The effect of gelatin cross-linking on the bioequivalence of hard and soft gelatin acetaminophen capsules.
OBJECTIVE
To determine if changes in the in vitro dissolution of hard and soft gelatin acetaminophen capsules, which result from gelatin crosslinking, are predictive of changes in the bioavailability of the capsules in humans.


METHODS
Both hard and soft gelatin capsules were "stressed" by a controlled exposure to formaldehyde, resulting in unstressed, moderately stressed and highly stressed capsules. In vitro dissolution studies were conducted using water or SGF with and without pepsin as the media. Separate 24-subject, 3-way crossover human bioequivalence studies were performed on the unstressed and stressed acetaminophen capsules. Plasma acetaminophen was determined by high performance liquid chromatography (HPLC) for 12 hr after each dose.


RESULTS
The in vitro rate of dissolution of hard and soft gelatin capsules was decreased by crosslinking. The bioequivalence studies showed that both hard and soft gelatin capsules, which failed to meet the USP dissolution specification in water, but complied when tested in SGF containing pepsin, were bioequivalent to the unstressed control capsules. The capsules that were cross-linked to the greatest extent were not bioequivalent to the unstressed control capsules, based on Cmax. A trend toward an increase in Cmax with increased level of cross-linking was observed, but this was only significant for the severely stressed capsules.


CONCLUSIONS
On the basis of this study a two-tier in vitro dissolution test was developed using enzymes to distinguish between bioequivalent and bioinequivalent gelatin capsules.
Meyer
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MC
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis 38163, USA. MMEYER@UTMEM.EDU
Straughn
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Mhatre
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Hussain
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Shah
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Cole
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Lesko
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Mallinowski
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Williams
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D000082:Acetaminophen / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002214:Capsules; D003432:Cross-Linking Reagents; D018592:Cross-Over Studies; D005079:Excipients / Q000737:chemistry*; D005780:Gelatin / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D012727:Sex Characteristics; D012995:Solubility; D013810:Therapeutic Equivalency
D018712:Analgesics, Non-Narcotic; D002214:Capsules; D003432:Cross-Linking Reagents; D005079:Excipients; D000082:Acetaminophen; D005780:Gelatin