Studies have shown that coenzyme Q10 has a variety of physiological activities and has a wide range of applications in clinical therapy, food and health care products, and cosmetics. However, its low water solubility, chemical instability, easy decomposition in the presence of light and low bioavailability have limited its application. In order to improve its water solubility, stability and bioavailability, researchers have carried out a lot of studies: on the one hand, using structural modification to improve its stability; on the other hand, adopting different preparation methods to make different dosage forms to improve its water solubility and stability.
1. Structural modification for coenzyme Q10
The lipophilic antioxidant coenzyme Q10 has a potential therapeutic effect on intracerebral vascular lesions associated with the presence of free radicals (reactive oxygen species) and liposome peroxidation. Coenzyme Q10 acts as an antioxidant and its antioxidant activity is realized when it is reduced to ubiquitin. In vitro and in vivo studies have shown that coenzyme Q10 has a protective effect on the blood-brain barrier. However, since coenzyme Q10 is a water-insoluble macromolecule, its intestinal absorption and bioavailability in the body are limited.
Therefore, the search for an analog of coenzyme Q10, which has better drug chemistry than coenzyme Q10, the same molecular activity in nature, and water solubility and bioavailability that are quite different from those of coenzyme Q10, has become a goal of researchers. Idebenone, an analog of coenzyme Q10, was developed by Japanese researchers in the 1980s for the treatment of brain diseases. Idebenone has the same oxygen-reducing benzoquinone moiety as coenzyme Q10, but its lipophilic side chain is significantly shorter and the terminal hydroxyl group increases its polarity, thus increasing its solubility. Figure 1-4 Structures of Coenzyme Q10 and Idebenone.
Figure 1- 4 Mode of conversion between Idebenone and Coenzyme Q10 [1].
The interconversion of edibenzoquinone and coenzyme [1]
The advantages of the structural modification are that it improves the effect of coenzyme Q10 and increases its water solubility and stability. The problem is that the safety of this new substance compared to the endogenous substance coenzyme Q10 needs to be investigated in multiple clinical trials, and the metabolic pattern in the body is different compared to that of coenzyme Q10.
2. Formulation studies of Coenzyme Q10
In recent years, the following studies have been conducted to effectively improve the solubility and bioavailability of Coenzyme Ql0 in humans by means of the development of related formulations:
(1) Liposomalization technology
Liposomes are gelatinous, vesicular structures consisting of one or more lipid bilayers surrounded by an equal number of aqueous compartments, and are made of natural substances and are therefore non-toxic and biocompatible. The use of liposome technology can improve the stability of unstable drugs and increase their permeability.2 Li et al.[31] prepared long-circulating liposomes of coenzyme Q10 by freeze-drying and determined the content of coenzyme Q10 in the liposomes, which was 98.2%, with an encapsulation rate of 93.2%, and the quality of the liposomes remained stable during storage.
David et al [3] prepared liposomes of coenzyme Q10 using soy lecithin as a carrier by a single-step supercritical carbon dioxide method, and the results showed that the loading, particle size and polydispersity index reached the maximum values at 30 MPa, 40 ℃, 6 MPamin 1, and 17 mol% of coenzyme Q10 (loading 4.2%, particle size 177 nm, and polydispersity index 0.313), and the encapsulation rate was 87.6-99.7%, forming hemispherical stable particles with a zeta potential of 70 mV. (4.2% loading, 177 nm particle size, 0.313 polydispersity index), with encapsulation rates ranging from 87.6 to 99.7%, and the formation of hemispherical stabilized particles with a zeta potential of 70 mV. Zhang et al [4] used orthogonal experiments to investigate the optimal prescription for the preparation of a liposome suspension of coenzyme Q10 using ethanol as the solvent, and phospholipids and cholesterol as the solvent in aqueous bath, and the results showed an improvement in the solubility and stability of coenzyme Q10.
(2) Supramolecular encapsulation technology
Cyclodextrins and other supramolecules have a conical barrel structure with internal hydrophobicity and external hydrophilicity. Cyclodextrins are used as drug carriers and the formation of cyclodextrin inclusion complexes protects the drug molecules and improves the aqueous solubility and stability of the drugs.5] Prosek et al.[6] prepared the inclusion complexes of coenzyme Q10 and β-cyclodextrin in the ratio of 1:1 molar ratio by stirring at a constant temperature and drying at a reduced pressure. After DSC and infrared scanning, it was proved that the inclusion complexes were different from the simple physical mixtures, and the inclusion complexes of coenzyme Q10 and β-cyclodextrin showed good water solubility. Yang Haiying et al[7] conducted a systematic study on the inclusion of coenzyme Q10 with β-cyclodextrin by polarographic method, and the results showed that coenzyme Q10 and β-cyclodextrin could form an inclusion complex, and the photostability of coenzyme Q10 was further improved.
(3) Micellar solubilization emulsification technology
Hiroyuki, Yamaguchi et al[8] showed that CoQ10 was cleared more rapidly in rats given intravenous injections of CoQ10 in a fat emulsion emulsified with yolk phospholipids (PL) than in CoQ10 solubilized in a hydrogenated castor oil polyoxyethylene derivative. Although CoQ10 in emulsion form is primarily distributed in the liver, the increased concentration of PL in the emulsion increased the distribution of CoQ10 to the heart, which is the target organ for CoQ10.
Sato, Yuki et al[9] investigated various formulations to improve the intestinal absorption of CoQ10, focusing on emulsification, and found that the emulsification technique improved the intestinal absorption of CoQ10 compared to suspension. Ma Japing et al[10] made an injectable fat emulsion by emulsifying CoQ10 with vegetable oil, emulsifier, co-emulsifier and isotonic modifier. Although the bioavailability of injectable fat emulsions is high, their application has been greatly restricted due to their small drug-carrying capacity and inconvenient use. Dong Yingjie, et al. [11] Coenzyme Q10, soybean oil, lecithin, glycerol, oleic acid, and water for injection were stirred by a high-speed homogenizer to form a colostrum, and then prepared by a high-pressure homogenizer to obtain a Coenzyme Q10 submicroemulsion. Coenzyme Q10 was encapsulated in the oil phase of the oil-in-water microspheres, which reduced the irritation reaction of injection, allergy, hemolysis and other side effects, and improved the efficacy of the drug.
(4) Tablet coating and other external modification methods
Josh et al [12] conducted a comparative bioavailability study between two new immediate-release formulations of coenzyme Q10 (effervescent tablets and instant tablets) and the marketed conventional formulations, such as hard gelatin capsules and soft gelatin capsules, in humans. The results showed that there was no significant difference in the absorption rates between the immediate-release and conventional formulations, but the absorption curves were significantly different, and the AUC of the immediate-release formulation was greater. Although the Cmax was not statistically different from that of softgel or powder-filled formulations, the immediate-release formulation of coenzyme Ql0 [13] had a faster absorption rate than the conventional formulation, and the Tmax of the new formulation was significantly shorter.
References:
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[13] JoshiSawantS, Shedge A , eta1. Comparative bioavailability of two novel Coenzyme Q10 preparations in humans[J] . International Journal of clinical pHarmacology and therapeutics, 2003, 41(1): 42-48 .
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