Tuesday, April 24, 2012

DELIVERY - Nanoparticles | Creating Nanostructures for Oral Drug Delivery

Neil Canavan
Creating Nanostructures for Oral Drug Delivery

Platforms prove elusive, but research persists

What the pharmaceutical industry needs is a plug-and-play nanotechnology plat- form, a suite of constituent parts and instructions that can facilitate the realization of new oral drug formulations. Just don’t hold your breath waiting for it.
“Even if all parts remain the same, the API may affect how the whole process works,” warned Ravi Kumar, PhD, professor of drug delivery, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, U.K.
Dr. Kumar spoke from knowledge of recent efforts: The first attempt looked at nanoparticle formulation of the immunosuppressant drug cyclosporine A, with a multi-block copolymer of lactic acid and ethylene glycol; the second used a similar approach with the chemotherapy agent paclitaxel and a charged surfactant.1,2 His most recent work was with amphotericin B (AMB), a polyene antibiotic administered intravenously to treat invasive aspergillosis, a life-threatening infection, and leishmaniasis, a condition caused by a parasite endemic to many developing countries. An oral formulation could increase bioavailability, potentially reducing the amount of drug needed and the cost due to ease of drug manufacture and administration.
In the most recent investigation, AMB was combined with poly(lactide-co-glycolode), dimethyl sulfoxide, and vitamin E TPGS, a non-ionic surfactant, to create nanoparticles of 113±20 nm in size with 70% entrapment efficiency at 30% AMB w/w of polymer.3
The resulting formulation was effective in murine models of aspergillosis; however, data for leishmaniasis was not as encouraging. Dr. Kumar suspects there are issues with the formulation’s release profile. “With leishmaniaisis, you would probably require a very fast release initially to combat the protozoa’s growth rate,” and to accommodate this would require a separate balancing act between drug loading and particle size—thus, not quite a platform.
For now, Dr. Kumar advises gaining a true understanding of the properties of the drug molecule itself first, and then studying what the drug is being used for. Once you have an idea about the delivery vehicle, “the simpler you can keep the formulation the better.” And always keep an eye on scale up—for instance, using TPGS facilitated the use of filters, rather than centrifugation, to harvest large quantities of nanoparticles.
Dr. Kumar also requested scientists working in the field to be more comprehensive in their reporting. “This is a key issue. Lots of publishing on this work doesn’t really describe how they are freeze drying these formulations.” Stating that the material was lyophilized is not enough; all players need to know the myriad tweaks that got you there.
continues below...

Case Study: Scaling Down for Faster Pain Relief?

A recent experiment performed by end Research in Bend, Ore., in collaboration Pfizer Pharmaceuticals, demonstrated the potential of drug/nanoparticle constructs for increasing the rate and extent of oral absorption of low solubility, high-permeability drugs—in this case, the anti-inflammatory agent celecoxib.1
click for larger view
“There was at least a two-fold purpose for choosing celecoxib,” said Michael Morgen, PhD, director of new technology development at Bend. “The first is that it serves as a model for showing the broad applicability of this technology to low-solubility, BCS class 2 compounds, and second, since celecoxib is used for pain relief, you can imagine wanting to increase the rate of absorption to achieve faster onset.”
Dr. Morgen and his team are creating drug/nanoparticles using high surface area dispersions of celecoxib, in combination with ethyl cellulose and either sodium caseinate or bile salt. This approach has previously been shown to be particularly well suited to rapid-release, rapid-onset applications.2
The architecture of the particle is such that the drug molecule is dispersed within the polymer matrix, with the stabilizing excipients located primarily on the exterior (see Figure 1).
“We used a variety of surface-stabilizing agents to help keep the particles from aggregating—for the in vivo experiments we used casein, which is a naturally occurring, charged polymer.”
Once prepared, Dr. Morgen’s nanoparticles proved in his in vivo study to have higher systemic exposure and faster attainment of peak plasma concentrations than commercial celecoxib capsules.
The technique, though successful, does not suggest a clear path forward. “The raw technical performance was pretty good, but we had a lot of difficulty trying to scale up just to do a small clinical study,” said Dr. Morgen. And he sees this problem in broader terms. “The particles could be broadly applicable, but there isn’t the developed infrastructure yet in the industry to handle the process development.” To perform large-scale trials, more emphasis must be placed on the commercial-scale manufacture of the small.


  1. Morgen M, Bloom C, Beyerinck R, et al. Polymeric nanoparticles for increased oral bioavailability and rapid absorption using celecoxib as a model of a low-solubility, high-permeability drug. Pharm Res. 2012;29(2):427-440.
  2. Yang W, Tam J, Miller DA, et al. High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers. Int J Pharm. 2008;361(1-2):177–188.

Sticky Situation

Unlike most of those working with oral formulations, Kevin Pojasek, PhD, vice president of corporate development for Kala Pharmaceuticals in Waltham, Mass., isn’t looking to increase systemic bioavailability. He would rather the drug’s activity remain on site.
In a recent investigation, AMB was combined with poly(lactide-co-glycolode), dimethyl sulfoxide, and vitamin E TPGS, a non-ionic surfactant, to create nanoparticles of 113±20 nm in size with 70% entrapment efficiency at 30% AMB w/w of polymer.
“At Kala, we’re looking at how can we better treat diseases of the GI tract through topical administration—essentially trapping the API at the site of infection or inflammation.” That goal first requires a thorough understanding of the mucosal lining of the GI tract, a knowledge foundation revealed and recently reviewed by Kala investigators.4 “We started with the engineering principles of mucus, the rheology,” said Dr. Pojasek, and then combined that with the observed properties of certain viruses that are able to penetrate a mucosal barrier. Taken together, these data guided the researchers to an effective GI-targeting nanoparticle design.
Leaving out proprietary details, proof-of-principle for this approach, described by Yang and colleagues, used Pluronic block copolymers to enable membrane translocation. Mindful of eventual marketing, the techniques evolving from this approach are only incorporating pre-FDA approved moieties, minimizing regulatory hurdles by skirting the definition of new chemical entities.5
Though still in early development, there is something resembling a platform in this work. “In essence, the secret sauce of what we do is engineering the coating on the outside of the particles,” said Dr. Pojasek. As for the core, “we can tailor the release kinetics to meet the challenge of whatever mucosal disease we’re trying to treat.”


  1. Ankola DD, Battisti A, Solaro R, Kumar MN. Nanoparticles made of multi-block copolymer of lactic acid and ethylene glycol containing periodic side-chain carboxyl groups for oral delivery of cyclosporine A. J R Soc Interface. 2010;7 Suppl 4:S475-S481.
  2. Bhardwaj V, Plumb JA, Cassidy J, Ravi Kumar MNV. Evaluating the potential of polymer nanoparticles for oral delivery of paclitaxel in drug-resistant cancer. Cancer Nanotechnol. 2010;1(1-6)29-34.
  3. Italia JL, Sharp A, Carter KC, Warn P, Kumar MN. Peroral amphotericin B polymer nanoparticles lead to comparable or superior in vivo antifungal activity to that of intravenous Ambisome® or Fungizone™. PLoS One. 2011;6(10):e25744.
  4. Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers [published online ahead of print Dec. 24, 2011]. Adv Drug Deliv Rev.
  5. Yang M, Lai SK, Wang YY, et al. Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angew Chem Int Ed Engl. 2011;50(11):2597-2600.
Neil Canavan a science/medical writer based in Brooklyn, N.Y., is a frequent contributor to PFQ and holds a master’s degree in molecular biology. In addition to covering medical meetings, he has been writing about pharmaceutical science for more than 10 years. Reach him at ncanavan@hotmail.com.
continues below...

Editor’s Choice

  1. Batrakova EV, Kabanov AV. Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers. J Control Release. 2008;130(2):98-106.
  2. Cai Z, Wang Y, Zhu LJ, Liu ZQ. Nanocarriers: a general strategy for enhancement of oral bioavailability of poorly absorbed or pre-systemically metabolized drugs. Curr Drug Metab. 2010 Feb;11(2):197-207.
  3. Wawrezinieck A, Péan JM, Wüthrich P, Benoit JP. Oral bioavailability and drug/carrier particulate systems [in French]. Med Sci (Paris). 2008;24(6-7):659-664.
  4. Roger E, Lagarce F, Garcion E, Benoit JP. Biopharmaceutical parameters to consider in order to alter the fate of nanocarriers after oral delivery. Nanomedicine (Lond). 2010;5(2):287-306.
  5. Yamanaka YJ, Leong KW. Engineering strategies to enhance nanoparticle-mediated oral delivery. J Biomater Sci Polym Ed. 2008;19(12):1549-1570.

No comments: