Development of a New Controlled-Release Formulation of Chlorpheniramine Maleate Using In Vitrolln Vivo Correlations ROGER L. WILLIAMS*^, ROBERTA. UPTON*, LUANNBALL§,RICHARDL. B R A U NEMIL ~ , T. LIN*, WINNIE LIANG-GEE*, AND LEWIS J. LEE SON^ Received July 12, 1989, from ‘The Drug Studies Unit, School of Pharmacy, University of California, San Francisco, CA 94143, the *Departments of Pharmacy and Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94 143, 3 Mediventures, 655 Phoenix Drive, Ann Arbor, MI 48108, ’Ciba Consumer Pharmaceuticals, 111 Raritan Plaza, Edison, NJ 08837, and ACiba-Geigy Corporation, 556 Morris Avenue, Summit, NJ 07901. Accepted for publication February 1 , 1990. Abstract 0 Development of a controlled-released formulation of chlor-
pheniramine maleate is described, using in vitrolin vivo correlates, according to a process that has been termed “biorelevantdissolution”. The process begins with simulations using several possible input rates combined with known disposition parameters of chlorpheniramine maleate. Based on desired plasma concentrations, an input rate is selected for further development which consists of a combination of clinical bioequivalence studies and further in vitro testing and simulations. The method is designed to reduce the requirements for trial and error clinical bioequivalence testing of a new controlled-release formulation. ~-
Development of a controlled-release formulation for selected drugs is a n increasingly common practice that can reduce the frequency of dosing, enhance compliance, improve the therapeutic index of a drug, and extend market exclusivity.’ A primary objective in the development of a controlled-release formulation is that the pharmacologic effects of the new formulation do not differ significantly from those of the immediate-release formulation. One way to confirm this is through the performance of clinical efficacy trials. An alternate way is to document that the new controlled-release formulation produces blood or plasma drug concentrations that are not significantly different from those produced by the immediate-release formulation when given in equivalent doses.2 New technologies permit relatively precise control of the release characteristics of a controlled-release product. Standard pharmacokinetic methods can simulate plasma drug concentrations when a drug is given according to a specific input. In this report, we describe the application of these capabilities, in a process that has been termed “biorelevant dissolution”,3 to the development of a new controlled-release formulation of chlorpheniramine maleate (CPM). The in vitrolin vivo procedures described offer a method of developing a new controlled-release formulation that minimizes the need for clinical testing, reduces unnecessary subject exposure, and saves time and expense.
Experimental Section General Procedures-The steps utilized in the development of the new controlled-release formulation of CPM were: (1 generation of a pharmacokinetic model employing literature values for disposition parameters of CPM to project CPM gastrointestinal zero-order input rates producing desirable plasma concentrations; (2)performance of an in vivo study in which CPM was administered by nasogastric infusion a t the zero-order rate suggested to be appropriate by the model; (3) development of the new controlled-release formulation with made-to-order release characteristics based on simulated and actual data from the first and second steps and confirmed by in vitro dissolution studies or by an in vivo pilot study; and (4) full scale bioequivalence testing of the new product. The four clinical studies 22 iJournal of Pharmaceutical Sciences Vol. 80, No. 1 , January 1991
performed for Steps 2 through 4 are described below. Clinical Methods-All studies were conducted in the Drug Studies Unit at the University of California, San Francisco, CA, using protocols and consent forms approved by the institutional review board of the University. Subjects in each of the four studies were healthy males between the ages of 18 and 40, with normal weight for height and frame. Unless noted, all doses were given orally at about 8 a.m. after a 10-h fast. Plasma samples collected just prior to and following dosing provided measurement of extrapolated or interdose area under the plasma concentration-time curve (AUC), maximum concentration (C,,,), and time of this concentration (tmax).The different treatment sequences were randomly assigned. Study 1-Study 1was a three-period study in six subjects given the following three treatments: (1)4 mg of CPM solution at 8 a.m., 12 noon, and 4 p.m.; (2) 4 mg of CPM solution a t 8 a.m. followed immediately by nasogastric infusion of the drug a t a rate of 0.67 mg/h for 12 h (total dose 12 mg); and (3)4 mg of CPM in solution at 8 a.m. followed immediately by nasogastric infusion of CPM a t a rate of 1.11 mg/h for 18 h (total dose 24 mg). The CPM in the second and third treatments was infused through a flexible rubber nasogastric tube connected to a syringe driven by a portable constant infusion pump (MSI6A external pump, Graseby Medical, Bushey-Watford, Hertfordshire, UK). Study 2-Study 2 was a two-period study in six subjects given the following two treatments: (1) 24 mg of CPM in the new 24-h controlled-release formulation (OROS); and (2) 6 mg of CPM in solution a t 8 a.m., 2 p.m., 8 p.m., and 2 a.m. Study 3-Study 3 was a three-period steady-state study in 12 subjects given the following three treatments: (1)24 mg of CPM in the new 24-h controlled-release formulation as a single daily dose at -8 a.m. for 7 days; ( 2 ) 12 mg of CPM in a commercially available controlled-release formulation (Chlor-Trimeton Long Acting Allergy Repetabs, lot #5AAE1; Schering Corporation, Kenilworth, NJ) at -8 a.m. and 8 p.m. for 7 days; and (3)4 mg of CPM in an immediaterelease formulation (Chlor-Trimeton, lot #5STW5; Schering Corporation) every 4 h beginning a t -8 a.m. for 7 days. In all treatments, the 8 a.m. dose of drug was given after a standard breakfast. Plasma was collected once daily predose on days 2 through 6 to assess attainment of steady state and also frequently throughout the 24-hr dosing period on day 7. Study 4-Study 4 was a three-period study in 12 subjects given the following three treatments: (1) 24 mg of CPM in the new 24-h controlled-release formulation after a 10-h fast; (2)the same formulation after a high-fat breakfast (scrambled eggs, bacon, hash browns, whole milk, two pieces of toast, and butter); and (3)a single 4-mg solution dose of CPM after a 10-h fast. In Vitro Dissolution Studies-The dissolution technique utilized a USP Apparatus 2 basket with 900 mL of standard dissolution medium (simulated intestinal fluid without enzymes) with a rotation speed of 100 rpm. Samples were collected at 30-min intervals for CPM analysis. Analytical Methods-Plasma samples were assayed for CPM according to a sensitive and specific high-pressure liquid chromatographic assay.4 The CPM concentrations in the dissolution studies were measured as the absorbency of the dissolution medium compared with a suitable standard. Data Analysis-Extrapolated and interdose AUC values were 0022-3549191/0100-0022$01.00/0 0 1991, American Pharmaceutical Association
calculated by the trapezoidal rule with log transformation after peak concentration. Maximum concentration (CmaX)and time of this concentration Ifmax)were measured directly without interpolation. In the steady-statestudy (Study 3), minimum concentration (C,,,,") was determined over a 12-24-h period on day 7 (interdosesampling day) to insure that this concentration reflected the minimum concentration produced by the 8-a.m.doses given on that day. Treatmentswere compared statistically by analysis of variance followed by post-hoc analyses for the three treatment studies. Computer SimulationgChlorpheniramine pharmacokinetic parameters employed in the initial computer simulations were as follows: kd = 0.034 h-l; k, = 1.04 h-'; and V, = 706.6 L,assuming monoexponential elimination.5 The CPM plasma concentration-time curve during zero-order delivery, coupled with an immediate-release dose, was described by the following equation:
W
z
5
10
U
a:
t
Z W I
a
a:
0
-1
I
where k, is the zero-order release rate from the new 24-h controlledrelease formulation (mgh), D,, is the immediate-releasedose (mg), k, is the absorption rate constant (h-'), kd is the elimination rate constant (h-l),Vd is volume of distribution (L),and f is the time (h). When t > fz (the duration of input), plasma concentration was described by the following equation:
0
H
(2) where A, (tz) is amount in plasma remaining to be eliminated at the end of zero-order delivery of amount of drug (D)in the controlledrelease formulation (eq 3); and A is the amount in gut to be absorbed at the end of zero-order release !?-om the controlled-release formulation (eq 4):
A,, (tz)
=
kdk, - [l - e-(ka'ko)]
(4)
Results An initial computer simulation (Figure 1)using eqs 1 and 2 and literature estimates for CPM disposition parameters suggested that 4 mg of CPM released immediately, followed by 20 mg released over a period of 18 h (1.11mgh), produced desirable plasma concentrations. Study 1 tested the simulation and confirmed good correspondence between the shapes of the simulated and observed plasma concentration-time curves generated by this input combination (Figure 1).Doseadjusted AUC data (Table I) document no statistically significant difference between the nasogastric infusion compared with the immediate-release formulation for extent of absorption. The time of the peak concentration was longest for the 18-h infusion treatment and shortest for the immediaterelease dose given a t 0, 4, and 8 h (Figure 1, Table I). Based on the data from the nasogastric infusion study, a new 24-h formulation of CPM was developed, using osmotic technology,e consisting of a 4-mg immediate-release portion surrounding a core designed to release 20 mg of CPM at a zero-order rate of 1.1m g h over a period of 18h for a total dose
Figure l-chlorpheniramine maleate concentrations in a representative subject after: (7) a 4-mg oral solution at 0, 4, and 8 h (open circles);(2) a 4-mg oral solution followed by nasogastric infusion of 1.1 mg/h for 12 h (closed triangles);and (3)a 4-mg oral solution followed by nasogastric infusion of 1.1 mg/h for 18 h (open squares).A simulation also appears in the figure (solid line). This curve was derived from eqs 1 and 2, assuming a 4-mg CPM immediate-release dose followed by 1.1 CPM mg/h for 18 h and using published CPM disposition parameters (see text).
of 24 mg. Formulation development was guided by in vitro dissolution testing and computer simulation of plasma levels. Alterations in the formulation were made before the next in vivo study was performed. In vitro dissolution data for the new 24-h formulation appear in Figure 2. In Study 2 (Table 111, AUCs for this formulation were not significantly different compared with a n oral solution of 6 mg of CPM given a t 0,6, 12, and 18 h. Peak CPM concentrations were not significantly different between the two treatments in this study. In Study 3 (Table 111, Figure 3), no statistically significant difference was observed a t steady state between the six times daily, twice daily, and once daily products for any variable, with the exception of Cminand tminin the 12-24-h post-dosing period. The Cminfor the 24-h controlled-release product was lower and tmin was longer in comparison with the 12-h controlled-release formulation, but not significantly different from the immediate-release formulation. Plasma concentrations for the 24-h product conformed closely with a steadystate computer simulation, using eq 1 and a variation3 of eq 2 in conjuction with mean CPM disposition parameters derived from the solution dose in the nasogastric infusion study (absorption rate constant: 1.04 h-1; elimination rate constant: 0.038 h-'; V d 530 L)and mean in vitro dissolution parameters (zero-order release rate: 1.57 mgh; time of zeroorder release: 10 h; time lag: 0.5 h; bolus dose: 4 mg; amount released by first-order processes: 5.1 mg; first-order dissolution rate constant: 0.186 h-'). The variation in eq 2 is based on the fact that the osmotic pump releases only a portion of the drug via zero-order kinetics and the remainder via first-order kinetics. Assuming that most drug release is zero-order, release of a smaller proportion according to first-order kinetics does not appear to be problematic. The additional constants required from this equation are obtained from the in vitro dissolution data. Journal of Pharmaceutical Sciences / 23 Vol. 80, No. 1. January 1991
Table I-Pharmacoklnetlc Data after Administration of Various Doses of ChlorpheniramlneMaleate'
Treatmenta
Parameter Cmaw @L tmaxv h
Extrapolated AUC, pg/L * h
Post Hocb
P
I
II
111
17.1 2 4.66 10.5 f 1.16 960 t 240'
15.3 2 4.46 13.7 2 5.86 1034 t 290'
25.4 2 6.97 19.1 2 4.88 1090 f 398
rnm
0.0023 0.0320 0.3730
mii ~~~~~~
Treatment I: 4 mg of CPM solution at 0, 4, and 8 h; treatment II: 4 mg of CPM solution at 0 h, then 0.67 mg/h via nasogastric infusion for 12 h ; treatment 111: 4 mg of CPM solution at 0 h, then 1.1 mg/h via nasogastric infusion for 18 h (values expressed as mean t SD). Treatments under the same line are not significantly different. Adjusted to 24-mg dose. a
Table Il-Pharmacoklnetlc Data after Admlnlstratlon of Either a 24-mg Controlled-ReleaseChlorphenlramlne Maleate Tablet (IV) as a Single Dose or Chlorpheniramlne Maleate Solutlon (6 mg) at Six-Hour Intervals for Four Doses (V)ll
Treatment Parameter
P
V
IV
~
Cmax, tmax!
/@-
h
Extrapolated AUC, pg/L . h a
0
4
8
12
16
20
24
H
Figure 2-In vitro dissolution data for the 24-h controlled-release product
used in the clinical bioequivalence trials (individual data points not shown).
The data in Study 4 (Table IV) indicate that absorption of the new 24-h controlled-release formulation was not significantly altered by the administration of a standard high-fat breakfast.
Discussion Chlorpheniramine is an antihistamine that reversibly blocks the H, histamine receptor and is usually given without prescription as the maleate salt. The drug is cleared from the body in the liver via demethylation to mono- and didesmethyl metabolites.7 Several reports have described the pharmacokinetics of chlorpheniramine after oral and iv dosing.Sl4 Following iv dosing to two subjects, Huang et al.14 estimated the following pharmacokinetic parameters for CPM (adjusted to a 70 kg individual): plasma clearance, 174 mL/min; plasma Vd,,, 222 L; and terminal half-life, 22.5 h. Average AUCcinfinityafter
Values expressed as mean
34.5 2 7.51 14.7 t 4.20 1710 2 605 2
NS 0.037 NS
35.9 2 6.83 21.9 f 3.59 1840 t 531
SD.
oral dosing, adjusted to a dose of 24 mg, was 1084 FgIL . h, a value that corresponds reasonably well with the data in this report. Chlorpheniramine maleate does not possess active metabolites, and there is no evidence that its protein binding or metabolism are saturable. Given these characteristics, the current availability of 8- and 12-h controlled-release formulations, and the labeling requirements for immediate-release dosing every 4 h, CPM became a candidate for development of a 24-h controlled-release formulation. Criteria considered in the development of a controlledrelease product include pharmacodynamic, pharmacokinetic, and biopharmaceutic factors.2 Several of these may contribute to alteration in drug effect when a controlled-release formulation is substituted for an immediate-release one, including the propensity for drug tolerance and the development of irreversible toxicity.*J5 From a pharmacokinetic standpoint, saturable metabolism, saturable protein binding, comparatively short half-life relative to the dosing interval (large peak-to-trough fluctuations), and the presence of active metabolites are factors that can result in alteration of the clinical effects when a controlled-formulation is substituted for an immediate-release formulation.15 The final test of the adequacy of a new controlled-release product rests on either clinical trials to confirm unchanged efficacy or bioequivalence studies to document that the new formulation produces blood or plasma concentrations equivalent to the immediate-release product it is designed to replace. It is desirable to confirm the release characteristics of
Table Ill-Steadystate lnterdose (0-24 h) Pharmacokhetic Dataa aiter Admlnlstratlon of a 24-1119 Controlled-ReleaseTablet (IV), a 12-mg Controlled-ReleaseTablet (VI), and a 4-mg lmmedlate Release Tablet (VII) ~
Treatment
Parameter Cm,, trnax,
CLgiL h
C,,,, h" tin,"? h
Cmax Cmm,
AUC, kg/L * h a
IV
VI
VII
56.8 2 23.9 10.0 L 5.51 34.6 2 16.3 22.3 2 0.8 23.4 t 9.26 1090 t 481
60.7 2 24.6 8.81 t 4.66 42.5 2 20.2 19.2 2 4.9 20.1 2 7.88 1200 t 520
63.5 2 24.7 8.13 2 6.50 41.1 t 19.0 20.4 t 1.7 22.9 t 8.32 1200 2 501
Values are expressed as mean
t SD.
24 I Journal of Pharmaceutical Sciences Vol. SO,No. 1, January 7997
~-
~~
P NS NS 0.01 13 0.0259 NS NS
Treatments under the same line are not significantly different. 12-24 interval (see text).
~~
Post Hocb
-
mrm VI
m m ii -
Table IV-Pharmacoklnetlc Data. after a 24-mg Controlled-ReleaseChlorphenlramlne Maleate Tablet Fastlng (IVa) and after Breakfast (IVb), and after a 4-ma lmmedlate-ReleaseChlorphenlramlne Maleate Tablet Fastlng (VII)
Treatment
Parameter C m w MIL fax. h
Extrapolated AUC,
pglL . h
IVa
IVb
VII
30.6 2 8.8 13.7 2 4.73 1440 2 766
28.4 f 12.9 13.0 f 2.85 1315 2 863
56.4 2 20.3‘ 2.98 ? 1.42 1709 t 1257‘
P 0.001 0.001 0.0278
Post Hocb
m m m
m m a
b
a Values expressed as mean t SD. Treatments under the same line are not significantlydifferent. Dose adjusted (increasedsixfold)to correspond to IVa and IVb.
process of trial and error, involving perhaps several pilot clinical bioequivalence studies before a suitable release pattern for the new formulation is determined. Utilizing the methodology described herein, a new 24-h CPM formulation was designed that appears to meet current regulatory requirement+ for substitution. The bioequivalence studies required to confirm the bioequivalence and substitutability of the new formulation to currently available immediate products were kept to a minimum, thus reducing unnecessary exposure of healthy human subjects to experimental procedures and also reducing time and expense. A
References and Notes
5i 01 0
1
1
1
I
I
1
1
I
3
6
9
12
15
18
21
25
H
Flgure3-Steady-state plasma CPM concentrations during the final day (Day 7) of continuous dosing in a representative subject after administration of: (1) 4 mg of immediate-release formulation every 4 h (open squares);(2)12-h controlled-release product every 12 h (open circles); and (3)24-h controlled-release product once daily (closed triangles).The solid line in the figure represents a simulation constructed from eqs 1 and 2 and using mean CPM disposition parameters from the oral solution treatment in the nasogastric infusion study (see text).
a new controlled-release formulation with in vitro data before performing clinical trials. Through the development of a pharmacokinetic model combining the disposition characteristics of CPM with predetermined input patterns, a new controlled-release formulation of the drug was developed according to a process that has been termed “biorelevant dissolution”. Although the theoretical steps for the process have been reported,3 this report describes the application of the method to the development of a specific controlled-release product. Without the application of methodology similar to that described in this report, this development can be more a
1. Silber, B. M.; Cheung, W. K.; Yacobi, A. In Oral Sustained Release Formulations: Design and Evaluation; Yacobi, A., Halperin-Walega, E., Eds.; Pergamon: New York, 1988; pp 1-33. 2. Skelly, J . P.; Barr, W. H.; Benet, L. Z.; Doluisio, J . T.; Goldberg, A. H.; Levy, G.; Lowenthal, D. T.; Robinson, J . R.; Shah, V. P.; Temple, R. J.; Yacobi, A. Pharmaceut. Res. 1987, 4, 75-77. 3. Leeson, L. J.; Adair, D.; Clevenger, J.; Chiang, N. J . Pharmacokinel. Biopharm. 1985,3,493-514. 4. Shi, R. J . Y.; Gee, W. L.; Williams, R. L.; Lin, E. T. J . Liq. Chromatogr. 1987,20,31013112. 5. Yacobi, A,; Stoll, G.; Chao, J.; Carter,.D.; Basske, D.; Kamath, B.; Amann, A.; Lai, C. M. J . Pharm. Scr. 1980, 69, 1077-1080. 6. Theeuwes, F.; Ayer, A. D. US.Patent 4 058 122, November 15, 1977. 7. Athanikar, N. K.; Peng, G. W.; Nation, R. L.; Huang, S. M.; Chiou. W. L. J . Chromatogr. 1979. 62. 367376. 8. Barhart, W.; Johnson, J . D. Anal..Chem. 1977,49, 1085-1086. 9. Hanna, S.;Tang, A. J . Pharm. Sci. 1974,63, 1954-1957. 10. Lange, W. E.; Theodore, J . M.; Pruyn, F. J . J . Pharm. Sci. 1968, 57, 124-127. 11. Peets, E. A.; Weinstein, R.; Billard, W.; Syrnchowicz. L. J . Pharmncol. Exp. Ther. 1972, 80, 304-374. 12. Sanders, S. W.; Warner, R. N.; Georgitis, J. W.; Eigen, H.; Gonzalez, M. A. Am. Pharm. Assn. 127th Annual Meeting, Washington. D.C.. 1980. 84. Abstract #45. 13. Simons, F. E.; Simons, K. J.; Chung, M.; Yeh, J . Ann. Allergy 1987,59,20-24. 14. Huang, S. M.; Athanikar, N. K.; Sridhar, K.; Huang, Y. C.; Chiou, W. L. Eur. J . Clin. Pharmacol. 1982,22, 359365. 15. Mordenti, J.; Williams, R. L. In Oral Sustained Release Formulations: Design and Eualuation; Yacobi, A.; Halperin-Walega, E., Eds., Pergarnon: New York, 1988; pp 195-216.
Journal of Pharmaceutical Sciences I 25 Vol. 80,No. 1, January 1991
pheniramine maleate is described, using in vitrolin vivo correlates, according to a process that has been termed “biorelevantdissolution”. The process begins with simulations using several possible input rates combined with known disposition parameters of chlorpheniramine maleate. Based on desired plasma concentrations, an input rate is selected for further development which consists of a combination of clinical bioequivalence studies and further in vitro testing and simulations. The method is designed to reduce the requirements for trial and error clinical bioequivalence testing of a new controlled-release formulation. ~-
Development of a controlled-release formulation for selected drugs is a n increasingly common practice that can reduce the frequency of dosing, enhance compliance, improve the therapeutic index of a drug, and extend market exclusivity.’ A primary objective in the development of a controlled-release formulation is that the pharmacologic effects of the new formulation do not differ significantly from those of the immediate-release formulation. One way to confirm this is through the performance of clinical efficacy trials. An alternate way is to document that the new controlled-release formulation produces blood or plasma drug concentrations that are not significantly different from those produced by the immediate-release formulation when given in equivalent doses.2 New technologies permit relatively precise control of the release characteristics of a controlled-release product. Standard pharmacokinetic methods can simulate plasma drug concentrations when a drug is given according to a specific input. In this report, we describe the application of these capabilities, in a process that has been termed “biorelevant dissolution”,3 to the development of a new controlled-release formulation of chlorpheniramine maleate (CPM). The in vitrolin vivo procedures described offer a method of developing a new controlled-release formulation that minimizes the need for clinical testing, reduces unnecessary subject exposure, and saves time and expense.
Experimental Section General Procedures-The steps utilized in the development of the new controlled-release formulation of CPM were: (1 generation of a pharmacokinetic model employing literature values for disposition parameters of CPM to project CPM gastrointestinal zero-order input rates producing desirable plasma concentrations; (2)performance of an in vivo study in which CPM was administered by nasogastric infusion a t the zero-order rate suggested to be appropriate by the model; (3) development of the new controlled-release formulation with made-to-order release characteristics based on simulated and actual data from the first and second steps and confirmed by in vitro dissolution studies or by an in vivo pilot study; and (4) full scale bioequivalence testing of the new product. The four clinical studies 22 iJournal of Pharmaceutical Sciences Vol. 80, No. 1 , January 1991
performed for Steps 2 through 4 are described below. Clinical Methods-All studies were conducted in the Drug Studies Unit at the University of California, San Francisco, CA, using protocols and consent forms approved by the institutional review board of the University. Subjects in each of the four studies were healthy males between the ages of 18 and 40, with normal weight for height and frame. Unless noted, all doses were given orally at about 8 a.m. after a 10-h fast. Plasma samples collected just prior to and following dosing provided measurement of extrapolated or interdose area under the plasma concentration-time curve (AUC), maximum concentration (C,,,), and time of this concentration (tmax).The different treatment sequences were randomly assigned. Study 1-Study 1was a three-period study in six subjects given the following three treatments: (1)4 mg of CPM solution at 8 a.m., 12 noon, and 4 p.m.; (2) 4 mg of CPM solution a t 8 a.m. followed immediately by nasogastric infusion of the drug a t a rate of 0.67 mg/h for 12 h (total dose 12 mg); and (3)4 mg of CPM in solution at 8 a.m. followed immediately by nasogastric infusion of CPM a t a rate of 1.11 mg/h for 18 h (total dose 24 mg). The CPM in the second and third treatments was infused through a flexible rubber nasogastric tube connected to a syringe driven by a portable constant infusion pump (MSI6A external pump, Graseby Medical, Bushey-Watford, Hertfordshire, UK). Study 2-Study 2 was a two-period study in six subjects given the following two treatments: (1) 24 mg of CPM in the new 24-h controlled-release formulation (OROS); and (2) 6 mg of CPM in solution a t 8 a.m., 2 p.m., 8 p.m., and 2 a.m. Study 3-Study 3 was a three-period steady-state study in 12 subjects given the following three treatments: (1)24 mg of CPM in the new 24-h controlled-release formulation as a single daily dose at -8 a.m. for 7 days; ( 2 ) 12 mg of CPM in a commercially available controlled-release formulation (Chlor-Trimeton Long Acting Allergy Repetabs, lot #5AAE1; Schering Corporation, Kenilworth, NJ) at -8 a.m. and 8 p.m. for 7 days; and (3)4 mg of CPM in an immediaterelease formulation (Chlor-Trimeton, lot #5STW5; Schering Corporation) every 4 h beginning a t -8 a.m. for 7 days. In all treatments, the 8 a.m. dose of drug was given after a standard breakfast. Plasma was collected once daily predose on days 2 through 6 to assess attainment of steady state and also frequently throughout the 24-hr dosing period on day 7. Study 4-Study 4 was a three-period study in 12 subjects given the following three treatments: (1) 24 mg of CPM in the new 24-h controlled-release formulation after a 10-h fast; (2)the same formulation after a high-fat breakfast (scrambled eggs, bacon, hash browns, whole milk, two pieces of toast, and butter); and (3)a single 4-mg solution dose of CPM after a 10-h fast. In Vitro Dissolution Studies-The dissolution technique utilized a USP Apparatus 2 basket with 900 mL of standard dissolution medium (simulated intestinal fluid without enzymes) with a rotation speed of 100 rpm. Samples were collected at 30-min intervals for CPM analysis. Analytical Methods-Plasma samples were assayed for CPM according to a sensitive and specific high-pressure liquid chromatographic assay.4 The CPM concentrations in the dissolution studies were measured as the absorbency of the dissolution medium compared with a suitable standard. Data Analysis-Extrapolated and interdose AUC values were 0022-3549191/0100-0022$01.00/0 0 1991, American Pharmaceutical Association
calculated by the trapezoidal rule with log transformation after peak concentration. Maximum concentration (CmaX)and time of this concentration Ifmax)were measured directly without interpolation. In the steady-statestudy (Study 3), minimum concentration (C,,,,") was determined over a 12-24-h period on day 7 (interdosesampling day) to insure that this concentration reflected the minimum concentration produced by the 8-a.m.doses given on that day. Treatmentswere compared statistically by analysis of variance followed by post-hoc analyses for the three treatment studies. Computer SimulationgChlorpheniramine pharmacokinetic parameters employed in the initial computer simulations were as follows: kd = 0.034 h-l; k, = 1.04 h-'; and V, = 706.6 L,assuming monoexponential elimination.5 The CPM plasma concentration-time curve during zero-order delivery, coupled with an immediate-release dose, was described by the following equation:
W
z
5
10
U
a:
t
Z W I
a
a:
0
-1
I
where k, is the zero-order release rate from the new 24-h controlledrelease formulation (mgh), D,, is the immediate-releasedose (mg), k, is the absorption rate constant (h-'), kd is the elimination rate constant (h-l),Vd is volume of distribution (L),and f is the time (h). When t > fz (the duration of input), plasma concentration was described by the following equation:
0
H
(2) where A, (tz) is amount in plasma remaining to be eliminated at the end of zero-order delivery of amount of drug (D)in the controlledrelease formulation (eq 3); and A is the amount in gut to be absorbed at the end of zero-order release !?-om the controlled-release formulation (eq 4):
A,, (tz)
=
kdk, - [l - e-(ka'ko)]
(4)
Results An initial computer simulation (Figure 1)using eqs 1 and 2 and literature estimates for CPM disposition parameters suggested that 4 mg of CPM released immediately, followed by 20 mg released over a period of 18 h (1.11mgh), produced desirable plasma concentrations. Study 1 tested the simulation and confirmed good correspondence between the shapes of the simulated and observed plasma concentration-time curves generated by this input combination (Figure 1).Doseadjusted AUC data (Table I) document no statistically significant difference between the nasogastric infusion compared with the immediate-release formulation for extent of absorption. The time of the peak concentration was longest for the 18-h infusion treatment and shortest for the immediaterelease dose given a t 0, 4, and 8 h (Figure 1, Table I). Based on the data from the nasogastric infusion study, a new 24-h formulation of CPM was developed, using osmotic technology,e consisting of a 4-mg immediate-release portion surrounding a core designed to release 20 mg of CPM at a zero-order rate of 1.1m g h over a period of 18h for a total dose
Figure l-chlorpheniramine maleate concentrations in a representative subject after: (7) a 4-mg oral solution at 0, 4, and 8 h (open circles);(2) a 4-mg oral solution followed by nasogastric infusion of 1.1 mg/h for 12 h (closed triangles);and (3)a 4-mg oral solution followed by nasogastric infusion of 1.1 mg/h for 18 h (open squares).A simulation also appears in the figure (solid line). This curve was derived from eqs 1 and 2, assuming a 4-mg CPM immediate-release dose followed by 1.1 CPM mg/h for 18 h and using published CPM disposition parameters (see text).
of 24 mg. Formulation development was guided by in vitro dissolution testing and computer simulation of plasma levels. Alterations in the formulation were made before the next in vivo study was performed. In vitro dissolution data for the new 24-h formulation appear in Figure 2. In Study 2 (Table 111, AUCs for this formulation were not significantly different compared with a n oral solution of 6 mg of CPM given a t 0,6, 12, and 18 h. Peak CPM concentrations were not significantly different between the two treatments in this study. In Study 3 (Table 111, Figure 3), no statistically significant difference was observed a t steady state between the six times daily, twice daily, and once daily products for any variable, with the exception of Cminand tminin the 12-24-h post-dosing period. The Cminfor the 24-h controlled-release product was lower and tmin was longer in comparison with the 12-h controlled-release formulation, but not significantly different from the immediate-release formulation. Plasma concentrations for the 24-h product conformed closely with a steadystate computer simulation, using eq 1 and a variation3 of eq 2 in conjuction with mean CPM disposition parameters derived from the solution dose in the nasogastric infusion study (absorption rate constant: 1.04 h-1; elimination rate constant: 0.038 h-'; V d 530 L)and mean in vitro dissolution parameters (zero-order release rate: 1.57 mgh; time of zeroorder release: 10 h; time lag: 0.5 h; bolus dose: 4 mg; amount released by first-order processes: 5.1 mg; first-order dissolution rate constant: 0.186 h-'). The variation in eq 2 is based on the fact that the osmotic pump releases only a portion of the drug via zero-order kinetics and the remainder via first-order kinetics. Assuming that most drug release is zero-order, release of a smaller proportion according to first-order kinetics does not appear to be problematic. The additional constants required from this equation are obtained from the in vitro dissolution data. Journal of Pharmaceutical Sciences / 23 Vol. 80, No. 1. January 1991
Table I-Pharmacoklnetlc Data after Administration of Various Doses of ChlorpheniramlneMaleate'
Treatmenta
Parameter Cmaw @L tmaxv h
Extrapolated AUC, pg/L * h
Post Hocb
P
I
II
111
17.1 2 4.66 10.5 f 1.16 960 t 240'
15.3 2 4.46 13.7 2 5.86 1034 t 290'
25.4 2 6.97 19.1 2 4.88 1090 f 398
rnm
0.0023 0.0320 0.3730
mii ~~~~~~
Treatment I: 4 mg of CPM solution at 0, 4, and 8 h; treatment II: 4 mg of CPM solution at 0 h, then 0.67 mg/h via nasogastric infusion for 12 h ; treatment 111: 4 mg of CPM solution at 0 h, then 1.1 mg/h via nasogastric infusion for 18 h (values expressed as mean t SD). Treatments under the same line are not significantly different. Adjusted to 24-mg dose. a
Table Il-Pharmacoklnetlc Data after Admlnlstratlon of Either a 24-mg Controlled-ReleaseChlorphenlramlne Maleate Tablet (IV) as a Single Dose or Chlorpheniramlne Maleate Solutlon (6 mg) at Six-Hour Intervals for Four Doses (V)ll
Treatment Parameter
P
V
IV
~
Cmax, tmax!
/@-
h
Extrapolated AUC, pg/L . h a
0
4
8
12
16
20
24
H
Figure 2-In vitro dissolution data for the 24-h controlled-release product
used in the clinical bioequivalence trials (individual data points not shown).
The data in Study 4 (Table IV) indicate that absorption of the new 24-h controlled-release formulation was not significantly altered by the administration of a standard high-fat breakfast.
Discussion Chlorpheniramine is an antihistamine that reversibly blocks the H, histamine receptor and is usually given without prescription as the maleate salt. The drug is cleared from the body in the liver via demethylation to mono- and didesmethyl metabolites.7 Several reports have described the pharmacokinetics of chlorpheniramine after oral and iv dosing.Sl4 Following iv dosing to two subjects, Huang et al.14 estimated the following pharmacokinetic parameters for CPM (adjusted to a 70 kg individual): plasma clearance, 174 mL/min; plasma Vd,,, 222 L; and terminal half-life, 22.5 h. Average AUCcinfinityafter
Values expressed as mean
34.5 2 7.51 14.7 t 4.20 1710 2 605 2
NS 0.037 NS
35.9 2 6.83 21.9 f 3.59 1840 t 531
SD.
oral dosing, adjusted to a dose of 24 mg, was 1084 FgIL . h, a value that corresponds reasonably well with the data in this report. Chlorpheniramine maleate does not possess active metabolites, and there is no evidence that its protein binding or metabolism are saturable. Given these characteristics, the current availability of 8- and 12-h controlled-release formulations, and the labeling requirements for immediate-release dosing every 4 h, CPM became a candidate for development of a 24-h controlled-release formulation. Criteria considered in the development of a controlledrelease product include pharmacodynamic, pharmacokinetic, and biopharmaceutic factors.2 Several of these may contribute to alteration in drug effect when a controlled-release formulation is substituted for an immediate-release one, including the propensity for drug tolerance and the development of irreversible toxicity.*J5 From a pharmacokinetic standpoint, saturable metabolism, saturable protein binding, comparatively short half-life relative to the dosing interval (large peak-to-trough fluctuations), and the presence of active metabolites are factors that can result in alteration of the clinical effects when a controlled-formulation is substituted for an immediate-release formulation.15 The final test of the adequacy of a new controlled-release product rests on either clinical trials to confirm unchanged efficacy or bioequivalence studies to document that the new formulation produces blood or plasma concentrations equivalent to the immediate-release product it is designed to replace. It is desirable to confirm the release characteristics of
Table Ill-Steadystate lnterdose (0-24 h) Pharmacokhetic Dataa aiter Admlnlstratlon of a 24-1119 Controlled-ReleaseTablet (IV), a 12-mg Controlled-ReleaseTablet (VI), and a 4-mg lmmedlate Release Tablet (VII) ~
Treatment
Parameter Cm,, trnax,
CLgiL h
C,,,, h" tin,"? h
Cmax Cmm,
AUC, kg/L * h a
IV
VI
VII
56.8 2 23.9 10.0 L 5.51 34.6 2 16.3 22.3 2 0.8 23.4 t 9.26 1090 t 481
60.7 2 24.6 8.81 t 4.66 42.5 2 20.2 19.2 2 4.9 20.1 2 7.88 1200 t 520
63.5 2 24.7 8.13 2 6.50 41.1 t 19.0 20.4 t 1.7 22.9 t 8.32 1200 2 501
Values are expressed as mean
t SD.
24 I Journal of Pharmaceutical Sciences Vol. SO,No. 1, January 7997
~-
~~
P NS NS 0.01 13 0.0259 NS NS
Treatments under the same line are not significantly different. 12-24 interval (see text).
~~
Post Hocb
-
mrm VI
m m ii -
Table IV-Pharmacoklnetlc Data. after a 24-mg Controlled-ReleaseChlorphenlramlne Maleate Tablet Fastlng (IVa) and after Breakfast (IVb), and after a 4-ma lmmedlate-ReleaseChlorphenlramlne Maleate Tablet Fastlng (VII)
Treatment
Parameter C m w MIL fax. h
Extrapolated AUC,
pglL . h
IVa
IVb
VII
30.6 2 8.8 13.7 2 4.73 1440 2 766
28.4 f 12.9 13.0 f 2.85 1315 2 863
56.4 2 20.3‘ 2.98 ? 1.42 1709 t 1257‘
P 0.001 0.001 0.0278
Post Hocb
m m m
m m a
b
a Values expressed as mean t SD. Treatments under the same line are not significantlydifferent. Dose adjusted (increasedsixfold)to correspond to IVa and IVb.
process of trial and error, involving perhaps several pilot clinical bioequivalence studies before a suitable release pattern for the new formulation is determined. Utilizing the methodology described herein, a new 24-h CPM formulation was designed that appears to meet current regulatory requirement+ for substitution. The bioequivalence studies required to confirm the bioequivalence and substitutability of the new formulation to currently available immediate products were kept to a minimum, thus reducing unnecessary exposure of healthy human subjects to experimental procedures and also reducing time and expense. A
References and Notes
5i 01 0
1
1
1
I
I
1
1
I
3
6
9
12
15
18
21
25
H
Flgure3-Steady-state plasma CPM concentrations during the final day (Day 7) of continuous dosing in a representative subject after administration of: (1) 4 mg of immediate-release formulation every 4 h (open squares);(2)12-h controlled-release product every 12 h (open circles); and (3)24-h controlled-release product once daily (closed triangles).The solid line in the figure represents a simulation constructed from eqs 1 and 2 and using mean CPM disposition parameters from the oral solution treatment in the nasogastric infusion study (see text).
a new controlled-release formulation with in vitro data before performing clinical trials. Through the development of a pharmacokinetic model combining the disposition characteristics of CPM with predetermined input patterns, a new controlled-release formulation of the drug was developed according to a process that has been termed “biorelevant dissolution”. Although the theoretical steps for the process have been reported,3 this report describes the application of the method to the development of a specific controlled-release product. Without the application of methodology similar to that described in this report, this development can be more a
1. Silber, B. M.; Cheung, W. K.; Yacobi, A. In Oral Sustained Release Formulations: Design and Evaluation; Yacobi, A., Halperin-Walega, E., Eds.; Pergamon: New York, 1988; pp 1-33. 2. Skelly, J . P.; Barr, W. H.; Benet, L. Z.; Doluisio, J . T.; Goldberg, A. H.; Levy, G.; Lowenthal, D. T.; Robinson, J . R.; Shah, V. P.; Temple, R. J.; Yacobi, A. Pharmaceut. Res. 1987, 4, 75-77. 3. Leeson, L. J.; Adair, D.; Clevenger, J.; Chiang, N. J . Pharmacokinel. Biopharm. 1985,3,493-514. 4. Shi, R. J . Y.; Gee, W. L.; Williams, R. L.; Lin, E. T. J . Liq. Chromatogr. 1987,20,31013112. 5. Yacobi, A,; Stoll, G.; Chao, J.; Carter,.D.; Basske, D.; Kamath, B.; Amann, A.; Lai, C. M. J . Pharm. Scr. 1980, 69, 1077-1080. 6. Theeuwes, F.; Ayer, A. D. US.Patent 4 058 122, November 15, 1977. 7. Athanikar, N. K.; Peng, G. W.; Nation, R. L.; Huang, S. M.; Chiou. W. L. J . Chromatogr. 1979. 62. 367376. 8. Barhart, W.; Johnson, J . D. Anal..Chem. 1977,49, 1085-1086. 9. Hanna, S.;Tang, A. J . Pharm. Sci. 1974,63, 1954-1957. 10. Lange, W. E.; Theodore, J . M.; Pruyn, F. J . J . Pharm. Sci. 1968, 57, 124-127. 11. Peets, E. A.; Weinstein, R.; Billard, W.; Syrnchowicz. L. J . Pharmncol. Exp. Ther. 1972, 80, 304-374. 12. Sanders, S. W.; Warner, R. N.; Georgitis, J. W.; Eigen, H.; Gonzalez, M. A. Am. Pharm. Assn. 127th Annual Meeting, Washington. D.C.. 1980. 84. Abstract #45. 13. Simons, F. E.; Simons, K. J.; Chung, M.; Yeh, J . Ann. Allergy 1987,59,20-24. 14. Huang, S. M.; Athanikar, N. K.; Sridhar, K.; Huang, Y. C.; Chiou, W. L. Eur. J . Clin. Pharmacol. 1982,22, 359365. 15. Mordenti, J.; Williams, R. L. In Oral Sustained Release Formulations: Design and Eualuation; Yacobi, A.; Halperin-Walega, E., Eds., Pergarnon: New York, 1988; pp 195-216.
Journal of Pharmaceutical Sciences I 25 Vol. 80,No. 1, January 1991
