- Email: [email protected]
Norethisterone-cholesterol eutectic mixture as an oral sustained-release hormonal preparation: Bioequivalence study in humans
CONTRACEPTION
NORETHISTERONE-CHOLESTEROL SUSTAINED-RELEASE
HORMONAL
EUTECTIC
MIXTURE
PREPARATION
:
AS
AN
ORAL
BIOEQUIVALENCE
STUDY IN HUMANS Leticia Yaiiezl, H-Jung', .J.Garza-Flores3,G.P&ez-Palacios3 3 and V. Diaz-Sanchez 1.
Dept.of Cell Biology, School of Medicine, Autbnoma de San Luis Potosi, S.L.P. Mhxico
Universidad
2.
Dept.of Pharmacy and Biochemistry, Faculty of Chemistry, Universidad National Autonoma de Mexico, Mexico City
3.
Instituto National Dept.of Reproductive Biology la Nutricibn "Salvador Zubir&", Mkxico City
de
ABSTRACT
A solid dispersion of norethisterone and cholesterol ( NET:CHOL ; eutectic 1:4 w/w ) was prepared by melting and rapid cooling. The fused material was then mixed with lactose as vehicle. Soft gelatin capsules were filled with 55 mg of the final mixture to give 0.35 mg of NET. One control formulation prepared with fused NET and lactose (NET:LAC) was capsuled with the same NET dosage, and one commercial tablet (Dianor, Syntex) with 0.35 mg NET were used as reference formulations. In a cross-over study,five female volunteers received, one month apart, in fasting state, each one of the three formulations. Blood samples were drawn at 0,0.5,1,1.5,2,4,8,12,24 and 36 hours after dosing. Immunoreactive plasma NET was measured by RIA to assess pharmacokinetic The parameters. NET:CHOL formulation showed a greater area under the serum concentration-time curve, lower peak concentrations and a smaller rate constant as release compared to the reference preparations. It is concluded that the NET:CHOL eutectic mixture is a modified release dosage form and a sound approach in regulating the drug access rate to the body's central compartment. Address correspondence to : V. Diaz-Sanchez M.D.,Dept.of Reproductive Biology, Instituto National de la Nutrition "Salvador Zubirbn", Vasco de Quiroga 15, Tlalpan 14000 D.F. Mexico. Submitted for publication September 16, 1987 Accepted for publication January 22, 1988
APRIL
1988 VOL. 37 NO. 4
349
CONTRACEPTION
INTRODUCTION
In the past few years the number of sustained release systems designed for therapeutic purposes have increased significantly (1,2). For fertility regulation, long-acting formulations have received a great deal of attention, particularly injectables and subdermal implants (3,4). However for oral contraceptives, considerably less information is available regarding improve the absorption characteriszs aP~;oachPu"rre~," formulations, which allow reduction of the amount of active ingredients without compromising the effectiveness of the method. Film coating of tablets has been proposed as the ideal process for the production of modified-release oral dosage forms (5); however, in practice it is very difficult to achieve a film layer of defined uniform thickness, particularly on a large scale. On the other hand,in some studies it has been suggested that progesterone and norethisterone contained in capsules, suspended in an oily vehicle, results in increased absorption and a greater bioavailability than the tablet formulation (6). Other approaches,although for parenteral administration,is to produce eutectic mixtures of steroids with compounds such a cholesterol or n-sistosterol (7). From previous reports it is clear that the addition of lipids or related substances affects the absorption characteristics of the active steroids. The aim of the present study was to relative cross-over study, the compare in a bioavailability and the pharmacokinetic properties of norethisterone in fasting healthy women following single dose oral administration of capsules of norethisteronecholesterol, norethisterone alone and tablets of Dianor (Syntex), using the last two products as reference formulations. SUBJECTS AND METHODS Clinical Study : Five healthy women between 24 and 27 years of age volunteered for the study. None of them had taken any kind of medication in the preceding two months before entering the study. Subjects were admitted to a metabolic unit at 0800 hr after an overnight fast (ten hours). On admission, an indwelling catheter was placed in a forearm vein. Each subject received randomly on three separate ocassions, between days 4 to 6 of their menstrual cycle, one of the following formulations: A) One soft of gelatin capsule containing 55 mg of a mixture composed 0.35 mg NET + 1.4 mg cholesterol fused as eutectic mixture plus 53.56 mg of lactose as vehicle; B) One soft gelatin capsule containing 0.35 mg of NET + 54.65 mg of lactose; C) One tablet of Dianor (Syntex) containing 0.35 mg of
350
APRIL
1988 VOL. 37 NO. 4
CONTRACEPTION
NET t vehicle. Medication was administered with 100 ml of water and neither food nor water was allowed until 4 hours after dosing when a standard light lunch was provided. Eight hours after medication,food and water were allowed ad libitum. Ten ml blood samples were taken through the catheter at 0, 0.5, 1, 1.5, 2, and 4 hours after dosing and then at 8, 12, 24 and 36 hours by direct allowed to room venipuncture. Blood was clot at temperature, serum was separated by centrifugation and stored at -20°C until analysis. Pharmaceutical Preparation: Under good manufacturing nractice conditions. one eutectic NET-cholesterol batch and one NET t lactose batch were produced. Eutectic NET-cholesterol Mixture: NET 35 mg (Syntex SA Mexico) was mixed with cholesterol 140 mg (Merck, Mexico) to obtain a 1:4 ratio. The mixture was fused under a nitrogen atmosphere at 130°C and then cooled in an acetone-dry ice bath to produce a solid film. The solid mixture was milled and sieved to obtain particles of a size less than 50 pm. Analytical quality control tests for NET content in the final powder were performed by in dissolution organic solvents and U.V. spectrophotometry. The procedure was continued when an NET content of 100 + 10% was found. Finally, lactose (Merck, Mexico) 5.325 g was added and blended thoroughly with the NET-cholesterol mixture for 6 hours. Quality control checks were carried out to ensure the uniform distribution of the eutectic mixture in the lactose vehicle. Soft gelatin capsules were filled manually with 55 mg of the final mixture. Each capsule contained 0.35 + 0.02 mg of NET and 1.4 1?:0.1 mg of cholesterol with coefficients of variation of 3.2% and 5.3%, respectively. Reference NET Preparations: Following the same procedure as described above, NET 35 mn were fused. cooled. milled and sieved to the same pariicle size as the eutectic mixture. Lactose 5.465 g was added as vehicle and soft gelatin capsules were filled manually with 55 mg of the mixture. Quality control checks for NET content were 0.35 + 0.03 mg with a coefficient of variation of 5.7%. Dianor (Syntex, Mexico) tablets containing 0.35 mg of NET were purchased locally. Hormonal Analysis: Immunoreactive non-conjugated NET serum concentrations were analyzed by RIA as previously described (8). Sensitivity of the assay was 25 pg/ml. Within and between assay coefficients of variation were 7% and 12%, respectively. Data analysis was performed after a logit-log transformation of the standard curve.
APRIL 1988 VOL. 37 NO. 4
351
CONTRACEPTION
Pharmacokinetic and Statistical Analysis : A linear one compartment open model with elimination taking place in the central compartment was used to approximate the absorption and elimination of NET (9). Data points were fitted to the biexponential function: C = B.e (exp - k2 t) - A.e (exp - kl t) where, C = concentration in serum (ng/ml), and A and B represent the rapid phase and the slow phase coefficients (q/ml) of the biexponential disappearence function. The calculated pharmacokinetic parameters associated with the model were: The area under the serum concentration-time curve from zero to infinity ( ALJC 0-m ) obtained by the trapezoidal rule; the maximum NET serum concentration the time to attain this maximum concentration (CP maxI; the time with NET serum values above 1 ng/ml l: [ExTj'>l ng/ml) ; and the release rate constant (k,) (10). Each of the parameters were analyzed by a two-way analysis of variance for randomized blocks and by the multiple comparisons test of Newman-Keuls (11). RESULTS The courses of NET after the plasma level-time administration of formulations A, B, and C are shown in Figure 1. All formulations were absorbed within 2.5 hours after dosing with no statistical differences in the time reach maximal NET serum concentrations (T max) Ezmparison of NET serum profiles showed that with NET:CHOi, a desired plateau serum level was reached 1 to 2 hours after administration and was maintained for 19 f 8 hours at concentrations above 1 ng/ml (p< 0.05 for NET:LAC and p< 0.01 for Dianor ). No differences were observed between reference preparations. Peak concentrations were 2.8+ 0.6 ng/ml ( mean f SD ) and 3.4 f 0.9 ng/ml for NET:LAC and Dianor, respectively (p>O.l) and 1.6 f. 0.6 ng/ml for NET:CHOL (p< 0.01). The data thus indicated a 55 % to reduction in plasma peak levels which can be attributed the slower release of norethisterone from the test formulation. The finding is consistent with the values calculated for the release rate constant (k,) which was significantly smaller for NET:CHOL (0.028 ng/ml.hr); p< 0.01 as compared with NET:LAC (0.225 ng/ml.hr) and with Dianor (0,309 ng/ml.hr). Moreover, the calculated AUC for NET:CHOL was considerably greater ( 64.3 ng/ml.hr ; p< 0.01 ) than the values obtained for NET:LAC ( 40.3 ng/ml.hr ) and Dianor ( 34.5 ng/ml.hr ). Mean pharmacokinetic data are listed in Table I.
352
APRIL
1988 VOL. 37 NO. 4
CONTRACEPTION
J-l-rc6
12
16
HOURS
Figure 1: Plasma levels-time course after oral administration of 0.35 mg of NET in three c¶ifferent formulations. (A ) mT:?.AC; ( 0 ) Dianor; ( 0 ) NET:CHOL (mean $ SD)
APRIL 1988VOL. 37 NO. 4
353
CONTRACEPTION
TABLE I: Pharmacokinetic parameters (95% confidence limits) of norethisterone following single administration of 0.35 mg in three different formulations to five healthy women
A
PARAMETER
Ko
(ng.ml -?h)
Cp max(ng.ml
Tmax
AUC
NET:
-1
)
(h)
O-
co
T[NETJ
lng.ml
OLP<
354
O*Oli
-1
b=p<
NET:
LACTOSE
DIANOR
O.OZa (0.01-0.04
0.22 (0.12-0.33)
0.30 (0.20-0.41)
1.4a (1.0 - 1.7)
2.9 (2.0 - 3.6)
3.4 (2.3 - 4.6)
2.4 (1.2 - 3.5)
1.6 (1.0 - 2.1)
1.6 (0.9 - 2.2)
64.3a
(ng.ml-'.h)
C
B
CliOLESTEROL
40.3
34.5
(37.5-91.2)
(34.3-46.33
(16.9r52.5)
19.7b'a (11.4 - 30)
7.6 (4.0 -11.2)
6.0 (O.S- 11.2)
0.05
APRIL
1988 VOL. 37 NO. 4
CONTRACEPTION
DISCUSSION
Previous studies (6) have suggested that there may be a different absorption of the steroid hormones when they are suspended in an oily medium in capsule form. A more rapid rate of absorption of NET with increased bioavailability of both NET and EE-2 has been demonstrated. The ability to improve the bioavailability of hormones by these suspending them in an oily medium could be due to the fact that some lymphatic absorption occurs which avoids the first pass clearance through the liver. In the present study the eutectic NET:CHOL mixture suspended in lactose might be absorbed by the same route. The effects on bioavailability of contraceptive when steroids administered orally to human subjects in conventional vehicles and in capsule or in a tablet formulation was investigated by Fotherby & Warren (12). These authors demonstrated that there was no significant difference in blood levels of the steroids after their administration. Therefore, the differences observed in the NET serum profile produced by the NET:CHOL formulation in the present study are neither due to the lactose vehicle nor to the capsule formulation, but to the physicochemical characteristics of the eutectic mixture itself. The pharmacokinetic and bioavailability properties of the NET:CHOL formulation, as evaluated in the present study, indicate a "modified release" of the active drug, which is not offered by conventional dosage forms. NET serum concentrations above 1 nglml reflect an unnecessary steroid load to block ovulation, since studies performed with NET-releasing vaginal devices (13) have demonstrated inhibition of ovulation with NET plasma levels around 0.5 ng/ml. The new approaches to improve contraceptive safety without compromising contraceptive effectiveness move towards the development of new schedules of administration of current contraceptive drugs, the development of new formulations, the improvement of delivery systems, and the design of new compounds (14). The time-lag between a substantial improvement in drug delivery using the extensively studied current contraceptive steroid seems to be shorter than the clinical application of a new drug. This work concentrates on the formulation, bioequivalence and pharmacokinetic aspects of an eutectic mixture of NET:CHOL as an approach in regulating the drug access rate to the body's central compartment by producing a modified release dosage form. Further studies using a synthetic estrogen and a combined progestogen-estrogen formulation are envisaged.
APRIL 1988 VOL. 37 NO. 4
355
CONTRACEPTION
ACKNOWLEDGMENTS
We wish to thank Juana Romero R.N. for the asistance in the clinical trial and Mr. Roberto Martinez for the artwork.
REFERENCES
1.
356
Langer,R.: Implantable controlled Pharmac Therap 21:35-51, 1983
release
systems.
2.
Urquhart,J.,Fara,J.W. and Willis,K.L.: Rate-controlled delivery systems in drug and hormone research. Ann Rev Pharmacol Toxic01 24:199-236, 1984
3.
Diczfa1usy.E.: New developments in oral, injectable and implantable contraceptives, vaginal rings and intrauterine devices. A review. Contraception 33:722 1986
4.
Hal1,E.P. and Fraser,S.I.: injectable Monthly contraceptives. In: Advances in Human Fertility and Reproductive Endocrinology. Vol II, Long-Acting Steroid Contraception ( Mishell,D.R.,Jr.,Ed. ). Raven Press, New York, pp 65-88, 1983
5.
Rowe,C.R.: Film-coating, the ideal process for the production of modified-release oral dosage forms. Pharm Int 6:14-17, 1985
6.
Nutall,I.D.,Elstun,M. and Fahmy,D.R.: Bioavailability of norethisterone (500 mcg) and ethinylestradiol (35 mcg) from different capsule and tablet formulations. Contraception 27~240-246, 1983
7.
Joshep,A.A., Hill,J.L., Patel,J., Patel,S. and Kincl, A.F.: Sustained-release hormonal preparations XV: Release of progesterone from cholesterol pellets in vivo. J Pharm Sci 66:490-493, 1977
8.
Garza-Flores,J., Diaz-SQnchez,V., Bedolla-Tovar, N. radioand Lozano-Ruy,S.A.: A rapid and sensitive inmunoassay for norethisterone. Steroids 41:693-701 1983
9.
Gibaldi,M. and Perrier, D.: Pharmacokinetics Pharmaceutical Sciences. Marcel Dekker Inc., pp 281-292, 1975
and the New York,
APRIL 1988 VOL. 37 NO. 4
CONTRACEPTION
10.
Luckow,V., Cawello,W. and Cordes,G.: Zerbe,H., Isosorbide-5-nitrate sustained-release pellets. An example of computer-supported drug development. Pharmac Res 1:30-36, 1985
11.
Armitage,P.: Statistical Methods in Medical Research. Blackwell Scientific Publications, Oxford, pp 202-207 1977
12.
Fotherby,K. and Warren,R.J.: Bioavailability of contraceptive steroids from capsules. Contraception 14:261-267, 1976
13.
Landgren,B.M., Johannson,E., Masironi,B., and Diczfalusy, E.: Pharmacokinetic and pharmacodynamic effects of small doses of norethisterone released from vaginal rings continuously during 90 days. Contraception 19:253-271, 1979
14.
long-acting fertility Diczfalusy,E.: Improved regulating agents ; What are the problems ? J Steroid Biochem 11:443-448, 1979
APRIL
1988 VOL. 37 NO. 4
357
NORETHISTERONE-CHOLESTEROL SUSTAINED-RELEASE
HORMONAL
EUTECTIC
MIXTURE
PREPARATION
:
AS
AN
ORAL
BIOEQUIVALENCE
STUDY IN HUMANS Leticia Yaiiezl, H-Jung', .J.Garza-Flores3,G.P&ez-Palacios3 3 and V. Diaz-Sanchez 1.
Dept.of Cell Biology, School of Medicine, Autbnoma de San Luis Potosi, S.L.P. Mhxico
Universidad
2.
Dept.of Pharmacy and Biochemistry, Faculty of Chemistry, Universidad National Autonoma de Mexico, Mexico City
3.
Instituto National Dept.of Reproductive Biology la Nutricibn "Salvador Zubir&", Mkxico City
de
ABSTRACT
A solid dispersion of norethisterone and cholesterol ( NET:CHOL ; eutectic 1:4 w/w ) was prepared by melting and rapid cooling. The fused material was then mixed with lactose as vehicle. Soft gelatin capsules were filled with 55 mg of the final mixture to give 0.35 mg of NET. One control formulation prepared with fused NET and lactose (NET:LAC) was capsuled with the same NET dosage, and one commercial tablet (Dianor, Syntex) with 0.35 mg NET were used as reference formulations. In a cross-over study,five female volunteers received, one month apart, in fasting state, each one of the three formulations. Blood samples were drawn at 0,0.5,1,1.5,2,4,8,12,24 and 36 hours after dosing. Immunoreactive plasma NET was measured by RIA to assess pharmacokinetic The parameters. NET:CHOL formulation showed a greater area under the serum concentration-time curve, lower peak concentrations and a smaller rate constant as release compared to the reference preparations. It is concluded that the NET:CHOL eutectic mixture is a modified release dosage form and a sound approach in regulating the drug access rate to the body's central compartment. Address correspondence to : V. Diaz-Sanchez M.D.,Dept.of Reproductive Biology, Instituto National de la Nutrition "Salvador Zubirbn", Vasco de Quiroga 15, Tlalpan 14000 D.F. Mexico. Submitted for publication September 16, 1987 Accepted for publication January 22, 1988
APRIL
1988 VOL. 37 NO. 4
349
CONTRACEPTION
INTRODUCTION
In the past few years the number of sustained release systems designed for therapeutic purposes have increased significantly (1,2). For fertility regulation, long-acting formulations have received a great deal of attention, particularly injectables and subdermal implants (3,4). However for oral contraceptives, considerably less information is available regarding improve the absorption characteriszs aP~;oachPu"rre~," formulations, which allow reduction of the amount of active ingredients without compromising the effectiveness of the method. Film coating of tablets has been proposed as the ideal process for the production of modified-release oral dosage forms (5); however, in practice it is very difficult to achieve a film layer of defined uniform thickness, particularly on a large scale. On the other hand,in some studies it has been suggested that progesterone and norethisterone contained in capsules, suspended in an oily vehicle, results in increased absorption and a greater bioavailability than the tablet formulation (6). Other approaches,although for parenteral administration,is to produce eutectic mixtures of steroids with compounds such a cholesterol or n-sistosterol (7). From previous reports it is clear that the addition of lipids or related substances affects the absorption characteristics of the active steroids. The aim of the present study was to relative cross-over study, the compare in a bioavailability and the pharmacokinetic properties of norethisterone in fasting healthy women following single dose oral administration of capsules of norethisteronecholesterol, norethisterone alone and tablets of Dianor (Syntex), using the last two products as reference formulations. SUBJECTS AND METHODS Clinical Study : Five healthy women between 24 and 27 years of age volunteered for the study. None of them had taken any kind of medication in the preceding two months before entering the study. Subjects were admitted to a metabolic unit at 0800 hr after an overnight fast (ten hours). On admission, an indwelling catheter was placed in a forearm vein. Each subject received randomly on three separate ocassions, between days 4 to 6 of their menstrual cycle, one of the following formulations: A) One soft of gelatin capsule containing 55 mg of a mixture composed 0.35 mg NET + 1.4 mg cholesterol fused as eutectic mixture plus 53.56 mg of lactose as vehicle; B) One soft gelatin capsule containing 0.35 mg of NET + 54.65 mg of lactose; C) One tablet of Dianor (Syntex) containing 0.35 mg of
350
APRIL
1988 VOL. 37 NO. 4
CONTRACEPTION
NET t vehicle. Medication was administered with 100 ml of water and neither food nor water was allowed until 4 hours after dosing when a standard light lunch was provided. Eight hours after medication,food and water were allowed ad libitum. Ten ml blood samples were taken through the catheter at 0, 0.5, 1, 1.5, 2, and 4 hours after dosing and then at 8, 12, 24 and 36 hours by direct allowed to room venipuncture. Blood was clot at temperature, serum was separated by centrifugation and stored at -20°C until analysis. Pharmaceutical Preparation: Under good manufacturing nractice conditions. one eutectic NET-cholesterol batch and one NET t lactose batch were produced. Eutectic NET-cholesterol Mixture: NET 35 mg (Syntex SA Mexico) was mixed with cholesterol 140 mg (Merck, Mexico) to obtain a 1:4 ratio. The mixture was fused under a nitrogen atmosphere at 130°C and then cooled in an acetone-dry ice bath to produce a solid film. The solid mixture was milled and sieved to obtain particles of a size less than 50 pm. Analytical quality control tests for NET content in the final powder were performed by in dissolution organic solvents and U.V. spectrophotometry. The procedure was continued when an NET content of 100 + 10% was found. Finally, lactose (Merck, Mexico) 5.325 g was added and blended thoroughly with the NET-cholesterol mixture for 6 hours. Quality control checks were carried out to ensure the uniform distribution of the eutectic mixture in the lactose vehicle. Soft gelatin capsules were filled manually with 55 mg of the final mixture. Each capsule contained 0.35 + 0.02 mg of NET and 1.4 1?:0.1 mg of cholesterol with coefficients of variation of 3.2% and 5.3%, respectively. Reference NET Preparations: Following the same procedure as described above, NET 35 mn were fused. cooled. milled and sieved to the same pariicle size as the eutectic mixture. Lactose 5.465 g was added as vehicle and soft gelatin capsules were filled manually with 55 mg of the mixture. Quality control checks for NET content were 0.35 + 0.03 mg with a coefficient of variation of 5.7%. Dianor (Syntex, Mexico) tablets containing 0.35 mg of NET were purchased locally. Hormonal Analysis: Immunoreactive non-conjugated NET serum concentrations were analyzed by RIA as previously described (8). Sensitivity of the assay was 25 pg/ml. Within and between assay coefficients of variation were 7% and 12%, respectively. Data analysis was performed after a logit-log transformation of the standard curve.
APRIL 1988 VOL. 37 NO. 4
351
CONTRACEPTION
Pharmacokinetic and Statistical Analysis : A linear one compartment open model with elimination taking place in the central compartment was used to approximate the absorption and elimination of NET (9). Data points were fitted to the biexponential function: C = B.e (exp - k2 t) - A.e (exp - kl t) where, C = concentration in serum (ng/ml), and A and B represent the rapid phase and the slow phase coefficients (q/ml) of the biexponential disappearence function. The calculated pharmacokinetic parameters associated with the model were: The area under the serum concentration-time curve from zero to infinity ( ALJC 0-m ) obtained by the trapezoidal rule; the maximum NET serum concentration the time to attain this maximum concentration (CP maxI; the time with NET serum values above 1 ng/ml l: [ExTj'>l ng/ml) ; and the release rate constant (k,) (10). Each of the parameters were analyzed by a two-way analysis of variance for randomized blocks and by the multiple comparisons test of Newman-Keuls (11). RESULTS The courses of NET after the plasma level-time administration of formulations A, B, and C are shown in Figure 1. All formulations were absorbed within 2.5 hours after dosing with no statistical differences in the time reach maximal NET serum concentrations (T max) Ezmparison of NET serum profiles showed that with NET:CHOi, a desired plateau serum level was reached 1 to 2 hours after administration and was maintained for 19 f 8 hours at concentrations above 1 ng/ml (p< 0.05 for NET:LAC and p< 0.01 for Dianor ). No differences were observed between reference preparations. Peak concentrations were 2.8+ 0.6 ng/ml ( mean f SD ) and 3.4 f 0.9 ng/ml for NET:LAC and Dianor, respectively (p>O.l) and 1.6 f. 0.6 ng/ml for NET:CHOL (p< 0.01). The data thus indicated a 55 % to reduction in plasma peak levels which can be attributed the slower release of norethisterone from the test formulation. The finding is consistent with the values calculated for the release rate constant (k,) which was significantly smaller for NET:CHOL (0.028 ng/ml.hr); p< 0.01 as compared with NET:LAC (0.225 ng/ml.hr) and with Dianor (0,309 ng/ml.hr). Moreover, the calculated AUC for NET:CHOL was considerably greater ( 64.3 ng/ml.hr ; p< 0.01 ) than the values obtained for NET:LAC ( 40.3 ng/ml.hr ) and Dianor ( 34.5 ng/ml.hr ). Mean pharmacokinetic data are listed in Table I.
352
APRIL
1988 VOL. 37 NO. 4
CONTRACEPTION
J-l-rc6
12
16
HOURS
Figure 1: Plasma levels-time course after oral administration of 0.35 mg of NET in three c¶ifferent formulations. (A ) mT:?.AC; ( 0 ) Dianor; ( 0 ) NET:CHOL (mean $ SD)
APRIL 1988VOL. 37 NO. 4
353
CONTRACEPTION
TABLE I: Pharmacokinetic parameters (95% confidence limits) of norethisterone following single administration of 0.35 mg in three different formulations to five healthy women
A
PARAMETER
Ko
(ng.ml -?h)
Cp max(ng.ml
Tmax
AUC
NET:
-1
)
(h)
O-
co
T[NETJ
lng.ml
OLP<
354
O*Oli
-1
b=p<
NET:
LACTOSE
DIANOR
O.OZa (0.01-0.04
0.22 (0.12-0.33)
0.30 (0.20-0.41)
1.4a (1.0 - 1.7)
2.9 (2.0 - 3.6)
3.4 (2.3 - 4.6)
2.4 (1.2 - 3.5)
1.6 (1.0 - 2.1)
1.6 (0.9 - 2.2)
64.3a
(ng.ml-'.h)
C
B
CliOLESTEROL
40.3
34.5
(37.5-91.2)
(34.3-46.33
(16.9r52.5)
19.7b'a (11.4 - 30)
7.6 (4.0 -11.2)
6.0 (O.S- 11.2)
0.05
APRIL
1988 VOL. 37 NO. 4
CONTRACEPTION
DISCUSSION
Previous studies (6) have suggested that there may be a different absorption of the steroid hormones when they are suspended in an oily medium in capsule form. A more rapid rate of absorption of NET with increased bioavailability of both NET and EE-2 has been demonstrated. The ability to improve the bioavailability of hormones by these suspending them in an oily medium could be due to the fact that some lymphatic absorption occurs which avoids the first pass clearance through the liver. In the present study the eutectic NET:CHOL mixture suspended in lactose might be absorbed by the same route. The effects on bioavailability of contraceptive when steroids administered orally to human subjects in conventional vehicles and in capsule or in a tablet formulation was investigated by Fotherby & Warren (12). These authors demonstrated that there was no significant difference in blood levels of the steroids after their administration. Therefore, the differences observed in the NET serum profile produced by the NET:CHOL formulation in the present study are neither due to the lactose vehicle nor to the capsule formulation, but to the physicochemical characteristics of the eutectic mixture itself. The pharmacokinetic and bioavailability properties of the NET:CHOL formulation, as evaluated in the present study, indicate a "modified release" of the active drug, which is not offered by conventional dosage forms. NET serum concentrations above 1 nglml reflect an unnecessary steroid load to block ovulation, since studies performed with NET-releasing vaginal devices (13) have demonstrated inhibition of ovulation with NET plasma levels around 0.5 ng/ml. The new approaches to improve contraceptive safety without compromising contraceptive effectiveness move towards the development of new schedules of administration of current contraceptive drugs, the development of new formulations, the improvement of delivery systems, and the design of new compounds (14). The time-lag between a substantial improvement in drug delivery using the extensively studied current contraceptive steroid seems to be shorter than the clinical application of a new drug. This work concentrates on the formulation, bioequivalence and pharmacokinetic aspects of an eutectic mixture of NET:CHOL as an approach in regulating the drug access rate to the body's central compartment by producing a modified release dosage form. Further studies using a synthetic estrogen and a combined progestogen-estrogen formulation are envisaged.
APRIL 1988 VOL. 37 NO. 4
355
CONTRACEPTION
ACKNOWLEDGMENTS
We wish to thank Juana Romero R.N. for the asistance in the clinical trial and Mr. Roberto Martinez for the artwork.
REFERENCES
1.
356
Langer,R.: Implantable controlled Pharmac Therap 21:35-51, 1983
release
systems.
2.
Urquhart,J.,Fara,J.W. and Willis,K.L.: Rate-controlled delivery systems in drug and hormone research. Ann Rev Pharmacol Toxic01 24:199-236, 1984
3.
Diczfa1usy.E.: New developments in oral, injectable and implantable contraceptives, vaginal rings and intrauterine devices. A review. Contraception 33:722 1986
4.
Hal1,E.P. and Fraser,S.I.: injectable Monthly contraceptives. In: Advances in Human Fertility and Reproductive Endocrinology. Vol II, Long-Acting Steroid Contraception ( Mishell,D.R.,Jr.,Ed. ). Raven Press, New York, pp 65-88, 1983
5.
Rowe,C.R.: Film-coating, the ideal process for the production of modified-release oral dosage forms. Pharm Int 6:14-17, 1985
6.
Nutall,I.D.,Elstun,M. and Fahmy,D.R.: Bioavailability of norethisterone (500 mcg) and ethinylestradiol (35 mcg) from different capsule and tablet formulations. Contraception 27~240-246, 1983
7.
Joshep,A.A., Hill,J.L., Patel,J., Patel,S. and Kincl, A.F.: Sustained-release hormonal preparations XV: Release of progesterone from cholesterol pellets in vivo. J Pharm Sci 66:490-493, 1977
8.
Garza-Flores,J., Diaz-SQnchez,V., Bedolla-Tovar, N. radioand Lozano-Ruy,S.A.: A rapid and sensitive inmunoassay for norethisterone. Steroids 41:693-701 1983
9.
Gibaldi,M. and Perrier, D.: Pharmacokinetics Pharmaceutical Sciences. Marcel Dekker Inc., pp 281-292, 1975
and the New York,
APRIL 1988 VOL. 37 NO. 4
CONTRACEPTION
10.
Luckow,V., Cawello,W. and Cordes,G.: Zerbe,H., Isosorbide-5-nitrate sustained-release pellets. An example of computer-supported drug development. Pharmac Res 1:30-36, 1985
11.
Armitage,P.: Statistical Methods in Medical Research. Blackwell Scientific Publications, Oxford, pp 202-207 1977
12.
Fotherby,K. and Warren,R.J.: Bioavailability of contraceptive steroids from capsules. Contraception 14:261-267, 1976
13.
Landgren,B.M., Johannson,E., Masironi,B., and Diczfalusy, E.: Pharmacokinetic and pharmacodynamic effects of small doses of norethisterone released from vaginal rings continuously during 90 days. Contraception 19:253-271, 1979
14.
long-acting fertility Diczfalusy,E.: Improved regulating agents ; What are the problems ? J Steroid Biochem 11:443-448, 1979
APRIL
1988 VOL. 37 NO. 4
357