Down the Track: Different Speeds with Multiple APIs - Pharmaceutical Technology

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Down the Track: Different Speeds with Multiple APIs
Formulators and manufacturers have many options for modifying release profiles in multiple-API products.

Pharmaceutical Technology
Volume 33, Issue 7, pp. 34-40


Figure 1: Engineering biopolymers as coatings, implants, or particles enables active ingredients to be delivered at various rates. (IMAGE IS COURTESY OF MEDIVAS)
By including well-characterized polymers in a formulation, scientists can control the release of multidrug dosage forms. Chih-Chang Chu, professor of fiber science and biomedical engineering at Cornell University, and Ramaz Katsarava, head of the Center for Medical Polymers and Biomaterials at the Technical University of Tbilisi, Georgia, invented an architecture that generates families of synthetic, biodegradable polymers. Using the architecture, the scientists developed an amino-acid-based, synthetic, biodegradable polyester amide (PEA) (see Figures 1, 2). MediVas (San Diego, CA) licensed the technology from Cornell and is using it for its oncology vaccine, which contains two antigens.

Figure 2: Scanning electron microscopic image of synthetic biodegradable saturated polyester amide fabricated at a homogenizer speed of 20k rpm. (IMAGE IS COURTESY OF C.C. CHU)
The family of PEAs and their biodegradation products (i.e., amino acids, diols, and diacids) are biocompatible with various cells and tissues, says William Turnell, senior vice-president and chief scientific officer of MediVas. The PEA is synthesized from scratch without animal materials that could carry pathogens. They cause no inflammation or immune response, regardless of whether they are engineered as a nanoparticle, hydrogel, fiber, or other form.

Scientists can change the PEA's physical and mechanical properties such as glass-transition temperature and hydrophobicity to suit the drug, says Turnell. The PEA can be engineered into forms such as hydrogels, gels, microspheres, and fibrous membranes, each of which provides a unique release profile.

The material can deliver small-molecule drugs, large-molecule drugs, and combinations of the two, says Turnell. Enzymes degrade PEA materials from the surface and work their way in, so PEAs maintain their structure better than commercial, absorbable materials such as polylactide or polyglycolide that undergo bulk degradation. PEA dissolves more like a jawbreaker than a sugarcube, which allows it to provide uniform, sustained release of drugs, says Kenneth Carpenter, the company's CEO. But scientists can engineer the PEA with separate layers of fibrous membrane or distinct types of nanospheres to carry various drugs with different release profiles.

Although this family of materials behaves like a protein in some respects and like a synthetic polyester in others, it is neither of those things, says Chu. The PEA consists of three building blocks—an amino acid, an alcohol, and carboxylic acid. By changing the building blocks, scientists can create various family members of PEA with properties adapted to specific clinical uses, including oral, transdermal, parenteral, and intranasal drugs.

To accommodate multiple APIs, scientists can engineer a PEA with several layers of fibrous membrane, and each layer can incorporate a separate drug. Another option would be to engineer the PEA into micro- or nanoparticles. A matrix could include several types of particles, each of which could carry a different drug.

Several members of the PEA family can be shaped into various forms in an aqueous environment, which eliminates the need for organic solvents that could cause toxic effects or denature protein-based drugs. MediVas developed the ability to add protein drugs to the PEA form in an aqueous environment, says Carpenter. This technique provides further protection to protein drugs' structure.

In addition, Turnell designed a system for adding proteins onto the PEA structure using a cation to create a self-forming nanoparticle for vaccines. The nanoparticles can then be lyophilized safely because the PEA protects the protein from becoming denatured. This process enables the production of vaccines that can be shipped and stored at ambient temperatures.

Although polymers typically do not interact with the drug, they may raise formulation concerns, depending on the administration route. "The biggest thing you have to worry about is the accumulation of a polymer," says Frank L. Sorgi, vice-president of research and development at DPT Laboratories (San Antonio, TX). "The body must have some mechanism to eliminate it. When you take the drug orally, it's not a big deal, because it just flushes through. If you're inhaling the drug, then the body must have a natural mechanism that will clear the polymer from the lung, otherwise you run the risk of accumulation of the byproducts of your delivery system that remain in the lung. That is the big issue." For this reason, biodegradable polymers are of increasing interest.

Regulatory approval for multiple-API drugs may present its own concerns. "When you have multiple APIs and multiple polymers, you run into trouble sometimes because there are more variables," says Sorgi. "When you make combination API products, you have to look at it in pieces. Typically, you have to show superiority over just taking three tablets. And you run the risk that one drug may affect the stability of another drug. It may cause it to degrade or have multiple effects."

For suspensions, usually formulators will bind a drug to a resin, and the degradation of the matrix over time controls the release. Multivitamins in suspension are one example of formulations that include more than one active ingredient. Multiple APIs are created in the same way. "Again, however, it gets to be more challenging the more APIs you put in suspension," says Sorgi.


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