Desarrollo y caracterización de formulaciones farmacéuticas adaptadas para pediatríamedicamentos antituberculosos

  1. Javier Suárez González
Supervised by:
  1. Ana María Santoveña Estévez Director

Defence university: Universidad de La Laguna

Year of defence: 2020

  1. Matias A. Llabres Martinez Chair
  2. Carmen Álvarez Lorenzo Secretary
  3. Carlos Mauricio Gonçalves Barbosa Committee member

Type: Thesis

Teseo: 623634 DIALNET lock_openRIULL editor


Appropriate medicines are need for pediatric requirements. However, the development of these medicines is challenging due to the composition of this group (from birth to 13-17 years old) which implies differences regarding absorption, distribution, metabolism and excretion of drugs. In addition, these medicines should be easy to swallow, have an adequate dose volume/content, correct composition for pediatrics and good organoleptic properties, etc. For this reason, individualized medicines for pediatrics are a useful alternative if there is no correct market dosage for this segment of population. However, a thorough investigation must be carried out in order to ensure quality testing, content uniformity, physical (homogeneity after shaking, in the case of liquid dosage forms), chemical, and microbiological stability. The quality of individualized medicines, used daily in pharmacy services (hospitals and community pharmacies), have been tested. These have been selected based on their demand, problems that arose during elaboration and the excipients used. In all cases, a new standard operative procedure, which ensures the quality of the individualized medicine, was developed for each active pharmaceutical ingredient studied and disseminated in the different services. The data obtained from the validation of the formulations previously mentioned, was used to elaborate a high-demanding strategy to ensure the highest quality standards of oral liquid individualized medicines for pediatric use. This included a first part related to the validation of the analytical method used, and a second part focused on the critical quality attributes that should be checked, some of them recommended by Pharmacopoeia. Following the European initiative to enhance the research in the pediatric field, the World Health Organization, the National Institutes of Health and the European Medicine Agency have been publishing lists about pediatric needs regularly (dosing, efficacy, pharmacokinetics, safety and formulation development). Active pharmaceutical ingredients used for the treatment of Tuberculosis were selected to develop medicines appropriate for children, based on the list previously mentioned. They were selected because of the number of children that died every year due to the lack of an appropriate dosage form. The treatment it is based on at least three drugs: Isoniazid, Pyrazinamide and Rifampicin, which are used as first-line treatment for treating tuberculosis in the intensive and in the continuation phase. This last phase is based on the combination of Isoniazid and Rifampicin. This last active pharmaceutical ingredient is the only drug which has an appropriate dosage form for pediatrics. For this reason, a formulation of isoniazid of 50 mg/ml was validated using the strategy previously mentioned; the continuation phase is covered. The treatment for the intensive phase is based on the combination of Isoniazid, Pyrazinamide and Rifampicin and, in resistant cases, Ethambutol. Therefore, for this phase a fixed-dose combination of the three active pharmaceutical ingredients is required. However, this is difficult to achieve in a liquid dosage form, which it is more accepted by the pediatric patient, due to the chemical incompatibility between Isoniazid and Rifampicin. Subsequently, a solid dosage form is preferred. Hence, a high-quality, child-friendly, fixed dose combination water- dispersible tablet of Isoniazid, Rifampicin and Pyrazinamide was developed according to international recommendations in terms of excipients for pediatrics and meeting pharmacopoeia requirements. In addition, its production has been optimized to be elaborated at maximum press speed while maintaining quality requirements. Stability studies according to the International Conference of Harmonization were carried out at accelerated, long-term and low relative humidity conditions. Moreover, the influence of light on the stability of the tablets was also tested. Tablets offred more stability when the humidity was low. No property, chemical or physical, suffered any significant change under this condition after three months storage. According to the results, a packaging which protects the tablets from moisture is needed.