Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds

Abstract

More than 40% of compounds identified through combinatorial screening programs are poorly soluble in water. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues. Formulating these compounds as pure drug nanoparticles is one of the newer drug-delivery strategies applied to this class of molecules. Nanoparticle dispersions are stable and have a mean diameter of less than 1 micron. The formulations consist of water, drug, and one or more generally regarded as safe excipients. These liquid dispersions exhibit an acceptable shelf-life and can be postprocessed into various types of solid dosage forms. Drug nanoparticles have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance, providing the discovery scientist with an alternate avenue for screening and identifying superior analogs. For the toxicologist, the approach provides a means for dose escalation using a formulation that is commercially viable. In the past few years, formulating poorly water-soluble compounds using a nanoparticulate approach has evolved from a conception to a realization whose versatility and applicability are just beginning to be realized.

Introduction

The use of nanoparticles as a drug-delivery approach for various difficult-to-formulate reagents is not a new concept (Poste et al., 1976; Poste and Kirsh, 1983; Davis et al., 1987; Douglas et al., 1987; Papahadjopoulos, 1988). In pharmaceutics, nanoparticles are typically defined as a discrete internal phase consisting of an active pharmaceutical ingredient having physical dimensions, less than 1 micron in an external phase. Also, nanoparticles can be designed to form de novo when exposed to the appropriate biological fluid (Shott, 1995). The pharmaceutical industry during the past three decades has developed and marketed several nanoparticlate pharmaceuticals with major emphasis on intravenous products—for example, intravenous nutritional fat emulsion (Intralipid^®) and liposomal products (Doxil^®, AmBisome^®). The inability to achieve high drug loading, the cost of ingredients and processing, and the restricted number of suitable excipients have hitherto limited the broader use of these formulation approaches. Elan’s NanoCrystal^® Technology, which focuses on poorly water-soluble drugs, has addressed many of these major concerns and has successfully expanded the scope and use of nanoparticulates or nanosuspensions to include the oral, inhalation, intravenous, subcutaneous (SubQ) and intramuscular (IM), and ocular routes of delivery (Merisko-Liversidge, Liversidge, et al., 2004)

Four oral products incorporating the NanoCrystal technology are currently marketed in the United States and other countries: Rapamune^®; Emend^®, TriCor 145^®, and MegaceES^® There are also other products in late-stage development delivered by oral, injectable, and inhalation routes using NanoCrystal Technology. Commercial success has spurred renewed interest in the area of nanoparticulate drug delivery, as evidenced by the establishment of several nanoparticle-based companies (Table 1) and a flurry of research activities in the past 10 years. This overview will focus on why this approach has gained such wide acceptance and the advantages of using such an alternate approach to formulate poorly water-soluble molecules for improving drug performance and patient compliance.

The Solubility Challenge

It is estimated that ~40% of active substances identified through combinatorial screening programs are difficult to formulate as a result of their lack of significant solubility in water (Lipper, 1999; Lipinski, 2000, 2002). In one sense, this is understandable. If a molecule must penetrate a biological membrane to be absorbed, the molecule generally must possess some hydrophobic or lipophilic characteristics. The classical approach to deal with this issue is to generate various salts of a poorly water-soluble molecule so as to improve solubility while retaining biological activity. Alternately, screening is continued to identify analogs or prodrugs with enhanced solubility. If successful, there would be little need to pursue a formulation approach that involves nanoparticle production. The problem is that, frequently, these approaches are not successful, and the molecule is abandoned early on in its development process or the product is launched with suboptimal properties including poor bioavailability, lack of fed/fasted equivalence, lack of optimal dosing, presence of extra excipients that pose limitations with respect to dose escalation, and ultimately, poor patient compliance (Table 2). When these types of situations arise, a nanoparticle formulation approach has proven to be very useful and invaluable in all stages of the drug development and has opened opportunities for revitalizing marketed products with suboptimal delivery.

Nanoparticle Formulations

There are various ways in which nanoparticles of poorly water-soluble molecules are generated (Horn and Rieger, 2001; Muller et al., 2001; Rabinow, 2004; Merisko-Liversidge, Liversidge, et al., 2004). The approaches can be viewed as being a building-up approach through synthesis (Liu and Frechet, 1999), self-assembly (Letchford and Burt, 2007; Kawakami et al., 2002; Pouton, 2000), or precipitation of drug molecules (Horn and Rieger, 2001). Alternatively, nanoparticles can be successfully generated using drug-fragmentation processes such as homogenization (Liedtke et al., 2000; Keck and Muller, 2006), microfluidation (Pace et al., 1999), or milling (Liversidge and Cundy, 1995). Milling, which is the process used in generating Elan’s NanoCrystal colloidal dispersions, is the recognized leader in the area of nanoparticulate research today.

No matter what approach is taken to generate drug nanoparticles, in comparison to particulates greater than 1 micron, surface area is increased (Figure 1). This increase in surface area and surface interactions can be positively used to enhance the dissolution rate and provide a platform for controlling the pharmacokinetic properties of the dosage form. However, unless properly dampened, this tremendous increase in surface energy can cause the nanometer-sized drug particles to spontaneously aggregate into a more thermodynamically stable state.

Critical to the generation of physically stable nanoparticles is the use of various excipients that act to dampen or sensitize the surface energy of the nanoparticles by way of steric and/or ionic stabilization. An acceptable stabilizer should first be a reagent that is generally recognized as safe for the intended route of administration. Secondly, a stabilizer must have properties that allow it to properly wet the surface of poorly water-soluble compounds. Finally, a stabilizer should possess properties so as to impart steric and/or ionic stabilization to the surface of the nanoparticles. It should be emphasized that surface stabilization does not necessarily involve chemical grafting of the surface stabilizer to the molecule. Stabilization is typically driven by the mere adsorption of the stabilizer to the surface of the poorly water-soluble compound.

Another consideration for obtaining a physically stable nanoparticle formulation is the ability to control the phenomenon referred to as Ostwald ripening. Ostwald ripening results from uncontrolled precipitation or crystallization of the active, leading to particle-size growth following stabilization (Ostwald, 1897; Boistelle and Astier, 1988; Ng et al., 1996). Ostwald ripening can be eliminated and/or reduced by controlling a number of formulation parameters such as particle size, particle-size distribution, solids content, choice of stabilizer, and a fluid phase with minimal potential to solubilize the poorly water-soluble compound. For instance, if a poorly water-soluble compound is an acid or a base, the pH of the fluid phase can be adjusted so as to minimize ionization; that is, acids would be processed under more acidic conditions, and free bases would be processed at a higher pH.

Nanoparticle dispersions generated using NanoCrystal technology consist of drug and stabilizer, and most commonly, the fluid phase is water. These dispersions are processed using a high-energy media mill with highly cross-linked polystyrene, which provides a highly durable milling media resulting in efficient processing of crude drug crystals to a homogenous nanoparticle–nanocrystalline dispersion with a particle size approximately 1 micron or less. The key characteristics of NanoCrystal formulations for poorly water-soluble molecules are

• the versatility of the approach: suitable for many different classes of compounds, provided the aqueous solubility is less than 10 mg/ml.

• the potential to achieve formulations with high drug loading: 300 mg/g or (30% w/w).

• a drug-to-stabilizer ratio on a weight basis typically 10:1 or lower: 30% drug to 3% or lower stabilizer concentration.

• usefulness for all routes of administration: oral, pulmonary, intravenous, SubQ, IM, and ophthalmic.

• the ability to be readily postprocessed into most commonly used dosage forms: tablets, capsules and sterile products.

• proven technology: four marketed products in the United States, Europe, and Canada.

Nanoparticles: The Biological Benefits

As previously discussed, the property of nanoparticle formulations that make this approach highly beneficial is related to the surface properties imparted on nanometer-sized entities. Although in recent years, tremendous emphasis and focus have been placed on nanotechnology research, as early as 1906, Ostwald published “The World of the Neglected Dimensions,” wherein colloidal nanoparticles exhibited special properties that resided between the molecular and the material sciences (Shott, 1995). In practice, applying NanoCrystal Technology or one of the alternate nanoparticle formulation approaches to the many formulation and performance issues associated with poorly water-soluble compounds in the pharmaceutical industry provide many benefits. These benefits can be categorized into three major areas: formulation-performance improvements related to enhanced dissolution, safer and more patient-compliant dosage forms, and the potential for dose escalation for improvements in efficacy.

Nanoparticles: Improved Performance

The activity of a compound depends on its ability to dissolve and interact with the relevant biological target, either through dissolution and absorption or dissolution and receptor interaction. The poor bioavailability of poorly water-soluble molecules that are not permeation-rate limited can be attributed to dissolution-rate kinetics. The dissolution rate is directly proportional to the surface area of the drug, according to the Noyes-Whitney model for dissolution kinetics (Noyes and Whitney, 1897). Drug crystals reduced in size from 10 microns to 100-nm particles generate a 100-fold increase in surface-area-to-volume ratio. This increase in surface area has a profound impact on the bioavailability of the molecule (Figure 1). For oral drug delivery, drug crystals must dissolve to be absorbed. Although there are some reports that uptake of nanoparticulate materials can be mediated by various cellular or paracellular processes (Jani et al., 1992; Hillery and Florence, 1996), improving absorption remains the primary means for increasing the bioavailability of a poorly water-soluble compound (Horter and Dressman, 2001). If the bioavailability of a poorly water-soluble compound is dissolution-rate limited, approaches that afford delivery using nanometer-sized particles of drug improve bioavailability by enhancing dissolution rate (Liversidge and Cundy, 1995; Peters and Muller, 1996; Horn and Rieger, 2001; Wu et al., 2004; Langguth et al., 2005; Jinno et al., 2006; Kocbek et al., 2006). This maximizes the amount of soluble drug that is free to be absorbed. This is especially true for poorly water-soluble compounds absorbed at a defined region of the gastrointestinal tract (Figure 2). For instance, a large percentage of compounds are absorbed maximally at the duodenal–jejunal area (Wilding, 2000). If dissolution is not complete when the dosage form transits this area, bioavailability will be seriously compromised (Figure 3a). Similarly, if bioavailability depends on the nutritional state of the subject or is not dose proportional, nanoparticle formulations have been shown to reduce or eliminate such effects (Figure 3b and 3c).

For parenteral applications, one of the first questions that should be addressed is when a nanoparticle approach should be considered for a poorly water-soluble drug candidate. If the drug candidate requires an excessive amount of cosolvents or extreme pH conditions or is a low-potency molecule requiring a high-dose, the nanoparticle approach would be of value. To reiterate, nanoparticle formulations basically consist of the drug, an external phase (which is typically water and a minimal amount of stabilizer), and a reagent that has a proven history of safe use for the intended application. Buffering and/or isotonicity agents can be added, provided they are compatible with the formulation and do not disrupt the colloidal stability of the nanoparticulate formulation. For sterility assurance, all current methods available have been applied (i.e., terminal heat, gamma irradiation, filtration, and aseptic production). The method of choice is dictated by the properties of the compound and properties of the colloidal dispersion so that the end product meets the appropriate specification for its intended purpose. In essence, the drug-particle formulation approach provides an opportunity to have safer, less toxic parenteral medications that lend themselves to opportunities for dose escalation, enhanced efficacy, and improved patient tolerability. A few examples demonstrating the benefits of using a nanoparticle technology such as NanoCrystal Technology for parenteral products in clinical studies have been published for intravenous (Mouton et al., 2006) and pulmonary applications (Kraft et al., 2004). Preclinical studies have been published for SubQ (Wisner et al., 1996; Wolf et al., 1994; Merisko-Liversidge, McGurk, et al., 2004) and IM (Shah et al., 2007) applications of NanoCrystal formulations. In all cases, the formulations have proven to be well tolerated and provide alternate formulation approaches for poorly water-soluble therapeutics, thus broadening their applications and use.

One final point that should be addressed is the potential alteration in biodistributional properties that can potentially result when a compound is dosed using a nanoparticulate platform. It is well established that various physical properties of a particulate carrier can affect tissue distribution (Bittner and Mountfield, 2002; Illum et al., 1982; Juliano, 1988). The tissue distribution following intravenous injection of nanoparticulate carriers that involve encasement or encapsulation technology such as lipo-somes and various polymeric carriers have been extensively studied (Moghimi et al., 2001; Gabizon et al., 2003; Singh et al., 2006). Size, surface, and shape are important if the intention is to target or avoid rapid uptake of the particulates by the mononuclear phagocytic system (MPS) of the lung, liver, spleen, and bone marrow.

For drug nanoparticles that do not involve encapsulation technology, tissue distribution is also dictated by the solubility of the compound. If a compound is soluble in the blood pool, the drug nanoparticle, on dosing, will exhibit a pharmacokinetic and tissue-distribution profile very similar to the compound dosed as a solution (Pace et al., 1999; Mouton et al., 2006). Alternatively, if the compound is practically insoluble in the blood pool, when dosed, drug nanoparticles will behave very similarly to the other nanoparticulate platforms described above; that is, size and coating can be used to target or avoid the MPS system (Merisko-Liversidge, Liversidge, et al., 2004; Rabinow, 2004). This ability to use a particulate carrier to control tissue distribution of a compound can be beneficially used to direct high concentrations of drug to diseased sites while limiting exposure to healthy tissue.

What The Future Holds

Nanoparticle-formulation technologies have provided the pharmaceutical industry with new strategies for resolving issues associated with poorly soluble molecules. For new chemical entities, the technology has been of value when used as a screening tool during preclinical efficacy and/or safety studies. “Go/no go” decisions can be made rapidly with a formulation approach that is scaleable and marketable. During development, robust nanoparticle formulations can be postprocessed into various types of patient-friendly dosage forms that provide maximal drug exposure. For marketed products requiring life-cycle management opportunities, nanoparticle formulation strategies provide a means to incorporate an old drug into a new drug-delivery platform, thus opening new avenues for addressing unmet medical needs (Figure 4). For the future, it is most likely that the drug-nanoparticle approaches that have been developed in the past decade would be complemented with the many new approaches for drug targeting and permeation enhancement that have, until now, been primarily academic and a research curiosity. It is also foreseeable that compound-selection strategies will change. Screening efforts to improve the water solubility of a compound will be a thing of the past, and more emphasis will be placed on efficacy and safety that will shorten development times and bring new therapies and diagnostic agents for challenging diseases that have yet to be controlled or eradicated. Since the inception of the area of science devoted to nanotechnology by R. Feynman in the late 1950s (Feynman, 1959), much has happened and many aspects of our material world and well-being have been and will most likely continue to be affected by new developments. The era of nanotechnology in the pharmaceutical industry has begun. During the next decade, it will be interesting to see if all the promises envisioned become a reality.