Tackling Solubility Challenges

Strategies to improve drug solubility are of crucial importance to the pharmaceutical industry. Advancement of high-throughput screening techniques for lead identification in drug discovery has had the benefit of generating more potential drug candidates, but with this increase in the diversity and number of drug molecules comes challenges (1). Most notably, more leads are being identified with high-molecular weights and lipophilicity and thus have poor water-solubility (1). Industry estimates are that as much as 60% of drugs currently in development may be classified as poorly water-soluble (2). Poor solubility is problematic because of the resulting decrease or variability in bioavailability, which affects clinical efficacy and safety, such as through necessitating higher dosing regimens to achieve therapeutic effects (1). Enhancing bioavailability of poorly water-soluble drugs, therefore, has strong clinical and commercial significance.

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Classifying poorly soluble drugs

The Biopharmaceutics Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability (2). When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption: dissolution, solubility, and intestinal permeability. According to the BCS, drug substances are classified as follows:

• Class I: high solubility and high permeability

• Class II: low solubility and high permeability

• Class III: high solubility and low permeability

• Class IV: low solubility and low permeability (3).

Various approaches can be used to address problems of solubility, such as particle engineering, salt selection, amorphization of the compound, use of surface-active agents or cosolvents, polymeric stabilizers to achieve supersaturation, and solid dispersions and solutions (2). Physical modifications may occur through such techniques as micronization, nanonization, and sonocrystallization (4). Although micronization of powders can be useful to improve solubility, the resulting particle size of drug powders of between 1 and 10 µm to increase the surface area and the dissolution velocity may be insufficient to overcome bioavailability problems of many poorly soluble BCS Class II drugs (4). Nanonization moves beyond micronization to further reduce particle size as a means to increase dissolution rates and bioavailability of poorly water-soluble drugs (4). Nanozination strategies include increasing the surface area-to volume ratios of drug powders, changing crystalline forms, and developing nanomaterials for drug delivery (5).

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 µm to about 0.5 µm 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 µm to about 1 µm 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).

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 µm. 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 µg/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.

References

1. R.O. Williams, A.B. Watts, and D.A. Miller, "Preface" in Formulating Poorly Water-Soluble Drugs, R.O. Williams, A.B. Watts, and D.A. Miller, Eds. (Springer, 2012), p. v–viii.

2. K.P. O'Donnell and R.O. Williams, "Optimizing the Formulation of Poorly Water- Soluble Drugs," in Formulating Poorly Water-Soluble Drugs, R.O. Williams, A.B. Watts, and D.A. Miller, Eds. (Springer, 2012), pp. 27–28.

3. FDA, Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification (Rockville, MD, Aug. 2000).

4. A.H. Jens-Uwe and R. H. Mueller, Int. J. Nanomedicine 3 (3), 295–310 (2008).

5. H. Chen et al., Drug. Discov. Today 16 (7–8), 354–360 (2011).

6. Alkermes, "NanoCrystal Technology" company information, www.alkermes.com/Contract-Services/Technologies/Bioavailability-Enhancement, accessed Feb. 13, 2012.

7. SkyePharma, "2011 Half-Year Results" (London, Aug. 18, 2011).

8. SkyePharma, "Insoluble Drug Delivery Platform" company information, www.skyepharma.com/Technology/Oral_Technology/Particle_Engineering_Technologies/Insoluble_Drug_Delivery_Platform/Default.aspx?id=80, accessed Feb. 13, 2012.

9. Aptalis Pharmaceutical Technologies, "Biorise Technology" company information, www.aptalispharmaceuticaltechnologies.com/tech_biorise.html, accessed Feb. 13, 2012.

10. B. Trout et al., J. Pharm. Sci. 101 (3), 1178–1188 (2012).

11. P. Van Arnum, Pharm. Technol. 32 (7), 96–98 (2007).

12. P. Van Arnum, Pharm. Technol. 35 (7), 46 (2011).

13. J.Q. Thomassen and P. Holm, presentation at the Nanomedicine and Drug Delivery Symposium (Toronto, Nov. 2008).