Effect of poly-l-arginine on the nasal absorption of FITC-dextran of different molecular weights and recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats

Miyamoto, Masahide; Natsume, Hideshi; Satoh, Izumi; Ohtake, Kazuo; Yamaguchi, Masatoshi; Kobayashi, Daisuke; Sugibayashi, Kenji; Morimoto, Yasunori

doi:10.1016/s0378-5173(01)00797-9

Cited by 42 publications

(33 citation statements)

References 33 publications

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“…Intravenous Bolus Injection Milnacipran hydrochloride in physiological saline (10,20, 60 mg/kg; 1.0 ml/kg; 10, 20, 60 mg/ml, respectively) was injected into the right jugular vein of the anesthetized rats (urethane, 25% (w/v), 1.0 g/kg i.p. ), and the animals underwent the same surgical procedure as in the i.n.…”

Section: Methodsmentioning

confidence: 99%

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Intranasal Administration of Milnacipran in Rats: Evaluation of the Transport of Drugs to the Systemic Circulation and Central Nervous System and the Pharmacological Effect

Uchida

Katoh

Mori

et al. 2011

Biological & Pharmaceutical Bulletin

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Section: Methodsmentioning

confidence: 99%

“…Milnacipran hydrochloride in physiological saline (10,20,30, 60 mg/kg; 2 ml/kg; 5, 10, 15, 30 mg/ml, respectively) was administered perorally via a sonde probe. The top of the sonde was placed in the cardiac region of the rat stomach.…”

Section: Methodsmentioning

confidence: 99%

Intranasal Administration of Milnacipran in Rats: Evaluation of the Transport of Drugs to the Systemic Circulation and Central Nervous System and the Pharmacological Effect

Uchida

Katoh

Mori

et al. 2011

Biological & Pharmaceutical Bulletin

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Section: )mentioning

confidence: 99%

“…Basic amino acid polymers such as poly-L-arginine (PLA) and poly-L-lysine (PLL) are also shown to effectively increase permeability of various compounds in nasal, tracheal, and kidney epithelia. [12][13][14] Although it is reported that PLL induces potential epithelial damages in tracheal epithelium, 13) PLA appears to enhance the absorption of hydrophilic molecules in mucosal tissues without producing any obvious epithelial changes, such as morphological alteration, leakage of cytosolic proteins, and release of phospholipids from the plasma membrane.15,16) Thus, PLA is considered to be an ideal permeation enhancer for epithelial drug delivery including ocular delivery.The purpose of the present study was to examine the enhancing effect of PLA on the permeability of hydrophilic compounds through the ocular epithelia. We investigated the permeability of FD-4 and pyridoxamine through the excised rabbit cornea, conjunctiva, and conjunctiva/sclera composite in the presence of different concentrations and molecular weights of PLA (14.0 kDa; PLA (10), 35.5 kDa; PLA (50), 141.4 kDa; PLA (100)).…”

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Effects of Poly-L-arginine on the Permeation of Hydrophilic Compounds through Surface Ocular Tissues

Nemoto¹,

Takahashi²,

Kobayashi³

et al. 2006

Biological & Pharmaceutical Bulletin

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Drugs that are topically applied to the cul-de-sac enter the intraocular area via both corneal and noncorneal pathways which are composed of cornea and conjunctiva-sclera, respectively.1) Although the corneal pathway is thought to be the primary route of intraocular entry for most drugs, penetration via the noncorneal pathway can also be important for the penetration of drugs which are poorly absorbed across the cornea. 2,3) In addition, the noncorneal pathway could be more important than the corneal pathway for the delivery of drugs to the posterior segment of the eye. 2,3)The first barrier to intraocular entry via the corneal and noncorneal pathways is the cornea and conjunctiva, respectively. These epithelial tissues are known to have tight junctions that act as a barrier in the paracellular spaces. 4,5) Because of this barrier structure in the epithelia, insufficient drug may be absorbed after instillation. Thus, subconjunctival and intravitreous injections are generally used in ocular pharmacotherapy.1) These invasive methods may not be acceptable to many patients and could potentially increase the risk of infection.6) In order to obtain a simpler and more acceptable form of application, the development of effective instilled formulations would be a major improvement. A number of ocular penetration enhancers, including calcium chelator (EDTA) and bile salts, have already been investigated, and it was found that those enhancers increased the apparent permeability coefficient (Papp) of FITC-dextran (MW: 4000, FD-4) by 2.9-to 15.5-fold in excised cornea and conjunctiva.7) However, these enhancers might not be acceptable from a safety point of view, because the following were observed: severe epithelial damage, such as a change in cellular morphology produced by EDTA and deoxycholate in the cornea, 8) leakage of cytosolic proteins produced by EDTA in the rectum, 9) and permeabilization caused by dissolution of the plasma membrane produced by bile salts. 10)Recently, a novel type of penetration enhancer has been developed for mucosal drug delivery. Illum et al. 11) showed that the polycationic compound, chitosan, greatly enhanced the absorption of insulin across the nasal mucosa in rats and sheep. Basic amino acid polymers such as poly-L-arginine (PLA) and poly-L-lysine (PLL) are also shown to effectively increase permeability of various compounds in nasal, tracheal, and kidney epithelia. [12][13][14] Although it is reported that PLL induces potential epithelial damages in tracheal epithelium, 13) PLA appears to enhance the absorption of hydrophilic molecules in mucosal tissues without producing any obvious epithelial changes, such as morphological alteration, leakage of cytosolic proteins, and release of phospholipids from the plasma membrane.15,16) Thus, PLA is considered to be an ideal permeation enhancer for epithelial drug delivery including ocular delivery.The purpose of the present study was to examine the enhancing effect of PLA on the permeability of hydrophilic compounds through the ocular epithelia....

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“…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.…”

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confidence: 91%

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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Effect of poly-l-arginine on the nasal absorption of FITC-dextran of different molecular weights and recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats

Cited by 42 publications

References 33 publications

Intranasal Administration of Milnacipran in Rats: Evaluation of the Transport of Drugs to the Systemic Circulation and Central Nervous System and the Pharmacological Effect

Intranasal Administration of Milnacipran in Rats: Evaluation of the Transport of Drugs to the Systemic Circulation and Central Nervous System and the Pharmacological Effect

Effects of Poly-L-arginine on the Permeation of Hydrophilic Compounds through Surface Ocular Tissues

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

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