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Posted: Mar 31, 2009

Nanoparticle processing dramatically increases bioavailability of cholesterol-lowering drug

(Nanowerk Spotlight) Millions of people with high cholesterol levels are treated with anti-hypolipidemic drugs based on statins that are commonly used to inhibit cholesterol synthesis and lower its serum level. Unfortunately, statins can have two major side effects, although they occur relatively rarely: raised liver enzymes and skeletal muscle pain or even damage. Pharmaceutical research efforts are therefore underway to develop alternative compounds that avoid these potential problems.
A promising drug that works via a different mechanism than statin-based drugs, Probucol (PBC), has several advantages over other drugs – better acceptance, ease of administration, and it is much cheaper. Its downside is that its solubility is extremely poor, which considerably lowers its efficiency to suppress cholesterol. A Japanese-U.S. team has now shown that a nanoparticle processing approach enhances the bioavailability of PBC and they demonstrate the design of a solid dosage form for practical use.
"The core of our recent work is uniting two conventional pharmaceutical technologies – grinding and spray-coating – with state-of-the-art characterization using nuclear magnetic resonance (NMR) spectroscopy," Toshiro Fukami explains to Nanowerk. "Both techniques have been utilized all over the world but developed individually until now. We have demonstrated that our new nanoparticle method increases the solubility of Probucol in water and its ability to permeate cell membranes."
This new method of processing the drug in a nanoparticle utilizes the grinding of PBC together with sodium dodecylsulfate and methacrylic copolymer. Solid-state NMR experiments reveal the polymorphic state of Probucol and the conversion of this drug from crystalline to amorphous state, and determine its nearness to the copolymer due to the grinding process that enables the formation of nanoparticles.
A schematic representation of the preparation of pharmaceutical fine granules containing probucol nanoparticles
A schematic representation of the preparation of pharmaceutical fine granules containing probucol nanoparticles. (Reprinted with permission from American Chemical Society)
In this study, which was conducted by scientists from the College of Pharmacy at Nihon University in Chiba, Japan, led by Kazuo Tomono, and the Ramamoorthy Lab at the University of Michigan in Ann Arbor, the team selected conventional materials and instruments which are commercially available in order to prepare drug nanoparticles. In addition, they used highly sophisticated solid-state NMR techniques along with an ultra-high field, 900 MHz, NMR instrument to reveal the intermolecular interactions among drug and pharmaceutical ingredients.
In this cooperative effort, the Japanese team prepared the pharmaceutical granules and the U.S. team carried out the elucidation of the mechanism of nanoparticles formation by using solid-state NMR. A paper describing the findings, first authored by Fukami, was published in the March 12, 2009 online edition of Molecular Pharmaceutics ("A nanoparticle processing in solid state dramatically increases the cell membrane permeation of a cholesterol-lowering drug, Probucol")
The technique of ternary co-grinding a drug/polymer/detergent blend was developed a few years ago by the research group of Keiji Yamamoto recently ("Nanoparticle formation of poorly water-soluble drugs from ternary ground mixtures with PVP and SDS"). This process enabled Fukami and his colleagues to obtain drug nanoparticles via solid-state reaction without any solvent.
"We successfully attempted to apply a methacrylate copolymer, which is used for film-coating of many pharmaceutics, as polymer component" says Fukami. The result is Probucol in nanoparticulate (∼72 nm) form.
While the ground nanoparticles were directly used in the team's experiments, they are too sticky and difficult to handle for practical use by patients. The scientists therefore uniformly spray-coated 350-500 µm sized carrier particles with the drug nanoparticle mixture for oral administration.
It is well known that the solubility of a drug plays an important role in the efficiency of the drug. The researchers therefore examined the dissolving behavior of their PBC containing nanoparticles in buffer at different pH values.
Generally, their experimental results suggest that nanoparticles permeate the cell membrane while the drug PBC alone or without grinding did not permeate the cell membrane even after an hour.
"Our results suggest that the solubility of nanoparticles is higher at neutral pH and low in acidic pH" says Fukami. "Therefore, the nanoparticles will be quite stable in acidic conditions like in the stomach while rapid drug release can be expected in intestines for better absorption. On the other hand, we didn't observe any drug release from physically mixed ternary components without grinding. These results suggest that the grinding process is crucial in promoting intermolecular interactions, leading to the formation of nanoparticles, and increasing the solubility of nanoparticles containing PBC."
Generally, this approach could prove to be beneficial for the formulation of other hydrophobic drugs or organic compounds which are poorly soluble in water.
Another major advantage of this technique – not only for Probucol but other drug substances as well – is that if pharmaceutical companies were to utilize ternary co-grinding as pretreatment for the production of ordinal medicines, the active pharmaceutical ingredients would exist as nanoparticles in dosage forms. This could enable a dose lower than the amount required with conventional drug formulations and provide cost-effectiveness to patients as well as pharmaceutical companies.
By , Copyright Nanowerk LLC

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