 th most common 2,734 th most common 256 10.8 18,718 th most common 4,737 th most common 2380 100,0 33,040 2,709 th most common 204 8.6 19,080 4,648 th most common 782 32.9 33,925 th most common 2,640 276 11.6 19,550 th most common 4,537 th most common 572 24,0 34,748 th most common 2,580 th most common 408 17,1 20,365 th most common 4,357 th most common 329 13,8 35,087 th most common 2,555 th most common 337 14.2 20,756 th most common 4,276 th most common 488 20.5 35,905 th most common 2,499 th most common 261 11,0 21,463 th most common 4,137 th most common 341 14.3

Table 5: Angles, distances and intensities in the X-ray powder diffractogram of the CDQ10 inclusion complex between CoQ10 and β-cyclodextrin.

Fall in as 2θ [°] D [Α] Intensity [Cpsj Intensity % [%] Fall in as 2θ [° j D [Α] Intensity [Cps] Intensity % [%] 2.88 30,652 24 1.3 15,610 th most common 5,672 th most common 427 24,0 4,313 th most common 20,470 th most common 22 1,2 17,688 th most common 5,010 th most common 625 35.1 4,702 th most common 18,779 th most common 41 2.3 18,773 th most common 4,723 th most common 1781 100,0 5,076 th most common 17,395 th most common 28 1.6 20,798 th most common 4,267 th most common 361 20.3 5.68 15,546 th most common 57 3.2 21,325 th most common 4,163 th most common 330 18.5 5,917 th most common 14,925 th most common 89 5.0 22,892 th most common 3,882 th most common 1089 61,1 6,241 th most common 14,151 th most common 98 5.5 23,932 3,715 th most common 418 23.5 7,261 th most common 12,165 th most common 241 13.5 26,192 3,399 th most common 311 17.5 9,040 9,774 th most common 87 4.9 28,784 th most common 3,099 296 16.6 9,720 9,092 th most common 165 9.3 29,520 3,023 th most common 319 17,9 10,020 th most common 8,820 th most common 201 11.3 32,375 th most common 2,763 th most common 299 16.8 11,440 7,729 th most common 222 12.5 33,118 2,703 th most common 273 15.3 12,000 7,369 th most common 532 29.9 35,120 2,553 th most common 326 18.3 12,525 th most common 7,061 th most common 212 11.9 35,280 2,542 th most common 313 17.6 14,570 th most common 6,074 th most common 314 17.6 36,821 th most common 2,439 th most common 335 18,8

EXAMPLE 2 Comparison of the solubility of CoQ10 and its CDQ10 in milk β-Cyclodextrin (1.575 g, 1.39 mmol) was dissolved in 13 mL of distilled water at 60-70 ° C. 1.00 g (1.16 mmol) of CoQ10 was added to the dissolved β-cyclodextrin and the mixture was stirred at 60-70 ° C for 20 minutes. After a few minutes of mixing, the CDQ10 complex began to precipitate. The reaction mixture was stirred for an additional 8 hours at 60-70 ° C and for 2 hours at room temperature until a homogeneous paste was formed. The resulting mixture was added to fresh milk with stirring at room temperature with 3.5% milk fat (Ljubljanske mlekarne) until saturated. To the second aliquot of milk was added to CoQ10 saturation under the same conditions. CoQ10 content was determined in both samples by filtering the sample, then extracting 10 g of each filtrate seven times with 2 ml of n-hexane and once with 2 ml of chloroform, the solvents from the combined organic fractions evaporated under reduced pressure, the oily residue dissolved in ethanol (3 ml), diluted 1: 1000 (v / v) and analyzed by HPLC (Thermo separation products Surveyor gradient pump, 20 pL loop automatic sampler, UV / VIS detector, ODS Hyperclone (Phenomenex) column, 150 x 4, 6 mm, particle size 5 pm; MeOH mobile phase: EtOH: 2-propanol at a volume ratio of 70: 15: 15 (v / v / v), room temperature 25 ° C, flow rate ml / min; OS2 software). The CoQ10 retention time was 10.7 ± 0.5 min. The results are shown in Table 6.

Table 6: CoQ10 content in milk a) no additives, b) after addition of CoOlO to saturation, c) after addition of CDQ10 complex to saturation.

sample a b c CoQ10 concentration in ug / g 1.7 1,4.10 ² 8.5.10 ³

EXAMPLE 3 Preparation of Dairy Products and Fruit Juices with Addition of CDQ10 β-Cyclodextrin (7.90 g, 6.95 mmol) was dissolved in distilled water (68 mL) at 65-70 ° C and CoQ10 (5.00 was added with stirring) g, 5.79 mmol). After about 30 minutes, the CDQ10 complex was eliminated, and the reaction mixture was stirred for an additional 10 hours at 70 ° C and 10 hours at room temperature until an intense yellow-colored paste formed. The resulting mixture was mixed in 200 aliquots of 500 μΙ (ca 37 mg CoQ10 in the form of CDQ10) in approximately 200 g of milk (3.5% milk fat, Ljubljana Dairy), liquid yogurt (1.3% milk fat, Ljubljana Dairy). , fruit yogurt (peaches, Ljubljanske mlekarne) and orange juice (100%, Rauch). The obtained preparations were organoleptically compared to milk, liquid yoghurt, fruit yoghurt and orange juice with no additives, and with the addition of ca 35-37 mg CoQ10 each. However, since CoQ10 did not dissolve in the products, we did not include these products in testing. 10-21 randomly selected consumers participated in the testing. The results are summarized in Table 7 and show good acceptance of products with CDQ10 additives.

Table 7: Results of organoleptic testing of products without and with the addition of CoQ10 in the form of CDQ10. The proportions of higher acceptability of individual preparations are shown - more acceptable a) sample without supplement, b) sample with addition of CDQ10, c) no differences were observed between sample without and with addition of CDQ10.

Product acceptability Appearance Smell Taste Milk a 57.1 33,3 33,3 (3.5% mm) b 14.3 23,8 33,3 c 28.6 42,9 33,3 Liquid a 63.6 36,4 36,4 yogurt b 27.3 27.3 45.5 (1.3% mm) c 9.1 36,4 18,2 Orange a 72.7 27.3 36,4 juice b 9.1 45.5 45.5 (100%) c 18,2 27.3 18,2 Sadni ^a 10,0 20,0 10,0 yogurt b 20,0 20,0 20,0 (peach) ^c 70,0 60.0 70,0

EXAMPLE 4 Preparation of Toothpaste with Addition of CDQ10 β-Cyclodextrin (7.90 g, 6.95 mmol) was dissolved in distilled water (68 ml) at 60-70 ° C. CoQ10 (5.00 g, 5.79 mmol) was added to the dissolved β-cyclodextrin and the mixture was stirred at 60-70 ° C for 8 hours and at room temperature for 2 hours until a homogeneous lubricant was formed. A portion of the resulting mixture (8.1 g) was stirred homogeneously at room temperature (49 g, Biodent, Lek) to contain about 1% CoQ10 as the inclusion complex of CDQ10 and used as a regular toothpaste.

EXAMPLE 5 Preparation of CDQ10 in 1: 5 Ratio β-Cyclodextrin (1.501 g, 1.32 mmol) was dissolved in 15 ml of distilled water at 70 ° C. 228.4 mg (0.265 mmol) of CoQ10 was added to the dissolved β-cyclodextrin and the mixture was stirred vigorously for 20 minutes at 70 ° C. After about 1 minute of stirring, the CDQ10 complex began to precipitate and the precipitation amount increased for about 20 minutes. The reaction mixture was stirred for an additional 10 hours at 60-70 ° C and for 2 hours at room temperature until a homogeneous paste was formed. The resulting mixture was quenched, the precipitate was washed with a little water and dried at 25-30 ° C under reduced pressure. 1.1 g of DCQ10 as a yellow-orange powder were obtained with a melting point at 295-297 ° C. The product was identified by IR spectroscopy, thermal analysis (DSC) and X-ray powder analysis.

The new water soluble form of coenzyme Q10 according to the invention is therefore an inclusion complex between β-cyclodextrin and coenzyme Q10 wherein the molar ratio of β-cyclodextrin to coenzyme Q10 is in the range of 1:10 to 10: 1, preferably 1: 5 to 5: 1, more preferably in a ratio of about 1: 1. Inclusion complexes between β-cyclodextrin and coenzyme Q10 are isolated or uninsulated from the reaction mixture.

The process of preparing a new water-soluble form is characterized by the fact that β-cyclodextrin is dissolved in water at elevated temperature, between 30 ° C and boiling point, preferably between 55 ° C and boiling point, added to coenzyme Q10 in solid form or dissolved in a suitable solvent , and stirred first at elevated temperature and then at room temperature or below room temperature. The molar ratio of β-cyclodextrin to coenzyme Q10 is in the range of 1:10 to 10: 1, preferably 1: 5 to 5: 1, more preferably in the ratio of about 1: 1. The new water soluble form of Coenzyme Q10 of the invention is useful as an adjunct to pharmaceutical, cosmetic and nutritional products, adding to the products isolated or uninsulated from the reaction mixture at any time during the preparation of the product, preferably into the finished product.

Claims (8)

A new water-soluble form of coenzyme Q10, characterized in that the inclusion complex is between β-cyclodextrin and coenzyme Q10, wherein the molar ratio between β-cyclodextrin and coenzyme Q10 is in the range of 1:10 to 10: 1, preferably 1: 5 to 5 : 1, preferably at a ratio of about 1: 1. A new water-soluble form of coenzyme Q10 according to claim 1, characterized in that the inclusion complexes between β-cyclodextrin and coenzyme Q10 are isolated or uninsulated from the reaction mixture. The new water-soluble form of coenzyme Q10 according to claims 1 to 2, characterized in that the coenzyme Q10 in the form of these complexes improves the solubility in aqueous media. A process for the preparation of a new water-soluble form according to claim 1, characterized in that the β-cyclodextrin is dissolved in water at elevated temperature, between 30 ° C and boiling point, preferably between 55 ° C and boiling temperature, added coenzyme Q10 in solid form or dissolved in a suitable solvent, and is first stirred at elevated temperature and then at room temperature or below room temperature. 5. The process of claim 4, wherein the molar ratio of βcyclodextrin to coenzyme Q10 is in the range of 1:10 to 10: 1, preferably 1: 5 to 5: 1, more preferably in the ratio of about 1: 1. Use of new water-soluble forms of coenzyme Q10 according to claims 1 to 3 as an adjunct to pharmaceuticals, cosmetics and food products. Use of new water soluble forms of coenzyme Q10 according to claim 6, characterized in that the products are added isolated or uninsulated from the reaction mixture. Use of new water-soluble forms of coenzyme Q10 according to claim 6, characterized in that they are added to the product at any time during the preparation of the product, preferably into the finished product.