Article

Enhancement of oral bioavailability of coenzyme Q 10 by complexation with γ-cyclodextrin in healthy adults

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Abstract

The objective of this study was to determine the effect of molecular encapsulation of coenzyme Q10 (CoQ10) by complexation with γ-cyclodextrin (γ-CD) (CoQ10-γ-CD) compared with a mixture of CoQ10 with microcrystalline cellulose (CoQ10-MCC) on absorption and bioavailability of CoQ10 in supplement form in healthy adults. Twenty-two volunteers received a single dose of a 150-mg capsule containing 30 mg CoQ10 under fasting conditions in an open-label, crossover design with a 2-week washout period. Blood was collected before dosing and after dosing periodically over 48 hours. Plasma levels of CoQ10 were determined by high-performance liquid chromatography using an electrochemical detector and an online reduction system. After 6 and 8 hours of dosing there was a significant increase in mean CoQ10 plasma levels of subjects after a single oral administration of the CoQ10-γ-CD capsule compared with those with the CoQ10-MCC capsule. In addition, the mean plasma levels at 24 and 48 hours tended to be higher after CoQ10-γ-CD administration in comparison with CoQ10-MCC administration. The area under the plasma CoQ10 concentration curve and the maximum plasma concentration (Cmax) values as well as their corresponding log-transformed values, log area under the plasma CoQ10 concentration curve, and log Cmax for the CoQ10-γ-CD formulation were significantly higher than those for the CoQ10-MCC formulation. These results indicate that the oral absorption and bioavailability of CoQ10 in healthy adult volunteers could be significantly enhanced by complexation with γ-CD, suggesting the potential use of γ-CD as formulation aid for orally administered CoQ10.

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... Different carrier systems have been developed previously to improve the coQ10 dispersibility in water, either with cyclodextrins [21,22], or polysaccharides [23,24] and using different encapsulation methods. ␣-, ␤-, ␥-Cyclodextrins (CyDs) were used to encapsulate coQ10 by a kneading method and ␥-CyD was the only one, which significantly increased the dissolution rate (up to ca. 0.3 mol/L) [21]. ...
... ␣-, ␤-, ␥-Cyclodextrins (CyDs) were used to encapsulate coQ10 by a kneading method and ␥-CyD was the only one, which significantly increased the dissolution rate (up to ca. 0.3 mol/L) [21]. In another study [22], the complexation of coQ10 with ␥-CyD by spray-drying was performed and compared to a mixture of coQ10 with microcrystalline cellulose (coQ10-MCC). Although no water dispersibility tests were done, the oral absorption and bioavailability of coQ10 in healthy adult volunteers was significantly enhanced by complexation with ␥-CyD [22]. ...
... In another study [22], the complexation of coQ10 with ␥-CyD by spray-drying was performed and compared to a mixture of coQ10 with microcrystalline cellulose (coQ10-MCC). Although no water dispersibility tests were done, the oral absorption and bioavailability of coQ10 in healthy adult volunteers was significantly enhanced by complexation with ␥-CyD [22]. Chan et al. [23] obtained microparticles using -carrageenan as a carrier material by preparing emulsions in palm kernel oil with an emulsifier (sodium stearoyl lactylate) followed by spray drying. ...
Article
The Pressurized Gas eXpanded (PGX) liquid technology was developed for simultaneously drying and purifying high molecular weight biopolymers, resulting in nano/micro-sized powders with large surface areas that can be loaded with various bioactives. The preparation of PGX-dried gum arabic (GA) and its loading by adsorptive precipitation with coenzyme Q10 (coQ10) was investigated in a two-step process. In step one, the effects of feed solution concentration, flow rates and flow rate ratios on the PGX-processed GA were studied. Low flow rates and high ratios resulted in larger (up to 65 m2/g) surface areas. In the second step, the impact of different recirculation flow rates and pressurization rates on the coQ10 loading was tested. Only an increased pressurization rate (4.5 vs. 1.5 MPa/min) showed an effect, increasing the coQ10 loading from 0.6 to 2.0% w/w. PGX drying followed by adsorptive precipitation shows great potential for the development of bioactive delivery systems.
... NLCs Hot high pressure homogenization Enhanced photo-protection in skin [51] NLCs Hot high pressure homogenization method Enhanced physicochemical stability and oral bioavailability [52] NLCs -Bioavailability was found similar to commercial formulations [53] NLCs Hot high pressure homogenization Improved water solubility, photo stability of CoQ10 [54] NLCs Solvent diffusion method Improved antioxidant activity [55] NLCs Ultrasonication method Reduced cellular damage was observed [56] us NLCs Hot high pressure homogenization method Improved dermal delivery of CoQ10 [57] us NLCs, NLCs, NEs Continental emulsification method usNLCs enhanced antioxidant potential as compared to NLCs and NEs [58] SEDDS -Two fold enhancement in oral bioavailability [59] Eutectic based semisolid SNEDDS -Improved dissolution profile of CoQ10 [60] SEDDS -Cytotoxicity evaluation of various oils carried out [61] SEDDS -Improved solubility and bioavailability [62] Witepsol ® H35 based SNEDDS -Improved stability and oral bioavailability [63] Solid SEDDS Spray drying Improved photochemical and pharmacokinetic behavior [64] SNEDDS -Enhanced solubility, dissolution velocity and in vivo hepatoprotective activity [65] Nanoemulsified composite systems -Improved oral absorption profile [ Nanocrystalline solid dispersions Modified cold wet-milling system Improved dissolution and pharmacokinetic behavior [72] CoQ10/γ-CD complexes Conventional spray-drying method Improved oral bioavailability [73] Cyclodextrin complex, NEs and dry emulsions ...
... In a research by Terao and coworkers, the effect of complexation of CoQ10 and γ-CD was studied. The CoQ10/γ-CD was compared with CoQ10-microcrystalline cellulose mixture in supplement form, in healthy adult volunteers (Outcomes discussed in section 4) [73]. ...
... The pharmacokinetic parameters were elucidated. Although, mean difference was not statistically significant but higher C max and AUC values indicated the enhanced oral absorption of CoQ10 from this system [73]. ...
Article
Background: Coenzyme Q10, a natural yellow benzoquinone, is a vitamin-like substance commonly found in blood and inner mitochondrial and cellular membranes. It is a natural antioxidant principle which plays an essential role in maintaining several biochemical pathways of body. It has exhibited many pharmacological activities in chronic heart failure, cardiofaciocutaneous syndrome, diabetes mellitus, carcinomas, autoimmune disease, cataract, asthma, periodontal disease and thyroid disorders. Moreover, it has demonstrated efficacy as nutritional supplement, in addition to its relevance in cosmetics. Objective: Coenzyme Q10 is a potent molecule but its high molecular weight and low aqueous solubility hamper its use as a therapeutic agent. Therefore, various novel drug delivery systems have been explored and developed to overcome these limitations in literature. Hence, objective of this review is to summarize the recent works on design and development of novel drug delivery systems for CoQ10, which include liposomes, polymeric nanoparticles, polymeric micelles, solid lipid nanoparticles, nanostructured lipid carriers, self-emulsifying drug delivery systems, nanoemulsions, solid and aqueous dispersions. Further, an account of pharmaceutical studies has also been given. Results & conclusion: The reported studies indicate the promise of nanotechnology in enhancing the therapeutic value of CoQ10, promoting its usage as first line therapeutic agent, thus, revolutionizing its role in current medical therapy. The application of CoQ10 in pharmaceutical industry has grown tremendously in the past decade, due to its versatile nature. The successful application of this molecule in medicine, cosmetics and nutraceuticals points the way for its future development.
... In particular, γ-CD forms inclusion complexes with larger-sized molecules such as macrocyclic compounds and lipophilic vitamins, which are used as nutraceutical ingredients in supplements and health foods with various human health benefits. The effects of the complexation of natural α-CDs, β-CDs, and γ-CDs on water solubility and bioavailability have been evaluated for some hydrophobic nutraceuticals, such as coenzyme Q10 (CoQ10) [5][6][7], curcumin [8,9], tocotrienol [10], menaquinone-7 (vitamin K 2 ) [11], lutein [12], and astaxanthin [13]. The formation of complexes of these hydrophobic nutraceuticals with natural CDs does not generally enhance water solubility. ...
... The bioavailability of CoQ10 is enhanced by complexation with γ-CD, which results in the Type 3 enhancement profile (Fig. 1). The CoQ10-γCD complex had excellent pharmacokinetic properties, with a significantly higher AUC (0-48 h) and higher C max , in 72 healthy adult subjects [5]. In addition, the CoQ10-γCD complex also showed mean plasma levels, even after 24 and 48 h, that were significantly higher after the administration of the CoQ10-γCD complex than after the administration of a commercially available CoQ10 formulation with oil emulsifier (so-called "water-soluble CoQ10") and a mixture of CoQ10 with microcrystalline cellulose (MCC) (Fig. 2). ...
Article
Full-text available
Natural hydrophobic bioactives that possess human health benefits often have undesirable characteristics that limit their use as nutraceuticals. These bioactives are usually unstable in the presence of oxygen, ultraviolet radiation, and heat. Furthermore, their solubility in water is low owing to their hydrophobicity or instability, which leads to low bioavailability. Much attention has recently been directed to the use of cyclodextrins (CDs) as complementary and alternative medicinal foods with human health benefits for the current aging population. Systematic studies have been performed to investigate improvements in the stability, water solubility, and bioavailability of hydrophobic nutraceuticals through complexation with CDs. Although hydrophobic nutraceuticals, such as coenzyme Q10, curcumin, and tocotrienol, form insoluble complexes with γ-CD, the bioavailability of the complex dramatically improves compared with conventional technologies. Recently, it was found that hydrophobic bioactives generally aggregate in water, but the dissociated bioactives from γ-CD are captured by bile acid to form micelles without aggregation; thus, both solubility and bioavailability are enhanced. Complexation with γ-CD is a promising method to achieve enhanced bioavailability of hydrophobic nutraceuticals. In this article, an outline of the innovative nanotechnologies that implement γ-CD to enhance stability and control of the solubility and bioavailability of key ingredients for health and beauty in the field of medicinal foods is presented.
... For example, coenzyme Q10, an endogenous component that plays an important part in mitochondrial electron transport, has been employed for treating heart disease and degenerative disorders (Rosenfeldt et al. 2003). Although the formulations with all three types of cyclodextrins are resistant to air/light-induced degradation and have a high water solubility, only γ-cyclodextrin can significantly improve the bioavailability of coenzyme Q10 (Terao et al. 2006). In fact, the bioavailability of coenzyme Q10 in complexation with γ-cyclodextrin is enhanced by almost 4.2-fold compared to that of the free substance (Moldenhauer and Cully 2003) and by about 35% compared to a microcrystalline cellulose-coenzyme Q10 complex (Terao et al. 2006). ...
... Although the formulations with all three types of cyclodextrins are resistant to air/light-induced degradation and have a high water solubility, only γ-cyclodextrin can significantly improve the bioavailability of coenzyme Q10 (Terao et al. 2006). In fact, the bioavailability of coenzyme Q10 in complexation with γ-cyclodextrin is enhanced by almost 4.2-fold compared to that of the free substance (Moldenhauer and Cully 2003) and by about 35% compared to a microcrystalline cellulose-coenzyme Q10 complex (Terao et al. 2006). In addition, it has also been found that γ-cyclodextrin can improve bioavailability of drugs by enhancing their membrane permeability (Matsuda and Arima 1999;Challa et al. 2005). ...
... Cyclodextrins are produced by the enzymatic conversion of starch and are widely used to improve the solubility and stability of pharmaceuticals and nutraceuticals [18,19]. It has previously been shown that the encapsulation of tocotrienols [20], lipoic acid [21,22], and coenzyme Q 10 [23] with γ-cyclodextrin (γCD, which is composed of eight monomers arranged in a cyclic ring) results in improved bioactivity in mice and humans. Furthermore, the encapsulation of propolis-derived CAPE with γCD significantly enhanced its anti-cancer properties in cultured cells and in mice [6]. ...
... Cyclodextrins are produced by the enzymatic conversion of starch and are widely used to improve the solubility and stability of pharmaceuticals and nutraceuticals [18,19]. It has previously been shown that the encapsulation of tocotrienols [20], lipoic acid [21,22], and coenzyme Q10 [23] with γ-cyclodextrin (γCD, which is composed of eight monomers arranged in a cyclic ring) results in improved bioactivity in mice and humans. Furthermore, the encapsulation of propolis-derived CAPE with γCD significantly enhanced its anti-cancer properties in cultured cells and in mice [6]. ...
Article
Full-text available
Ageing is often accompanied by chronic inflammation. A fat-and sugar-rich Western-type diet (WTD) may accelerate the ageing phenotype. Cell culture studies have indicated that artepillin C-containing Brazilian green propolis exhibits anti-inflammatory properties. However, little is known regarding its anti-inflammatory potential in mouse liver in vivo. In this study, female C57BL/6NRj wild-type mice were fed a WTD, a WTD supplemented with Brazilian green propolis supercritical extract (GPSE) encapsulated in γ-cyclodextrin (γCD) or a WTD plus γCD for 10 weeks. GPSE-CD did not affect the food intake, body weight or body composition of the mice. However, mRNA levels of the tumour necrosis factor α were significantly downregulated (p < 0.05) in these mice compared to those in the WTD-fed controls. Furthermore, the gene expression levels of other pro-inflammatory markers, including serum amyloid P, were significantly (p < 0.001) decreased following GPSE-γCD treatment. GPSE-γCD significantly induced hepatic ferritin gene expression (p < 0.01), which may contribute to its anti-inflammatory properties. Conversely, GPSE-γCD did not affect the biomarkers of endogenous antioxidant defence, including catalase, glutathione peroxidase-4, paraoxonase-1, glutamate cysteine ligase and nuclear factor erythroid 2-related factor-2 (Nrf2). Overall, the present data suggest that dietary GPSE-γCD exhibits anti-inflammatory, but not antioxidant activity in mouse liver in vivo. Thus, GPSE-γCD has the potential to serve as a natural hepatoprotective bioactive compound for dietary-mediated strategies against chronic inflammation.
... This was a field-based study using privately-owned horses with samples not obtainable prior to the morning meal, so only the accumulation and not the acute phase (0-24 h), of oral CoQ 10 supplementation could be evaluated. However, the acute phase was inferred using sample timing based on prior studies in human subjects, that demonstrated that plasma concentrations peaked within 4-5 h of oral administration of a CoQ 10 -β-cyclodextrin inclusion complex (Cuomo and Rabovsky, 2000;Terao et al., 2006). Although not assessed in the present study, the CoQ 10 -β-cyclodextrin inclusion complex used in the study has been shown in human subjects to have sustained release, resulting in the maintenance of plasma CoQ 10 concentrations approximately six times higher than baseline for 24 h following oral administration (Madhavi and Kagan, 2010). ...
... Although not assessed in the present study, the CoQ 10 -β-cyclodextrin inclusion complex used in the study has been shown in human subjects to have sustained release, resulting in the maintenance of plasma CoQ 10 concentrations approximately six times higher than baseline for 24 h following oral administration (Madhavi and Kagan, 2010). This effect has been reported for other oral cyclodextrin complex CoQ 10 -based delivery systems, although lower sustained plasma CoQ 10 concentrations were achieved (Terao et al., 2006). An increase in mean skeletal muscle CoQ 10 content was observed in the current study following prolonged oral CoQ 10 supplementation, reflected by the significant increases in CoQ 10 -dependent skeletal muscle mitochondrial function above basal activity. ...
Article
Coenzyme Q 10 (CoQ 10 ) is an essential component of the mitochondrial electron transport chain (ETC). Decreased skeletal muscle CoQ 10 content may result in decreased ETC activity and energy production. This study tested the hypotheses that supplementation with oral CoQ 10 will increase plasma CoQ 10 concentrations and that prolonged supplementation will increase skeletal muscle CoQ 10 content in young, healthy untrained Thoroughbreds. Nineteen Thoroughbreds (27.5±9.7 months old; 11 males, eight females) from one farm and maintained on a grass pasture with one grain meal per day were supplemented daily with 1.5 mg/kg body weight of an oral CoQ 10 -β-cyclodextrin inclusion complex. Whole-blood and skeletal muscle biopsies were collected before (T 0 ) and after (T 1 ) nine weeks of supplementation. Plasma CoQ 10 concentrations were determined via high-performance liquid chromatography. Skeletal muscle mitochondrial ETC combined complex I+III enzyme activity (indirect measurement of CoQ 10 content) was assessed spectrophotometrically and normalised to mitochondrial abundance. Horses accepted supplementation with no adverse effects. Plasma CoQ 10 concentration increased in all horses following supplementation, with mean plasma CoQ 10 concentration significantly increasing from T 0 to T 1 (0.13±0.02 vs 0.25±0.03 μg/ml; mean difference 0.12±0.03; P=0.004). However, variability in absorbance resulted in a 58% response rate (i.e. doubling of T 1 above T 0 values). The mean skeletal muscle complex I+III activity significantly increased from T 0 to T 1 (0.36±0.04 vs 0.59±0.05 pmol/min/mg of muscle, mean difference 0.23±0.05; P=0.0004), although T 1 values for three out of 19 horses decreased on average by 23% below T 0 values. In conclusion, oral supplementation with CoQ 10 in the diet of young, healthy untrained Thoroughbreds increased mean plasma CoQ 10 concentration by 99% with prolonged daily supplementation increasing mean skeletal muscle complex I+III activity by 65%. Additional research is warranted investigating training and exercise effects on skeletal muscle CoQ 10 content in CoQ 10 supplemented and un-supplemented Thoroughbreds.
... In addition, it is vulnerable to heat, light, and oxygen (Fir, Smidovnik, Milivojevic, Zmitek, & Prosek, 2009). For this reason, research has been focused in overcoming the issues that limit its formulation into food supplements and medicinal products, such as solubility, oral bioavailability (Balakrishnan et al., 2009;Nepal, Han, & Choi, 2010;Terao et al., 2006), and stability (Bule et al., 2010;Zhao & Tang, 2016). ...
... As for cyclodextrin inclusion, it is widely used in the pharmaceutical and food supplement industry since it provides improved stability against heat, oxidation, and UV. In addition, cyclodextrins can form inclusion complexes with lipophilic substances such as CoQ10, leading to improved stability, water solubility, and bioavailability (Terao et al., 2006). SEDDS, which are composed of an oil, surfactant, and cosurfactant, as well as the vehiculized active ingredient, are also used to enhance solubility and bioavailability of poorly water-soluble substances like CoQ10 (Balakrishnan et al., 2009). ...
Article
World population growth and aging are posing unprecedented challenges in sustaining the health of 9.1 billion people that will be occupying the planet by 2050. Although noncommunicable diseases such as cardiovascular and neurodegenerative diseases, cancer, and diabetes are among the top 10 global causes of death, they can be prevented by risk factor reduction, early detection, and adequate treatment. Since a healthy diet along with dietary supplementation could play an important role to reduce morbidity and cut off its associated health care costs, research in the food and nutrition area is required to find solutions to global challenges affecting health. As a result of the healthy living trend, dietary supplements category is growing fast, leading to an urgent need for dietitians, physicians, and policy makers to broaden the scientific evidence on the efficacy and safety of a wide range of active ingredients. Coenzyme Q10 (CoQ10), as the third most consumed dietary supplement, and as a potential candidate for the treatment of various noncommunicable diseases that are among the global top 10 causes of death, has gained interest over years. Scientific evidence regarding mainly CoQ10 efficacy and safety, as well as formulation challenges, is addressed in this review.
... 또한 coenzyme Q 10 의 경우 구조상 큰 잔기를 포함하고 있기 때문에 포접할 수 있는 내부공동이 가장 큰 γ-cyclodextrin 이 복합체를 형성할 수 있는 확률이 가장 크기 때문에 coenzyme Q 10 과 복합체를 형성함에 있어 가장 유리할 것이라고 보고하였다 (28)(29)(30)(31). 뿐만 아니라 coenzyme Q 10 -cyclodextrin 복합체를 제조후 복합체의 용해도, 열 및 광 안정성 개선, 생체이용율 개선을 보 고한바 있다 (32)(33)(34)(35) ...
... In vitro 소화 방출 패턴Cyclodextrin은 이미 안전한 약물 전달 캐리어로 중요한 역할 을 하는 것으로 알려져 있다(49). 또한 coenzyme Q 10 와 γ-cyclo-dextirn으로 제조된 복합체를 가지고 in vitro, in vivo 실험을 통해 생체이용율 개선이 확인된바 있다(34,35). 본 연구의 cyclodextrin 복합체는 구강 조건에서 control solution에서 방출된 양(8.4%)과 α-amylase가 첨가된 simulation solution에서 방출된 양(10%)의 차 이는 약 1.6%로 유의적 차이를 보이지 않았고 위장 조건에서는 control solution에서 방출된 양(11.3%)과 pepsin이 첨가된 simulation solution에서 방출양(8.6%)도 ...
Article
This study focused on assessing the solubility and structural characteristics of two types of coenzyme Q10(CoQ10) complexes: the CoQ10-starch and the CoQ10-cyclodextrin complexes. The solubility of CoQ10-starch complex increased significantly as the temperature was increased. However, the solubility of CoQ10-cyclodextrin complex reached a peak at 37°C, and strong aggregation occurred at 50°C. When the temperature was raised to 80°C, the CoQ10-cyclodextrin complex dissociated owing to the weakening of bonds, resulting in CoQ10 emerging at the surface of water. Therefore, CoQ10-cyclodextrin complexes have lower solubility, due to their reduced heat-stability, than do the CoQ10-starch complexes. Structural differences between the two CoQ10 complexes were confirmed by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffractometer (XRD), and differential scanning calorimeter (DSC). The CoQ10-cyclodextrin complex included an isoprenoid chain of CoQ10, while the CoQ 10-starch complex included both the benzoquinone ring and the isoprenoid chain of CoQ10. These results suggest that CoQ 10-starch complexes possess higher heat-stability and solubility than do the CoQ10-cyclodextrin complexes.
... Terao ve ark. (2006)[46], γ-siklodekstrin koenzim Q10 kompleksi ile mikrokristalin selüloz koenzim Q10 karışımının biyoyararlılığını karşılaştırmışlardır. γ-siklodekstrin koenzim Q10 kompleksi alımından sonra plazma koenzim Q10 miktarında %47.60 oranında artış olurken, mikrokristalin selüloz koenzim Q10 karışımı alımında % 13.83 artış olmuştur[46]. Bir çalışmada, β-siklodekstrin ile kompleks formdaki koenzim Q10'un sıvı veya toz formda, stabil, sulu ortamda çözünebilir, tatsız, kokusuz olduğu ve biyoyararlılığının arttığı belirtilmiştir[41].Biyoyararlılığı arttırmak için diğer bir stratejide partikül boyutunun mikro veya nano ölçüye getirilmesidir. ...
... Terao ve ark. (2006)[46], γ-siklodekstrin koenzim Q10 kompleksi ile mikrokristalin selüloz koenzim Q10 karışımının biyoyararlılığını karşılaştırmışlardır. γ-siklodekstrin koenzim Q10 kompleksi alımından sonra plazma koenzim Q10 miktarında %47.60 oranında artış olurken, mikrokristalin selüloz koenzim Q10 karışımı alımında % 13.83 artış olmuştur[46]. Bir çalışmada, β-siklodekstrin ile kompleks formdaki koenzim Q10'un sıvı veya toz formda, stabil, sulu ortamda çözünebilir, tatsız, kokusuz olduğu ve biyoyararlılığının arttığı belirtilmiştir[41].Biyoyararlılığı arttırmak için diğer bir stratejide partikül boyutunun mikro veya nano ölçüye getirilmesidir. Biyoyararlılığı arttırmak için yapılan çeşitli çalışmalarda, emilim yol izi ve etkinliğinin partikül boyutunu nano boyuta küçültmekle etkilendiği görülmüştür. ...
... [114]. In parallel, in vivo bioavailability improvement of coenzyme Q10 by solubilization [116,117] -cyclodextrin [118] Caco-2 cell monolayers. However, these studies used undigested (native or formulated) curcumin at very high doses and therefore did not reflect the conditions present in the human intestine [28,29,32,33]. ...
Thesis
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Curcumin, the bioactive component of turmeric (Curcuma longa L.), has been used for thousands of years in traditional medicine for the prevention or treatment of several diseases and symptoms. Nowadays, curcumin is investigated worldwide as a nutritional supplement. To overcome the central limitation of its naturally low oral bioavailability, several formulation strategies have been developed, such as its co-administration with turmeric oils or piperine to inhibit its metabolism and efflux or its incorporation into micelles, cyclodextrin complexes or phospholipid bilayers to improve its stability and solubility. So far, the different formulations have not been compared directly, in one cohort of participants and at equal doses. The present doctoral thesis aimed, for the first time, at a direct comparison of the bioavailability of curcumin in form of a native curcuma extract or seven formulations, namely polysorbate 80 micelles, g-cyclodextrin complexes, liposomes, phytosomes, submicron-particle curcumin or curcumin administered with turmeric oils or piperine, in healthy adults. The project further aimed to investigate several critical factors for curcumin bioavailability in vitro and to explain thereby the observations made in vivo. In a randomized, double-blind crossover trial with 12 healthy participants (6 females, 6 males), curcumin pharmacokinetics, namely AUC (area under the plasma concentration-time curve), Cmax (maximum plasma concentration) and tmax (time to reach Cmax) were compared after administration of a single oral dose of 207 mg curcumin in form of a native curcuma extract or one of the seven formulations. Curcumin incorporated into polysorbate 80 micelles or g-cyclodextrin complexes showed 57-fold and 30-fold improved bioavailability compared to the native extract, whereas all other formulations showed no or minor effects. tmax of the better bioavailable formulations was smaller (1 to 2 hours) compared to all others (up to 7 hours). To compare the formulations regarding their digestion characteristics and transepithelial transport, in vitro digestion experiments followed by Caco-2 cell transport assays were conducted with the formulations normalized to their curcumin content. In parallel to the effects in vivo, curcumin showed higher stability, solubility and micellization efficiency when it was incorporated into polysorbate 80 micelles (100%, 80%, 55%) or g-cyclodextrin complexes (73%, 33%, 23%), whereas curcumin permeability through Caco-2 cell monolayers was not affected by its formulation. In the next study, curcumin efflux, partially mediated by P-glycoprotein (P-gp), was investigated, because the inhibition of curcumin efflux from the intestinal cells back to the intestinal lumen is targeted by the co-administration of curcumin with turmeric oils or piperine. In LS180 (colon adenocarcinoma) cells, native curcuma extract and the seven formulations were studied regarding cellular curcumin uptake within 1 hour and efflux within further 8 hours, as well as their effects on P-gp activity. Independently from its formulation, curcumin inhibited the activity of P-gp. Cellular curcumin uptake and efflux showed significant variability between formulations but no consistent effects. Cellular uptake and efflux may thus not be important for curcumin bioavailability in vivo. Another potential factor influencing bioavailability, that was investigated for native and micellar curcumin, was the time-dependent intracellular distribution in intestinal cells. Uptake and intracellular distribution in Caco-2 cells mainly did not differ between native and micellar curcumin. After 30 minutes, both were localized in lysosomes and mitochondria, after 180 minutes in peroxisomes and native curcumin also in mitochondria. The temporary localization in lysosomes is in line with the involvement of endocytosis in cellular uptake of curcumin. Nevertheless, the intracellular localization of curcumin was not affected by its incorporation into polysorbate 80 micelles. The data generated in this doctoral project thus demonstrate that the incorporation of curcumin into polysorbate 80 micelles or g-cyclodextrin complexes successfully improve its bioavailability. The improved bioavailability of both formulations can be explained by enhanced digestive stability, solubility and micellization efficiency and appears to be independent from post-digestive processes, such as intestinal permeability, cellular uptake, cellular efflux or intracellular distribution. Consequently, the present doctoral thesis delivers relevant information for the therapeutical application of curcumin, for the development of highly bioavailable formulations, as well as the basis for further clinical research on the health beneficial effects of curcumin.
... We observed no changes in T max and T 1/2 in response to a single oral dose of R-LA or R-LA/CD. Improvement of the oral bioavailability through complexation with CDs were reported in previous studies on a variety of drugs in rabbits (e.g., tolbutamide/CD complexes) [37] and humans (coenzyme Q10/CD complex) [38] and it was reviewed thoroughly by Carrier et al. [39] and Loftsson et al. [40]. Tolbutamide and coenzyme Q10 (CoQ10) are practically insoluble in water; the bioavailability of them is therefore very low. ...
Article
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R-α-lipoic acid (R-LA) is a cofactor of mitochondrial enzymes and a very strong antioxidant. R-LA is available as a functional food ingredient but is unstable against heat or acid. Stabilized R-LA was prepared through complexation with γ-cyclodextrin (CD), yielding R-LA/CD. R-LA/CD was orally administered to six healthy volunteers and showed higher plasma levels with an area under the plasma concentration-time curve that was 2.5 times higher than that after oral administration of non-complexed R-LA, although the time to reach the maximum plasma concentration and half-life did not differ. Furthermore, the plasma glucose level after a single oral administration of R-LA/CD or R-LA was not affected and no side effects were observed. These results indicate that R-LA/CD could be easily absorbed in the intestine. In conclusion, γ-CD complexation is a promising technology for delivering functional but unstable ingredients like R-LA.
... Also recently, improvements in the biological activity of the complex formation between Q10 and CD and the development of functional foods have been made. Therefore, applications to the food and pharmaceutical sectors have been increasingly expected [21]. These findings are expected to lead to greater clinical use of drugs complexed with a CD in the fields of health care products and herbal medicines. ...
Article
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Piperine (PP) is a pungent component in black pepper that possesses useful biological activities; however it is practically insoluble in water. The aim of the current study was to prepare a coground mixture (GM) of PP and β -cyclodextrin ( β CD) (molar ratio of PP/ β CD = 1/1) and subsequently evaluate the solubility of PP and physicochemical properties of the GM. DSC thermal behavior of the GM showed the absence of melting peak of piperine. PXRD profile of the GM exhibited halo pattern and no characteristic peaks due to PP and β CD were observed. Based on Job’s plot, the PP/ β CD complex in solution had a stoichiometric ratio of 1/1. Raman spectrum of the GM revealed scattering peaks assigned for the benzene ring (C=C), the methylene groups (CH 2 ), and ether groups (C-O-C) of PP that were broaden and shifted to lower frequencies. SEM micrographs showed that particles in the GM were agglomerated and had rough surface, unlike pure PP and pure β CD particles. At 15 min of dissolution testing, the amount dissolved of PP in the GM was dramatically increased (about 16 times) compared to that of pure PP. Moreover the interaction between PP and β CD cavity was detected by 1 H- 1 H NMR nuclear Overhauser effect spectroscopy NMR spectroscopy.
... Likewise, Uekama et al. reported that 2,6-di-O-methyl-β-CyD (DM-β-CyD) or γ-CyD markedly improves solubility and oral bioavailability of CoQ10 in rats, dogs or humans. [16][17][18] Thus, CyDs have been utilized to improve the pharmaceutical properties of isoprenoid compounds. ...
Article
The purpose of this study was to design cyclodextrin (CyD)-based pseudorotaxane-like supramolecular complexes with various isoprenoid compounds, such as reduced coenzyme Q10 (R-CoQ10), squalene, tocotrienol, and teprenone, and to evaluate their pharmaceutical properties. Squalene, tocotrienol, and teprenone formed precipitates with β-CyD and γ-CyD in aqueous solution, whereas R-CoQ10 formed precipitates with γ-CyD aqueous solution. The results of powder X-ray diffraction and 1H-NMR analyses indicated that these precipitates are derived from pseudorotaxane-like supramolecular complexes. The photostability of teprenone was markedly improved by complexation with CyDs, especially in the γ-CyD system. In addition, the dispersion rates of teprenone in the γ-CyD system were higher than those in the β-CyD system, compared with the corresponding physical mixtures. In conclusion, pharmaceutical properties such as photostability and dispersion rates of isoprenoid compounds were improved by the formation of pseudorotaxane-like supramolecular complexes with β-CyD and/or γ-CyD.
... CDs are consequently capable of forming host-guest complexes with water-insoluble substances, such as lipophilic substrates by completely or partially encapsulating these molecules in their cavity through a series of non-covalent interactions. Notably, these interactions can have a significant improvement for the non-water soluble and/or vulnerable guest molecules [1][2][3][4][5]. The structures of these host-guest complexes have attracted considerable interest from numerous researchers, and there have been several studies aimed at developing a better understanding of these complexes focusing on the relation of the binding constants and the ring size of the CD [6,7]. ...
Article
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R(+)-α-lipoic acid (RALA) is a naturally-occurring substance, and its protein-bound form plays significant role in the energy metabolism in the mitochondria. RALA is vulnerable to a variety of physical stimuli, including heat and UV light, which prompted us to study the stability of its complexes with cyclodextrins (CDs). In this study, we have prepared and purified a crystalline RALA-αCD complex and evaluated its properties in the solid state. The results of ¹H NMR and PXRD analyses indicated that the crystalline RALA-αCD complex is a channel type complex with a molar ratio of 2:3 (RALA:α-CD). Attenuated total reflection/Fourier transform infrared analysis of the complex showed the shift of the C=O stretching vibration of RALA due to the formation of the RALA-αCD complex. Raman spectroscopic analysis revealed the significant weakness of the S-S and C-S stretching vibrations of RALA in the RALA-αCD complex implying that the dithiolane ring of RALA is almost enclosed in glucose ring of α-CD. Extent of this effect was dependent on the direction of the excitation laser to the hexagonal morphology of the crystal. Solid-state NMR analysis allowed for the chemical shift of the C=O peak to be precisely determined. These results suggested that RALA was positioned in the α-CD cavity with its 1,2-dithiolane ring orientated perpendicular to the plane of the α-CD ring.
... We have reported that the bioavailability of CoQ10 could be significantly enhanced by the complexation with γCD among natural CDs for the use in nutrition applications. [1][2][3][4][5] Interestingly, the CoQ10 -γCD gives not only significantly higher area under the plasma CoQ10 concentration curve from time 0-48 hr (AUC) and maximum plasma concentration (C max ), but also the mean plasma levels at 24 and 48 hours tended to be significantly higher after CoQ10 -γCD complex administration to healthy adult volunteers when compared with CoQ10 formulated in microcrystalline cellulose and administrated in the same way as the complex. ...
Conference Paper
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Coenzyme Q10 (CoQ10) is a fat-soluble, vitamin-like, benzoquinone compound that functions primarily as an antioxidant, as a membrane stabilizer and as a cofactor in the production of adenosine triphosphate (ATP) by oxidative phosphorylation. The solubility of CoQ10 in water is extremely low, resulting in a low bioavailability by oral administration. Therefore, we attempted to improve the low dissolution and bioavailability of CoQ10 by means of complexation with various cyclodextrins. We found that the bioavailability of CoQ10 could be significantly enhanced by complexation with cyclodextrins, especially by the use of γCD. The CoQ10 - γCD complex reveals excellent pharmacokinetic properties not only significantly higher area under the CoQ10 concentration curve in blood plasma from time 0-48 hr (AUC) and higher maximum plasma concentration (Cmax), but also the mean plasma levels even after 24 and 48 hours tended to be significantly higher after CoQ10 - γCD complex administration to healthy adult volunteers when compared with CoQ10 formulated in microcrystalline cellulose and administrated in the same way as the complex. We found that this long lasting high CoQ10 concentration in plasma provides various health benefits. The proven benefits are: 1) Curative effects on damaged human skins by aging, UV and other pollutants in the air, 2) Anti-oxidant activity (study on the reduction of 8-hydroxy-2-deoxy guanosine (8-OHdG) in urine), 3) Protection of muscle cells (study on the reduction of myogenic enzymes, Creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH)).
... • krystalick˘ polymorf nebo amorf [50][51][52][53] • fiízená krystalizace (sonokrystalizace, krystalizace ze superkritick˘ch médií) 54-57) • lyofilizace 58,59) • sprejové su‰ení [60][61][62][63] • mikronizace léãivé látky 53,64,65) • nanonizace 66) 3. Technologické moÏnosti zvy‰ování biologické dostupnosti léãiv • zprostfiedkované rozpou‰tûní 13) • zv˘‰ení smáãivosti [67][68][69] • micelární solubilizace [69][70][71] • pouÏití kosolventÛ [72][73][74][75] • hydrotropní látky 76, 77) • tvorba cyklodextrinov˘ch komplexÛ 44,53,69,78) • zmûna pH 74,79,80) • pfiíprava pevn˘ch disperzí 81,82) • uÏití interaktivní prá‰kové smûsi 83,84) • mikrogranulace 80,85) • impregnace 86) • samoemulgující systémy 87) • mikro-a nanosuspenze 88) • formulace liquisolid systémÛ 89,90) • nanoãásticové systémy 91) • lipozomální formulace 92) • pouÏití enhancerÛ absorpce 93,94) Stfiet zájmÛ: Ïádn˘. ...
Article
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Bioavailability can be defined as the rate and range of active ingredient absorption, when it becomes available in the systemic circulation or at the desired site of drug action, respectively. Drug bioavailability after oral administration is affected by anumber of different factors, including physicochemical properties of the drug, physiological aspects, the type of dosage form, food intake, biorhythms, and intra- and interindividual variability of the human population. This article is the first from the series dealing with the bioavailability and methods leading to its improvement. The aim of the present paper is to provide an overview of aspects influencing the rate of bioavailability after oral administration of the active ingredient. Subsequentarticles will provide detailed descriptions of methods used for dug bioavailability improvement, which are here only summarized.
... One report on the bioavailability enhancement of lipophilic coenzyme Q10 (CoQ10) by complexing with γ -CD provided a clue about how new nanotechnology innovation using γ -CD could be used in functional food and cosmetic applications [9] . According to the report, the bio -absorption of CoQ10 could be greatly enhanced after oral administration of a CoQ10 – γ -CD complex in spite of poorly soluble characteristics of the complex in water. ...
Chapter
A report on the bioavailability enhancement of coenzyme Q10 (CoQ10) by complexing with γ-cyclodextrin (γ-CD) provided a clue about a new innovation in nanotechnology for applications in nanomedicinal foods and cosmetics. The bioavailability-enhancing mechanism is as follows. CoQ10 is released from a CoQ10–γ-CD complex by the substitution with bile acid in the intestine. Hydrophobic CoQ10 generally agglutinates, but the dissociated CoQ10 from γ-CD is captured by bile acid to form nanometer molecular micelles without aggregation, and therefore both solubility and bioavailability could be enhanced. Further studies proved the generality of this new nanotechnology system. The bioavailability-enhancing effects obtained by complexing γ-CD could also be achieved with various hydrophobic nutraceuticals used in the medicinal food field besides CoQ10. Furthermore, it could be expanded into the personal care field through the use of dipotassium glycyrrhizate (GZK2) instead of bile acid. The skin absorption of bioactives could also be significantly enhanced by the combination of cosmeceutical–γ-CD complexes with GZK2.
... γCD, widely accepted for use in food, pharmaceutical, agricultural and chemical industry constitutes of 8 glucose monomers arranged in the form of a cyclic ring. It has been reported to enhance the bioavailability of hydrophobic ingredients such as coenzyme Q10 [42][43][44]. ...
Article
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Caffeic Acid Phenethyl Ester (CAPE) is a key component in New Zealand propolis, known for a variety of health promoting and therapeutic potentials. We investigated the molecular mechanism of anticancer and anti-metastasis activities of CAPE. cDNA array performed on the control and CAPE-treated breast cancer cells revealed activation of DNA damage signaling involving upregulation of GADD45α and p53 tumor suppressor proteins. Molecular docking analysis revealed that CAPE is capable of disrupting mortalin-p53 complexes. We provide experimental evidence and demonstrate that CAPE induced disruption of mortalin-p53 complexes led to nuclear translocation and activation of p53 resulting in growth arrest in cancer cells. Furthermore, CAPE-treated cells exhibited downregulation of mortalin and several other key regulators of cell migration accountable for its anti-metastasis activity. Of note, we found that whereas CAPE was unstable in the culture medium (as it gets degraded into caffeic acid by secreted esterases), its complex with gamma cyclodextrin (γCD) showed high efficacy in anti-tumor and anti-metastasis assays in vitro and in vivo (when administered through either intraperitoneal or oral route). The data proposes that CAPE-γCD complex is a potent anti-cancer and anti-metastasis reagent.
... On the other hand, there have been many reports that CD inclusion can achieve good oral bioavailability of poorly absorbable drugs [27]. Specifically, several studies have revealed that γ-CD inclusion complexes enhanced the bioavailability of drugs such as digoxin in dogs, diazepam in rabbits, and artemisinin and coenzyme Q10 in humans [28][29][30][31], but there have been no studies to test RLA. In our present study, comparing the AUC0-120 of RLA after oral administration of α-, β-and γ-CD inclusion complexes to rats, it was found that RLA/γ-CD showed the highest plasma exposure among the groups (Figure 1 and Table 1). ...
Article
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R-α-lipoic acid (RLA) is an endogenous organic acid, and works as a cofactor for mitochondrial enzymes and as a kind of antioxidant. Inclusion complexes of RLA with α-, β- or γ-cyclodextrins (CD) were prepared and orally administered as a suspension to rats. Among them, RLA/γ-CD showed the highest plasma exposure, and its area under the plasma concentration-time curve (AUC) of RLA was 2.2 times higher than that after oral administration of non-inclusion RLA. On the other hand, the AUC after oral administration of non-inclusion RLA and RLA/γ-CD to pylorus-ligated rats did not differ. However, the AUC after intraduodenal administration of RLA/γ-CD was 5.1 times higher than that of non-inclusion RLA, and was almost comparable to the AUC after intraduodenal administration of RLA-Na solution. Furthermore, the AUC after intraduodenal administration of RLA/γ-CD was not affected by biliary ligation or co-administration of an amylase inhibitor. These findings demonstrated that RLA was absorbed from the small intestine effectively when orally administered as a γ-CD inclusion complex, which could be easily dissolved in the lumen of the intestine. In conclusion, γ-CD inclusion complex is an appropriate formulation for supplying RLA as a drug or nutritional supplement with respect to absorption.
... CDs interact with the nutraceuticals enhancing the stability, solubility, reducing bitter taste, etc. (Mazzobre et al., 2010). It is clearly seen from the literature that the easily digestible gCD is an appropriate complex forming candidate for a lot of bio-active compounds, such as antioxidants, vitamins (Terao et al., 2006), carotenoids (Mele et al., 1999;Reuscher et al., 2004), and flavonoids (Koontz et al., 2009). Application of gCD in functional foods can hinder aggregation and improve the uptake of these important compounds therefore the nutrition-originated deficiency diseases can be successfully decreased (Uekaji et al., 2013). ...
Article
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Cyclodextrins are tasteless, odorless, non-digestible, non-caloric, non-cariogenic saccharides, which reduce the digestion of carbohydrates and lipids. They have low glycemic index and decrease the glycemic index of the food. They are either non- or only partly digestible by the enzymes of the human gastrointestinal tract and fermented by the gut microflora. Based on these properties, cyclodextrins are dietary fibers useful for controlling the body weight and blood lipid profile. They are prebiotics, improve the intestinal microflora by selective proliferation of bifidobacteria. These antiobesity and anti-diabetic effects make them bioactive food supplements and nutraceuticals. In this review, these features are evaluated for α-, β- and γ-cyclodextrins, which are the cyclodextrin variants approved by authorities for food applications. The mechanisms behind these effects are reviewed together with the applications as solubilizers, stabilizers of dietary lipids, such as unsaturated fatty acids, phytosterols, vitamins, flavonoids, carotenoids and other nutraceuticals. The recent applications of cyclodextrins for reducing unwanted components, such as trans-fats, allergens, mycotoxins, acrylamides, bitter compounds, as well as in smart active packaging of foods are also overviewed.
... The dimethyl b-CD as well as g-CD members improved the dissolution rate and oral absorption of CoQ10 complexes in dogs (Lutka & Pawlaczyk, 1996b). In human volunteers, CoQ10/g-CD inclusion complexes furnished a significantly higher C max and AUC values than CoQ10-MCC mixtures (Terao et al., 2006). Sikorska et al. (2003) derivatized a-tocopherol (vitamin E) to a water-soluble polyoxyethanyl-a-tocopheryl sebacate product (PTS) and used it for the solubilization of CoQ10. ...
Article
Abstract Coenzyme Q10 (CoQ10), also known as ubiquinone or ubidecarenone, is a powerful, endogenously produced, intracellularly existing lipophilic antioxidant. It combats reactive oxygen species (ROS) known to be responsible for a variety of human pathological conditions. Its target site is the inner mitochondrial membrane (IMM) of each cell. In case of deficiency and/or aging, CoQ10 oral supplementation is warranted. However, CoQ10 has low oral bioavailability due to its lipophilic nature, large molecular weight, regional differences in its gastrointestinal permeability and involvement of multitransporters. Intracellular delivery and mitochondrial target ability issues pose additional hurdles. To maximize CoQ10 delivery to its biopharmaceutical target, numerous approaches have been undertaken. The review summaries the current research on CoQ10 bioavailability and highlights the headways to obtain a satisfactory intracellular and targeted mitochondrial delivery. Unresolved questions and research gaps were identified to bring this promising natural product to the forefront of therapeutic agents for treatment of different pathologies.
... They have hydrophilic hydroxyl groups on the outer surface and a hydrophobic cavity at the center ( Figure 1). As a result, CDs are capable of forming complexes with a variety of ionic and lipophilic substances by taking the entire molecule or part of it into the cavity and can affect the aqueous solubility, stability or bioavailability of the guest [1][2][3][4]. The molecular recognition phenomena by CDs have therefore been a subject of special attention in the past decades as suitable models for enzyme-substrate binding process and/or receptor-drug interactions in which the various functionalized groups play an important role [5][6][7]. ...
Article
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α-Lipoic acid (ALA) has a chiral center at the C6 position, and exists as two enantiomers, R(+)-ALA (RALA) and S(-)-ALA (SALA). RALA is naturally occurring, and is a cofactor for mitochondrial enzymes, therefore playing a major role in energy metabolism. However, RALA cannot be used for pharmaceuticals or nutraceuticals because it readily polymerizes via a 1,2-dithiolane ring-opening when exposed to light or heat. So, it is highly desired to find out the method to stabilize RALA. The purpose of this study is to provide the spectroscopic information of stabilized RALA and SALA through complexation with cyclodextrins (CDs), α-CD, β-CD and γ-CD and to examine the physical characteristics of the resultant complexes in the solid state. The RALA-CD structures were elucidated based on the micro fourier transform infrared (FT-IR) and Raman analyses. The FT-IR results showed that the C=O stretching vibration of RALA appeared at 1717 cm-1 and then shifted on formation of the RALA-CD complexes. The Raman spectra showed that the S-S and C-S stretching vibrations for RALA at 511 cm-1 (S-S), 631 cm-1 (C-S) and 675 cm-1 (C-S) drastically weakened and almost disappeared upon complexation with CDs. Several peaks indicative of O-H vibrations also shifted or changed in intensity. These results indicate that RALA and CDs form host-guest complexes by interacting with one another.
... Since the increased absorption of CoQ10 has been reported for some solubilized formulations [37,43,44] , this was also expected in the case of Q10Vital . Further, ␥ -cyclodextrin complex has already been shown to have increased bioavailability [45] but, unfortunately, the study was based on CoQ10 powder as a reference product, with extremely poor absorption capacity. ...
Article
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Coenzyme Q10 (CoQ10) is a naturally occurring compound that plays a fundamental role in cellular bioenergetics and is an effective antioxidant. Numerous health benefits of CoQ10 supplementation have been reported, resulting in growing demands for its use in fortifying food. Due to its insolubility in water, the enrichment of most food products is not easily achievable and its in vivo bioavailability is known to be poor. Water solubility was increased significantly with the use of an inclusion complex with beta-cyclodextrin. This complex is widely used as Q10Vital in the food industry, while its in vivo absorption in humans has not previously been studied. A randomized three-period crossover clinical trial was therefore performed in which a single dose of CoQ10 was administered orally to healthy human subjects. The pharmacokinetic parameters of two forms of the novel CoQ10 material were determined and compared to soft-gel capsules with CoQ10 in soybean oil that acted as a reference. The mean increase of CoQ10 plasma concentrations after dosing with Q10Vital forms was determined to be over the reference formulation and the area under the curve values, extrapolated to infinity (AUC(inf)), were also higher with the tested forms; statistically significant 120 and 79% increases over the reference were calculated for the Q10Vital liquid and powder, respectively. The study revealed that the absorption and bioavailability of CoQ10 in the novel formulations are significantly increased, probably due to the enhanced water solubility.
... Pristupi za ostvarenje toga cilja u praksi su vrlo razli~iti, npr. izrada razli~itih inkluzijskih kompleksa, micelarnih otopina i sli~no, {to je primijenjeno i u tijeku ispitivanja mogu}nosti pove}anja vodotopivosti koenzima Q 10 (44,46,48,(51)(52)(53)(54). ...
Article
Full-text available
Coenzyme Q10 has an important role in the mitochondrial respiratory chain, where it acts as an electron carrier, and is the only endogenous antioxidant in the human body. A part of Q10 is also supplied to the body by food. The biological role of CoQ10 is built on its redox equilibrium and continuous transformation between ubiquinone and ubiquinol. Due to natural reduction of CoQ10 during or following intestinal absorption its function in the body is not affected by the form in which it is consumed. A decline in CoQ10 levels can be observed with increasing age, especially in the most active organs, while the beneficial effect of supplementation has been observed in many medical conditions. Due to its physical properties CoQ10 is very poorly absorbed from the gastrointestinal tract. A general rule is that the higher the dose that is orally administered, the lower is the percent of the dose absorbed. Oil suspensions (soft-gel capsules) of ubiquinone and later ubiquionol represent the first important steps in increasing the bioavailability, while a further breakthrough was achieved with the development of water-soluble forms.
... Greater bioavailability of CoQ10 can be obtained if it is taken with meals, because of the action of secreted bile acids [1,[16][17][18][19]. ...
Article
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Coenzyme Q10 is the only endogenously synthesized lipid with a redox function which exhibits broad tissue and intracellular distribution in mammals. Beneficial effects of CoenzymeQ10 supplementation were observed in several age-related diseases including heart failure. CoQ10 (coenzyme Q10) level is significantly decreased in patients with this disease, which correlates with severity of clinical symptoms. Supplementation with various pharmaceutical formulations of CoQ10 improves impaired cardiac function and clinical course of heart failure. Current data from clinical trials indicate that CoQ10 can significantly reduce morbidity and mortality of heart failure patients in addition to guideline recommended pharmacotherapy.
... Gamma CD, widely accepted as food constituent, consists of 8 glucose monomers arranged in the form of a cyclic ring. It has been reported to enhance the bioavailability of hydrophobic ingredients such as coenzyme Q10 [52][53][54]. We recruited CDs for aqueous extraction of bioactives from Ashwagandha leaves. ...
Article
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Ashwagandha (Withania somnifera) is an Ayurvedic herb commonly used in world-renowned traditional Indian home medicine system. Roots of Ashwagandha have been traditionally known to possess a variety of therapeutic and health promoting potentials that have not been sufficiently supported by laboratory studies. Nevertheless, most, if not all, of the preventive and therapeutic potentials have been assigned to its bioactive components, steroidal alkaloids and lactones. In contrast to the traditional use of roots, we have been exploring bioactivities in leaves of Ashwagandha. Here, we report that the leaves possess higher content of active Withanolides, Withaferin-A (Wi-A) and Withanone (Wi-N), as compared to the roots. We also established, for the first time, hydroponic cultivation of Ashwagandha and investigated the effect of various cultivation conditions on the content of Wi-A and Wi-N by chemical analysis and bioassays. We report that the Withanone/Withaferin A-rich leaves could be obtained by manipulating light condition during hydroponic cultivation. Furthermore, we recruited cyclodextrins to prepare extracts with desired ratio of Wi-N and Wi-A. Hydroponically grown Ashwagandha and its extracts with high ratio of withanolides are valuable for cancer treatment.
... The utilization of CoQ10 as a biofunctional ingredient in food products is also undesirable due to its limited water solubility and CoQ10 is prone to degrade under environmental stresses (e.g., light, heat, oxygen, etc.) (Nakatsuka, Homma, & Aozasa, 2014 (Paroha, Chandel, & Dubey, 2017). Recently, some formulations have been developed to overcome these limitations, such as nanoparticles (Swarnakar et al., 2011), liposomes (Shao, Yang, & Han, 2015), solid lipid particles (Korkm, Gokce, & Ozer, 2013), emulsions (Kaci et al., 2018) and cyclodextrin complexes (Terao et al., 2006). Among these strategies, biodegradable nanoparticles were regarded as one of most promising nanotechnologies because of their high safety and good biocompatibility. ...
... In animals, the administration of tocotrienol-γ-cyclodextrin complex resulted in higher plasma and tissue tocotrienol concentrations by enhancing intestinal absorption [27]. After a single dose of a capsule containing the inclusion complex of coenzyme Q10 with γ-cyclodextrin, the coenzyme Q10 plasma levels were significantly elevated [28]. These findings suggest that the complexation of lipophilic curcumin with γ-cyclodextrin may improve its bioavailability. ...
Article
Full-text available
PurposeThe optimal health benefits of curcumin are limited by its low solubility in water and corresponding poor intestinal absorption. Cyclodextrins (CD) can form inclusion complexes on a molecular basis with lipophilic compounds, thereby improving aqueous solubility, dispersibility, and absorption. In this study, we investigated the bioavailability of a new γ-cyclodextrin curcumin formulation (CW8). This formulation was compared to a standardized unformulated curcumin extract (StdC) and two commercially available formulations with purported increased bioavailability: a curcumin phytosome formulation (CSL) and a formulation of curcumin with essential oils of turmeric extracted from the rhizome (CEO). Methods Twelve healthy human volunteers participated in a double-blinded, cross-over study. The plasma concentrations of the individual curcuminoids that are present in turmeric (namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were determined at baseline and at various intervals after oral administration over a 12-h period. ResultsCW8 showed the highest plasma concentrations of curcumin, demethoxycurcumin, and total curcuminoids, whereas CSL administration resulted in the highest levels of bisdemethoxycurcumin. CW8 (39-fold) showed significantly increased relative bioavailability of total curcuminoids (AUC0−12) in comparison with the unformulated StdC. Conclusion The data presented suggest that γ-cyclodextrin curcumin formulation (CW8) significantly improves the absorption of curcuminoids in healthy humans.
... We have reported that the bioavailability of CoQ10 could be significantly enhanced by the complexation with γCD among natural CDs for the use in nutrition applications [7][8][9][10][11]. Interestingly, the CoQ10 -γCD complex gives not only significantly higher area under the plasma CoQ10 concentration curve (AUC) for 0-48 hr and maximum plasma concentration (C max ), but also the mean plasma levels at 24 and 48 hours tended to be significantly higher after CoQ10 -γCD complex administration to healthy adult volunteers when compared with CoQ10 formulated in microcrystalline cellulose and administrated in the same way as the complex. ...
... It has recently been shown that γ-CD inclusion can uniquely increase the efficiency of micelle formation by bile acids secreted in the intestine and greatly improve the absorption of the guest ingredient into the body with improved water solubility, especially in the case of highly fat-soluble guest ingredients (Uekaji et al. 2013). The above technique has been used as a γ-CD inclusion body to enhance the absorption of supplement ingredients, such as coenzyme Q10 and curcumin, a component of turmeric (Terao et al. 2006;Purpura et al. 2018). ...
Chapter
This chapter introduces the basic properties, safety, inclusion effects of cyclodextrins (CDs) and applications in the food industry. CDs are very attractive materials with a unique structure and the simple function of inclusion of guest molecules shows a variety of effects. CDs have long been used for foods, as they are able to improve and stabilize the physical properties and flavor of food, and enhance the bioavailability of functional and nutraceutical ingredients.
... In general, the stability of CoQ10 is affected by heat, light, and oxygen [28]. Some of the researched approaches to enhance CoQ10 bioavailability, such as complexation with γ-cyclodextrins [69], use of self-emulsifying delivery systems [70], or solid dispersions [71] may also lead to increased CoQ10 stability. However, the CoQ10 stability issues were not addressed within these studies. ...
Article
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The efficiency of coenzyme Q10 (CoQ10) supplements is closely associated with its content and stability in finished products. This study aimed to provide evidence-based information on the quality and stability of CoQ10 in dietary supplements and medicines. Therefore, ubiquinol, ubiquinone, and total CoQ10 contents were determined by a validated HPLC-UV method in 11 commercial products with defined or undefined CoQ10 form. Both forms were detected in almost all tested products, resulting in a total of CoQ10 content between 82% and 166% of the declared. Ubiquinol, ubiquinone, and total CoQ10 stability in these products were evaluated within three months of accelerated stability testing. Ubiquinol, which is recognized as the less stable form, was properly stabilized. Contrarily, ubiquinone degradation and/or reduction were observed during storage in almost all tested products. These reactions were also detected at ambient temperature within the products’ shelf-lives and confirmed in ubiquinone standard solutions. Ubiquinol, generated by ubiquinone reduction with vitamin C during soft-shell capsules’ storage, may lead to higher bioavailability and health outcomes. However, such conversion and inappropriate content in products, which specify ubiquinone, are unacceptable in terms of regulation. Therefore, proper CoQ10 stabilization through final formulations regardless of the used CoQ10 form is needed.
... One of the most prominent setbacks for the application of CoQ10 as a supplement is its poor dispersibility and solubility in polar solvents such as water and ethanol. Terao et al. reported that the aqueous solubility of CoQ10 is less than 0.1 µg/mL [6]. Hence, the absorption of CoQ10 from the gastrointestinal tract is limited by its poor solubility and large molecular weight (863.34 g/moL) [7]. ...
Article
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The purpose of this study is to examine the possible use of rice glycosphingolipids (RGSLs) as an emulsifier to form food grade microemulsions (mean particle size, 10–20 nm) and improve the absorption of CoQ10 with a poor solubility property by prepared emulsion. Because RGSLs could act as an auxiliary emulsifying agent, its addition to the surfactant/oil mixture decreased the emulsion’s particle size. This suggests that RGSLs exist between the water and oil phases to decrease oil droplet size via reduced interfacial tension. CoQ10-loaded microemulsion was also successfully prepared with RGSLs and powdered after freeze-drying with a cryoprotectant. CoQ10’s solubility in freeze-dried particles was dramatically improved compared to that of CoQ10 powder. Moreover, oral absorption of CoQ10 was significantly enhanced when administered via CoQ10-loaded microemulsion. The area under the plasma concentration–time curve for the microemulsion improved up to seven-fold compared to CoQ10 powder. The use of RGSLs could, therefore, be an effective processing technique for improving CoQ10’s solubility and absorption.
... Also, c-CD shows the highest water solubility and it is the only form digested in the intestinal tract. Consequently, c-CD widely accepted by the food, pharmaceutical, agricultural and chemical industries which constitutes of 8 glucose monomers arranged in the form of a cyclic ring (Terao et al. 2006). Therefore, much attention has been recently given to the uses of c-CD as a ''host'' molecule of the inclusion complex in oral bioavailability experiments and as a promising nutrition delivery system (Miyoshi et al. 2011;Uchida et al. 2015). ...
Article
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Flavonoids are the polyphenolic compounds widely found in plants, which possess several pharmacological activities such as, antioxidant, antinociceptive, anti-inflammatory, antiviral, antidiabetic and anticancer effects. Meanwhile, the aqueous solubility of these flavonoid compounds were very less which limits its oral administration also decreases the bioavailability and pharmacological activities. Recently, the cyclodextrin inclusion complexation method effectively improve the solubility and bioavailability of the flavonoids. The purpose of this review was to evaluate the bioavailability enhancement of flavonoid compounds after complexation with cyclodextrins. The search terms “flavonoids”, “pharmacokinetics”, “bioavailability” and “cyclodextrins” were used to retrieve the articles from, PubMed, Scopus and Web of Science until May 2018. 272 publications were identified and 20 studies were selected finally for the discussion of this review. From the selected studies the pharmacokinetic results reveal that the bioavailability of flavonoid compounds, complexed with cyclodextrins were extensively improved when compared to uncomplexed flavonoids, including the parameters such as, area under curve (AUC) and maximum plasma concentration (Cmax). The use of cyclodextrins can improve the oral bioavailability of flavonoids and it can also be a way to increase the therapeutic effects. Therefore, the incorporation of flavonoids in cyclodextrins increases the development of new pharmaceutical products for the clinical application.
Article
Phytosterol (PSE)/γ-cyclodextrin (γ-CD) microparticles have a capsule-like structure, wherein the hydrophobic PSE core is surrounded by outer layers of the hydrophilic PSE/γ-CD inclusion complex crystal. The microparticles could mask the undesirable taste of capsaicin (CAP) by encapsulation of CAP into the microparticles. In the present study, the dissolution of CAP from PSE/γ-CD microparticles into artificial intestinal fluids was examined using the paddle method. The dissolution of CAP from the microparticles was suppressed at pH 1.2 and 5.0. On the other hand, the dissolution was significantly enhanced in fasted and fed state simulated intestinal fluid (FaSSIF and FeSSIF) . Taurocholate (TCA), contained in these artificial fluids, induced rapid dissolution of CAP from microparticles. The mechanism of CAP dissolution from the microparticles in the presence of TCA was investigated using in situ1H NMR spectroscopy. During the incubation of the mixed suspension of the microparticles and TCA, γ-CD peaks started to appear, and the TCA peak showed a gradual upfield shift. Quantitative analysis of NMR results showed that the TCA/γ-CD inclusion complex could form during incubation, according to the dissolution of γ-CD from the microparticles via the guest exchange reaction of PSE by TCA. The collapse of the PSE/γ-CD inclusion complex crystal at the outer shell of microparticles could trigger the release of CAP into the intestinal fluid. Thus, PSE/γ-CD microparticles can be used as an enteric controlled-release system that releases encapsulated drugs not via the conventional pH changes but via guest exchange reaction with TCA.
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Fat-soluble bioactive substances, such as nutraceuticals and vitamins, often have unfavorable properties for use in dietary supplements and cosmetics. Many are unstable to oxygen, ultraviolet light, and heat; as they are hydrophobic, they are less soluble in water, which leads to poor bioavailability. Therefore, systematic studies have been conducted on improving the stability, water solubility, and bioavailability of fat-soluble substances by complexation with cyclodextrin (CD). Molecules of a fat-soluble substance aggregate in water, so they are difficult to dissolve. In addition, when a fat-soluble substance is orally ingested, it is difficult to take up with micelles of bile acid in the intestinal tract, so its bioavailability is extremely low. In contrast, a fat-soluble substance–γ-CD complex incorporates molecules of the fat-soluble substance in the γ-CD cavity one by one, and it disperses well in water. When this complex is taken orally, it replaces the bile acid–γ-CD complex in the intestinal tract, at which time one molecule of the fat-soluble substance is released from the complex. This fat-soluble substance released is taken up rapidly by micelles of bile acid and absorbed in the body. As a result, ingestion of the γ-CD complex enhances the bioavailability of the fat-soluble substance. This innovative encapsulation with γ-CD improves the bioavailability of nutraceuticals and vitamins, and it can be applied to a variety of fat-soluble bioactive substances, such as coenzyme Q10, curcumin and δ-tocotrienol (vitamin E).
Article
Among the natural cyclodextrins (CyDs), bioadaptable γ-cyclodextrin (γ-CyD) is particularly useful in the design of CyD-based pharmaceutical formulations. In addition, the multi-functional characteristics of 2,6-di-O-methyl-β-CyD (DM-β-CyD) is capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes. The objective of this contribution is to outline the recent findings on the potential of γ-CyD and DM-β-CyD as advanced drug carriers, focusing on their ability to increase the drug absorption across biological barriers, the ability to control the rate and time profiles of drug release, and the ability to deliver adrug to a targeted site. Moreover, a novel approach for the selective isolation of Ostwald's intermediate of metastable polymorphs occurring during an early stage of crystallization will be discussed by utilizing the complex formed with DM-β-CyD.
Article
About 40% of newly-discovered entities are poorly soluble in water, and this may be an obstacle in the creation of new drugs. To address this problem, the present review article examines the structure and properties of cyclodextrins and the formation and potential uses of drug – cyclodextrin inclusion complexes. Cyclodextrins are cyclic oligosaccharides containing six or more D-(+)-glucopyranose units linked by α-1,4-glycosidic bonds which are characterized by a favourable toxicological profile, low local toxicity and low mucous and eye irritability; they are virtually non-toxic when administered orally. They can be incorporated in the formulation of new drugs in their natural form (α-, β-, γ-cyclodextrin) or as chemically-modified derivatives. They may also be used as an excipient in drugs delivered by oral, ocular, dermal, nasal and rectal routes, as described in the present paper. Cyclodextrins are promising compounds with many beneficial properties, and their use may be increasingly profitable for pharmaceutical scientists.
Article
Aqueous coenzyme Q10 (CoQ10) dispersions were prepared by blending CoQ10 (60 mg) in aqueous maize starch dispersion (300 mg in 30 mL water) at 60-100 °C for up to 6 h. The CoQ10 agglomerates were removed by centrifugation (5000 × g, 30 min) and filtration through a glass filter. As the temperature increased, the amount of CoQ10 which was stably dispersed increased. Normal maize starch was more effective in dispersing the CoQ10 (57.3%) than waxy and high-amylose maize starches (9.8% and 21.9%, respectively). A light scattering analysis revealed that ultrasonication during cooling was effective in preventing the formation of CoQ10 agglomerates. The average particle size of dispersed CoQ10 was <150 nm. Differential scanning calorimetry and X-ray diffraction analysis revealed that dispersed CoQ10 particles had no amylose complex crystals. The CoQ10 dispersion, however, remained homogeneous without forming precipitates during ambient storage for 2 weeks.
Article
The purpose of this study was to investigate the potential of bacterial cellulose nanofiber suspension (BCNs) as stabilizer in anti-solvent precipitation and its effect on improving bioavailability of coenzyme Q10. Bacterial cellulose (BC) was hydrolyzed by sulfuric acid followed by the oxidation with hydrogen peroxide to prepare BCNs. The suspension of BCNs-loaded CoQ10 (CoQ10-BCNs) were prepared by antisolvent precipitation. The zeta potential of CoQ10-BCNs was about −36.01 mV. The properties of CoQ10, BCNs and CoQ10-BCNs were studied by scanning electron microscopy, transmission electron microscope, Fourier-transform infrared spectroscopy, X–ray diffraction, differential scanning calorimetry and thermo gravimetric analysis. The crystallinity of CoQ10 decreased in CoQ10-BCNs compared with the raw CoQ10, and CoQ10-BCNs have good physicochemical stability. In oral bioavailability studies, the area under curve (AUC) of CoQ10-BCNs was about 3.62 times higher than the raw CoQ10 in rats.
Article
The water-solubility of coenzyme Q10 (CoQ10) is extremely low because of its hydrophobicity, which results in low bioavailability. In this study, peptide mixtures derived from different proteins (casein, albumin, gelatin, lysozyme, zein and hemoglobin) were prepared and used as dispersants ofCoQ10. Most peptide mixtures, except for that derived from lysozyme, enhanced the water-dispersibility of CoQ10 by forming complexes with CoQ10. In particular, the apparent solubility of CoQ10complexed with the casein hydrolysate (Pepcas) was the highest. Pepcas was fractionated by ammonium sulfate precipitation and ultrafiltration to find the most effective peptides for enhancing water-dispersibility of CoQ10. The peptide fraction that had a relatively hydrophobic nature and peptides of higher-than-average molecular weights (PepcasA) was found to be the most effective. Results from differential thermal analysis and powder X-ray diffraction revealed that the complex between CoQ10 and PepcasA in the solid state was amorphous. In solution, the complex is a hydrocolloid with particle sizes of 154-279 nm.
Article
Potential applications of engineered nanomaterials (ENM) in food have shown great potential benefits and improvements over existing technologies. Many of the applications are still in the research and developmental stage and would require rigorous food safety testing and ultimately consumer acceptance. Within the European Union, which has taken active role in regulating ENM, nano/size-specific provisions have been implemented into several food-related directives and regulations. The lack of standardized methods for the detection and characterization of ENM in foods as well as their potential absorption renders the effective implementation of the legal requirements presently difficult. One favored approach is the combination of field-flow fractionation and ICP-MS for successive quantitative and qualitative nanomaterial analysis. For simultaneous characterization of size and chemical composition of inorganic nanoparticles, single-particle ICP-MS arose as a promising technique.
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One of the modern technologies of how to ensure sufficient bioavailability of drugs with limited water solubility is represented by the preparation of liquisolid systems. The functional principle of these formulations is the sorption of a drug in a liquid phase to a porous carrier (aluminometasilicates, microcrystalline cellulose, etc.). After addition of further excipients, in particular a coating material (colloidal silica), a powder is formed with the properties suitable for conversion to conventional solid unit dosage forms for oral administration (tablets, capsules). The drug is subsequently administered to the GIT already in a dissolved state, and moreover, the high surface area of the excipients and their surface hydrophilization by the solvent used, facilitates its contact with and release to the dissolution medium and GI fluids. This technology, due to its ease of preparation, represents an interesting alternative to the currently used methods of bioavailability improvement. The article follows up, by describing the specific aspects influencing the preparation of liquid systems, on the already published papers about the bioavailability of drugs and the possibilities of its technological improvement.Key words: liquisolid systems bioavailability porous carrier coating material preformulation studies.
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Cancer metastasis is an extremely complex multistep process that is regulated by multiple module interactions of genetic, environmental factors. It leads to movement of cancer cells from the primary tumor site to distant sites in the body through blood or lymph circulation. Tightly regulated by migratory, invasive characteristics of the tumor cells as well as micro-environment, it poses major hurdles to the cancer therapy. In this chapter, we sketch a simple picture of ayurvedic description of cancer and metastasis, provide a review on the metastatic targets and discuss findings on Ashwagandha bioactives for therapy of metastatic cancers.
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Coenzyme Q10 is an antioxidant present in the human body. Coenzyme Q10 has an essential role in various biochemical reactions. The deficiency of coenzyme Q10 in the body leads to disorders including neurological degeneration, ageing and cancer. Clinical trials have tested coenzyme Q10 as a drug or a dietary supplement. However, the major pharmaceutical issue of coenzyme Q10 delivery is its high molecular weight and poor water solubility. This limitation leads to its poor oral bioavailability. Several methods have been designed to overcome the poor water solubility of coenzyme Q10, such as size reduction and ionization. This article presents nanotechnology-based drug delivery systems for coenzyme Q10 with special emphasis on pharmacokinetic perspectives and clinical relevance. Systems include nanoparticles, solid dispersions, liposomes, nanoemulsions, self-emulsifying drug delivery systems, nanostructured lipid carriers, cyclodextrins and nanocapsules.
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Some of functional food ingredients having health promotion functions and/or beauty care effects are unstable under UV light, air oxygen, elevated temperature and in the presence of incompatible substances. Cyclodextrins can be used for the stabilization of such active substances by complex formation even under above mentioned degradable circumstances. Here we show some of our investigation results for the stabilization of actives like unsaturated fatty acids, R-α-lipoic acid and Coenzyme Q10.
Article
Coenzyme Q10 (CoQ10) is widely used in preventive or curative treatment of cardiovascular diseases. However, CoQ10 exhibits an extremely low solubility in aqueous medium as well as a poor oral bioavailability. Therefore, solanesyl poly(ethylene glycol) succinate (SPGS) and CoQ10 were formulated as CoQ10-SPGS micelles with a high content of CoQ10 to improve the bioavailability of CoQ10 in rat. Findings indicate that, in the CoQ10-SPGS micelles, SPGS is self-assembled into stable nanosized micelles with a CoQ10 loading capacity of more than 39%. The CoQ10-SPGS micelles exhibit an enhanced photostability upon exposure to simulated sunlight. In vivo experiments demonstrate that, as compared to that of the coarse suspensions of CoQ10, there was three-fold enhancement of oral bioavailability for CoQ10-loaded SPGS micelles depending on varying molecular weight of SPGS. In the encapsulation of CoQ10 by SPGS micelles, the self-assembled nanocarriers with strong muco-adhesive properties lead to increases in the solubility and oral absorption of lipophilic CoQ10 nanoparticles.
Article
The composite material formed by phytosterol ester (PSE) and γ-cyclodextrin (γ-CD) disperses readily in water and has been used to mask undesirable flavours. This paper elucidates the structure of the PSE/γ-CD particle. Cryogenic scanning electron microscopy and contact angle measurements showed that the PSE/γ-CD particles formed a capsule-like structure with a hydrophilic surface. A phase-solubility study using cholesteryl oleate (ChO), one of the components of PSE, showed that ChO formed a hydrophilic and stoichiometric inclusion complex with γ-CD at a molar ratio of 2:5. The structure of the PSE/γ-CD inclusion complex was similar to that of ChO/γ-CD, based on differential scanning calorimetry and powder X-ray diffractometry results. Thus, we propose that the PSE/γ-CD particle has a capsule-like structure wherein a hydrophobic PSE droplet is surrounded by an outer layer of the hydrophilic PSE/γ-CD inclusion complex.
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Coenzyme Q10 is an antioxidant essential for biochemical reactions in the human body. The deficiency of the coenzyme Q10 in the body leads to several disorders including neurological degeneration, ageing, and cancer. In cell mitochondria, coenzyme Q10 is a cofactor as electron transport system and is responsible for the synthesis of adenosine triphosphate (ATP), a major source of energy. Clinical trials reported the role of coenzyme Q10 in as the drug or dietary supplement. The major issue concerning coenzyme Q10 delivery is its high molecular weight and poor water solubility. This limitation ultimately leads to its poor oral bioavailability. Traditional approaches has been made to overcome poor water solubility, such as size reduction and ionization. New drug delivery carriers include nanoparticles, solid dispersions, liposomes, nanoemulsions, self-emulsifying drug delivery system, nanostructured lipid carrier, cyclodextrins and nanocapsules. These nanocarriers facilitate absorption of coenzyme Q10 from gastrointestinal tract and increase oral bioavailability. Here we review nanotechnology-based drug delivery system for coenzyme Q10 with special emphasis on pharmacokinetic perspective and clinical relevance.
Article
Micelles can be formed from coenzyme Q10 (CoQ10) and dipotassium glycyrrhizate (GZK2) by using an inclusion complex of CoQ10 with γ-cyclodextrin (γ-CD). The mechanism of micelle formation was kinetically investigated. Adding GZK2 to a supersaturated solution of the CoQ10/γ-CD inclusion complex led to a linear increase in the solubility of CoQ10 due to the formation of micelles of CoQ10 when the molar ratio of GZK2/γ-CD increased to ~1.6, after which the concentration remained constant. The equilibrium constant K for micelle formation was 0.68 (-) and the ratio of GZK2 to CoQ10 was 1. These results suggest that the formation of CoQ10 micelles with GZK2 might proceed via the displacement of CoQ10 by GZK2 in the γ-CD cavity followed by the formation of CoQ10 micelles.
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Purpose: The solubility of coenzyme Q10 (CoQ10) in water is extremely low, resulting in a low oral bioavailability. In this study, we attempted to improve the low dissolution and bioavailability of CoQ10, by means of the complexation with natural α-, β- and γ-cyclodextrins (CyDs) and 2-hydroxypropyl-β-CyD (HP-β-CyD). Methods: The complexation of CoQ10 with CyDs was studied by the solubility method. Solid CoQ10/CyD complexes with different molar ratios were prepared by the kneading method using ethanol/water (1: 1) mixed solvent. Results: Among these CyDs, γ-CyD signifi cantly increased the solubility of CoQ10 at lower CyD concentrations. The powder X-ray diffraction peaks of CoQ10 disappeared following solid complexation with γ-CyD, although the endothermic peak due to the melting of the drug did not disappear completely. The dissolution rate of CoQ10 was signifi cantly increased by complexation with γ-CyD, probably due to soluble complex formation and/or nanometer-sized particle formation, which was refl ected in the enhanced oral absorption in dogs. Conclusion: The results indicated that γ-CyD is useful for improving the oral bioavailability of CoQ10.
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The effects of coenzyme Q(10) (CoQ(10)) and alpha-tocopherol on the rate of mitochondrial superoxide anion radical (O2(./-)) generation were examined in skeletal muscle, liver, and kidney of 24-month-old mice. Mice were orally administered alpha-tocopherol (200 mg.kg(-1).day(-1)) alone, CoQ(10) (123 mg.kg(-1).day(-1)) alone, or the two together for 13 wk. Administration of alpha-tocopherol resulted in an approximately sevenfold elevation of mitochondrial alpha-tocopherol content. Intake of CoQ(10) alone caused an approximately fivefold increase in CoQ content (CoQ(9) and/or CoQ(10)) and alpha-tocopherol of mitochondria. The rate of (O2(./-)) generation by submitochondrial particles (SMPs) was inversely related to their alpha-tocopherol content but unrelated to CoQ content. Experimental in vitro augmentation of SMPs with varying amounts of alpha-tocopherol caused an up to approximately 50% decrease in the rate of O2(./-) generation. Similar in vitro augmentations of SMPs with CoQ(10) had previously been found to have no effect on the rate of O2(./-) generation The CoQ(10)-induced elevation of alpha-tocopherol in the present study was inferred to be due to a 'sparing/regeneration' by CoQ. Results indicate the involvement of alpha-tocopherol in the elimination of mitochondrially generated O2(./-)
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The biopharmaceutical properties-especially the solubility and permeability-of a molecule contribute to its overall therapeutic efficacy. The newer tools of drug discovery have caused a shift in the properties of drug-like compounds, resulting in drugs with poor aqueous solubility and permeability, which offer delivery challenges, thus requiring considerable pharmaceutical manning. The modulation of solubility is a more viable option for enhancing bioavailability than permeability, because of the lack of "safe" approaches to enhance the latter. Solid-state manipulation in general, and amorphization in particular, are preferred ways of enhancing solubility and optimizing delivery of poorly soluble drugs. This review attempts to address the diverse issues pertaining to amorphous drug delivery systems. We discuss the various thermodynamic phenomenon such as glass transition, fragility, molecular mobility, devitrification kinetics, and molecular-level chemical interactions that contribute to the ease of formation, the solubility advantage, and the stability of amorphous drugs. The engineering of pharmaceutical alloys by solubilizing and stabilizing carriers, commonly termed solid dispersions, provide avenues for exploiting the benefits of amorphous systems. Carrier properties, mechanisms of drug release, and study of release kinetics help to improve the predictability of performance. The review also addresses the various barriers in the design of amorphous delivery systems, use of amorphous form in controlled release delivery systems, and their in vivo performance.
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Micellar solubilization is a powerful alternative for dissolving hydrophobic drugs in aqueous environments. In this work, we provide an insight into this subject. A concise review of surfactants and micelles applications in pharmacy was carried out. Initially, a description of surfactants and aqueous micellar systems is presented. Following, an extensive review on micellar drug solubilization, including both the principles involved on this phenomenon and the work already done regarding solubilization of drugs by micelles is presented. The application of micelles in drug delivery, in order to minimize drug degradation and loss, to prevent harmful side effects, and to increase drug bioavailability, is also presented. Special emphasis is given to the more recent use of polymeric micelles. Finally, we briefly discuss the importance of surfactants and micelles as biological systems models as well as its application in micellar catalysis. As can be seen from the review presented, the use of micelles in pharmacy is an important tool that finds numerous applications.
Article
Inclusion complexation of coenzyme Q10 (CoQ10) with γ-cyclodextrin (γ-CD) and methyl-β-cyclodextrin (MS = 0.97) (M-β-CD0.97) in aqueous solution was studied using phase solubility and spectral shift methods. The apparent stability constants calculated from the slope and intercept of solubility diagrams and Benesi-Hildebrand plots were compared. The stability constants obtained from solubility studies and spectral shift method in the case of γ-CD were of the same order of magnitude, while in the case of M-β-CD0.97 the difference was of one order of magnitude.
Article
Inclusion complexes of coenzyme Q10 (CoQ10) with γ-cyclodextrin (γ-CD) and methyl-β-cyclodextrin (MS = 0.7) (M-β-CD0.97) in the solid state were prepared at 55°C, 60°C, 65°C using 'heating' method. The influence of the heating temperature on solubility of complexes thus obtained was investigated. The activation energy of complexation reactions was calculated from the Arrhenius equation. The formation of inclusion complexes was evaluated using IR studies, X-ray diffractometry and differential scanning calorimetry.
Article
Coenzyme Q10 its physical mixtures and inclusion complexes with γ-cyclodextrin (γ-CD) or methyl-β-cyclodextrin (MS = 0.97) (M-β-CD) in solution and in the solid state were exposed to UV radiation. The samples of coenzyme and physical mixtures in the solid state a w0ere also stored at 323K, 353K, 363K and 373K. Changes of coenzyme Q10 concentration during photolysis and storage were followed using UV and IR spectrophotometry. The activation energy of degradation reaction of coenzyme was calculated from Arrhenius equation. γ-CD and M-β-CD catalysed the photolysis or coenzyme Q10, however addition of these cyclodextrins to the stored samples decelerated the degradation of coenzyme.
Article
Inclusion complexes of 13 benzodiazepines with 3 cyclodextrins (α-, β-, γ-CyDs) in aqueous solution and in the solid phase were studied by solubility methods, spectroscopy (UV, CD, IR), thermal analysis, and X-ray diffractometry, and their modes of interaction were assessed. The importance of the hydrophobicity of the guest molecule and the spatial relationship between host and guest molecules were clearly reflected in the magnitude of the stability constant of the inclusion complexes. The solid complexes of some benzodiazepines with γ-CyD were obtained in a variety of molar ratios, and dissolution and membrane permeation behaviors were examined. The rates of dissolution and permeation of benzodiazepines through a cellophane membrane were significantly increased by γ-CyD complexation. As an example, the rapid dissolving form of diazepam-γ-CyD complex was found to significantly increase the serum levels of drug after oral administration to rabbits.
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The fundamental role of coenzyme Q(10) (CoQ(10)) in mitochondrial bioenergetics and its well-acknowledged antioxidant properties constitute the basis for its clinical applications, although some of its effects may be related to a gene induction mechanism. Cardiovascular disease is still the main field of study and the latest findings confirm a role of CoQ(10) in improving endothelial function. The possible relation between CoQ(10) deficiency and statin side effects is highly debated, particularly the key issue of whether CoQ(10) supplementation counteracts statin myalgias. Furthermore, in cardiac patients, plasma CoQ(10) was found to be an independent predictor of mortality. Studies on CoQ(10) and physical exercise have confirmed its effect in improving subjective fatigue sensation and physical performance and in opposing exercise-related damage. In the field of mitochondrial myopathies, primary CoQ(10) deficiencies have been identified, involving different genes of the CoQ(10) biosynthetic pathway; some of these conditions were found to be highly responsive to CoQ(10) administration. The initial observations of CoQ(10) effects in Parkinson's and Huntington's diseases have been extended to Friedreich's ataxia, where CoQ(10) and other quinones have been tested. CoQ(10) is presently being used in a large phase III trial in Parkinson's disease. CoQ(10) has been found to improve sperm count and motility on asthenozoospermia. Moreover, for the first time CoQ(10) was found to decrease the incidence of preeclampsia in pregnancy. The ability of CoQ(10) to mitigate headache symptoms in adults was also verified in pediatric and adolescent populations.
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The ground mixture of phenytoin and microcrystalline cellulose was prepared by grinding in a vibrational ball mill. The X-ray diffraction patterns indicated the amorphous nature of the ground mixture. Comparative studies were made concerning the in vitro dissolution and in vivo absorption of fine phenytoin powder, phenytoin sodium powder, and the ground mixture. The ground mixture showed a greater dissolution rate than the fine powder and attained supersaturation in the pharmacopeial disintegration media at pH 1.2 and 7.4. In vivo absorption studies of each preparation were carried out in five subjects, using a crossover design, by measuring the urinary excretion rate of a main metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin. The blood levels of phenytoin and the corresponding urinary excretion patterns of the metabolite were determined in two subjects. The ground mixtures significantly improved the bioavailability of phenytoin. The drug was completely and rapidly absorbed after oral administration of the ground mixture. The vibrational ball milling technique for a poorly water-soluble drug with microcrystalline cellulose provides a promising way of improving the in vivo drug absorption.
Article
One of the important characteristics of cyclodextrins is the formation of an inclusion complex with a variety of drug molecules in solution and in the solid state. As a consequence of intensive basic research, exhaustive toxic studies, and realization of industrial production during the past decade, there seem to be no more barriers for the practical application of natural cyclodextrins in the biomedical field. Recently, a number of cyclodextrin derivatives and cyclodextrin polymers have been prepared to obtain better inclusion abilities than parent cyclodextrins. The natural cyclodextrins and their synthetic derivatives have been successfully utilized to improve various drug properties, such as solubility, dissolution and release rates, stability, or bioavailability. In addition, the enhancement of drug activity, selective transfer, or the reduction of side effects has been achieved by means of inclusion complexation. The drug-cyclodextrin complex is generally formed outside of the body and, after administration, it dissociates, releasing the drug into the organism in a fast and nearly uniform manner. In the biomedical application of cyclodextrins, therefore, particular attention should be directed to the magnitude of the stability constant of the inclusion complex. In the case of parenteral application, a rather limited amount of work has been done because the cyclodextrins in the drug carrier systems have to be more effectively designed to compete with various biological components in the circulatory system. However, the works published thus far apparently indicate that the inclusion phenomena of cyclodextrin analogs may allow the rational design of drug formulation and that the combination of molecular encapsulation with other carrier systems will become a very effective and valuable method for the development of a new drug delivery system in the near future.
The pharmacokinetics of coenzyme Q10 (CoQ10) in man was studied by utilizing deuterium-labelled coenzyme Q10 (d5-CoQ10). The absence of an isotope effect in the disposition of d5-CoQ10 in man was confirmed from the plasma concentration time curves after simultaneous oral dosing of d5-CoQ10 and unlabelled CoQ10. After oral administration of 100 mg of d5-CoQ10 to 16 healthy male subjects, the mean plasma CoQ10 level attained a peak of 1.004 +/- 0.370 micrograms/ml at 6.5 +/- 1.5 h after administration, and the terminal elimination half-life was 33.19 +/- 5.32 h. In most of the subjects, plasma d5-CoQ10 showed a second peak at 24 h after dosing. This unusual plasma level curve was well described by a newly proposed compartment model based upon the assumption that absorbed CoQ10 is taken up by the liver and then transferred mainly to VLDL and redistributed from the liver to the systemic blood.
Article
The bioavailability of four different Coenzyme Q10 (CoQ) formulations was compared in ten healthy volunteers in a four-way randomised cross-over trial. The included formulations were: A hard gelatin capsule containing 100 mg of CoQ and 400 mg of Emcompress. Three soft gelatin capsules containing: 100 mg of CoQ with 400 mg of soy bean oil (Bioquinon); 100 mg of CoQ with 20 mg of polysorbate 80, 100 mg of lecithin and 280 mg of soy bean oil; and 100 mg of CoQ with 20 mg of polysorbate 80 and 380 mg of soy bean oil, respectively. The result suggests that the soya bean oil suspension of CoQ (Bioquinon has the highest bioavailability. A difference in basic AUC and AUC after p.o. administration of CoQ was observed with respect to sex. A characteristic two peak-pattern was observed at the concentration-time profile.
Article
Some cyclodextrins are produced industrially, and available in pharmaceutical quality, at reasonable prices. Their medicinal use means mainly--but not exclusively--the complexation of problematic drugs (poorly soluble, unstable, irritating, difficult to formulate substances). The CD complexation generally results in improved wettability, dissolution, and solubility; improved stability; reduced side effects; or in mildering of other undesired properties (e.g., bitter tastes, bad smells). CDs can be used advantageously practically in any drug forms: oral, rectal, pulmonary, external, ocular, etc. formulations. In oral solid and liquid formulations the chemical and physical stability and bioavailability, but particularly the role of absorption is improved. With appropriate highly soluble chemically modified CDs aqueous parenteral formulations can be prepared from poorly soluble drugs. Using CDs the transdermal penetration or nasal absorption of such drugs becomes possible, which earlier could not be administered through these ways. The direct therapeutic effects of CDs (or their derivatives) are demonstrated in several examples as well as the use of beta CD as vehicle in tabletting.
Article
Coenzyme Q10 (CoQ10) levels in human plasma were determined by high-performance liquid chromatography (HPLC) with UV detection. CoQ10 was dissociated from lipoproteins by methanol and subsequently cleaned-up on silica gel and octadecyl silica solid-phase extraction cartridges. HPLC separation was performed on a C18 reversed-phase column. The methanol-hexane mobile phase provided a greater possibility of separation procedure adjustment allowing the shortest possible elution time without loss of resolution than a two-alcohol mobile phase. Quantitation was based on the peak heights using a standard addition method. The lower limit of detection was 8 ng on-column, corresponding to 90 micrograms ubiquinone per litre of plasma in an actual sample. Thirty-one randomly selected plasma samples from apparently healthy, 18 to 56-year-old individuals (males and females) were analyzed for total CoQ10. The average level in these subjects was 0.47 +/- 0.18 mg/l with the range of 0.26-1.03 mg/l. The method was also applied to the determination of ubiquinone plasma level changes in one healthy volunteer over a period of one month and after oral intake of CoQ10.
Article
Cyclodextrins (CDs) complex hydrophobic drugs, increasing their aqueous solubility and stability. CD complexation enables the creation of formulations for water-insoluble drugs that are difficult to deliver with more traditional formulations. Currently, 10 pharmaceutical products are marketed as CD formulations. A CD-based formulation, like any other, is evaluated for quality and safety. The 6 CDs currently available for use in pharmaceutical products are alpha-, beta-, and gamma-CD and the methyl (M), hydroxypropyl (HP), and sulfobutylether (SBE) derivatives of beta-CD. The structural features of these CDs are evaluated for their affect on complexation performance. Optimal specifications, quality production, and safety of each CD is presented. The current and future regulatory process facing excipients is summarized, and the current regulatory status of the CDs in Japan, the United States, and Europe is presented.
Article
Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has as its objective, a critical assessment of the current status of cyclodextrins in the formulation and delivery of pharmaceuticals and commentary on their potential future uses. The emphasis will be on answers to common questions often asked of pharmaceutical scientists working in this area. Why use cyclodextrins for drug solubilization and stabilization when alternative techniques are available? Why the greater interest in modified cyclodextrins and not the parent cyclodextrins? If a drug forms a strong cyclodextrin inclusion complex, how is the drug released in vivo? Dose the injection of a cyclodextrin/drug complex alter the pharmacokinetics of the drug? Are there drug products on the market which contain cyclodextrins? What is the regulatory status of cyclodextrins? Although definitive answers to all these questions are not possible at this time, many of these questions are answerable, and educated and informed responses are possible for the rest.
Article
A method is described for the simultaneous detection of ubiquinol-10 and ubiquinone-10 in human plasma. In this procedure, heparinized human plasma was mixed with 5 vol of methanol and 10 vol of hexane. After vigorous shaking and centrifugation, an aliquot of the hexane phase (5 microl) was injected immediately and directly onto a reversed-phase HPLC to minimize the oxidation of ubiquinol to ubiquinone. A post-separation, on-line reduction column converts ubiquinone to ubiquinol which is quantified by electrochemical detection. The detection limit of plasma ubiquinol-10 and ubiquinone-10 is about 4 nM with excellent reproducibilities. Tocopherols, lycopene, and beta-carotene are also detectable in this method. In addition, free cholesterol, and cholesteryl esters can be quantified by their absorption at 210 nm. Using this method we have determined the ratio of ubiquinol to ubiquinone is about 95/5 in human plasma from healthy donors. We suggest that this method will be useful since the ratio of ubiquinol to ubiquinone has been suggested as a good marker of oxidative stress.
Article
The coenzyme Q10 content of the average Danish diet was estimated from consumption data and from analysis of food items to be 3-5 mg coenzyme Q10 per day, primarily derived (64% of the total) from meat and poultry. To investigate if coenzyme Q10 was absorbed to any significant degree from a food item, a randomized cross-over study with single doses of coenzyme Q10 (30 mg/person), administered either as a meal or as capsules, was carried out in healthy subjects. The serum coenzyme Q10 concentration increased significantly, and the maximum concentrations did not differ significantly for the two forms of administration. The study indicates that coenzyme Q10 is present in food items and absorbed to a significant degree. Thus, dietary coenzyme Q10 may contribute to the plasma coenzyme Q10 concentration.
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The General Linear Models procedure (PROC GLM) in SAS/STAT software can be programmed to perform the standard statistical analyses used for relative bioavailability studies. The first steps are validity checks to test for statistical validity (linearity), fundamental validity (intersection of regression lines at 0 supplemental level), and equality of the basal diet mean to the point of intersection. The CLASS variable capabilities of PROC GLM can be exploited to expedite these tests. After the validity checks, the GLM procedure can be used to obtain parameter estimates for calculation of relative bioavailability. Optional output provides an inverse matrix to calculate standard errors of slopes and slope ratios. Logarithmic and other transformations of the dependent variable to reduce variance heterogeneity or achieve linearity for subsequent calculation of appropriate bioavailability values also can be accomplished within the SAS System. When nonlinear regression models are more appropriate than linear models, the NLIN procedure can be used.
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For poorly soluble drugs, the digestive absorption depends on their rate of dissolution. Decreasing the particle size of these drugs improves their rate of dissolution. Fine grinding mills are use to micronize powders: either jar mills or fluid energy mills. Theses processes were applied to griseofulvin, progesterone, spironolactone and diosmin. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy.
Article
Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of poorly water-soluble drugs, their commercial use has been very limited, primarily because of manufacturing difficulties and stability problems. Solid dispersions of drugs were generally produced by melt or solvent evaporation methods. The materials, which were usually semisolid and waxy in nature, were hardened by cooling to very low temperatures. They were then pulverized, sieved, mixed with relatively large amounts of excipients, and encapsulated into hard gelatin capsules or compressed into tablets. These operations were difficult to scale up for the manufacture of dosage forms. The situation has, however, been changing in recent years because of the availability of surface-active and self-emulsifying carriers and the development of technologies to encapsulate solid dispersions directly into hard gelatin capsules as melts. Solid plugs are formed inside the capsules when the melts are cooled to room temperature. Because of surface activity of carriers used, complete dissolution of drug from such solid dispersions can be obtained without the need for pulverization, sieving, mixing with excipients, etc. Equipment is available for large-scale manufacturing of such capsules. Some practical limitations of dosage form development might be the inadequate solubility of drugs in carriers and the instability of drugs and carriers at elevated temperatures necessary to manufacture capsules.
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The purpose of this article is to summarise our studies, in which the main determinants and absorption of plasma coenzyme Q10 (Q10, ubiquinone) have been assessed, and the effects of moderate dose oral Q10 supplementation on plasma antioxidative capacity, lipoprotein oxidation resistance and on plasma lipid peroxidation investigated. All the supplementation trials carried out have been blinded and placebo-controlled clinical studies. Of the determinants of Q10, serum cholesterol, serum triglycerides, male gender, alcohol consumption and age were found to be associated positively with plasma Q10 concentration. A single dose of 30 mg of Q10, which is the maximum daily dose recommended by Q10 producers, had only a marginal elevating effect on plasma Q10 levels in non-Q10-deficient subjects. Following supplementation, a dose-dependent increase in plasma Q10 levels was observed up to a daily dose of 200 mg, which resulted in a 6.1-fold increase in plasma Q10 levels. However, simultaneous supplementation with vitamin E resulted in lower plasma Q10 levels. Of the lipid peroxidation measurements, Q10 supplementation did not increase LDL TRAP, plasma TRAP, VLDL+LDL oxidation resistance nor did it decrease LDL oxidation susceptibility ex vivo. Q10 with minor vitamin E dose neither decreased exercise-induced lipid peroxidation ex vivo nor muscular damage. Q10 supplementation might, however, decrease plasma lipid peroxidation in vivo, as assessed by the increased proportion of plasma ubiquinol (reduced form, Q10H2) of total Q10. High dose vitamin E supplementation decreased this proportion, which suggests in vivo regeneration of tocopheryl radicals by ubiquinol.
Article
Coenzyme Q(10) (CoQ(10)), a highly lipophilic compound present in the inner mitochondrial membrane, is essential for production of cellular energy in the form of ATP. CoQ(10) is used as a dietary supplement and for treatment of various cardiovascular disorders. Our goal was to compare the CoQ(10) levels in Asians following multiple oral doses administered as sustained release or regular tablets. Twenty healthy male volunteers (19-23 years old) were divided into two equal groups. Each subject in Group I received 50 mg oral doses of coenzyme Q(10) as sustained release tablets once a day for fifteen days, while subject in Group II received 50 mg doses of coenzyme Q(10) regular tablets. The CoQ(10) levels were measured by HPLC-UV (reverse phase ODS column, 10 microm, 250 x 4.6 mm; oven temperature 30 degrees C). Mobile phase was constituted by methanol-ethanol 9 : 1 v/v. Flow rate was 1.5 ml/min and UV detection was carried out at 275 nm. Coenzyme Q(9) was used as an internal standard. CoQ(10) baseline in the morning was 0.88+/-0.48 mg/l. Following 1 week 50 mg/d dosing of CoQ(10), plasma CoQ(10) concentrations increased to 1.85+/-1.03 mg/l for sustained release tablets and up to 1.37+/-0.74mg/l for regular tablets. The net increment proportion in AUC for sustained release and regular tablets were 148.26+/-176.56%, 102.57+/-130.00%, respectively. Both preparations significantly increased the systemic exposure when compared to endogenous baseline.
Article
To determine the absorptive properties of 2 novel coenzyme Q10 preparations, a fast-melting tablet and an effervescent tablet, compared with currently available formulations. In the first trial, the absorptive properties of 4 different coenzyme Q10 preparations (fast-melting, effervescent, soft gelatin, and powder-filled hard shell) were studied in a randomized, single-dose, crossover study. Twenty-four male subjects were given a 60 mg dose of coenzyme Q10 and plasma coenzyme Q10 was measured over the next 12 hours. Pharmacokinetic properties including area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and elimination half-life (t 1/2) were measured. In a separate single-dose study, the absorptive characteristics of a different coenzyme Q10 soft gel (Q-Gel) were studied in 6 male subjects. Area under the curve (microg/ml x h) for the fast-melting and effervescent formulations, while marginally greater, was not significantly different when compared to the soft gelatin and powder-filled preparations, 5.4 +/- 1.04 (110%) and 5.5 +/- 0.589 (112%) versus 5.0 +/- 0.859 (102%) and 4.9 +/- 0.812 (100%), respectively. Cmax for the 2 novel formulations was also not statistically different from the soft gelatin or powder-filled preparations, 0.87 +/- 0.14 and 0.86 +/- 0.074 versus 0.70 +/- 0.010 and 0.81 +/- 0.159 (microg/ml). Tmax however, was significantly shorter for the fast-melting and effervescent formulations compared with the soft gel and powder-filled forms, 1.3 +/- 0.348 and 2.0 +/- 0.552 versus 3.7 +/- 0.702 and 4.1 +/- 0.993 (h), respectively. The results of the second trial were similar to those of the powder-filled and soft gel formulations from the first study. The novel fast-melting and effervescent formulations provide a more rapid delivery of CoQ10 to the blood while exhibiting a similar AUC compared with current formulations. The potential clinical significance of this finding should be further evaluated.
Article
The purpose of these studies was to prepare and characterize nanoparticles into which Coenzyme Q10 (CoQ10) had been incorporated (CoQ10-NPs) using a simple and potentially scalable method. CoQ10-NPs were prepared by cooling warm microemulsion precursors composed of emulsifying wax, CoQ10, Brij 78, and/or Tween 20. The nanoparticles were lyophilized, and the stability of CoQ10-NPs in both lyophilized form and aqueous suspension was monitored over 7 days. The release of CoQ10 from the nanoparticles was investigated at 37 degrees C. Finally, an in vitro study of the uptake of CoQ10-NPs by mouse macrophage, J774A.1, was completed. The incorporation efficiency of CoQ10 was approximately 74% +/- 5%. Differential Scanning Calorimetry (DSC) showed that the nanoparticle was not a physical mixture of its individual components. The size of the nanoparticles increased over time if stored in aqueous suspension. However, enhanced stability was observed when the nanoparticles were stored at 4 degrees C. Storage in lyophilized form demonstrated the highest stability. The in vitro release profile of CoQ10 from the nanoparticles showed an initial period of rapid release in the first 9 hours followed by a period of slower and extended release. The uptake of CoQ10-NPs by the J774A.1 cells was over 4-fold higher than that of the CoQ10-free nanoparticles (P < .05). In conclusion, CoQ10-NPs with potential application for oral CoQ10 delivery were engineered readily from microemulsion precursors.
Article
Coenzyme Q10 is administered for an ever-widening range of disorders, therefore it is timely to illustrate the latest findings with special emphasis on areas in which this therapeutic approach is completely new. These findings also give further insight into the biochemical mechanisms underlying clinical involvement of coenzyme Q10. Cardiovascular properties of coenzyme Q10 have been further addressed, namely regarding myocardial protection during cardiac surgery, end-stage heart failure, pediatric cardiomyopathy and in cardiopulmonary resuscitation. The vascular aspects of coenzyme Q10 addressing the important field of endothelial function are briefly examined. The controversial issue of the statin/coenzyme Q10 relationship has been investigated in preliminary studies in which the two substances were administered simultaneously. Work on different neurological diseases, involving mitochondrial dysfunction and oxidative stress, highlights some of the neuroprotective mechanisms of coenzyme Q10. A 4-year follow-up on 10 Friedreich's Ataxia patients treated with coenzyme Q10 and vitamin E showed a substantial improvement in cardiac and skeletal muscle bioenergetics and heart function. Mitochondrial dysfunction likely plays a role in the pathophysiology of migraine as well as age-related macular degeneration and a therapy including coenzyme Q10 produced significant improvement. Finally, the effect of coenzyme Q10 was evaluated in the treatment of asthenozoospermia. The latest findings highlight the beneficial role of coenzyme Q10 as coadjuvant in the treatment of syndromes, characterized by impaired mitochondrial bioenergetics and increased oxidative stress, which have a high social impact. Besides their clinical significance, these data give further insight into the biochemical mechanisms of coenzyme Q10 activity.
Article
Micronization is a commonly used enabling technology to improve the bioavailability of compounds where absorption is dissolution rate limited. However, decreasing particle size often results in increased Van der Waals' interactions and electrostatic attraction between particles. This causes agglomeration of particles, thereby compromising the increase in surface area gained by micronization. Comicronization with excipients has been reported to offer significant advantages over neat micronization. The present work describes the comicronization of a model compound CI-1040 at a high drug load that shows an increase in the dissolution rate and bioavailability in male Wistar rats. Physicochemical characterization of the comicronized and neat micronized material is presented to help explain the in-vitro and in-vivo data.
Article
The safety profile of Coenzyme Q10 (Kaneka Q10) at high doses for healthy subjects was assessed in a double-blind, randomized, placebo-controlled study. Kaneka Q10 in capsule form was taken for 4 weeks at doses of 300, 600, and 900 mg/day by a total of eighty-eight adult volunteers. No serious adverse events were observed in any group. Adverse events were reported in 16 volunteers with placebo, in 12 volunteers with the 300 mg dose, in 20 volunteers with the 600 mg, dose and in 16 volunteers with the 900 mg dose. The most commonly reported events included common cold symptoms and gastrointestinal effects such as abdominal pain and soft feces. These events exhibited no dose-dependency and were judged to have no relationship to Kaneka Q10. Changes observed in hematology, blood biochemistry, and urinalysis were not dose-related and were judged not to be clinically significant. The plasma CoQ10 concentration after 8-month withdrawal was almost the same as that before administration. These findings showed that Kaneka Q10 was well-tolerated and safe for healthy adults at intake of up to 900 mg/day.