NOVA VODOTOPNA OBLIKA KOENCIMA Q10 V OBLIKI INKLUZIJSKEGA KOMPLEKSA Z β-CIKLODEKSTRINOM, POSTOPEK NJEGOVE PRIPRAVE IN NJEGOVA UPORABAA NEW WATER-SOLUBLE FORM OF COENZYM Q10 IN THE FORM OF INCLUSION COMPLEX WITH β-CYCLODESTRIN, PROCEDURE FOR ITS PREPARATION AND ITS USE
Predmet izuma je nova vodotopna oblika koencima Q10, postopek njegove priprave in njegova uporaba. Koencim Q10 po izumu je v obliki inkluzijskega kompleksa z βciklodekstrinom.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.
Izum se nanaša na inkluzijski kompleks koencima Q10 z β-ciklodekstrinom. Izum se nanaša tudi na postopke priprave tega kompleksa in uporabo v obliki samostojnih pripravkov ali kot dodatkov farmacevtskim, kozmetičnim in prehrambenim izdelkom.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.
V nadaljevanju bodo uporabljene naslednje enakopomenke:The following equivalents will be used below:
- za koencim Q10: CoQ10,- for coenzyme Q10: CoQ10,
- za inkluzijski kompleks koencima Q10 z β-ciklodekstrinom: CDQ10.- for the inclusion complex with coenzyme Q10 with β-cyclodextrin: CDQ10.
Koencim Q10 (CoQ10) je lipofilna v vodi netopna substanca, nujno potrebna za delovanje človeškega organizma, saj sodeluje kot koencim v številnih metabolnih procesih. Človek zagotavlja zadostne količine CoQ10 v organizmu s sintezo in prehrano. Vnos eksogenega CoQ10 oz. drugih koencimov Q (CoQ) v človeški organizem vpliva tudi na sintezo endogenega CoQ10. Še zlasti je vnos zadostnih količin eksogenega CoQ10 oz. drugih koencimov Q nujen v starejših letih, ko sinteza endogenega CoQ10 peša in je potrebno primanjkljaj nadomestiti s hrano oz. z dodatki v obliki različnih pripravkov. Ker pri različnih postopkih predelave hrane pogosto pride do bistvenega zmanjšanja količine CoQ v njej, je nadomeščanje primanjkljaja v obliki dodatkov toliko pomembnejše, pomembno pa bi bilo CoQ, zlasti CoQ10 tudi dodajati v nekatera ključna živila. Vendar pa je prav zaradi lipofilnega značaja oz. netopnosti CoQ, zlasti CoQ10 v vodi oblikovanje primernih pripravkov težavno in zato obstaja stalna potreba po pripravi vodotopne oblike ubikinona z boljšo biorazpoložljivostjo, ki bi omogočala izdelavo pripravkov z izboljšanimi biofarmacevtskimi oz. prehranskimi lastnostmi CoQ10 in ki bi omogočala tudi dodajanje v živila in druge izdelke.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.
Komercialno dostopni pripravki vsebujejo CoQ10 bodisi v obliki oljnih suspenzij, npr. v mehkih želatinskih kapsulah, bodisi v praškastih oblikah z različnimi polnili, npr. v trdih kapsulah.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.
V pripravkih na oljni osnovi je CoQ10 zaradi svojih lipofilnih lastnosti delno solubiliziran, tako da se po zaužitju hitreje absorbira in doseže razmeroma visoke krvne koncentracije, vendar pa številni avtorji ugotavljajo, da se nato iz organizma z urinom tudi hitro izloči. Tako so fiziološki učinki slabši od pričakovanih.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.
Po drugi strani pa bi se naj v vodnih medijih raztopljeni CoQ10 zelo hitro absorbiral v celice, kot so npr. mišične, in se zato mnogo počasneje izločal iz organizma in bi torej dalj časa učinkoval. Vendar pa je topnost CoQ10 v vodi praktično zanemarljiva, zato je tudi njegova biorazpoložljivost zelo slaba. Zato je potrebno za učinkovito uporabo CoQ10 kot dodatka prehrani oz. v samostojnih oblikah razviti obliko, ki bo omogočala boljšo vodotopnost in s tem boljšo biorazpoložljivost in učinkovitost. Raziskave namreč kažejo neposredno povezanost hitrosti raztapljanja (disolucije) in biorazpoložljivost! CoQ10. Vodotopnost je še posebej pomembna pri lokalnih aplikacijah, npr. v ustni votlini, na koži oz. mišicah ipd.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.
Zato številni avtorji poskušajo na različne načine izboljšati vodotopnost CoQ10, da bi s tem povečali njegovo biorazpoložljivost in učinkovitost.Therefore, many authors are trying to improve the water solubility of CoQ10 in various ways in order to increase its bioavailability and effectiveness.
Japonska firma BioTakenaka Pharm. je razvila posebno tehnologijo za izboljšanje topnosti CoQ10, znano pod imenom Bio-Coenzyme Q10 purum. Tehnologija temelji na kombinaciji z encimom in omogoča dobro topnost ter bistveno povečano biorazpoložljivost. Preparate na tej osnovi trži Kampoyaki Research SDN BHD (Malezija) v obliki gela, tablet in kapsul. Tehnologija pa je zaradi kombinacije z encimom razmeroma zahtevna, draga in občutljiva.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.
Iz članka A. Lutka, J. Pawlaczyk, Acta Poloniae Pharm. - Drug Res. 1995, 52, pp 379-386 so znani tudi poskusi izboljšanja vodotopnosti CoQ10 z vključitvijo v različne ciklodekstrine. Iz članka J. Szejtli, J. Materials Chem. 1997, 7, pp 575-587 je namreč znano, da se s pripravo kompleksov lipofilnih snovi s ciklodekstrini poveča njihova topnost v vodi. Avtorji so poskušali pripraviti inkluzijske komplekse CoQ10 z α-ciklodekstrinom, βciklodekstrinom, metil^-ciklodekstrinom (0,97 in 1,8), hidroksipropil ciklodekstrinom in γciklodekstrinom. Kot kaže, so uspeli pripraviti kompleks med CoQ10 in γ-ciklodekstrinom, verjetno pa tudi s substituiranimi β-ciklodekstrini, medtem ko z α-ciklodekstrinom kompleks ni nastal. Prav tako niso uspeli pripraviti kompleksa z β-ciklodekstrinom, ki je zaradi nizke cene, lastnostni in raziskanosti s stališča varnosti za človeka sicer komercialno najprimernejši. Sam β-ciklodekstrin se namreč razen v ZDA že dolgo uporablja v prehrani. Tako se na Japonskem brez omejitev uporablja že od I. 1983, uporaba pa je odobrena tudi v mnogih evropskih državah. Nedavno sta Food and Agriculture Organization in World Health Organization (WH0) skupaj priporočili maksimalni dnevni odmerek za človeka 5 mg β-ciklodekstrina na kg telesne teže človeka - članek Z. H. Qi, C. T. Sikorski, Pharm. Techol. Europe 1002, 13 (11), pp 17-27. Avtorji tako kljub uporabi razmeroma zahtevne opreme niso dosegli cilja pripraviti vodotopno obliko CoQ10 s cenenim in fiziološko sprejemljivim β-ciklodekstrinom.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.
Problem, ki doslej ni bil ustrezno rešen, je primerna vodotopna oblika koencimov Q, zlasti CoQ10, posebej ne takšna, ki bi jo bilo mogoče enostavno pripraviti na ekonomičen način. Zato kljub številnim raziskavam in rezultatom v zvezi z uporabo CoQ10 doslej ni znana njegova uporaba kot dodatka prehrambenim izdelkom ter kozmetičnim in farmacevtskim pripravkom na nelipofilni osnovi, niti niso znani pripravki CoQ10, ki bi jih lahko dodajali tovrstnim izdelkom na način, da bi dosegali primerne koncentracije CoQ10 v njih.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.
Naloga in cilj izuma je vodotopna oblika koencima Q10 z β-ciklodekstrinom, postopek njegove priprave in njegova uporaba v obliki samostojnih pripravkov ali kot dodatkov farmacevtskim, kozmetičnim in prehrambenim izdelkom.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.
Po izumu je naloga rešena z vodotopno obliko inkluzijskega kompleksa CoQ10 z βciklodekstrinom (CDQ10), postopkom njegove priprave in njegova uporaba po neodvisnih patentnih zahtevkih.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.
Slike prikazujejo:Pictures show:
Slika 1: IR spekter CDQ10 in fizikalne mešanice β-ciklodekstrina in CoQ10,Figure 1: IR spectrum of CDQ10 and physical mixtures of β-cyclodextrin and CoQ10,
Slika 2: DSC krivulja β-ciklodekstrina,Figure 2: DSC curve of β-cyclodextrin,
Slika 3: DSC krivulja CoQ10,Figure 3: CoSC10 DSC curve,
Slika 4: DSC fizikalne mešanice β-ciklodekstrina in CoQ10 ter CDQ10,Figure 4: DSC physical mixtures of β-cyclodextrin and CoQ10 and CDQ10,
Slika 5: Praškovna rentgenska difraktograma CDQ10 in fizikalne mešanice βciklodekstrina in CoQ10,Figure 5: Powder X-ray diffractograms of CDQ10 and physical mixtures of βcyclodextrin and CoQ10,
Kompleksi so pripravljeni na presenetljiv in izviren način tako, da so na osnovi lastnosti βciklodekstrina in CoQ10 izbrani pogoji, pri katerih je nastanek inkluzijskega kompleksa CDQ10 mogoč. Bistvo postopka priprave CDQ10 je, da β-ciklodekstrin raztopimo v vodi pri povišani temperaturi, t.j. temperaturi višji od sobne temperature, prednostno pri temperaturi med 55°C in temperaturo vrelišča, nato pa med intenzivnim mešanjem dodamo CoQ10 v trdni obliki ali raztopljen v minimalni količini primernega topila, v katerem se CoQ10 raztaplja, se meša z vodo in je fiziološko sprejemljivo, kot je etanol, aceton ipd. Inkluzijski kompleks se tvori tako, da se molekula CoQ10 oz. njeni deli, inkludirajo v eno ali več molekul β-ciklodekstrina, in sicer se zaradi strukture, posebno pa zaradi dolžine molekule CoQ10 le-ta vključi v 1 do 10 molekul β-ciklodekstrina. Zato z razmerjem med CoQ10 in β-ciklodekstrinom vplivamo na delež in stopnjo kompleksacije CoQ10. Delno izboljšanje topnosti CoQ10 oz. njegove biorazpoložljivosti dosežemo že s subekvimolarnimi količinami β-ciklodekstrina glede na CoQ10 (npr. v razmerju 1:10), delež kompleksiranega CoQ10 in stopnja kompleksacije (t.j. razmerje med CoQ10 in βciklodekstrinom v inkluzijskem kompleksu), pa se povečuje z večanjem razmerja v prid βciklodekstrina. Zato uporabimo poljubno razmerje med β-ciklodekstrinom in CoQ10 od 1:10 do 10:1, prednostno 1:5 do 5:1, prednostno v razmerju okoli 1:1, pri katerem so doseženi optimialni učinki glede lastnosti inkluzijskega kompleksa in stroškov sinteze.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.
Prednostno dodamo CoQ10 v trdni obliki in uporabimo 10-20% molarni prebitek βciklodekstrina glede na CoQ10. Intenzivno mešamo, dokler CoQ10 ne izgine oz. dokler se ne začne izobarjati inkluzijski kompleks CDQ10. Reakcijsko zmes ohladimo in CDQ10 izoliramo z dekantiranjem, filtriranjem ali odparevanjem vode. Po potrebi ga posušimo, uporabimo pa lahko tudi raztopljen oz. nesušen kompleks CDQ10, saj postopek priprave poteka v vodnem mediju, tako da dobljena zmes ne vsebuje zdravju škodljivih topil. Nastanek CDQ10 je praktično kvantitativen, CoQ10 pa se v obliki dobljenega CDQ10 v vodnih medijih bistveno boljše raztaplja, tako da presega topnost, potrebno za vnos dnevnega odmerka CoQ10 za odraslega človeka v obliki samostojnih pripravkov, ali v obliki primesi prehrambenim in drugim izdelkom.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.
Zato se izum nanaša tudi na pripravke, ki vsebujejo kompleks CDQ10, in njegovo uporabo kot dodatek k prehrani oz. samostojno v prehrambene, preventivne, terapevtske, kozmetične in druge namene.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.
Izboljšane lastnosti CoQ10 v obliki CDQ10 omogočajo tehnično enostavno in komercialno primerno pripravo pripravkov, ki ne temeljijo na lipidnih podlagah, temveč izkazujejo primerno disolucijo oz. raztapljanje v vodnih medijih, s čimer se izboljša absorpcija v tkiva in povečajo fiziološki učinki. Poleg tega je zato tudi mogoča njihova širša uporabnost za različne namene oz. za različne načine uporabe, kot so npr. oralna, bukalna in topična. Pripravki so lahko trdni, poltrdni, ali tekoči, npr. v obliki kapsul, tablet, praškov, sirupov, raztopin, gelov, kapljic, krem ali drugih oblikah oz. dostavnih sistemih. Uporabljajo se za doseganje različnih sistemskih in lokalnih učinkov, med drugim v preventivi in terapiji kardiovaskularnih bolezni, zvišanega holesterola, diabetesa, raka, imunskih bolezni, distrofije mišic, bolezni ustne votline, zlasti dlesni ipd.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.
Tako je zlahka mogoče pripraviti vodno raztopino za spiranje dlesni, ki ji lahko dodamo še druge sestavine za povečanje sprejemljivosti za uporabnika. Prav tako lahko CDQ10 dodamo v zobne kreme, kar ugodno vpliva na jačanje dlesni. Podobno velja za različne kreme in tekočine za zunanjo uporabo.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.
Poleg tega se izum nanaša tudi na uporabo kompleksa CDQ10 kot sestavine prehrambenih izdelkov tako, da izoliranega ali neizoliranega primešamo v živila oz. prehrambene izdelke, kot so mleko, jogurti, skuta, sir, maslo in drugi mlečni izdelki, marmelade in džemi, sadni in zelenjavni sokovi in nektarji ter različne pijače, kompoti, kaše, žitni izdelki, čokoladni izdelki, čaji, izdelki iz medu, mesni izdelki in podobno. Inkluzijske komplekse po izumu, zlasti kot npr. CDQ10 lahko vmešamo v te izdelke v eni od faz tehnološkega postopka priprave izdelka, v primeru tekočih, poltrdnih in poltekočih izdelkov pa tudi, ko je izdelek že v končni obliki. Možnost dodajanja npr. CDQ10 ob koncu procesa predstavlja dodatno prednost, saj omogoča enostavno organizacijo in usmerjanje proizvodnje v osnovni izdelek, ali izdelek z dodatkom CDQ10 ali oboje. Poleg tega pa je mogoče npr. CDQ10 dodajati v prehrambene in druge izdelke tudi na mestu uporabe oz. tik pred uporabo tako, da dodamo kompleks v tak izdelek v primerni obliki za uporabo, npr. v obliki raztopine, sirupa, kapljic, praška, kapsul ipd.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.
Tako je mogoče na primer v mleko ali jogurt primešati zadostno količino CDQ10, da odrasel človek v enem obroku zaužije dnevni ali celo večkratni dnevni odmerek CoQ10. Topnost CoQ10 v obliki CDQ10 je npr. v mleku pri sobni temperaturi namreč kar ca 60krat večja kot topnost samega CoQ10, in sicer se pri sobni temperaturi raztopi kar ca 8,5 mg CoQ10 v obliki CDQ10 v 1 g mleka. S tem lahko povečamo vsebnost CoQ10 v mleku ali jogurtih tudi za 5000 krat in več, saj vsebuje npr. naravno mleko ca 1,7.10-3 mg CoQ10/g mleka, mnoge vrste mleka in mlečnih izdelkov pa še mnogo manj, celo pod mejo detekcije z običajnimi metodami. Zato je možnost dodajanja CoQ10 toliko bolj pomembna. Jogurt ali mleko z dodatkom CDQ10 pripravimo prednostno tako, da jima med mešanjem dodamo željeno količino CDQ10, npr. od 30-150 mg CoQ10 v obliki kompleksa v primerni obliki. Prednostno dodamo nesušen kompleks ali v obliki reakcijske zmesi, prednostno v obliki reakcijske zmesi v primerni obliki, kot je npr. raztopina, sirup, kapljice ipd. Nato mleko oz. jogurt z dodanim CDQ10 zaužijemo, če postopek poteka v proizvodnji, pa ga ustrezno embaliramo.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.
Podobno lahko dodajamo CDQ10 npr. v pomarančni, jagodni, breskov in druge sokove, nektarje in pijače v poljubnih količinah, ki jih omogoča topnost CDQ10, prednostno v količinah običajnih dnevnih odmerkov do 150 mg CoQ10 v obliki CDQ10, in sicer tako, da kompleks CDQ10 med mešanjem pri običajni temperaturi uporabe raztopimo v soku, nektarju ali pijači pred zaužitjem ali pred embaliranjem. Kot dodatek uporabimo izoliran, sušen ali nesušen kompleks, ali pa neizoliran kompleks; prednostno uporabimo nesušen oz. neizoliran kompleks.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.
Na analogni način dodajamo CDQ10 v poltrdne izdelke. Tako vmešamo CDQ10 pred uporabo ali pred embaliranjem v zobno kremo, jetrno pašteto, med, marmelado, džem ipd. tako, da med mešanjem dodamo željeno količino izoliranega, sušenega ali nesušenega, ali neizoliranega CDQ10 v primerni obliki.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.
Izum se nanaša tudi na uporabo kompleksa CDQ10 in izdelkov z njim v zvezi s funkcijami človekovega organizma, ki so povezane s koencimom Q10.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.
Izum pojasnjujejo, vendar ne omejujejo izvedbeni primeri.The invention is explained but not limited to the embodiments.
Uporabljen je bil β-ciklodekstrin Roquette, Francija in CoQ10 Vivati Pharma GmbH, !Β-Cyclodextrin Roquette, France and CoQ10 Vivati Pharma GmbH was used!
Nemčija.Germany.
PRIMER 1 - Priprava kompleksa CDQ10EXAMPLE 1 Preparation of the CDQ10 Complex
a) Postopek priprave β-ciklodekstrin (1,575 g, 1,39 mmol) smo raztopili v 13 mL destilirane vode pri 70 °C. Raztopljenemu β-ciklodekstrinu smo dodali 1,00 g (1,16 mmol) CoQ10 in zmes mešali 20 minut pri 70 °C. Po ca 1 minuti mešanja se je začel obarjati kompleks CDQ10, količina oborine pa se je povečevala ca 20 min. Reakcijsko zmes smo mešali še ca 10 ur pri 60-70 °C in nekaj ur pri sobni temperaturi, dokler ni nastala homogena pasta. Dobljeno zmes smo centrifugirali, ločili fazi, suspenzijo sprali z malo vode in posušili pri 30-35 °C pod znižanim tlakom. Dobili smo 1,9 g kompleksa DCQ10 v obliki rumeno-oranžnega prahu z razkrojem pri temperaturi nad 273 °C. Produkt smo identificirali z IR spektroskopijo, termično analizo (DSC) in rentgensko praškovno analizo.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 spektroskopijab) IR spectroscopy
Primerjava IR spektrov po sliki 1 in tabeli 1, kjer so prikazana valovna števila trakov, ki so različni v obeh spektrih, kaže na razlike med fizikalno zmesjo β-ciklodekstrina in CoQ10 ter inkluzijskega kompleksa CDQ10. Spektri so bili posneti s FT-IR spektrometrom SPECTRUM 1000 (Perkin-Elmer).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).
Tabela T. Primerjava valovnih števil izbranih trakov v IR spektru CDQ10 ter fizikalne zmesi β-ciklodekstrina in CoQ10 in razlika med posameznimi trakovi.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.
c) Termična analiza (DSC)c) Thermal Analysis (DSC)
Slike 2, 3 in 4 prikazujejo DSC krivulje β-ciklodekstrina, CoQ10, fizikalne zmesi obeh in kompleksa CDQ10. Krivulje so bile dobljene na sistemu za termično analizo SDT 2960 (TA Instruments Inc.). Značilne so razlike v premikih vrhov oz. obliki krivulje, zlasti okoli 50 in 330 °Cter med 100 in 150 °C.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) rentgenska praškovna analizad) X-ray powder analysis
Razlike v difraktogram ih kompleksa CDQ10 in fizikalne zmesi CoQ10 in β-ciklodekstrina po sliki 5 oz. razlike v kotih, mrežnih razdaljah in intenzitetah vrhov CoQ10, βciklodekstrina, njune ekvimolarne fizikalne zmesi ter CDQ10, ki so prikazane v tabelah od 2 do 5 potrjujejo nastanek inkluzijskega kompleksa CDQ10.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.
Tabela 2: Koti, razdalje in intenzitete v rentgenskem praškovnem difraktogramu β ciklodekstrina.Table 2: Angles, distances and intensities in the X-ray powder diffractogram of β cyclodextrin.
Tabela 3: Koti, razdalje in intenzitete v rentgenskem praškovnem difraktogramu CoQ10Table 3: Angles, distances and intensities in CoQ10 X-ray powder diffractograms
Tabela 4: Koti, razdalje in intenzitete v rentgenskem praškovnem difraktogramu fizikalne mešanice β-ciklodekstrina in CoQ10.Table 4: Angles, distances and intensities in the X-ray powder diffractogram of a physical mixture of β-cyclodextrin and CoQ10.
Tabela 5: Koti, razdalje in intenzitete v rentgenskem praškovnem difraktogramu inkluzijskega kompleksa CDQ10 med CoQ10 in β-ciklodekstrinom.Table 5: Angles, distances and intensities in the X-ray powder diffractogram of the CDQ10 inclusion complex between CoQ10 and β-cyclodextrin.
PRIMER 2 - Primerjava topnosti CoQ10 in njegovega CDQ10 v mleku β-Ciklodekstrin (1,575 g, 1,39 mmol) smo raztopili v 13 mL destilirane vode pri 60-70 °C. Raztopljenemu β-ciklodekstrinu smo dodali 1,00 g (1,16 mmol) CoQ10 in zmes mešali 20 minut pri 60-70 °C. Po nekaj minutah mešanja se je začel obarjati kompleks CDQ10. Reakcijsko zmes smo mešali še ca 8 ur pri 60-70 °C in ca 2 uri pri sobni temperaturi, dokler ni nastala homogena pasta. Dobljeno zmes smo med mešanjem pri sobni temperaturi dodali v sveže mleko s 3,5 % mlečne maščobe (Ljubljanske mlekarne) do nasičenja. V drugi alikvot mleka smo pod enakimi pogoji dodajali do nasičenja CoQ10. V obeh vzorcih smo določili vsebnost CoQ10 tako, da smo vzorca filtrirali, nato pa 10 g vsakega filtrata po sedemkrat ekstrahirali z 2 ml n-heksana in enkrat z 2 ml kloroforma, topila iz združenih organskih frakcij odparili pod znižanim tlakom, oljna preostanka raztopili v etanolu (3 ml), redčili 1:1000 (v/v) in analizirali s HPLC (Thermo separation products Surveyor gradientna črpalka, avtomatski vzorčevalnik z 20 pL zanko, UV/VIS detektor, kolona ODS Hyperclone (Phenomenex), 150 x 4,6 mm, velikost delcev 5 pm; mobilna faza MeOH : EtOH : 2-propanol v volumskem razmerju 70 : 15 : 15 (v/v/v), sobna temperatura 25 °C, pretokul ml/min; programska oprema OS2). Retenzijski čas CoQ10 je bil 10,7 ± 0,5 min. Rezultati so prikazani v Tabeli 6.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.
Tabela 6: Vsebnost CoQ10 v mleku a) brez dodatkov, b) po dodatku CoOlO do nasičenja, c) po dodatku kompleksa CDQ10 do nasičenja.Table 6: CoQ10 content in milk a) no additives, b) after addition of CoOlO to saturation, c) after addition of CDQ10 complex to saturation.
PRIMER 3 - Priprava mlečnih izdelkov in sadnih sokov z dodatkom CDQ10 β-Ciklodekstrin (7,90 g, 6,95 mmol) smo raztopili v destilirani vodi (68 mL) pri 65-70 °C in med mešanjem dodali CoQ10 (5,00 g, 5,79 mmol). Po ca 30 minutah se je izoboril kompleks CDQ10, reakcijsko zmes pa smo mešali še približno 10 ur pri 70 °C in 10 ur pri sobni temperaturi, dokler ni nastala intenzivno rumeno obarvana pasta. Dobljeno zmes smo v enakih alikvotih po 500 μΙ (ca 37 mg CoQ10 v obliki CDQ10) vmešali v po ca 200 g mleka (3,5% mlečne maščobe, Ljubljanske mlekarne), tekočega jogurta (1,3 % mlečne maščobe, Ljubljanske mlekarne), sadnega jogurta (breskev, Ljubljanske mlekarne) in pomarančnega soka (100%, Rauch). Dobljene pripravke smo organoleptično primerjali z mlekom, tekočim jogurtom, sadnim jogurtom in pomarančnim sokom brez dodatkov in z dodatkom po ca 35-37 mg CoQ10. Ker pa se CoQ10 v izdelkih ni raztopil, teh izdelkov nismo vključili v testiranje. V testiranju je sodelovalo 10-21 naključno izbranih potrošnikov. Rezultati so zbrani v Tabeli 7 in kažejo dobro sprejemljivost izdelkov z dodatki CDQ10.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.
Tabela 7: Rezultati organoleptičnega preiskušanja izdelkov brez in z dodatkom CoQ10 v obliki CDQ10. Prikazani so deleži večje sprejemljivosti posameznih pripravkov - bolj sprejemljiv a) vzorec brez dodatka, b) vzorec z dodatkom CDQ10, c) niso opazili razlik med vzorcem brez in z dodatkom CDQ10.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.
PRIMER 4 - Priprava zobne paste z dodatkom CDQ10 β-Ciklodekstrin (7,90 g, 6,95 mmol) smo raztopili v destilirani vodi (68 ml) pri 60-70 °C. Raztopljenemu β-ciklodekstrinu smo dodali CoQ10 (5,00 g, 5,79 mmol) in zmes mešali ca 8 ur pri 60-70 °C in ca 2 uri pri sobni temperaturi, dokler ni nastala homogena mazava zmes. Del dobljene zmesi (8,1 g) smo pri sobni temperaturi homogeno vmešali v zobno pasto (49 g, Biodent, Lek), tako da je vsebovala ca 1 % CoQ10 v obliki inkluzijskega kompleksa CDQ10, in jo uporabili kot običajno zobno pasto.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.
PRIMER 5 - Priprava CDQ10 v razmerju 1:5 β-Ciklodekstrin (1,501 g, 1,32 mmol) smo raztopili v 15 ml destilirane vode pri 70 °C. Raztopljenemu β-ciklodekstrinu smo dodali 228,4 mg (0,265 mmol) CoQ10 in zmes intenzivno mešali 20 minut pri 70 °C. Po ca 1 minuti mešanja se je začel obarjati kompleks CDQ10, količina oborine pa se je povečevala ca 20 min. Reakcijsko zmes smo mešali še ca 10 ur pri 60-70 °C in 2 uri pri sobni temperaturi, dokler ni nastala homogena pasta. Dobljeno zmes smo nučirali, oborino sprali z malo vode in posušili pri 25-30 °C pod znižanim tlakom. Dobili smo 1,1 g DCQ10 v obliki rumeno-oranžnega prahu s tališčem pri 295-297 °C. Produkt smo identificirali z IR spektroskopijo, termično analizo (DSC) in rentgensko praškovno analizo.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.
Nova vodotopna oblika koencima Q10 po izumu je torej inkluzijski kompleks med βciklodekstrinom in koencimom Q10 pri čemer je molarno razmerje med β-ciklodekstrinom in koencimom Q10 v območju od 1:10 do 10:1, prednostno 1:5 do 5:1, še prednostno v razmerju okoli 1:1. Inkluzijski kompleksi med β-ciklodekstrinom in koencimom Q10 so izolirani ali neizolirani iz reakcijske zmesi.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.
Postopek priprave nove vodotopne oblike je značilen po tem, da se β-ciklodekstrin raztopi v vodi pri povišani temperaturi, med 30 °C in temperaturo vrelišča, prednostno med 55 °C in temperaturo vrelišča, doda koencim Q10 v trdni obliki ali raztopljen v primernem topilu, ter meša najprej pri povišani temperaturi, nato pa pri sobni temperaturi ali temperaturi pod sobno temperaturo. Pri tem je molarno razmerje med β-ciklodekstrinom in koencimom Q10 v območju od 1:10 do 10:1, prednostno 1:5 do 5:1, še prednostno v razmerju okoli 1:1. Nova vodotopna oblika koencima Q10 po izumu je uporabna kot dodatek farmacevtskim, kozmetičnim in prehrambenim izdelkom, pri čemer se izdelkom doda izolirana ali neizolirana iz reakcijske zmesi in to kadarkoli v procesu priprave izdelka, prednostno v pripravljen izdelek.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.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200400144ASI21783A (en) | 2004-05-18 | 2004-05-18 | New water soluble form of coenzyme q10 in the form of inclusion complex with beta-cyclodextrine, procedure for its preparation and its application |
| RU2006140641/15ARU2375053C2 (en) | 2004-05-18 | 2005-05-10 | New water-soluble form of coenzyme q10 representing incorporation complex with beta-cyclodextrine, method for making and application thereof |
| US11/569,110US20070202090A1 (en) | 2004-05-18 | 2005-05-10 | Water Soluble Form Of Coenzyme Q10 In The Form Of An Inclusion Complex With Beta-Cyclodextrin, Process Of Preparing, And Use Thereof |
| PCT/SI2005/000013WO2005111224A2 (en) | 2004-05-18 | 2005-05-10 | Water-soluble coenzyme q10 in inclusion complex with beta-cyclodextrin, process of preparing, and use thereof |
| EP05738276AEP1755683A2 (en) | 2004-05-18 | 2005-05-10 | Water-soluble coenzyme q10 inclusion complex with beta-cyclodextrin, process of preparing, and use thereof |
| IL179143AIL179143A0 (en) | 2004-05-18 | 2006-11-09 | New water-soluble form of coenzyme q10 in the form of an inclusion complex with beta-cyclodextrin, process of preparing, and use thereof |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200400144ASI21783A (en) | 2004-05-18 | 2004-05-18 | New water soluble form of coenzyme q10 in the form of inclusion complex with beta-cyclodextrine, procedure for its preparation and its application |
| Publication Number | Publication Date |
|---|---|
| SI21783Atrue SI21783A (en) | 2005-12-31 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI200400144ASI21783A (en) | 2004-05-18 | 2004-05-18 | New water soluble form of coenzyme q10 in the form of inclusion complex with beta-cyclodextrine, procedure for its preparation and its application |
| Country | Link |
|---|---|
| SI (1) | SI21783A (en) |
| Publication | Publication Date | Title |
|---|---|---|
| US20120083460A1 (en) | Readily water-soluble isoquercitrin composition | |
| JP5207611B2 (en) | Saccharification inhibitor | |
| RU2375053C2 (en) | New water-soluble form of coenzyme q10 representing incorporation complex with beta-cyclodextrine, method for making and application thereof | |
| CN106036793A (en) | Fat-binding compositions | |
| US20050085454A1 (en) | Phenolic antioxidant-chromium complexes for treatment or prevention of type 2 diabetes or glucose intolerance | |
| CN101500549A (en) | Casein complexes | |
| JP2008271839A (en) | Water-soluble flavonoid composition and production method thereof, food containing water-soluble flavonoid composition, etc. | |
| JP2009084214A (en) | Glycation inhibitor | |
| JP2007277183A (en) | Composition having brain cell-activating effect by virtue of ginkgo leaf extract nano fine particle | |
| TWI225789B (en) | Compositions inhibiting muscle atrophy | |
| CN104837366A (en) | Composition comprising natural polyphenol compounds, and composition for oral administration comprising same | |
| US20120015090A1 (en) | Readily water-soluble myricitrin composition | |
| SI21783A (en) | New water soluble form of coenzyme q10 in the form of inclusion complex with beta-cyclodextrine, procedure for its preparation and its application | |
| Madhavi et al. | A study on the bioavailability of a novel sustained-release coenzyme Q10-β-cyclodextrin complex | |
| SI21992A (en) | New water soluble form of coenzyme q10 in the form of inclusion complex with beta-cyclodextrine, procedure of its preparantion and its application | |
| JP7122727B2 (en) | Beverage containing ferulic acid | |
| JP2018138610A (en) | Composition for preventing or treating liver cancer containing ginsenoside f2 as active ingredient | |
| JP4627999B2 (en) | Anti-oxidant | |
| JP4011594B2 (en) | Complex with enhanced stability and bioavailability and method for producing the same | |
| JP4704007B2 (en) | Skin moisture improver | |
| KR102337016B1 (en) | Composition | |
| AU2006347123B2 (en) | Composition for preventing and/or treating tumor containing component originating in the bark of tree belonging to the genus Acacia | |
| RU2776298C1 (en) | Biologically active food additives based on ascorbic acid and stevia extract | |
| JP2006321784A (en) | Alpha lipoic acid aqueous solution and production method thereof | |
| JP5766173B2 (en) | Foods and drinks containing chlorogenic acids |
| Date | Code | Title | Description |
|---|---|---|---|
| OO00 | Grant of patent | Effective date:20050412 | |
| KO00 | Lapse of patent | Effective date:20150109 |