Eur J Clin Pharmacol (1990) 38:207-208 European J. . . . I of
~ @~(~
© Springer-Verlag 1990
Comparative bioavailability of diclofenac hydroxyethylpyrrolidine vs diclofenac sodium in man C. A. Maggi 1, R Lualdi% and G. Mautone 2 J Ospedale Costantino Cantu; Abbiategrasso, Italy and 2 Istituto Biochimico SA, Lugano, Switzerland
Summary. A pharmacokinetic study in man has been made of a new dosage form of diclofenac hydroxyethylpyrrolidine ( D I E P ) ; soluble salt p a c k e d in sachets was c o m p a r e d with diclofenac s o d i u m as enteric coated tablets. Oral D I E P 2 x 50 mg s h o w e d a significant difference in absorption kinetics (ka, lag time and tmax) as c o m p a r e d to oral diclofenac sodium 2 x 50 mg. A relevant plasma c o n c e n t r a t i o n of diclofenac was detected just 15 min after D I E R while diclofenac s o d i u m p r o d u c e d a m e a s u r a b l e plasma c o n c e n t r a t i o n only 0 . 5 - 1 h after the treatment.
f~
\
\
\
1600
•
DtEP ( s a c h e t s )
[]
(tablets)
1200
D i c l o f e n a c Na
800
/ •
~'\\N
S
[] I
ability, healthy subjects, diclofenac h y d r o x y e t h y l p y r r o lidine
Diclofenac, a nonsteroidal anti-inflammatory agent (NSAID) of the aryl-acetic acid class has potent and well
The investigation was carried out on 12 in-patients, 6 women and 6 men, mean age 51.9 (SD 5.7) y. All the subjects suffered from chronic arthrosis, which periodically became acute. The subjects were otherwise healthy, and they did not have any serious cardiovascular, liver or kidney disorders. No patient suffered from gastric or gastroduodenal ulcers. The patients were given, at random, according to a cross-over design, one of the two preparations tested: DIEP asachets 50 mg (as diclofenac sodium) or diclofenac sodium b 50 mg enteric coated tablets. The oral treatment consisted of 2 sachets DIEP (corresponding to 100 mg diclofenac) dissolved in half a glass of
o
,
0
Key words: diclofenac; oral administration, bioavail-
Material and methods
\ \ \ \ \ \ \
400
100% ).
k n o w n antiphlogistic, analgesic and antipyretic p r o p e r ties. Diclofenac is e m p l o y e d as the sodium salt in preparations for oral, rectal and intramuscular use. It has b e e n p r o v e d to be very efficacious in i n f l a m m a t o r y and degenerative r h e u m a t i c conditions, as well as in the treatm e n t of painful diseases and fevers [1]. A new salt of diclofenac with h y d r o x y e t h y l p y r r o l i d i n e ( D I E P ) has recently b e e n developed, which is m u c h m o r e soluble in water than the sodium salt E u r o p e a n Patent application No: 87116513.0. T h e n e w salt allows the p r e p a r a t i o n of stable granular formulations in sachets for oral use. T h e bioavailability in m a n of the n e w granular f o r m and m a r k e t e d tablets of diclofenac s o d i u m are c o m p a r e d here.
2000 I\
Cmaxand tl/2 after D I E P and diclofenac s o d i u m were comparable. C o m p a r i s o n of the two A U C values s h o w e d that D I E P was bioequivalent to diclofenac s o d i u m (Q =
3
,
4 Time (h)
,
T
5
6
7
8
Fig. 1. Mean plasma concentrations of diclofenac (ng/ml) after oral administration of DIEP sachets and enteric coated diclofenac sodium tablets. Dose in both treatments was 100 mg diclofenac
FLECTOR, granules in sachets (50 mg as diclofenac sodium) Batch 19/IB-9, IBSA Institut Biochimique S.A., Lugano, CH. b VOLTARENE, enteric coated tablets 50 mg, Batch 047800, Geigy, Basel, CH, from the hospital pharmacy.
C. A. Maggi et al.: Bioavailability of Diclofenac
208 Table 1. Mean (SD) plasma concentrations (ng/ml) of diclofenac
after oral administration of DIEP sachets or diclofenac sodium enteric coated tablets to 12 patients. (100 mg didofenac sodium given in both instances) Time h
Treatment DIEP
0.25 224 0.5 1970 1 1700 2 742 3 358 4 197 6 71.7 8 30.5 a = Means "not detectable"
diclofenac sodium
(83.8) (847) (570) (229) (149) (82.9) (19.7) (11.5)
a 80.7 226 1380 1240 520 104 38.8
(25.9) (152) (990) (912) (373) (40.5) (19.0)
Table 2. Mean ( + SD) pharmacokinetic parameters of DIEP and
diclofenac sodium Pharmacokinetic parameter Tmax (h)
diclofenac sodium 2.5 (0.67)
DIEP
Cma~(ng. ml- 1)
2100 (660)
2330 (497)
NS a
AUC (ng.ml l-h)
3810 (884)
3620 (715)
NS a
ha (h)
0.91 (0.22)
0.84 (0.38)
NS a
ka
0.92 (0.30) 0.25 (0.11)
1.32 (0.30) 0.012 (0.028)
< 0.001
lag time
0.62 (0.22)
P (Student's t test) < 0.001
curve) s h o w e d an i m p o r t a n t difference in the kinetic absorption p a r a m e t e r s (Table 2): the m e a n lag time (appearance of drug in the b l o o d stream) was 0.012 (0.028) h for D I E P and 0.25 (0.11) h for diclofenac s o d i u m (P < 0.001). R e l e v a n t concentrations of diclofenac were detected in the b l o o d of 11 patients 15 min after D I E P treatment, while after diclofenac s o d i u m drug could only be d e t e c t e d in certain plasma samples after 0.5-1 h. T h e m e a n absorption rate (ka) was 1.32 (0.3) for D I E P and 0.92 (0.3) for diclofenac sodium (P < 0.001). T h e time required to reach the p e a k level after the single doses of the two forms of diclofenac was 0.62 (0.25) h for D I E P and 2.5 (0.67) h for diclofenac s o d i u m (P < 0.001). With b o t h formulations, appreciable plasma concentrations of diclofenac were o b s e r v e d up to the 6 t h - 8 t h h after treatment. T h e m e a n values for Cmax, tla and A U C o b t a i n e d after D I E P and diclofenac sodium administrations are shown in Table 2. Statistical analysis of these p a r a m e t e r s did not show any significant difference.
Discussion
< 0.001
Q% Quotient of 100.7 Bioavailability b (31.2) a NS = not significant b The Quotient of bioavailability of diclofenac sodium was considered to be 100%
T h e p h a r m a c o k i n e t i c results o b t a i n e d here for the enteric c o a t e d tablets of diclofenac s o d i u m are in a g r e e m e n t with those described previously by Riess [4] and Willis [5] in healthy volunteers. A f t e r oral administration of enteric c o a t e d tablets of diclofenac sodium, diclofenac only app e a r e d in the b l o o d s t r e a m 30-60 min after dosing, and its m e a n p e a k level was o b t a i n e d 2.5 (0.67) h after treatment. Diclofenac h y d r o x y e t h y l p y r r o l i d i n e ( D I E P ) sachets were f o u n d to be entirely bioequivalent to diclofenac s o d i u m enteric c o a t e d tablets, as s h o w n by their respective A U C values. O n the other hand, oral D I E P was a b s o r b e d faster than diclofenac sodium, p r o d u c i n g a detectable b l o o d level of diclofenac 15 min after treatment.
References
water, or 2 tablets diclofenac sodium (corresponding to 100 mg diclofenac) taken with half a glass of water. Blood was collected 0, 0.25, 0.5,1, 2, 3, 4, 6 and 8 h after treatment. Plasma concentrations of diclofenac were determined by the gas chromatographic method of Geiger [2], and pharmacokinetic parameters were calculated using the "GPHARM" programme [3]. The bioavailability (Q %) was calculated as: Q% =
AUC (DIEP) .100 AUC (diclofenac sodium)
The difference between the two oral formulations was evaluated by the paired Student's "t" test.
Results
T h e m e a n plasma concentrations of diclofenac in all 12 patients after oral t r e a t m e n t with D I E P 50 m g sachets (2 x 50 mg) or diclofenac sodium 50 mg enteric coated tablets (2 x 50 mg), are shown in Table 1, and are graphically illustrated in Fig. 1. C o m p a r i s o n of the plasma D I E P and diclofenac sodium concentrations versus time (c, t,
1. Brogden RN (1980) Diclofenac sodium: a review of its pharmacological properties and therapeutic use in rheumatic diseases and pain of varying origin. Drugs 20:24-48 2. Geiger P (1975) Quantitative assay of diclofenac in biological material by gas liquid chromatography. J Chromatogr 111:293-298 3. Gomeni C, Gomeni R (1978) GPHARM: Interactive Graphic Package for Pharmacokinetics Analysis. Comput B iomed Res 11: 345-361 4. Riess W (1978) Pharmacokinetics and metabolism of the anti-inflammatory agent Voltarene. Scand J Rheumatol [Suppl] 22: 1729 5. Willis JV et al. (1979) The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmaco116: 405-410 Received: June 30,1989 Accepted in revised form: September 5,1989 Dr. G. Mautone IBSA-Institut Biochimique SA Via al Ponte 13 CH-6903 Lugano, Switzerland
~ @~(~
© Springer-Verlag 1990
Comparative bioavailability of diclofenac hydroxyethylpyrrolidine vs diclofenac sodium in man C. A. Maggi 1, R Lualdi% and G. Mautone 2 J Ospedale Costantino Cantu; Abbiategrasso, Italy and 2 Istituto Biochimico SA, Lugano, Switzerland
Summary. A pharmacokinetic study in man has been made of a new dosage form of diclofenac hydroxyethylpyrrolidine ( D I E P ) ; soluble salt p a c k e d in sachets was c o m p a r e d with diclofenac s o d i u m as enteric coated tablets. Oral D I E P 2 x 50 mg s h o w e d a significant difference in absorption kinetics (ka, lag time and tmax) as c o m p a r e d to oral diclofenac sodium 2 x 50 mg. A relevant plasma c o n c e n t r a t i o n of diclofenac was detected just 15 min after D I E R while diclofenac s o d i u m p r o d u c e d a m e a s u r a b l e plasma c o n c e n t r a t i o n only 0 . 5 - 1 h after the treatment.
f~
\
\
\
1600
•
DtEP ( s a c h e t s )
[]
(tablets)
1200
D i c l o f e n a c Na
800
/ •
~'\\N
S
[] I
ability, healthy subjects, diclofenac h y d r o x y e t h y l p y r r o lidine
Diclofenac, a nonsteroidal anti-inflammatory agent (NSAID) of the aryl-acetic acid class has potent and well
The investigation was carried out on 12 in-patients, 6 women and 6 men, mean age 51.9 (SD 5.7) y. All the subjects suffered from chronic arthrosis, which periodically became acute. The subjects were otherwise healthy, and they did not have any serious cardiovascular, liver or kidney disorders. No patient suffered from gastric or gastroduodenal ulcers. The patients were given, at random, according to a cross-over design, one of the two preparations tested: DIEP asachets 50 mg (as diclofenac sodium) or diclofenac sodium b 50 mg enteric coated tablets. The oral treatment consisted of 2 sachets DIEP (corresponding to 100 mg diclofenac) dissolved in half a glass of
o
,
0
Key words: diclofenac; oral administration, bioavail-
Material and methods
\ \ \ \ \ \ \
400
100% ).
k n o w n antiphlogistic, analgesic and antipyretic p r o p e r ties. Diclofenac is e m p l o y e d as the sodium salt in preparations for oral, rectal and intramuscular use. It has b e e n p r o v e d to be very efficacious in i n f l a m m a t o r y and degenerative r h e u m a t i c conditions, as well as in the treatm e n t of painful diseases and fevers [1]. A new salt of diclofenac with h y d r o x y e t h y l p y r r o l i d i n e ( D I E P ) has recently b e e n developed, which is m u c h m o r e soluble in water than the sodium salt E u r o p e a n Patent application No: 87116513.0. T h e n e w salt allows the p r e p a r a t i o n of stable granular formulations in sachets for oral use. T h e bioavailability in m a n of the n e w granular f o r m and m a r k e t e d tablets of diclofenac s o d i u m are c o m p a r e d here.
2000 I\
Cmaxand tl/2 after D I E P and diclofenac s o d i u m were comparable. C o m p a r i s o n of the two A U C values s h o w e d that D I E P was bioequivalent to diclofenac s o d i u m (Q =
3
,
4 Time (h)
,
T
5
6
7
8
Fig. 1. Mean plasma concentrations of diclofenac (ng/ml) after oral administration of DIEP sachets and enteric coated diclofenac sodium tablets. Dose in both treatments was 100 mg diclofenac
FLECTOR, granules in sachets (50 mg as diclofenac sodium) Batch 19/IB-9, IBSA Institut Biochimique S.A., Lugano, CH. b VOLTARENE, enteric coated tablets 50 mg, Batch 047800, Geigy, Basel, CH, from the hospital pharmacy.
C. A. Maggi et al.: Bioavailability of Diclofenac
208 Table 1. Mean (SD) plasma concentrations (ng/ml) of diclofenac
after oral administration of DIEP sachets or diclofenac sodium enteric coated tablets to 12 patients. (100 mg didofenac sodium given in both instances) Time h
Treatment DIEP
0.25 224 0.5 1970 1 1700 2 742 3 358 4 197 6 71.7 8 30.5 a = Means "not detectable"
diclofenac sodium
(83.8) (847) (570) (229) (149) (82.9) (19.7) (11.5)
a 80.7 226 1380 1240 520 104 38.8
(25.9) (152) (990) (912) (373) (40.5) (19.0)
Table 2. Mean ( + SD) pharmacokinetic parameters of DIEP and
diclofenac sodium Pharmacokinetic parameter Tmax (h)
diclofenac sodium 2.5 (0.67)
DIEP
Cma~(ng. ml- 1)
2100 (660)
2330 (497)
NS a
AUC (ng.ml l-h)
3810 (884)
3620 (715)
NS a
ha (h)
0.91 (0.22)
0.84 (0.38)
NS a
ka
0.92 (0.30) 0.25 (0.11)
1.32 (0.30) 0.012 (0.028)
< 0.001
lag time
0.62 (0.22)
P (Student's t test) < 0.001
curve) s h o w e d an i m p o r t a n t difference in the kinetic absorption p a r a m e t e r s (Table 2): the m e a n lag time (appearance of drug in the b l o o d stream) was 0.012 (0.028) h for D I E P and 0.25 (0.11) h for diclofenac s o d i u m (P < 0.001). R e l e v a n t concentrations of diclofenac were detected in the b l o o d of 11 patients 15 min after D I E P treatment, while after diclofenac s o d i u m drug could only be d e t e c t e d in certain plasma samples after 0.5-1 h. T h e m e a n absorption rate (ka) was 1.32 (0.3) for D I E P and 0.92 (0.3) for diclofenac sodium (P < 0.001). T h e time required to reach the p e a k level after the single doses of the two forms of diclofenac was 0.62 (0.25) h for D I E P and 2.5 (0.67) h for diclofenac s o d i u m (P < 0.001). With b o t h formulations, appreciable plasma concentrations of diclofenac were o b s e r v e d up to the 6 t h - 8 t h h after treatment. T h e m e a n values for Cmax, tla and A U C o b t a i n e d after D I E P and diclofenac sodium administrations are shown in Table 2. Statistical analysis of these p a r a m e t e r s did not show any significant difference.
Discussion
< 0.001
Q% Quotient of 100.7 Bioavailability b (31.2) a NS = not significant b The Quotient of bioavailability of diclofenac sodium was considered to be 100%
T h e p h a r m a c o k i n e t i c results o b t a i n e d here for the enteric c o a t e d tablets of diclofenac s o d i u m are in a g r e e m e n t with those described previously by Riess [4] and Willis [5] in healthy volunteers. A f t e r oral administration of enteric c o a t e d tablets of diclofenac sodium, diclofenac only app e a r e d in the b l o o d s t r e a m 30-60 min after dosing, and its m e a n p e a k level was o b t a i n e d 2.5 (0.67) h after treatment. Diclofenac h y d r o x y e t h y l p y r r o l i d i n e ( D I E P ) sachets were f o u n d to be entirely bioequivalent to diclofenac s o d i u m enteric c o a t e d tablets, as s h o w n by their respective A U C values. O n the other hand, oral D I E P was a b s o r b e d faster than diclofenac sodium, p r o d u c i n g a detectable b l o o d level of diclofenac 15 min after treatment.
References
water, or 2 tablets diclofenac sodium (corresponding to 100 mg diclofenac) taken with half a glass of water. Blood was collected 0, 0.25, 0.5,1, 2, 3, 4, 6 and 8 h after treatment. Plasma concentrations of diclofenac were determined by the gas chromatographic method of Geiger [2], and pharmacokinetic parameters were calculated using the "GPHARM" programme [3]. The bioavailability (Q %) was calculated as: Q% =
AUC (DIEP) .100 AUC (diclofenac sodium)
The difference between the two oral formulations was evaluated by the paired Student's "t" test.
Results
T h e m e a n plasma concentrations of diclofenac in all 12 patients after oral t r e a t m e n t with D I E P 50 m g sachets (2 x 50 mg) or diclofenac sodium 50 mg enteric coated tablets (2 x 50 mg), are shown in Table 1, and are graphically illustrated in Fig. 1. C o m p a r i s o n of the plasma D I E P and diclofenac sodium concentrations versus time (c, t,
1. Brogden RN (1980) Diclofenac sodium: a review of its pharmacological properties and therapeutic use in rheumatic diseases and pain of varying origin. Drugs 20:24-48 2. Geiger P (1975) Quantitative assay of diclofenac in biological material by gas liquid chromatography. J Chromatogr 111:293-298 3. Gomeni C, Gomeni R (1978) GPHARM: Interactive Graphic Package for Pharmacokinetics Analysis. Comput B iomed Res 11: 345-361 4. Riess W (1978) Pharmacokinetics and metabolism of the anti-inflammatory agent Voltarene. Scand J Rheumatol [Suppl] 22: 1729 5. Willis JV et al. (1979) The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmaco116: 405-410 Received: June 30,1989 Accepted in revised form: September 5,1989 Dr. G. Mautone IBSA-Institut Biochimique SA Via al Ponte 13 CH-6903 Lugano, Switzerland
