Improved nasal absorption of drugs using poly-l-arginine: effects of concentration and molecular weight of poly-l-arginine on the nasal absorption of fluorescein isothiocyanate–dextran in rats

Miyamoto, Masahide; Natsume, Hideshi; Iwata, Satoko; Ohtake, Kazuo; Yamaguchi, Masatoshi; Kobayashi, Daisuke; Sugibayashi, Kenji; Yamashina, Motoaki; Morimoto, Yasunori

doi:10.1016/s0939-6411(01)00149-7

Cited by 59 publications

(36 citation statements)

References 32 publications

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“…In the present study, PLA enhanced the nasal rhGH absorption, and the effects of the concentration and molecular weight of PLA were different from the results in our previous study using FDs, 11) largely because of the interaction between the rhGH and PLA with various concentrations and molecular weights, as well as other components present in the formulation after preparation and administration. However, it seems that the PLA concentration affects the absorption-enhancing effect of PLA on rhGH, and the molecular weight affects T max after i.n.…”

Section: Discussioncontrasting

confidence: 99%

“…It has been reported that PLA does not induce significant damage to the nasal mucosa. 11,13) Therefore, a transnasal rhGH delivery system using PLA as an enhancer is a promising alternative to s.c. injection provided that the interactions among rhGH, PLA and additives are sufficiently controlled.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, we reported that PLA, a cationic polymer that consists of polymerized L-arginine, enhanced the nasal absorption of fluorescein isothiocyanate-dextrans (FDs) with various molecular weights (MW 12.0-167.0 kDa) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) (MW 18.8 kDa) in rats. [10][11][12] We also reported that the absorption-enhancing effect of PLA was dependent on its concentration and molecular weight, which was associated with the charge density of the PLA molecule. Moreover, the increased absorption was reversible, without toxic effects on epithelial cells.…”

mentioning

confidence: 92%

“…Moreover, the increased absorption was reversible, without toxic effects on epithelial cells. 11,13) In the studies on the mechanism of enhanced absorption by PLA in the mucosa, it has been found that PLA induces the enhanced paracellular permeability by the dispersion of tight junction proteins (claudin-4, occludin, zonula occludens-1 (ZO-1) and tricellulin) into the cytoplasm through the cell-cell junction. [14][15][16][17] In particular, it was known that occludin was important for macromolecular permeation among tight junction proteins.…”

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confidence: 99%

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Development of a Transnasal Delivery System for Recombinant Human Growth Hormone (rhGH): Effects of the Concentration and Molecular Weight of Poly-L-arginine on the Nasal Absorption of rhGH in Rats

Kawashima

Uchida

Yamaki

et al. 2016

Biological & Pharmaceutical Bulletin

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A novel system for delivering recombinant human growth hormone (rhGH) that is noninvasive and has a simple method of administration is strongly desired to improve the compliance of children. The aim of this study was to investigate the potential for the intranasal (i.n.) co-administration of rhGH with poly-L-arginine (PLA) as a novel delivery system by evaluating the effects of the concentration and molecular weight of PLA on the nasal absorption of rhGH. The influence of the formation of insoluble aggregates and a soluble complex in the dosage formulation on nasal rhGH absorption was also evaluated by size-exclusion chromatography and ultrafiltration. PLA enhanced the nasal absorption of rhGH at each concentration and molecular weight examined. Nasal rhGH absorption increased dramatically when the PLA concentration was 1.0 % (w/v) due to the improved solubility of rhGH in the formulation. A delay in rhGH absorption was observed when the molecular weight of PLA was increased. This appeared to be because the increase in molecular weight caused the formation of a soluble complex. It seems that the PLA concentration affects the absorptionenhancing effect on rhGH, while the molecular weight of PLA affects the time when the maximum plasma rhGH concentration was reached (T max ) of rhGH after i.n. administration, mainly because of the interactions among rhGH, PLA, and additives. Therefore, the transnasal rhGH delivery system using PLA is considered to be a promising alternative to subcutaneous (s.c.) injection if these interactions are sufficiently controlled.Key words poly-L-arginine; nasal absorption; enhancer; recombinant human growth hormone Most peptide and protein medicinal drugs are administered clinically by injection. This invasive administration with a needle and syringe is associated with various problems, such as pain for the patients, the risk of trouble at the injection site, increased medical waste and the potential for complicated operation. Hence, an alternative route of administration is strongly desired. There have been numerous studies on the transmucosal delivery of peptide and protein drugs, such as oral, nasal, and pulmonary administration.1-3) However, these types of drugs are rapidly destroyed by the enzymes present in various organs, especially in the gastrointestinal tract, and have a limited permeation across the mucous membrane. Therefore, these drugs have low bioavailability.Recombinant human growth hormone (rhGH), a single polypeptide chain of 191 amino acids and a molecular mass of 22.1 kDa, is used to treat short stature in children caused by growth hormone deficiency, Turner's syndrome, or chronic renal failure. At present, rhGH is administered daily by subcutaneous (s.c.) injections. Therefore, compliance with rhGH therapy is often low, because children hate the pain caused by such injections. The compliance of patients affects the therapeutic outcome, because it is necessary to regularly administer injections of rhGH for the limited period of growth. 4,5) Hence, a novel rhGH deliver...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

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Development of a Transnasal Delivery System for Recombinant Human Growth Hormone (rhGH): Effects of the Concentration and Molecular Weight of Poly-L-arginine on the Nasal Absorption of rhGH in Rats

Kawashima

Uchida

Yamaki

et al. 2016

Biological & Pharmaceutical Bulletin

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“…22) Although Wang et al 23) reported that cationized gelatin with ethylenediamine enhanced the absorption of FD-4 after nasal administration, its enhancing potency were lower than that of PLA, 24) suggesting that amount of positive charge in a molecule may have a significance for the enhancing potency of polycations because there is a significant difference in number of amine residue between PLA and ethylenediaminated gelatin with comparable molecular weight. Thus, PLA appears to have the ability to increase drug absorption into the aqueous humor in a manner similar to that of those enhancers.…”

Section: Discussionmentioning

confidence: 99%