ABSTRACT
The amorphous solid dispersion is one of the most effective formulation approaches to enhance the oral bioavailability of poorly water-soluble drugs. However, the amorphous drugs tend to crystallize during storage or dissolution due to inadequate formulations, preparation techniques, storage and dissolution conditions, thus negating their advantages. Meanwhile, it is often difficult to establish in vitro-in vivo correlation for amorphous solid dispersions owing to the difference between dissolution media and physiological environments and between the apparent concentration and membrane transport flux, the dynamic process of the in vivo absorption, which put great challenges to the development of amorphous solid dispersion products. This review covers the recent progress on the mechanistic study of the in vitro dissolution and in vivo absorption of amorphous solid dispersions, aiming to provide guidance for the formulation development of poorly soluble drugs.
ABSTRACT
Cyclodextrin can increase the solubility of poorly soluble drugs, but also decrease the permeability of poorly soluble drugs in inclusion complexes simultaneously, which partially or completely counteracts the contribution of improvement in solubility to the oral absorption of poorly soluble drugs. If a competing agent is added to the system to compete binding sites of cyclodextrins with drugs, drug permeability can be improved by increasing the concentration of free drugs in the inclusion complex system. In this paper, a rapid in vitro screening method for competing agents of cyclodextrin inclusion complex is proposed based on the principle that good drug permeability is in accord with good cell uptake. The equilibrium constants between drugs and hydroxypropyl-beta-cyclodextrin (HPCD) were determined by phase equilibrium solubility method. Cinnarizine (CN) with a high equilibrium constant was selected as a competing agent, coumarin 6 (C6) and 9-octadecyl berberine (BD) with smaller equilibrium constants were selected as model drugs. Both changes of solubility and uptake by Caco-2 and A549 cells of C6 and BD were investigated different concentrations of CN to the HPCD solution of C6 and BD. The results showed that the uptake of C6 and BD increased in a CN concentration-dependent manner, and the solubility of C6 and BD in HPCD solution decreased with the prolongation of equilibrium time. It might be due to increased free drug concentrations that resulted from the competition of CN for drug binding sites with HPCD. In our study, in vitro cell uptake method was firstly used to validate the ability of CN as a competing agent to increase drug permeability (cell uptake). This method can be used for preliminarily screening of competing agents for drug-cyclodextrin inclusion complexes.
ABSTRACT
Transscleral drug delivery has emerged as an attractive method for treating posterior segment eye disorders due to its less invasive,large scleral surface,and good capability for targeted drug delivery.However,in the clinical retina of posterior segment diseases,transscleral drug delivery is less efficient than intravitreal injection.This is due to the fact that drug is subjected to the multiple barriers before crossing into retina or vitreous,such as the sclera,choroid,retinal pigment epithelium,and even the counter-directional intraocular pressure and the associated fluid movement as well as choroidal circulation.At the same time,the properties of the drug itself,such as water solubility,dissolution rate,molecular weight and radius,and hydrophobicity also significantly affect the drug crossing into retina.Out of these factors,water solubility is the key factor for optimal transscleral drug delivery to achieve greater retina bioavailability.When a drug has high water solubility and applied to sclera surface,high local drug concentration will be absorbed into systemic circulation and cause side effects;when a drug has very limited water solubility,local drug concentration on the sclera cannot reach a high enough concentration gradient across the sclera and choroid,therefore the limited available drug will be cleared by the blood and lymphatic circulation of the conjunctiva and episcleral tissues.Therefore,water solubility has become a good venue for scientists to develop various formulations to improve the solubility and the delivery efficiency for transscleral drug delivery.The drugs which can be utilized to treat chorioretinal diseases are often of hydrophobicity or low water solubility.These drugs can be formulated into various suspensions with the help of altered crystallinity,addition of excipient,or solubility promoting agents,as well as various particulates,such as liposomes or nanoparticles to optimize the drug solubility or dissolution rate.Therefore,increasing the solubility of poorly soluble drugs is a commonly used means of developing transscleral drug delivery formulations to promote drug penetration into the sclera.In this review,we synthesized the updated information regarding effect of drug solubility on transscleral drug delivery in hope that the article will benefit both basic and clinical researches for further exploration of transscleral drug delivery.
ABSTRACT
Objective:To prepare fenofibrate PEG2000-DSPE micelles in order to improve the solubility of fenofibrate, and study the oral pharmacokinetics of the micelles in SD rats. Methods:Fenofibrate PEG2000-DSPE micelles were prepared and characterized. The rats were administrated with fenofibrate PEG2000-DSPE micelles and fenofibrate suspension, respectively. The blood samples were collected from eye socket and determined by HPLC. The compartmental pharmacokinetics was analyzed by DAS software. Results:Fenofibrate PEG2000-DSPE micelles were prepared successfully. The mean particle size was (23. 40 ± 3. 62) nm, the drug loading and the entrapment efficiency was (97. 65 ± 3. 32) % and (1. 33 ± 0. 32) %, respectively. The mean plasma concentration-time curves of fenofibric acid were both in accordance with two-compartment mode after oral administration of fenofibrate PEG2000-DSPE micelles and fenofibrate suspension in rats. After the oral administration, AUC(0-24) and Cmax of fenofibrate PEG2000-DSPE micelles was respectively 7-fold and 14-fold higher than that of fenofibrate suspension [(61. 41 ± 5. 71)μg·h·ml-1 vs (8. 49 ± 0. 66)μg·h·ml-1, and (9.67±1.65) μg·ml-1 vs (0.71 ±0.09) μg·ml-1]. The relative bioavailability of fenofibrate PEG2000-DSPE micelles was 723. 3%. Conclusion:The bioavailability and absorption rate of fenofibrate are both increased by the micelles remarkably when com-pared with those of fenofibrate suspension after oral administration. The PEG2000-DSPE micelles served as drug carrier for oral delivery present promising application perspectives.
ABSTRACT
OBJECTIVE: To prepare valsartan nano-suspensions and solidify the suspensions.
ABSTRACT
The solid dispersion has become an established solubilization technology for poorly water soluble drugs. Since a solid dispersion is basically a drug-polymer two-component system, the drug-polymer interaction is the determining factor in its design and performance. In this review, we summarize our current understanding of solid dispersions both in the solid state and in dissolution, emphasizing the fundamental aspects of this important technology.
ABSTRACT
OBJECTIVE: Learning about the progress of the nanoemulsion drug carrier in the application of the insoluble medicament. METHODS: According to the recent literature and our groups work in this area, the nanoemulsion in improving the bioavailability of poorly soluble drugs has been discussed in many aspects, including its formulation mechanism, preparation methods, Pharmacokinetic, pharmacodynamics and modern application of the traditional Chinese medicine preparation in the recent research. RESULTS: Nanoemulsion carrier insoluble drugs could significantly improve oral absorption rate and bioavailability, enhance targeting effect and reduce the drugs toxicity. CONCLUSION: The select of the optimal scale of production based on the medicinal properties process allowed the nanoemulsion insoluble drugs to achieve a good therapeutic effect after oral administration.