Acta pharmacol. et toxicol. 1966, 24, 33 1-345

From The Department of Pharmacology, Royal Danish School of Pharmacy (Professor Erik Jacobsen M.D.) and from The Department of Pharmacology, University of Copen-

hagen (Professor Knud 0. Msller M.D.), Copenhagen, Denmark

Intestinal Absorption of Quinine from Enteric Coated Tablets

BY

Seren Rasmussen (Received March 4, 1966)

The fact that many drugs cause gastric irritation when administrated orally has a.0. increased the interest in enteric coated preparations i.e. granulates, pills or tablets coated with a layer that allows passage through the stomach and disintegration in the upper part of the intestine (DRAG- STED 1958; MORRISON & CAMPBELL 1965.

Numerous papers have been published on the properties of such preparations, especially on methods for examining the in vitro disintegra- tion, Most pharmacopoieas include tests for their enteric coated prepara- tions, all based on the principle that they remain intact when placed in an acid solution and disintegrate when placed in a neutral or slightly alkaline one. These pharmacopoiee methods have been rewiewed (in danish) by NU~PENAU (1965).

Reports of in vivo studies are less frequent. Two different types of techniques have been used, Some have measured the in vivo disintegration time of BaS04-containing enteric coated tablets by X-rays. The experi- ments of this type have been rewiewed by HODGEet al. (1944) and LAZA- RUS & COOPER (1959). The method there has given proportionality between the in vitro and the in vivo disintegration times (WAGNER et al. 1958 and WAGNER et al. 1960).

A different method of examining the time of disintegration involves measuring when the active substance from the tablets appears in the blood: it has the advantage that it not only gives a measure of the dis- integration time but also makes it possible to determine the amount absorbed. 23.

332 SQREN RASMUSSEN

The absorption of acetylsalicylic acid from enteric coated preparations has been investigated by LEONARDS & LEVY (1965), HOLLISTER & KANTER (1965) and by CLARK & LASAGNA (1965) The last named authors found less complete absorption from the coated tablets than from the uncoated tablets. Quinidine absorption has been investigated by SAMPSON et al. (1952), who in some experiments found a failure in disintegration and a decreased therapeutic effect from the enteric coated preparations.

A corresponding failure in absorption was reported by HAAPANEN & RIKKOLA (1964) who worked with p-aminosalicylic acid. In a note on oral potassium salts, PIRNIE & STAFFURTH (1961) report a complete failure of absorption of potassium from an enteric coated preparation, though the preparation fulfilled the in vitro tests of the British Pharmacopoiea.

WY" & LONDON (1963) examined the absorption from enteric coated tablets containing NaCl and KC1 and found complete absorption from all.

In these experiments the absorption was measured from commercial preparations, and no information on the nature of the coating material and the thickness of the coating layer are given in the reports. From the investigations it appears that in vitro examinations may give some in- formation on the preparations, but that they cannot predict how the absorption in vivo of the active substance will proceed.

Moreover, no systematic examination of the correlation between the delay in disintegration time and the amount absorbed has been found in the literature.

In our study the effect of the thickness of the coating layer on the absorption of different drugs from tablets coated with cellulose acetate phthalate has been examined. This paper reports the results of experiments on the absorption of quinine hydrochloride, a substance well suited for the investigation, because it is easily determined in the plasma at non- toxic concentrations.

Methods Eighteen healthy, adult volunteers of both sexes served as experimental subjects. Their

diet was not restricted, and during the experiments they carried out their usual work in the laboratory. Only males took part in the experiments in which urinary excretion was measured.

Blood samples were drawn from the ear-lobe immediately before the test dose and later a t intervals of approximately one hour. In some experiments the urine was collected for 10-12 hours before the administration and at intervals of 1-6 hours up to 48 hours after.

Tablets had the compositions given below.

50 mg rablers. No 100,000. Diameter 6 mm. Quinine hydrochloride .................... 5,000 g Starch .................................. 4,000 g Spiritus gelatinae 5 % Ph.Nord. (1965a) . . . . . a sufficient quantity Talc .................................... ad 10,000 g

ABSORPTION FROM ENTERIC COATED TABLETS 333

500 mg fablers. No 10,OOO. Diameter 12 mm. Quinine hydrochloride .................... 5,OOO g

Spiritus gelatinae 5 % Ph.Nord. (1965a) . . . . . a sufficient quantity Talc .................................... ad 7,000 g

.................................. Starch 1,500 g

From these two batches, subbatches of 4000 and 2000, respectively, were coated. The coating was made with vernix enterosolubile Ph.Nord. (1965 b), consisting of

Cellulose acetate phthalate. 200 g Oleum ricini 10 g

................ .............................

Acetone.. ............................... 1,790 g

To compare the thicknesses of the coating on the tablets of the different sizes, it was calculated as mg vernix per mm2 surface. The average difference between the weight of coated and uncoated tablets was determined on 200 tablets, and the surface of each tablet was calculated geometrically from its dimensions.

Preparations were made with various thickness of the coating layer, as seen from table 1. Quinine was determined in plasma by the method of BRODIE & UDENPRIEND (1943), quantitatively modified to allow determination in 0.1 ml plasma. The readings were made on a Photovolt fluorometer with the filters P = Hg:l and S = B:540 and compared with standard curves for known amounts of quinine dissolved in human plasma, in order to compensate for the quenching effect of the chloride ions.

Table 1. Thickness of the coating layer on the different prepara-

tions expressed as mg vernix per mm2 surface.

Preparation no: I mg/mm*

50 mg tablets

I 5 ...................... 6 ......................... 7 ......................... 8 ......................... 9 .........................

15 .........................

0.0423 0.03 1 5 0.130 0.0324 0.0687 0.178

500 mg tablets

11 ......................... 12 ......................... 13 ......................... 14 .........................

0.0336 0.0585 0.121 0.242

Preparation no 2 and 10 are uncoated tablets of 50 and 500 mg, respectively, from which all the coated prepara- tions were manufactured.

334 S0REN RASMUSSEN

In the urine analysis, the extraction procedure of BRODIE ef al. (1947), which was first tried, showed no advantage over a determination directly on the urine identical to that for plasma. Standards were dissolved in the urine collected before the administration, which eliminate most of the basic fluorescence in the urine. The blank fluorescence in the samples could vary in amounts corresponding to an “excretion” of 0-9 mg quinine in 48 hours. HAAO ef al. (1943) report an “excretion” of 0-4 mg in 24 hours. The effect of the variations in this blank value was estimated as negligable compared with the amount excreted after the doses given.

Results Plasma concentrations after administration of 0.2,0.3 and 0.5 g quinine

HCl in aqueous solutions to the same person are shown in fig. 1. The concentrations of plasma quinine determined 2 hours after the same dose varied somewhat from person to person, after 0.5 g, between 2.36 and 5.30 pg/ml with an average of 4.12 pg/ml f 20.6% (s) d.f. = 8. The variation from time to time in the same person was considerably smaller, s = 10.7% d.f. = 24. The graphically calculated rate of elimination showed variations of &13.6% (s) d.f. = 16, within individuals and &36% (s) d.f. = 24 between individuals.

The results from all experiments with various doses are given in table 2. A clear proportionality is seen between the dose administrated and the plasma concentration measured at any time in the test period. This means that it is possible to estimate the amount absorbed from a given dose when equilibrium of the distribution in the body is reached, if the plasma con- centration is compared with that obtained at the same time after a known dose in aqueous solution.

- 0.5 g

” 0.359

n 0.29

180 300 420 min

Fig. 1. Plasma concentrations of quinine HC1 after oral intake of 0.50, 0.35 and 0.20 g quinine HCI in aqueous solution.

(Experimental subject no I).

Abscissa: Minutes after the intake. Ordinate: Concentration in bg/ml.

ABSORPTION FROM ENTERIC COATED TABLETS 335

Hours after ingestion:

Table 2.

Plasma concentration : Dose:

I 200 mg (n = 5 ) 300 mg (n = 3)

2 .............................. 3 .............................. 4 .............................. 5 .............................. 6 .............................. 7 ..............................

38 % (37-40) 38 % (37-41) 39 % (35-42)

36 % (27-41) 36% (29-40)

39 % (28-42)

Average ....................... Dose as percentage of 500 mg ....

72 % (71-73) 72 % (70-76)

68 % (66-71)

69 % (66-74)

72 % (68-79)

70% (67-76)

Fig. 2 shows an example of plasma concentrations measured in experi- ments in which 0.5 g quinine HC1 was given as one single dose (1) or as 10 doses of 50 mg each at intervals of 10 minutes (2) or of 30 minutes (3). The results from all experiments of this type are collected in table 3. The plasma concentration measured when divided doses are given naturally increases.more slowly than after one single full dose, and the maximum is reached about one hour after the last fraction is given, but at this point the concentration reaches or often even exceeds that from the single dose.

Table 3. Plasma concentrations after intake of 0.5 g quinine hydrochloride as 10 x 50 mg in aqueous solution at intervals of 10.20 and 30 minutes between divided doses as percentages of the corresponding concentration after intake of 0.5 g as a single dose in aqueous solu-

tions (= 100% & 1 0 . 7 % ~ )

Plasma concentrations (see text) Min. between divided doses

10 (n = 2) I 20 (n = I ) 1 30 (n = 2)

Hours after the first dose

I I I 2 . . . . . . . . . . . . . . . . . 3 . . . . . . . . . . . . . . . . . 4 . . . . . . . . . . . . . . . . . 5 . . . . . . . . . . . . . . . . . 6 ................. 7 . . . . . . . . . . . . . . . . .

76-81 % 90-110% 91-117% 89-1 10% 87-108 % 87-1 00 %

3 6 4 9 % 57-73 % 78-102%

100-134%

100-118% 108-1 32 %

I

336 S0REN RASMUSSEN

Fig. 2. Plasma concentrations after intake of 0.5 g quinine HCI in aqueous solution. (Experimental subject no 1).

= 500 mg at zero time. 0 = 10 x 50 mg at 10 minute intervals. X = 10 x 50 mg at 30 minute intervals.

The arrows indicate the time of intake. Abscissa: Time in minutes. Ordinate: Concentration in pg/ml.

It is further seen that slower the absorption the less steep is the slope of the ascending branch of the plasma concentration curve.

In fig. 3 these slopes, recorded from all experiments similar to that represented in fig. 2, are plotted against the time between the doses, which is inversely proportional to the rate of absorption. As seen, there is proportionality between the slope and the rate of absorption at least when it is completed within 5-6 hours.

This means that it is possible to estimate the least expected peak con- centration of a given dose when the rate of absorption and the curve from ingestion of a standard dose of 0.5 g quinine HC1 to the same person are known. Similarly, it is possible to estimate the amount absorbed from a given dose, if the rate of absorption and the elimination curve of a standard dose are known.

As will be seen below, the absorption from the coated tablets may be prolonged over a considerable time. The principle just described is applied here in order to estimate approximately how much of a given dose

ABSORPTION FROM ENTERIC COATED TABLETS 337

I 1 I I

0 10 20 30 min Fig. 3. Relation between the reciproced, recorded slope (a) of the ascending branch of the plasma concentration curve and the rate of absorption, measured as the intervals between

the divided doses.

Abscissa: Intervals between the dose fractions in minutes. Ordinate : 1 :a.

has in fact been absorbed. Examples of the procedure are given in fig. 4A to D. From the test itself (4A and C) the maximal plasma concentration a, is recorded. The slope of the line drawn through the ascending branch of the concentration curve is conveniently determined graphically. A line is drawn parallel to this through the zero point on the curve obtained from administering a standard dose of 0.5 g quinine HC1 in aqueous solution to the same person. The point where this line intersects the curve, repre- sents the concentration b, which should have been reached provided that the total dose has been absorbed. The approximate amount absorbed is

a b

calculated by the formula: Rc = -. This ratio represents the part of the

dose of 0.5 g that is absorbed. If complete absorption takes place, the value should be equal to or exceed one.

Rc-values calculated from tests with known amounts in aqueous solu- tions are given in fig. 5. The Rc-values calculated in this way give measures of the amounts absorbed relative to the absorption from 0.5 g in aqueous solution sufficiently reliable to be used in our investigation.

338 SQREN RASMUSSEN

B x

1

60 120 180 a0 3eomin360

Fig. 4, A to D. Plasma concentrations after intake of 0.5 g quinine HCI in different preparations.

4A. Intake of 0.5 g in tablets coated with 0.0687 mg/mm* (preparation no. 9). Experimental subject no. 3.

4B. 0 = 0.5 g in aqueous solution. 0 = 0.5 g i n aqueous solution. x = 0.5 g in uncoated tablets (preparation no. 2). Experimental subject no. 3.

Abscissa: Time in minutes after intake. Ordinate: Concentration in pg/ml.

The broken lines in 4B and D represent the measured slope of the ascending branch of the curves in fig. 4 A and C, respectively, displaced to the zero point. The letters a and b indicate the concentrations mentioned in the text from which the amount absorbed, the Revalues are calculated. For further explanation see text.

From tests on ingestion of uncoated tablets, the total amount always being 0.5 g quinine HCl, the calculated Rc-values were found to average 1.01 & 0.044 (s.e.m.) n = 1 1, which means that the absorption from the uncoated tablets is the same as from the aqueous solution.

The plasma concentration curves in fig. 4A and C obtained from two administrations of the coated preparation no. 9 show a delay in the onset of absorption, which is not found in tests with uncoated tablets. The nearest whole hour after the ingestion when detectable amounts of quinine

ABSORPTION FROM ENTERIC COATED TABLETS 339

D

4C. Intake of 0.5 g in tablets coated with 0.0687 mg/mm2 (preparation no. 9). Experimental subject no. 2.

4D. 0 = 0.5 g in aqueous solution. x = 0.5 g in uncoated tablets (preparation no. 2). Experimental subject no. 2.

are found in the plasma is taken as the in vivo disintegration time of the preparation.

In fig. 6 the in vivo disintegration times are plotted against the thickness of the coating layer and found proportional to it. From the curves in fig. 4A and C it is further seen that the absorption rate from the coated tablets is lower than from the aqueous solution. The slopes of the ascend- ing branches from all tests with coated and uncoated tablets are shown in fig. 7, plotted against their corresponding in vivo disintegration times, indicated as the interval between two plasma determinations in which the fmt increase in plasma quinine was found. From the figure it is seen that if the in vivo disintegration time exceeds one hour, the slope is significantly lower than that found for the uncoated tablets (P < 0.001). This delay in absorption rate could be explained as a difference in the disintegration times of the tablets if all tests involved administration of 10 tablets of 50 mg each, but this is disproved by the fact that a similar decrease was found in tests with 500 mg coated tablets (broken lines in fig. 7).

340

L

8 x x

a

SBREN RASMUSSEN

a1 ~2 a3 OA 059

Fig. 5. Absorbed amounts, calculated as Rc-values in relation to the doses ingested.

Abscissa: Dose in g. Ordinate: Rc-values. The value 1.0 indicates an absorption equal to the absorption from

0.5 g in aqueous solution. dose in mg

500 Broken line: Theoretical Rc-values: Rc =

hours 7 -

49

3.

t 8

8

I

i 0.05 WO 0.15 0.20 0.25 mg/mm2

Fig. 6. I n vivo disintegration time in relation to the thickness of the coating layer.

Abscissa: Thickness of the coating layer in mg vernix per mm* tablet surface. Ordinate: I n vivo disintegration time in hours.

@, dose given as one 500 mg tablet. x , dose given as 10 tablets of 50 mg each.

ABSORPTION FROM ENTERIC COATED TABLETS

0.6

0.4

02-

. 1. ' 2. 3. a 4. 5. 'hours

-

-

Fig. 7. The slope of the ascending branch a, of the plasma concentration curve, recorded from all tests with uncoated and coated

tablets, in relation to the in vivo disintegration time.

Abscissa: I n vivo disintegration time in whole hours. Ordinate: Slope in arbitrary units. Broken lines: Tests with 500 mg tablets. Unbroken lines: Tests with 10 x 50 mg tablets.

x

1 ....a - 0.05 0.10 " 0.15 0.20 0125mg/mm2

Fig. 8. Relation between the amount absorbed, calculated as Rc-values, and the thickness of the coating.

Abscissa: Thickness of the layer in mg/mmz. Ordinate : Calculated Revalues.

341

342

50-

20-

10

SBREN RASMUSSEN

- - 40L""' -

30: - - - -

- -

- -- - -- -

Q O - L

1. 2. 3. 4. 5. *hours Fig. 9. Relation between the absorbed amount, calculated as Rc-values,

and the in vivo disintegration time. Abscissa: In vivo disintegration time in whole hours. Ordinate: Calculated Rc-values. Broken lines: Tests with 500 mg tablets. Unbroken lines: Tests with 10 x 50 mg tablets.

The amount absorbed, calculated as the Rc-values, from all tests with tablets, are plotted in fig. 8 against the thickness of the coating layer and found to decrease with increasing thickness. With small tablets only, this might be explained by assuming that some of tablets did not disintegrate, but results from 500 mg coated tablets show a similar decrease.

Fig. 10. Excretion in the urine as percentage of the ingested dose ( 5 0 0 mg) in relation to the in vivo disintegration time.

Abscissa: In vivo disintegration time in whole hours. Ordinate: Excreted amount as percentage of the dose, 500 mg. Dotted line: Test with 10 uncoated tablets of 50 mg each (preparation no. 2) administrated

as 10 single ingestions at 30 minute intervals.

ABSORPTION FROM ENTERIC COATED TABLETS 343

Fig. 9 shows the relation between the delay in onset of absorption - the in vivo disintegration time - and the Revalues. With increasing in vivo disintegration time the amount absorbed is decreased.

Results of determinating the urinary excretion are shown in fig. 10, where the excretion, as a percentage of the dose administered, is plotted against the recorded in vivo disintegration time. With an increase in the latter the amount excreted is seen to decrease. This decrease cannot be due to the decrease in the absorption rate found with the increasing in vivo disintegration time, as one of the highest excretions was found in a test in which the dose was administrated as 10 uncoated tablets of 50 mg each ingested one by one at intervals of 30 minutes (the dotted line in fig. 10).

Discussion From the urinary excretion (fig. 10) and the calculated Rc-values in

fig, 9, the Rc-value seems to be a reliable measure of the amount absorbed. As the rate of absorption and the amount absorbed were found to be

the same from aqueous solutions and the uncoated tablets, the observed differences in the absorption pattern for the coated tablets must be caused by the coating layer. With increasing thickness of the vernix layer an inceasred in vivo disintegration time is found. Stomach retention, such as that found in patients kept in a supine position during the experiments, as reported by PRBTORIUS & FABER (1950), is not a likely explanation of the delayed disintegration observed here, as the experimental subjects were normally active during the experiments. Moreover, stomach reten- tion would not explain the decrease in rate of absorption and the decrease in amount absorbed found in the experiments reported here.

The slow absorption rate and the decrease in amount absorbed with increasing thickness of the coating is observed both with the dose given as 10 tablets of 50 mg each and with the dose given as a single coated tablet of 500 mg and can thus not be due to a difference in the disintegration times of the 50 mg tablets.

Apparently the coated tablets disintegrate in the lower parts of the small intestine where quinine is more slowly and less completely absorbed.

A difference in absorption rate from the various parts of the small intestine is well known for substances actively absorbed, but is not an established fact for substances that, like quinine, must be assumed to be absorbed by simple diffusion processes. However, a few indications that this might be so are found in litterature.

SJOGREN & STH HOLM (1961) investigated the absorption of different drugs from a sustained release preparation and found creatinine and potassium penicillin-V less completely absorbed than from conventional

344 SQREN RASMUSSEN

tablets, although both substances were completely released in vitro. These authors suggests a decreased power of absorption ability by the lower parts of the intestine as a possible explanation.

Creatinine absorption from a different prolonged action preparation (“Gitter” tablets) has been investigated by LUNDHOLM & SVEDMYR (1963), who found that the dose had to be doubled in order to obtain the same plasma concentration and urinary excretion as after a dose of conven- tional tablets. Neither SJ~GREN & STH HOLM nor LUNDHOLM & SVEDMYR have compared the absorption rate with that after divided dosage.

The experiments reported here were conducted with quinine hydro- chloride and the results must not be generalized. None the less, they indicate that enteric coated or sustained release preparations cannot be used therapeutically before the effect of the delayed release on absorption is known for each particular drug. Evaluation of such preparations cannot be based on in vitro tests alone.

summary The effect of the thickness of the coating on the absorption of quinine

hydrochloride from tablets coated with cellulose acetate phthalate has been investigated. A method for calculating the amount absorbed from the plasma concentration curve is described, and the calculated values are compared with the urinary excretion. With the coated tablets the in vivo disintegration time was found to increase in proportion to the thickness of the coating. The rate of absorption was decreased with increasing layer thickness and generally also the amount absorbed. The findings suggest that the ability to absorb quinine is decreased in the distal parts of the intestine.

Acknowledgements This work has been carried out in the Department of Pharmacology,

Royal Danish School of Pharmacy, Copenhagen (head : Professor Erik Jacobsen M.D.) by the request of the Danish Pharmacopoiea Commission and supported financially by The Danish Ministry of the Interior. The Pharmaceutical preparations were made by the University Hospital Pharmacy, Copenhagen (head: Professor S. A. Schou Ph.D.) to whose staff I offer my cordial thanks. For skilful technical assistance I thank Mrs. Lone Kasper.

ABSORPTION FROM ENTERIC COATED TABLETS 345

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24 Acta pharmacologica. vol. 24. fasc. 4.