title: Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies.
abstract: BACKGROUND
  Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats).
  
  
  OBJECTIVE
  The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions.
  
  
  METHODS
  Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies.
  
  
  RESULTS
  The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil(®), 13.44% Cremophor(®) RH40, 6.72% Labrasol(®), and 5.04% Transcutol(®) HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro(®)). The microemulsion gel irritated the skin less than Neupro.
  
  
  CONCLUSIONS
  A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability.
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Hong-Jie
authors.initials: HJ
authors.lastname: Mu
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Peng-Kai
authors.initials: PK
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Lian
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Feng-Pu
authors.initials: FP
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chu
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China ; State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, Shandong Province, People's Republic of China.
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, Shandong Province, People's Republic of China.
authors.forename: Wen-Yan
authors.initials: WY
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Yantai University, Yantai, Shandong Province, People's Republic of China.
authors.forename: Kao-Xiang
authors.initials: KX
authors.lastname: Sun
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D004337:Drug Carriers / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D004655:Emulsions / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D012867:Skin / Q000187:drug effects*; D023422:Skin Irritancy Tests; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D004337:Drug Carriers; D004655:Emulsions; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; C047508:rotigotine
keywords: central composite design; pseudoternary phase diagrams; transdermal