Preactivated thiomers for intranasal delivery of apomorphine: In vitro and in vivo evaluation.
The purpose of this study was to synthesize preactivated thiomers with different degrees of preactivation and to evaluate their potential as novel excipient for nasal apomorphine administration. The thiomer (PAA-cys) was synthesized by addition of thiol groups on poly(acrylic acid) with various molecular mass including 100, 250and450kDafollowed by immobilization of 2-mercaptonicotinic acid (2MNA) to thiol groups by disulfide bond formation resulting in PAA-cys-2MNA. These thiomers (PAA100-cys, PAA250-cys and PAA450-cys) were in the next step preactivated by 56.3, 59.5 and 46.5% (medium degree), and 80.1, 81.6 and 87% (high degree), respectively. Apomorphine permeation across porcine nasal mucosa in the presence of PAA100-cys-2MNA, PAA250-cys-2MNA and PAA450-cys-2MNA with high degree of preactivation was 3.1-, 4.4- and 4.1-fold, while 2.7-, 3.4- and 3.0-fold higher than control for medium degree of preactivation, respectively. Administration of apomorphine in the presence of PAA250-cys-2MNA showed in rats 9 and ∼2-fold improvement of relative bioavailability compared with oral and intranasal administration of apomorphine solution, respectively. Because of the pronounced improvement among other polymers, PAA250-cys-2MNA with high degree of preactivation could be considered as promising excipient for nasal delivery of apomorphine.
Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria; Faculty of Pharmacy, Thammasat University, Rungsit Campus, Phahonyothin Road, Khlong Luang, Pathumthani 12120, Thailand.
Kesinee
K
Netsomboon
Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Alexandra
A
Partenhauser
Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Julia
J
Rohrer
Division of Developmental Immunology, Center of Biomodels and Experimental Medicine (CBEM), Innsbruck Medical University, Innrain 80/82, 6020 Innsbruck, Austria.
Nadine
N
Elli Sündermann
Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Felix
F
Prüfert
Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Wongsakorn
W
Suchaoin
Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Flavia
F
Laffleur
Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
Andreas
A
Bernkop-Schnürch
D000180:Acrylic Resins / Q000737:chemistry; D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage* / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects; D009539:Nicotinic Acids / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013552:Swine
D000180:Acrylic Resins; D004220:Disulfides; D004337:Drug Carriers; D009539:Nicotinic Acids; D011108:Polymers; D013438:Sulfhydryl Compounds; C000616114:poly(acrylic acid)-cysteine-2-mercaptonicotinic acid; C083470:2-mercaptonicotinic acid; D003545:Cysteine; D001058:Apomorphine
2-Mercaptonicotinic acid; Nasal mucosa; Permeation; Poly(acrylic acid); l-Cysteine