Innovations in Pharma Science

Pharmaceutical Technology is pleased to recognize the winners of its Innovations in Pharma Science Awards. These awards honor achievements in drug delivery, formulation, dosage-form manufacturing, pharmaceutical analysis, and the synthesis and manufacturing of active ingredients. We received 20 nominations, based on original research or already published work, from companies around the world. Fourteen members of our Editorial Advisory Board reviewed the nominations to determine the winners, showcased here.

Orally therapeutic proteins

Created by Lila Drittanti, Fernanda Sanchez, Thierry Guyon, Sophie Guillier, Mathilde Breton, and Manuel Vega

Nautilus Biotech SA (Evry, France)

Nautilus scientists adopted a strategy using protein engineering technology to create a "third generation" of protein drugs. Using a patented proprietary systematic approach, the team designed specific point mutations to protect therapeutic protein molecules from degradation by a wide range of proteases. In most cases, a single point mutation is enough to confer high resistance to proteolysis even though biological activity is not affected; Nautilus used this fact to design variants that are highly protected in vivo in skin, blood, and other fluids. These molecules degrade slower than the corresponding native proteins in the intestinal tract and can be readily absorbed into the blood.

(COURTESY OF NAUTILUS BIOTECH SA)

The proteins can be administered orally in the form of a lyophilized powder, which can be filled into gastro-resistant capsules or used to make tablets. Nautilus developed a product pipeline around this innovation since 2002 that includes two orally available versions of Belerofon, a novel form of interferon alpha, and Vitatropin, a single point mutation of native human growth hormone. Both are designed for higher resistance to proteolysis in blood and other tissues. Nautilus is exploring additional routes of delivery (sublingual, buccal, and nasal).

Nautilus' protease–resistant proteins are intrinsically bioavailable when delivered orally, thereby providing for better patient compliance. The US Food and Drug Administration approved the company's investigational new drug application (IND) for the oral administration of Belerofon in a Phase I clinical trial; an IND for Vitatropin is underway.

Intravail macromolecular absorption enhancers

Created by Dennis J. Pillion and Eli Meezan

Pharmacology & Toxicology, University of Alabama (Birmingham, AL) & Aegis Therapeutics (San Diego, CA)

Peptide and protein drugs are among the most selective, potent, and effective drugs but their susceptibility to denaturation, hydrolysis, and poor absorption, makes them unsuitable for oral administration. Professors Pillion and Meezan developed a new class of patented alkylsaccharide transmucosal delivery-enhancement agents, collectively designated as "Intravail" absorption enhancers. Intravail excipients provide unsurpassed intranasal, buccal, and oral bioavailabilities, often comparable to those achieved by injection, for protein, peptide, and other macromolecular therapeutics. They circumvent the two primary limitations of intranasal drug delivery (mucosal irritation and poor bioavailability) and offer more convenient, effective, and safe therapeutics.

(COURTESY OF AEGIS THERAPEUTICS)

Intravail excipients also provide controlled transient permeation of the mucosal barrier by both the paracellular and transcellular routes. In intranasal administration, they speed onset of action. Nasal delivery also circumvents "first-pass" metabolism in the liver. The technology has been demonstrated to work in human and animal studies with more than 20 drugs. Intravail formulations can be administered using off-the-shelf metered nasal spray pumps.

Solid complexes with ionic polymers

Created by Navnit Shah, Harpreet Sandhu, Wantanee Phuapradit, Raman Iyer, Anthony Albano, D. Desai, Duk Choi, Kin Tang, Hung Tian, Hitesh Chokshi, Zenaida Go, Waseem Malick, Roumen Radinov, Ashish Shankar, Steven Wolff, and Hans Mair

Hoffmann-LaRoche (Nutley, NJ)

Poor solubility and bioavailability present significant hurdles for the optimal oral delivery of compounds. Roche scientists were faced with one such compound having excellent in vitro potency but very low oral bioavailability. A team of Roche scientists discovered novel approaches to converting a crystalline drug into its amorphous form and simultaneously embedding it in an ionic polymer to immobilize the amorphous molecules and prevent nucleation, thus stabilizing the amorphous form. The selection of an ionic polymer along with an innovative process created a stable amorphous form that provided desirable pharmacokinetic profile of the drug. The pharmacokinetic profile produced not only the desired efficacy but also improved the safety margin by reducing side effects. Overall, the drug is precipitated in an ionic polymer in an amorphous form (microprecipitated bulk powder, MBP) at the nano-size or molecular level, thus enhancing its bioavailability (10- to 20-fold higher compared with micronized form of the drug). The stabilization of the amorphous form is imparted by the ionic nature of the polymer due to its high molecular weight and high-glass transition temperature. This technology was scaled-up and is being used for Phase I– II clinical studies of several Biopharmaceutical Classification System Class 2 (low solubility and high permeability) and Class 4 (low solubility and low permeability) compounds (see manufacturing process above). Several technology patents have been issued, and some are pending.

(COURTESY OF HOFFMAN-LAROCHE)

HONORABLE MENTIONS

Raltegravir API process design

Created by Guy Humphrey and Ross Miller

Process Research, Merck Research Laboratories (Rahway, NJ)

Approved in the United States in October 2007, "Isentress" (raltegravir) is a first-in-class HIV integrase inhibitor for the treatment of HIV/AIDS. While the first-generation process for making the active pharmaceutical ingredient (API) provided a reliable method to support the launch of raltegravir, a more productive and greener process was required for long-term manufacturing purposes. Merck chemists redesigned the original process, culminating in a vastly more efficient process. Key features include a highly innovative N-methylation step in which an initial mixture of N- and O-methylated products are funneled to the desired product; a 1.6-fold increase in overall yield (83% versus 52%); and a >3-fold increase in productivity, resulting in reduced waste byproducts of 253 kg per kg of API of raltegravir, as well as elimination of hazardous methyl iodide. This process recently has been implemented at manufacturing scale.

(COURTESY OF ABBOTT LABORATORIES)

Dual-variable domain immunoglobulin (DVD-Ig)

Created by Chengbin Wu and Tariq Ghayur

Biologics, Abbott Laboratories (Abbott Park, IL)

Targeting a single-disease mediator with a traditional monoclonal antibody (mAb) can result in limited efficacy or partial response. Preclinical studies in disease models demonstrated that targeting two or more disease mechanisms is far more effective than targeting a single mechanism, potentially due to the additive or synergistic effect of the dual-targeting strategy. Combining large molecules in the past has been a significant challenge because multi-specificity-based mAbs had poor pharmacokinetics, stability, and manufacturing feasibility. The dual-variable domain immunoglobulin (DVD-Ig) platform, discovered by Abbott scientists, is the first technology to successfully combine the function and specificity of two or more mAbs into one molecule, thereby creating a combination therapy in a single drug. The DVD-Ig approach has distinct technological and scientific advantages compared to mAbs. The technology enables the development of new generation biologics that target multiple disease mediators simultaneously, while displaying excellent drug-like properties and manufacturing efficiency. The approach allows for the creation of new, improved biologic medicines for complex diseases such as cancer and autoimmune diseases.

(COURTESY OF MERCK RESEARCH LABORATORIES)