Oral Drug Carrier Research Articles

Multifunctional Delivery Systems for Advanced oral Uptake of Peptide/Protein Drugs

In recent years, advances in biotechnology and protein engineering have enabled the production of large quantities of proteins and peptides as important therapeutic agents. Various researchers have used biocompatible functional polymers to prepare oral dosage forms of proteins and peptides for chronic use and for easier administration to enhance patient compliance. However, there is a need to enhance their safety and effectiveness further. Most macromolecules undergo severe denaturation at low pH and enzymatic degradation in the gastrointestinal tract. The macromolecules' large molecular size and low lipophilicity cause low permeation through the intestinal membrane. The major strategies that have been used to overcome these challenges (in oral drug carrier systems) can be classified as follows: enteric coating or encapsulation with pH-sensitive polymers or mucoadhesive polymers, co-administration of protease inhibitors, incorporation of absorption enhancers, modification of the physicochemical properties of the macromolecules, and site-specific delivery to the colon. This review attempts to summarize the various advanced oral delivery carriers, including nanoparticles, lipid carriers, such as liposomes, nano-aggregates using amphiphilic polymers, complex coacervation of oppositely charged polyelectrolytes, and inorganic porous particles. The particles were formulated and/or surface modified with functional polysaccharides or synthetic polymers to improve oral bioavailability of proteins and peptides. We also discuss formulation strategies to overcome barriers, therapeutic efficacies in vivo, and potential benefits and issues for successful oral dosage forms of the proteins and peptides.

Mucoadhesive drug carrier based on functional-modified cellulose as poorly water-soluble drug delivery system

The purpose of this study was to design and characterise an oral mucoadhesive micellar drug carrier. In this regard, a mucoadhesive hydrophobic cationic aminocellulose was easily synthesised under mild homogeneous conditions with high yield. The cellulose derivative resulted in strongly improved mucoadhesive properties but was pH dependent. Furthermore, the hydrophobic anticancer drug camptothecin was successfully encapsulated into the mucoadhesive cellulose derivative micelles with spherical shape stability of 233 nm in diameter and low particle size distribution. The CPT-loaded nanocarriers provided high encapsulation efficiency about 86.4%. In vitro release, CPT-loaded cellulose derivative micelles showed a reduction in release rate compared with physically pure CPT solution. The release results also indicated that a sustained release of CPT to >80% over 4 d for pH 6.8 and 7.4. Therefore, mucoadhesive hydrophobic cationic aminocellulose micelles seem to be a promising carrier for various pharmaceutical applications especially for poorly water-soluble drug delivery system.

Preparation of pH-sensitive nanoparticles with core-shell-corona morphology as an oral drug carrier

In this study, an oral cancer drug delivery system based on quercetin encapsulated polymeric nanoparticles was evaluated. Oral delivery of quercetin achieved using a pHresponsive nanoparticle system composed of amphiphilic brushlike copolymer, which were prepared from poly(ethylene glycol) as a hydro� philic domain, poly(e�caprolactone) as a hydrophobic part and ma lic acid as a pH sensitive fragment. Syn� thesis of the brushlike copolymer was started by ring opening polymerization of e�caprolactone (CL) in pres� ence of DLmalic acid as an initiator. The polycaprolactone and methoxy poly(ethylene glycole) were acry� lated with acryloyl chloride and then their copolymer were synthesized via free radical polymerization. All products were identified by FTIR and 1H NMR analysis. The nanoprecipitation method was used for preparing drug (quercetin) loaded nanoparticles. The TEM images and zetasizer results showed that the size of the particles increases with increasing pH of media. The nanoparticles have coreshellcorona (CSC) mor� phology, and carboxyl groups in the shell are responsible for changing in the particle size during variation of the pH value. The drug release pattern was found biphasic with an initial burst followed by a slow, sustained release, which was remarkably affected by the pH of media.

Improving the oral delivery efficiency of anticancer drugs by chitosan coated polycaprolactone-grafted hyaluronic acid nanoparticles.

Sequentially overcoming the obstacles mainly from the low water solubility of lipophilic anticancer drugs, gastrointestinal microenvironment and systemic circulation is the major concern for designing oral anticancer drug carriers. Herein, we prepared the multifunctional polyelectrolyte complex nanoparticles (CNPs), engineered by hyaluronic acid (HA) grafted polycaprolactone (PCL) nanoparticles (HA-g-PCL NPs) coated with chitosan (CS) electrostatically, as a platform to improve the oral delivery efficiency of lipophilic anticancer drugs. Paclitaxel (PTX) and doxorubicin (DOX) were used as the model medicine and fluorescence probe, respectively. The size, zeta potential, morphology and pH-sensitivity of the NPs were studied systematically. The results indicated that the core-shell structure of CS/HA-g-PCL CNPs was formed at pH 5.0, which remained intact in the pH ranging from 3.0 to 6.8, while the CS layer detached gradually with the increase of pH to 7.4 and the HA-g-PCL NPs were released. In vitro drug release studies showed that accelerated drug release was triggered by hyaluronidase-1 (Hyal-1), which was a major HA degradation enzyme abundant within tumor cells. Cell uptake studies showed that HA-g-PCL NPs were internalized into cancer cells (EC109) via receptor-mediated endocytosis, but were rarely taken up by normal fibroblasts (NIH3T3). Furthermore, intracellular drug release indicated that HA-g-PCL NPs could provide an effective approach for transport of loaded cargoes into the cytoplasm. Therefore, higher cytotoxicity for PTX loaded HA-g-PCL NPs (HA-g-PCL/PTX NPs) against cancer cells EC109 but lower cytotoxicity against normal cells NIH3T3 was observed. In vivo studies showed that CS/HA-g-PCL CNPs via oral administration were able to preferentially deliver drugs into tumor tissue with commendable antitumor efficiency and few side effects. Overall, CS/HA-g-PCL CNPs showed great potential for improving oral delivery efficiency of lipophilic anticancer drugs.

Second generation lipid nanoparticles (NLC) as an oral drug carrier for delivery of lercanidipine hydrochloride

Lercanidipine hydrochloride is a calcium channel blocker used in the treatment of hypertension. It is a poor water soluble drug with absolute bioavailability of 10%. The aim of this study was to design lercanidipine hydrochloride-loaded nanostructured lipid carriers to investigate whether the bioavailability of the same can be improved by oral delivery. Lercanidipine hydrochloride nanostructured lipid carriers were prepared by the method of solvent evaporation at a high temperature and solidification by freeze drying. The nanostructured lipid carriers were evaluated for particle size analysis, zeta potential, entrapment efficiency, in vitro drug diffusion, ex vivo permeation studies and pharmacodynamic study. The resultant nanostructured lipid carriers had a mean size of 214.97nm and a zeta potential of −31.6±1.5mV. More than 70% lercanidipine hydrochloride was entrapped in the NLCs. The SEM studies indicated the formation of type 2 nanostructured lipid carriers. The in vitro release studies demonstrated 19.36% release in acidic buffer pH 1.2 indicating that the drug entrapped in the nanostructured lipid carriers remains entrapped at acidic pH. The ex vivo studies indicated that the drug release was enhanced from 10% to 60.54% at blood pH in 24h. The in vivo pharmacodynamic study showed that NLCs released lercanidipine hydrochloride in a controlled manner for a prolonged period of time as compared to plain drug. These results clearly indicate that nanostructured lipid carriers are a potential controlled release formulation for lercanidipine hydrochloride and may be a promising drug delivery system for the treatment of hypertension.

Gastrointestinal actions of orally-administered single-walled carbon nanohorns

Carbon nanomaterials, such as single-walled carbon nanohorns (SWCNHs) and carbon nanotubes, demonstrate great potential as drug delivery systems. However, no reports to date have detailed the use of SWCNHs as oral drug carriers. This study shows for the first time the actions of orally-administered SWCNHs in normal mice and mice with dextran sulfate sodium (DSS)-induced colitis. SWCNHs labeled with gadolinium oxide for quantification purposes were detected in the gastrointestinal tract and the feces of mice, but not in the blood or other bodily organs. These results indicate that the nanohorns were not absorbed into the body from the gastrointestinal tract. SWCNH absorption was not influenced by the functionalization or size control of SWCNH. Neither death nor behavioral aberrations were observed in normal mice following SWCNH administration. However, histological observation of mice with DSS-induced colitis at 24h after oral administration of SWCNHs revealed the presence of black particles, presumed to be SWCNHs, in the inflamed areas of the colon and the cecum. Thus, SWCNHs might serve as efficacious drug delivery carriers for the treatment of ulcerative colitis.

Synthesis of uniform core–shell gelatin–alginate microparticles as intestine‐released oral delivery drug carrier

A core-shell gelatin-alginate composite used for intestine-released oral delivery drug carrier was synthesized through microfluidic technique. At the fixed continuous phase flow rate, the size of the core-shell gelatin-alginate microparticles increases with the dispersed phase flow rate, and monodispersity can be retained (the variation coefficient for the diameter distribution can be kept less than 10%). The fabricated microparticles could remain intact in gastric juice for at least 3 h, indicating that the gelatin core could be well protected by alginate shell in acid environment. However, the alginate shell of the microparticles would swell or collapse in alkali environment in half an hour, assuring the controlled drug release in intestinal juice. The fabricated uniform core-shell gelatin-alginate microparticles were potential as pH-responsive drug carriers.

Preparation and characterization of tetrandrine-phospholipid complex loaded lipid nanocapsules as potential oral carriers

BackgroundTetrandrine is an active constituent that is extracted from the root tuber of the Chinese herb Stephania tetrandra S. Moore. It has shown various pharmacological effects, such as antitumor activity, multidrug resistance reversal, and hepatic fibrosis resistance. In clinical applications, it has been used to treat hypertension, pneumosilicosis, and lung cancer. However, the poor water solubility of tetrandrine has limited its application. In this study, a newly emerging oral drug carrier of phospholipid complex loaded lipid nanocapsules was developed to improve the oral bioavailability of tetrandrine.MethodsThe phospholipid complex was prepared with the solvent-evaporation method to enhance the liposolubility of tetrandrine. The formation of the phospholipid complex was confirmed with a solubility study, infrared spectroscopy, and a differential scanning calorimetry (DSC) analysis. The tetrandrine-phospholipid complex loaded lipid nanocapsules (TPC-LNCs) were prepared using the phase inversion method. Lyophilization was performed with mannitol (10%) as a cryoprotectant. TPC-LNCs were characterized according to their particle size, zeta potential, encapsulation efficiency, morphology by transmission electron microscopy, and crystallinity by DSC. In addition, the in vitro release of tetrandrine from TPC-LNCs was examined to potentially illustrate the in vivo release behavior. The in vivo bioavailability of TPC-LNCs was studied and compared to tetrandrine tablets in rats.ResultsThe liposolubility of tetrandrine in n-octanol improved from 8.34 μg/mL to 35.64 μg/mL in the tetrandrine-phospholipid complex. The prepared TPC-LNCs were spherical-shaped particles with a small size of 40 nm and a high encapsulation efficiency of 93.9%. DSC measurements revealed that the crystalline state was less ordered in lipid nanocapsules. The in vitro release study demonstrated a fast release of approximately 25% in the first 1 hour, which was followed by a sustained release of 70% over 12 hours. The relative bioavailability of TPC-LNCs compared to that of tablets was 208%, indicating a significant improvement in the oral absorption of tetrandrine.ConclusionThe TPC-LNCs system developed in this study is a promising carrier that improves the oral bioavailability of tetrandrine in rats. The phospholipid complex loaded lipid nanocapsules have great potential for use as an oral drug delivery system for moderately lipophilic drugs that are encapsulated in the lipid nanocapsules.

Thiomer-coated liposomes harbor permeation enhancing and efflux pump inhibitory properties

An ideal oral drug carrier should facilitate drug delivery to the gastrointestinal tract and its absorption into the systemic circulation. To meet these requirements, we developed a thiomer-coated liposomal delivery system composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and a maleimide-functionalized lipid, to which chitosan-thioglycolic acid (CS-TGA) was covalently coupled. In addition to conventional 77kDa CS-TGA (CS-TGA77), we tested the 150kDa homologue (CS-TGA150) as well as an S-protected version of this polymer (CS-TGA150-MNA), in which some of the free SH-groups are conjugated with 6-mercaptonicotinamide to protect them from oxidation. Coupling of CS-TGA to the liposomal surface led to an increase in the particle size of at least 150nm and an increase in the zeta potential from approximately −33mV to a maximum of about +36mV, depending on the polymer. As revealed by fluorescence dequenching the formulations have a storage stability of at least two weeks without releasing any encapsulated compounds. In simulated gastric fluid, the system was shown to be stable over 24h, while in simulated intestinal fluid, a slow, sustained release of encapsulated compounds was observed. According to our experiments, thiomer-coated liposomes did not induce immunogenic reactions after an oral administration to mice. To evaluate the permeation enhancing and efflux pump inhibiting properties of CS-TGA coated liposomes we monitored the transport of fluoresceinisothiocyanate-dextran (FD4) and rhodamine-123 (Rho-123), respectively, through rat small intestine. Permeation studies showed a 2.8-fold higher permeation of FD4 in the presence of CS-TGA77 coated liposomes and an even 4-fold higher permeation in the presence of CSA-TGA150-MNA coated liposomes. The latter also performed best when we evaluated P-glycoprotein inhibiting properties by monitoring the transport of Rho-123, revealing a 4.2-fold enhancement respective to the buffer control. Taken together, thiomer-coated liposomes were shown to protect encapsulated drugs in the stomach, slowly release them in the small intestine and enhance their absorption through the intestinal tissue by opening tight junctions and inhibiting efflux pumps.

Biocompatibility, cellular uptake and biodistribution of the polymeric amphiphilic nanoparticles as oral drug carriers

Oleoyl-carboxymethyl-chitosan (OCMCS) was synthesized and were soluble at neutral pH. The critical micelle concentration (CMC) of OCMCS in deionized water was 0.021mg/ml. OCMCS nanoparticles were successfully prepared via self-assembly with mean diameter of 215.34nm, zeta potential of 19.26mV and an almost spherical shape as determined by electron microscopy. The OCMCS nanoparticles showed low erythrocyte membrane-damaging effect. The MTT survival assay indicated no significant cytotoxicity to Caco-2 cells and MEFs cells. The uptake of FITC labeled OCMCS nanoparticles by Caco-2 cells was confirmed via confocal laser scanning microscope (CLSM). In vivo toxicity assays were performed via histopathological evaluation, and no specific anatomical pathological changes or tissue damage was observed in the tissues of carps. The extent of tissue distribution and retention following oral administration of FITC-OCMCS nanoparticles was analyzed for 3 days. After 3 days, the nanoparticles remained detectable in the muscle, heart, kidney, liver, intestine, and spleen. The results showed that 34.32% of the particles were localized in the liver, 18.79% in the kidney, and 17.36% in the heart. The lowest percentage was observed in the muscle. These results implied that OCMCS nanoparticles had great potential to be applied as safe carriers for the oral administration of protein drugs.

Cyclodextrins as Oral Drug Carrier Molecular Devices: Origins, Reasons and In-vitro Model Applications

Cyclodextrins are cyclic oligomers of glucose that can form water-soluble inclusion complexes with small molecules and por- tions of large compounds. These biocompatible, cyclic oligosaccharides do not elicit immune responses and have low toxicities in ani- mals and humans. Cyclodextrins are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current cyclodextrin-based therapeutics are described and possible future applications discussed with particular focus on oral drug administration. This article focuses on development of in vitro reliable and simple prototypes for oral drug delivery by combing chemical, structural and pharmacological knowledge available to date in order to create an optimal oral drug delivery system based on modified cyclodextrins. Practical in vitro model is also demonstrated.

Cellular transport pathways of polymer coated gold nanoparticles

The different transport pathways of 5-nm polymer-coated gold nanoparticles (Au NPs) crossing epithelial Caco-2 cell monolayers were explored. We found that the majority of cationic and neutral Au NPs depended heavily on endocytosis for cellular uptake and transport, and the anionic charged nanoparticles trafficked preferentially through the tight junctions (i.e., a paracellular pathway). The current study demonstrates that the surface chemistry of neutral polymer coatings dictate the trafficking through Caco-2 cell monolayers; poly(ethylene glycol)-coated Au NPs traffic via an endocytosis pathway assisted by microtubules; poly(2,3-hydroxy-propylacrylamide)-coated Au NPs traffic via endocytosis but assisted by other nonmicrotubular pathways. The Au NPs coated with poly( N-isopropylacrylamide) (hydrophobic above the lower critical solution temperature of 32°C) traffic via either the microtubule-assisted endocytosis pathway or the paracellular pathway depending on the temperature. This knowledge will aid in the future of the design of nanoparticles as potential oral drug carriers. From the Clinical Editor The authors examined different transport pathways of polymer-coated gold nanoparticles to cross epithelial Caco-2 cells, concluding that surface chemistry of neutral polymer coatings dictates the trafficking through monolayers.

Gel-based EEG electrode for Brain–Machine Interface

Wheat bran arabinoxylan (AX) discard from wheat production was utilized to form pH-responsive microgels. AX was modified by carboxymethylation, and the carboxymethylated arabinoxylans (CMAX) were characterized by FT-IR, NMR, gel permeation chromatography (GPC), and rheological analysis. The CMAX microgel was cross-linked by Fe3+ using an inverse emulsification polymerization. The morphology, particle size, pH sensitivity, and mechanism of cross-linking between COO− and Fe3+ of the CMAX microgel was investigated. The CMAX microgel was used to be an oral protein drug carrier. The CMAX microgel particles exhibited a stable spherical structure. FT-IR spectral analysis of the CMAX microgel indicated that the microgel was crosslinked by bridging Fe3+ and COO− with unidentate binding. The CMAX microgel exhibited good pH sensitivity and high stability in acid condition. Additionally, BSA was used as the embedding protein, and the controlled release effect of CMAX microgel was explored in gastrointestinal tract simulation.

Nanoparticles: a boon for modernisation of drug delivery: a review

In the medical field, the active ingredient is in the form of solid particles for 90% of all medicines. Because of development in nanotechnology, it is now possible to produce drug nanoparticles that can be utilised in a variety of innovative ways according to the need. From few decades, there had been considerable interest in area of nanotechnology and many works have been done in order to deliver drugs using particulate delivery systems (nanoparticles) as carriers for small and large molecules. Development of nanoparticles arose in response to vast and broad medical needs, common to a number of therapeutic areas and targets. The potential advantages of nanoparticles as oral drug carriers are enhancement of bioavailability, delivery of vaccine antigens to the gut-associated lymphoid tissues (GALT), controlled release, and reduction of the gastrointestinal irritation caused by drugs. Beside this nanoparticles also offer other route of administrations. Various polymers have been used in the formulation of nanoparticles for drug delivery research to increase therapeutic benefit, while minimising side effects. This review article laid emphasis on various aspects of nanoparticles, their uptake, formulation, characterisation and applications of nanoparticles approach in delivery of drugs molecules and genes.

Enhancement of Oral Bioavailability of Puerarin by Polybutylcyanoacrylate Nanoparticles

The interest using novel drug delivery systems to improve oral bioavailability of drug with poor solubility is increasing. In this study, a new oral delivery system, polybutylcyanoacrylate nanoparticles (PBCNs), was introduced to improve the oral bioavailability of puerarin (PUE). PUE-loaded PBCN was successfully prepared by anionic polymerization method. Characterization of PUE-loaded PBCN was evaluated with morphology, size, zeta potential, and in vitro release study. The PBCN loading PUE exhibited a spherical shape under transmission electron microscopy with an average size of 159.4 nm, and the zeta potential was −15.0 mV. The in vitro release of PUE-loaded PBCN showed an initial burst release followed by a sustained release. Physicochemical state of PUE in PBCN was investigated by differential scanning colorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy. The results indicated that PUE in PBCN was in a noncrystalline state. The oral pharmacokinetic study in rats showed that the relative bioavailability of PUE-encapsulated PBCN to the crude PUE was more than 550%. It can be concluded that PBCN as an oral drug carrier can significantly improve the oral bioavailability of PUE.

Recent Advances in Lipid Nanoparticle Formulations with Solid Matrix for Oral Drug Delivery

Lipid nanoparticles based on solid matrix have emerged as potential drug carriers to improve gastrointestinal (GI) absorption and oral bioavailability of several drugs, especially lipophilic compounds. These formulations may also be used for sustained drug release. Solid lipid nanoparticle (SLN) and the newer generation lipid nanoparticle, nanostructured lipid carrier (NLC), have been studied for their capability as oral drug carriers. Biodegradable, biocompatible, and physiological lipids are generally used to prepare these nanoparticles. Hence, toxicity problems related with the polymeric nanoparticles can be minimized. Furthermore, stability of the formulations might increase than other liquid nano-carriers due to the solid matrix of these lipid nanoparticles. These nanoparticles can be produced by different formulation techniques. Scaling up of the production process from lab scale to industrial scale can be easily achieved. Reasonably high drug encapsulation efficiency of the nanoparticles was documented. Oral absorption and bioavailability of several drugs were improved after oral administration of the drug-loaded SLNs or NLCs. In this review, pros and cons, different formulation and characterization techniques, drug incorporation models, GI absorption and oral bioavailability enhancement mechanisms, stability and storage condition of the formulations, and recent advances in oral delivery of the lipid nanoparticles based on solid matrix will be discussed.

Enhanced Oral Bioavailability of Doxorubicin in a Dendrimer Drug Delivery System

PAMAM dendrimers can permeate across intestinal epithelial barriers suggesting their potential as oral drug carriers. In the present study, we have developed a drug–PAMAM complex for oral administration. The loading of a model drug, doxorubicin into PAMAM, the cellular uptake and Pharmacokinetics of the doxorubicin–PAMAM complex were studied. As the results, the cellular uptake of doxorubicin in Caco-2 cells treated with the doxorubicin–PAMAM complex was increased significantly with an increase in concentration and time, as compared to that treated with free doxorubicin. And the transport efficiency of the doxorubicin–PAMAM complex from the mucosal side to the serosal side was 4–7 times higher than that of free doxorubicin in different segments of small intestines of rat. The doxorubicin–PAMAM complex led to the bioavailability that was more than 200-fold higher than that of free doxorubicin after oral administration. These results indicate that PAMAM dendrimer is a promising novel carrier to enhance the oral bioavailability of drug, especially for the P-glycoprotein (P-gp) substrates.

PH-sensitive and mucoadhesive thiolated Eudragit-coated chitosan microspheres

The aim of this study was using Eudragit–cysteine conjugate to coat on chitosan microspheres (CMs) for developing an oral protein drug delivery system, having mucoadhesive and pH-sensitive property. Bovine serum albumin (BSA) as a protein model drug was loaded in thiolated Eudragit-coated CMs (TECMs) to study the release character of the delivery system. After thiolated Eudragit coating, it was found that the release rate of BSA from BSA-loaded TECMs was observably suppressed at pH 2.0 PBS solution, while at pH 7.4 PBS solution the BSA can be sustainingly released for several hours. The structural integrity of BSA released from BSA-loaded TECMs was guaranteed by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and circular dichroism (CD) spectroscopy. The mucoadhesive property of TECMs was evaluated and compared with CMs and Eudragit-coated chitosan microspheres (ECMs). It was confirmed that after coating thiolated Eudragit, the percentage of TECMs remained on the isolated porcine intestinal mucosa surface was significantly higher than those of CMs and ECMs. Likewise, gamma camera imaging of Tc-99 m labeled microsphere distribution in rats after oral administration also suggested that TECMs had comparatively stronger mucoadhesive characters. Therefore, our results indicated that TECMs have potentials to be an oral protein drug carrier.

Acute oral toxicity evaluation of biodegradable and pH‐sensitive hydrogel based on polycaprolactone, poly(ethylene glycol) and methylacrylic acid (MAA)

In this article, a novel biodegradable and pH-sensitive hydrogel based on polycaprolactone, poly(ethylene glycol) and methylacrylic acid (MAA), was prepared by UV-initiated free radical polymerization. The obtained hydrogel was characterized by (1)H NMR and FTIR. The acute toxicity tests and histopathological study were performed in BALB/c mice. In acute oral toxicity test, mice were orally administered with a total 15 g/kg body weight (b.w.) of P(CL-MAA-EG) hydrogels, and were observed continuously for 14 days. For histopathologic study, samples including heart, liver, lung, kidneys, spleen, stomach, and intestine, were histochemically prepared and stained with hematoxylin-eosin for histopathologic examination. No mortality or significant signs of acute toxicity was observed during the whole observation period, and no macroscopic alteration was found in the organs. Histopathological analysis of various organs also did not show any significant pathological changes. Thus, the maximal tolerance dose of P(CL-MAA-EG) hydrogels was calculated to be higher than 15 g/kg b.w. in BALB/c mice. It was suggested that the studied P(CL-MAA-EG) hydrogel in this article were nontoxic after acute oral administration and it might be a promising candidate as a novel oral drug carrier.

Investigation of pluronic and PEG-PE micelles as carriers of meso-tetraphenyl porphine for oral administration

Meso-tetraphenyl porphine (mTPP) is a highly lipophilic, florescent porphyrin derivate and it is used as photosensitizer on the treatment of malign neoplasms. The aim of this study was to prepare mTPP loaded pluronic F127 and polyethylene glycol-distearoyl phosphatidylethanolamine (PEG 2000-DSPE) micelles to evaluate polymeric micelles potential for the transport of drugs through intestinal mucosa. Transport and bioadhesion behaviors of polymeric micelles was investigated using Caco-2 cell monolayer and everted rat intestine models. In order to show that Caco-2 cells can be used as a transport model cytotoxicity of formulations was tested. Cell viability was more than 80%, showing that Caco-2 cells will keep their viability during the transport studies demonstrating that prepared formulations can be securely used as oral drug carrier systems. Plain micelles were labeled with a fluorescent agent rhodamine-phosphatidylethanolamine (Rh-PE) and their transport through Caco-2 cells was investigated beside mTPP loaded micelles. At the end of 4 h transport study through Caco-2 cells, cumulative transport (%) of fluorescent agents were around 14% and 1% in Rh-PE labeled and mTPP loaded micelles This difference was attributed to the different placement of mTPP and Rh-PE in the micellar core. Drug transport was not estimated in everted rat intestine model but the bioadhesion was 79% and 70% for mTPP loaded pluronic F127 and PEG 2000-DSPE micelles. These good bioadhesion rates are promising for oral drug delivery.