Cariogenic and erosive potential of pediatric medicines and vitamin supplements

Potencial cariogênico e erosivo de medicamentos e suplementos vitamínicos pediátricos

Luciene Souza COUTINHO Ana Caroline Magalhães Neri SANDE Natália Novais Vasconcelos NUNES Rafaela Silva OLIVEIRA Elisângela de Jesus CAMPOS About the authors

Abstract

Introduction

Pharmaceutical pediatric formulations with low in pH and high in total titratable acidicity used frequently and over long periods of time, have the potential to produce erosive lesions in teeth. On the other hand, high concentration of sucrose, the nocturnal use and the lack of hygiene after its administration, are some factors that can contribute to the cariogenic potential of these formulations.

Objective

To evaluate in vitro the cariogenic and erosive potential of medicines and liquid vitamins and mineral supplements for pediatric use.

Material and method

Medicines (n=41) and liquid vitamins and mineral supplements (n=12) childish were selected and analyzed for their physicochemical properties, pH, total titratable acidity (TTA) and total soluble solids concentration (TSS/°Brix). The package inserts and labels were analyzed to identify the composition regarding the content of sugars and acidulants, in addition to the side effects related to salivary flow.

Result

The pH analysis indicated that there was greater variation in the observed averages in the medication group. As for the TTA at pH 5.5, supplements and medicines groups showed significant variation between the means found (p<0.05). The TTA results at pH 7.0 showed that the highest mean found was in the class of antihistamines and the lowest in the class of drugs that contain the association of antitussives and antihistamines. The analyses TSS demonstrated that across all drug classes and supplements the amount of TSS varied significantly (p<0.05) in all classes of medicines and supplements.

Conclusion

Most medicines and pediatric liquid vitamin and mineral supplements demonstrated significantly different behaviors within the group itself regarding the variables analyzed that constitute risk factors for the development of dental caries and erosion.

Descriptors:
Dental caries; tooth erosion; pharmaceutical preparations

Resumo

Introdução

Formulações farmacêuticas pediátricas com baixo pH e alta acidez titulável usadas com frequência e por longos períodos de tempo têm potencial para produzir lesões erosivas nos dentes. Por outro lado, alta concentração de sacarose, uso noturno e falta de higiene bucal após a administração são fatores que podem contribuir para o potencial cariogênico dessas formulações.

Objetivo

Avaliar in vitro o potencial cariogênico e erosivo de medicamentos e suplementos vitamínicos e minerais líquidos de uso pediátrico.

Material e método

Medicamentos (n=41) e suplementos vitamínicos e minerais (n=12) líquidos infantis foram selecionados e analisados quanto às suas propriedades físico-químicas, pH, acidez total titulável (ATT) e concentração de sólidos solúveis totais (SST/°Brix). Bulas e rótulos foram analisados para a identificação do conteúdo em açúcares e acidulantes, além dos efeitos colaterais relacionados ao fluxo salivar.

Resultado

A análise do pH indicou que no grupo medicamentos houve maior variação nas médias observadas. Quanto à ATT em pH 5,5, os grupos medicamentos e suplementos apresentaram variação significativa entre as médias (p<0,05). Os resultados da ATT em pH 7,0 demonstraram que a maior média encontrada foi na classe dos anti-histamínicos e a menor na classe dos medicamentos que contém a associação de antitussígenos e anti-histamínicos. A análise de SST demonstrou que em todas as classes de medicamentos e nos suplementos a quantidade de SST variou significativamente (p<0,05).

Conclusão

Os medicamentos e suplementos vitamínicos e minerais líquidos apresentaram comportamentos diferentes dentro do mesmo grupo quanto às variáveis analisadas, apresentando potencial cariogênico e erosivo em sua maioria.

Descritores:
Cárie dentária; erosão dentária; preparações farmacêuticas

INTRODUCTION

Children with recurrent acute diseases and chronic respiratory diseases make frequent and regular use of liquid oral medicines, which may represent a possible causal factor for caries11 Mahmoud EF, Omar OM. Erosive and cariogenic potential of various pediatric liquid medicaments on primary tooth enamel: a SEM study. Dent Med Probl. 2018 Jul-Sep;55(3):247-54. http://dx.doi.org/10.17219/dmp/91539. PMid:30328301.
http://dx.doi.org/10.17219/dmp/91539...
,22 Babu KL, Doddamani GM, Naik LR, Jagadeesh KN. Pediatric liquid medicaments: are they cariogenic? An in vitro study. J Int Soc Prev Community Dent. 2014 Maio;4(2):108-12. http://dx.doi.org/10.4103/2231-0762.137637. PMid:25254195.
http://dx.doi.org/10.4103/2231-0762.1376...
and dental erosion22 Babu KL, Doddamani GM, Naik LR, Jagadeesh KN. Pediatric liquid medicaments: are they cariogenic? An in vitro study. J Int Soc Prev Community Dent. 2014 Maio;4(2):108-12. http://dx.doi.org/10.4103/2231-0762.137637. PMid:25254195.
http://dx.doi.org/10.4103/2231-0762.1376...
due to their sugar content and acidulants. These compounds are also present in vitamins and mineral supplements prescribed for children, who represent a group of high vulnerability to macro- and micro-nutrient deficiencies as a result of their rapid growth and development33 Fernandes TF. Suplementação de nutrientes. Pediatra atualize-se. 2019 Set-Out;4(5):4-5..

Dental caries is a multifactorial44 Al Humaid J. Sweetener content and cariogenic potential of pediatric oral medications: a literature. Int J Health Sci. 2018 May-Jun;12(3):75-82. PMid:29896075.,55 Noronha JC, Gomes HE, Mordente CM, Souki BQ. Saúde bucal na infância e na adolescência. Rev Med Minas Gerais. 2019;29(Supl 13):S86-S90. and behavioral disease that involves biological and psychosocial factors66 Baldasso CN, Weber JBB, Coelho EMRB, Alves NM, Kramer PF. Açúcar e saúde bucal: uma revisão crítica da literatura. Stomatos. 2020;26(50):46-55.. Its etiology is mainly related to the presence of free sugars55 Noronha JC, Gomes HE, Mordente CM, Souki BQ. Saúde bucal na infância e na adolescência. Rev Med Minas Gerais. 2019;29(Supl 13):S86-S90.,66 Baldasso CN, Weber JBB, Coelho EMRB, Alves NM, Kramer PF. Açúcar e saúde bucal: uma revisão crítica da literatura. Stomatos. 2020;26(50):46-55. which are metabolized into weak organic acids by cariogenic bacteria of the dental biofilm. These acids cause the pH of the oral environment to reach values below 5.5, which is considered critical for enamel dissolution, resulting in its demineralization and the progression of caries44 Al Humaid J. Sweetener content and cariogenic potential of pediatric oral medications: a literature. Int J Health Sci. 2018 May-Jun;12(3):75-82. PMid:29896075.,77 Leal WMS, Lambrecht J, Almeida LS, Rehbein KD, Silva TF, Almeida LHS. Entendendo a relação entre medicamentos de uso pediátrico e cárie dentária. Rev Ped SOPERJ. 2015 Set;15(2):16-21..

Dental erosion, on the other hand, consists of the wear of hard dental tissues caused by the action of acids88 Lussi A, Carvalho TS. Analyses of the erosive effect of dietary substances and medications on deciduous teeth. PLoS One. 2015 Dec;10(12):e0143957. http://dx.doi.org/10.1371/journal.pone.0143957. PMid:26700481.
http://dx.doi.org/10.1371/journal.pone.0...
, of intrinsic or extrinsic origin99 Arora R, Mukherjee U, Arora V. Erosive potential of sugar free and sugar containing pediatric medicines given regularly and long term to children. Indian J Pediatr. 2012 Jun;79(6):759-63. http://dx.doi.org/10.1007/s12098-011-0543-5. PMid:21830024.
http://dx.doi.org/10.1007/s12098-011-054...
, or of idiopathic cause1010 Scatena C, Galafassi D, Gomes-Silva JM, Borsatto MC, Serra MC. In vitro erosive effect of pediatric medicines on deciduous tooth enamel. Braz Dent J. 2014 Jan-Feb;25(1):22-7. http://dx.doi.org/10.1590/0103-6440201302344. PMid:24789287.
http://dx.doi.org/10.1590/0103-644020130...
. Changes in eating habits and the high consumption of acidic beverages and foods have contributed to the increased incidence of dental erosion. In addition, the frequent use of liquid medicines with low pH also seems to be related to the occurrence of this type of dental wear1010 Scatena C, Galafassi D, Gomes-Silva JM, Borsatto MC, Serra MC. In vitro erosive effect of pediatric medicines on deciduous tooth enamel. Braz Dent J. 2014 Jan-Feb;25(1):22-7. http://dx.doi.org/10.1590/0103-6440201302344. PMid:24789287.
http://dx.doi.org/10.1590/0103-644020130...
.

Excipients are added to the active ingredients of the formulations to improve their palatability, acceptance and preservation1111 Santinho AJP, Waldow C, Santos SB. Estudo sobre a correlação do potencial cariogênico e do pH de xaropes pediátricos. Rev Bras Farm. 2008;89(2):92-4.,1212 Balbani AP, Stelzer LB, Montovani JC. Pharmaceutical excipients and the information on drug labels. Braz J Otorhinolaryngol. 2006 May-Jun;72(3):400-6. http://dx.doi.org/10.1016/S1808-8694(15)30976-9. PMid:17119779.
http://dx.doi.org/10.1016/S1808-8694(15)...
. Dyes, sweeteners, flavors and acidulants are examples of excipients1313 Araujo ACF, Borin MF. Influência de excipientes farmacêuticos em reações adversas a medicamentos. Brasília Med. 2012;49(4):267-78. that, despite being added in low concentrations, can trigger adverse reactions which are often mistakenly associated with the active ingredient of the medicine, compromising the medicinal therapy1212 Balbani AP, Stelzer LB, Montovani JC. Pharmaceutical excipients and the information on drug labels. Braz J Otorhinolaryngol. 2006 May-Jun;72(3):400-6. http://dx.doi.org/10.1016/S1808-8694(15)30976-9. PMid:17119779.
http://dx.doi.org/10.1016/S1808-8694(15)...
.

Most medicines developed for pediatric use have some type of sugar1111 Santinho AJP, Waldow C, Santos SB. Estudo sobre a correlação do potencial cariogênico e do pH de xaropes pediátricos. Rev Bras Farm. 2008;89(2):92-4. and acid preservatives11 Mahmoud EF, Omar OM. Erosive and cariogenic potential of various pediatric liquid medicaments on primary tooth enamel: a SEM study. Dent Med Probl. 2018 Jul-Sep;55(3):247-54. http://dx.doi.org/10.17219/dmp/91539. PMid:30328301.
http://dx.doi.org/10.17219/dmp/91539...
in their composition. Sugars are added to children's medicines primarily to mask the unpleasant taste of the active ingredients1414 Subramaniam P, Nandan N. Cariogenic potential of pediatric liquid medicaments--an in vitro study. J Clin Pediatr Dent. 2012;36(4):357-62. http://dx.doi.org/10.17796/jcpd.36.4.nt11584612462t84. PMid:23019832.
http://dx.doi.org/10.17796/jcpd.36.4.nt1...
. Acidulants are added to these formulations in order to ensure their chemical stability and preservation11 Mahmoud EF, Omar OM. Erosive and cariogenic potential of various pediatric liquid medicaments on primary tooth enamel: a SEM study. Dent Med Probl. 2018 Jul-Sep;55(3):247-54. http://dx.doi.org/10.17219/dmp/91539. PMid:30328301.
http://dx.doi.org/10.17219/dmp/91539...
, in addition to contributing to their palatability1515 Babu KL, Rai K, Hedge AM. Pediatric liquid medicaments: do they erode the teeth surface? An in vitro study: part I. J Clin Pediatr Dent. 2008;32(3):189-94. http://dx.doi.org/10.17796/jcpd.32.3.j22m7t8163739820. PMid:18524267.
http://dx.doi.org/10.17796/jcpd.32.3.j22...
.

Although the addition of sugars and acidulants ensures the palatability of liquid preparations, they can cause changes in hard dental tissues22 Babu KL, Doddamani GM, Naik LR, Jagadeesh KN. Pediatric liquid medicaments: are they cariogenic? An in vitro study. J Int Soc Prev Community Dent. 2014 Maio;4(2):108-12. http://dx.doi.org/10.4103/2231-0762.137637. PMid:25254195.
http://dx.doi.org/10.4103/2231-0762.1376...
, such as dental caries and erosion, due to their sugar content, pH11 Mahmoud EF, Omar OM. Erosive and cariogenic potential of various pediatric liquid medicaments on primary tooth enamel: a SEM study. Dent Med Probl. 2018 Jul-Sep;55(3):247-54. http://dx.doi.org/10.17219/dmp/91539. PMid:30328301.
http://dx.doi.org/10.17219/dmp/91539...
,77 Leal WMS, Lambrecht J, Almeida LS, Rehbein KD, Silva TF, Almeida LHS. Entendendo a relação entre medicamentos de uso pediátrico e cárie dentária. Rev Ped SOPERJ. 2015 Set;15(2):16-21. and titratable acidity88 Lussi A, Carvalho TS. Analyses of the erosive effect of dietary substances and medications on deciduous teeth. PLoS One. 2015 Dec;10(12):e0143957. http://dx.doi.org/10.1371/journal.pone.0143957. PMid:26700481.
http://dx.doi.org/10.1371/journal.pone.0...
. Thus, it is necessary to evaluate the cariogenic and erosive potential of liquid formulations for children's use, since the literature regarding the cariogenic effect of these formulations is not conclusive, as well as being limited as to their erosive potential.

The objective of the present study was to evaluate in vitro the cariogenic and erosive potential of medicines and liquid vitamins and mineral supplements for pediatric use. The null hypothesis tested was that there is no difference among the formulations within each group regarding the cariogenic and erosive potential.

MATERIAL AND METHOD

In vitro experimental study developed by analyzing the physicochemical properties, pH, total titratable acidity (TTA) and concentration of total soluble solids (TSS) of drugs (n=41) of different therapeutic classes, and pediatric liquid vitamin and mineral supplements (n=12).

Sample Selection

The sample was selected through an informal consultation with pharmacists responsible for pharmacies located in the city of Salvador, Bahia, Brazil, from April to July 2021, to identify the most prescribed and marketed children's medicines and liquid vitamins and mineral supplements. Forty-one medicines and 12 vitamins and mineral supplements, in liquid form for pediatric use, were selected. Three units of each selected formulation were purchased from different batches, allowing the analyses to be performed in triplicate, totaling 159 measurements.

Determination of pH

The determination of the pH of the medicines and liquid vitamin supplements and minerals was conducted at room temperature of 25ºC, using a microprocessor pH meter (Quimis®/Q400MT, Diadema, São Paulo, Brazil) and magnetic stirrer EV2.017 (EVLAB-®, Curitiba, Paraná, Brazil). Initially, the pH meter was calibrated with buffer solutions of pH 4.0 and 7.0, and then the pH was measured in 50 mL of each medicine and vitamin and mineral supplement, in triplicate.

Determination of Total Titratable Acidity

Total titratable acidity (TTA) was determined using sodium hydroxide (NaOH), microprocessor pH meter (Q400MT, Quimis®, São Paulo, Diadema, Brazil) and magnetic stirrer EV2.017 (EVLAB- ®, Curitiba, Paraná, Brazil). Using a burette, under constant agitation, 0.1 N of NaOH was added to the 50 mL volume of each medicine and vitamin and mineral supplement. The volumes of the NaOH solution necessary to reach pH 5.5 and pH 7.0 levels were recorded, which corresponded to the TTA value for each pH. The TTA at pH 5.5 was not conducted for pharmaceutical preparations with pH ≥ 5.5, nor was TTA conducted at pH 7.0 for formulations with pH ≥ 7.0. The total volume of 0.1N NaOH solution necessary to reach pH 5.5 and pH 7.0 was recorded, and it corresponded to the TTA value at each pH level.

Determination of Total Soluble Solids (TSS)

TSS was determined by refractometry, using a refractometer model HI 96801 (Hanna®, Woonsocket, Rhode Island, USA) calibrated with distilled water at 25°C. Readings from the samples were performed using the °Brix scale, in triplicate, according to the methodology adapted from Xavier et al.1616 Xavier AFC, Cavalcanti AL, Oliveira MC, Vieira FF. Antibióticos líquidos de uso pediátrico: caracterização físico-química. HU Revista. 2011;37(4):397-401.. The quantification of TSS by refractometry, on the °Brix scale, allows inference of the sugar content of solutions1616 Xavier AFC, Cavalcanti AL, Oliveira MC, Vieira FF. Antibióticos líquidos de uso pediátrico: caracterização físico-química. HU Revista. 2011;37(4):397-401., since this numerical scale measures the amount of soluble solids present in the solution.

Analysis of Package Inserts and Labels

Analysis of the package inserts and labels was conducted to identify the composition of the medicines and the liquid pediatric vitamin supplements and minerals regarding the presence of sugars, sweeteners, acidulants and acidity regulators (Table 1), as well as the side effects related to salivary flow.

Table 1
Distribution of medicines and pediatric liquid vitamin supplements and minerals according to composition, trademark and manufacturer

Statistical Analysis

Initially, descriptive and exploratory analyses of all data were conducted. Next, the variables that met the assumptions of an analysis of variance (ANOVA) were analyzed using one-way ANOVA and Tukey's test. The variables that did not meet the ANOVA assumptions were analyzed using generalized linear models. All analyses were conducted using the R program (Foundation for Statistical Computing, Vienna, Austria), with a significance level of 5%.

RESULT

The medicines varied in terms of pH values, with the lowest mean obtained in the class of antihistamines found for Loratadine (pH 2.86), and the highest in the class of corticosteroids found for Prednisolone Sodium Phosphate (pH 7.11). There was also a significant difference (p<0.05) in the group of vitamin and mineral supplements. pH values below 5.5 were obtained for all supplements analyzed, with the lowest value found for the Lavitan Tonic supplement (pH 1.81) (Table 2 and Figure 1).

Table 2
Mean (standard deviation) of pH, TTA (pH 5.5 and pH 7.0) and TSS of medicines and vitamin and mineral supplements
Figure 1
Mean and standard deviation of pH as a function of medicines, by therapeutic class, and vitamin and mineral supplements.

As for the results of the TTA at pH 5.5, there was a significant variation in the means in the group of medicines. A higher mean was found for Loratadine (185.27 mL) in the class of antihistamines, and a lower mean was found for Brondilat ® (0.10 mL) in the class of bronchodilators. The supplements analyzed also showed significant variation between the TTA averages at pH 5.5 (p<0.05). The lowest value (3.60 mL) was found for the Abcalcium® supplement, and the highest value (31.33 mL) was found for Lavitan Tonic (Table 2 and Figure 2A).

The TTA results at pH 7.0 showed that the highest mean found was for Loratadine (233.23 mL) in the class of antihistamines, and the lowest mean found was for Seki® (0.50 mL) in the class of medicines that contained the association of antitussives and antihistamines. Among the supplements, the highest mean was found for Lavitan Tonic, and the lowest means were found for the Scott and Beritin BC supplements (p<0.05) (Table 2 and Figure 2B).

The TSS analysis (°Brix) showed that, for all medicines and supplements analyzed, this amount varied significantly (p<0.05). An SST °Brix of 1.43 was found for the bronchodilator Aerolin®, and of 64.03 for the expectorant Bronquivita ® (p<0.05) (Table 2 and Figure 3).

Figure 3
Mean and standard deviation of the concentration of total soluble solids (TSS) ºBrix as a function of the medicines, by therapeutic class, and vitamin and mineral supplements.
Figure 2
A- Mean and standard deviation of total titratable acidity (TTA) at pH 5.5 depending on the drugs, by therapeutic class, and vitamin and mineral supplements. B- Mean and standard deviation of total titratable acidity (TTA) at pH 7.0 depending on the drugs, by therapeutic class, and vitamin and mineral supplements.

The components identified, from the package inserts and labels of the medicines and supplements, are described in Table 1. Analysis of the labeling showed that 52.83% (n=28) of all formulations investigated reported the presence of sucrose in the composition, either alone (16.98%/n=9) or associated with other sweeteners (35.84%/n=19). In 42.85% (n=12) of the formulations that contained sucrose, there was a warning regarding the use by diabetic patients. The main sweeteners found in the formulations, alone or in combination, were sorbitol, sodium saccharin, sodium cyclamate, aspartame and acesulfame.

Regarding the acid content, the presence of acidulating agents in the formulations was verified, either in isolation or in association. The main acidulants found were citric acid, identified in 50.94% (n=27) of all pharmaceutical preparations, and benzoic acid, present in 11.32% (n=6) of the formulations. The presence of other acids such as hydrochloric acid, phosphoric acid, tartaric acid and lactic acid was also identified.

Xerostomia was reported as an adverse reaction in 33.96% (n=18) of the package inserts and labels of the medicines and supplements analyzed. This information was identified in the therapeutic classes of the antihistamines (n=4), in the medicines that contained antitussives and antihistamines (n=2), bronchodilators (n=2), corticosteroids (n=2), expectorants (n=5) and in the group of supplements (n=3). No formulation analyzed referred to hyposalivation as an adverse reaction.

DISCUSSION

The pharmaceutical preparations analyzed showed significant differences in pH, TTA and TSS content. The analysis of the physicochemical characteristics of most oral formulations showed cariogenic and erosive potential due to the presence of sucrose and acidulants, respectively, as modulating agents of these effects.

Acidulants are substances capable of imparting acid flavor to the formulations, increasing their acidity by decreasing pH and inhibiting microbial growth1717 Aun MV, Mafra C, Philippi JC, Kalil J, Agondi RC, Motta AA. Aditivos em alimentos. Rev Bras Alerg Imunopatol. 2011;34(5):177-86.. In general, the acidulant most used in pharmaceutical formulations is citric acid, which has a complex chemical structure capable of reacting and releasing three hydrogen ions (H+) from each molecule. At low pH values, the released H+ ions react with the carbonate and phosphate ions and thus can solubilize the hydroxyapatite crystals, the main component of the enamel, causing demineralization of the dental surface1818 Featherstone JDB, Lussi A. Understanding the chemistry of dental erosion. Monogr Oral Sci. 2006;20:66-76. http://dx.doi.org/10.1159/000093351. PMid:16687885.
http://dx.doi.org/10.1159/000093351...
.

The predominance of the use of citric acid as an acidulant in pharmaceutical formulations is confirmed in the present study. Citric acid constitutes the acidulant found in most of the medicines and vitamin and mineral supplements analyzed. Similarly, in a study conducted using antihistamine drugs for pediatric use, Sousa et al.1919 Sousa RIM, Oliveira MC, Clementino MA, Cavalcanti AL, Vieira FF. Potencial erosivo e cariogênico de anti-histamínicos de uso infantil. RFO UPF. 2010;15(3):255-60. demonstrated the presence of this acid in the composition of most of the formulations analyzed, in addition to indicating that citric acid had strong chelating properties and can promote erosive lesions on the dental surface.

pH value is an important property to be analyzed in formulations for children's use, since the decrease in oral pH in the presence of acidic substances can contribute to progressive losses of dental structure. This loss occurs because, with the decrease in the pH, there is an increase in the solubility of hydroxyapatite2020 Dawes C. What is the critical pH and why does a tooth dissolve in acid? J Can Dent Assoc. 2003 Dec;69(11):722-4. PMid:14653937.. The pH of the formulations analyzed in the present study varied among classes, which is in accordance with findings of prior in vitro studies1414 Subramaniam P, Nandan N. Cariogenic potential of pediatric liquid medicaments--an in vitro study. J Clin Pediatr Dent. 2012;36(4):357-62. http://dx.doi.org/10.17796/jcpd.36.4.nt11584612462t84. PMid:23019832.
http://dx.doi.org/10.17796/jcpd.36.4.nt1...
,2121 Xavier AF, Moura EF, Azevedo WF, Vieira FF, Abreu MH, Cavalcanti AL. Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters. BMC Oral Health. 2013 Dec;13(1):71. http://dx.doi.org/10.1186/1472-6831-13-71. PMid:24325544.
http://dx.doi.org/10.1186/1472-6831-13-7...
.

Critical pH is the pH value at which a solution is saturated with respect to a specific mineral, such as dental enamel2020 Dawes C. What is the critical pH and why does a tooth dissolve in acid? J Can Dent Assoc. 2003 Dec;69(11):722-4. PMid:14653937.. pH values below 5.5 are considered critical for the dissolution of dental enamel, resulting in its demineralization44 Al Humaid J. Sweetener content and cariogenic potential of pediatric oral medications: a literature. Int J Health Sci. 2018 May-Jun;12(3):75-82. PMid:29896075.,77 Leal WMS, Lambrecht J, Almeida LS, Rehbein KD, Silva TF, Almeida LHS. Entendendo a relação entre medicamentos de uso pediátrico e cárie dentária. Rev Ped SOPERJ. 2015 Set;15(2):16-21.. Most of the medicines and supplements analyzed showed pH values below 5.5. This result is corroborated by studies that verified the erosive potential of liquid pediatric oral medicines by analyzing their physicochemical properties and identified that most formulations had a pH below 5.588 Lussi A, Carvalho TS. Analyses of the erosive effect of dietary substances and medications on deciduous teeth. PLoS One. 2015 Dec;10(12):e0143957. http://dx.doi.org/10.1371/journal.pone.0143957. PMid:26700481.
http://dx.doi.org/10.1371/journal.pone.0...
,2121 Xavier AF, Moura EF, Azevedo WF, Vieira FF, Abreu MH, Cavalcanti AL. Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters. BMC Oral Health. 2013 Dec;13(1):71. http://dx.doi.org/10.1186/1472-6831-13-71. PMid:24325544.
http://dx.doi.org/10.1186/1472-6831-13-7...
. However, they differ from the findings of other in vitro studies that demonstrated pH values above 5.5 in most pharmaceutical preparations99 Arora R, Mukherjee U, Arora V. Erosive potential of sugar free and sugar containing pediatric medicines given regularly and long term to children. Indian J Pediatr. 2012 Jun;79(6):759-63. http://dx.doi.org/10.1007/s12098-011-0543-5. PMid:21830024.
http://dx.doi.org/10.1007/s12098-011-054...
,1515 Babu KL, Rai K, Hedge AM. Pediatric liquid medicaments: do they erode the teeth surface? An in vitro study: part I. J Clin Pediatr Dent. 2008;32(3):189-94. http://dx.doi.org/10.17796/jcpd.32.3.j22m7t8163739820. PMid:18524267.
http://dx.doi.org/10.17796/jcpd.32.3.j22...
. The differences observed between the studies can be explained by the differences in the composition of the formulations in relation to the presence of acidulants and their concentrations, as well as by the brand/manufacturer and country of origin of the medicine.

In addition to pH, other parameters, such as the chelating property, should also be considered to analyze the erosive potential of a pharmaceutical preparation. Chelation consists of the process of absorbing metal ions through the action of the chelating agent whose molecules can form several bonds with the calcium ions of the hydroxyapatite crystals, solubilizing it, causing the demineralization of the hard tissues of the teeth, such as dental enamel. The chelation process interferes with the tissue composition and is independent of the pH of the medium2222 Babu KLG, Rai K, Hegde AM. pH of medicated syrups–does it really matter? – An in vitro study: part II. J Clin Pediatr Dent. 2008;33(2):137-42. http://dx.doi.org/10.17796/jcpd.33.2.q5280t3744827v0h. PMid:19358381.
http://dx.doi.org/10.17796/jcpd.33.2.q52...
. An in vitro study using scanning electron microscopy, conducted with the objective of investigating the erosive effect of liquid pediatric medicines on the enamel of deciduous teeth, demonstrated that all the formulations analyzed presented an erosive effect on the enamel surface despite having a pH above 5.5. This can be justified by the presence of chelating agents1515 Babu KL, Rai K, Hedge AM. Pediatric liquid medicaments: do they erode the teeth surface? An in vitro study: part I. J Clin Pediatr Dent. 2008;32(3):189-94. http://dx.doi.org/10.17796/jcpd.32.3.j22m7t8163739820. PMid:18524267.
http://dx.doi.org/10.17796/jcpd.32.3.j22...
. Biotonic Fontoura was the only supplement that stated the presence of EDTA in its composition, which can act as a chelating agent.

The findings of the present study demonstrated that, in relation to the therapeutic class of bronchodilators, Salbutamol Sulfate contained the acidulant citric acid in its composition, which may justify the higher TTA at both pH 5.5 and pH 7.0. Babu et al.2222 Babu KLG, Rai K, Hegde AM. pH of medicated syrups–does it really matter? – An in vitro study: part II. J Clin Pediatr Dent. 2008;33(2):137-42. http://dx.doi.org/10.17796/jcpd.33.2.q5280t3744827v0h. PMid:19358381.
http://dx.doi.org/10.17796/jcpd.33.2.q52...
quantified calcium from enamel solubilization after its immersion in eight liquid pediatric medicines. They demonstrated that the formulation of Salbutamol had higher potential for enamel decalcification compared to other medicines, in time intervals of 1 minute, 10 minutes and 8 hours, increasing according to the contact time. This result was explained by the authors as due to the presence of acidulants with chelating action added to this medicine. However, it was not specified which acidulants were part of its composition.

The erosive potential of pharmaceutical formulations depends not only on their pH but also on their TTA, which consists of determining the amount of a base necessary to neutralize the acids present in a solution. This is a variable to be considered, since it influences the buffer capacity of the solution1414 Subramaniam P, Nandan N. Cariogenic potential of pediatric liquid medicaments--an in vitro study. J Clin Pediatr Dent. 2012;36(4):357-62. http://dx.doi.org/10.17796/jcpd.36.4.nt11584612462t84. PMid:23019832.
http://dx.doi.org/10.17796/jcpd.36.4.nt1...
. In the present study, the large variation in the means found for TTA at pH 5.5 and pH 7.0 indicates that the medicines and supplements differed not only in type but also in the concentration of acidulants in their composition.

The TSS concentrations identified in the pharmaceutical preparations analyzed, both in the medicines group and in the supplements group, showed significant differences. These findings agree with the results of Xavier et al.2121 Xavier AF, Moura EF, Azevedo WF, Vieira FF, Abreu MH, Cavalcanti AL. Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters. BMC Oral Health. 2013 Dec;13(1):71. http://dx.doi.org/10.1186/1472-6831-13-71. PMid:24325544.
http://dx.doi.org/10.1186/1472-6831-13-7...
, who also found differences in the TSS and sugar content in the different therapeutic classes studied.

Siddiq et al.2323 Siddiq H, Pentapati KC, Shenoy R, Velayutham A, Acharya S. Evaluation of sugar content and erosive potential of the commonly prescribed liquid oral medications. Pesqui Bras Odontopediatria Clin Integr. 2020;20:1-10. http://dx.doi.org/10.1590/pboci.2020.023.
http://dx.doi.org/10.1590/pboci.2020.023...
(2020), when evaluating the pH, TTA and TSS of liquid medicines commonly prescribed for children, found lower TSS values than those found in the present study. This difference can be justified by the use of different techniques to determine sugar content. However, the results were similar regarding the TTA at pH 7.0 since, in both studies, the highest value was observed in the class of antihistamines.

Analysis of the package inserts and labels identified information about the composition of the formulations regarding their active ingredients and excipients. However, only the concentrations of the former were described. It is worth noting that, according to legislation in force in Brazil, there is no requirement for quantitative descriptions of the excipients in the formulations, only qualitative. Subramaniam and Nandan1414 Subramaniam P, Nandan N. Cariogenic potential of pediatric liquid medicaments--an in vitro study. J Clin Pediatr Dent. 2012;36(4):357-62. http://dx.doi.org/10.17796/jcpd.36.4.nt11584612462t84. PMid:23019832.
http://dx.doi.org/10.17796/jcpd.36.4.nt1...
developed an in vitro experiment to evaluate the pH, viscosity, type and concentration of sugars present in liquid pediatric medicines. They demonstrated that 90% of the formulations analyzed contained sucrose in their composition, a percentage higher than that found in the present study.

The literature has documented the relationship between sugar-containing medicines and the development of dental caries99 Arora R, Mukherjee U, Arora V. Erosive potential of sugar free and sugar containing pediatric medicines given regularly and long term to children. Indian J Pediatr. 2012 Jun;79(6):759-63. http://dx.doi.org/10.1007/s12098-011-0543-5. PMid:21830024.
http://dx.doi.org/10.1007/s12098-011-054...
,2424 Silva CO, Reis MES, Santana KFP, Maestri FP, Saatkamp CJ, Maestri RP. Avaliação do potencial cariogênico de anti-histamínicos de uso pediátrico. Rev Eletrônica Farm. 2015;12(3):15-22. http://dx.doi.org/10.5216/ref.v12i3.34971.
http://dx.doi.org/10.5216/ref.v12i3.3497...
, especially when used chronically77 Leal WMS, Lambrecht J, Almeida LS, Rehbein KD, Silva TF, Almeida LHS. Entendendo a relação entre medicamentos de uso pediátrico e cárie dentária. Rev Ped SOPERJ. 2015 Set;15(2):16-21.. In the present study, 52.83% of the formulations analyzed stated the presence of sucrose in their formulation, contributing to their cariogenic potential. Although there are medicines that use sweeteners to replace sucrose, this sugar is present in most pharmaceutical preparations because it has a low cost, has no residual taste and also has properties with a preservative and antioxidant effect1919 Sousa RIM, Oliveira MC, Clementino MA, Cavalcanti AL, Vieira FF. Potencial erosivo e cariogênico de anti-histamínicos de uso infantil. RFO UPF. 2010;15(3):255-60..

As for the presence of sucrose, according to the information on the package inserts, this sugar was found mainly among the medicines of the therapeutic class of antihistamines and in the group of supplements. However, their concentrations were not described. Among those medicines that contained sucrose, most did not warn against their use by diabetic patients, and only one supplement provided information regarding the risk of caries.

Considering that saliva represents a factor that interferes with the process of demineralization of the dental surface, it is noteworthy that the cariogenic potential of pediatric medicines should be discussed. In addition to the presence of sucrose, the adverse effects of the active ingredients on salivary flow should also be considered2525 Passos IA, Freitas CHSM, Sampaio FC. Potencial cariogênico de medicamentos pediátricos: papel na etiologia da cárie dentária. Rev Inst Ciêns Saúde. 2008;26(1):125-9.. Among all the package inserts analyzed, 18 of them mentioned xerostomia as an adverse reaction and that it acts on the central nervous system or the neuroglandular junction, suppressing the production of acetylcholine or occupying the muscarinic receptors that participate in salivary secretion. In addition, it was identified that the supplements that reported this adverse reaction also have an antimuscarinic effect, which can cause the sensation of dryness in the oral cavity.

The low pH and the presence of sugars in liquid pediatric medicines may represent a risk factor for oral health22 Babu KL, Doddamani GM, Naik LR, Jagadeesh KN. Pediatric liquid medicaments: are they cariogenic? An in vitro study. J Int Soc Prev Community Dent. 2014 Maio;4(2):108-12. http://dx.doi.org/10.4103/2231-0762.137637. PMid:25254195.
http://dx.doi.org/10.4103/2231-0762.1376...
, especially in children with chronic diseases such as respiratory allergies, bronchial asthma, allergic rhinitis and sinusitis, who frequently use these medicines1919 Sousa RIM, Oliveira MC, Clementino MA, Cavalcanti AL, Vieira FF. Potencial erosivo e cariogênico de anti-histamínicos de uso infantil. RFO UPF. 2010;15(3):255-60.. In addition, medicines that have a high concentration of sucrose, low pH and high TTA have both cariogenic and erosive potential since they promote a rapid drop in oral pH. This can remain low for prolonged periods of time77 Leal WMS, Lambrecht J, Almeida LS, Rehbein KD, Silva TF, Almeida LHS. Entendendo a relação entre medicamentos de uso pediátrico e cárie dentária. Rev Ped SOPERJ. 2015 Set;15(2):16-21..

The results found in the present study showed that there was a significant difference between liquid pediatric medicines and vitamin supplements and minerals in terms of pH, TTA and TSS. Thus, the null hypothesis is rejected. This difference can be justified by the presence of acidulants, chelating agents, sugars and sweeteners in different concentrations in the formulations analyzed.

CONCLUSION

The low pH values, the high TTA and the presence of sucrose found in most medicines, regardless of the therapeutic class, and the liquid pediatric vitamin and mineral supplements allow us to infer that these formulations may represent a risk factor for the development of dental caries and erosion. Thus, it is essential to provide clear and objective guidelines on oral hygiene after the administration of children's medicines. This is especially relevant regarding those medicines in liquid form, which have low pH, sugar content and reduce salivary flow, in order to prevent the development of caries and dental erosion.

ACKNOWLEDGEMENTS

To the Oral Biochemistry Laboratory of the Health Science Institute of the Federal University of Bahia.

  • How to cite: Coutinho LS, Sande ACMN, Nunes NNV, Oliveira RS, Campos EJ. Cariogenic and erosive potential of pediatric medicines and vitamin supplements. Rev Odontol UNESP. 2022;51:e20220006. https://doi.org/10.1590/1807-2577.00622

REFERENCES

  • 1
    Mahmoud EF, Omar OM. Erosive and cariogenic potential of various pediatric liquid medicaments on primary tooth enamel: a SEM study. Dent Med Probl. 2018 Jul-Sep;55(3):247-54. http://dx.doi.org/10.17219/dmp/91539 PMid:30328301.
    » http://dx.doi.org/10.17219/dmp/91539
  • 2
    Babu KL, Doddamani GM, Naik LR, Jagadeesh KN. Pediatric liquid medicaments: are they cariogenic? An in vitro study. J Int Soc Prev Community Dent. 2014 Maio;4(2):108-12. http://dx.doi.org/10.4103/2231-0762.137637 PMid:25254195.
    » http://dx.doi.org/10.4103/2231-0762.137637
  • 3
    Fernandes TF. Suplementação de nutrientes. Pediatra atualize-se. 2019 Set-Out;4(5):4-5.
  • 4
    Al Humaid J. Sweetener content and cariogenic potential of pediatric oral medications: a literature. Int J Health Sci. 2018 May-Jun;12(3):75-82. PMid:29896075.
  • 5
    Noronha JC, Gomes HE, Mordente CM, Souki BQ. Saúde bucal na infância e na adolescência. Rev Med Minas Gerais. 2019;29(Supl 13):S86-S90.
  • 6
    Baldasso CN, Weber JBB, Coelho EMRB, Alves NM, Kramer PF. Açúcar e saúde bucal: uma revisão crítica da literatura. Stomatos. 2020;26(50):46-55.
  • 7
    Leal WMS, Lambrecht J, Almeida LS, Rehbein KD, Silva TF, Almeida LHS. Entendendo a relação entre medicamentos de uso pediátrico e cárie dentária. Rev Ped SOPERJ. 2015 Set;15(2):16-21.
  • 8
    Lussi A, Carvalho TS. Analyses of the erosive effect of dietary substances and medications on deciduous teeth. PLoS One. 2015 Dec;10(12):e0143957. http://dx.doi.org/10.1371/journal.pone.0143957 PMid:26700481.
    » http://dx.doi.org/10.1371/journal.pone.0143957
  • 9
    Arora R, Mukherjee U, Arora V. Erosive potential of sugar free and sugar containing pediatric medicines given regularly and long term to children. Indian J Pediatr. 2012 Jun;79(6):759-63. http://dx.doi.org/10.1007/s12098-011-0543-5 PMid:21830024.
    » http://dx.doi.org/10.1007/s12098-011-0543-5
  • 10
    Scatena C, Galafassi D, Gomes-Silva JM, Borsatto MC, Serra MC. In vitro erosive effect of pediatric medicines on deciduous tooth enamel. Braz Dent J. 2014 Jan-Feb;25(1):22-7. http://dx.doi.org/10.1590/0103-6440201302344 PMid:24789287.
    » http://dx.doi.org/10.1590/0103-6440201302344
  • 11
    Santinho AJP, Waldow C, Santos SB. Estudo sobre a correlação do potencial cariogênico e do pH de xaropes pediátricos. Rev Bras Farm. 2008;89(2):92-4.
  • 12
    Balbani AP, Stelzer LB, Montovani JC. Pharmaceutical excipients and the information on drug labels. Braz J Otorhinolaryngol. 2006 May-Jun;72(3):400-6. http://dx.doi.org/10.1016/S1808-8694(15)30976-9 PMid:17119779.
    » http://dx.doi.org/10.1016/S1808-8694(15)30976-9
  • 13
    Araujo ACF, Borin MF. Influência de excipientes farmacêuticos em reações adversas a medicamentos. Brasília Med. 2012;49(4):267-78.
  • 14
    Subramaniam P, Nandan N. Cariogenic potential of pediatric liquid medicaments--an in vitro study. J Clin Pediatr Dent. 2012;36(4):357-62. http://dx.doi.org/10.17796/jcpd.36.4.nt11584612462t84 PMid:23019832.
    » http://dx.doi.org/10.17796/jcpd.36.4.nt11584612462t84
  • 15
    Babu KL, Rai K, Hedge AM. Pediatric liquid medicaments: do they erode the teeth surface? An in vitro study: part I. J Clin Pediatr Dent. 2008;32(3):189-94. http://dx.doi.org/10.17796/jcpd.32.3.j22m7t8163739820 PMid:18524267.
    » http://dx.doi.org/10.17796/jcpd.32.3.j22m7t8163739820
  • 16
    Xavier AFC, Cavalcanti AL, Oliveira MC, Vieira FF. Antibióticos líquidos de uso pediátrico: caracterização físico-química. HU Revista. 2011;37(4):397-401.
  • 17
    Aun MV, Mafra C, Philippi JC, Kalil J, Agondi RC, Motta AA. Aditivos em alimentos. Rev Bras Alerg Imunopatol. 2011;34(5):177-86.
  • 18
    Featherstone JDB, Lussi A. Understanding the chemistry of dental erosion. Monogr Oral Sci. 2006;20:66-76. http://dx.doi.org/10.1159/000093351 PMid:16687885.
    » http://dx.doi.org/10.1159/000093351
  • 19
    Sousa RIM, Oliveira MC, Clementino MA, Cavalcanti AL, Vieira FF. Potencial erosivo e cariogênico de anti-histamínicos de uso infantil. RFO UPF. 2010;15(3):255-60.
  • 20
    Dawes C. What is the critical pH and why does a tooth dissolve in acid? J Can Dent Assoc. 2003 Dec;69(11):722-4. PMid:14653937.
  • 21
    Xavier AF, Moura EF, Azevedo WF, Vieira FF, Abreu MH, Cavalcanti AL. Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters. BMC Oral Health. 2013 Dec;13(1):71. http://dx.doi.org/10.1186/1472-6831-13-71 PMid:24325544.
    » http://dx.doi.org/10.1186/1472-6831-13-71
  • 22
    Babu KLG, Rai K, Hegde AM. pH of medicated syrups–does it really matter? – An in vitro study: part II. J Clin Pediatr Dent. 2008;33(2):137-42. http://dx.doi.org/10.17796/jcpd.33.2.q5280t3744827v0h PMid:19358381.
    » http://dx.doi.org/10.17796/jcpd.33.2.q5280t3744827v0h
  • 23
    Siddiq H, Pentapati KC, Shenoy R, Velayutham A, Acharya S. Evaluation of sugar content and erosive potential of the commonly prescribed liquid oral medications. Pesqui Bras Odontopediatria Clin Integr. 2020;20:1-10. http://dx.doi.org/10.1590/pboci.2020.023
    » http://dx.doi.org/10.1590/pboci.2020.023
  • 24
    Silva CO, Reis MES, Santana KFP, Maestri FP, Saatkamp CJ, Maestri RP. Avaliação do potencial cariogênico de anti-histamínicos de uso pediátrico. Rev Eletrônica Farm. 2015;12(3):15-22. http://dx.doi.org/10.5216/ref.v12i3.34971
    » http://dx.doi.org/10.5216/ref.v12i3.34971
  • 25
    Passos IA, Freitas CHSM, Sampaio FC. Potencial cariogênico de medicamentos pediátricos: papel na etiologia da cárie dentária. Rev Inst Ciêns Saúde. 2008;26(1):125-9.

Publication Dates

  • Publication in this collection
    16 May 2022
  • Date of issue
    2022

History

  • Received
    12 Feb 2022
  • Accepted
    23 Mar 2022
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