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

Approaches in nanonization

Several drug-delivery companies and specialty pharmaceutical companies have developed technology platforms involving nanozination. Perhaps the most well known and established technology is the NanoCrystal technology of the former Elan Drug Delivery Technology, which was acquired by Alkmeres in 2011 (4). The technology has been manufactured at a commercial scale since 2001, according to company information. NanoCrystal technology involves reducing the size of drug particles, typically to less than 2000 nm. By reducing particle size, the drug's exposed surface area is increased. The nanoparticles are then stabilized to maintain their reduced particle size. The result is a stable drug formulation that shows an increased dissolution rate. Five products have been launched using the company's NanoCrystal technology, according to the company (6).

The specialty pharmaceutical company SkyePharma has several technologies in its solubilization toolbox: the IDD (insoluble drug delivery) platform, which coats particles with phospholipids; DissoCubes, which reduces drug particle size to enable rapid absorption; and SLN (solid lipid nanoparticles), which takes advantage of lipid digestion to promote drug absorption by the gastrointestinal tract (4, 7).

DissoCubes are crystalline nanoparticles of active substance obtained by a liquid state high-energy process using a high-pressure piston gap homogenizer to reduce the drug particle size in the presence of surface modifiers that associate at the freshly generated drug interface (4, 8). A particle-size reduction from approximately 50 m to about 0.5 m is achieved resulting in a homogenous and stable formulation. The nanosuspensions can be formulated into various dosages forms (8).

The IDD platform consists of three main technologies focused on dispersible narrow particle-size distribution dosage forms derived from surface-modified micrometer to submicrometer-sized particles or droplets stabilized by surface modifiers, specifically phospholipids. The IDD-P (MicroParticle) is a microparticulate variation of the IDD drug-delivery system, which consists of a pure solid drug in the core of the particle. IDD-D formulations (MicroDroplet) involve liquid drug substances (8).

IDD-P and IDD-D formulations are produced by application of high shear, cavitation, or impaction (e.g., attrition, homogenization, microfluidization, milling, ultrasonication) to reduce the drug particle size in the presence of phospholipids (and/or other surface modifiers) that associate at the freshly generated drug surface. A particle-size reduction from approximately 100–200 m to about 1 m is achieved resulting in a homogeneous and stable formulation (8).

The company's IDD-D and IDD-P technology apply physical or mechanical processes to achieve the desired particle size. The third technology in SkyePharma's IDD platform, IDD-SE (Self-Emulsifying), involves self-generation of surface-stabilized micrometer- to submicrometer-sized particles or droplets when the dosage form is exposed to an aqueous medium such as those in gastrointestinal or vascular compartments (8).

An example of a commercial drug using SkyePharma's IDD technology platform is Triglide (fenofibrate), an oral treatment for elevated blood lipid disorders, launched in 2005 and marketed in the United States by Shionogi Pharma. Some fenofibrate-based products are insoluble in water, which may result in variable uptake from the stomach and require the patient to take the tablets with food. Triglide, SkyePharma's formulation of fenofibrate, uses the company's IDD platform technology, which has comparable absorption under both fed and fasting conditions. Triglide is manufactured at the company's Lyon, France, manufacturing facility leased by SkyePharma to Aenova (8).

Aptalis Pharma, a specialty pharmaceutical company formed from the merger of Axcan and Eurand in 2011, provides bioavailability-enhancement technology through Aptalis Pharmaceutical Technologies, which includes its Biorise technology. The Biorise technology breaks down the crystalline drug into nanocrystals and/or an amorphous (noncrystalline) drug that is stabilized in a carrier system to maintain the drug in its activated form for the duration of its shelf life (9). This approach creates a greater surface-area-to-volume ratio that increases the intrinsic solubility and dissolution rate of poorly water-soluble drugs, thereby enhancing their rate and extent of absorption. The analgesic megestrol acetate and the nonsteroidial anti-inflammatory drug nimesulide are two examples of drugs using the Biorise technology (9).

Researchers at the Novartis–MIT Center for Continuous Manufacturing, Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), recently reported on the development of nanocrystals in a continuous manufacturing environment. Specifically, they used an electrospray technology followed by annealing at high temperatures to produce nanocrystals of carbamazepine, a poorly water-soluble drug, in a continuous manufacturing process. The researchers reported that the solubility and dissolution rates of carbamazepine nanocrystals increased significantly as compared with carbamazepine bulk particles (10).


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