Pulmonary absorption enhancement of peptides by absorption enhancers and protease inhibitors

The polyamidoamine (PAMAM) dendrimer is a highly efficient absorption promoter. In the present study, we studied the absorption-enhancing effects and the mechanism of PAMAM dendrimers with generation 0 to generation 3 (G0–G3) and concentrations (0.1–1.0%) on the pulmonary absorption of macromolecules. The absorption-enhancing mechanisms were elucidated by microarray, western blotting analysis, and PCR. Fluorescein isothiocyanate-labeled dextrans (FDs) with various molecular weights were used as model drugs of poorly absorbable drugs. The absorption-enhancing effects of PAMAM dendrimers on the pulmonary absorption of FDs were in a generation- and concentration-dependent manner. The G3 PAMAM dendrimer with high effectiveness was considered to the best absorption enhancer for improving the pulmonary absorption of FDs. G3 PAMAM dendrimers at three different concentrations were non-toxic to Calu-3 cells. Based on the consideration between efficacy and cost, the 0.1% G3 PAMAM dendrimer was selected for subsequent studies. The results showed that treatment with a 0.1% G3 PAMAM dendrimer could increase the secretion of organic cation transporters (OCTs), OCT1, OCT2, and OCT3, which might be related to the absorption-enhancing mechanisms of the pulmonary absorption of FDs. These findings suggested that PAMAM dendrimers might be potentially safe absorption enhancers for improving absorption of FDs by increasing the secretion of OCT1, OCT2, and OCT3.

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Impact of Sodium N-[8-(2-Hydroxybenzoyl)amino]-caprylate on Intestinal Permeability for Notoginsenoside R1 and Salvianolic Acids in Caco-2 Cells Transport and Rat Pharmacokinetics

Molecules ◽

10.3390/molecules23112990 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2990 ◽

Cited By ~ 3

Author(s):

Ying Li ◽

Dandan Yang ◽

Chunyan Zhu

Keyword(s):

Membrane Permeability ◽

Cell Monolayer ◽

Salvianolic Acid B ◽

Absorption Enhancement ◽

Enhancement Effect ◽

Absorption Enhancers ◽

Salvianolic Acid ◽

Salvianolic Acids

For drugs with high hydrophilicity and poor membrane permeability, absorption enhancers can promote membrane permeability and improve oral bioavailability. Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) is a new kind of absorption enhancer that has good safety. To investigate the absorption enhancement effect of SNAC on non-polar charged and polar charged drugs and establish the absorption enhancement mechanism of SNAC, SNAC was synthesized and characterized. Two representative hydrophilic drugs—notoginsenoside R1 (R1) and salvianolic acids (SAs)—were selected as model drugs. In vitro Caco-2 cells transport and in vivo rat pharmacokinetics studies were conducted to examine the permeation effect of SNAC on R1 and SAs. R1, rosmarinic acid (RA), salvianolic acid B (SA-B) and salvianolic acid B (SA-A) were determined to compare the permeation enhancement of different drugs. The MTT assay results showed that SNAC had no toxicity to Caco-2 cells. The transepithelial electrical resistance (TEER) of Caco-2 cell monolayer displayed that SNAC facilitated passive transport of polar charged SAs through the membrane of epithelial enterocytes. The pharmacokinetics results demonstrated that area under the curve (AUC) of RA, SA-B and SA-A with administration of SAs containing SNAC was 35.27, 8.72 and 9.23 times than administration of SAs. Tmax of RA, SA-B and SA-A were also prolonged. The AUC of R1 with administration of R1 containing SNAC was 2.24-times than administration of R1. SNAC is more effective in promoting absorption of SAs than R1. The study demonstrated that SNAC significantly improved bioavailability of R1 and SAs. What’s more, the effect of SNAC on absorption enhancement of charged drugs was larger than that of non-charged drugs. The current findings not only confirm the usefulness of SNAC for the improved delivery of R1 and SAs but also demonstrate the importance of biopharmaceutics characterization in the dosage form development of drugs.

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Effect of absorption enhancers on pulmonary absorption of fluorescein isothiocyanate dextrans with various molecular weights

International Journal of Pharmaceutics ◽

10.1016/0378-5173(91)90311-b ◽

1991 ◽

Vol 77 (2-3) ◽

pp. 141-150 ◽

Cited By ~ 19

Author(s):

Toshihide Ohtani ◽

Masahiro Murakami ◽

Akira Yamamoto ◽

Kanji Takada ◽

Shozo Muranishi

Keyword(s):

Fluorescein Isothiocyanate ◽

Pulmonary Absorption ◽

Absorption Enhancers ◽

Molecular Weights

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Chitosan Oligomers as Potential and Safe Absorption Enhancers for Improving the Pulmonary Absorption of Interferon-α in Rats

Journal of Pharmaceutical Sciences ◽

10.1002/jps.20454 ◽

2005 ◽

Vol 94 (11) ◽

pp. 2432-2440 ◽

Cited By ~ 38

Author(s):

Keigo Yamada ◽

Masaaki Odomi ◽

Naoki Okada ◽

Takuya Fujita ◽

Akira Yamamoto

Keyword(s):

Interferon Α ◽

Pulmonary Absorption ◽

Absorption Enhancers

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Nasal Delivery of Recombinant Human Growth Hormone: In Vivo Evaluation with Pheroid™ Technology and N-Trimethyl Chitosan Chloride

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3cs3f ◽

2010 ◽

Vol 13 (2) ◽

pp. 263 ◽

Cited By ~ 15

Author(s):

Dewald Steyn ◽

Lissinda Hester Du Plessis ◽

Awie Kotze

Keyword(s):

Growth Hormone ◽

Human Growth Hormone ◽

Recombinant Human Growth Hormone ◽

Subcutaneous Administration ◽

Human Growth ◽

Absorption Enhancement ◽

Control Group ◽

Absorption Enhancers ◽

Trimethyl Chitosan

Purpose. It was the aim of this study to investigate the possible enhancement of the absorption of recombinant human growth hormone (rhGH) in the nasal cavity, in the presence of a polymeric absorption enhancer, N-trimethyl chitosan chloride (TMC) and a fatty acid-based delivery system, Pheroid™. Methods. Two types of Pheroid™ formulations, Pheroid™ vesicles and Pheroid™ microsponges were characterized and evaluated with regard to particle size and morphology. In vivo bioavailability studies in rats were performed and the nasal bioavailability of Pheroid™ vesicles and Pheroid ™microsponges were compared relative to subcutaneous administration. The results were also compared with different N-trimethyl chitosan chloride (TMC) formulations, TMC H-L and TMC H-H, well studied absorption enhancers. Results. Pheroid™ vesicles and Pheroid™ microsponges showed a size distribution of approxiamately 2-3 µm and 3-4 µm for Pheroid™ vesicles and Pheroid™ microsponges respectively. Using specific RIA, the relative bioavailability of rhGH after comparison with subcutaneous injection was determined to be 38.9, 128.5, 39.9, 136.3, and 8.3 % for Pheroid™ microsponges, Pheroid™ vesicles, TMC H-H, TMC H-L and control group (intranasal rhGH alone), respectively. All the enhancers showed significant absorption enhancement (P < 0.05) with the highest effect observed with TMC H-L. Conclusion. All the enhancers may have promising potential as safe and effective nasal absorption enhancers of rhGH.

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