Design and optimization of a child-friendly dispersible tablet containing isoniazid, pyrazinamide, and rifampicin for treating tuberculosis in pediatrics.

Objective: Develop a child-friendly Fixed Dose Combination (FDC) water-dispersible tablet for Tuberculosis (TB) treatment, with 50, 150, and 75 mg of isoniazid, pyrazinamide and rifampicin respectively. This new formulation must contain the lowest number of excipients accepted for pediatrics and fulfill all the pharmacopeia requirements.Significance: At present, there is no adequate market dosage form available for children. There is, however, one in a prequalification phase by the World Health Organization but its composition contains excipients which may not be suitable for pediatrics. Therefore, this new formulation would cover this therapeutic gap.Methods: A factorial design, based on three quantitative factors (compression force and concentration of AcDiSol® and Explosol®) at three levels each, was performed to elucidate their influence over disintegration time and friability. In addition, the influence of the press speed on disintegration time, friability, tensile strength, fineness of dispersion and content uniformity over the target tablet was tested. A stability test was done following ICH guideline for accelerated conditions.Results: Tablets developed with 9% w/w of Explosol® and a compression force of 16 kN disintegrated in less than 3 min and showed a friability below 1% when 15-mm punches were used. The tableting process could be done up to 25 and 50 cycles/minute ensuring good quality attributes when 15 and 12-mm punches were used, respectively. All APIs remained inside the limit of ± 5% of drug content till 6 months of storage.Conclusion: A high-quality child-friendly FDC water-dispersible tablet was developed improving the treatment of TB in pediatric.

Development of a novel physico-chemically and microbiologically stable oral solution of flecainide for pediatrics.

There is as yet no commercialized preparation for oral administration of flecainide acetate (FA) to children. In such cases, manipulation of commercial tablets is the usual practice in pharmacy services of hospitals and compounding pharmacies, to provide a suitable dosage form for this vulnerable pediatric population group. In this study, we have formulated FA as an oral solution, as an alternative to the suspension elaborated from commercial tablets. Due to this sensitivity of young patients, we have used the pure active pharmaceutical ingredient (API) and the lowest permitted levels of pediatric excipients. Despite being a highly soluble API, only one of the formulations appears as a transparent solution due to complete FA solubilization. The proposed formulation is physico-chemically and microbiologically stable and the mass and dose uniformity is appropriate for 30 days' storage at 25 °C.

A pharmaceutical monitoring system to assess the quality of antituberculosis drug products used in Mauritania.

The quality of drug products may be affected from manufacture to dispensing, particularly at high temperature and humidity as in Mauritania. This country is not included in the World Health Organization reports on poor quality products due to the lack of a qualified laboratory and monitoring system. Ensuring the quality of medicine is even more relevant in the case of diseases such as Tuberculosis, due to its high prevalence, complex treatment and continuous bacterial resistance. The aim was to develop a monitoring system to assess the quality of antituberculosis drugs products, by the substandard detection based on European and United States Pharmacopeial recommendations regarding quality control. In addition to studying the influence of accelerated storage conditions (40 ± 2°C/75 ± 5% relative humidity) on their qualities and comparing the dissolution profiles to contrast the quality. 18 antituberculosis drug products were taken from Europe and Mauritania, and quality was studied through visual inspection and according to the compliance of the mass uniformity, uniformity of dosage units, dissolution, disintegration and friability pharmacopeial tests. Furthermore, a dissolution profile comparison was carried out to examine quality. A stability study was conducted to assess the influence of climatic conditions on the content and the dissolved amount of the active pharmaceutical ingredients, which were determined by an ultra-performance liquid chromatography system. As result, 69.3% of 13 Mauritanian formulations had a substandard quality mainly due to non-compliance with the test for friability or content uniformity of these medicines. All European drug products complied with pharmacopeia specifications. In addition, storage conditions affected the dissolution rate of ethambutol and the uniformity of the 4 antituberculosis combination drug products.

Stability Study of Isoniazid and Rifampicin Oral Solutions Using Hydroxypropyl-Β-Cyclodextrin to Treat Tuberculosis in Paediatrics.

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) Methods: The active pharmaceutical ingredients stability under in vitro paediatric digestive pH conditions have been checked. The samples were studied as individual or fixed combined paediatric dosages to determine the pH of maximum stability. The use of hydroxypropyl-ß-cyclodextrin to improve Rifampicin solubility and the use of ascorbic acid to increase the stability of the formulation have been studied. (3) Results: Maximum stability of combined doses was determined at pH 7.4, and maximum complexation at pH 8.0. Taking this into account, formulations presented the minimum dose of two active pharmaceutical ingredients dissolved. The addition of ascorbic acid at 0.1% w/v enables the detection of a higher remaining quantity of both drugs after three days of storage at 5 °C. (4) Conclusions: a formulation which combines the minimum paediatric dosages dissolved recommended by WHO for Isoniazid and Rifampicin has been developed. Future assays are needed to prolong the stability of the formulation with the aim of incorporating Pyrazinamide to the solution.

Effectiveness of Antimicrobial Preservation of Extemporaneous Diluted Simple Syrup Vehicles for Pediatrics.

OBJECTIVES: Extemporaneous or magistral formulation of active pharmaceutical ingredients using traditional compounding techniques is a common practice when no commercial form is available for pediatrics. For this vulnerable group of patients, the formulation must be prepared with the minimum quantity and lowest proportion of excipients approved for pediatrics, avoiding the use of preservatives. Often the vehicles used for these preparations are dilutions of simple syrup with water. The objective of this study is to assess the effectiveness of antimicrobial preservation in simple syrup diluted with aqua conservans (conserved water), without propylene glycol or with a reduced proportion of parabens. METHODS: The European Pharmacopoeia test of efficacy of antimicrobial preservation was applied to 5 trial vehicles prepared with simple syrup diluted with water. RESULTS: Simple syrup is stable during 14 days. Vehicles prepared with simple syrup diluted with purified water did not meet the microbiological quality criteria, but when they are diluted with water that incorporates propylene glycol and parabens (aqua conservans), then they meet the criteria. In addition, if the water is prepared with parabens and without propylene glycol, the criteria for the dilution are met. Nevertheless, if the dilution is done with water prepared with an insufficient proportion of parabens to act as preservatives, the dilution does not meet the pharmacopoeia microbiological criteria. CONCLUSIONS: Dilution of simple syrup (50:50 v/v) to prepare a vehicle for extemporaneous or magistral preparation is microbiologically safe when water with methylparaben and propylparaben is used in a proportion of 0.08% and 0.02% (w/w), respectively, avoiding the use of propylene glycol as a solvent and thus its toxic effects in pediatrics.