Bioavailability of a Poorly Water-Soluble Drug from Tablet and Solid Dispersion in Humans

Bioavailability of a Poorly Water-Soluble Drug from Tablet and Solid Dispersion in Humans To the Editor: The use of solid dispersions and solid solutions in pharmaceutical dosage forms to improve the dissolution rate of sparingly water-soluble drugs has been investigated extensively.l.2 However, as discussed earlier,3 very few of the formulations have been marketed due to problems associated with their processing and stability. Some of the problems associated with processing (e.g., pulverization, compression, etc.) of a solid dispersion may be avoided by encapsulating the formulation directly in hard or soft gelatin capsules as a liquid melt.3.4 The melt solidifies at room temperature. Complete dissolution of a poorly water-soluble drug from such a system may be obtained if a surface-active vehicle is used.3.5 In the present report, the human bioavailability of a-pentyl3-(2-quinolinylmethoxy)benzenemethanol(REV 5901; l), a 5-lipoxygenase inhibitor orally active against hypersensitivity diseases,6.7 from a conventional tablet formulation and a solid dispersion in a surface-active vehicle is compared. There are very few reports in the literature on the comparative bioavailability of solid dispersions and conventional dosage forms (e.g., tablets, powder-filled capsules, etc.) in humans. Griseofulvin is the only drug for which the human bioavailability of a solid dispersion has been compared with that of a tablet.Sl0 The extensive literature on the solid dispersions of other compounds deals mostly with their in vitro dissolution rates and, in some cases, with the bioavailability in animal models.2 Therefore, it is important that the enhanced bioavailability of 1 from solid dispersions observed in dogs3 be confirmed in humans. The physicochemical properties of 1 were described earlier.11 It is a basic compound with a pK, value of 3.7 and a solubility of -0.002 mg/mL in water at 37 "C (pH -6). The tablets were prepared by wet granulation and then they were film coated. Micronized drug with an average particle diameter of 5 to 7 pm, as measured by the Coulter counter (Coulter Electronics, Hialeah, FL) and also estimated by using a microscope, was used in the tablet. Each 535-mg core tablet contained 250 mg of 1, while microcrystalline cellulose, lactose, croscarmellose sodium, sorbitan monolaurate, and magnesium stearate served as the excipients. Sorbitan monolaurate (Span 20, ICI; 2%) was incorporated in the formulation to enhance the wettability of the drug. The core tablets were coated with Opadry white (21 mg) and Opadry clear (1 mg) supplied by Colorcon (West Point, PA). The method of preparation of soft gelatin capsules containing the solid dispersion of 1was described earlier.4 Each capsule contained 125 mg of 1 dissolved in 575 mg of Gelucire 44/14polyethylene glycol 400 mixture (6:1). Gelucire 44/14 (Gattefosse Corporation, Elmsford, NY)is a surface-active vehicle with a melting point of 44°C and an HLB value of 14. Chemically, it is a mixture of glyceryl and PEG 1500 esters of long-chain fatty acids. As noted earlier,4 polyethylene

1

712 I Journal of Pharmaceutical Sciences Vol. 80, No. 7, July 1991

glycol 400 was incorporated in the formulation to lower the congealing point of the vehicle from -44 "C to -38 "C so that it could be encapsulated in a soft gelatin capsule. Microscopic examination showed that the drug remained dissolved in the vehicle a t room temperature. The dissolution of 1 from a tablet or a capsule in 900 mL of simulated gastric fluid (USP, without enzyme) was studied at 37 "C according to the USP paddle method (50 rpm). The aliquots collected a t various intervals of time were filtered through 0.45-pm Millipore filters and analyzed spectrophotometrically a t a wavelength of 239 nm after suitable dilution with 0.1M HC1. The presence of excipients in a dissolution medium did not influence the drug assay. In the bioavailability study, each of eight healthy male volunteers (age 18 to 40 years) received two separate doses (500mg each: four capsules or two tablets) of each formulation according to a randomized four-way crossover schedule. A 1-week washout period was allowed between two successive dosings. One dose of each formulation was given with 240 mL water after an overnight fast and the other was given with 120 mL water after a standard breakfast. The breakfast consisted of 180 mL of orange juice, -30 g of corn flakes with 120 mL of whole milk and 1teaspoonful of sugar, two slices of toasted bread, lightly buttered and served with 15 g of jam or jelly, and 180 mL of tea or coffee (decaffeinated), with or without milk and sugar. An additional 240 mL of water was consumed 1 h post-dose and ad libitum thereafter. All food was withheld until 4 h post-dose. Blood was sampled at 0 (predose), 0.5,1, 2, 3, 4, 6, 12, and 24 h post-dose. It was centrifuged after each collection and the plasma was frozen until analyzed for the concentration of 1 by a specific gas chromatographic procedure.12 After rapid disintegration ofthe tablet (<3 m i d , 67,81, and 89% of 1dissolved in the dissolution medium in 30,60, and 90 min, respectively (Figure 1). Preliminary experiments had shown that the dissolution rate of the tablet increased with the decrease in the particle size of 1. The smallest particle size (5-7 pm) which did not compromise the processability of tablets was selected for the study. Unlike the tablet, the solid dispersion dissolved by erosion and complete dissolution of 1 was obtained within 30 min whether one (125 mg) or two capsules (250 mg) were used. The saturation solubility of 1in the simulated gastric fluid a t 37 "C is 0.7 mg/mL and, therefore, the maximum amount of drug present in a formulation (250 mg) was below the saturation limit in 900 mL of the medium used. The results of the dissolution study indicate that a solid dispersion may provide a higher dissolution rate than a tablet, even though the micronized drug is used in the latter formulation. The plasma level profiles of 1 following the administration of the tablet and the solid dispersion filled into capsule, both with and without food, are shown in Figure 2. The effect of food was studied because it had earlier been observed13 that bile salts, lecithin, and lipid digestion products, which may be present in the intestine a t a higher concentration after the ingestion of food, increase the aqueous solubility of 1. The bioavailability parameters such as area under the plasma level curve (AUC), maximum plasma concentration (&-I, and time to reach maximum plasma concentration (tm-) are given in Table I, and indicate that the solid dispersion 0022-3549/91/0700-0712$01.OO/O 0 1991, American Pharmaceutical Association

100 0

80

n W

g3

6o

v,

n

5 40 0

W

a

2

6

4

8

24

1 0 1 2

HOURS

Flgure 2-Plasma levels of 1 in humans following oral administration of the solid dispersion (filled into soft gelatin capsule) and conventional tablet under fasted and fed regimens. Each curve represents the average solid dispersion plasma concentrations from eight subjects. Key: (0) after fasting; (0)solid dispersion after food; (0)tablet after fasting; (A) tablet after food.

20

0

30

60

90

MINUTES Flgure 1-Dissolution

of solid dispersion and tablet dosage forms of 1 in simulated gastric fluid (without enzyme) according to the USP paddle method (50 rpm). Key: (M) solid dispersion, 250 mg (two capsules);(0) tablet, 250 mg (one tablet). provided superior bioavailability of 1 as compared with tablets. Food increased the bioavailability of tablets by a factor of almost two, while there was no significant effect of food on the bioavailability of the solid dispersion. The AUC values of various treatment groups are compared in Table 11. A ratio > 1 would indicate that the bioavailability of the treatment group in the numerator would be higher than that in the denominator. The statistical analysis of the data in Table I1 confirmed that the solid dispersion (capsule) with both fasted and fed regimens had significantly higher bioavailability than the tablet under fasting conditions. However, when the capsule and the tablet were administered under the fed regimen, the difference in bioavailability was not significant. One possible reason for the absence of an effect of food on the bioavailability of the solid dispersion may be that the maximum bioavailability from this formulation was attained in the fasted regimen and no further increase in bioavailability

by food was possible. This hypothesis, however, could not be confirmed because the absolute bioavailability of the formulation was not determined due to the difficulty in administering a comparable iv dose. The high bioavailability of the solid dispersion even in the fasted regimen may be due to the liberation of 1from the solid dispersion in an aqueous medium as fine oily globules (- 1 pm1.3 Such a metastable form of the compound has a very high surface area and dissolves more rapidly than the solid drug particles present in tablets. An increase in the bioavailability of tablets in the presence of food appears to be related to the increase in solubility and dissolution rate and the delay in gastric emptying time. Although only the effect of a standard breakfast was investigated in the present study, it is also possible that food composition (high fat, protein, etc.) may be a factor in the bioavailability of the drug from the tablet. In conclusion, the human bioavailability of the solid dispersion of a poorly water-soluble drug in a surface-active vehicle under a fasting regimen was observed to be higher than that of a tablet formulation even though the micronized drug and a wetting agent were used in the tablet. While food enhanced the bioavailability of tablets by a factor of two, there was no significant difference between the bioavailability of the solid dispersion under fasting and fed regimens. Thus, the bioavailability of a poorly water-soluble and errat-

Table CBloavallablllty Parameters of Compound 1 In Normal Subjects under Fasted and Fed Condltlons

Tablet after Fasting Subject

AUC, ng.h/mL

, C ng/mL

402 83 877 140

97 31 230

338

156 66 16 60 87 73 83

Tablet after Food

C,,,

Capsule after Fasting

Capsule after Food AUC, ng.h/mL

C-,

AUC, ng.h/mL

ng/mL

L'

AUC, ng.h/mL

ng/mL

698 481 1038 264 368 808 119 975 594 338 57

150 157 200 78 145 195 113 31 1 169 70 42

2.0 1.o 2.0 2.0 2.0 2.0 1.o 1.o 1.8 0.5 27

1113 372 1758 253 399 656 160 1359 759 584 77

551 170 820 168 291 124 110 521 344 259 75

Cmaxl ng/mL

~

1 2 3 4 5 6 7 8

Mean SD

cv. %

143 23 495 313 282

90

40

0.5 2.0 1.o 1.o 2.0 1.o 1.o

1.o 1.2 0.5 45

1.o 1 .o 1.o 1.o 1.o 0.5 1.o

1.o 0.9 0.2 19

908 758 1065 467 470 677 406 956 713 250 35

410 309 309 181 170 219 272 204 259 82 32

2.0 1.o 2.0 1.o 1.o 1.o 1.o

2.0 1.4 0.5 38

Journal of Pharmaceutical Sciences / 713 Vol. so,No. 7, Ju/y 1991

Table IUndlvldual AUC Ratios of Varlous Treatment Groups Subject

1 2 3 4 5 6

7 8 Mean SD 95% Confidence Interval"

Cap. Fasted

Cap. Fed

Cap. Fasted

Cap. Fed

Tab. Fed

Cap. Fed

Tab. Fasted

Tab. Fasted

Tab. Fed

Tab. Fed

Tab. Fasted

Cap. Fasted

2.77 4.48 2.00 1 .81 1.18 4.58 6.85 2.74 3.30 1.88 1.77-4.636

2.26 9.13 1.21 3.34 1.39 4.72 17.42 1.93 5.18 5.58 1.56-7.456

1.59 0.77 1.69 0.96 1.08 0.81 1.35 1.39 1.21 0.35 0.90-1.49

1.30 1.57 1.02 1.77 1.28 0.84 3.42 0.98 1.52 0.83 0.96-2.00

1.73 5.79 1.18 1 .89 1.09 5.64 5.08 1.97 3.05 2.07 1.3W.42'

0.81 2.04 0.61 1.84 1.18 1.03 2.54 0.70 1.34 0.71 0.76-1.85

Confidence intervals are based on logarithmic values of the individual ratios. Mean ratio significantly > 1 at 0.05testing level. ically absorbed drug may be increased and the variation in bioavailability due to the effect o f food may be decreased by f o r m ulatingit as a solid dispersion in a surface-active vehicle.

11. Serajuddin, A. T. M.; Sheen, P. C.; Mufson, D.; Bernstein, D. F.; Augustine, M. A. J . Pharm. Sci. 1986, 75, 492-496. 12. Analytical method is available from P.C. Sheen. 13. Serajuddin, A. T. M.; Sheen, P. C.; Mufson, D.; Bernstein, D. F.; Augustine, M.A. J . Pharrn. Sci. 1988, 77,325-329.

References and Notes 1. Chiou, W. L.; Riegelman, S. J . Pharrn. Sci. 1971,60, 1281-1302. 2. Ford, J. L. Pharm. Acta Helu. 1986, 61,69-88. 3. Serajuddin, A. T. M.; Sheen, P. C.; Mufson, D.; Bernstein, D. F.; Augustine, M. A. J.Pharrn. Sci. 1988, 77,414-417. 4. Serajuddin, A. T. M.; Sheen, P. C.; Augustine, M. A. J . Pharrn. Sci. 1986, 75, 62-64. 5. Serduddin, A. T. M.; Sheen, P. C.; Augustine, M. A. J . Pharrn. Sci.1990, 79, 463-464. 6. Van Inwegen, R. G.; Khandwala, A.; Gordon, R.; Sonnino, P.; Coutts, S.; Jolly, S. J . Pharnacol. Exp. Ther. 1987, 241, 117-124. 7. Kusner, E. J.; Marks, R. L.; Aharony, D.; Krell, R. D. Biochem. P h a r m o l . 1989,38,4183-4189. 8. Chiou, W. L.; Riegelman, S.J . Pharrn. Sci. 1971, 60, 13761380. 9. Barrett, W. E.; Hanigan, J. J. Cum. Ther. Res. 1975, 18,491400. 10. Barrett, W. E.; Bianchine, J. R. Cum. Ther. Res. 1975, 18, 501609.

714 I Journal of Ph8f7718~8Ufic8/Sciences Vol. SO, No. 7,July 1 9 9 1

Acknowledgments The authors thank Dr. James J . Bergum for the statistical analysis of data and Ms. Joan Kuhn for her secretarial assistance.

PAI-CHANGSHEEN* Soo-ILKIM* JOHNJ. PETILLO* ABU T. M. SERAIUDDIN**~ 'Rorer Central Research Horsham, PA 19044 'Present address: Bristol-MyersSquibb Pharmaceutical Research Institute New Brunswick, NJ 08903 Received Januay 22, 1990. Accepted for pub ication September 20,1990.