Drug Carrier For Oral Administration Research Articles

Bioconjugation of Captopril-Light Subunit of Agaricus bisporus Mushroom Tyrosinase: Characterization and Potential Use as a Drug Carrier for Oral Delivery.

We show that a lectin like protein from the mushroom Agaricus bisporus (LSMT) is capable to permeate the epithelial monolayer barrier of the intestine ex vivo. The protein is not toxic or immunogenic upon prolonged administration and elevated dose in mice. Thus, it could be a candidate as a drug carrier for oral administration. However, its permeability should be tested after the protein has been modified, mimicking the condition in which it is used as a drug carrier. The protein was conjugated to captopril, the selected model of a Biopharmaceutical Classification System (BCS) class III drug, with high solubility but poor permeability. The drug was conjugated to LSMT that had been modified with 4-succinimidyloxycarbonyl-alpha-methyl-2-pyridyldithiotoluene (SMPT) as a linker. The success of LSMT modification was confirmed with TLC and MS; the latter also indicated the amount of captopril molecule linked. The modified LSMT could permeate through the intestinal monolayer barrier, and thus could be absorbed in the intestine after modification. The modified protein appears to remain stable after incubation in simulated gastrointestinal fluids. This pioneering work provides an essential basis for further development of the protein as a drug carrier for oral administration.

PH- and Amylase-Responsive Carboxymethyl Starch/Poly(2-isobutyl-acrylic acid) Hybrid Microgels as Effective Enteric Carriers for Oral Insulin Delivery.

Oral delivery of insulin has the potential to revolutionize diabetes care since it is regarded as a noninvasive therapeutic approach without the side effects caused by frequent subcutaneous injection. However, the insulin delivery efficiency through oral route was still limited, likely due to the chemical, enzymatic and absorption barriers. In this study, a novel type of pH- and amylase-responsive microgels as an insulin drug carrier for oral administration was developed to improve the drug delivery efficiency. The microgels were prepared via aqueous dispersion copolymerization of acrylate- grafted-carboxymethyl starch (CMS- g-AA) and 2-isobutyl-acrylic acid ( iBAA). The resulting hybrid microgels with the P iBAA contents of 13.6-45.3 wt% exhibited sharp pH-sensitivity, which was revealed by the changes in particle size of the microgels and the transmittance of the microgel aqueous solution. The accelerated decomposition of the CMS-containing microgels in response to amylase was demonstrated by chromogenic reaction and morphology change. Insulin was loaded into the microgels by swelling-diffusion method, and the insulin release from the insulin-loaded microgels in vitro was found to be triggered by pH change and addition of amylase, which was highly dependent on the microgel component. Cytotoxicity assay was performed to show the good biocompatibility of the microgels. In addition, the tests of cellular uptake by Caco-2 cells and transmembrane transport through the Caco-2 cell monolayers were carried out to confirm the intestinal absorption ability of the insulin-loaded microgels. Finally, the oral administration of insulin-loaded microgels to STZ-induced diabetic rats led to a continuous decline in the fasting blood glucose level within 2 to 4 h, and the hypoglycemic effect maintained over 6 h in vivo. The relative pharmacological availability of the insulin-loaded microgels was enhanced 23-38 times compared to free-form insulin solution through oral route. Therefore, the novel starch-based microgels may have potential as an efficient platform for oral insulin delivery.

Biological responses in Balb/c mice after long-term parenteral administration of the light subunit of mushroom tyrosinase.

Light subunit of mushroom tyrosinase (LSMT) is a protein of unknown function from mushroom Agaricus bisporus that has been demonstrated to permeate through rat intestine ex vivo. Thus, it can be absorbed in the intestine, thereby holding a promise as a drug carrier for oral administration, similar to HA-33 protein from botulinum, one of the closest structural homologs of LSMT. However, the safety of LSMT should be ensured prior to its use. Here, we described biological response of LSMT upon weekly intraperitoneal administration of 50μg/day to the Balb/c mice for 12 weeks. Motoric and behavior profiles, as well as the index of main organs (liver, spleen, lung, heart, and kidney), and body weight, were not significantly changed as compared with the control group. Also, no IgG was detected in the serum. The results suggest that LSMT is safe for further development.

Oral delivery of insulin-loaded nanoparticles in diabetic rabbits and in sheep

The objective of this study was to produce Eudragit<sup>®</sup> RS 100 microparticles (ERS) containing insulin (ILNP), and to evaluate the potential of these nanoparticles as a drug carrier for oral administration in alloxan-induced diabetic rabbits and in sheep. After oral administration of ILNP to diabetic rabbits, a significant hypoglycemic effect was observed and this effect lasted for 2 days. Concentrations of blood glucose were significantly decreased in ILNP-treated sheep compared to those in control and ERS groups on day 5 of the experiment. Orally ILNP-treated sheep exhibited higher concentrations of progesterone compared to control and ERS in all sampling times. Sheep in the ILNP group had lower concentrations of cortisol than the animals in the control group on days 1 and 3. However, other blood hormone parameters were not affected by the treatments. The results show that encapsulation of insulin into nanoparticles allows the preservation of its biological activity when going through digestive system of rabbit and sheep to the blood stream.  

Effects of pH‐Sensitive Groups on Poly(ethylene oxide)‐block‐poly(ϵ‐caprolactone) Block Copolymer Micelles Used as Drug Carriers

AbstractA new type of drug delivery system consisting of an amphiphilic polymer micelle with pH‐sensitive groups is reported. The polymer comprises mPEG [poly(ethylene glycol) monomethyl ether], PCL [poly(ϵ‐caprolactone)], and either PAA [poly(acrylic acid)] or PMAA [poly(methacrylic acid)]. Both mPEG‐b‐PCL and mPEG‐b‐PCL‐b‐PAA/PMAA are characterized by 1H NMR, FTIR, and gel permeation chromatography (GPC). The diameters of the mPEG‐b‐PCL‐b‐PAA/PMAA micelles are found to increase with increases in pH and studies show that in vitro release of nifedipine from mPEG‐b‐PCL‐b‐PAA/PMAA micelles becomes faster as the pH value of phosphate‐buffered saline (PBS) increases. This new type of pH‐sensitive polymeric micelle can potentially be used as a drug carrier for oral administration of water‐insoluble drugs.

Polyelectrolyte complex of carboxymethyl starch and chitosan as drug carrier for oral administration

A novel polyelectrolyte complex (PEC) of carboxymethyl starch (CMS) and chitosan was prepared, characterized and tested in vitro as a carrier for oral drug delivery. This PEC, containing 14% (w/w) of chitosan, showed a polymorphism with a lower order degree than those of CMS and of chitosan. Under conditions simulating the gastrointestinal transit, NMR imaging analysis showed slower fluid diffusion inside PEC monolithic tablets than inside CMS tablets. The PEC seems to be a more suitable drug carrier for colon targeting than CMS, since it can prolong acetaminophen release time from 8h to 11h and aspirin release time from 13h to 30h. In contrast, chitosan used as a coexcipient accelerated aspirin release from matrices based on a CMS:chitosan physical mixture.

Poly(ε-caprolactone)/eudragit nanoparticles for oral delivery of aspart-insulin in the treatment of diabetes

Nanoparticles prepared with a blend of a biodegradable polyester (poly(ε-caprolactone)) and a polycationic nonbiodegradable acrylic polymer (Eudragit® RS) have been used as a drug carrier for oral administration of a short-acting insulin analogue, aspart-insulin. Insulin-loaded nanoparticles, about 700 nm in diameter, encapsulated 97.5% of insulin and were able to release about 70% of their content in vitro in a neutral medium over 24 h. When administered orally to diabetic rats, insulin-loaded nanoparticles (50 IU/kg) decreased fasted glycemia for a prolonged period of time and improved the glycemic response to glucose in a time-dependent manner, with a maximal effect between 12 and 24 h after their administration. In parallel, plasma insulin levels increased. However, higher (100 IU/kg) and lower (25 IU/kg) doses of insulin did not exert any biological effect. It is concluded that polymeric nanoparticles composed of poly(ε-caprolactone)/Eudragit® RS are able to preserve the biological activity of the insulin analogue aspart-insulin; however, the postprandial peak suppression was prolonged more than 24 h by comparison with regular insulin working only 6–8 h. This effect may be explained by the monomeric configuration of aspart-insulin, which is probably better taken up by the intestinal mucosa than regular insulin. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:879–889, 2010

Preparation of silk sericin beads using LiCl/DMSO solvent and their potential as a drug carrier for oral administration

Silk sericin (SS) was fabricated into beads using LiCl/DMSO solution as a solvent. Up to 30 % (w/v) of SS could be dissolved within 3 hours, and the shape of solidified SS depends on the concentration of SS. Ethanol was the best coagulant among alcohols, making beads with suitable mechanical strength for further application. SS beads swell more at a pH above the isoelectric point (pl) than below the pl. The pH and the presence of an enzyme greatly affect the dissolution rate of SS beads. Whereas only 10 % of SS beads were dissolved at pH 2.2 in the presence of pepsin, more than 45 % of SS beads were dissolved at pH 7.4 in the presence of trypsin. The release of drug was suppressed in a stomach-like environment while promoted in an intestine-like environment.

Oral delivery of insulin associated to polymeric nanoparticles in diabetic rats

Nanoparticles prepared with a blend of a biodegradable polyester (poly(-ε-caprolactone)) and a polycationic non-biodegradable acrylic polymer (Eudragit® RS) have been used as a drug carrier for oral administration of insulin. The rate of encapsulation of insulin was around 96%. The therapeutic efficiency of oral insulin nanoparticles (25, 50 and 100 IU/kg) in diabetic rats and the intestinal uptake of fluorescein isothiocyanate (FITC) labelled insulin were studied. When administered orally by force-feeding to diabetic rats, insulin nanoparticles decreased fasted glycemia in a dose dependant manner with a maximal effect observed with 100 IU/kg. These insulin nanoparticles also increased serum insulin levels and improved the glycemic response to an oral glucose challenge for a prolonged period of time. FITC-Insulin-loaded nanoparticles strongly adhered to the intestinal mucosa and labeled insulin, either released and/or still inside nanoparticles, was mainly taken up by the Peyer's patches. It is concluded that polymeric nanoparticles allows the preservation of insulin's biological activity. In addition, the antidiabetic effect can be explained by the mucoadhesive properties of the polycationic polymer (Eudragit ® RS) allowing the intestinal uptake of insulin.

Oral bioavailability of cyclosporine: Solid lipid nanoparticles (SLN ®) versus drug nanocrystals

For the development of an optimized oral formulation for cyclosporine A, 2% of this drug has been formulated in solid lipid nanoparticles (SLN™, mean size 157 nm) and as nanocrystals (mean size 962 nm). The encapsulation rate of SLN was found to be 96.1%. Nanocrystals are composed of 100% of drug. For the assessment of the pharmacokinetic parameters the developed formulations have been administered via oral route to three young pigs. Comparison studies with a commercial Sandimmun Neoral/Optoral ® used as reference have been performed. The blood profiles observed after oral administration of the commercial microemulsion Sandimmun ® revealed a fast absorption of drug leading to the observation of a plasma peak above 1000 ng/ml within the first 2 h. For drug nanocrystals most of the blood concentrations were in the range between 30 and 70 ng/ml over a period of 14 h. These values were very low, showing huge differences between the measuring time points and between the tested animals. On the contrary, administration of cyclosporine-loaded SLN led to a mean plasma profile with almost similarly low variations in comparison to the reference microemulsion, however with no initial blood peak as observed with the Sandimmun Neoral/Optoral ®. Comparing the area under the curves (AUC) obtained with the tested animals it could be stated that the SLN™ formulation avoids side effects by lacking blood concentrations higher than 1000 ng/ml. In this study it has been proved that using SLN™ as a drug carrier for oral administration of cyclosporine A a low variation in bioavailability of the drug and simultaneously avoiding the plasma peak typical of the first Sandimmun ® formulation can be achieved.

Transmucosal passage of polyalkylcyanoacrylate nanocapsules as a new drug carrier in the small intestine.

The enteral absorption of particles has been investigated in the dog using a colloidal drug carrier, polyalkylcyanoacrylate nanocapsules loaded with an iodized oil (Lipiodol), as a tracer for X-ray microprobe analysis in a scanning electron microscope. Nanocapsules are spherical capsules, 100 to 200 nm in diameter, with a continuous polymeric wall surrounding a cavity which encapsulates the drug. Administered in the jejunal lumen, Lipiodol nanocapsules improved the absorption of the tracer as indicated by increased concentration of iodine in the plasma of mesenteric blood. In order to follow nanocapsules at the cellular level, all tissue compartments were preserved in a life-like state by cryofixation and freeze-drying of intestinal biopsies. Nanocapsules appeared in the intestinal lumen close to the mucus, then in intercellular spaces and defects of the mucosa and finally in the lamina propria and blood capillaries; in this latter compartment, the iodine content was four-fold higher than after intra-jejunal administration of Lipiodol emulsion. This complete phenomenon occurred only at the tip of the villi and happened within less than 60 min. We conclude that nanocapsules enhance the rate of absorption of Lipiodol and transport the drug from the intestinal lumen to the vascular compartment using a paracellular pathway. Thus they may be useful as drug carrier for oral administration of many chemicals.