40
Journal of the association of physicians of india • june 2013 • VOL. 61
Original Article
Comparison of Seven Oxethazaine Containing
Antacids Available in the Indian Market
Suvarna Bhoir*, AM Bhagwat*
Abstract
Objective: This in-vitro study was designed to measure the quantity of acid neutralized by a suspension of a
commercial antacid available in Indian markets at a labeled dose and to test the concept of the relative effectiveness
of 7 different commercial antacids containing Oxethazaine.
Methods: A simple back titration methodology was used to determine the acid neutralization capacity (ANC)
of antacids.
Results: It was observed that different antacids vary widely in their in vitro ANC. There was also a batch to batch
variation noted for each brand of antacid. The analysis indicated that there was a significant difference of ANC
in favor of AD versus other antacids studied.
Conclusion: Comparison of relative effectiveness indicates that AD has highest ANC in vitro amongst other
antacids. However, the present study being in vitro, the effects of antacid may vary in vivo, as individual variations
also contribute to the ultimate effectiveness of an antacid.
Abbreviations : M: Molar; HCL: Hydrochloric Acid; NaoH: Sodium Hydroxide; H2CO3: Carbonic acid; CO2: Carbon
dioxide; CaCO3: Calcium carbonate; Na2CO 3: Sodium Carbonate; mEq: mili-equivalents; ANC: Acid neutralizing
capacity; GERD: gastro-oesophageal reflux disease; OTC: over the counter; USP: United States Pharmacopeia;
ANOVA: Analysis of variance
A
Introduction
ntacids are commonly used world over as over the counter
(OTC) or prescribed medications. They have been used
as the mainstay of treatment for peptic ulcers, gastritis, gastrooesophageal reflux disease (GERD), and functional dyspepsia.1
Approximately 8% of the population in the United Kingdom
visits their general practitioner each year with dyspeptic
symptoms, and 50% of gastroenterology referrals are attributed
to these symptoms.2 Although there is no published evidence
about the exact cost of dyspepsia to the Indian community, it
represents a considerable burden to the health care services.
Antacids mostly consist of magnesium and aluminium
salts and sodium/calcium carbonate in various compounds or
combinations. Antacids act by neutralising the hydrochloric acid
(HCl) secreted by the gastric parietal cells and thereby elevating
the gastric pH. When the pH is raised above 3 most of the gastric
HCl is neutralised and the proteolytic activity of pepsin (which is
capable of digesting the gastric mucosal membrane) is reduced.3
An effective antacid is characterised by its ability to react
rapidly with acid, buffer in the pH range of 3 to 6, have a high
acid neutralising capacity (ANC), and cause few or minimal
side effects.4 Besides these, a physician also needs to consider
the following factors; the antacid should neutralise the greatest
amount of acid per unit cost; should be both palatable and
conveniently consumed by the patient, its sodium content, its
constipating or diarrheogenic effects, and its physical form.5
Antacids are available in both liquid suspensions as well as
solid dosage forms. Liquid antacids are generally preferred as
*C. B. Patel Research Centre, 3rd Floor, Bhaidas Hall, Vile Parle (W),
Mumbai – 4000 56.
Received : 09.04.2012; Revised : 19.07.2012; Re-revised : 25.03.2013;
Accepted : 23.04.2013
400
they have a higher neutralization capacity which is attributed
to their smaller particle size resulting in a greater surface area.6
Besides the aluminium and magnesium salts, some
antacids also contain oxethazaine. Oxethazaine, or
2,2’-(2-hydroxyethylimino) bis[N-(l,l-dimethyl-2-phenylethyl)N-methylacetamide], a glycine amide resembling lidocaine, is a
potent, safe local anaesthetic agent. Following topical application,
it provides prolonged anaesthesia of mucous membranes. Its
salient feature includes its ability to remain un-ionised even at a
pH of 1, unlike most of the other local anaesthetics.7 There have
been many published reports in recent years of the prompt and
prolonged relief of pain obtained by Oxethazaine plus antacid
combination in patients with esophagitis, gastritis, and peptic
ulcers.7,8 Some investigators have shown that, in addition to
providing symptomatic relief, this medication produced an
increase in gastric pH above 3.5 for varying time periods.8
Various in-vitro tests have been developed to evaluate the
performance of antacids which are intended to reflect their
in-vivo efficacy. The measurement of ANC is one such widely
used test. Other tests are pH-stat test, monitoring the reaction
rate, and measuring the performance under conditions intended
to resemble the in vivo environment.4In 1973, Fordtran and coworkers9 established the methods and evaluated the ANCs of
antacids available at that time. Since then, their published results
have served as a guide for physicians prescribing antacids.
Several antacids are marketed in India, with a wide variability
in their ANC. A study was conducted by Gadad et al10, to assess
the effects of various disintegrating agents on the ANC of antacid
tablets. However, the liquid Indian antacid products have not yet
been studied independently to determine their ANC, and labels
on antacid products do not include this information.
The objective of this in-vitro study was to determine the
ANC of seven Oxethazaine containing antacid suspensions
(AD, AM, AU, AS, AC, AO, and AT) which were randomly
© JAPI • june 2013 • VOL. 61
41
Journal of the association of physicians of india • june 2013 • VOL. 61 Table 1 : Grand mean of ANC of all antacids
Antacid
AD
AM
AU
AS
AC
AO
AT
Grand mean
(mEq) of
antacid
28.84
16.81
13.29
14.26
17.12
18.7
14.43
Table 2 : Relative Effectiveness of Commercially available
Antacid Brands with respect to AD
Antacid
selected commonly prescribed brands, commercially available
in the Indian market and to test the concept of their relative
effectiveness, wherein the ANC of AD was compared with the
ANC of the other products. As Oxethazaine commonly features
in antacids having local anaesthetic action, hence Digecaine
containing Oxethazaine was considered as the reference drug
for this study.
S.D.
C.V.
Relative Effectiveness
AD
28.84
0.4212
1.460
100
AM
16.81
0.5505
3.275
58.28
AU
13.29
3.377
25.40
46.08
AS
14.26
0.090
0.6361
49.44
AC
17.12
0.3579
2.090
59.36
AO
18.70
0.9127
4.879
64.84
AT
14.43
0.080
0.5600
50.03
S.D= Standard deviation; C.V = Coefficient of Variance
Materials and Methods
Procedure
The container of the product was shaken until the contents
were uniform, and the density was determined. An accurately
weighed quantity of the uniform mixture; equivalent to the
minimum labelled dosage was transferred to a flask and deionised water was added to make a total volume of about 70 mL.
Standardized 1.0 N of HCl solution (30.00 mL) was dispensed
into a flask and about 70 mL of de-ionised water was added.
The sample was dissolved in this solution and then the mixture
was magnetically stirred for 15 minutes to get a homogenous
suspension.. The minimum labelled dosage form was pipetted
out to a beaker containing 0.1 N of HCl solution and de-ionised
water and the pH of this solution was noted. Standardized 0.5 N
of NaOH solution was used for titration of the sample solution
until the pH value 3.5 was reached. Amount of acid consumed
expressed in terms of mEq of acid consumed per gram of acid
used was calculated.. The mEq was calculated by the following
formula:
Practical mEq = (VHCl x NHCl) – (VNaOH x NNaOH)
Where;
VHCl : volume of HCl added to sample
NHCl : normality of HCl
VNaOH : volume of NaOH added to sample
NNaOH: normality of NaOH
For each batch, six readings of ANC were obtained and the
mean (per batch) was calculated. The grand mean was calculated
by considering all 18 readings (3 batches) for each brand (Table 1).
Materials
Seven antacids in suspension form containing oxethazaine
were procured from the market. Sodium hydroxide (NaOH),
HCl, and sodium carbonate (Na2CO3) anhydrous of GR grade
used for back-titration were obtained from Merck.
Methods
Principle
A strong acid-strong base titration was used to test the
capacity of various commercial antacids to neutralise an acidic
environment (simulated acidic stomach). For studying the batch
to batch effect, three batches of each antacid were evaluated. Six
trials from each batch ensured reproducibility of the experiments.
Antacid samples were dissolved in the solution containing a
known amount and concentration of the HCl solution. The
amount of excessive HCl (non reacted acid) that remained in
the solution was determined by back-titration of the solution to
neutrality with a standardised solution of NaOH. The amount
of NaOH solution required was used to estimate the amount
of HCl which was neutralised by each antacid. Hence the ANC
(Nsample) was calculated by the following equation:
Nsample = NA - NB
Where
NA the number of moles of HCl used for dissolving the
antacid sample
NB the number of moles of NaOH needed to back-titrate
the excess HCl
Nsample the number of moles neutralized by the sample
In the present study, United States Pharmacopeia (USP)
ANC was studied for antacids and the results were expressed
in milliequivalents (mEq) of HCl consumed, as Indian
Pharmacopeia doesn’t specify ANC in terms of mEq of HCl
consumed.10
As per the final protocol, 10 mL of antacid sample was to be
used for the process of titration. To each sample 30 mL of 1N HCl
was to be added to determine the neutralising capacity of the
sample. It was assumed that upon taking 30 mL acid, there will
always be some excess left after neutralising the antacid, and that
can be quantified by back-titration. The amount of acid reacted
would therefore give the neutralizing capacity for the antacid
sample. Following the same analysis with each antacid sample
would finally provide the variation in the ANC of the antacids
under study. All experiments were carried out at a controlled
laboratory temperature (25°C ± 5°C). Standardization of NaOH
and HCl solutions was carried out as per USP method.11
© JAPI • june 2013 • VOL. 61 Grand Mean of
ANC (mEq)
Statistical analysis
The standard deviation and coefficient of variation was
calculated for each brand of antacid. The post-hoc analysis used
the Tukey’s Test and no adjustment for P-value was done. The
level of significance considered was 5%. Analysis of variance
(ANOVA) was performed with post-hoc analysis, using data
presented in Table 2. Software program SPSS version 19 was
used for statistical calculations. Data generated from the sample
volumes of 5mL were analyzed for brand to brand comparison
of commercially available samples using ANOVA. For this
comparison, readings for all three batches of a product were
pooled to obtain a mean value.
All formulae were as per the USP method.11
Results
When 10 mL antacid as sampling volume was used as per
protocol, it was observed that some samples neutralised the
entire 30 mL HCl added, leaving no excess. Thus back-titration
was not possible unless the initial quantity of acid added was
401
42
Comparison of ANC of Antacids containing Journal
Oxethazaine
of the association of physicians of india • june 2013 • VOL. 61
and antibiotics, shall be not less than 90 per
cent and not more than 110 per cent of the
labelled content; however, for enzymes and
vitamins, only the lower limit of 90 per cent
shall apply”.12 Thus, it seems that permissible
20
limit ± 10% of active ingredient may be
Grand Mean of
leading to difference in the ANC for different
ANC
batches. Similar trend in liquid antacids was
observed in a study conducted by MacCara
10
et al6 comparing the lot-to-lot consistency in
the ANCs of various new antacids in Canada.
We have compared only the oxethazaine
0
containing antacids in our study which were
AD
AM
AU
AS
AC
AO
AT
randomly selected commercially available
brands. Several authors have demonstrated the
Fig. 1 : Comparison of Antacid Neutralising Capacity of Antacids containing Oxethazaine
benefits of oxethazaine/antacid combination
when compared to antacid alone. In vivo study
by Novaes et al8 showed that oxethazaine/antacid combination
increased to a higher value. Therefore to get ANC values for all
when compared to antacid alone produced a more rapid rise in
the brands, the next option chosen was to use 5 mL of antacid
pH, a significantly higher peak pH, and a significantly greater
samples to initiate further analysis of ANC for all antacids.
period of an acidity between the time of medication and the
This change in methodology was not expected to result in any
peak pH, and a significantly greater overall period of an acidity
measurement bias, and would in fact improve the yield of valid
from the time of medication until the period returned to the acid
results for ANC.
range. In a study by Pontes et al13, significantly fewer doses of
When the grand mean of all the three batches were calculated
oxethazaine/antacid combination than that of antacid alone
per formulation, AD was shown to have the highest mean
gave satisfactory relief of ulcer pain and significantly fewer pain
ANC value (28.84 mEq) in comparison with others (Figure 1)
episodes occurred in the group treated with the combination
(Table 1). The relative effectiveness of the other antacids was then
than with the antacid alone.
calculated considering AD as 100 (Table 2). The mean difference
A limitation of this study was that, we only studied the ability
in the ANC of AD and the rest of the antacids was statistically
of antacids to elevate the pH above 3.5 in the presence of HCl.
significant at 5% level of significance (P = 0).
However, the onset of action, rate of neutralisation, and duration
of action are also important factors determining the efficacy of
Discussion
an antacid.3,10
In our study we have compared the oxethazaine containing
Another limitation of our study was that, it was an in-vitro
antacid suspensions which are presently commercially available
study. Studies done in this therapeutic area are usually
in the Indian markets. Our results clearly demonstrate that, there
in-vitro studies which simulate an in-vivo environment.
is considerable variation in the in vitro ANC of equal volumes
Similarly this study was conducted in an in-vitro scenario to
of different antacids. However, this difference in ability to
compare commercially available antacid-local anaesthetic drug
neutralise acid is not reflected on the labels of antacid products.
combination. Although in vitro tests can approximate in vivo
The actual ANC is not mentioned on the product label, and thus
conditions with respect to acid-consuming capacity, speed and
most manufacturers recommend a standard dose of 5 to 10 mL,
duration of action, and maximum buffering capacity of the
regardless of the antacid’s ANC.6
antacid, they cannot precisely account for variations in antacid
In our experiment, with 5 ml as uniform dose, all antacids have
activity due to gastric emptying, variability in the acid secretion
shown ANC variation with statistically significant difference. The
rate in the fasting and postprandial states, interaction of antacids
potency varied from 28.84 mEq (AD) to 13.29 mEq (AU). In 1975,
with glycoproteins and mucoproteins of gastric juice, coating
Fordtran et al9 demonstrated that the potency per milliliter of
of the gastric mucosa by antacids, and the effect of antacids on
antacids varied 17-fold among different commercial products.
endogenous control of gastric acid secretion.14
5
The same fact was reiterated in the study by Drake et al , wherein
30
they demonstrated a tenfold difference in the ANC between the
least and the most effective preparations. Because of this wide
variation in neutralising ability, the product and its ANC must
be known, when antacid therapy is being recommended.
The fact to consider is that, the antacids with a higher ANC
will provide effectiveness with the lowest dosage volume. In
our experiment, relative effectiveness was used to compare
potency of antacids. AD having higher ANC is expected to be
providing effectiveness at lower dosage volume compared to
other antacids in the study.
In our experiment, we have also observed batch to batch
variation in the same formulation. Various reasons, such as
manufacturing, formulation etc may contribute to variation.
Further, this could also be attributed to actual variation in
the amount of the active ingredient. As mentioned in Drugs
and Cosmetics act: “for Patent or proprietary medicines, the
contents of active ingredients, other than vitamins, enzymes
402
Conclusion
Based on this in vitro experiment, we can conclude that, the
seven oxethazaine containing antacid suspensions evaluated
in this study, varied in potency as measured in terms of their
ANC. This fact may be taken into account when antacid drugs
are prescribed.
Comparison of relative effectiveness indicates that AD has
highest ANC in vitro amongst other antacids. However, the
present study being in vitro, the effects of antacid may vary in
vivo, as individual variations also contribute to the ultimate
effectiveness of an antacid.
Acknowledgement and Disclosure
This study was funded by Abbott India. AD is an oxetacaine
containing antacid of Abbott India.
© JAPI • june 2013 • VOL. 61
Journal of the association of physicians of india • june 2013 • VOL. 61 References
1.
Maton PN, Burton ME. Antacids Revisited: A review of their
clinical pharmacology and recommended therapeutic use. Drugs
1999;57:855-870.
2.
Moayyedi P, Axon ATR. Is there a rationale for eradication
of Helicobacter pylori? Cost benefit: the case for. Br Med Bull
1998;54:243-250.
3.
Duffy TD, Fawzy SZ, Ireland DS, Rubinstein MH. A comparative
evaluation of liquid antacids commercially available in the United
Kingdom. J Clin Hosp Pharm 1982;7:3-58.
4.
Thomson AR, Pinchbeck B, Kirdeikis J, Kirdeikis P, Zuk L, Brunet
K. Evaluation of antacid tablets and liquid in fasting and fed men
and women. Clin Ther 1988;10:158-168.
5.
Drake D, Hollander D. Neutralizing capacity and cost effectiveness
of antacids. Ann Intern Med 1981;94:215-217.
6.
MacCara ME, Nugent FJ, Garner JB. Acid neutralization capacity of
Canadian antacid formulations. Can Med Assoc J 1985;132:523-527.
7.
Cordeiro FM, Sartoretto JN, Richards DJ. Oxethazaine combined
with aluminium and magnesium hydroxide (Oxaine® M) in
duodenal ulcer pain: a double-blind clinical pharmacology study.
Curr Ther Res 1976;19:230-236.
© JAPI • june 2013 • VOL. 61 43
8.
Novaes CC, Richards DJ, Davis GR . A comparison of the acid
neutralizing effects of a combination of antacid plus oxethazaine
(Oxaine® M) compared to antacid alone (Aludrox®) in duodenal
ulcer patients. Curr Ther Res 1975:18:124-131.
9.
Fordtran JS, Morawski SG, Richardson CT. In vivo and in vitro
evaluation of liquid antacids. N Engl J Med 1973;288:923–928.
10. Gadad AP, Dandagi PM, Mastiholimath VS, Patil MB, Rasal
VP, Dasankoppa FS. Non-chewable antacid formulations: Effect
of different disintegrating agents on their acid neutralization
properties. Indian J Pharm Sci 2006;68:269-273.
11. United States Pharmacopeia XX – National Formulary XV, US
Pharmacopial Convention, Rockville, Md, 1979:912.
12. The Drugs and Cosmetics Act and Rules. (23 of 1940) (As Amended
Up To The 30th June, 2005) P-499.
13. Pontes JF, Richards DJ, Sartoretto JN. Double-blind comparison
of an oxethazaine-antacid combination (Oxaine M®) against the
antacid alone (Aludrox®) in the treatment of duodenal ulcer pain.
Curr Ther Res 1975;18:315-323.
14. Smyth Rd, Herczeg T, Wheatley TA, Hause W, Cantwell-Reavey
NH. Correlation of in vitro and in vivo methodology for evaluation
of antacids. J Pharm Sci 1976;65:1045-1047.
403