The use of excipients in medicines administered to neonates in Europe
Date
2017-02-22
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Abstract
Abiained on vajalikud erinevate ravimvormide disainimiseks ja väljatöötamiseks. Neil on ravimites erinevaid funktsioone, mis võimaldavad tehnoloogiliselt ravimvormide valmistamist ja parandavad nii toimeaine (stabiilsus, biosaadavus) kui ka lõpliku ravimvormi omadusi (stabiilsus, maitseomadused jt.). Arvestades ainevahetuse iseärasusi, on teatud abiainete kasutamisega seotud riskid enam väljendunud vastsündinutel. Enam kui tuhandest kasutusel olevast abiainest on kõrvaltoimeid vastsündinutel kirjeldatud vaid üksikutel – parabeenid, polüsorbaat 80, propüleenglükool, etanool, bensoehape, naatriumbensoaat, bensüülalkohol, sorbitool, naatriumsahhariin ja bensalkooniumkloriid. Käesolevas töös keskendusime nende potentsiaalse ohtlikkuse seisukohalt enim huvi pakkuvate abiainete (excipients of interest, EOI) kasutuse uurimisele.
Meie töö eesmärkideks oli iseloomustada ravimites olevate EOI kasutamise ulatust Euroopa vastsündinute osakondades, s.h. hinnata uuringumetoodika mõju saadud tulemustele, leida EOI manustamisega seotud riskifaktorid ning hinnata ravimite asendamise võimalusi vältimaks EOI manustamist vastsündinutele.
Viisime Euroopa vastsündinute osakondades läbi 3-päevase küsimustik- (service evaluation survey, SES) ja ühepäevase hetklevimusuuringu (point prevalence study, PPS). Kahe uuringu metoodika hea omavaheline korrelatsioon andis võimaluse kasutada kogutud tulemusi teineteist täiendavana.
Kokku osales SES ja PPS uuringus vastavalt 20 ja 21 Euroopa riiki 115 ja 89 osakonnaga. SES registreeriti 313 toimeainet, mida manustati 1065 erineva ravimpreparaadina. PPS 726-le vastsündinule registreeriti 2199 ravimikorraldust. Kolmandik ravimitest sisaldasid vähemalt ühte EOI; kaks kolmandikku vastsündinutest said nendest vähemalt ühte. Uuritavate demograafilistele parameetritele ja aktiivainete struktuurile tasakaalustatud regressioonanalüüsis leidsime erinevused Euroopa regioonide vahel. Siit järeldasime, et on võimalik asendada ühes riigis kasutatava EOI sisaldav ravimpreparaat teises riigis kasutusel oleva EOI-vaba analoogiga. Leidsime, et ainuüksi sageli kasutatavate ravimite asendamine vähendaks kõigi EOI saavate vastsündinute arvu peaaegu poole võrra. Euroopa vastsündinutele manustatakse sageli EOI, kusjuures alati pole see tegelikult hädavajalik. Olemasolevate asendamisvõimaluste rakendamine säästaks paljud vastsündinud ebavajalikust ekspositsioonist.
Pharmaceutical excipients are essential components of medicines necessary to maintain quality and patient acceptability. Due to organ immaturity there is a higher risk of adverse effects associated with the administration of excipients in neonates compared to adults. While thousands of excipients are in use, only some have been associated with the toxicity in neonates – excipients of interest (EOI). In this work EOI included parabens, polysorbate 80, propylene glycol, ethanol, benzoic acid, sodium benzoate, benzyl alcohol, sorbitol, saccharin sodium and benzalkonium chloride. We aimed to describe the scale of neonatal exposure to EOI in Europe, to identify factors related to EOI administration and explore the opportunity of product substitution to reduce exposure to EOI. We conducted a 3-day questionnaire (service evaluation survey, SES) and a 1-day point prevalence study (PPS). We showed a high correlation in the frequency of medicine use between the two methods. The choice of method in future studies depends on the research question, whether priority is given to a more comprehensive list of products (SES) or individual exposure data (PPS). Altogether 20 and 21 countries with 115 and 89 units participated in the SES and PPS, respectively. In the SES 313 active pharmaceutical ingredients (APIs) representing 1065 products were registered. In the PPS 726 neonates received 2199 prescriptions. One third of products contained EOI and two thirds of the neonates were administered at least one of them. We found regional variations in the administration of some EOI. This indicates possibilities to use EOI-free products available in one but not another country. Substitution of only the most frequently used products would reduce the overall number of exposed neonates almost by a half. In conclusion, EOI are not rare in medicines used in European neonatal intensive care units, whereas EOI-free products available on the European market allow to reduce neonatal exposure to EOI substantially.
Pharmaceutical excipients are essential components of medicines necessary to maintain quality and patient acceptability. Due to organ immaturity there is a higher risk of adverse effects associated with the administration of excipients in neonates compared to adults. While thousands of excipients are in use, only some have been associated with the toxicity in neonates – excipients of interest (EOI). In this work EOI included parabens, polysorbate 80, propylene glycol, ethanol, benzoic acid, sodium benzoate, benzyl alcohol, sorbitol, saccharin sodium and benzalkonium chloride. We aimed to describe the scale of neonatal exposure to EOI in Europe, to identify factors related to EOI administration and explore the opportunity of product substitution to reduce exposure to EOI. We conducted a 3-day questionnaire (service evaluation survey, SES) and a 1-day point prevalence study (PPS). We showed a high correlation in the frequency of medicine use between the two methods. The choice of method in future studies depends on the research question, whether priority is given to a more comprehensive list of products (SES) or individual exposure data (PPS). Altogether 20 and 21 countries with 115 and 89 units participated in the SES and PPS, respectively. In the SES 313 active pharmaceutical ingredients (APIs) representing 1065 products were registered. In the PPS 726 neonates received 2199 prescriptions. One third of products contained EOI and two thirds of the neonates were administered at least one of them. We found regional variations in the administration of some EOI. This indicates possibilities to use EOI-free products available in one but not another country. Substitution of only the most frequently used products would reduce the overall number of exposed neonates almost by a half. In conclusion, EOI are not rare in medicines used in European neonatal intensive care units, whereas EOI-free products available on the European market allow to reduce neonatal exposure to EOI substantially.
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