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A multifaceted approach is needed to resolve the myriad of challenges in developing oral formulations of poorly soluble drugs.
Bringing a drug candidate to successful commercialization is always a challenging task, but it is one that has been made more difficult through the increase of poorly water-soluble drugs. It is estimated that 40% of new drug compounds may be regarded as poorly soluble with that percentage even higher for certain therapeutic classes (1). Improving the oral absorption and bioavailability of poorly soluble drugs is crucial for pharmaceutical companies seeking to bring efficacious drugs to patients in dosing regimens and product forms that are easy to use, affordable, and facilitate patient compliance.
Image Courtesy of Catalent Pharma Solutions
To understand the extent of this challenge and the technologies for bioavailability/solubility enhancement, Pharmaceutical Technology partnered with the Catalent Applied Drug Delivery Institute (see sidebar, "Advancing drug delivery") in the second annual Catalent–Pharmaceutical Technology Landscape Drug Delivery Survey. The study surveyed formulation scientists involved with oral product development in pharmaceutical companies in the United States, Canada, and Europe to understand their key concerns and the technologies used to resolve problems of solubility and bioavailability. The results showed that there are a myriad of technical concerns attendant to solubility/bioavailability and many factors have to be taken into consideration in deciding which approach is optimal for a given API.
Adding complexity to formulations
Consistent with the 2012 survey (2), solubility/bioavailability enhancement remains a major issue. Ninety-two percent of the 2013 survey respondents have worked with Biopharmaceutics Classification System (BCS) Class II (low solubility, high permeability) or Class IV (low solubility, low permeability) compounds, and half always or often work with these compounds.
A poorly soluble compound adds to the complexity of formulation development. "Countless poorly soluble compounds never reach human clinical studies," comments Kurt Nielsen, PhD, chief technology officer and senior vice-president of R&D at Catalent Pharma Solutions. "Better understanding the chemistry of the drug, solubilizers (e.g., polymers, surfactants, and lipids) and the various salt/crystal forms can get more drug candidates through preclinical testing."
The survey results confirm these observations. The two top problems identified by respondents when working with poorly soluble drugs were optimizing the drug-release profile (71% of respondents cited) and stability (66% cited) (see Figure 1). More than half (58%) cited difficulties in identifying excipients with optimal properties, and 49% identified excipient–API interactions as a concern. As would be expected, permeability and absorption in the gastrointestinal tract were also key issues.
Figure 1: Problems encountered when developing oral formulations of poorly soluble APIs. (ALL FIGURES COURTESY OF AUTHORS)
Figure 2 provides more in-depth insight. Fifty-three percent of respondents said that stability of the API was either "always" or "often" a challenge, and 46% cited inter- and intra-patient variability. Other formulation challenges, such as dose uniformity and the food effect on absorption, also were commonly encountered problems (see Figure 2). "Often times, the bioavailability of a poorly soluble drug increases when given with high-fat meals," explains Catalent's Nielsen. "The changes in bioavailability induced by food can negatively impact assessment of safety and efficacy. In addition, eliminating the food effect simplifies dosing instructions for patients," he adds.
Figure 2: Frequency of challenges when developing a formulation for a poorly soluble API.
Other concerns, such as swallowing/taste masking, were cited as frequent problems by 35% of respondents. "Child- and senior-friendly products rely on taste masking for dosing convenience," says Nielsen. "Poorly soluble drugs often need multiple technologies in the same engineered particle to achieve the required taste profile."
Evaluating the technologies
Given the complexity of formulation challenges when working with poorly soluble drugs, the survey examined the importance of factors in deciding on a solubilization strategy. The physiochemical properties of the API and safety were both major factors (see Figure 3). Interestingly, the depth and availability of expertise, including third-party expertise, were significant factors. Ninety-three percent of respondents said that internal expertise and knowledge were "very important" or "somewhat important," and access to third-party expertise and knowledge were commensurately important (see Figure 3). More than half (53%) said bioavailability and solubility issues were a reason to partner.
Figure 3: Importance of factors in choosing a solubilization strategy.
The survey also asked respondents to evaluate solubilization/bioavailability enhancement strategies (see Figure 4). "Enhancing bioavailability is multifactorial and involves approaches to optimize the API, the formulation, and the processing technology to develop the final product form," explains Nielsen. "These factors are codependent and synergistic in most cases, so a 'best-in-class' toolkit for solubility enhancement includes multiple technologies," he adds. For example, a solubilization approach may first address salt formation and excipient selection. Other technologies, such as particle milling/micronization, nanoparticles, spray-drying, hot-melt extrusion, liquid-filled capsules, and softgels, can be further evaluated for suitability for a given formulation challenge.
Figure 4: Evaluation of strategies/technologies in addressing poor solubility.
Ralph Lipp, PhD, head of Lipp Life Sciences, member of the advisory board of the Catalent Applied Drug Delivery Institute, and formerly vice-president of pharmaceutical sciences R&D at Eli Lilly, offered several examples of commercial drugs to illustrate the diversity of solubility/bioavailability enhancement strategies (3). The HIV treatment Kaletra (ritonavir and lopinavir) uses solid dispersions produced by hot-melt extrusion, and the antifungal drug Sporanox (itraconazole) is produced as a solid dispersion by spray-drying. The antinausea drug Emend (aprepitant) uses particle engineering (i.e., nanocrystals/media milling) to improve bioavailability. And the protease inhibitor Fortovase (saquinavir) is formulated in a self-emulsifying drug-delivery system in a softgel capsule (3).
These advances in solubility and bioavailability enhancement are an integral part of meeting the needs of patients for efficacious drugs. "Several essential medicines based on advanced oral drug-delivery technologies provide significant value to patients around the globe today already," says Lipp. "In light of the current trend toward low solubility and poor bioavailability drug candidates in the pipelines of innovators, this class of technologies is of increasing relevance. Formulation scientists applying proven and novel oral drug-delivery technologies will significantly contribute to enabling the next generation of important medicines," concludes Lipp.
1. A. Fahr and D. Douroumous, "Preface" in Drug Delivery Strategies for Poorly Water Soluble Compounds, A. Fahr and D. Douroumous, Eds. (John Wiley & Sons, Chichester, UK, 2013), p xxiii.
2. P. Van Arnum, Pharm. Technol. 36 (4), 128-131 (2012).
3. R. Lipp, "The Innovator Pipeline: Bioavailability Challenges," presented at DCAT Week, Mar. 14, 2013.
Editorial podcast: strategies for bioavailability enhancement
Kurt Nielsen, PhD, chief technology officer and senior vice-president of R&D at Catalent Pharma Solutions, discusses solubilization strategies and bioavailability enhancement with Pharmaceutical Technology Executive Editor Patricia Van Arnum. Listen to the podcast at