- Email: [email protected]
Bioavailabilities of enteric coated and buffered salicylate tablets marketed in turkey in comparison with aspirinR tablets
(B), the jejunum (C,), the colon ascendens (Dr) and the colon descendens (4). 2. Rectal of an enema (R). 3. Oral application of I solution (repeated, Ar + A,). les were drawn 0 to 15 (A;B;C;D), and 0 to 4 (R) hours after drug application or release and I was an HPLC method. Differences in the absorption parameters were obtained by comparisons of data for each region of the GIT (starting point of the absorption process is the area in and beyond the drug release occurs). The I-concentration fell below the detection limit (2.5 ng/ml) within 8 hours after tion in 2/17 and after 15 hours in all cases. AUC was calculated using the trapezoidal rule, and ; C,, was obtained from the plasma concentration/time curves. The table shows the results (median,
~~~~~~on
nclusion: The intra-individual comparison of the AUC-values indicate a three-fold increase in the amount of 1 in the lower GIT, but C,_ is only slightly increased. Any first-pass effect of ipsapirone seems limited to gastrointestinal tract. Table AWC and C,_
of ipsapirone-HCI after application at different regions of the human gastrointestinal
AUC (g*h”mI-‘) median
Q
tract
4+2
B
c,
Q+2
it
337 129-1617
331 278-468
291 89492
1103 968-2053
1121 485-1578
18.5 9.6-29.2 7
15.9 12.1-17-l 4
28.1 25530.7 2
22.7 22.0-28.6 4
29.4 24.8-43.1 4
A-H. Staib, B-G. Woodcock, D. Loew, 0. Schuster (1989) Remote control of gastrointestinal drug delivery in man. In: Novel drug delivery and its therapeutic application (eds. L.F. Prescott, W.S. Nimmo), Chapter 8: John Wiley and Sons Ltd., Chichester.
icylate tablets markete tablets Ayanoglu-Dlger, Mamma
Univ. Sch. of Phamuaq
G., Kulaq, B. and Kabasakal,
Dept. of Pharmacology
Biiyiik+jlik
L.
sok. 6, 80200 Niqantqi,
Istanbul, Turkey
Salicylate therapy is often associated with gastric distress and irritation leading to gastrointestinal blood loss, especially on long-term treatment. In order to prevent or decrease this side effect salicylates are sometimes administered in enter&-coated or buffered tablets. In this study we investigated the bioavailabilities of two entericcoated (EC-l and EC-2) and two buffered (B-l and B-2) tablets marketed in Turkey in comparison with the ccmventirmal ---. -----_
acetvlralicvlirr ____,____~__
kid [ASA ..-a_ \. _I. -, tablet . ..‘aW.) .AmkimR “y”a..
(p_).
The study was carried out on two different occasions; in the first part 6, in the second part 8 healthy volunteers participated. Volunteers received the dosage forms in asingle dose,cross-over fashion. In each study one EC and one B tablet was compared with A and the bioavailabilities were determined from the total amount excreted in urine in 24 hrs. The total salicylate excreted was determined spectrophotometrically (Levy and Procknal, 1968) and was expressed as the percentage of dose administered. The statistical analysis of data was done according to the two way analysis of Variance. In both studies, enteric coating significantly delayed absorption; salicylate appeared in the urine only after two hours after a&str&~n, This was emectrd cinre thecp ~A=ron Akinteoaatinn U..” snrl .a~UI”.Y.~“I. Aiccnlldnn nnlv nftpr --I -.-r-----_a--____I_ tahlrtc II-I-.” ~~‘~“.~~ -“*‘a.‘~...~.“*. “S..J -a.“.
395
passing into the small intestine and the drug release rate of a well formulated EC tablet is primarily a furaction of gastric emptying time which is affected by many physiological factors even when the druey .~ is administered on --__-_--_-_-_ ___ an _ emntv ___r_= stomach. The total bioavailabiity of EC-l was significantly less than A whereas EC-2 had an availability close to that of A (Table 1). According to these findings we may suggest that even well formulated EC tablets should not be preferred when acute effect is desirable, but they may be the product of choice for long-term treatment with salicylates. Rate of absorption of B-l was somewhat slower and its total bioavailability was also significantly less than A. On the other hand, B-2 appeared in the urine at insignificantly higher levels than A during initial hours and showed good bioavailability (Table 1). AssuminQ rate of excretion is an indication of rate of absorption, our finding with salicvlate -----~~---y that __~~the ~~~_ -_-. the ___-buffered ---_---___,_-__ tablets raise the question that these formulations may not always be better than the conventional tablets in terms of disintegration, dissolution, oral absorption and therefor side-effects on gastrointestinal tract, supporting previous reports (Leonards and Levy, 1965, Chiou and Onyemelukwe, 1974). Table 1 nifferent C.I.V.V...
ralirvlsre Jx..e_.._.” nrrlm-t< 1mrp11 cttldv --am-l their .n....-,....-1-w .in . . the .-._ “_.._, . .._.. ~~~~y&!&il;t;e~.
Product
Content
Bioavaitability
A (AspirinR)
500 mg ASA
B-l B-2
450 mg ASA + 125 mg CaCq = 500 mg CaASA Ca carbasalate 500 mg + 400 mg AI(
95.85 f 0.49. and 95.56 f 4.87 79.26 f 4.21 94.45 f 5.30
EC-1 EC-2
500 mg Na Salicylate 500 mg ASA
76.99 + 3.47 90.84* 7.16
References LevyG. and Pracknal
J.A., 1968, J. Pharm Sci. 57,133O. Leonards J.R. and Levy G., 1968. J.A.M.A. 193.99. Chiou W.L. and Onyemelukwe I., 1974, J. Clin. Pharmacol. Nov. Dec., 597.
El
P.mo.224
ioavailability of (Ad*‘) Clementi,
rmr,;+u,a 2 xDhnrvn~nlnmv ~,,O‘,I”‘C v, ,,” ,,,I YLY.“~,
~nknnl
G., Parini nf
MoAiri.rp
*, J., Mazzetti
Ilninerritu
nf
fhtnnin
*, A. and Prato, A.
-..UC,.““. v, ..a-w......-, ~,..“_‘“.., -, ___-.__- aad
*
I,S_F: Resewch
L.&r~torv ,t Milan, Ita&
The comparative pharmacokinetics of the a-aminosuberic acid of eel-calcitonin [(As&‘)eel-CT] after single i-m. or after nasal spray administration was investigated in 12 healthy volunteers in a cross-over study. For the i-m. administration, 40 MRC units were used; for the nasal spray route, two dose levels (1 puff of 20 MRC units each nostril = 40 MRC units; B puff of 40 MRC units each nostril = 80 MRC units) were administered. Blood samples were collected at time 0, and 5, 10, 15, 20, 25, 30, 35, 40 and 45 minutes after (Asu’*‘)eel-CT administration, immediately frozen and stored at -20°C. The analytical determination of plasma (Asu’*‘)eel-CT in each sample was performed in triplicate by RIA. The Cmax values (plasmatic concentration at the Tmax) after nasal spray administration of 40 and 80 MRC of (Asul~‘)eel-CT were 96.5 f 6.8 and 192.6 f 14.0 pg/ml, respectively; the value obtained after injection of 40 MRC i.m. was 244.0 _b 20.8 pg/ml; no significant difference was present between the doses of 80 MRC (Asu’*‘)eel-CT by nasal spray and 40 MRC admitistered i.m. The areas under the curve (AUC) after the dose of 40 MRC and 80 MRC nasal spray were 2058 of 153 and 3405 f 114 pg. min./ml, respectively. Administration of 40 MRC i.m. determined an AUC -._I-.__c -DC,?# ICI? __ _:_ ,_, 7q.a,, A,* n rmmnnnc+ *k-t n hk=nn~kmlenr~ &ctc hetween the au~K+r IYI u “rv”y”. . . ..w.._v _._“._ --.- ---_--- doses of 40 and 80 MRC WiIuC 01 JOOJ r 17L p&IlUll/ LLII. 1 1,585 “Qua l
~~~~~~on
nclusion: The intra-individual comparison of the AUC-values indicate a three-fold increase in the amount of 1 in the lower GIT, but C,_ is only slightly increased. Any first-pass effect of ipsapirone seems limited to gastrointestinal tract. Table AWC and C,_
of ipsapirone-HCI after application at different regions of the human gastrointestinal
AUC (g*h”mI-‘) median
Q
tract
4+2
B
c,
Q+2
it
337 129-1617
331 278-468
291 89492
1103 968-2053
1121 485-1578
18.5 9.6-29.2 7
15.9 12.1-17-l 4
28.1 25530.7 2
22.7 22.0-28.6 4
29.4 24.8-43.1 4
A-H. Staib, B-G. Woodcock, D. Loew, 0. Schuster (1989) Remote control of gastrointestinal drug delivery in man. In: Novel drug delivery and its therapeutic application (eds. L.F. Prescott, W.S. Nimmo), Chapter 8: John Wiley and Sons Ltd., Chichester.
icylate tablets markete tablets Ayanoglu-Dlger, Mamma
Univ. Sch. of Phamuaq
G., Kulaq, B. and Kabasakal,
Dept. of Pharmacology
Biiyiik+jlik
L.
sok. 6, 80200 Niqantqi,
Istanbul, Turkey
Salicylate therapy is often associated with gastric distress and irritation leading to gastrointestinal blood loss, especially on long-term treatment. In order to prevent or decrease this side effect salicylates are sometimes administered in enter&-coated or buffered tablets. In this study we investigated the bioavailabilities of two entericcoated (EC-l and EC-2) and two buffered (B-l and B-2) tablets marketed in Turkey in comparison with the ccmventirmal ---. -----_
acetvlralicvlirr ____,____~__
kid [ASA ..-a_ \. _I. -, tablet . ..‘aW.) .AmkimR “y”a..
(p_).
The study was carried out on two different occasions; in the first part 6, in the second part 8 healthy volunteers participated. Volunteers received the dosage forms in asingle dose,cross-over fashion. In each study one EC and one B tablet was compared with A and the bioavailabilities were determined from the total amount excreted in urine in 24 hrs. The total salicylate excreted was determined spectrophotometrically (Levy and Procknal, 1968) and was expressed as the percentage of dose administered. The statistical analysis of data was done according to the two way analysis of Variance. In both studies, enteric coating significantly delayed absorption; salicylate appeared in the urine only after two hours after a&str&~n, This was emectrd cinre thecp ~A=ron Akinteoaatinn U..” snrl .a~UI”.Y.~“I. Aiccnlldnn nnlv nftpr --I -.-r-----_a--____I_ tahlrtc II-I-.” ~~‘~“.~~ -“*‘a.‘~...~.“*. “S..J -a.“.
395
passing into the small intestine and the drug release rate of a well formulated EC tablet is primarily a furaction of gastric emptying time which is affected by many physiological factors even when the druey .~ is administered on --__-_--_-_-_ ___ an _ emntv ___r_= stomach. The total bioavailabiity of EC-l was significantly less than A whereas EC-2 had an availability close to that of A (Table 1). According to these findings we may suggest that even well formulated EC tablets should not be preferred when acute effect is desirable, but they may be the product of choice for long-term treatment with salicylates. Rate of absorption of B-l was somewhat slower and its total bioavailability was also significantly less than A. On the other hand, B-2 appeared in the urine at insignificantly higher levels than A during initial hours and showed good bioavailability (Table 1). AssuminQ rate of excretion is an indication of rate of absorption, our finding with salicvlate -----~~---y that __~~the ~~~_ -_-. the ___-buffered ---_---___,_-__ tablets raise the question that these formulations may not always be better than the conventional tablets in terms of disintegration, dissolution, oral absorption and therefor side-effects on gastrointestinal tract, supporting previous reports (Leonards and Levy, 1965, Chiou and Onyemelukwe, 1974). Table 1 nifferent C.I.V.V...
ralirvlsre Jx..e_.._.” nrrlm-t< 1mrp11 cttldv --am-l their .n....-,....-1-w .in . . the .-._ “_.._, . .._.. ~~~~y&!&il;t;e~.
Product
Content
Bioavaitability
A (AspirinR)
500 mg ASA
B-l B-2
450 mg ASA + 125 mg CaCq = 500 mg CaASA Ca carbasalate 500 mg + 400 mg AI(
95.85 f 0.49. and 95.56 f 4.87 79.26 f 4.21 94.45 f 5.30
EC-1 EC-2
500 mg Na Salicylate 500 mg ASA
76.99 + 3.47 90.84* 7.16
References LevyG. and Pracknal
J.A., 1968, J. Pharm Sci. 57,133O. Leonards J.R. and Levy G., 1968. J.A.M.A. 193.99. Chiou W.L. and Onyemelukwe I., 1974, J. Clin. Pharmacol. Nov. Dec., 597.
El
P.mo.224
ioavailability of (Ad*‘) Clementi,
rmr,;+u,a 2 xDhnrvn~nlnmv ~,,O‘,I”‘C v, ,,” ,,,I YLY.“~,
~nknnl
G., Parini nf
MoAiri.rp
*, J., Mazzetti
Ilninerritu
nf
fhtnnin
*, A. and Prato, A.
-..UC,.““. v, ..a-w......-, ~,..“_‘“.., -, ___-.__- aad
*
I,S_F: Resewch
L.&r~torv ,t Milan, Ita&
The comparative pharmacokinetics of the a-aminosuberic acid of eel-calcitonin [(As&‘)eel-CT] after single i-m. or after nasal spray administration was investigated in 12 healthy volunteers in a cross-over study. For the i-m. administration, 40 MRC units were used; for the nasal spray route, two dose levels (1 puff of 20 MRC units each nostril = 40 MRC units; B puff of 40 MRC units each nostril = 80 MRC units) were administered. Blood samples were collected at time 0, and 5, 10, 15, 20, 25, 30, 35, 40 and 45 minutes after (Asu’*‘)eel-CT administration, immediately frozen and stored at -20°C. The analytical determination of plasma (Asu’*‘)eel-CT in each sample was performed in triplicate by RIA. The Cmax values (plasmatic concentration at the Tmax) after nasal spray administration of 40 and 80 MRC of (Asul~‘)eel-CT were 96.5 f 6.8 and 192.6 f 14.0 pg/ml, respectively; the value obtained after injection of 40 MRC i.m. was 244.0 _b 20.8 pg/ml; no significant difference was present between the doses of 80 MRC (Asu’*‘)eel-CT by nasal spray and 40 MRC admitistered i.m. The areas under the curve (AUC) after the dose of 40 MRC and 80 MRC nasal spray were 2058 of 153 and 3405 f 114 pg. min./ml, respectively. Administration of 40 MRC i.m. determined an AUC -._I-.__c -DC,?# ICI? __ _:_ ,_, 7q.a,, A,* n rmmnnnc+ *k-t n hk=nn~kmlenr~ &ctc hetween the au~K+r IYI u “rv”y”. . . ..w.._v _._“._ --.- ---_--- doses of 40 and 80 MRC WiIuC 01 JOOJ r 17L p&IlUll/ LLII. 1 1,585 “Qua l