ABSTRACT
Protein polypeptides and polysaccharides, the indispensable macromolecular active components in traditional Chinese medicine, are widely found in Chinese medicine decoction after the decoction of traditional Chinese medicine. However, through oral administration, these macromolecules are digested by the stomach and intestine and thus fail to be absorbed in prototype. This is inconsistent with the actual clinical efficacy of Chinese medicine decoction. According to modern research, new phase structures and effects of the macromolecules emerge during the decoction of traditional Chinese medicine, but the phase change law caused by the interaction among the components of traditional Chinese medicine and the relationship between phase structure and effect are still unclear. Thus, this study reviewed the oral absorption of macromolecular components of traditional Chinese medicine, analyzed the internal relationship of the form of macromolecules in traditional Chinese medicine with the absorption and effect based on phase structure, and summarized the research mode of oral absorption and effect of macromolecules in traditional Chinese medicine with phase structures as the core, providing new ideas and methods for future research.
Subject(s)
Medicine, Chinese Traditional , Drugs, Chinese Herbal/chemistry , Stomach , Administration, OralABSTRACT
@#Polyethylene glycol (PEG) of different lengths were prepared to investigate their effects on oral absorption of nanostructured lipid carrier (NLCs).Three kinds of PEG-modified NLCs with different chain lengths, including polyethylene glycol (100) monostearate (S100), polyethylene glycol (55) monostearate (S55), polyethylene glycol (40) monostearate (S40), were prepared by film dispersion method.Coumarin 6 was chosen as a fluorescent probe to characterize the physicochemical properties of NLCs with different lengths.Meanwhile, the stability of NLCs in simulate buffer, the release behavior, cytotoxicity of NLCs, the uptake kinetics and cellular uptake mechanisms were evaluated. This work demonstrated that the thickness of the hydrated layer increased with the increase of PEG length. Of note, S100-modified NLCs (pNLC-EG100) exhibited higher cellular uptake efficiency compared with other formulations. Thus, S100 was optimized as the best molecular weight for PEG-modified NLCs on oral drug delivery system.
ABSTRACT
Nanocrystals self-stabilized Pickering emulsion(NSSPE) is a new kind of emulsion where only nanocrystals of poorly soluble drugs are used as stabilizers. Our previous study showed that NSSPE with Ligusticum chuanxiong oil as the main oil phase can significantly promote oral absorption of puerarin. The present study aimed to explore its absorption mechanism in oral administration. The in vitro dissolution test was carried out to study the effect of NSSPE on release of puerarin. The effects and mechanism of NSSPE on uptake and transport of puerarin across Caco-2 cell were investigated. The results showed that the drug release rate of NSSPE was similar to that of nanocrystals, with their cumulative dissolution of puerarin not affected by pH of releasing mediums, both significantly higher than that of crude material. The uptake of puerarin in NSSPE was concentration-dependent and significantly higher than that of solution or surfactant stabilized emulsion. Genistein and indomethacin, inhibitors of lipid rafts/caveolin, could significantly reduce the uptake of puerarin in NSSPE. Compared with solution, NSSPE and surfactants stabilized emulsion obviously increased transport rate K_a and apparent permeability coefficient P_(app) of puerarin in AP → BL direction, but there was no significant difference in BL → AP direction. It could be inferred that there were both passive and active transport mechanisms, as well as lipid raft/caveolin mediated endocytosis for absorption of NSSPE. The promoted oral absorption of puerarin in NSSPE was mainly related to the existing nanocrystal form which could promote dissolution, puerarin as well as Ligusticum chuanxiong oil which could promote drug transmembrane transport and inhibit drug efflux. It is the unique structure and composition of the compound NSSPE that promoted the oral absorption of puerarin.
Subject(s)
Humans , Caco-2 Cells , Drugs, Chinese Herbal , Emulsions , Isoflavones , NanoparticlesABSTRACT
BCS Ⅱ drugs are characterized by low solubility and high permeability. Improving their solubility is considered an important approach to improve its oral absorption. Recent strategies to increase the solubility of poorly-soluble drugs may unexpectedly result in greatly depressed permeability, ultimately leading to failure in improving oral absorption. Based on the mathematics of membrane permeability coefficient of a drug, the membrane/aqueous partition coefficient is dependent on the drug's solubility in the gastrointestinal milieu, suggesting a unique interplay between the solubility and permeability of the drug, and treating the one irrespectively of the other may be insufficient. When we focus on the increase of drug solubility and overlook the efficacy of drug permeability, the positive effect of increased solubility to drug oral absorption might be traded off by depressed permeability. To provide rational formulary designs, by optimizing excipients and evaluation, this review summarizes solubility- permeability interplay for different types of solubilizing techniques, such as cyclodextrin, surfactants-based vehicle, cosolvent, amorphous solid dispersions, other infectors such as P-gp transporters and new techniques for simultaneous evaluation of drug solubility and permeability.
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Chinese materia medica is mostly taken orally. The permeability of a drug’s biofilm (e.g. cell membrane) reflects its ability of absorption and transportation in the body. It is of guiding significance to evaluate the membrane permeability of the active components of Chinese materia medica by using appropriate drug permeation model, so as to clarify, the oral absorption and transport mechanism of active ingredients, pharmacodynamic substance basis and dosage form design. The evaluation method of oral drug membrane permeability, as well as the application of various methods in Chinese medicine was summarized for reference in this review.
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Hesperetin, an abundant bioactive component of citrus fruits, is poorly water-soluble, resulting in low oral bioavailability. We developed new formulations to improve the water solubility, antioxidant activity, and oral absorption of hesperetin. Two nano-based formulations were developed, namely hesperetin-TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) micelles and hesperetin-phosphatidylcholine (PC) complexes. These two formulations were prepared by a simple technique called solvent dispersion, using US Food and Drug Administration (FDA)-approved excipients for drugs. Differential scanning calorimetry (DSC) and dynamic light scattering (DLS) were used to characterize the formulations’ physical properties. Cytotoxicity analysis, cellular antioxidant activity assay, and a pharmacokinetic study were performed to evaluate the biological properties of these two formulations. The final weight ratios of both hesperetin to TPGS and hesperetin to PC were 1:12 based on their water solubility, which increased to 21.5- and 20.7-fold, respectively. The hesperetin-TPGS micelles had a small particle size of 26.19 nm, whereas the hesperetin-PC complexes exhibited a larger particle size of 219.15 nm. In addition, the cellular antioxidant activity assay indicated that both hesperetin-TPGS micelles and hesperetin-PC complexes increased the antioxidant activity of hesperetin to 4.2- and 3.9-fold, respectively. Importantly, the in vivo oral absorption study on rats indicated that the micelles and complexes significantly increased the peak plasma concentration (Cmax) from 2.64 μg/mL to 20.67 and 33.09 μg/mL and also increased the area under the concentration–time curve of hesperetin after oral administration to 16.2- and 18.0-fold, respectively. The micelles and complexes increased the solubility and remarkably improved the in vitro antioxidant activity and in vivo oral absorption of hesperetin, indicating these formulations’ potential applications in drugs and healthcare products.
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Supersaturated drug delivery systems (SDDS) are defined as systems that are able to generate and maintain a sustained drug supersaturation in the gastrointestinal tract, facilitating the oral absorption of drugs with poor water solubility. Supersaturated drug solution is generated from a higher energy form of the drug or rapid dissolution through various formulation options. However, supersaturated solution is a thermodynamically unstable system that can easily lead to drug precipitation, missing the aim of improving the absorption. Therefore, maintenance of the supersaturated state is essential for the development of SDDS. Polymer-based SDDS take polymers as the precipitation inhibitor,which can effectively prevent the precipitation of drugs, generating an excellent effect on maintenance of the stability of supersaturated solution. However, different polymers have distinct anti-precipitation ability, and the mechanisms of such activity supported by the polymer remain unrevealed. In this review, we summarize the research advances in the absorption-enhancing mechanisms and in vitro evaluations of polymers-based SDDS. This review provides a reference for the design of rational SDDS.
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The therapeutic potential of curcumin (Cur) is hampered by its poor aqueous solubility and low bioavailability.The aim of this study was to determine whether Cur nanoemulsions enhance the efficacy of Cur against prostate cancer cells and increase the oral absorption of Cur.Cur nanoemulsions were developed using the self-microemulsifying method and characterized by their morphology,droplet size and zeta potential.The results showed that the cytotoxicity and cell uptake were considerably increased with Cur nanoemulsions compared to free Cur.Cur nanoemulsions exhibited a significantly prolonged biological activity and demonstrated better therapeutic efficacy than free Cur,as assessed by apoptosis and cell cycle studies.In siru single-pass perfusion studies demonstrated higher effective permeability coefficient and absorption rate constant for Cur nanoemulsions than for free Cur.Our study suggested that Cur nanoemulsions can be used as an effective drug delivery system to enhance the anticancer effect and oral bioavailability of Cur.
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A solvent diffusion method was used to prepare pegylated asiatic acid (AA) loaded nanostructured lipid carriers (p-AA-NLC), and the ligated intestinal circulation model was established to observe the absorption and distribution in small intestine. The concentration of AA in bile after oral administration of p-AA-NLC was detected by HPLC in healthy SD rats to indirectly evaluate the oral absorption promoting effect of PEG-modified namoparticles. The results showed that the penetration of p-AA-NLC was enhanced significantly and the transport capacity was increased greatly in small intestinal after PEG modification. As compared with the normal nanoparticles (AA-NLC), the Cmax of the drug excretion was increased by 76%, the time to reach the peak (tmax ) was decreased and the elimination half-life t1/2 was doubled in the rats after oral administration of p-AA-NLC, and the AUC0→t was 1.5 times of the AA-NLC group, indicating that the oral bioavailability of AA-NLC was significantly improved by hydrophilic modification of PEG.
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Polyelectrolyte layer-by-layer assembled lipid nanoparticles (NPs) were prepared to improve their stability against lipolysis in gastrointestinal tract, and efficiency of oral absorption of doxorubicin (DOX). The lipid NPs were prepared by hot melt-probe sonication method. The polyelectrolyte layer-by-layer assembled lipid NPs (DOX-NPs/CS/γ-PGA) was prepared by layer-by-layer self-assembling polyelectrolytes cationic chitosan (CS) and anionic poly (γ-glutamic acid) (γ-PGA) on the surface of lipid NPs based on electrostatic interaction. The particle size, polydispersity index (PDI) and zeta potential of lipid NPs and DOX-NPs/CS/γ-PGA were determined by dynamic light scattering (DLS). The in vitro drug release was determined in pH 1.2 HCl solution and pH 6.8 phosphate buffer solution (PBS). The stability of lipid NPs against lipolysis was evaluated in simulated gastrointestinal medium containing lipase. The cellular uptake of lipid NPs and DOX-NPs/CS/γ-PGA was evaluated in Caco-2 cell model. The pharmacokinetic of DOX after oral absorption was studied in SD rats. Results showed that the average particle size and zeta potential of DOX-NPs/CS/γ-PGA were 180.6±5.4 nm and -38.53±0.29 mV, respectively. The DOX-NPs/CS/γ-PGA effectively slowed down the release of DOX from nanoparticles, and decreased the lipolysis of lipid NPs in simulated gastrointestinal medium. The cell study showed that DOX-loaded lipid NPs and DOX-NPs/CS/γ-PGA remarkably enhanced the cell uptake in comparison with DOX solution. The DOX-NPs/CS/γ-PGA significantly improved oral absorption of DOX compared with DOX-loaded lipid NPs. The Cmax, tmax were 0.76±0.25 μg·mL-1 and 0.5 h, respectively; AUC0-24h was 3.02 folds and the relative bioavailability was 302.46% with DOX solution as reference. The stability of lipid NPs against lipolysis and drug release were significantly improved by layer-by-layer assembling, leading to an improved oral absorption.
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In this study, the effect of D-cellobiose on oral bioavailability of gentiopicroside (GPS) was investigate. The influence of D-cellobiose on GPS was achieved by calculating the residual GPS after being degraded with β-glucosidase or intestinal flora, and the data demonstrated D-cellobiose could inhibit the degradation of GPS in intestines; in bioavailability experiment, D-cellobiose could significantly improve the oral bioavailability (P<0.05) of GPS at the mass ratio of 1∶5, 1∶10 (GPS-D-cellobiose). D-cellobiose applied in this study may improve the oral bioavailability of GPS through delaying the degradation in intestines.
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Tumor immunotherapy is one of the most significant scientific progresses. The idea of applying the traditional Chinese theory of "the balance of Yin and Yang" to treat cancer is in accordance with that of modern tumor immune strategy. Researches indicated that polysaccharide of Chinese medicine through regulation in immune responses could offer better paradigm for tumor immune treatment under the traditional Chinese theory. However, current studies related to tumor immunotherapy largely focus on the immunity enhancement while lack of the exploration of suppressive factors. Meanwhile, the complex analysis and detection on composition as well as structure definitely increase the difficulty in mechanism of oral absorption and function in vivo. To better exploit novel Chinese medicine of polysaccharide for tumor immune treatment, this article will provide some constructive thoughts on regulation of tumor immune responses based on up to date researches of structure-function relationship, absorbent process and molecular mechanisms responsible for tumor immune as well.
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Hydrosafflor yellow A (HSYA), the main active ingredient of the safflower plant (Carthamus tinctorius L.), has the effect of activating circulation to remove blood stasis, and is usually used to treat cardiovascular and cerebrovascular diseases clinically. However, it is difficult to develop its oral dosage forms due to its low bioavailability. In recent years, studies on the biopharmaceutics of HSYA have made significant progress. This paper reviews physic-chemical properties, pharmacokinetics, strategies for promoting bioavailability and progress in pharmaceutics of HSYA, aiming to provide reference for related studies.
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OBJECTIVE: To study the oral absorption of paclitaxel-loaded mixed micelles made of D-α-tocopherol polyethylene glycol 1000 succinate(TPGS) and sodium cholate(NaC) in rats. METHODS: Paclitaxel-loaded mixed micelles were prepared by film dispersion method. The Zeta potential and diameter distribution of TPGS/NaC mixed micelles were measured using laser size scattering determinator. The morphology of micelles was observed by transmission electron microscope. Dialysis method was used to evaluate the release behavior of drug-loaded micelles in vitro. The absorption kinetics was obtained by in situ perfusion method in rats. RESULTS: Most of the mixed micelles were spherical with an average diameter of 24.2 nm and the Zeta potential was -7.84 mV. Compared to the bulk drug, the apparent absorption rate constant (Ka)of paclitaxel-loaded mixed micelles was increased significantly. CONCLUSION: TPGS/NaC mixed micelles can improve the oral absorption of paclitaxel and increase its oral bioavailability.
ABSTRACT
Biopartitioning micellar chromatography (BMC) is a potentially high throughput and low cost alternative for in vitro prediction of drug absorption, which can mimic the drug partitioning process in biological systems. In this paper, a data set of 56 compounds representing acidic, basic, neutral and amphoteric drugs from various structure classes with human oral absorption (HOA) data available were employed to show the effect of acidity of drugs in oral absorption prediction. HOA was reciprocally correlated to the negative value of the capacity factor (kBMC) determined by BMC at pH 7.4 and 6.5. The relationships between kBMC and the corresponding HOA values of all compounds were rather poor, but the correlations were improved when the acidity of drugs was taken into consideration. Moreover, the proposed models allowed obtaining of good predictive values for both highly and poorly absorbed compounds. It is demonstrated that the constructed models derived from compounds with the same kind of charge property are of more practically meaningful and rigorous.
ABSTRACT
Biopartitioning micellar chromatography (BMC) is a potentially high throughput and low cost alternative for in vitro prediction of drug absorption, which can mimic the drug partitioning process in biological systems. In this paper, a data set of 56 compounds representing acidic, basic, neutral and amphoteric drugs from various structure classes with human oral absorption (HOA) data available were employed to show the effect of acidity of drugs in oral absorption prediction. HOA was reciprocally correlated to the negative value of the capacity factor (kBMC) determined by BMC at pH 7.4 and 6.5. The relationships between kBMC and the corresponding HOA values of all compounds were rather poor, but the correlations were improved when the acidity of drugs was taken into consideration. Moreover, the proposed models allowed obtaining of good predictive values for both highly and poorly absorbed compounds. It is demonstrated that the constructed models derived from compounds with the same kind of charge property are of more practically meaningful and rigorous.