Abstract:SettingIn most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets.ObjectiveTo determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis.DesignDrug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high per… Show more
“…It is estimated that 3000 compounding pharmacies fill more than 30 million prescriptions per year in the United States in an attempt to customize drugs for individual patients (6). Tablet division is achieved mainly using hands, knives or tablet splitters, which introduce dose variations due to uneven weight distribution after splitting (7)(8)(9)(10)(11)(12). Splitting solid dosage forms could also impact on release kinetics, especially for controlled or extended release formulations (13,14).…”
The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such as extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, including design flexibility and control and manufacture which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry.
“…It is estimated that 3000 compounding pharmacies fill more than 30 million prescriptions per year in the United States in an attempt to customize drugs for individual patients (6). Tablet division is achieved mainly using hands, knives or tablet splitters, which introduce dose variations due to uneven weight distribution after splitting (7)(8)(9)(10)(11)(12). Splitting solid dosage forms could also impact on release kinetics, especially for controlled or extended release formulations (13,14).…”
The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such as extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, including design flexibility and control and manufacture which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry.
“…However, significant differences were found between young and old children for all drugs but INH when the dosing of fast and slow acetylators was compared. This is likely an inevitable consequence of larger relative body weight differences for younger children enhanced by the need to fit the weight bands and the lack of uniformity when tablets have to be split [ 27 ]. Fig.…”
Background: Among the various forms of TB, tuberculous meningitis (TBM) is the most severe, with about 30 % mortality and 50 % of survivors left with neurological sequelae. Children suffer more frequently from TBM than adults and outcomes are often poor due to difficulties in making the diagnosis and uncertainty regarding the best anti-tuberculosis drug regimen. The aim of this prospective study was to describe the pharmacokinetics of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of children with tuberculous meningitis treated with the standard TBM regimen. Methods: We performed a prospective observational study of 100 consecutively treated children (≤15 years of age) with tuberculous meningitis in Ho Chi Minh City, Vietnam. Children were treated according to the 2006 WHO recommended pediatric treatment regimen consisting of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. Pyrazinamide, isoniazid and rifampicin concentrations were measured in plasma at day 14 and in cerebrospinal fluid (CSF) at 1 month by HPLC-UV. A naïve-pooled noncompartmental data analysis was used to describe the pharmacokinetic properties of drugs in the two-age groups of children ≤ 4 years or > 4 years of age. Results: Younger children, when compared to older children, presented a higher body weight-normalized clearance and volume of distribution, and lower median total plasma exposures for the three studied drugs with −14 %, −22 % and −16 % for Pyrazinamide, Isoniazid and Rifampicin, respectively. In CSF, individual concentrations of isoniazid and pyrazinamide were comparable to that in plasma in both age groups; but rifampicin concentrations were lower than the minimum inhibitory concentration of susceptible bacteria in all but two children. Conclusions: There is an age-dependent variation in the plasma and cerebrospinal fluid pharmacokinetics of rifampicin, isoniazid and pyrazinamide. The safety and efficacy of higher doses of rifampicin should be investigated for the treatment of childhood tuberculous meningitis.
“…Thus far, the greatest challenge to the successful treatment of TB in children is the significant shortage of efficient pediatric pharmaceutical formulations [1,[10][11][12]. Despite the alarming statistics reported on the number of active TB cases in children, it is indeed shocking to note that to date, childhood TB has been generally neglected worldwide, evidenced by treatment and clinical care schemes mostly extrapolated from studies in adults [1,[13][14][15]. Over the years, children have been largely excluded from clinical trials resulting in weak evidence-based treatment of pediatric TB infection.…”
Section: Introductionmentioning
confidence: 99%
“…With the shortage of suitable child-friendly anti-TB pharmaceutical formulations, it is common global practice to split adult fixed-dose combination (FDC) preparations: (i) into fractions; (ii) crushed to be taken with food, milk, and other liquids; or (iii) extemporaneous compounding to allow for easy use as needed per child. These practices can lead to dose inaccuracies, reduced active drug potencies, impaired dosage stability, irregular bioavailability, and poor compliance [14][15][16]. Consequently, there is an urgent need for innovative treatment strategies that can contribute towards combating the TB epidemic in pediatric patients.…”
Tuberculosis (TB) is a major cause of childhood death. Despite the startling statistics, it is neglected globally as evidenced by treatment and clinical care schemes, mostly extrapolated from studies in adults. The objective of this study was to formulate and evaluate a reconstitutable dry suspension (RDS) containing isoniazid, a first-line anti-tubercular agent used in the treatment and prevention of TB infection in both children and adults. The RDS formulation was prepared by direct dispersion emulsification of an aqueous-lipid particulate interphase coupled with lyophilization and dry milling. The RDS appeared as a cream-white free-flowing powder with a semi-crystalline and microparticulate nature. Isoniazid release was characterized with an initial burst up to 5 minutes followed by a cumulative release of 67.88% ± 1.88% (pH 1.2), 60.18% ± 3.33% (pH 6.8), and 49.36% ± 2.83% (pH 7.4) over 2 h. An extended release at pH 7.4 and 100% drug liberation was achieved within 300 min. The generated release profile best fitted the zero order kinetics (R2 = 0.976). RDS was re-dispersible and remained stable in the dried and reconstituted states over 4 months and 11 days respectively, under common storage conditions.
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