| Since the term “the neither hydrophilic nor lipophilic drugs” can be defined as drugs that have low solubility in both water and many oils,which would result in poor absorption by the body,low bioavailability and efficacy whether administered orally or topically.Meanwhile,the clinical use of such compounds has also been restrained by the lack of a suitable delivery system or carrier,which may present a major challenge in their formulation development.In this thesis,a novel formulation design was developed based on non-aqueous emulsions,Pickering emulsions,double emulsions,and conventional self-double-emulsifying drug delivery system(SDEDDS),etc.Generally,conventional SDEDDS was the formulated mixture of water-in-oil(W/O)emulsions and hydrophilic surfactant,meanwhile the hydrophilic drugs were mainly dissolved in inner aqueous phase.Herein,after the inner water phase of conventional SDEDDS was replaced by polar solvents(such as glycerol,propylene glycol,etc.),a completely non-aqueous system(N-SDEDDS)was obtained with different stable forms.The new system was the formulated mixture of oil-in-oil(O/O)emulsions and hydrophilic surfactant,and the water-insoluble and simultaneously oil-insoluble drugs were mainly dissolved in the inner oil phase(like glycerol,propylene glycol,etc.).In addition,rutin and quercetin were selected as two model drugs and loaded in N-SDEDDS,respectively.On one hand,the rutin-loaded N-SDEDDS was kinetically stabilized by addition of solid particles and nonionic surfactants when glycerol was used as the inner oil phase.On the other hand,the quercetin loading of formulation could be further improved when short-chain ether/alcohol mixture(or short-chain alcohol mixture)was employed was used as the inner oil phase.Meanwhile,the effect of encapsulation on enhancement of drug loading content and bioavailability should also be studied both in vitro and in vivo for oral and skin applications,respectively.Concrete research contents were as follows.(1)Firstly,the preparation and evaluation of rutin-loaded N-SDEDDS stabillzed by fat crystals(Glycerol monostearate,GMS)and nonionic surfactants were investigated.The new formulation was prepared through a two-step emulsification process,and glycerol was used as the inner oil phase.It appeared that the addition of 12%(w/w)of GMS crystals,12%(w/w)of PGPR,and 10%(w/w)of Tween 60 could effectively improve the stability of rutin-loaded N-SDEDDS,and at the same time enhance the self-emulsification efficiency of the system.The N-SDEDDS could spontaneously form oil-in-oil-in-water(O/O/W)double emulsions in gastrointestinal environment,with drugs mainly encapsulated in the inner oil phase.In addition,the mean droplet size of resultant O/O/W double emulsions and loading content were measured to be 17.94 ± 2.24 ?m and(0.62 ± 0.01)%,respectively.Besides,it was stable at both conditions(4°C and 25°C)investigated for 4 weeks and could enhance the drug dissolution properties,and the dissolution was found to follow Higuchi model with Fickian diffusion mechanism for rutin-loaded N-SDEDDS.More than 80% of rutin remained in the solubilized form after 2 h of digestion when formulations containing 12%(w/w)of GMS crystals.In situ intestinal perfusion study in rats showed improved absorption rate and extent of rutin from the N-SDEDDS as compared to pure drug,the main absorption sites were jejunum and ileum,and the intestine absorption of rutin could be described as a passive diffusion mechanism.Meanwhile,the P-glycoprotein(P-gp)and multidrug resistance-associated protein 2(MRP2)inhibitors had no obvious synergistic effects with rutin-loaded N-SDEDDS.The in vivo study demonstrated that the oral absolute bioavailability of rutin obtained from N-SDEDDS(8.62%)was 1.76-fold higher than that of drug suspension(4.90%),and the absorption-enhancing effect of N-SDEDDS did not cause mucosal damage.(2)Secondly,the preparation and evaluation of rutin-loaded N-SDEDDS containing both hydrophobic silica particles and nonionic surfactants were also performed.The new formulation was prepared through a two-step process,and glycerol was utilized as the inner oil phase.It appeared that the addition of 1%(w/w)of hydrophobic silica particles,1%(w/w)of PGPR,and 6%(w/w)of Tween 20 could effectively increase the tridimensional network structure strength and stability of rutin-loaded N-SDEDDS,and at the same time enhance the self-emulsification efficiency of the system.Besides,the hydrophobic silica particles could be adsorbed at the oil-oil interface and distributed in outer oil phase,and the PGPR concentration could be decreased with addition of solid particles.After dilution with aqueous medium,the optimized formulation could self-emulsify to O/O/W double emulsions,with inner oil phase mainly containing the drug.Meanwhile,the mean droplet size of resultant O/O/W double emulsions and loading content were obtained as 13.43 ± 3.21 ?m and(0.76 ± 0.04)%,respectively.Subsequently,a good stability was achieved over a period of 3 months at 4°C and 25°C.The results of in vitro antioxidant studies showed the antioxidant capacity of rutin increased in a concentration-dependent manner,and the drug molecules can be encapsulated in the N-SDEDDS without loss of biological activity.The selected formulation exhibited a sustained release profile up to 12 h,and the Weibull model described the release dependant on Fickian diffusion mechanism.Compared to rutin solution,the N-SDEDDS presented higher ability to enhance skin permeation of rutin,and significantly increased drug distribution in the skin as well.(3)Thirdly,the preparation and evaluation of rutin-loaded N-SDEDDS were performed in the presence of both hydrophobic bentonite and nonionic surfactants.The new formulation was prepared through a two-step emulsification process,and glycerol was employed as the inner oil phase.It appeared that the addition of 0.6%(w/w)of hydrophobic bentonite,3%(w/w)of PGPR,and 10%(w/w)of Tween 60 could effectively increase the stability of rutin-loaded N-SDEDDS,and at the same time enhance the self-emulsification efficiency of the system.Besides,the hydrophobic bentonite could be adsorbed at the oil-oil interface and distributed in outer oil phase,and the PGPR concentration could be decreased with addition of solid particles.After dilution with aqueous medium,the optimized formulation could spontaneously produce O/O/W double emulsions,with inner oil phase mainly containing the drug.Meanwhile,the mean droplet size of resulting O/O/W double emulsions and loading content were obtained as 4.63 ± 0.46 ?m and(1.33 ± 0.02)%,respectively.The selected formulation was found to be stable up to 3 months under 4°C and 25°C.Furthermore,the release of rutin from N-SDEDDS suggested a prolonged release profile.The release data showed a good fit with the Weibull model,and indicated Fickian diffusion.Compared with rutin aqueous solution,the N-SDEDDS could significantly enhance rutin retention in the skin and permeation through the skin.The skin interaction studies revealed that the N-SDEDDS could enhance drug flux through skin by perturbing both stratum corneum lipids and keratin.Skin histological study demonstrated that the N-SDEDDS could exert a direct action on the stratum corneum and without causing significant skin damage.Meanwhile,the cytotoxicity test also showed low cell toxicity of the N-SDEDDS.(4)To further expand the scope of application of the water-insoluble and simultaneously oil-insoluble drugs,meanwhile the solubility of quercetin in glycerol(5.63 ± 0.12 mg/g)was still low,thus the preparation and evaluation of quercetin-loaded N-SDEDDS were performed when short-chain ether/alcohol mixture was applied as the inner oil phase.The new formulation was prepared through a two-step emulsification process,and a mixture of dipropylene glycol and glycerol(4:6,w/w)was used as the inner oil phase.The new N-SDEDDS loaded with quercetin was successfully optimized and could self-emulsify to O/O/W double emulsions in aqueous media,with inner oil phase mainly containing the drug.Meanwhile,the mean droplet size of resultant O/O/W double emulsions and loading content were obtained as 21.16 ± 3.55 ?m and(1.05 ± 0.11)%,respectively.The stability study revealed that the selected formulation remained stable over a period of 30 days both at 4°C and 25°C.Furthermore,the production of free radicals were inhibited by quercetin concentration-dependently,and the drug molecules can be incorporated in the N-SDEDDS without loss of biological activity.The N-SDEDDS formulation gave a prolonged release of quercetin for 12 h,and the release data was found to follow Weibull model with Fickian diffusion mechanism.Compared with quercetin solution,the N-SDEDDS could effectively promote the retention of quercetin in the deeper skin.The cytotoxicity test showed low cell toxicity of the N-SDEDDS.(5)Lastly,the preparation and evaluation of quercetin-loaded N-SDEDDS were performed when short-chain alcohol mixture was adopted as the inner oil phase.The new formulation was prepared through a two-step emulsification process,and a mixture of propylene glycol and glycerol(4:3,w/w)was employed as the inner oil phase.The N-SDEDDS formulation was successfully optimized and could spontaneously emulsify to O/O/W double emulsions in gastrointestinal environment,with drugs mainly encapsulated in the inner oil phase.In addition,the mean droplet size of resulting O/O/W double emulsions and loading content were measured to be 18.82 ± 3.25 ?m and(0.78 ± 0.10)%,respectively.The stability study revealed that the selected formulation was stable up to 21 days under 4°C and 25°C.The in vitro dissolution indicated a significant improvement in quercetin dissolution from N-SDEDDS formulation compared to pure drug powder.The dissolution profiles of drug from N-SDEDDS in simulated gastric fluids(SGF)and simulated gastric fluids(SIF)were fitted in Weibull and Higuchi models,respectively,and both of the processes were likely to be a combination of diffusion and erosion mechanism.The absolute bioavailability(26.67%)of quercetin increased about 5.22-fold after oral administration of the N-SDEDDS,compared with that of drug suspension(5.11%).Through the above studies,the solubilizing capacity and loading content of N-SDEDDS formulation for rutin and quercetin would be increased,which provided a new scientific basis for the loading of water-insoluble and simultaneously oil-insoluble drugs.Effects of formula compositions of N-SDEDDS on formulation stability and self-emulsification efficiency were also investigated,which possessed important guiding significance for the development of new carrier systems.In addition,the effects of different encapsulation forms on drug dissolution/release mechanism,small intestine/skin absorption mechanism,oral/skin bioavailability,and biocompatibility were comprehensively studied from oral and skin applications,which would have certain theoretical and practical significance in pharmaceutical,food,and cosmetics applications. |
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