Tackling Solubility Challenges - Pharmaceutical Technology

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Tackling Solubility Challenges
Nanosupensions are among the ways formulation scientists seek to address the problem of solubility.


Pharmaceutical Technology
Volume 36, Issue 3, pp. 40-44

Controlled agglomeration

Dispersing a poorly soluble compound in a polymeric matrix to improve solubility and therefore bioavailability is another strategy. To produce the solid solutions or solid dispersions, various methods can be used, such as hot-melt extrusion, spray-drying, melt congelation, and nanocrystal technology (11, 12). Veloxis Pharmaceuticals (formerly called LifeCycle Pharma), a technology spinoff from the Danish pharmaceutical company H. Lundbeck, uses a proprietary process, MeltDose, based on controlled agglomeration, to address the problem of poorly soluble drugs (12–13).

Under the MeltDose approach, a low water-soluble drug substance is dissolved in a vehicle system that is optimized for each drug substance. The drug substance is spray-dried on an inert particulate carrier using fluid-bed equipment and solidified when disposed on the carrier. The carrier captures the active drug in a nanocrystalline or microcrystalline state or as an amorphous solid dispersion. This step is followed by agglomeration that is controlled by optimizing temperature and feed rate to produce the granules, which are directly compressed into tablets. Once in tablet form, the dissolution profile and particle size remain stable (12-13).

The selection of the vehicle to match the physiochemical properties of the API is an important consideration in the process. In some formulations, the API will be present as an amorphous solid dispersion, such as in hot-melt extrusion and spray drying, but in other formulations, the API will be present as crystals in nanometer or micrometer size, resembling nanoproducts more (12–13).

MeltDose, the proprietary process that Veloxis Pharmaceuticals has developed, centers on the controlled agglomeration process. The controlled agglomeration process has some similarities to fluid-bed granulation. Controlled agglomeration involves placing solid carrier particles in a conventional fluid bed, unto which a liquefied vehicle containing the API is sprayed. When the liquid vehicle is cooled down on the carrier, it agglomerates and forms granules. The controlled agglomeration process is water-free, and in contrast to conventional fluid-bed granulation, uses liquefied (i.e., melted) polymers as the polymeric vehicle. The polymeric vehicle is melted in a specially designed heated melt unit that controls temperature and pressure of the melted vehicle, which passes from the melt unit to a specially designed spray nozzle in the fluid bed. The produced granules are compressed to tablets using conventional tablet presses (12–13).

The polymer vehicles used in the MeltDose process can include a range of hydrophilic and lipophilic materials and are selected for their solubility-enhancing properties and compatibility with subsequent processing steps. Examples of vehicle systems are solid or semisolid polymers with a melting point between 40 and 80 C, such as polyethylene glycol 6000, poloxamers, and various types of gelucires. The resulting granule size varies with the choice of excipients and lies typically in the range of 200 to 500 m. The vehicle temperature, the spray rate, the atomizing air volume, and product temperature all are important process parameters to consider during the controlled agglomeration step. Also, the addition of different surfactants can result in different sizes of API crystals in the granule (12-13).

Fenofibrate, a lipid-regulating agent to control cholesterol and marketed as Fenoglide in the United States, was the first product approved in the US using the MeltDose technology. Veloxis Pharmaceuticals is working on other formulations that use the MeltDose process. The company has developed a once-daily modified-release formulation of tacrolimus, a poorly soluble compound with a water solubility of 4–12 g/m, and the same API as in Astellas's Prograf, an immunosuppression drug used in kidney and liver transplants. Veloxis Pharmaceuticals has developed an amorphous solid-dispersion formulation of tacrolimus. The API was dissolved in a melted vehicle at elevated temperature. The solution was sprayed onto an inert carrier in a fluid bed. The resulting granulate was blended with a disintegrant and lubricant and compressed into tablets. The modified-release tablet formulation using the MeltDose technology was developed and tested in humans and is currently in late Phase III testing for the prevention of organ rejection with kidney transplants. Veloxis Pharmaceuticals expects to file for regulatory approval for the product, LCP-Tacro, in the US and European Union in the first half of 2013 (12).

On the horizon: carbon nanoparticles in drug delivery

A mixture of current drugs and carbon nanoparticles shows potential to enhance treatment for head-and-neck cancers, according to research by Rice University in Houston and the University of Texas MD Anderson Cancer Center. The therapy uses carbon nanoparticles to encapsulate chemotherapeutic drugs and sequester them until they are delivered to cancer cells.

The new strategy by Rice chemist James Tour and Jeffrey Myers, a professor of head-and-neck surgery at MD Anderson, combines paclitaxel and cetuximab with hydrophilic carbon clusters functionalized with polyethylene glycol, known as PEG-HCC, according to a Feb. 16, 2012, Rice University press release. Cetuximab, the targeting agent, is a humanized monoclonal antibody that binds exclusively to the epidermal growth factor receptor (EGFR), a cell-surface receptor overexpressed by a large percentage of head-and-neck squamous cell cancers. Because paclitaxel is hydrophobic, the substances are generally combined with Cremophor EL, a castor oil-based carrier that allows the compound to be delivered intravenously to patients. The researchers found a simple way to mix paclitaxel and cetuximab with carbon clusters that adsorb the active ingredients. The new compound is water-soluble and is more effective at targeting tumors than when paclitaxel is administered with Cremophor, according to the release.


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