Excipients in Polymeric Drug Delivery and Formulations

A roundtable with John Doney, Jiao Yang, Hans Baer, and Elena Draganoiu.
Jul 01, 2008

Excipients play an important role in polymeric drug delivery. They may be used to modulate the release of a drug, stabilize a drug, and faciliate localized delivery of a drug. In addition, the excipient itself may be a polymer that can add important functionality to a formulation. To gain a perspective of these issues, we asked several leading scientists to provide their input on noteworthy advances of polymer-based excipients. Participating in the roundtable are: John Doney, PhD and manager of research and development, and Jiao Yang, PhD and research chemical engineer, both with ISP Pharma Technologies (Columbia, MD); Hans Baer, senior scientist of the Pharma Polymers business line with Evonik Röhm GmbH (Darmstadt, Germany); and Elena Draganoiu, PhD and a senior research and development pharmacist in the Pharmaceutical Ingredients business with The Lubrizol Corporation (Wickliffe, OH).

Drug-polymer solid solutions and dispersions

Doney and Yang: Greater sophistication in drug discovery is leading to a growing number of potent new molecular entities (NMEs). These compounds present challenges to the formulator when they exhibit extreme water insolubility. Indeed, nearly 40% of the drugs on the market today and nearly 60% of drugs in development are poorly soluble. These formulation problems can be compounded as new disease states emerge. Pharmaceutical companies no longer enjoy the luxury of dropping these "brick-dust" candidates from development, yet conventional formulation strategies may not adequately deliver them. A need for nontraditional technologies, including drug-polymer solid solutions and solid dispersions, arises.

Despite a perceived newness, solid solutions and dispersions have been around for almost 50 years. Their pharmaceutical application to enhance oral bioavailability was first envisioned in 1961 (1). Since then, five commercial products use the solid solution/dispersion approach:
  • A solid dispersion of crystalline griseofulvin in polyethylene glycols (gris-PEG) was marketed that cut the crystalline 500-mg dose in half while maintaining plasma concentrations (2)
  • The antiemetic "Cesamet" (nabilone) (Valeant Pharmaceuticals, Costa Mesa, CA) contains a solid dispersion of nabilone in polyvinylpyrrolidone (3)
  • Solid solutions of lopinavir and ritonavir in polyvinylpyrrolidone-vinyl acetate copolymer successfully enabled a reformulation of "Kaletra" (Abbott Laboratories, Abbott Park, IL). In addition to reducing the dosage burden from six softgel capsules to four tablets, tablets made with the solid solutions eliminate the need for refrigeration.
  • "Sporanox" (Janssen Pharmaceutica, Titusville, NJ) is a solid dispersion of itraconazole in hypromellose that has been layered onto sugar spheres (4)
  • The most recently approved product is the nonnucleoside reverse transcriptase inhibitor "Intelence" (Tibotec, Yardley, PA), an amorphous, spray-dried solid dispersion of etravirine, hypromellose, and microcrystalline cellulose (5, 6).

In addition, an ever-growing body of pharmacokinetic literature points to drug-polymer solid solutions/dispersions to enhance bioavailability. For example, three solid solutions of "R103757," (Johnson & Johnson, Beerse, Belgium), an inhibitor of microsomal triglyceride transfer protein, were formulated with hypromellose (and other adjuvants) using solvent evaporation and hot-melt methods. In a clinical trial, the three solid solutions provided greater plasma concentrations than the crystalline drug form, for which exposure was not detected. Of particular note, an amorphous solid solution made by a solvent evaporation method was estimated to be bioequivalent to a liquid solution of the drug complexed with hydroxypropyl-β-cyclodextrin (4).

The terms solid solution and solid dispersion define related compositions in which at least one active ingredient is dispersed in an inert matrix (7). In solid dispersions, separate regions of drug and polymer exist throughout the matrix, and the drug may be crystalline or be rendered in its amorphous state. A special subset of solid dispersions, solid solution refers to the case in which drug-polymer miscibility is attained at the molecular level, and the drug exists in its amorphous form. Pharmaceutically acceptable polymers are ideal to create this matrix, due to the wide range in functionalities attained with polymer chemistries and molecular weights. Commonly used polymers include polyvinylpyrrolidones, polyvinylpyrrolidone-vinyl acetate copolymer, and the family of cellulosics (such as hypromellose and hypromellose phthalate). Polymer selection is based on many factors, including physicochemical (e.g., drug-polymer miscibility and stability) and pharmacokinetic (e.g., rate of absorption) constraints.