Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

 Improving bioavailability of poorly water-soluble drugs is an ongoing challenge for formulation scientists and is of crucial importance to advance clinically promising drug candidates. A 

Bioavailability Enhancement through Lipid-Based Drug Delivery

, will examine advances in lipid-based drug delivery systems for enhancing the bioavailability of absorption-limited small and large molecules.

		Strategies for addressing the challenges posed by these drugs will be discussed, such as designing formulations to maintain drug solubility, increase permeability, target lymphatic transport, bypass first pass metabolism, and mitigate food effects as well as 

methodologies that can be used to predict their 

 performance. Given that lipid-based drug-delivery systems are most often delivered orally using softgel technology, this webcast will also discuss the manufacture of softgels and recent advances in softgel technology, including the use of vegetable-based capsule systems.

		Among the panelists will be Anette Muellertz, PhD, Associate Professor and Head of Bioneer–FARMA, Danish Drug Development Center, the Faculty of Pharmaceutical Sciences (FARMA), University of Copenhagen, Denmark and head of the AAPS Lipid-Based Drug Delivery Systems Focus Group.

		The webcast will be held on Wed. June 20th at 10:00 AM EST and also will available for on-demand viewing. Additional information may be found

Articles

Improving bioavailability of poorly water-soluble drugs is an ongoing challenge for formulation scientists and is of crucial importance to advance clinically promising drug candidates.

As we enter the second half of 2012, the pharmaceutical majors are proceeding at a cautious pace. Facing patent expiries for certain key drugs, first-quarter 2012 sales either decreased or increased modestly for many of the large companies. Manufacturing investment proceeded at a measured pace, and companies made select bolt-on acquisitions to boost their pipelines.

For Pfizer, perhaps the most important development thus far in 2012 is the revenue loss as a result of the US patent expiry for its top-selling product, the anticholesterol product, Lipitor (atorvastatin), which lost US patent exclusivity in November 2011. For the first quarter of 2012, Pfizer’s US revenues declined 15% to $6 billion, and its global revenues declined 7% to $15.4 billion compared to the first quarter of 2011.  US branded sales of Lipitor decreased to $383 million in the first quarter of 2012 compared to $1.3 billion in the first quarter of 2011. 

 Other key developments in the first half of 2012 for Pfizer were the sale of its nutrition business to Nestlé for $11.85 billion. On the product front, the company received US approval for Inlyta (axitinib), a drug to treat patients with advanced kidney cancer. In its late-stage pipeline, Pfizer expects to have regulatory action in 2012 for three key drugs: Eliquis (apixaban), a drug to prevent strokes, which is being developed  with Bristol-Myers Squibb; tofacitinib, a drug to treat arthritis; and the anticancer drug bosutinib. The company also expects to have Phase III data for bapineuzumab, a drug to treat Alzheimer’s diseases in mid 2012.

 For Sanofi, key developments thus far in 2012 concern continued strength in emerging markets and regulatory approval of a new manufacturing facility of its subsidiary Genzyme in Framingham, Massachusetts. In the first quarter of 2012, Sanofi’s sales to emerging markets increased 9.9% to EUR 2.6 billion ($3.3 billion). Sales to BRIC (Brazil, Russia, India, and China) countries were EUR 917 million ($1.1 billion), up 16.5% year over year. Sanofi’s sales to emerging markets in the first quarter were slightly higher than its sales in the United States, which were EUR 2.6 million ($3.3 billion) and Western Europe, which were EUR 2.2 billion ($2.8 billion). Sales to the US increased 15.2% and declined 1.5% in Western Europe in the first quarter of 2012. 

On the manufacturing front, in May 2012, Sanofi inaugurated a new assembling and packaging line for producing its prefilled insulin injection pen Lantus SoloStar at its facility in Beijing. The company announced a second phase $90-million project to install a cartridge aseptic product line at the facility. The facility has a designed capacity of 48 million units. Sanofi also began production of  the enzyme-replacement therapy Fabrazyme (agalsidase beta) at its new facility in Framingham, Massachusetts, following approval of the facility by FDA and EMA in January 2012. In May 2012, EMA and FDA approved a second operation for fill–finish at Genyzme’s Waterford, Ireland, manufacturing plant, which nearly doubles capacity for fill–finish for Myozyme and Lumizyme (alglucosidase alfa) at the 4000-L scale. These developments follow a 2010 consent decree issued by FDA to Genzyme for manufacturing violations at its Allston, Massachusetts, facility and resulting requirements to transfer fill–finish production out of that facility. 

 In March 2012, GlaxoSmithKline (GSK) announced plans to invest more than £500 million ($798 million) in the United Kingdom across its manufacturing sites to increase production of key active ingredients for its pharmaceutical products and vaccines. The company announced selection of Ulverston in Cumbria as the location for the first new GSK manufacturing facility to be built in the UK in almost 40 years. Investment also will be made at the company’s two manufacturing sites in Scotland at Montrose and Irvine. 

GSK’s announcement followed plans by the UK government to implement a “patent box” to encourage investment in R&D and related manufacturing in the UK by introducing a lower rate of corporation tax on profits generated from UK-owned intellectual property. Following a feasibility study conducted through 2011, GSK said it will locate a new £350 million ($559 million) biopharmaceutical manufacturing facility in Ulverston, Cumbria. Detailed planning and design of the new facility is underway with an anticipated start date for construction of 2014–2015, dependent on portfolio timing and obtaining necessary planning and related consents. Once construction starts, it is likely to take at least six years before the plant is fully operational, according to GSK. 

GSK also announced in March that it is considering additional manufacturing investment at Ulverston which could double the total investment at the site to approximately £700 million ($1.1 billion). GSK also will invest more than £100 million ($160 million) in its two manufacturing sites in Scotland. This investment includes new funding at Montrose to enable the manufacture of key materials for GSK’s portfolio of respiratory medicines. Investment will also be made at Montrose to produce aluminum adjuvants used in the manufacture of vaccines. This investment will be the first time an UK GSK site will participate in the company’s vaccine-manufacturing supply chain. At Irvine, GSK will increase production capacity for antibiotics. GSK will also invest in sustainable green-energy production and environmentally friendly manufacturing technologies at both sites. The company is making other investments totaling £80 million ($128 million) at its sites in Ware in Hertfordshire to increase manufacturing capacity for its respiratory-inhalation device and at Barnard Castle in County Durham to establish a dermatology-manufacturing center of excellence. 

 On the acquisition front, GSK is proceeding with its unsolicited offer to acquire the biopharmaceutical company Human Genome Sciences for $2.6 billion. It also increased its stake in the biopharmaceutical company Theravance from 18.3% to 26.8%. The companies are partnered in developing long-acting beta

 agonists for treating asthma and other pulmonary diseases.

 Novartis saw its first quarter pharmaceutical revenues increase moderately by 2% to $7.8 billion, but sales in its consumer health business declined 20% to $932 million and by 10% to $2.1 billion in Sandoz, its generic-drug business. 

On the manufacturing side, Novartis said it is making progress for resolving quality-control issues at its consumer healthcare operations in Lincoln, Nebraska, and at three facilities of Sandoz. In December 2011, Novartis suspended production at is Lincoln manufacturing site in conjunction with a voluntary recall of all lots of select, bottle-packaged configurations of Excedrin, NoDoz, Bufferin, and Gas-X Prevention. The recall followed consumer complaints of chipped or broken pills and inconsistent bottle packaging-line clearance practices that could lead to stray tablets, capsules, or caplets from other Novartis products. In December 2011, FDA cited quality-control issues at three Sandoz  manufacturing facilities in Broomfield, Colorado; Wilson, North Carolina; and Boucherville, Canada. In its April 24, 2012, first-quarter earnings release, Novartis said that it is making progress in remediating the quality issues at the Lincoln site as well as the three Sandoz production sites. 

 In May 2012, in a move to bolster the generic-drug business of Sandoz, Novartis agreed to acquire the specialty dermatology generic-drug company Fougera Pharmaceuticals for $1.5 billion. Sandoz also is active in biosimilar development with three approved biosimilars: human growth hormone, epoetin alfa, and filgrastim. Sandoz also is developing generic versions of pegfilgrastim. It has three ongoing Phase III trials for biosimilars and eight to ten molecules at various stages of biosimilar development. 

AstraZeneca will begin the second half of 2012 with a new interim CEO following the retirement of David Brennan as CEO, effective June 1, 2012. Simon Lowth, formerly, chief financial officer, will serve as interim CEO beginning in June until a new successor can be found. In February 2012, AstraZeneca announced new restructuring initiatives aimed at delivering annual cost-savings of $1.6 billion by the end of 2014. The restructuring will reduce headcount by 7300. The job cuts include 1350 positions in supply-chain and manufacturing operations. R&D reductions will affect 2200 positions. Part of these reductions result from a new R&D model for its neuroscience research that will employ a virtual model using staff from its R&D facilities in Boston and Cambridge, England. As a result,  R&D activity at sites in Sodertalje, Sweden, and Montreal will end. In 2011, AstraZeneca reported a decline of nearly $2 billion in revenues resulting from generic-drug competition and a further $1 billion revenue decline due to government price interventions. It posted 2011 revenues of $33.6 billion. 

 In April, AstraZeneca agreed to acquire the biopharmaceutical company Ardea Biosciences for $1 billion (net of existing cash). Ardea is focused on small-molecule drug development. Its lead candidate is lesinurad, which is in Phase III development for treating gout. AstraZeneca also joined forces with Amgen to jointly develop and commercialize five monoclonal antibodies in Amgen’s clinical inflammation portfolio. 

 Roche’s first-quarter 2012 pharmaceutical sales increased modestly by 2% to CHF 8.6 billion ($8.95 billion). The company received US regulatory approval for Erivedge (vismodegib), an oral, once-a-day capsule for treating adults with basal cell carcinoma. It also received EU approval for Zelboraf (vemurafeni) for treating metastatic melanoma; the drug had received US approval in 2011. The company also received priority review from FDA for its biologics license application for pertuzumab, a monoclonal antibody, to be used in combination with Herceptin (trastuzumab) and docetaxel chemotherapy for people with HER2-positive metastatic or locally recurrent, unresectable breast cancer, who have not received previous treatment or whose disease has relapsed after adjuvant therapy. FDA is scheduled to take action later this month. 

 Merck & Co. reported a 3% gain in first-quarter 2012 sales for its pharmaceutical business. Strong performers included the company’s diabetes medicine, Januvia/Janumet (sitagliptin), which posted a 26% gain in sales to $1.3 billion, and sales to emerging markets. Sales from emerging markets accounted for 17% of the company’s first-quarter pharmaceutical sales, which included 19% growth in sales in China. Merck announced earlier this year that it plans to form a joint venture with the Brazilian pharmaceutical company Supera Farma Laboratorios. 

In other product developments, Merck received FDA approval for Janumet XR, an extended-release combination therapy consisting of sitagliptin and metformin hydrochloride. The company also plans to file a new drug application in 2012 for suvorexant, a dual orexin receptor antagonist for treating insomnia. And in April, Merck signed an agreement with the Endocyte to develop and commercialize the anticancer drug vintafolide. 

In May 2012, FDA approved Bristol-Myers Squibb’s biologics manufacturing facility in Devens, Massachusetts, for commercial production of the company’s arthritis drug Orencia (abatacept). The $750-million multiproduct bulk biologics manufacturing facility in Devens represents the largest capital project in the company's history. Also, Bristol-Myers Squibb acquired Inhibitex, a clinical-stage biopharmaceutical company in February 2012. The company’s lead compound is INX-189, a nucleotide polymerase inhibitor and antivral drug candidate in Phase II development.

 In the first-quarter of 2012, Eli Lilly reported a 4% decline in revenue to $5.6 billion, which was in part due to the loss of patent exclusivity for the antipsychotic drug Zyprexa (olanzapine).  In May, Eli Lilly announced the opening of a new diabetes R&D center in Shanghai. The center employs 150 scientists and staff hired primarily from China. Eli Lilly also is constructing a new insulin production, packaging, and warehouse facility in Suzhou, China, which is expected to open later this year. 

The key activity of the pharmaceutical majors influencing drug development and manufacturing thus far in 2012.

Big Pharma's Mid-Year Review

Drug-delivery approaches that better control and target delivery are important to achieve clinical efficacy. Several recent interesting approaches involve an improved method of delivery for needle-free injection systems, gold nanoparticles for targeting tumor sites, and elastic capsules using nanosized flakes. 

Researchers at the Massachusetts Institute of Technology (MIT) recently developed a jet-injection drug-delivery system based on a custom high-stroke Lorentz-force motor to mitigate some of the problems typically associated with controlling drug delivery through jet injection. The researchers noted that needle-free drug delivery by jet injection typically is achieved by ejecting a liquid drug through a narrow orifice at high pressure, thereby creating a fine high-speed fluid jet that can readily penetrate skin and tissue. The researchers assert that such injection systems use force- and pressure-generating principles that cause injection in an uncontrolled manner with limited ability to regulate delivery volume and injection depth. To address these shortcomings, the researchers developed a controllable jet injection device, based on a custom high-stroke linear Lorentz-force motor that is feed-back controlled during the time-course of an injection (1). 

The key part of the design is the Lorentz-force actuator, a magnet surrounded by a coil of wire that is attached to a piston inside a drug ampul, according to a May 24, 2012, MIT press release. When a current is applied, it interacts with the magnetic field to produce a force that pushes the piston forward, ejecting the drug at very high pressure and velocity out through the ampul’s nozzle. The speed of the coil and the velocity can be controlled by the amount of current applied. The resulting waveforms generally consist of two distinct phases: an initial high-pressure phase in which the device ejects drug at a high-enough velocity to breach the skin and reach the desired depth, then a lower-pressure phase where drug is delivered in a slower stream that can easily be absorbed by the surrounding tissue, according to the MIT press release.  Through testing, the group found that various skin types may require different waveforms to deliver adequate volumes of drugs to the desired depth. 

The team is also developing a version of the device for transdermal delivery of drugs ordinarily found in powdered form by programming the device to vibrate, turning powder into a fluidized form that can be delivered through the skin much like a liquid, according to MIT release. Such a powder-delivery vehicle may help mitigate the problems associated with needing a cold-chain system for delivering vaccines and other biopharmaceuticals. 

Researchers at the University of Sydney in Australia, led by Nial Wheate, senior lecturer in the Faculty of Pharmacy, and researchers from the University of Strathclyde and the University of Glasgow in Scotland recently reported on delivering the anticancer drug cisplatin using gold-coated iron oxide nanoparticles for enhanced tumor targeting (2). The researchers used this approach to overcome some challenges of cisplatin, namely poor bioavailability, severe dose-limiting side effects, and rapid development of drug resistance (2). The iron oxide core was coated in a protective layer of gold before the anticancer drug cisplatin was attached to the gold coating using spaghetti-like strings of polymer, according to a May 31, University of Sydney press release. 

"When we take regular medication, it is difficult to manage where it goes,” said Wheate, in the release. “But this discovery means we can potentially direct exactly where in the human body a drug goes. We can move it to the desired cancer tumor site using powerful magnetic fields. Otherwise, a strong magnet could be implanted into a tumor and draw the drug into the cancer cells that way." The technology was demonstrated when the team grew cancer cells in plates. When they placed a magnet under the plates, the drug affected and killed only those cells growing near the magnet, leaving the others unharmed, The potential benefit of this targeted drug- delivery method is reduction of side-effects due to the chemotherapeutic drug traveling to other cells. 

The iron oxide nanoparticles (FeNPs) were synthesised via a coprecipitation method before gold was reduced onto its surface (Au@FeNPs). Aquated cisplatin was used to attach {Pt(NH

} to the nanoparticles by a thiolated polyethylene glycol linker forming the desired product (Pt@Au@FeNP). The nanoparticles were characterized by dynamic light scattering, scanning transmission electron microscopy, UV visible spectrophotometry, inductively coupled plasma mass spectrometry, and electron probe microanalysis. Nanoparticle drug loading was found to be 7.9 × 10

 moles of platinum per gram of gold. External magnets were used to show that the nanoparticles could be accumulated in specific regions and that cell-growth inhibition was localized to those areas (2). 

Researchers at the National Institute for Material Science in Japan recently developed a new elastic capsule using an inorganic nanometer-thickness flake-shaped material (nanosheets). Tests of the new capsule demonstrated that the release duration of anticancer drugs and other drugs can be controlled freely and can also be extended by several times by using the newly developed capsule. 

The researchers were seeking to overcome some of the challenges of  inorganic and organic materials conventionally used in capsules, according to a May 9, 2012, press release of the National Institute for Material Science. Inorganic capsules are hard, strong, and durable, but their structures are not easily adjusted to adapt to conditions.  Organic capsules are flexible and structural adjustment is possible, but they have the drawback of low mechanical strength. Thus, the development of a drug-carrier capsule structure with the advantages of both types has been desired. 

 In this research, a soft capsule was developed by creating an assembly of nanosheets of silica, which is an inorganic material. While this capsule consists of a mechanically stable inorganic material, free control of its structure is also possible.

This capsule expands and contracts when heated and cooled, and the size of the pores in the outer wall, which are formed by the spaces between the nanosheets and serve as passages for drug release, can be controlled over a wide range by adjusting pH to various levels, according to the press release. As a result, the sustained-release time of the anticancer drug DOX was successfully extended by several times in comparison with conventional porous capsules having a simple structure. It was also possible to control the drug-release duration and drug-storage amount by changing the pore structure of the capsule, thereby changing the drug-release routes under appropriate pH conditions.

1. A. Taberner, N.C. Hogan, and I.W. Hunter, “Needle-free Jet Injection Using Real-time Controlled Linear Lorentz-Force Actuators, 

, online, DOI/10.1016/j.medengphy.2011.12.010, Jan. 13, 2012. 

2. N. Wheate et al., “Cisplatin Drug Delivery Using Gold-Coated Iron Oxide Nanoparticles for Enhanced Tumor Targeting with External Magnetic Fields,” 

 online, DOI10.1016/j.ica.2012.05.012, May 30, 2012. 

 3. Q. Ji et al.,"Flake-Shell Capsules: Adjustable Inorganic Structures," 

, online, DOI: 10.1002/chin.201223201, May 7, 2012. 

Needle-free jet injection systems, gold-coated nanoparticles, and elastic capsules with nanosized flakes advance targeted drug delivery.

Technical Insights: Targeted Drug Delivery

Financing into the life-sciences industry is an important barometer of the health of the industry, particularly for small and emerging biotechnology companies, which are a key part of drug-development activity. In looking at the first five months of 2012, funding into the global and US-based life-sciences industry shows mixed results as global private financing made strong gains, but global public financing declined. 

Venture-capital funding is the strong spot in biotechnology financing. During the first five months of 2012, global biotechnology venture-capital financing was nearly $4.9 billion, up 29.6% from a year ago, according to an analysis by Burrill & Company. US venture-capital funding increased to nearly $3.5 billion through the end of May, a 27.5% increase over the same period last year. 

While venture-capital funding was robust, public biotechnology financing is dragging thus far in 2012. Overall global public financing for life-sciences companies declined 34.9% to $23 billion for the first five months of 2012, according to the Burrill & Company analysis. US public financing, however, was up 9.9% to $15.3 billion for the first five months of 2012. 

Initial public offerings (IPOs) in the life sciences also are down in 2012 compared to 2011. “The IPO market for life-sciences companies continues to be challenging,” said G. Steven Burrill, CEO of Burrill & Company, in a June 1, 2012, press release. “Anyone who was hoping for a lift from the Facebook IPO or improving economic news out of Europe can forget about that.”

For the first five months of 2012, there have been 17 global biotechnology-based IPOs, down from 28 during the same period last year. The 17 IPOs thus far in 2012 have raised $1.15 billion, down 58.2% from the nearly $2.8 billion raised in the year-ago period, according to the Burrill and Company analysis. A similar weak IPO front has hit the US biotechnology industry. Through the first five months of 2012, there were eight IPOs in the US biotechnology industry, down from 11 in the same period in 2011. The eight IPOs raised $549 million, a nearly 40% decline from the $911 million raised in the 11 IPOs through the first five months of 2011, according to the Burrill & Company analysis. 

In looking at other forms of public financing, private investments in public equity (PIPEs) were up on a global basis but declined in the US for the first five months of 2012. Global PIPEs increased 135.6% to nearly $3.2 billion through the end of May, but US PIPEs declined 7.2% to $666 million. Global follow-on offerings declined 55% to $2.7 billion, and US follow-ons increased modestly, by 4.2% to nearly $2.6 billion, according to the Burrill & Company analysis.

 Global debt offerings in the life-sciences decreased both globally and in the United States. Global debt offerings declined 64.8% to $7.9 billion, and US debt offerings decreased 44.4% to $5.0 billion. Other debt instruments in the life sciences, however, increased both globally and in the US. On a global basis, other forms of debt increased 212.6% to $7.2 billion and by 678.8% to $5.8 billion in the US.

Funding raised from corporate partnering deals between life-sciences and bio/pharmaceutical companies also declined in the first five months of 2012. On a global basis, funding from partnering deals declined 18.4% to $12.5 billion through the end of May, according to the Burrill & Company analysis. US-based partnering/licensing deals also fell, declining by 37.1% to $6.95 billion. In May, partnering deals accounted for just $432 million, the lowest level of activity since Burrill and Company began tracking this data monthly in 2009. “...The lack of traditional alliances announced during the month is concerning since these agreements play such a critical role in funding development of the biotech industry’s most promising products,” said G. Steven Burrill in the June 1 press release. 

Although traditional alliances between companies are down in 2012, there has been a recent uptick in partnerships between pharmaceutical companies, academia, nonprofit organizations, and government. In May alone, 15 such agreements were announced, according to Burrill & Company. Among the most significant of corporate–academic partnerships in May was the $285 million collaboration among five European pharmaceutical companies (GlaxoSmithKline, AstraZeneca, Sanofi, Janssen, and Basilea Pharmaceutica) and academic institutions for drug-resistant antibiotics. 

 Another important deal in the US was an agreement between Pfizer, Eli Lilly, AstraZeneca, and the National Institutes of Health’s National Clinical and Translational Sciences program for grants to fund preclinical and clinical feasibility studies for new uses of more than 20 compounds that had been previously abandoned. The initiative, Discovering New Therapeutic Uses for Existing Molecules, will direct researchers’ attention to a part of the therapeutic pipeline that traditionally has been difficult for them to access: compounds that already have cleared several key steps in the development process, including safety testing in humans. Approximately $20 million will be provided to support research grants of up to three years for preclinical and clinical feasibility studies.  These studies will test more than 20 compounds from industry partners for their effectiveness against a variety of diseases and conditions. The companies will provide the researchers with access to the compounds and related data.

Venture-capital funding is up in 2012, but public financing remains sluggish in the biopharmaceutical industry.

An Uneven Path for Biotech Financing

Catalysis plays a crucial role in the synthesis of pharmaceutical intermediates and APIs. Catalysts can enable more efficient chemical transformations, improve reaction conditions, better product yields, and produce greater enantioselectivity. Some key recent developments involve palladium-catalyzed hydrogenation, visible-light photocatalysis, chemocatalytic approaches for making heterocyclic compounds, and advances in biocatalysis.  

Palladium-catalyzed hydrogenation reactions are important in industrial chemistry and fine-chemicals manufacture, but precious metal catalysts, such as palladium, are costly. Researchers at Tufts University's School of Arts and Sciences and School of Engineering in Medford, Massachusetts, recently reported on the arrangement of individual atoms in a metal alloy and their ability to catalyze hydrogenation reactions.  

Hydrogenation requires the presence of a catalyst, usually a metal or an alloy of both precious and common metals, which allows the hydrogen atoms to bind with other molecules. It is difficult to produce alloys that are selective hydrogenation catalysts and are able to attach the hydrogen atoms to specific sites of another molecule. Tufts chemists and chemical engineers reported that when single atoms of palladium were added to copper, which is much cheaper and readily available, the resulting "single atom alloy" became active and selective for hydrogenation reactions, according to a Mar. 9, 2012, Tufts University press release.   

NICHOLAS EVELEIGH/STOCKBYTE/GETTY IMAGES 

The Tufts scientists scattered single atoms of palladium less than half a nanometer wide onto a copper support. For this research, the Tufts team heated small amounts of palladium to almost 1000 °C. At that temperature, individual atoms embedded themselves on the copper surface. A scanning tunneling microscope enabled the team to see how these single atoms dispersed in the copper and how molecular hydrogen could then dissociate at individual, isolated palladium sites and spill over onto the copper surface layer, according to the Tufts release. 

Specifically, the researchers used desorption measurements in combination with high-resolution scanning tunneling microscopy to show that the individual, isolated palladium atoms in a copper surface substantially lowered the energy barrier to both hydrogen uptake on and subsequent desorption from the copper metal surface. The hydrogen dissociation at the palladium atom sites and weak binding to copper allowed for very selective hydrogenation of styrene and acetylene as compared with pure copper or palladium metal alone (1). 

A team of University of Arkansas (US) researchers reported on using visible-light photocatalysis with a ruthenium catalyst to produce a building block in pharmaceutical synthesis. Specifically, the researchers reported on a visible-light-mediated intermolecular [3+2] cycloaddition of mono- and bicyclic cyclopropylamines with olefins catalyzed by [Ru(bpz)

O to produce aminocyclopentane derivatives in good yields. Saturated 5,5- and 6,5-fused heterocycles were obtained in synthetically useful yields and diastereoselectivity (2). 

Heterocyclic compounds are important in pharmaceutical applications, and researchers at the California Institute of Technology (Caltech) recently reported on an advance in the synthesis of such compounds. They reported on their work in the enantioselective construction of quaternary 

-heterocycles by palladium-catalyzed decarboxylative allylic alkylation of lactams (3).  

"We think it's going to be a highly enabling reaction, not only for preparing complex natural products, but also for making pharmaceutical substances that include components that were previously very challenging to make," said Brian Stoltz, professor of chemistry at Caltech, in a Jan. 13, 2012, university press release. "This has suddenly made them quite easy to make, and it should allow medicinal chemists to access levels of complexity they couldn't previously access. 

Specifically, the researchers reported on the highly enantioselective palladium-catalyzed decarboxylative allylic alkylation of lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams,  and structurally related lactams. The researchers assert that the synthesis provides a new approach for the asymmetric synthesis of such structures, an important development given the prevalence of quaternary 

-heterocycles in biologically active alkaloids and pharmaceutical agents. The researchers reported that the catalysis provided enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the 

 alkaloids, quebrachamine and rhazinilam, but that were previously produced by chiral auxiliary approaches or as racemic mixtures (3). 

Codexis, a biocatalysis company, reported last month on its work with Merck & Co. for developing an enzyme-based production method for a key intermediate in the production of boceprevir, the API in Merck's Victrelis, a drug to treat hepatitis C. The companies reported on a chemoenzymatic process for manufacturing the boceprevir bicyclic proline intermediate based on amine oxidase-catalyzed desymmetrization. The key structural feature in boceprevir is the bicyclic proline moiety, which during development stages, was produced by a classical resolution. As the drug candidate advanced, Codexis and Schering–Plough (now Merck) jointly developed a chemoenzymatic asymmetric synthesis where the net reaction was an oxidative Strecker reaction. The key part of the reaction sequence is an enzymatic oxidative desymmetrization of a prochiral amine substrate (4).  

According to Codexis, the new method increased chemical intermediate yield 150% over the previous process. It also reduced raw material use by 60%, water use by 61%, and overall process waste by 63%. Codexis used its proprietary CodeEvolver directed evolution technology to develop the custom enzyme for use in the commercial-scale manufacturing of the boceprevir intermediate. 

Codexis had earlier partnered with Merck & Co. for another biocatalytic route. In 2010, Merck and Codexis reported on the biocatalytic asymmetric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the API in Merck's antidiabetes drug Januvia. The biocatalytic process replaced a rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of sitagliptin. The researchers started from an (

)-selective transaminase that showed slight activity on a smaller truncated methyl ketone analogue of the sitagliptin ketone. After creating this transaminase, which had marginal activity for the synthesis of the chiral amine, they further engineered the enzyme through directed evolution to optimize its use for large-scale manufacturing (5–8). 

)-selective transaminase was a homologue of an enzyme from 

)-specific transamination of methyl ketones and small cyclic ketones. For the sitagliptin synthesis, the researchers generated a structural homology model of this transaminase and found that the enzyme would not bind to the prositagliptin ketone because of steric interference and potentially undesired interactions. The evolved transaminase was a successful biocatalyst that synthesized the chiral amines that previously were accessible only through resolution (5–8). 

Codexis and Merck were recognized in 2010 with an Environmental Protection Agency's Presidential Green Chemistry Challenge Award, an annual recognition of advances in green chemistry. Codexis also submitted for consideration in 2010 and 2011 a biocatalytic route for making simvastatin, the active ingredient in Merck & Co.'s anticholesterol drug Zocor, which is now off patent (5, 8, 9). 

For the simvastatin route, Codexis licensed technology from Yi Tang, professor in the Department of Chemical and Biomolecular Engineering at the University of California at Los Angeles. The previous synthetic routes to simvastatin involved converting lovastatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthesis. In the first route, lovastatin was hydrolyzed to the triol, monacolin J, followed by protection with selective silylation, esterification with dimethyl butyryl chloride, and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2' carbon with methyl iodide, and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were mass-intensive due to protection and deprotection (5, 8). 

The route developed by Tang and his group circumvented protection and deprotection and resulted in greater atom economy, reduced waste, and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase produced by 

 that is involved in synthesizing lovastatin and that can accept nonnatural acyl donors. Recognizing that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (5, 8–10). Codexis licensed Tang's technology, engineered the enzyme further, and optimized the process for pilot-scale simvastatin manufacture.  

Codexis is an example of a firm specializing in biocatalysis. Another is evocatal GmbH, which was founded in 2006 as a spin-off of the Institute for Molecular Enzyme Technology at the University of Düsseldorf in the Research Center Jülich. Last November, evocatal issued a carbon–carbon coupling kit using thiamine pyrophosphate-dependent (TPP) enzymes to produce enantiopure 2-hydroxy-ketones, an important intermediate class for pharmaceutical syntheses. The kit includes seven different TPP-enzymes with the relevant cofactor.  

 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, 

8 EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2010 Award Entries and Recipients" (Washington, DC, 2010). 

9. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2011 Award Entries and Recipients" (Washington, DC, 2011). 

Advances in palladium-catalyzed hydrogenation, visible-light photocatalysis, and chemocatalyisis for heterocycles are some recent developments.

Seeking Chemocatalytic and Biocatalytic Solutions

The Sixty-fifth World Health Assembly adopted 21 resolutions and three decisions on a broad range of health issues. The six days of discussions, held last month, involved nearly 3000 delegates, including health ministers and senior health officials from the 194 member states of the World Health Organization (WHO) as well as representatives from civil society and other stakeholders.

“As challenges, let me mention noncommunicable diseases and ageing, maternal and child health, under- and over- nutrition, the eradication of polio, and health demands during humanitarian emergencies,” said Margaret Chan, WHO Director-General, in a May 26, 2012, WHO press release. Chan also was re-appointed to a second five-year term as WHO Director-General. “As opportunities, let me mention immunization, and the decade of vaccines, and the new multisectoral strategies made possible when we take a social determinants approach.” At the meeting, delegates expressed broad acceptance of the proposed five categories: communicable diseases, noncommunicable diseases, health through the life-course, health systems, and preparedness, surveillance, and response, according to the WHO release.

 Member states endorsed the report on the progress and achievements of the health-related United Nations’ Millennium Development Goals (MDG) and health goals after 2015. While the pace of progress has accelerated in many member states, it was also acknowledged that more still needs to be done in the remaining three years to achieve the goals, according to the WHO release. A second report on The Commission on Information and Accountability for Women’s and Children’s Health, established at the request of the United Nations Secretary-General in the context of the Global Strategy for Women’s and Children’s Health, presented 10 recommendations to improve accountability in countries and globally. The focus is on the 75 countries, which together account for more than 95% of all maternal and child deaths in the world. Many countries and global partners have made specific commitments to accelerate action toward the achievement of MDG 4 (reduce child mortality) and MDG 5 (improve maternal health). 

 The Health Assembly adopted several resolutions and decisions on noncommunicable diseases (NCDs). Delegates approved the development of a global monitoring framework for the prevention and control of NCDs, including indicators and a set of global targets. Member states agreed to adopt a global target of a 25% reduction in premature mortality from NCDs, such as cardiovascular disease, cancer, diabetes, and chronic respiratory diseases, by 2025.

Another resolution focuses on strengthening NCD policies to promote active ageing. The resolution urges member states to encourage the active participation of older people in society, increase healthy ageing, and promote the highest standard of health and well-being for older persons by addressing their needs.

The building of partnerships at national and global levels was discussed by member states as an  important way to prevent NCDs through action involving other sectors than health to prevent premature deaths and to reduce exposure to risk factors for NCDs, mainly tobacco use, harmful use of alcohol, unhealthy diet, and physical inactivity. Delegates also received a report on the progress of the implementation of the global action plan for the prevention of avoidable blindness and visual impairment. 

Member states acknowledged that the pandemic influenza preparedness framework is a crucial development for global health security, based on the lessons from the 2009 influenza pandemic. Delegates recognized that industry and other partners play important roles in the development of vaccines to counter outbreaks.Delegates agreed on a 70% and 30% share of resources between preparedness and response respectively, but that this would be regularly reviewed. They welcomed the role of the framework’s advisory group, but stressed the need for extra resources – both human and financial – to support WHO capacity and leadership, according to the WHO release

 The Health Assembly also acknowledged the report of the Consultative Expert Working Group on Research and Development: Financing and Coordination containing recommendations for securing new funds for health research and development on diseases that affect people in developing countries. It adopted a resolution to hold member states’ consultations at national, regional, and global levels to analyze the report and the feasibility of the recommendations.

Delegates also approved a draft resolution on a new member state mechanism proposing international cooperation on substandard, spurious, falsely labeled, falsified or counterfeit (SSFFC) medical products. Many countries stressed the need for strengthening regulatory authorities and the important role that WHO plays in enhancing regional and international networking among the regulators. Emerging channels of distribution such as Internet sales pose a significant threat and require specific solutions. Representatives of nongovernmental organizations and the pharmaceutical sector expressed their support for the mechanism, according to the WHO release. 

The pharmaceutical industry weighs in on WHO global health initiatives, including R&D for diseases of the developing world, a global vaccine action plan, neglected tropical diseases, and counterfeit medicines.