Development of Extended-Release Formulations Containing Cyclobenzaprine Based on Physiologically Based Biopharmaceutics Modeling and Bioequivalence Safe Space.

The use of physiologically based biopharmaceutics modeling (PBBM) and bioequivalence safe space is increasingly common for immediate-release drug products. However, for extended-release (ER) formulations there are only a few examples of this application. In this study, we developed ER formulations containing cyclobenzaprine 15 mg, supported by PBBM and bioequivalence safe space. Four formulations were prepared, F1, F2, F3 (ER mini-tablet formulations) and F4 (ER tablet formulation), and the dissolution profiles were evaluated. The dissolution profile of the reference drug product was also evaluated and used to set a bioequivalence safe space. A PBBM was set up, evaluated, and used to predict the in vivo behavior of the formulations. The bioequivalence safe space was calculated to be between - 25% and + 75% of the k1 and Tlag values of the dissolution profile of the reference drug product when applying the first-order dissolution kinetic model. All time points of the dissolution profile of the ER mini-tablet formulation F2, were within the safe space, and was approved in 10 of 10 trials of crossover virtual bioequivalence studies. Based on the PBBM strategy and bioequivalence safe space, it was possible to develop an ER mini-tablet formulation virtually bioequivalent to the reference drug product, even though this formulation failed the f2 test.

Development of Biopredictive Dissolution Method for Extended-Release Desvenlafaxine Tablets.

This study aimed to develop a biopredictive dissolution method for desvenlafaxine ER tablets using design of experiments (DoE) and physiologically based biopharmaceutics modeling (PBBM) to address the challenge of developing generic drug products by reducing the risk of product failure in pivotal bioequivalence studies. For this purpose, a PBBM was developed in GastroPlus® and combined with a Taguchi L9 design, to evaluate the impact of different drug products (Reference, Generic #1 and Generic #2) and dissolution test conditions on desvenlafaxine release. The influence of the superficial area/volume ratio (SA/V) of the tablets was observed, mainly for Generic #1, which presented higher SA/V than the others, and a high amount of drug dissolved under similar test conditions. The dissolution test conditions of 900 mL of 0.9% NaCl and paddle at 50 rpm with sinker showed to be biopredictive, as it was possible to demonstrate virtual bioequivalence for all products, despite their release-pattern differences, including Generic #3 as an external validation. This approach led to a rational development of a biopredictive dissolution method for desvenlafaxine ER tablets, providing knowledge that may help the process of drug product and dissolution method development.

Model-Informed drug development of gastroretentive release systems for sildenafil citrate.

Gastroretentive drug delivery systems (GRDDS) are modified-release dosage forms designed to prolong their residence time in the upper gastrointestinal tract, where some drugs are preferentially absorbed, and increase the drug bioavailability. This work aimed the development of a novel GRDDS containing 60 mg of sildenafil citrate, and the evaluation of the feasibility of the proposed formulation for use in the treatment of pulmonary arterial hypertension (PAH), for once a day administration, by using in silico pharmacokinetic (PK) modeling and simulations using GastroPlusTM. The Model-Informed Drug Development (MIDD) approach was used in formulation design and pharmacokinetic exposure prospecting. A 22 factorial design with a central point was used for optimization of the formulation, which was produced by direct compression and characterized by some tests, including buoyancy test, assay, impurities, and in vitro dissolution. A compartmental PK model was built using the GatroPlusTM software for virtual bioequivalence of the proposed formulations in comparison with the defined target release profile provided by an immediate release (IR) tablet formulation containing 20 mg of sildenafil administered three times a day (TID). The results of the factorial design showed a direct correlation between the dissolution rate and the amount of hydroxypropyl methyl cellulose (HPMC) in the formulations. By comparing the PK parameters predicted by the virtual bioequivalence, the formulations F1, F2, F3 and F5 failed on bioequivalence. The F4 showed bioequivalence to the reference and was considered the viable formulation to substitute the IR. Thus, GRDDS could be a promising alternative for controlling the release of drugs with a pH-dependent solubility and narrow absorption window, specifically in the gastric environment, and an interesting way to reduce dose frequency and increase the drug bioavailability. The MIDD approach increases the level of information about the pharmaceutical product and guide the drug development for more assertive ways.

Biopredictive tools for the development of injectable drug products.

INTRODUCTION: Biopredictive release tests are commonly used in the evaluation of oral medicines. They support decision-making in formulation development and allow predictions of the expected in-vivo performances. So far, there is limited experience in the application of these methodologies to injectable drug products. AREAS COVERED: Parenteral drug products cover a variety of dosage forms and administration sites, including subcutaneous, intramuscular, and intravenous injections. In this area, developing biopredictive and biorelevant methodologies often confronts us with unique challenges and knowledge gaps. Here, we provide a formulation-centric approach and explain the key considerations and workflow when designing biopredictive assays. Also, we outline the key role of computational methods in achieving clinical relevance and put all considerations into context using liposomal nanomedicines as an example. EXPERT OPINION: Biopredictive tools are the need of the hour to exploit the tremendous opportunities of injectable drug products. A growing number of biopharmaceuticals such as peptides, proteins, and nucleic acids require different strategies and a better understanding of the influences on drug absorption. Here, our design strategy must maintain the balance between robustness and complexity required for effective formulation development.

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.