In Vitro Study of Gastric Antacids*

In Vitro Study of Gastric Antacids* By GEORGE M. NAIMARK Ten antacid preparations were evaluated, using the Holbert modification ( 4 ) of the Johnson and Duncan procedure (3) and simulating typical in vim dosages and physical forms. Several of the antacids rapidly raised the pH of gastric juice to a point above that usullly considered desirable while one preparation raised the pH to a maximum of 3.7. The importance of the antacid dosage form in releasing the active ingredients is stressed.

HE NEED FOR gastric antacids to lower the Tacidity of the stomach contents continues unabated since Paracelsus prescribed powdered pearls and Pliny commended crushed coral (1). Although the use of such agents by physicians and the laity continues to increase, much work has yet to be done in evaluating the characteristics of the many available antacid materials (2). The successful evolution of in oitro procedures, closely simulating in vivo conditions, has provided a practical technique for comparative study of antacids under standardized and reproducible circumstances. This refinement in methodology suggested the following procedure as one that closely parallels intragastric conditions: the antacid is added in usual dosage and in appropriate physical form to synthetic gastric juice, maintained at body temperature and stirred continuously a t a constant rate; portions of the reaction mixture are removed at definite intervals (to simulate periodic emptying of the stomach) and replaced with equivalent volumes of fresh gastric juice also maintained at body temperature (to simulate continual secretion of gastric juice) ; pH changes are checked throughout the test. This is essentially the method of Johnson and Duncan ( 3 ) which has been used with modification by many workers (4-8). A useful modification of the method (4) was selected by us for comparative evaluation of miscellaneous antacid preparations, including several that had not previously been studied by this procedure.

antacid materials into the artificial gastric juice in physical forms that would correspond to in vivo use. The dosage and physical state of each antacid product are summarized in Table I. Criteria of Eff ectiveness.-In clinical use, an antacid preparation should have the ability t o raise and maintain the pH of the gastric contents within a range sufficiently high t o control the symptoms of hyperacidity, but not so high as to result in the possibility of acid rebound. Dale and Booth (9) have recently reviewed the lack of agreement concerning this desired pH range. Nonetheless, in our work we have been guided by the opinion expressed in New and Nonofficial Remedies (10) to the effect that effective neutralization involves raising the pH t o 4.0 or 5.0, and that of Kirsner and co-workers (11) : “Effective neutralization may be defined as maintenance of the pH between 4.0 and 5.5 or higher.” In the evaluation of antacids in our laboratory, a pH range of 4.0 to 6.0 has been selected as the desired range. RESULTS The results are graphically shown in Figs. 1 and 2. Each curve represents an average of duplicate determinations for each antacid studied.

EXPERIMENTAL Test Method.-The Holbert modification (4) of the Johnson and Duncan procedure (3) was used. Artificial Gastric Juice.-The U. S. P. XV artificial gastric juice was used with pH adjusted to 1.6 to approximate closely the initial pH utilized by Holbert and co-workers (4, 5, 8). Antacid Addition.-It was considered practical to adhere to typical dosages and t o introduce the

*

Received May 25, 1956 from Medical Research Department, White Laboratories, Inc., Kenilworth, N. J.

344

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Fig. 1 .--Neutralization characteristics of samples A through D.

SCIENTIFIC EDITION

June 1957

345

TABLEI

Antacid Product

Dosage Used in Evaluation

Magnesium hydroxide tablets Magnesium hydroxide suspension Magnesium trisilicate Calcium carbonate Magnesium hydroxide tablets Sodium bicarbonate Magnesium carbonate Bismuth subnitrate powder Magnesium glycinate powder Sodium bicarbonate powder Calcium carbonate Magnesium carbonate Magnesium trisilicate tablets Calcium carbonate Magnesium trisilicate Chewing gum tablet

a

2 tabs. ( 1 . 2 Gm.) I tsp.

(1) Ground tabs. (2) Intact tabs. As is

2 tabs. ( 1 . 2 Gm.)

(1) Ground tabs. (2) Intact tabs.

Sample Designation

(1) A,

1 tsp.

As is

D

900 mg. (450 mg. initially, 450 mg. after 2 min.) '/z tsp.

As is

E

As is

F

Ground tabs.

G

As is

H

Intact tabs.

I

2 tabs. ( 2 . 7 Gm.) 305 mg. calcium carbonate and 145 mg. magnesium trisilicate initially. repeated after 2 minUtesa 2 tabs. (2.4 Gm.)

Calcium carbonate Magnesium carbonate Magnesium trisilicate tablets Dihydroxy aluminum sodium carbonate tablets

Physica State of Antacid as Used in Test

Ground tabs .

2 tabs. ( 3 . 0 Gm.)

Simulating actual release of ingredients from two tablets.

Under the conditions of this study, the antacid preparations depicted in Fig. 1 acted rapidly but tended t o raise and maintain the pH within an alkaline range and thus, in clinical use, may possibly induce acid rebound. Also noteworthy are the differences in rapidity of action, maximum pH achieved, etc. when the physical state of a given antacid was altered. For example, with intact

DISCUSS4ON

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tablets (samples A' and C'), the maximum pH was less and the time required to attain this pH greater than with tablets that had been comminuted (samples A and C) before addition to the gastric juice. With the exception of samples H and J most of the antacid preparations for which results are shown in Fig. 2 raised the p H of the artificial gastric juice to a level which might result in acid rebound. Sample J, which had been added to the reaction mixture in the form of ground tablets, maintained the pH above 3.5 for 27 minutes while achieving a maximum pH of 3.7.

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Fig. 2.-Neutralization characteristics of samples E through I.

Generally speaking, most of the antacids tested rapidly brought the pH to a point above that usually considered desirable. Sample J maintained the pH above 3.5 for 27 minutes and never raised the pH to an objectionably high level. Sample H, under the conditions of this study, kept the pH between 5.0 and 6.0 for most of the test period. The results depicted in Fig. 1 on the antacid activity of different physical forms of the same formulation serve to emphasize the importance of the mode of administration of the antacid materials to the stomach. Kirsner and Palmer (12) emphasized that magnesium trisilicate in powder form was more effective than as tablets because of better interaction between the antacid and the free hydrochloric acid. Goodman and Gilman (13) also stress that a large surface area is necessary for effective action of magnesium trisilicate. Similarly, Rossett and Rice

346

JOURNAL OF THE

AMERICANPHARMACEUTICAL ASSXIATION

(14), have shown that the liquid preparations of aluminum hydroxide are much more reactive than the tablet form, also presumably because of the increased surface area available when the antacid is suspended in a liquid medium. Obviously, then, it is an oversimplification t o evaluate an antacid formulation solely through consideration of its active constituents. The success of an antacid product is equally dependent upon the ability of the dosage form to yield the active ingredients at the proper rate and with the maximum possible surface area. If a tablet, or pieces of a tablet, disintegrate slowly in the stomach, release of the antacid ingredients may be too slow for effective neutralization or may even pass into the intestine before completely reacting with the gastric acid. In this connection, Kirsner and Palmer (15), state that, in their experience, the neutralizing value of any antacid in tablet form is distinctly inferior t o that of powder or liquid preparations, because of passage of the former into the intestinal tract before reaction is complete. It appears to be essential, therefore, in antacid formulation or evaluation, t o give consideration to the dosage form of the material and to its ability to release its active constituents at the desired rate and in the most active therapeutic physical form.

SUMMARY 1. Ten antacid products were tested for antacid effectiveness using the Holbert (4) modification of the Johnson and Duncan procedure (3) and simulating typical dosages and usual in vivo modes of administration. 2. The majority of the antacid materials

vol. XLVI, No. 6

rapidly raised the pH of gastric juice to a point above that usually considered desirable. One sample maintained the pH above 3.5 for 27 minutes while reaching a maximum pH of 3.7. Another product kept the pH between 5.0 and 6.0 for most of the test period. 3. The importance of the antacid vehicle was discussed from the standpoint of rate of release and physical form of the active ingredients.

REFERENCES (1) Wyllie D . Edinburgh Med. J . 47 336(1940). 2) Booth,’R.’E., and D h e , J . K:, $HIS JOURNAL, 44, 694i19.55). ~~..~,. (3) Johnson, E. H., and Duncan, J., Quart. J . Pharm. and Pharmacol., 18,251(1945). (4) Holbert, J. M., Noble, N . , and Grote, I . W., THIS JOURNAL, 37,292(1948). ( 5 ) Lemaistre, 3. W., Holbert, J. M., and Grote, I. PI., ibid.. 38.595(1949). (6) Murphey, R. S., ibid., 41,361(1952). (7) Armstrong. J., and Martin, M., J . Pharm. and Pharmacol., 5,6?2(1953). (8) Grote, I. W.,Holbert, J. M., and For, M., THIS JOURNAL, 44,219(1955). (9) Dale, J. K., and Booth, R. E., THIS JOVRNAL, 44, 170f1955). (10) ,Amyican Medical Association “New and Nonofficial Remedies. J . B . Lippincott Co., Phil;., 1957 p. 381. (11) Kirsner, J. B., Palmer, W. L.. Levin,’E., and Klotz. A. P. A n n . Infernal Med. 35 ?85(1951). (li) Kirsner, J. B., add Galmer, W. L., A m . J . Digest. Discascs, 7.85(1940). (13) Goodman, L. S., and Gilman A. “The Pharmacological Basis of Therapeutics,” ed. ’2, &ew York, MacMillan Co., 1955, p. 1029. (14) Rossett, N. E., and Rice, M. L., Ir., Gastroenterology, 26,490(1954). (15) Kirsner, L. B., and Palmer, W. L., Ann. Internal Mcd., 35,785(1951). ~

Hypotensive Activity of a New Ganglionic Blocking Agent and Its Comparative Effectiveness on Normotensive Unanesthetized Dogs” . _

By W. E D W F D O’MALLEY, GISELA WINKLER, LEONARD M. RICE, and CHARLES F. GESCHICKTER Methodology was established for comparison of hexamethonium, pentolinium, and H-2 for their vasodepressive responses on intact, unanesthetized dogs. Comparisons were made at various dosage levels. Intravenous toxicities on dogs and intraperitoneal toxicities on rats were also performed for the three agents. It was found that H-2 was moderately more potent and markedly less toxic than either hexamethonium or pentolinium. ITH THE INTRODUCTION of hexamethonium win 1948 by Paton and Zaimis (1) it became possible to significantly deter the progress of hypertensive vascular disease, especially the

*

Received August 18, 1956 from the Georgetown University Medical Center, Department of Pathology, Washington ?, D. C. Supported by a research grant for the Geschickter Fund for Medical Research, Inc.

malignant variety, by the use of pharmacologic agents. The value of hexamethonium was confirmed by Restall and Smirk (2) in New Zealand, Campbell and Robertson (3) in Great Britain, and Finnerty and Freis (4) in the United States. Wien and Mason (5) and Smirk (6) in 1953 introduced pentolinium, a ganglionic blocking agent chemically and pharmacologically similar to