Development of near zero-order release dosage forms using three-dimensional printing (3-DP) technology.
Three near zero-order controlled-release pseudoephedrine hydrochloride (PEH) formulations demonstrating proportional release rates were developed using 3-Dimensional Printing (3-DP) technology. Mixtures of Kollidon SR and hydroxypropylmethyl cellulose (HPMC) were used as drug carriers. The release rates were adjusted by varying the Kollidon SR-HPMC ratio while keeping fabrication parameters constant. The dosage forms were composed of an immediate release core and a release rate regulating shell, fabricated with an aqueous PEH and an ethanolic triethyl citrate (TEC) binder, respectively. The dosage form design called for the drug to be released via diffusional pathways formed by HPMC in the shell matrix. The release rate was shown to increase correspondingly with the fraction of HPMC contained in the polymer blend. The designed formulations resulted in dosage forms that were insensitive to changes in pH of the dissolution medium, paddle stirring rate, and the presence/absence of a sinker. The near zero-order release properties were unchanged regardless of the dissolution test being performed on either single cubes or on a group of eight cubes encased within a gelatin capsule shell. The chemical and dissolution properties of the three formulations remained unchanged following 1 month's exposure to 25 degrees C/60% RH or 40 degrees C/75% RH environment under open container condition. The in vivo performance of the three formulations was evaluated using a single-dose, randomized, open-label, four-way crossover clinical study composed of 10 fasted healthy volunteers. The pharmacokinetic parameters were analyzed using a noncompartmental model. Qualitative rank order linear correlations between in vivo absorption profiles and in vitro dissolution parameters (with slope and intercept close to unity and origin, respectively) were obtained for all three formulations, indicating good support for a Level A in vivo/in vitro correlation.
McNeil Consumer and Specialty Pharmaceuticals, Fort Washington, Pennsylvania 19034, USA. cwang12@mccus.jnj.com
Chen-Chao
CC
Wang
Monica R
MR
Tejwani Motwani
Willie J
WJ
Roach
Jennifer L
JL
Kay
Jaedeok
J
Yoo
Henry L
HL
Surprenant
Donald C
DC
Monkhouse
Timothy J
TJ
Pryor
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004809:Ephedrine / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D011205:Povidone / Q000737:chemistry*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000295:instrumentation*; D014867:Water / Q000737:chemistry
D003692:Delayed-Action Preparations; D014867:Water; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D011205:Povidone; D004809:Ephedrine