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Xavier et al. BMC Oral Health 2013, 13:71http://www.biomedcentral.com/1472-6831/13/71 Erosive and cariogenicity potential of pediatricdrugs: study of physicochemical parameters Alidianne Fábia C Xavier1*, Eline FF Moura1, Waldeneide F Azevedo2, Fernando F Vieira3, Mauro HNG Abreu4and Alessandro L Cavalcanti1 Background: Pediatric medications may possess a high erosive potential to dental tissues due to the existence ofacid components in their formulations. The purpose was to determine the erosive and cariogenic potential ofpediatric oral liquid medications through the analysis of their physicochemical properties in vitro.
Methods: A total of 59 substances were selected from the drug reference list of the National Health SurveillanceAgency (ANVISA), which belong to 11 therapeutic classes, as follows: analgesics, non-steroidal anti-inflammatory,corticosteroids, antihistamines, antitussives, bronchodilators, antibacterials, antiparasitics, antiemetics, anticonvulsantsand antipsychotics. Measurement of pH was performed by potentiometry, using a digital pH meter. For the TotalTitratable Acidity (TTA) chemical assay, a 0.1 N NaOH standard solution was used, which was titrated until drug pHwas neutralized. The Total Soluble Solids Contents (TSSC) quantification was carried out by refractometry using Brixscale and the analysis of Total Sugar Content was performed according to Fehling’s method. In addition, it wasanalyzed the information contained in the drug inserts with regard to the presence of sucrose and type of acid andsweetener added to the formulations.
Results: All drug classes showed acidic pH, and the lowest mean was found for antipsychotics (2.61 ± 0.08). Therewas a large variation in the TTA (0.1% - 1.18%) and SST (10.44% - 57.08%) values. High total sugar contents wereidentified in the antitussives (53.25%) and anticonvulsants (51.75%). As described in the drug inserts, sucrose wasadded in 47.5% of the formulations, as well as citric acid (39.0%), sodium saccharin (36.4%) and sorbitol (34.8%).
Conclusion: The drugs analyzed herein showed physicochemical characteristics indicative of a cariogenic anderosive potential on dental tissues. Competent bodies’ strategies should be implemented in order to broaden theknowledge of health professionals, drug manufacturers and general consuming public about the risks from theconsumption of medicines potentially harmful to dental tissues.
Keywords: Dental caries, Drug evaluation, Hydrogen-ion concentration The use of medicines in childhood is high particu- Oral liquid pharmaceutical dosage forms such as syrups, larly among children under two years old so that the solutions and suspensions are the therapeutic choice for the chronic use of medicines to treat asthma and attention- treatment of pediatric patients The use of these liquid deficit or hyperactivity disorders has been increasing preparations, despite being generally for short periods, can In Brazil, the prevalence of drug use from three to be considered as prolonged occurrence especially in pa- 12 months of age was estimated to be 65.0%, whereas at tients who suffer from chronic conditions, such as respira- 24 months it is 54.7%, with changes observed in the tory allergies, asthma and convulsions, or recurrent acute diseases as tonsillitis, otitis, sinusitis and allergic rhinitis The fact of the tooth being affected by the use of drugs is based on the assumption that these can reduce saliva flow and buffering capacity Liquid formulations used 1Department of Preventive Dentistry, School of Dentistry, State University of for a three-month minimum period are considered a risk Paraiba, Avenida das Baraunas, S/N, Bodocongo, Campina Grande, PB58109-970, Brazil factor for increased levels of dental caries Hence, Full list of author information is available at the end of the article 2013 Xavier et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the CreativeCommons Attribution License which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.
Xavier et al. BMC Oral Health 2013, 13:71 http://www.biomedcentral.com/1472-6831/13/71 children who use vitamin C supplements are 4.7 times comparing the measures of TTA and TSSC of a reference more likely to develop dental erosion lesions research (PhD in Chemistry) and the calibrated researcher Studies investigating the physicochemical parameters at the Laboratory of Analytical Chemistry, Department of of pharmaceutical products have provided valuable in- Industrial Chemistry, State University of Paraiba, Campina formation on their cariogenic and erosive potential by Grande, PB, Brazil. The Intraclass Correlation Coefficients determining hydrogen potential (pH), titratable acidity, The endogenous pH of each sample was determined by using the digital pH meter HI-253 (Hanna Instruments Brazil Imp. and Exp Ltd., Sao Paulo, SP, Brazil). Initially, This study aimed to evaluate the erosive and cariogenic samples underwent dilutions in distilled water, so that potential of pediatric oral liquid medications through the 10 mL of each medicine were transferred to a 100-mL analysis of their physicochemical properties in vitro.
volumetric flask, and the total volume was reached byadding 90 mL of distilled water. Then 50 mL of the mixture were transferred to a beaker, a glass electrode The drugs of this study comprised 94 liquid medicines was immersed therein, and it was proceeded with readings for children, included in the list of reference drugs by the National Agency for Sanitary Surveillance (ANVISA). As In order to investigate the total titratable acidity (TTA), such, this list contains the names of products registered by measure by acidic percentage, it was used a volume of the Brazilian Ministry of Health, whose effectiveness, safety 50 mL of the diluted solution, maintained under constant and quality have been scientifically proven stirring by using a magnetic stirrer (model 78HW1, The sample was composed by medicines commercially Coleman laboratory equipment Com. and Imp. Ltd., available as oral solution or suspension, elixir, syrup and Santo Andre, SP, Brazil). The pH meter electrode (HI-253, oral suspension powder, which should belong only to the Brazil Hanna Imp. Ltd. and Exp. Sao Paulo, SP, Brazil) was therapeutic classes marketed in three or more types of immersed into this diluted solution at the same time a formulations. Therefore, in accordance with the estab- 0.1 N sodium hydroxide (NaOH) solution was titrated until lished parameters, the sample consisted of 59 medicines the pH fell 8.2-8.4, which corresponds to the turning point (62.8% of the universe) categorized in 11 classes and pre- of phenolphthalein (acid–base indicator that changes color pared according to their therapeutic indication (Table in well-defined pH values). Subsequently, the NaOH Tests were performed in triplicate by a properly calibrated volume used was recorded and the acidic percentage of researcher. The Intra-Class Coefficients were determined by the substance was calculated using the chemical formula Table 1 Distribution of medicines according to the therapeutic class, trademark and manufacturer Tylenol bebê (Janssen Cilag)a, Tylenol criança (Janssen Cilag)a, Tylenol gotas (Janssen Cilag)a,Novalgina (Sanofi-Aventis)a, Novalgina pediátrica (Sanofi-Aventis)a, Alivium (Mantecorp)b Amoxil BD (Glaxosmithkline)c, Zinnat (Glaxosmithkline)c, Ceclor (Sigma Pharma)b, Keflex (Bagó)b,Pen-ve-oral (Eurofarma)c, Unasyn (Pfizer)c Depakene (Abbott)d, Tegretol (Novartis Biociência)b, Rivotril (Roche)a, Gardenal (Sanofi-Aventis)a,Trileptal (Novartis Biociência)b Digesan (Sanofi-Aventis)a, Motilium (Janssen Cilag)b, Plasil (Sanofi-Aventis)b Profenid (Sanofi-Aventis)a, Profenid (Sanofi-Aventis)d, Nisulid (Aché)b, Cataflam (Novartis Biociência)b Zyrtec (Glaxosmithkline)a, Zaditen (Novartis Biociência)a, Desalex (Mantecorp)d,Polaramine (Mantecorp)a, Talerc (Aché)d, Allegra (Sanofi-Aventis)b, Claritin (Mantecorp)d Zentel (Glaxosmithkline)b, Flagyl (Sanofi-Aventis)b, Pantelmin (Janssen Cilag)b, Pyr-pam (UCI Farma)b,Thiaben (UCI Farma)b, Annita (Famacoquímica)b Amplictil (Sanofi-Aventis)a, Haldol (Jansseng Cilag)a, Neozine (Sanofi-Aventis)a Benalet (Johnson & Johnson)d, Vibral (Solvay Farma)a, Vibral (Solvay Farma)d,Cloridrato de Clobutinol (Medley)d Brondilat (Aché)d, Fluimucil (Zambon)d, Mucolsovan (Boehringer)a, Mucolsovan (Boehringer)d,Bisolvon (Boehringer)d, Berotec (Boehringer)d, Aerolin (Glaxosmithkline)d, Bricanyl (Astrazeneca)d,Transpulmin (Aché)d, Xarope Vick (Procter & Gamble)d, Xarope Vick Mel (Procter & Gamble)d Celestone (Mantecorp)e, Decadron (Aché)e, Prelone (Aché)a, Predsim (Mantecorp)a aSolution, bSuspension, cOral suspension powder, dSyrup, eElixir.
Xavier et al. BMC Oral Health 2013, 13:71 http://www.biomedcentral.com/1472-6831/13/71 described below, whose result had to be adjusted due In addition to the in vitro analysis, information concern- to the dilution process and expressed as percentage of ing the type of acid and sweetener contained in the formu- lations were gathered from the medicine package inserts.
Data were recorded on study-specific charts and orga- Acidity ¼ V  Nap  F  meq‐g  100 nized with the aid of the Statistical Package for Social Sciences (SPSS) version 18 and presented by means ofdescriptive statistics (mean, standard deviation, minimum V = NaOH volume; Nap = standard concentration of the KOH (potassium hydroxide) base; F = correctionfactor; meq-g = milliequivalents per gram of citric acid; The pH values were in the range 2.43 (Claritin) to 7.48 The measurements of the Total Soluble Solids Contents (Predsim); the mean was 5.01 (± 1.47 SD) and 55.9% of (TSSC) or degrees Brix (oBx) were made by refractom- the medicines were found to show a pH below 5.5. The etry through Brix scale using the Abbe refractometer analysis of the mean of each group highlighted the fact (PZO-RL1R, Warsaw, Poland). With the aid of a pipette, that all samples exhibited an acidic pH, and the lowest two to three drops of the medicine were placed on the mean value (2.61) was found for antipsychotics.
surface of the measurement prism, avoiding the formation The TTA analysis by treatment group showed a variation of bubbles in the liquid, since these reduce the contrast of in the means obtained (0.10% to 1.17%). Individually, the boundary line that should be located between a light the occurrence of high acidity for the medicines: Vibral and dark fragment at the intersection point of the reticle.
solution (1.23%); Ceclor (1.57%); Amplictil (1.54%) and Subsequently, it was necessary to wait a few minutes until the liquid came into thermal equilibrium with the set of Evaluation of medicine package inserts demonstrated prisms. The refractometer was positioned before a natural that although citric acid has been often added (39.0%) in light source. Also, the incidence angle was adjusted through the composition of the formulations, other acids such as the activation button and the percentage provided by the benzoic, sorbic, acetic, hydrochloric, tartaric, estereatic, ascorbic and lactic acids are also incorporated.
The determination of the total sugar content in the Total Soluble Solids Contents were measured in all samples was made by the Lane-Eynon method (Fehling) medicines, and the lowest contents were found for Aerolin Initially, it was made the inversion of sucrose (acid (1.42%); Digesan (1.0%); and Haldol (1.0%); while the high- hydrolysis) using 25 mL of the medicine, followed by est contents were identified in Tylenol drops (69.67%) and addition of 5 ml of hydrochloric acid (HCl) and 75 mL Depakene (65.33%). The mean percentage of total sugars of distilled water. The diluted solution contained in a identified was 30.9% (± 15.5); the minimum value of 7.31% flask was heated to 70°C and remained in water-bath for was estimated for the antibiotic Keflex, while Vibral solu- ten minutes, in order to obtain glucose and fructose tion, Pen-v-oral and Unasyn reached the mark of 54.8%.
molecules. Then, the mixture was cooled in water and The mean, minimum and maximum values for TSSC and had its pH neutralized by titrating with 30.0% NaOH.
The neutral solution obtained was then transferred to a According to the analysis of the inserts, sucrose was 25-mL burette. In parallel, 5 ml of solution A and 5 ml found in 47.5% of the medicines, and the antiemetics of solution B of the Fehling reagents were mixed in a drug class was the only one devoid of sugar products porcelain capsule; 40 ml of distilled water were added (Table With regard to the samples lacking sucrose, and the mixture underwent boiling for four minutes. It it was found that saccharin and sorbitol were the artifi- was used the content of the burette as titrant agent and cial substitutes of choice, since these were added to the emergence of a red brick-like precipitate as an indi- about 37.0% and 35.0% of the medicines, respectively.
cator of the turning point. The end point of the reaction Other sweeteners like sodium cyclamate, aspartame, was indicated by methylene blue, which was reduced to acesulfame, xylitol and sucralose were also used, either a colorless form by slight excess of reducing sugar.
alone (37.3%) or associated. The combination of two, The volume required was recorded and the percentage three and four sweeteners was found in 25.4%, 5.1% of total sugars present in the sample was calculated ac- and 1.7% of the cases, respectively.
The wide range of products available in the national therapeutic arsenal ranks Brazil among the countries FEQ = Equivalence factor; VTITRATION = Titration vol- that have a strong consumer market. Nevertheless, there is consensus among health professionals that liquid dosage Xavier et al. BMC Oral Health 2013, 13:71 http://www.biomedcentral.com/1472-6831/13/71 Table 2 Distribution of medicines according to the therapeutic class, mean, standard deviation (SD), median (Md), andminimum (Min) and maximum (Max) values of pH and TTA forms, particularly oral solutions and suspensions, are the shows that there is a range from 2.5 [to 6.9 for most appropriate ones for use in pediatrics, because in pH values of medicines. Specifically, according to the addition to facilitating the administration and contributing findings reported herein most samples were found to to patient compliance to therapy, these preparations have show an acidic pH below 5.5, which points to their sub- great flexibility, allowing to adjust the doses given during saturated condition in relation to the tooth hydroxyapatite.
treatment simply and rapidly, depending on the pathology Despite the shortcomings of an in vitro study, it is specu- lated that the presence of a lower pH in the formulations is A number of investigations on liquid medicines belong- characterized as a predictor of dental erosion. Some users ing to different therapeutic classes have been conducted manual gives mostly the advice to take the medicine since the last decade, in order to produce reliable in- with water. If family compliance with this advice, the formation on the physicochemical profile of medicines risk of dental erosion could be lower.
used by children, both in international and Brazilian Antipsychotics and antitussives were the therapeutic classes showing the lowest pH values. This feature should The analysis of pH is an important variable involved be observed carefully, since the therapy using antipsychotic in the process of dental erosion Current literature drugs requires, in many cases, ingestion of the solution Table 3 Distribution of medicines according to the therapeutic class and mean, standard deviation (SD), median (Md),and minimum (Min) and maximum (Max) values of TSSC and sugar content aAbsence of sugar in the composition.
Xavier et al. BMC Oral Health 2013, 13:71 http://www.biomedcentral.com/1472-6831/13/71 Table 4 Distribution of medicines according to the acids was observed in a number of medicines, confirming therapeutic class and presence of sucrose as described in The estimation of total titratable acidity establishes an indirect measure of the amount of saliva buffer required to provide the medicine with a neutral pH. Saliva buffering capacity is directly associated to the presence of bicarbon-ate in the salivary flow. During the resting period, the con- centration of this compound is decreased, though there are peptides, amino acids and phosphates that are also involved in the buffering mechanism. Nevertheless, after administra- tion, acidic medicines stimulate saliva flow and release of Therefore, it was investigated the percentage of acid of the formulations by titrimetric analysis, in which a known standard NaOH solution was used. It is emphasized that we could not perform the tests in the medicine whose active ingredient was ibuprofen. This might be explained by the fact that such drug is practically insoluble in water. For the other samples, it was found a wide spectrum of vari- ation, possibly due to the peculiarities of the active ingredi-ents. Studies analyzing antitussive medicines with similar methodologies have shown TTA means of 0.18% and0.29% These results are lower than 0.39% obtained in several times a day and for an indefinite period of time.
this study for the antitussive samples.
Moreover, it is knowingly reported in the literature that The test for detection of soluble solids in medicines cough is a common condition occurring in children, so used refractometry as the method of choice, because that antitussive drugs are widely used, sometimes with- despite some drawbacks (such as loss of sensitivity and temperature dependency) it has been used in studies The acidic pH prevents liquid medicines from being assessing physicochemical parameters of oral liquid contaminated with microorganisms Additionally, it medicines ]. In this study, the soluble solids means can be mentioned the fact that this characteristic is directly differed among the samples, with lower values found for related to factors such as chemical stability and biocompati- the antiemetics class, which did not have sugar in their composition. High percentages were found for antibiotics Pharmacologically, it is clear that the establishment of and analgesics, which supposedly have the potential to inappropriate pH values during the drug formulation process may either favor the decomposition of the active Sugars are multifunctional ingredients added to drug ingredient or harm its therapeutic activity ]. From formulations due to the unpleasant taste of many active the perspective of dentistry, it is configured an alarming constituents. In addition, sucrose is easily processed and and conflicting situation as on one hand it is recognized available in different dry particle sizes, chemically and phys- the importance of the medicine as an irreplaceable tool ically stable, acting as an oxidant and solvent, and providing for restoring and maintaining children’s health status, viscosity to the medicine. It is not hygroscopic and is less on the other hand it is perceived the possibility of organ costly, which influences the final product price involvement by dental caries and dental erosion.
With regards to the use of medicines containing sugary The acidic contents are added to medicines as they act vehicles, it was found that approximately half of the sam- as buffering agents, responsible for maintaining chemical ples tested had sugar in their composition, reaching a mean stability, controlling tonicity, ensuring the physiological rate of 53.2% for antitussives, which is slightly higher than compatibility and improving flavor, which make medicines the 48.0% rate identified in a recent study . However, higher sugar contents were observed in other studies with In this study, citric acid was found in the most part of percentages ranging from 65.0% [] to 86.9% .
the medicines tested, corroborating data from previous The presence of sucrose in the medicines is noteworthy, studies [This acid is a potent erosive agent, because given that all antipsychotics had such disaccharide con- it has the ability to chelate calcium, increasing dental en- tained in their formulations. Moreover, it was observed that amel dissolution rates upon the acid challenges that are im- the dosage description of Neozine explicitly recommends posed25. The presence of benzoic, tartaric and hydrochloric its dilution in “sugared-water”. Thus, children using this Xavier et al. BMC Oral Health 2013, 13:71 http://www.biomedcentral.com/1472-6831/13/71 substance may have a harmful cumulative effect that might be manifested as carious and erosive lesions on the tooth Department of Preventive Dentistry, School of Dentistry, State University of Paraiba, Avenida das Baraunas, S/N, Bodocongo, Campina Grande, PB surface, taking into account that such medicine has a pH 58109-970, Brazil. 2Posgraduate Programa in Public Health, State University of value below that for enamel dissolution, high acidity and Paraiba, Avenida das Baraunas, S/N, Bodocongo, Campina Grande, PB 58109-970, Brazil. 3Department of Sanitary and Environmental Engineering,State University of Paraiba, Avenida das Baraunas, S/N, Bodocongo, Campina As aforementioned, liquid medicines usually have un- Grande 58109-970, PB, Brazil. 4Department of Community and Preventive pleasant taste, so it has been necessary to include various Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Av.
sweeteners in the same product to overcome this. In this Antônio Carlos, 6627, Belo Horizonte 31270.901, Brazil.
research, in addition to sucrose, the sweeteners commonly Received: 17 May 2013 Accepted: 5 December 2013 found were sodium saccharin, sorbitol and sodium cyc- lamate. Hypothetically, it is assumed that the choice forone or another type of sweetener, or even the combination of many, as seen in 25.0% of the medicines studied, is not Standing J, Tuleu C: Paediatric formulations - getting to the heart of the only due to the given degree of sweetness, but also to its problem. Int J Pharm 2005, 300:56–66.
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doi:10.1186/1472-6831-13-71Cite this article as: Xavier et al.: Erosive and cariogenicity potential ofpediatric drugs: study of physicochemical parameters. BMC Oral Health2013 13:71.
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