Development of Extended-Release Mini-Tablets Containing Metoprolol Supported by Design of Experiments and Physiologically Based Biopharmaceutics Modeling.

The development of extended-release dosage forms with adequate drug release is a challenge for pharmaceutical companies, mainly when the drug presents high solubility, as in Biopharmaceutics Classification System (BCS) class I. This study aimed to develop extended-release mini-tablets containing metoprolol succinate (MS), while integrating design of experiments (DOE) and physiologically based biopharmaceutics modeling (PBBM), to predict its absorption and to run virtual bioequivalence (VBE) studies in both fasted and fed states. Core mini-tablet formulations (F1, F2, and F3) were prepared by direct compression and coated using nine coating formulations planned using DOE, while varying the percentages of the controlled-release and the pore-forming polymers. The coated mini-tablets were submitted to a dissolution test; additional formulations were prepared that were optimized by simulating the dissolution profiles, and the best one was submitted to VBE studies using GastroPlus® software. An optimized formulation (FO) containing a mixture of immediate and extended-release mini-tablets showed to be bioequivalent to the reference drug product containing MS when running VBE studies in both fasted and fed states. The integration of DOE and PBBM showed to be an interesting approach in the development of extended-release mini-tablet formulation containing MS, and can be used to rationalize the development of dosage forms.

New Orodispersible Mini Tablets of Enalapril Maleate by Direct Compression for Pediatric Patients.

BACKGROUND: In many countries, hypertension in the pediatric population is considered a serious risk of mortality and morbidity. In this respect, it is central to design and develop new pharmaceutical forms for pediatric patients with hypertension. The development of Orodispersible Mini-Tablets (ODMTs) for pediatric use has gained importance in recent years. Therefore, regulations for developing suitable and palatable dosage forms for pediatric patients have been established by WHO authorities. OBJECTIVE: This study aimed to design and develop orodispersible mini tablets of enalapril maleate (EnM ODMTs) for pediatric use. METHODS: Five pharmaceutical formulations (A, B, C, D and E, shown in Table 1) were designed. The effects of different co-processed excipients and active pharmaceutical ingredients at different doses were studied. Lactose co-processed excipients selected were the following: Tablettose® 80, Microce- Lac® 100 and StarLac®. The micromeritic properties for all the physical mixtures were examined. The mini tablets were obtained by direct compression. Quality control parameters were determined in accordance with US Pharmacopeia. RESULTS: Three OMDTs with StarLac® showed good results of hardness, flow ability and fast disintegration. The formulation with 0.1 mg of enalapril maleate presented the best results for the official parameters of hardness (4.0 kp), friability (< 1%), disintegration time (28 s), drug content uniformity (103.6 %), and wetting time (23 s). CONCLUSION: The three OMDTs with StarLac® showed good quality parameters, according to official requirements. Formulation A exhibited the best wetting time, complying with the dose recommended for pediatric patients. This formulation could be considered eligible for being manufactured at industrial scale.

Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs.

Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (<0.1%). The melt-granulated captopril in matrix systems containing 50% EC (45P, 100P or 100FP) and the melt-granulated metformin hydrochloride in reservoir systems coated with Kollicoat® SR 30D and Opadry® II (80:20 with 10% weight gain or 70:30 with 20% weight gain) exhibited release profiles adequate to sustained release formulations, for over 450min. Therefore, carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs.

Development of a multiparticulate system containing enteric-release mini-tablets of omeprazole

The main aim of this study was to develop a multiparticulate system containing mini-tablets of omeprazole formulated with an enteric polymer with pH-dependent solubility. Pre-formulation studies showed good flow and compaction capacity, leading to the production ofhigh quality mini-tablets. The mini-tablets were coated in a fluidized bed with hydroxypropylmethylcellulose /Eudragit(r) L30D55 and packed into hard gelatin capsules. The dissolution profile showed gastro-resistance and zero-order kinetics. The dissolution profile for the formulation containing lactose as the diluent and coated with 12% (tablet weight gain) of polymer was similar to that ofthe reference drug.

O presente trabalho teve como objetivo desenvolver e avaliar um sistema multiparticulado de liberação modificada, composto por mini-comprimidos revestidos com polímero de liberação pH-dependente, utilizando como fármaco modelo o omeprazol. Os mini-comprimidos (diâmetro de 2,5 mm) foram obtidos em máquina de compresssão excêntrica, revestidos em leito fluidizado com hidroxipropilmetilcelulose/Eudragit(r)L30D55 e, em seguida, acondicionados em cápsulas gelatinosas duras. A partir dos resultados obtidos no perfil de dissolução foi possível demonstrar a liberação gastro-resistente e comportamento cinético de ordem zero. A formulação contendo lactose como diluente, com revestimento de 12% de polímero, demonstrou semelhança com o medicamento referência.