PMID- 17174048
OWN - NLM
STAT- MEDLINE
DCOM- 20070622
LR  - 20190303
IS  - 0378-5173 (Print)
IS  - 0378-5173 (Linking)
VI  - 335
IP  - 1-2
DP  - 2007 Apr 20
TI  - In vitro formulation optimization of intranasal galantamine leading to enhanced 
      bioavailability and reduced emetic response in vivo.
PG  - 138-146
LID - S0378-5173(06)00970-7 [pii]
LID - 10.1016/j.ijpharm.2006.11.013 [doi]
AB  - The purpose of the current investigation was to optimize an intranasal (IN) 
      galantamine (an acetylcholinesterase inhibitor used for treatment of Alzheimer's 
      disease) formulation using an in vitro tissue model, to correlate those results 
      to in vivo bioavailability, and to compare emetic response to oral dosing. A 
      design-of-experiments (DOE) based formulation screening employing an in vitro 
      tissue model of human nasal epithelium was used to assess drug permeability, 
      tight junction modulation, and cellular toxicity. In vivo studies in rats 
      compared pharmacokinetic (PK) profiles of different formulations dosed 
      intranasally. Finally, studies in ferrets evaluated PK and gastrointestinal (GI) 
      related side effects of oral compared to nasal dosage forms. Galantamine 
      permeation was enhanced without increasing cytotoxicity. Pharmacokinetic testing 
      in rats confirmed the improved drug bioavailability and demonstrated an in 
      vitro-in vivo correlation. Compared to oral dosing, IN galantamine resulted in a 
      dramatically lowered incidence of GI-related side effects, e.g., retching and 
      emesis. These findings illustrate that IN delivery represents an attractive 
      alternative to oral dosing for this important Alzheimer's disease therapeutic. To 
      our knowledge, the data herein represent the first direct confirmation of 
      reducing GI-related side effects for IN galantamine compared to oral dosing.
FAU - Leonard, Alexis Kays
AU  - Leonard AK
AD  - Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, 
      USA.
FAU - Sileno, Anthony P
AU  - Sileno AP
AD  - Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, 
      USA.
FAU - Brandt, Gordon C
AU  - Brandt GC
AD  - Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, 
      USA.
FAU - Foerder, Charles A
AU  - Foerder CA
AD  - Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, 
      USA.
FAU - Quay, Steven C
AU  - Quay SC
AD  - Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, 
      USA.
FAU - Costantino, Henry R
AU  - Costantino HR
AD  - Nastech Pharmaceutical Company Inc., 3450 Monte Villa Parkway, Bothell, WA 98021, 
      USA. Electronic address: rcostantino@nastech.com.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20061116
PL  - Netherlands
TA  - Int J Pharm
JT  - International journal of pharmaceutics
JID - 7804127
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Excipients)
RN  - 0 (Phosphatidylcholines)
RN  - 0 (beta-Cyclodextrins)
RN  - 0 (didecanoylphosphatidylcholine)
RN  - 0 (methyl-beta-cyclodextrin)
RN  - 0D3Q044KCA (Galantamine)
RN  - 9G34HU7RV0 (Edetic Acid)
SB  - IM
MH  - Administration, Intranasal
MH  - Administration, Oral
MH  - Analysis of Variance
MH  - Animals
MH  - Biological Availability
MH  - Cell Membrane Permeability/drug effects
MH  - Cells, Cultured
MH  - Chemistry, Pharmaceutical
MH  - Cholinesterase Inhibitors/*administration & dosage/adverse 
      effects/chemistry/*pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Drug Compounding
MH  - Edetic Acid/pharmacology
MH  - Electric Impedance
MH  - Epithelial Cells/drug effects/metabolism
MH  - Excipients/chemistry/*pharmacology
MH  - Factor Analysis, Statistical
MH  - Ferrets
MH  - Galantamine/*administration & dosage/adverse effects/chemistry/*pharmacokinetics
MH  - Humans
MH  - Phosphatidylcholines/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Respiratory Mucosa/cytology/drug effects/metabolism
MH  - Tight Junctions/drug effects/metabolism
MH  - Vomiting/*chemically induced
MH  - beta-Cyclodextrins/pharmacology
EDAT- 2006/12/19 09:00
MHDA- 2007/06/23 09:00
CRDT- 2006/12/19 09:00
PHST- 2006/08/08 00:00 [received]
PHST- 2006/11/02 00:00 [revised]
PHST- 2006/11/03 00:00 [accepted]
PHST- 2006/12/19 09:00 [pubmed]
PHST- 2007/06/23 09:00 [medline]
PHST- 2006/12/19 09:00 [entrez]
AID - S0378-5173(06)00970-7 [pii]
AID - 10.1016/j.ijpharm.2006.11.013 [doi]
PST - ppublish
SO  - Int J Pharm. 2007 Apr 20;335(1-2):138-146. doi: 10.1016/j.ijpharm.2006.11.013. 
      Epub 2006 Nov 16.