The Development of Innovative Dosage Forms of the Fixed-Dose Combination of Active Pharmaceutical Ingredients

Abstract

The development of innovative forms of combination drugs is closely related to the invention of the multilayer tablet press, polymers for pharmaceutical applications, the hot-melt extrusion process, and 3D printing in the pharmaceutical industry. However, combining multiple drugs within the same dosage form can bring many physicochemical and pharmacodynamic interactions. More and more new forms of fixed-dose combinations (FDCs) have been developed due to work to overcome the incompatibility of active substances or to obtain different drug release profiles in the same dosage form. This review provides discussions of the application of various innovation formulation technologies of FDC drugs such as bilayer system, multilayer tablet, active film coating, hot-melt extrusion, and 3D printing, taking into account the characteristics of the key ingredients in the FDC formulation and presenting technological problems and challenges related to the development of combination drugs. Moreover, the article summarizes the range of dosage forms that have been made using these technologies over the past 30 years.

Keywords: bilayer; fixed-dose combination (FDC); gastric retention of oral dosage forms; history of innovative forms; hot-melt extrusion; multilayer tablets; three-dimensional (3D) printing.

Figure 1

The structure of the Combodart/Jalyn: A softgel capsule filled with a liquid additive. The above softgel capsule was introduced into a hard size-00 HPMC capsule. Pellets from the other additive fill the HPMC capsule to accompany the softgel in the final dosage form.

Figure 2

The Fuster-CNIC-Ferrer CV Polypill (Trinomia ^®, Sincronium ^®, Iltria ^®) technology [13,14].

Figure 3

Soft gelatin capsules for fixed-dose combination drugs—Unigel™ technology that allows the use of other delivery systems, such as tablets, capsules, micro granules, or pellets, closed in one soft capsule, the so-called “softgel” [21].

Figure 4

Bilayer tablet according to the Stephenson patent from 1964 [23].

Figure 5

Diagram of a multilayer tablet structure.

Figure 6

Hydrodynamically balanced system (HBS): Structure of a floating capsule. Mode of action of HBS capsules made of gelatin mass with specific density < 1 [59].

Figure 7

Star-shaped gastric retention dosage form developed by Lyndra (b). The stellate dosage form is administered in a capsule. Upon dissolution, the capsule releases a large star that remains in the stomach for approximately 7 days to provide a constant release of the drug (a). After the drug is released, the matrix breaks down into smaller components that pass safely through the digestive tract [69].