of Canadian antacid formulations

Transcription

1 Acid neutralization capacity of Canadian antacid formulations Mary E. MacCara,* Pharm D F. James Nugent,t PhD J. Barry Garner,4 PhD A study was designed to determine the acid neutralization capacities (ANCs) of the new Canadian antacid formulations and to compare these products with standard antacid products in terms of lot-to-lot consistency, ANC, sodium and "calorie" contents, and price to the pharmacist. Twenty-three liquid and 18 tablet antacids were tested. The concentrated liquid antacids (Mylanta-2 Extra Strength, Amphojel 500, Gelusil Extra Strength, Maalox TC and Diovol Ex) were found to have the highest ANCs. Six of the tablet antacids (Amphojel, Amphojel Plus, Camalox, Gelusil-400, Maalox and Mylanta-2) were found to have greater ANCs than 15 of the liquid antacids. Between-lot variation exceeded that of within-lot variation in 10 of the 14 liquid antacids for which this variation could be tested. The concentrated liquid antacids provide the highest ANCs with the lowest dosage volume and sodium and calorie contents. Some tablet antacids have the potential to be used as alternatives to liquid antacids because of their high ANC and patient convenience. The inclusion of ANC on the labels of antacid products would assist in the rational determination of the dose of these products. On s'est propose de determiner le pouvoir neutralisant (PN) des nouveaux anti-acides sur le marche canadien et de le comparer a celui des produits connus. On compare aussi la constance du PN d'un lot a l'autre, la teneur en sodium et en "calories", et le prix de revient pour le pharmacien. Il s'agit de 23 liquides et de 18 comprimes. Les plus grands PN appartiennent aux liquides concentres: Mylanta-2 extra-puissant, Amphojel 500, Gelusil extra-puissant, Maalox TC et Diovol Ex. Six des comprimes, soit Amphojel, Amphojel plus, Camalox, Gelusil-400, Maalox et Mylanta-2, ont un plus grand PN que 15 des liquides. La variation d'un lot a l'autre est plus forte que celle qui existe a l'interieur d'un lot dans le cas de 10 des 14 produits liquides ou on a pu les etudier. Ce sont les anti-acides liquides concentres qui possedent le plus grand PN sous le volume le plus reduit et la plus faible teneur en sodium et en calories. Quelques-uns des *Associate professor, College of Pharmacy, Faculty of Health Professions, and assistant professor, Department of Family Medicine, Faculty of Medicine, Dalhousie University, Halifax tformerly assistant professor, College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax; currently senior research pharmacist, G.D. Searle and Co. of Canada, Limited, Oakville, Ont. tassociate professor and director, Biostatistics Division, Department of Community Health and Epidemiology, Faculty of Medicine, Dalhousie University, Halifax Reprint requests to: Dr. Mary E. MacCara, College of Pharmacy, Dalhousie University, Halifax, NS B3H 3J5....,,...~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~......,, comprimes pourraient y Wtre substitues, vu leur grand PN et leur commodite pour le malade. La mention du PN sur I'etiquette des produits anti-acides en favoriserait la posologie rationnelle. During the past 10 years many changes have occurred in Canadian and American antacid formulations. Many new products have been marketed, and the wide variability in acid neutralization capacity (ANC) has been narrowed, from a sevenfold difference in 1973' to a threefold difference in Because the efficacy of antacids in reducing gastric acidity is related to their ANC, it is important to know the ANC of currently marketed products. Canadian antacid products have not been studied independently to determine ANC, and labels on antacid products do not include information on ANC. This study was designed to determine the ANC of the new concentrated Canadian antacid products and to compare these products with standard antacid products in terms of lot-to-lot consistency, ANC, sodium and "calorie" contents, and price to the pharmacist. Methods The ANC of 41 antacids, purchased from pharmacies Conversion to the International System of Units (SI) includes the change from the calorie to the joule as the unit of food energy. The Canadian Intersectoral Kilojoule Committee prepared a report on the adoption of the kilojoule (available from the Metric Commission, 255 Argyle Ave., Ottawa, Ont. KIA 0C9) in September It recommends "working towards the acceptance of the word 'energy' to replace 'calorie' in referring to the metabolic concept in publications and promotional materials".3 However, since the energy values for the antacids we discussed were supplied as "calorie" content, we use the latter throughout the paper. Table I-Analysis of variance of acid neutralization capacity (ANC) of 14 liquid antacids, each measured in triplicate and in four lotṣ Variable freedom Mean square F Liquids Lots Error Table 11-Analysis liquid antacids of variance of lot-mean ANCs of 23 Variable freedom Mean square F Liquid lot means Error CAN MED ASSOC J, VOL. 132, MARCH 1,

2 Table III-Characteristics of 23 liquid antacids* Average price ANC group; Ingredients ANC Sodium content Calorie content to pharmacist product (mg/5 ml)t (meq/5 ml) (mg/5 ml) (mg/5 ml) per 100 ml ($)4 High Mylanta-2 Extra Strength Al(OH) Mg(OH)2 350 Simethicone 30 Amphojel 500 Al(OH) Mg(OH)2 500 Gelusil Extra Strength Al(OH) Mg(OH)2 350 Intermediate-high Maalox TC Al(OH) Diovol Ex Al(OH) Intermediate Amphojel Plus AI(OH) Titralac CaCO Camalox AI(OH) CaCO3 250 Low Phillip's Milk of Magnesia Mg(OH) NA Nil 0.59 Maalox Plus AI(OH) (lemon flavoured) Maalox AI(OH) Diovol AI(OH) Antacid Plus AI(OH) NA Diovol (fruit flavoured) AI(OH) Maalox Plus AI(OH) Univol AI(OH) Gelusil AI(OH) Mylanta DiGel AI(OH) Mg(OH)2 87 Rioplus Magaldrate Riopan Magaldrate Amphojel AI(OH) Kolantyl Al(OH) Mg(OH)2 165 *NA = not available. tsome formulations have changed since the time of analysis. tcalculated from prices quoted by Alberta National Drug Company Ltd., Eastern Drug Services, Drug Trading Company Ltd. and National Drug Ltd. between October and December CAN MED ASSOC J, VOL. 132, MARCH 1, 1985

3 in the Halifax area, was determined in triplicate with the "United States Pharmacopeia XX-National Formulary XV" (USPXX-NFXV) acid neutralizing test for Table IV-Analysis of variance of ANC of 18 tablet antacids without between-lot variation Variable freedom Mean square F Tablets Error liquids.4 We modified this test for tablet antacids: we used an intact tablet, rather than a crushed tablet, powdered and sieved to a uniform size, as the sample. Although we realized that an intact tablet would produce a low ANC, patients do not chew tablets uniformly in the clinical setting. We assumed that chewing of an antacid tablet would result in an increased ANC. The liquid antacids were arranged into groups according to ANC with multiple t-tests; the levels of significance were adjusted with the Bonnferroni inequality test to allow for the number of comparisons planned a priori Table V-Characteristics of tablet antacids* ANC Average price Ingredients (meq Sodium content Calorie content to pharmacist Product (mg per tablet)t per tablet) (mg per tablet) (mg per tablet) for 10 tablets ($)t Maalox Al(OH) Amphojel Al(OH) Gelusil-400 Al(OH) Mylanta-2 AI(OH) Nil 0.92 Simethicone 30 Camalox Al(OH) CaCO3 250 Amphojel Plus Univol Mg(OH)2 100 Maalox Plus Gelusil Riopan Magaldrate Diovol Mg(OH)2 100 Phillip's Milk of Magnesia Mg(OH) NA Tums CaCO DiGel AI(OH) MgCO3 282 Mg(OH)2 85 Dimethicone 25 Kolantyl Al(OH) Mg(OH)2 170 Titralac CaCO Rolaids Dihydroxy aluminum sodium carbonate 334 Mylanta Nil 0.72 *NA = not available. tsome formulations have changed since the time of analysis. tcalculated from prices quoted by Alberta National Drug Company Ltd., Drug Trading Company Ltd. and National Drug Ltd. in November CAN MED ASSOC J, VOL. 132, MARCH 1,

4 that is, for the 23 liquid antacids 253 a-priori ANC (10.05 to meq/5 ml). The five concentratcomparisons of mean values were anticipated, so a t ed antacids (Mylanta-2 Extra Strength, Amphojel 500, value of was used to give an overall level of Gelusil Extra Strength, Maalox TC and Diovol Ex) significance of 5%; for the 18 tablet antacids 144 mean were classified as having either a high or an intermedicomparisons were anticipated, so a t value of 3.95 was ate-high ANC, and the 18 standard antacids were used. classified as having an intermediate or a low ANC. Four lots of 14 liquid antacids were titrated using the For all the groups except the intermediate group the USPXX-NFXV method. Each lot was tested in tripli- ANCs related well to the total amount of antacid cate, and the ANCs were analysed for consistency with ingredients in the product: the antacids with high ANCs analysis of variance. contained 1000 mg, those with intermediate-high ANCs The sodium and calorie contents of the antacids were 900 mg and those with low ANCs approximately 400 supplied by the manufacturers. Four pharmaceutical mg. The products in the intermediate group contained wholesalers (two from central Canada and one each between 600 and 1000 mg of antacid ingredients. from eastern and western Canada) provided the "price to the pharmacist" of the liquid antacids. The ANCs of the antacids that contained flavouring agents other than mint (i.e., Diovol [fruit flavoured] and Maalox Plus [lemon flavoured]) did not differ signifi- Results cantly when compared with those of the "regular" flavoured antacids. Similarly, the presence of an anti- Liquid antacids flatulent did not significantly change the ANC of the antacid tested (e.g., Riopan v. Rioplus). Fourteen liquid antacids were tested for lot-to-lot consistency of ANC: Amphojel, Amphojel 500, Ampho- Tablet antacids jel Plus, Antacid Plus, Diovol, Diovol (fruit flavoured), Diovol Ex, Gelusil, Maalox, Maalox Plus, Maalox Plus Different lots were not available for the 18 tablet (lemon flavoured), Maalox TC, Mylanta and Riopan. antacids tested. The results of analysis of variance of the Only four of the products - Diovol (fruit flavoured), actual ANCs are shown in Table IV. The standard Gelusil, Maalox and Maalox Plus - were found to give deviation for the within-lot replication error was esticonsistent ANCs between the four lots at the 5% level of mated to be The tablet antacids fall naturally into significance. The results of analysis of variance for the two ANC groups (Table V). Six of them (i.e., Ampho- 14 products are shown in Table I. From the figures in jel, Amphojel Plus, Camalox, Gelusil-400, Maalox and the table we estimated the standard deviation to be 0.23 Mylanta-2) have ANCs that correspond with those of for the replication error, 0.92 for the between-lot error, the liquid antacids in the intermediate group. There is 0.95 for the single-observation error and 0.93 for the lot- statistical evidence that the lowest ANC of these six mean error. tablet antacids is greater than the ANC of any of the As different numbers of lots were available for the other 12 tablets as long as the standard deviation of the antacids in general, the treatment means were compared lot-to-lot variation (unexamined in this study) does not by Yates's technique of replacing the three observations exceed in each lot by their arithmetic mean. The results of analysis of variance for all 23 liquids are shown in Table Sodium and calorie contents and price II. The standard deviation of the lot-mean error was to the pharmacist 0.89, which is consistent with the 0.93 found earlier. The ANCs of the 23 liquid antacids are shown in The sodium and calorie contents and the price to. the Table III. The antacids can be classified into four pharmacist of the antacids we tested are given in Tables statistically different (p < 0.05) groups according to III and V. their ANCs: those with a high ANC (31.90 to meq/5 ml), those with an intermediate-high ANC Discussion (26.84 to meq/5 ml), those with an intermediate ANC (18.24 to meq/5 ml) and those with a low The ANC of the most potent liquid antacid tested Table VI-Comparison of liquid antacids according to ANC group Variable; amount of acid to be neutralized Single dose Daily* sodium Daily calorie Price to volume (ml) intake (mg) intake (mg) pharmacist ($) ANC group 80 meq 144 meq 80 meq 144 meq 80 meq 144 meq 80 meq 144 ieq High intermeitve-igh Intermediate Low LI)4ose administered I and 3 hours after meals and at bedtime (seven doses).l 526 CAN MED ASSOC J, VOL. 132, MARCH 1, 1985

5 was three times that of the least potent. This difference in ability to neutralize acid is not reflected, however, on the labels of antacid products. Indeed, the actual ANC is not shown on the product label. Most manufacturers recommend a standard dose of 5 to 10 ml of antacid, regardless of the product's ANC. This dose will neutralize 10.1 to 32.3 meq/5 ml to 20.2 to 64.6 meq/10 ml of acid, depending on the antacid selected. Because of this wide variation in neutralizing ability, the product and the dosage must be known when antacid therapy is being recommended or assessed. We found no significant difference in the ANCs within each of the four groups of liquid antacids. Table VI gives average single-dose volumes required to neutralize 80 and 144 meq of acid according to the four groups of liquid antacids. The doses were chosen as representative of a maximum low-dose and a maximum high-dose antacid regimen. It is clear from the table that the antacids with a high or an intermediate-high ANC provide the highest ANC with the lowest dosage volume. The use of these antacids also results in the lowest sodium and calorie intake and the lowest price to the pharmacist. Within each of the four groups are variations in the sodium and calorie contents of the products that should be considered before one chooses an antacid for patients with restrictions on their sodium and calorie intake. Liquid rather than tablet antacids have been recommended in the treatment of peptic ulcer disease because they have smaller particles, and hence a greater surface area, which is thought to be the main reason for their superior neutralization capacity.5 However, six of the tablet antacids we tested were found to have ANCs that were similar to those of liquid antacids in the intermediate ANC group and higher than those of the liquid antacids in the low ANC group. These tablet antacids contained approximately twice the amount of ingredients as the liquid antacids in the low ANC group. As well, these tablets were formulated so as to dissolve readily, an important factor in determining the ANC of a tablet. Tablet antacids are more palatable and portable than liquid antacids6 and therefore provide a reasonable alternative within a liquid antacid regimen when doses have to be taken outside the home. Four to eight tablets of Amphojel, Amphojel Plus, Camalox, Gelusil-400, Maalox or Mylanta-2 would need to be taken with water (50 to 100 ml) to provide an ANC of 80 to 144 meq. It is recommended that all tablet antacids be chewed, thus speeding dissolution and resulting in a higher ANC. The sodium content of one dose of one of these six tablet antacids would be higher than that of an equal neutralizing dose of a liquid antacid in the high or intermediate-high ANC group, but all but one (Amphojel Plus) of these tablet antacids can provide 144 meq of neutralization capacity while containing less than 1 meq (23 mg) of sodium. Conclusions When high-dose antacid therapy is required for the treatment of peptic ulcer disease liquid antacids (concentrated) with a high or an intermediate-high ANC are the preferred agents. These products provide the highest neutralization capacity with the lowest dosage volume, the lowest sodium and calorie contents, and the lowest price to the pharmacist. Some tablet antacids can be used as alternatives to liquid antacids because of their high neutralization capacity and their portability. Lot-to-lot variability of liquid antacids does exist. It is impossible to predict when such variability will occur, but it may help explain a sudden change in the effectiveness or the ANC of the antacid. Finally, if antacids are to be used in rational doses it is important that the ANC be included on the labels of these products. This study was supported by a grant from Rorer Canada Inc. teferences 1. Fordtran JS, Morawski SG, Richardson CT: In vivo and in vitro evaluation of liquid antacids. N Engl J Med 1973; 288: Drake D, Hollander D: Neutralizing capacity and cost effectiveness of antacids. Ann Intern Med 1981; 94: Summary of the report of the Intersectoral Committee on the adoption of the kilojoule. In The SI Manual in Health Care, 2nd ed, Metric Commission, Ottawa, 1982: United States Pharmacopeia XX-National Formulary XV, US Pharmacopeial Convention, Rockville, Md, 1979: Littman A, Pine BH: Antacids and anticholinergic drugs. Ann Intern Med 1975; 82: Baker LL, Canik CA: Antacids: relevant considerations for the pharmacist. Wis Pharm 1980; 49: , 211 Remember, life For starting therapy: LOPRESOR 50 mg b.i.d. increased to LOPRESOR 100 mg b.i.d. if necessary For once-a-day maintenance: LOPRESOR SR 200 mg WRITE 'NO SUBSTITUTION' meorlltartrate) Geigy [ Mississauga, Ontario L5N 2W5 CAN MED ASSOC J-, VOL. 132, MARCH 1,