A team of researchers led by Gérard Férey, professor of the Institut Lavoisier de Versailles at the Université de Versailles Saint–Quentin en Yvelines, and researchers from the Université Paris–Sud, reported on the use of porous hybrid crystalline solids (MILs for Materials Institut Lavoisier) as nanocarriers for drug delivery and imaging applications. One of the challenges found with existing nanocarriers is that they show poor drug loading (usually less than 5% of the transported drug versus the carrier material). They also release the drug too quickly, causing the drug to be adsorbed at the external surface of the nanocarrier (1).

To resolve that challenge, the researchers used nanocarriers based on a porous iron (III)-based metal–organic framework for delivering several drugs: busulfan, azidothymidine triphosphate, doxorubicine, and cidofovir. The hybrid crystalline solids with the inorganic–metal framework allowed for greater flexibility in the structure and porosity to improve drug interactions and drug loading. Drug loading improved up to 40% by weight, and the release time increased as well, according to a press release by the Le Centre National de la Recherche Scientifique (National Center for Scientific Research), a French government-funded research organization. Additionally, the activity of the MIL-based nanocarriers may allow for medical imaging and the tracking of the drugs to the target, thereby potentially opening the way for their application in theranostics

Interestedly, MILs are also being explored in environmental applications such as a vehicle for carbon dioxide sequesteration. The metal–organic framework of the MILs creates cages and channels that permit the storage of large molecules, such as drug molecules, as well as the capture of other molecules, such as carbon dioxde. The organic–inorganic framework of the MILs creates flexibility in the structure, allowing it to be responsive to external conditions such as temperature and pressure, according to a recent press release by the European Synchrotron Radiation Facility, which conducted research with the Institut Lavoisier de Versailles in this area.

Nanotechnology offers great promise in many scientific areas, including drug delivery, and it is interesting to see how nanoporous materials are being explored in this application.

Reference
1. P. Horcajada, Nature Materials, Dec. 13, 2009, online DOI:10.1038/nmat2608.

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The researchers created micrometer-sized capsules by wrapping metabolism-resistant material around spherical particles that they later dissolved in acid. The scientists filled the empty capsules by heating them in a solution that contained the drug compound. Heat made the capsules shrink, thereby trapping the drug inside. These capsules can be inserted into live cells through electroporation (i.e., the administration of a small electric shock).

In one experiment, the researchers exposed capsules to an infrared laser beam. The laser changed the structure of nanogold particles in the capsule and released drug into the host cell, which was unaffected by the laser beam. The capsules could also be made to release drug in response to a biological trigger such as a drop in blood sugar.

The researchers said that their technique could deliver DNA for gene therapy or insulin to manage diabetes. I imagine that it might also deliver small molecules. The capsules can be designed to be stable in the body to protect drugs that are easily degraded and store them for later use.

Like the magnetite nanoparticles, the micrometer-sized capsules are not ready for use in humans, but they seem full of possibility. To some patients, administration through electroporation might be more palatable than that through injection. This delivery method could enable various release profiles and might be appropriate for acute and chronic conditions.

Developments such as this are encouraging reminders of researchers’ ingenuity. One day, drugmakers and patients alike might benefit from this work.

The team encapsulated a drug in a specially engineered membrane that included magnetite nanoparticles. If you’re not up on your rocks, magnetite is a mineral that has magnetic properties. When a magnetic field is turned on outside the patient’s body, the magnetite nanoparticles heat up and collapse some of the gels in the membrane. This structural change opens pores that allows the drug to be delivered into the body within about one or two minutes. When the magnetic field is turned off, the nanoparticles cool, the gels reeexpand, and drug delivery is halted.

Aside from being totally cool, this drug-delivery method has several advantages. For starters, it doesn’t require any electronics to be implanted in the patient’s body. The membranes have not shown any toxicity or immunogenicity in studies. The gels would not collapse under normal body temperatures, or even fevers. And the method could potentially provide precise, repeated, long-term delivery of drugs on demand. It could be a good system for drugs that manage chronic pain, for example.

The magnetite-nanoparticle system is not yet ready for use in humans, but the research shows how ingenious and exciting some of the current research in drug-delivery methods already is. If funding for drug development stays at its current increased level, we might be seeing more fascinating delivery methods in the laboratory and, later, in hospitals and pharmacies.

Kalorama Information’s recent market-research report titled “Drug Delivery Markets” predicts a heightened interest in needle-free and implantable delivery methods for vaccines. The report describes the potential growth in delivery devices, particularly autoinjectors and pen injectors such as the EpiPen. Formulation techniques such as PEGylation, microspheres, and nanoparticles make up another portion of the report.

The document also includes inhaled insulin, that tantalizing prospect for diabetics that has not yet found commercial success. For example, Kalorama mentions the ProMaxx pulmonary-insulin product that Baxter Biopharma Solutions (Round Lake, IL) is developing. The report also assesses the prospects of drug-delivery companies such as Alkermes (Cambridge, MA) and Nektar (San Carlos, CA) that have tried to develop inhaled insulin.

This report is another reminder that vaccines and other biologicals seem to be where the excitement is in the drug industry today. Even if the industry’s pipelines are not impressive, it looks like innovations will still emerge in the form of drug-delivery methods. Who knows, maybe the demand for biopharmaceuticals will inspire the development of unconventional ways to administer vaccines. MedImmune’s (Gaithersburg, MD) inhaled swine-flu vaccine could point the way for other therapies.

And today’s research will almost surely affect the way we deliver small-molecule drugs, too. Maybe the dominance of oral solid-dosage forms will end in the not-too-distant future. The economic pressures that are leading the industry to focus on drug-delivery methods make this a distinct possibility.

Last Wednesday, the US Food and Drug Administration opened its Center for Tobacco Products. Lawrence Deyton, a public-health expert, administrative leader, scientist, and clinician, was named the Center’s first director. Tobacco use is the leading cause of preventable death in the United States, Deyton said in an FDA statement.

The Center’s goals will be to reduce the number of deaths that the products cause annually and to help implement the Family Smoking Prevention and Tobacco Control Act. Under the Act, FDA is required to set standards for tobacco products, review premarket applications for new and modified-risk tobacco products, and establish and enforce advertising restrictions for the products.

The day before FDA opened its new Center, the American Chemical Society issued a press release that described how scientists used tobacco plants to create a vaccine for “the second most common viral infection in the United States.” The infection is novovirus, aka “cruise-ship virus.” It causes diarrhea and vomiting and incapacitates its victims for several days. Novovirus spreads rapidly and can force wings of hospitals, schools, and homes for the elderly to close down.

A research team reengineered plant viruses to produce high levels of specially designed nanoparticles in tobacco plants. The nanoparticles were about the same size as the norovirus, about 25 nm in diameter, but consisted only of the outer surface protein, which is what the human immune system recognizes. Although the nanoparticles didn’t contain the novovirus’s infectious material, they did stimulate a strong immune response to fight off an infection.

Although I understand that most things have both good and bad qualities, the idea that tobacco plants could produce vaccines caught me by surprise. It just shows that one must keep an open mind, especially when trying to solve problems. And it reminded me of Hamlet’s observation: “There is nothing either good or bad, but thinking makes it so.”

Yesterday I read about one interesting approach to the successful lyophilization of a nanodrug. Scientists at AlphaRx (Markham, Ontario), a small biopharmaceutical company, say they have lyophilized the company’s inhalable Zysolin nanomedicine (a Tobramycin compound for the adjunctive treatment of Gram-negative pneumonia). Joseph Schwarz, the company’s chief scientist has called this “a technological milestone” for the nanomedicine industry, noting that “It is well known that many FDA-approved ingredients used in nanomedicine formulations cannot be readily lyophilized.” According to the release, Schwarz identifies this difficulty as “the major obstacle” to the therapeutic development of nanomedicines. The company now plans to move on to clinical batch material manufacturing.

One of the objectives behind the US Food and Drug Administration’s science-based approach to drug manufacture is gaining better process understanding, making the link between drug quality and critical process attributes. It is of a fortunate coincidence, then, that at the same time the industry is gaining this understanding, formulators are presenting the industry with the unique challenges from nanoparticle-based products.

A key to the insulin release and delivery is that the pH level of the skin, usually 7.4, reaches a more basic level when it is healing, according to a release by the team directed by Dean Ho, assistant professor of biomedical engineering and mechanical engineering at Northwestern. “It’s a tricky problem because proteins, even small ones like insulin, bind so well to the nanodiamonds. But, in this case, the right pH level effectively triggers the release of the insulin.”

The next step in the study is to incorporate the nanodiamond-insulin clusters into gels for clinical trials. Other possible formulations may include ointments, bandages, and sutures. Ho’s group is also studying the use of nanodiamonds to release a chemotherapy agent, Doxorubicin, to fight cancer and to disperse some insoluble drugs in water.

If your research team is working toward finding alternative routes to deliver therapeutic proteins, PharmTech would be glad to hear from you.

Peer Fischer and Ambarish Ghosh created nanoscale “propellers” that look like corkscrews or bacterial flagella. The team successfully steered the propellers using a magnetic field. This technique allowed Fischer and Ghosh to push 5-µm silica nanobeads along a precise and reproducible path. After additional research, the propellers could one day deliver particles in the bloodstream, possibly after being injected.

The scientists demonstrated the degree of control they achieved in a short video that reminds me of an Etch-A-Sketch. Actually, they show greater control than I ever managed with an Etch-A-Sketch.

Fischer’s team created billions of the propellers from a glass substrate with a simple manufacturing method. The propellers could be made from other materials, and biocompatible and biodegradable propellers would likely be ideal.

These propellers show that the inspiration for beneficial technology can come from seemingly frivolous places. They also make me wish I still had my old toybox.

PharmTech Talk: Can you explain the shift from a compliance-focused market to the concentration on tying supply-chain processes to business processes? Why is the shift moving away from compliance?

Pino: A year ago, compliance was the single-most important driver for supply-chain technology adoption. The economic downturn has manufacturers and distributors facing unprecedented pressure to cut costs and reduce inventory while simultaneously responding to new customer demands. Increased reliance on trading partners such as contract manufacturers, 3PLs [third-party logistics partners], and component suppliers adds additional complexity to the challenge of managing supply-chain networks.

Pharmaceutical manufacturers and suppliers are quickly recognizing that not having accurate and readily accessible information results in higher operational costs, waste, reduced revenues, damaged brand image, and competitive disadvantage. Cleaner, more reliable, error-free data is the goal for businesses in integrating supply-chain and business processes to positively impact the bottom line.

PharmTech Talk: What are your customers saying that indicates there is a shift?

Pino: Rather than implement supply-chain execution systems to meet a government or retailer generated mandate, customers are looking to “do more with less.” Of course the importance of compliance for manufacturers and suppliers remains, but the primary focus is on optimizing supply-chain execution, visibility and control. Customers are looking to reduce costs and labor requirements and streamline supply-chain operations immediately, and they are really focusing on near-term benefits with long-term benefits as a secondary focus.

PharmTech Talk: How is this approach different?

Pino: The difference is the level to which supply-chain execution systems are automated and integrated with business systems and processes, and how quickly companies are expecting implementations to yield return-on-investment (ROI). Manufacturers and suppliers are focused on spending money on projects that deliver near term ROI and cut costs quickly.

PharmTech Talk: How is the economy affecting your clients’ positions and options for supply-chain optimization?

Pino: Businesses are focused on the “here and now” and positioning themselves to be stronger and more competitive coming out of the economic downturn. Customers are searching for ways to leverage existing ERP [enterprise resource planning] investments and extending them through the supply chain with automated data-collection technology. By unlocking large stores of data and integrating this information throughout the supply chain, enterprises are targeting a more efficient operational environment both inside and outside the four walls. The clear objective is to optimize the existing business and supply-chain infrastructure holistically, in a timeframe adapted to the changing market.

In addition to the economic factors, this change in focus on ROI and seeing compliance as a secondary concern could be because the legislation is not yet in place. California’s ePedigree implementation requirements, thought to be a trial-run for a national standard once it was put into action, has been delayed from 2009 to 2011 and now to 2015. After the delay was announced, PharmTech discussed the implications and future of the implementation deadline with Arvindh Balakrishnan, vice-president of the Life Sciences Industry Business Unit at Oracle.

In the meantime, the US Food and Drug Administration is working to “develop standards and identify and validate effective technologies for the purpose of securing the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs,” under Section 913 of the Food and Drug Administration Amendments Act of 2007 (FDAAA), titled “Assuring Pharmaceutical Safety.” The agency is considering RFID, nanotechnology, encryption technologies, and other track-and-trace or authentication technologies in the development of its standards. FDA’s deadline is March 2010.

Videos from November 17, 2008

THE FUTURE OF INHALABLE MACROMOLECULES
Dr. Igor Gonda, President and Chief Executive Officer, Aradigm
Interviewed by Michelle Hoffman, Editor-in-Chief, Pharmaceutical Technology
The future for all inhalable macromolecular drugs, following the market withdrawal of Pfizer’s inhaled insulin product, Exubera.

ANALYTICAL METHODS FOR QbD
Dr. Moheb Nasr, Director, Office of New Drug Quality Assessment, The US Food and Drug Administration
Interviewed by Maribel Rios, Senior Editor, Pharmaceutical Technology
The current state of FDA’s quality by design initiative as it applies to analytical methods.
>>Read Maribel’s related post here.

AN EDUCATION AGENDA FOR ASPIRING PHARMACEUTICAL SCIENTISTS AND ENGINEERS
Dr. Karen Habucky, President, American Association of Pharmaceutical Scientists (AAPS)
Interviewed by Michelle Hoffman, Editor-in-Chief, Pharmaceutical Technology
How to encourage students to go into the pharmaceutical sciences and what to teach them.

Videos from November 18, 2008

NANOTECHNOLOGY IN PHARMACEUTICAL APPLICATIONS
Dr. Lee Jia, Project Officer, Developmental Therapeutics Program, Division of Cancer Therapy and Diagnostics, National Cancer Institute, National Institutes of Health
Interviewed by Patricia Van Arnum, Senior Editor, Pharmaceutical Technology
The potential roles for polymer-based, lipid-based, and metal-based nanostructures in drug design and delivery.
>>Read Patricia’s related post here.

STRATEGIES FOR POORLY WATER SOLUBLE DRUGS
Dr. Albert W. Brzeczko, Vice President of Global Pharmaceutical Research and Development and Pharmaceutical Technologies, ISP Pharma Systems
Interviewed by Patricia Van Arnum, Senior Editor, Pharmaceutical Technology
How to improve the dissolution rate and in vivo exposure of poorly water soluble drugs using high-energy solids and polymer matrices.
>>Read Patricia’s related post here.

LIQUID-FILLED HARD CAPSULE TECHNOLOGY
Brian Jones, Qualicaps, Europe
David Fulper, Patheon
Moderated by: Dr. Panayiotis Constantinides, Biopharmaceutical & Drug Delivery Consulting
The benefits and challenges of developing this dosage form, including shell systems, and how they can be used in early clinical studies as a quick-to-market option.

FUNDAMENTAL ISSUES OF PARTICLES AND POWDERS
Ulf Willen, Malvern Instruments
Reg Freeman, Freeman Technology
Moderated by Maribel Rios, Senior Editor, Pharmaceutical Technology
Small variations in flowabiity, morphology, and performance under pressure of small particles can mean the difference between success and failure during tableting, compression, and compaction of solid-dose products.

OUTSOURCING TO INDIA AND CHINA
Timothy Tyson, Executive Chairman and Acting CEO, Aptuit
Dr. Wouter Huizinga, Senior Director, Sales and Business Development, Dr. Reddy’s Laboratories
Moderated by Jim Miller, President, PharmSource
The advantages and challenges of outsourcing across borders.

QUALITY BY DESIGN, PAT, AND EXCIPIENTS
Dr. Brian A. C. Carlin, Global Manager of Pharmaceutical R&D, FMC BioPolymer
Dr. Stuart C. Porter, Senior Science Fellow, Film Coating Technology, ISP
Moderated by Patricia Van Arnum, Senior Editor, Pharmaceutical Technology
Insights into statistical design of experiments and other approaches to understanding formulation and process variables essential to designing a quality dosage form.
>>Read Patricia’s related post here.