Ability of Poly-L-arginine to Enhance Drug Absorption into Aqueous Humor and Vitreous Body after Instillation in Rabbits

The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential t...

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Published inBiological & pharmaceutical bulletin Vol. 30; no. 9; pp. 1768 - 1772
Main Authors Ueda, Hideo, Nemoto, Eiichi, Morimoto, Yasunori, Akimoto, Masayuki, Natsume, Hideshi
Format Journal Article
LanguageEnglish
Published Japan The Pharmaceutical Society of Japan 01.09.2007
Japan Science and Technology Agency
Subjects
Online AccessGet full text
ISSN0918-6158
1347-5215
1347-5215
DOI10.1248/bpb.30.1768

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Abstract The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-α, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-α, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation.
AbstractList The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-alpha, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-alpha, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation.The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-alpha, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-alpha, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation.
The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-α, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-α, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation.
The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-alpha, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-alpha, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation.
Author Nemoto, Eiichi
Natsume, Hideshi
Morimoto, Yasunori
Akimoto, Masayuki
Ueda, Hideo
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References_xml – reference: 8) Ohtake K., Maeno T., Ueda H., Natsume H., Morimoto Y., Pharm. Res., 20, 153—160 (2003).
– reference: 20) Podder S. K., Moy K. C., Lee V. H., Exp. Eye Res., 54, 747—757 (1992).
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– reference: 9) Ohtake K., Maeno T., Ueda H., Ogihara M., Natsume H., Morimoto Y., Pharm. Res., 20, 1838—1845 (2003).
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– reference: 21) Ismail I. M., Chen C. C., Richman J. B., Andersen J. S., Tang-Liu D. D., Pharm. Res., 9, 817—821 (1992).
– reference: 7) Nemoto E., Takahashi H., Kobayashi D., Ueda H., Morimoto Y., Biol. Pham. Bull., 29, 155—160 (2006).
– reference: 12) Bisp M., Bor M. V., Heinsvig E. M., Kall M. A., Nexo E., Anal. Biochem., 305, 82—89 (2002).
– reference: 5) Natsume H., Iwata S., Ohtake K., Miyamoto M., Yamaguchi M., Hosoya K., Kobayashi D., Sugibayashi K., Morimoto Y., Int. J. Pharm., 185, 1—12 (1999).
– reference: 14) Holzer M. P., Solomon K. D., Vroman D. T., Vargas L. G., Sandoval H. P., Kasper T. J., Apple D. J., J. Cataract Refract. Surg., 29, 542—549 (2003).
– reference: 26) Cunningham E. T., Jr., Adamis A. P., Altaweel M., Aiello L. P., Bressler N. M., D'Amico D. J., Goldbaum M., Guyer D. R., Katz B., Patel M., Schwartz S. D., Ophthalmology, 112, 1747—1757 (2005).
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– reference: 16) Sakanaka K., Kawazu K., Tomonari M., Kitahara T., Nakashima M., Kawakami S., Nishida K., Nakamura J., Sasaki H., Pharm. Res., 21, 770—776 (2004).
– reference: 3) van der Lubben I. M., Verhoef J. C., Borchard G., Junginger H. E., Eur. J. Pharm. Sci., 14, 201—207 (2001).
– reference: 19) Yamamura K., Sasaki H., Nakashima M., Ichikawa M., Mukai T., Nishida K., Nakamura J., Pharm. Res., 16, 1596—1601 (1999).
– reference: 18) Acheampong A. A., Shackleton M., John B., Burke J., Wheeler L., Tang-Liu D., Drug Metab. Dispos., 30, 421—429 (2002).
– reference: 2) Thanou M., Verhoef J. C., Junginger H. E., Adv. Drug Deliv. Rev., 50 (Suppl. 1), S91—S101 (2001).
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– reference: 23) Wang J., Sakai S., Deguchi Y., Bi D., Tabata Y., Morimoto K., J. Pharm. Pharmacol., 54, 181—188 (2002).
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Snippet The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in...
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StartPage 1768
SubjectTerms Absorption
absorption enhancer
Animals
Aqueous Humor - drug effects
Aqueous Humor - metabolism
Blotting, Western
Chromatography, High Pressure Liquid
Corneal Stroma - drug effects
Corneal Stroma - metabolism
Epithelium, Corneal - drug effects
Epithelium, Corneal - metabolism
inflammation
Inflammation - pathology
instillation
Lipopolysaccharides - pharmacology
Male
Peptides - pharmacology
Pharmaceutical Preparations - metabolism
poly-L-arginine
Rabbits
Stimulation, Chemical
Tumor Necrosis Factor-alpha - pharmacology
Vitreous Body - drug effects
Vitreous Body - metabolism
Title Ability of Poly-L-arginine to Enhance Drug Absorption into Aqueous Humor and Vitreous Body after Instillation in Rabbits
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