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38 March 2018 Tablets & Capsules effective, and safe and that it will contain the optimal drug ratios as determined by dose-ranging studies. Solid dosage forms The solid dosage form of an FDC may be a monolayer tablet, a bilayer tablet, or a multi-particulate/mini-tablet system depending on the release profiles and chemical and physical compatibility of the APIs as well as clinical and dosing requirements. Monolayer tablets. A monolayer tablet is similar to a single-entity tablet except that it contains two or more APIs. To be processed together into a monolayer tablet, the APIs must be physically and chemically compatible with each other, and the dose of each API should not be too high. Additionally, the APIs should have similar dissolution profiles to ensure that the FDC can achieve bioequivalence to each single-entity drug product [6]. Bilayer tablets. A bilayer tablet (Photo 1), is similar to a conventional single-layer tablet but with two separate f o r m u l a t i o n s p r e s s e d t o g e t h e r . B y s e p a r a t i n g incompatible components, a bilayer tablet formulation can significantly improve an FDC's overall chemical stability. In addition, a bilayer tablet is a convenient way to combine an immediate-release dose and a sustained- release dose of either the same drug or different drugs. To avoid potential formulation challenges such as inadequate compression or content uniformity, the granular or powder materials that comprise the two tablet layers should have similar physical properties, including particle size distribution, bulk density, and flow characteristics. It's also good practice to maintain a weight ratio between the two layers of not more than 6 to 1. Furthermore, if high drug loading (500 to 600 milligrams) is required in one layer to achieve pharmacological action, or if the weight of one layer must be kept high (800 to 1,200 milligrams) for formulation reasons, it's important to keep the overall tablet weight low enough (1,000 to 1,500 milligrams) for patient compliance. If maintaining a similar weight or composition between the layers isn't possible due to Photo 3: The mini-tablet's small size allows developers to encap- sulate multiple mini-tablets into a single FDC capsule. Pharmaceutical manufacturers are developing and introducing more FDC's into the market because these drug products offer a promising strategy to repurpose, repackage, and expand indications for existing and novel therapeutic agents. Reformulating and combining approved drugs that are proven to be safe and effective into an FDC allows a company to extend and maintain patents or increase market share, which are potent financial incentives. Development considerations Aside from the approval status of the APIs to be combined, the primary consideration when developing an FDC is the development strategy. Companies typically select APIs for FDC development based on clinical experience and manufacturing feasibility along with the pharmacological mechanisms, biopharma- ceutical properties, metabolic pathways, pharmacok- inetics, drug-drug interactions, and required doses of the individual APIs [5]. The APIs to be combined should: • act by different mechanisms; • have similar pharmacokinetics; • treat closely related diseases (such as hypertension and hyperlipidemia) or the same disease using different mechanisms (such as antidiuretics and angiotensin converting enzyme inhibitors); • have minimal drug-drug interaction. An FDC formulation and development program typically involves a pilot-stage program followed by bioequivalence (BE) studies, which compare the FDC to the constituent drugs co-administered as individual entities. Food-effect bioavailability studies are also required to register the drug product with the FDA. The regulatory requirements may be particularly challenging for FDCs that combine two NCEs. Developing a good strategy and designing appropriate trials to evaluate the formulations, drug-drug interactions, and bioavailability are critical to ensure that the FDC will be stable, Photo 2: Mini-tablets have a diameter smaller than 3 millimeters and are manufactured using a conventional tablet press with spe- cialized multi-tip tooling.