Solubilizing the Insoluble - Pharmaceutical Technology

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Solubilizing the Insoluble
An analysis of the approaches and tools used to tackle the problem of poorly soluble drugs.


Pharmaceutical Technology
pp. 50-56

Charting industry developments

Several companies have recently announced developments supporting activities for solid dispersions and other approaches in their toolbox to tackle the problem of solubility. In addition to MEMFIS, Evonik is positioned in solid-dispersions through its methylacrylate polymers (Eudragit). Several late-stage products have been developed with these excipients in solid-solution formulations. Evonik has hot-melt extrusion and spray-drying capabilities in the United States, Germany, and India, as well as spray-drying capabilities in Japan. In 2009, Evonik partnered with the contract manufacturer Rottendorf Pharma (Ennigerloh, Germany) for capabilities in hot-melt extrusion.

In October 2009, International Specialty Products (ISP, Wayne, NJ) launched a drug-solubility initiative to support pharmaceutical companies working with drug actives that exhibit poor solubility. The initiative focuses on solubilization technologies that involve excipients, formulation, and related processing services, which includes solid-dispersion technology, both hot-melt extrusion and spray drying. ISP has been engaged in the formulation of spray-dried solid dispersions since 2004 and has developed formulations for approximately 100 compounds during that time through its contract-research division. In 2009, ISP partnered with the equipment manufacturer Coperion (Stuttgart, Germany) for advancing hot-melt extrusion technology by providing ingredient technology in polymers and disintegrants as well as expertise in material science. Coperion is providing equipment for testing and knowledge of the physical systems used in extrusion.

As part of its solubility initiative, ISP is also emphasizing ingredient technology such as cyclodextrins and disintegrants."Drug–cyclodextrin inclusion complexes are well known to increase solubility and enhance bioavailability," said Tim Bee, senior global technical director of pharmaceuticals at ISP, in an Oct. 5, 2010, press release issued at CPhI Worldwide in Paris. Cyclodextrins are bucket-shaped oligosaccharides with a hydrophobic cavity and hydrophilic exterior. Given their molecular structure and shape, cyclodextrins function as molecular containers by entrapping guest molecules such as APIs within the internal cavities. This structure–function relationship can produce formulation advantages that include the ability to increase the solubility of poorly soluble drug actives. As part of an alliance with Wacker-Chemie (Munich), ISP markets and provides technical support for cyclodextrin products.

Also at CPhI last month, ISP announced that it will launch a high-purity crospovidone (Polyplasdone Ultra and Polyplasdone Ultra-10) in November 2010 as part of its toolkit for increasing the bioavailability of poorly water-soluble drugs. The product will be manufactured at its facility in Texas City, Texas. ISP recently published results of a study demonstrating the solubilization benefits of Polyplasdone crospovidione in formulations of poorly water-soluble drugs (6).

Other companies are emphasizing their technology for solid dispersions. BASF (Ludwigshafen, Germany) was recognized for innovation at CPhI for its excipient, Soluplus, which is used in hot-melt extrusion applications. BASF launched the polymeric solubilizer in 2009. Earlier this year, BASF partnered with the equipment manufacturer GEA Niro (Søborg, Denmark) to allow BASF to make in accordance with current good manufacturing practice spray-drying tests and pilot productions of APIs at GEA's test station in Copenhagen. Dow Wolf Cellulosics (Horgen, Switzerland) offers several expicients for hot-melt extrusion applications, including poly (ethylene) oxide resins (e.g., Polyox) and cellulosic derivatives [e.g., Ethocel (ethylcellulose ethers) and Methocel (cellulose ethers)].

In September 2010, Bend Research (Bend, OR), a formulation development and manufacturing company, expanded manufacturing capabilities for hot-melt extrusion. The company purchased intermediate-scale equipment, an 18-mm extruder, to complement existing extruder capacity of 7.5 mm and 27 mm. The three extruders enable scale-up of a formulation from small-scale development work through large-scale manufacture of clinical supplies.

LifeCycle Pharma (LPC, Hørsholm, Denmark), an emerging speciality pharmaceutical company that was spun off from the pharmaceutical company H. Lundbeck (Copenhagen) in 2002, bases its business model on taking marketed drugs that are poorly water-soluble and applying a proprietary technology (MeltDose) to improve bioavailability. The company has patented a controlled-agglomeration process, which works by incorporating the drug substance with low water-solubility into a meltable vehicle. The drug is then sprayed on an inert particulate carrier using fluid-bed equipment. The melt is solidified when deposited on the particle carrier, thereby capturing the active drug in a solid dispersion either as a solid solution or in a nanocrystalline state. The particle size is increased by controlling and optimizing the product temperature and feed rate (7). The company is using this approach as opposed to other drug-delivery technologies, which seek to increase bioavailability of compounds with low water solubility through reduction of the particle size of the drug substance, which increases the surface area available for dissolution.

LCP has one commercial product that uses the MeltDose technology, Fenoglide (fenofibrate), which is marketed in the United States as a treatment for hyperlipidemia and mixed dyslipidemia. The company's lead pipeline candidate is LCP-Tacro (tacrolimus), currently in Phase III trials, to treat immunosuppression in kidney and liver transplantation. It is also developing two other products: LCP-AtorFen, a fixed-dose combination tablet of fenofibrate and atorvastatin, and LCP-Feno, a generic 145-mg fenofibrate tablet.


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