Enhanced oral bioavailability of insulin using PLGA nanoparticles co-modified with cell-penetrating peptides and Engrailed secretion peptide (Sec)

Abstract

Biodegradable polymer nanoparticle drug carriers are an attractive strategy for oral delivery of peptide and protein drugs. However, their ability to cross the intestinal epithelium membrane is largely limited. Therefore, in the present study, cell-penetrating peptides (R8, Tat, penetratin) and a secretion peptide (Sec) with N-terminal stearylation were introduced to modify nanoparticles (NPs) on the surface to improve oral bioavailability of peptide and protein drugs. In vitro studies conducted in Caco-2 cells showed the value of the apparent permeability coefficient (P_app) of the nanoparticles co-modified with Sec and penetratin (Sec-Pen-NPs) was about two-times greater than that of the nanoparticles modified with only penetratin (Pen-NPs), while the increase of transcellular transport of nanoparticles modified together with Sec and R8 (Sec-R8-NPs), or Sec and Tat (Sec-Tat-NPs), was not significant compared with nanoparticles modified with only R8 (R8-NPs) or Tat (Tat-NPs). Using insulin as the model drug, in vivo studies performed on rats indicated that compared to Pen-NPs, the relative bioavailability of insulin for Sec-Pen-NPs was 1.71-times increased after ileal segments administration, and stronger hypoglycemic effects was also observed. Therefore, the nanoparticles co-modified with penetratin and Sec could act as attractive carriers for oral delivery of insulin.     

Tyrphostin-8 Enhances Transferrin Receptor-Mediated Transcytosis in Caco-2 Cells and Increases Hypoglycemic Effect of Orally Administered Insulin-Transferrin Conjugate in Diabetic Rats

Purpose. To investigate the effect of tyrphostin 8 (T-8), a GTPase inhibitor, on transferrin receptor (TfR)-mediated transcytosis of insulin-transferrin (In-Tf) conjugate in cultured enterocyte-like Caco-2 cells and on gastrointestinal (GI) absorption of In-Tf in streptozotocin (STZ)-induced diabetic rats. Methods. Caco-2 cells and diabetic rats were used as in vitro and in vivo models, respectively. TfR-mediated transcytosis was measured using ¹²⁵I-In-Tf. The absorption of insulin in diabetic rats was demonstrated by the hypoglycemic effect. Rat blood glucose level was determined using a ONE TOUCH® blood glucose monitoring system. Results. T-8 increased apical-to-basolateral transport of In-Tf conjugate by enhancing TfR-mediated transcytosis in filter-grown Caco-2 cell monolayer, and this enhancement was higher and faster than the previously reported brefeldin A (BFA)-induced effect. The measurement of transepithelial electrical resistance (TEER) during the transport study showed that T-8 was less destructive on the cell tight junction than BFA. The GI absorption of In-Tf was evaluated by its hypoglycemic effect after oral administration in STZ-induced diabetic rats. The glucose-lowering effect of orally administered In-Tf in STZ-induced diabetic rats was improved by either T-8 or BFA. However, the effect of T-8 was more potent than that of BFA, especially at 7 h after administration. Either non-conjugated insulin or insulin-human serum albumin (In-HSA) conjugate by itself or in combination with T-8 did not show any hypoglycemic effect after oral administration, indicating that T-8-enhanced hypoglycemic activity of In-Tf was due to a selective enhancement of TfR-mediated transcytosis. Conclusions. Our data indicated that T-8 could be used to increase the GI absorption of insulin as a transferrin conjugate. T-8, as an enhancer of TfR-mediated transcytosis, is better than the previously reported BFA. T-8 produces a higher increase on the transport of In-Tf and a lower toxicity on epithelial cells. Our findings provide an alternative approach to promote the GI absorption of insulin, as well as other peptide or protein drugs.     

Influence of magnesium stearate on the physicochemical and pharmacodynamic characteristics of insulin-loaded Eudragit entrapped mucoadhesive microspheres

Abstract

Effective oral insulin delivery has remained a challenge to the pharmaceutical industry. This study was designed to evaluate the effect of magnesium stearate on the properties of insulin-loaded Eudragit® RL 100 entrapped mucoadhesive microspheres. Microspheres containing Eudragit® RL 100, insulin, and varying concentrations of magnesium stearate (agglomeration-preventing agent) were prepared by emulsification-coacervation method and characterized with respect to differential scanning calorimetry (DSC), morphology, particle size, loading efficiency, mucoadhesive and micromeritics properties. The in vitro release of insulin from the microspheres was performed in simulated intestinal fluid (SIF, pH 7.2) while the in vivo hypoglycemic effect was investigated by monitoring the plasma glucose level of the alloxan-induced diabetic rats after oral administration. Stable, spherical, brownish, mucoadhesive, discrete and free flowing insulin-loaded microspheres were formed. While the average particle size and mucoadhesiveness of the microspheres increased with an increase in the proportion of magnesium stearate, loading efficiency generally decreased. After 12?h, microspheres prepared with Eudragit® RL 100: magnesium stearate ratios of 15:1, 15:2, 15:3 and 15:4 released 68.20?±?1.57, 79.40?±?1.52, 76.60?±?1.93 and 70.00?±?1.00 (%) of insulin, respectively. Reduction in the blood glucose level for the subcutaneously (sc) administered insulin was significantly (p?≤?0.05) higher than for most of the formulations. However, the blood glucose reduction effect produced by the orally administered insulin-loaded microspheres prepared with four parts of magnesium stearate and fifteen parts of Eudragit® RL 100 after 12?h was equal to that produced by subcutaneously administered insulin solution. The results of this study can suggest that this carrier system could be an alternative for the delivery of insulin.     

Poly(N-vinylcaprolactam-co-methacrylic acid) hydrogel microparticles for oral insulin delivery

pH-sensitive copolymeric hydrogels prepared from N-vinylcaprolactam and methacrylic acid monomers by free radical polymerization offered 52% encapsulation efficiency and evaluated for oral delivery of human insulin. The in vitro experiments performed on insulin-loaded microparticles in pH 1.2 media (stomach condition) demonstrated no release of insulin in the first 2?h, but almost 100% insulin was released in pH 7.4 media (intestinal condition) in 6?h. The carrier was characterized by Fourier transform infrared, differential scanning calorimeter, thermogravimetry and nuclear magnetic resonance techniques to confirm the formation of copolymer, while scanning electron microscopy was used to assess the morphology of hydrogel microparticles. The in vivo experiments on alloxan-induced diabetic rats showed the biological inhibition up to 50% and glucose tolerance tests exhibited 44% inhibition. The formulations of this study are the promising carriers for oral delivery of insulin.     

Study on the Influencing Factors of Hypoglycemic Effect of Folate Targeted Polymersomes Encapsulating Insulin

PurposeTo study the effects of the density of folic acid (FA) on the hypoglycemic ability of FA-targeted polymersomes as oral insulin carriers. Also to study the change of the hypoglycemic effect of FA-targeted mixed polymersomes added with various mass ratio of d-α-tocopherol polyethylene glycol 1000 succinate (TPGS).MethodsThe FA-targeted polymersomes with different FA molar contents were prepared. The in vitro insulin release experiments in different media for FA-targeted polymersomes with various FA contents were studied. Their quantitative cellular uptake in Caco-2 cells was examined. The in vivo hypoglycemic activity of FA-targeted polymersomes was also studied with diabetic rats. The polymersomes with the optimal FA molar content was chosen to prepare mixed polymersomes with various TPGS contents.ResultsAmong insulin-loaded FA-targeted polymersomes with four different FA molar contents, insulin-loaded polymersomes with 10% FA molar content (insulin-loaded 10%FA-Ps) showed the hightest cellular uptake and the best hypoglycemic response. In addition, the insulin-loaded FA-Ps/TPGS5:1 mixed polymersomes exhibited higher cellular uptake and better hypoglycemic response than the other two insulin-loaded mixed polymersomes adding TPGS did.ConclusionsFA-Ps/TPGS5:1 could be a promising formulation for the oral administration of insulin.     

Development of poly(hydroxyethyl methacrylate) nanogel for effective oral insulin delivery

Abstract

Because of uncomfortable, painful and even deleterious effects of daily injection of insulin, extensive efforts are being made worldwide for developing noninvasive drug delivery systems, especially via the oral route. In this study, we synthesized hydroxyethyl methacrylate (HEMA) nanogel via emulsion polymerization method. The morphology and stability of the nanogel were characterized by scanning electronic microscope and dynamic light scattering. In vivo results showed the soft HEMA nanogel had longer half-live in the body circulation and exhibited almost negligible uptake by the macrophage cells as compared with blank cells. For the FITC-dextran tracking for intestinal penetration, the results indicated that the FITC-dextran in the soft nanogel penetrated faster from the inner side of the abdominal segment, which explained why the soft HEMA nanogel could promote intestinal absorption of encapsulated insulin. In vivo delivery of insulin encapsulated in the soft HEMA nanogel sustained blood glucose control for 12?h, and the overall bioavailability of administrated insulin was much higher than free insulin. Our results showed that the insulin-loaded HEMA nanogel was able to efficiently control blood glucose as a delivery system, suggesting the HEMA nanogel using emulsion polymerization could be an alternative carrier for oral insulin delivery.     

Gastrointestinal Responsive Polymeric Nanoparticles for Oral Delivery of Insulin: Optimized Preparation,Characterization, and In Vivo Evaluation

Gastrointestinal responsive polymeric nanospheres (NPs) based on hydroxypropyl methylcellulose phthalate were prepared using spontaneous emulsification solvent diffusion method for improved oral administration of insulin. The NPs prepared under optimized conditions have an encapsulation efficiency of 90% and a particle size of about 200 nm. In vitro drug release experiments demonstrated that the NPs exhibited a gradient release profile of loaded drug when the pH value gradually increased from 3.0 to 7.4. Enzyme resistance experiments showed that under simulated gastrointestinal conditions, the NPs protected more than 60% of the drug from being degraded by trypsin. The oral hypoglycemic experiments revealed that insulin-loaded NPs could significantly reduce blood glucose levels in diabetic rats with a relative bioavailability of 8.6%. Ex vivo imaging investigation of rat tissues showed that the drug-loaded NPs could promote the absorption of insulin in the ileum and colon. The work described here suggests that the gastrointestinal responsive polymeric NPs may be promising candidates for improving gastrointestinal tract delivery of hydrophilic biomacromolecules. Accordingly, the results indicated that hydroxypropyl methylcellulose phthalate NPs with gastrointestinal stimuli responsiveness could be a promising candidate for oral insulin delivery.     

Epithelial transport of Noscapine across cell monolayer and influence of absorption enhancers on in vitro permeation and bioavailability: implications for intestinal absorption

Abstract

The purpose of this study was to investigate the permeation of Noscapine (Nos) across the Caco-2 and Madin–Darby canine kidney (MDCK) cell monolayers and to evaluate the influence of absorption enhancers on in vitro and in vivo absorption of Nos. The bidirectional transport of Nos was studied in Caco-2 and MDCK cell monolayers at pH 5.0–7.8. The effect of 0.5% w/v chitosan (CH) or Captisol (CP) on Nos permeability was investigated at pH 5.0 and 5.8. The effect of 1–5% w/v of CP on oral bioavailability of Nos (150?mg/kg) was evaluated in Sprague–Dawley rats. The effective permeability coefficients (P_eff) of Nos across Caco-2 and MDCK cell monolayers was found to be in the order of pH 5.0?>?5.8?>?6.8?>?7.8. The efflux ratios of P_eff?<?2 demonstrated that active efflux does not limit the absorption of Nos. The use of CH or CP have shown significant (***, p?<?0.001) enhancement in P_eff of Nos across cell monolayer compared with the control group. The CP (1–5% w/v) based Nos formulations resulted in significant (***, p?<?0.001) increase in the bioavailability of Nos compared with Nos solution. The use of CP represents viable approach for enhancing the oral bioavailability of Nos and reducing the required dose.     

In vitro and in vivo evaluation of thermosensitive chitosan hydrogel for sustained release of insulin

Injectable In situ gel-forming chitosan/β-glycerol phosphate (CS/β-Gp) solution can be introduced into the body in a minimally invasive manner prior to solidifying within the target tissue. This hydrogel is a good candidate for achieving a prolonged drug delivery system for insulin considering its high molecular weight. In addition to the physicochemical characterization of this hydrogel, in vitro and in vivo applications were studied as a sustained insulin delivery system. In the in vitro release studies, 19–63% of total insulin was released from the CS/β-Gp hydrogel within 150?h at different β-Gp and insulin concentrations. The best formulation was selected for in vivo experimentation to control the plasma glucose of diabetic mice models. The hypoglycemic effect of this formulation following subcutaneous injection in diabetic mice lasted 5?d, significantly longer than that of free insulin solution which lasted several hours.     

Polymeric nanoparticle drug delivery technologies for oral delivery applications

Introduction: Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles (NPs) are one technology being developed to enable clinically feasible oral delivery.

Areas covered: This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal (GI) barriers using polymeric NPs will be considered, including mucoadhesive biomaterials and targeting of NPs to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations.

Expert opinion: There have been many approaches used to overcome the transport barriers presented by the GI tract, but most have been limited by low bioavailability. Recent strategies targeting NPs to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and NPs across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric NP technologies and enable the translation of these technologies to clinical practice.     

The limited intestinal absorption via paracellular pathway is responsible for the low oral bioavailability of doxorubicin

Abstract

1. Doxorubicin exhibited dose-independent pharmacokinetics after intravenous (5–20?mg/kg) and oral (20–100?mg/kg) administration to rats. Nearly all (82.1–99.7%) of the orally administered doxorubicin remained unabsorbed, and the hepatic first-pass extraction ratio and oral bioavailability of doxorubicin were approximately 0.5% and 1%, respectively. Based on these results, it is likely that the primary factor responsible for the low oral bioavailability of doxorubicin is the limited intestinal absorption, rather than the CYP3A4-mediated first-pass metabolism.

2. Moreover, the in vitro transport and cellular uptake studies using Caco-2 cell monolayers have revealed that doxorubicin crosses the intestinal epithelium primarily via the paracellular pathway (accounting for 85.6% of the overall absorptive transport) probably due to its physicochemical properties (hydrophilic cation; pK_a?=?9.67, log?P?=??0.5). These results suggest that P-glycoprotein (P-gp)-mediated efflux activity does not play a significant role in limiting the intestinal absorption of doxorubicin, attenuating the absorptive transport by only 5.56–13.2%.

3. Taken together, the present study demonstrated that the limited and paracellular intestinal absorption of doxorubicin was a major factor responsible for its low oral bioavailability, restricting the role of CYP3A4-mediated first-pass metabolism and P-gp-mediated efflux.     

Bioadhesive Chitosan-Coated Cationic Nanoliposomes With Improved Insulin Encapsulation and Prolonged Oral Hypoglycemic Effect in Diabetic Mice

Oral administration of insulin is hampered by the lack of carriers that can efficiently achieve high encapsulation, avoid gastric degradation, overcome mucosal barriers, and prolong the hypoglycemic effect. Chitosan (CS)-coated insulin-loaded cationic liposomes have been developed and optimized for improved oral delivery. Liposomes were prepared cationic to improve insulin encapsulation. CS was selected as a mucoadhesive coat to prolong the system's residence and absorption. The performance of CS-coated liposomes compared with uncoated liposomes was examined in vitro, ex vivo, and in vivo in streptozotocin-induced diabetic mice. Free uncoated liposomes showed high positive zeta potential of +58.8 ± 2.2 mV that reduced (+29.9 ± 1.4 mV) after insulin encapsulation, confirming the obtained high entrapment efficiency of 87.5 ± 0.6%. CS-coated liposomes showed nanosize of 439.0 ± 12.3 nm and zeta potential of +60.5 ± 1.9 mV. In vitro insulin release was limited to 18.9 ± 0.35% in simulated gastric fluid, whereas in simulated intestinal fluid, 73.33 ± 0.68% was released after 48 h from CS-coated liposomes. Ex vivo intestinal mucoadhesion showed increased tissue residence of CS-coated liposomes compared with uncoated liposomes. A striking reduction in the glucose level was observed 1 h after oral administration of CS-coated liposomes and maintained up to 8 h (p <0.01 vs. insulin solution or uncoated liposomes) within the normal value 129.29 ± 3.15 mg/dL. In conclusion, CS-coated insulin-loaded cationic liposomes improved loading efficiency with promising prolonged pharmacological effect.     

[6]-Shogaol/β-CDs inclusion complex: preparation,characterisation, in vivo pharmacokinetics,and in situ intestinal perfusion study

Abstract

Aims: The aim was to improve the absorption and bioavailability of [6]-shogaol with β-cyclodextrin (β-CD) prior to in vitro and in vivo evaluation.

Methods: [6]-Shogaol/β-CDs inclusion complexes (6-S-β-CDs) were developed using saturated aqueous solution method and characterised with appropriate techniques. The absorption and bioavailability potential of [6]-shogaol was evaluated via in vivo pharmacokinetics and in situ intestinal perfusion.

Results: The results of characterisation showed that 6-S-β-CDs (drug loading, 7.15%) were successfully formulated. In vitro release study indicated significantly improved [6]-shogaol release. Pharmacokinetic parameters such as C_max, AUC_0–36?h, and oral relative bioavailability (about 685.36%) were substantially enhanced. The in situ intestinal perfusion study revealed that [6]-shogaol was markedly absorbed via passive diffusion in the intestinal segments, and duodenum followed by ileum and jejunum.

Conclusions: Cyclodextrin inclusion technology could enhance the intestinal absorption and oral bioavailability of hydrophobic drugs like [6]-shogaol.     

Polymeric micelles for oral drug administration enabling locoregional and systemic treatments

Introduction: Amphiphilic block copolymers are recognized components of parenteral drug nanocarriers. However, their performance in oral administration has barely been evaluated to any great extent.

Areas covered: This review provides an overview of the methods used to prepare drug-loaded polymeric micelles and to evaluate their stability in gastrointestinal (GI) fluids, and then analyzes in detail recent in vitro and in vivo results about their performance in oral drug delivery. Oral administration of polymeric micelles has been tested for a variety of therapeutic purposes, namely, to increase apparent drug solubility in the GI fluids and facilitate absorption, to penetrate in pathological regions of the GI tract for locoregional treatment, to carry the drug directly toward the blood stream minimizing presystemic loses, and to target the drug after oral absorption to specific tissue or cells in the body.

Expert opinion: Each therapeutic purpose demands micelles with different performance regarding stability in the GI tract, ability to overcome physiological barriers and drug release patterns. Depending on the block copolymer composition and structure, a wealth of self-assembled micelles with different morphologies and stability can be prepared. Moreover, copolymer unimers can play a role in improving drug absorption through the GI mucosa, either by increasing membrane permeability to the drug and/or the carrier or by inhibiting drug efflux transporters or first-pass metabolism. Therefore, polymeric micelles can be pointed out as versatile vehicles to increase oral bioavailability of drugs that exhibit poor solubility or permeability and may even be an alternative to parenteral carriers when targeting is pursued.     

Design of Virus-Mimicking Polyelectrolyte Complexes for Enhanced Oral Insulin Delivery

The viscous and elastic mucus layer is still an undesirable barrier for oral insulin delivery. To solve the problem, virus-mimicking nanosized polyelectrolyte complex (PEC) was designed and their capacity in enhancing peroral insulin absorption in combination with bifunctional material sodium dodecyl sulfate (SDS) coating was investigated. Inspired by nature, virus-mimicking chitosan (CS)-modified L-Phe derivatives were synthesized to simulate the components of viral envelopes and then PECs between CS-g-N-Phe copolymers and insulin were prepared to achieve both structure and composition simulation of virus envelope. Based on the results from both in vitro and in vivo studies, it was concluded that in vitro mucodiffusion and in vivo hypoglycemic effect were dependent on L-Phe graft ratio, with CS-g-N-Phe_20.2%/insulin PECs presenting 2.0- to 2.2-fold higher relative pharmacological bioavailability than nonmodified CS/insulin PECs. Thereafter, SDS solution was applied as outer layer coating on the surface of virus-mimicking PECs. The coated PECs showed improved enzymatic stability, enhanced transport across mucus layer as well as intestinal epithelium in an SDS concentration–dependent manner, with 0.6% SDS coating presenting the best effect, with further enhanced relative pharmacological bioavailability in healthy rats and prolonged therapeutic effect up to 9 h.     

Mathematical modeling of oral absorption and bioavailability of a fluoroquinolone after its precipitation in the gastrointestinal tract

Abstract

1. The objective was to characterize the in vivo absorption and bioavailability (BA) of a low solubility, high permeability fluoroquinolone (CNV97101) that precipitates in the gastrointestinal (GI) tract by mathematical modeling approach.

2. In situ rat intestinal perfusion studies were performed to characterize the absorption mechanism. The oral fraction absorbed in vivo was lower than the predicted based on the in situ intestinal permeability. Two additional routes of administration, intraduodenal (ID) and intraperitoneal (IP) were investigated to explore if precipitation in stomach and subsequent partial re-dissolution were the causes of the lower in vivo BA. Ex vivo precipitation studies with the stomach content of fasted rats were also carried out. Fitting procedures were performed with NONMEM VII 1.2.

3. The in situ experiments confirmed simultaneous passive and carrier-mediated absorption processes. The ex vivo experiments confirmed precipitation in stomach lowering in vivo the oral fraction absorbed compared with the IP and ID administrations. Due to the almost complete availability of CNV97101 following IP administration, a first hepatic pass could be excluded. The ex vivo assay results and the pharmacokinetic modeling of in vivo data supported the hypothesis of precipitation in the stomach and partial re-dissolution. Nevertheless, other factors such as residence time in the GI may reduce the fraction absorbed even for low oral doses for which re-dissolution was almost complete in vivo.     

胰岛素超多孔水凝胶控释制剂的制备及其检测

目的 制备一种可实现控释的超多孔水凝胶,以胰岛素为模型药,考察超多孔水凝胶的载药、释药性能,初探给药途径及药效.方法 采用聚合物互穿网络法制备超多孔水凝胶(SPH-IPN);通过傅立叶变换红外光谱和核磁共振碳谱考察凝胶的结构;通过测定溶胀比、孔隙率考察凝胶的性能;并以胰岛素为模型药研究超多孔水凝胶的载药量及载药后的药效...     

Active Apical Secretory Efflux of the HIV Protease Inhibitors Saquinavir and Ritonavir in Caco-2 Cell Monolayers

Purpose. To investigate in vitro the mechanisms involved in the gastrointestinal absorption of the HIV protease inhibitor, saquinavir mesylate (Invirase^®), whose oral bioavailability is low, variable, and significantly increased by co-administration with ritonavir, also an HIV protease inhibitor but with higher oral bioavailability. Methods. Confluent epithelial layers of human Caco-2 cells mimicking the intestinal barrier. Results. Both saquinavir and ritonavir showed polarized transport through Caco-2 cell monolayers in the basolateral to apical direction (secretory pathway), exceeding apical to basolateral transport (absorptive pathway) by factors of 50-70 and 15-25, respectively. Active efflux was temperature dependent, saturable and inhibited by verapamil and cyclosporin A. Saquinavir and ritonavir decreased each other's secretory permeability and hence elevated their net transport by the absorptive pathway. Conclusions. Saquinavir and ritonavir are both substrates for an efflux mechanism in the gut, most likely P-glycoprotein, which acts as a counter-transporter for both drugs. Together with sensitivity to gut-wall metabolism by cytochrome P-450 3A, this may partially account for the low and variable oral bioavailability of saquinavir in clinical studies and for its increased bioavailability after co-administration with ritonavir.     

Use of a Dynamic in Vitro Lipolysis Model to Rationalize Oral Formulation Development for Poor Water Soluble Drugs: Correlation with in Vivo Data and the Relationship to Intra-Enterocyte Processes in Rats

Purpose To examine the correlation between the in vitro solubilization process of lipophilic compounds from different lipid solutions and the corresponding in vivo oral bioavailability data. In particular, to assess the influence of intra-enterocyte processes (metabolism and lymphatic absorption) on this correlation.Materials and Methods The dissolution of progesterone and vitamin D₃ in long (LCT), medium (MCT) and short (SCT) chain triglyceride solutions were tested in a dynamic in vitro lipolysis model. The absolute oral bioavailability of the drugs from the tested formulations was investigated in rats. Vitamin D₃ bioavailability was also examined following lymphatic transport blockage induced by cycloheximide (3 mg/kg).Results The dynamic in vitro lipolysis experiments indicated a rank order of MCT > LCT > SCT for both progesterone and vitamin D₃. The bioavailability of progesterone correlated with the in vitro data, despite its significant pre-systemic metabolism. For vitamin D₃, an in vivo performance rank order of LCT > MCT > SCT was obtained. However, when the lymphatic transport was blocked the bioavailability of vitamin D₃ correlated with in vitro data.Conclusions The in vitro lipolysis model is useful for optimization of oral lipid formulations even in the case of pre-systemic metabolism in the gut. However, when lymphatic transport is a significant route of absorption, the in vitro lipolysis data may not be predictive for actual in vivo absorption.     

Advances in oral macromolecular drug delivery

Introduction: Various macromolecules including polypeptides, proteins, genes and polysaccharides have been drawing attention for their therapeutic potential. The passage through intestinal epithelium is the major barrier for the oral delivery of macromolecules, by either paracellular or transcellular pathways. However, most macromolecules are poorly absorbed in oral route due to their high molecular weight and low stability in the gastrointestinal (GI) tract. Nonetheless, advancing in oral macromolecular drug delivery will be significant in expanding the clinical use of therapeutic macromolecules.

Areas covered: Technologies using chemical conjugation, absorption enhancers and nano-/micro-particulate systems have been developed to improve oral bioavailability of macromolecules, and some of them are in the process of clinical trials. In this review, they are discussed in the context of their progression states, hurdles and modes of action.

Expert opinion: According to the better understanding of receptor or transporter structure and transport mechanisms in the GI tract, the progress ineffective oral delivery systems for therapeutic macromolecules is anticipated over the next decades. In addition, the advent of numerous particulate systems will also speed up the development of novel drug delivery technologies. This offers an optimistic perspective on the potential clinical usage of oral macromolecular drugs.