Transcript P94_Screening-ul in vitro al potentialului alcoolului de a induce

In-vitro screening of a potential alcohol-induced dose-dumping effect
for modified release formulations containing tramadol hydrochloride
Burcea Dragomiroiu George Traian Alexandru1, Miron Dalia Simona2, Ginghină Octav3*, Lupuliasa Dumitru4, Bârcă Maria1, Popa Daniela Elena1, Ciobanu Anne-Marie1, Rădulescu Flavian Ștefan5
University of Medicine and Pharmacy „Carol Davila” București
1Faculty of Pharmacy, Department of Drug Control, 6, Traian Vuia Street, 020956, Bucharest, România
2Faculty of Pharmacy, Department of Pharmaceutical Physics and Informatics, 6, Traian Vuia Street, 020956, Bucharest, România
3Faculty of Dental Medicine, Department of Oncological Surgery, „Sf Ioan” Hospital, 13, Vitan-Bârzești Street, 042122, Bucharest, România
4Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, 6, Traian Vuia Street, 020956, Bucharest, România
5Faculty of Pharmacy, Department of Drug Industry and Pharmaceutical Biotechnologies, 6, Traian Vuia Street, 020956, Bucharest, România
Corresponding author: [email protected]
OBJECTIVES
MATERIALS AND METHODS
Based on the specific composition and manufacturing process, the modified
release formulations have increased patient compliance, as well as improved
safety and efficacy profiles. Several regulatory guidance are focused on the
evaluation of factors susceptible to alter the in-vivo exposure profiles, after oral
administration, such as food intake. In 2005, Food and Drug Administration issued
an alert letter for healthcare professionals, pointing out a significant dosedumping effect induced by ethanol consumption on controlled release capsules
containing hydromorphone, leading to withdrawal of the product from the market.
The in-vitro dissolution tests were adopted as an adequate surrogate to evaluate
the changes in product performance, using ethanol in simulated gastric or
intestinal fluid without enzymes. The current paper presents the results obtained
by applying these tests to modified release formulations containing 100, 150 and
200 mg tramadol hydrochloride.
The in-vitro dissolution tests were
performed on 8 MR solid oral dosage
forms using USP apparatus 2 at 50
rpm and 900 ml simulated gastric fluid
containing 0, 5, 20 and 40% ethanol
(v/v, degassed by filtration under
vacuum). Each test was performed on
three dosing units, at 37°C. Samples
of 5 ml were collected every 15 min for
2 hours. The quantitative analysis of
tramadol hydrochloride was performed
by a spectrophotometric method
(λmax=271-272 nm).
RESULTS AND DISCUSSION
No dose dumping effect was observed. The fractions dissolved varied from 25-37% to 17-27% as the concentration of ethanol
was increased from 5 to 40%. The rank order of release rates, as well as the kinetic model adequately describing the release
process (Korsmeyer-Peppas model, except for Z100 and Z150 formulations, fitted with Higuchi model), were independent on
the composition of the release media.
The similarity was concluded between each generic product and the reference listed drug, and for different dose strengths of
the same product (qualitatively similar, according to the labeled composition). Nevertheless, it seems that increasing the
quantity of ethanol in the media reduces the in-vitro differences initially observed in the simulated gastric media.
A possible explanation is that several excipients present in the formulation, including macromolecular agents are insoluble in
ethanol or the swelling process in inhibited, compared to the aqueous media.
60
K100
K150
K150
K150
K200
50
L150
L150
L200
L200
L200
Z150
R
30
20
40
Z100
Fraction dissolved (%)
Z100
Z150
R
30
20
0%
ethanol
10
0
30
60
90
120
K150
40
5%
ethanol
10
L150
L200
Z100
Z150
R
30
30
60
90
120
40
Z100
Z150
R
30
20
20%
ethanol
10
40%
ethanol
10
0
0
Time (min)
K200
50
20
0
0
K100
K200
50
L150
Fraction dissolved (%)
Fraction dissolved (%)
40
60
K100
K200
50
60
K100
Fraction dissolved (%)
60
0
0
30
Time (min)
60
90
120
Time (min)
0
30
60
90
120
Time (min)
CONCLUSIONS
The in-vitro results indicated that the tested modified release formulations containing tramadol hydrochloride were robust with
respect to co-administration of ethanol. No dose-dumping effect was observed. The release rates were decreased as the
amount of ethanol was increased, probably due to the presence of insoluble excipients and/or inhibited swelling process.
ACKNOWLEDGEMENT
REFERENCES
This work was suported by the Sectorial Operational Programme Human
Resources (SOP HRD) 2007-2013, financed from the European Social
Fund and by the Romanian Gouvernment under the contract number
POSDRU/159/1.5/S/133377, „Program de excelență în cercetare
doctorală și postdoctorală” and by PN-II-PT-PCCA-2013-4-1903.
Roth W., Setnik B., Zietsch M., Burst A., Breitenbach J., Sellers E., Brennan D., Ethanol effects on drug
release from Verapamil Meltrex, an innovative melt extruded formulation. Int J Pharm. 2009;368(1-2):72-5.
Smith A.P., Moore T.W., Westenberger B.J., Doub W.H., In vitro dissolution of oral modified-release tablets
and capsules in ethanolic media. Int J Pharm. 2010;398(1-2):93-96.
U.S. FDA alert for healthcare professionals. Alcohol-PalladoneTM interaction. 2005.