Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

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, 

 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. 

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 

). 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)			

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 

). "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."  

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 

). 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 

. 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 

). "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.  

 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 

 Executive Editor Patricia Van Arnum. Listen to the podcast at 

Articles

A multifaceted approach is needed to resolve the myriad of challenges in developing oral formulations of poorly soluble drugs.

Industry Perspectives: Achieving Solutions for the Challenge of Poorly Water-Soluble Drugs

Amgen and Astellas have entered into a strategic alliance to provide new medicines for serious unmet medical needs of Japanese patients. The alliance leverages the complementary capabilities of both companies through an innovative business model that combines Amgen's pipeline candidates with Astellas' deep knowledge of Japanese patient and physician needs, long-term commercial and regulatory experience, and strong presence as a leading company in Japan. 

Both companies will collaborate on the development and commercialization in Japan of five Amgen pipeline medicines, which include four biologics and one small molecule – AMG 145 for the treatment of hyperlipidemia; romosozumab (AMG 785) for osteoporosis; rilotumumab (AMG 102) and AMG 337 for gastric cancer; and blinatumomab (AMG 103) for acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). These medicines range from early to late stages of development in Japan, with the first potential commercial launch expected as early as 2016. 

Amgen and Astellas will also establish a Tokyo-based company under the name Amgen Astellas BioPharma KK. Through this joint venture, which is expected to begin operations on Oct. 1, 2013, both companies will work together to enable Amgen to rapidly build on-the-ground capabilities in Japan. It will become a wholly owned Amgen affiliate in 2020 with the long-term collaboration continuing. 

"Through this alliance, Amgen will work closely with Astellas to leverage its extensive knowledge of the local market," said Robert A. Bradway , chairman and chief executive officer at Amgen, in a 

. "With Astellas' strong capabilities and excellent reputation, this alliance will help accelerate development and commercialization of Amgen medicines for patients in Japan. This alliance reflects our long-term commitment to the Japan market and is an important step in our global expansion efforts."  

"We look forward to entering this alliance with Amgen and believe it will strengthen our pipeline to address unmet medical needs, as well as enable us to obtain growth drivers," said Yoshihiko Hatanaka, president and CEO of Astellas. "We will work closely with Amgen to build the joint venture, which will provide innovative medicines to patients in Japan." 

Amgen and Astellas have entered into a strategic alliance to provide new medicines for serious unmet medical needs of Japanese patients. The alliance leverages the complementary capabilities of both companies through an innovative business model that combines Amgen's pipeline candidates with Astellas' deep knowledge of Japanese patient and physician needs, long-term commercial and regulatory experience, and strong presence as a leading company in Japan.

Amgen and Astellas Form Joint Venture to Address Unmet Medical Needs in Japan

Pfizer has discontinued a Phase III study of its investigational cancer drug, inotuzumab ozogamicin, in relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) after it failed to show benefit in overall survival. The company has notified study investigators and appropriate regulatory authorities of the decision. Investigators will work with patients in the study on an individual basis to determine an appropriate course of action. 

The randomized, open-label, two-arm study (B1931008) evaluated the safety and efficacy of inotuzumab ozogamicin in patients with relapsed or refractory CD22+ aggressive NHL who are not candidates for intensive high-dose chemotherapy. The drug was administered once a month in combination with Roche's Rituxan (rituximab) and compared with either Teva's Treanda (bendamustine) plus rituximab , or Eli Lilly's Gemzar (gemcitabine) plus rituximab. 

An independent data monitoring committee concluded during an interim analysis that treatment with inotuzumab ozogamicin plus rituximab would not meet the primary endpoint of improving overall survival when compared to the comparator arm. No new or unexpected safety issues were identified. 

 “We are working to better understand the findings from this review to determine if there are any patterns of outcome that may help us gain greater understanding of the potential effect of inotuzumab ozogamicin in specific patient subsets within the heterogeneous patient population enrolled in this trial,” said Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs for Pfizer’s Oncology Business Unit, in a 

. “Hematologic cancers are a complex group of diseases, with more than 70 different types of lymphomas, leukemias or myelomas that require unique treatment options. We remain committed to evaluating inotuzumab ozogamicin in patients with hematologic malignancies.” 

Inotuzumab ozogamicin is an antibody-drug conjugate comprised of a monoclonal antibody targeting CD22, a cell surface antigen expressed on about 90% of B-cell malignancies, linked to a cytotoxic agent. The molecule was developed by Pfizer and Celltech, which is now owned by UCB. Pfizer stated that it will continue evaluating inotuzumab ozogamicin in adult acute lymphoblastic leukemia (ALL). The INO-VATE ALL Study (B1931022) is an open-label, randomized, Phase III study comparing inotuzumab ozogamicin to a defined investigator’s choice of chemotherapy in patients with relapsed or refractory CD22+ ALL. 

Pfizer has discontinued a Phase III study of its investigational cancer drug, inotuzumab ozogamicin, in relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) after it failed to show benefit in overall survival.

Pfizer Halts Phase III Trial of Cancer Drug in NHL Due to Futility

Novo A/S, the holding company of Denmark's Novo Nordisk, has acquired Xellia Pharmaceuticals and purchased all shares of the group for approximately US$ 700 million. Xellia will now revert to Danish ownership with headquarters in Copenhagen. Closing of the transaction is expected to take place during the third quarter of 2013 and will be subject to relevant competition law approvals. 

Xellia was spun-out from Alpharma in 2008. The company’s management and international investor 3i have successfully transformed the business from an API manufacturer to a specialty pharmaceutical focused on the development and manufacturing of anti-infective therapies for multidrug resistant infections. Products are manufactured using fermentation-based biological processes at Xellia’s facilities in Denmark, Norway, Hungary and China. 

Xellia has a substantial pipeline of generic anti-infective treatments, which will be advanced towards commercialization in years to come. Novo’s investment will strengthen Xellia’s R&D capacity and expand its global manufacturing footprint to further scale its finished-dosage-form business. 

 “When the management team bought out Xellia in 2008, we had ambitious plans, which we were able to implement with 3i’s support, expertise and commitment. We have successfully transitioned the business in order to become a world leader in the supply of certain anti-infective products,” said Carl-Åke Carlsson, CEO of Xellia in a 

. “Now, as we focus on the future and the further development of the business, including the launch of our novel antibiotics pipeline, we look forward to working with Novo and benefitting from their expertise in the life science sector. Together with Novo, we can strengthen the positive development that Xellia has achieved over the past few years, and at the same time, the investment by Novo will help accelerate our developments further.” 

Novo’s CEO, Henrik Gürtler, said, “Xellia strongly complements our portfolio of significant life science companies in which we have major investments. This acquisition is well aligned with our strategy, and is one of the largest investments made by Novo A/S to date. The products that Xellia supplies are critical life-saving treatments for many patients around the globe, and are manufactured by use of fermentation technologies, which is a manufacturing approach similar to that of Novo Nordisk, Novozymes and Chr. Hansen. Xellia is a leader in its business area, and a company with a long Scandinavian heritage, which we are proud to bring back into long-term Danish ownership. We look forward to establishing a strong relationship with Xellia’s experienced management team and invest together in the future success of the Company.” 

Novo A/S, the holding company of Denmark's Novo Nordisk, has acquired Xellia Pharmaceuticals and purchased all shares of the group for approximately US$ 700 million.

Novo Acquires Xellia for US$ 700 Million

AbbVie and Galapagos have extended their collaboration on the clinical development of GLPG0634 to include Crohn's disease. Under the terms of the collaboration, in addition to previously agreed upon financial terms, Galapagos will fund and complete a Phase II program in Crohn's disease, designed to facilitate rapid progression into Phase III. The Phase II study is expected to complete in the second quarter of 2015 and AbbVie will pay Galapagos $50 million upon successful completion. AbbVie will fund and conduct clinical development programs beyond Phase II, including regulatory and commercialization activities. 

A 20-week Phase II A/B study evaluating GLPG0634 in 180 patients with Crohn's disease will begin in early 2014. Induction of disease remission and early maintenance of the agent’s beneficial effects in Crohn's disease will be measured as study endpoints, with topline results expected in the second quarter of 2015. Galapagos will conduct this Phase II trial in parallel with a Phase IIB study in rheumatoid arthritis (RA) patients. 

Crohn's disease is a serious chronic, inflammatory autoimmune disease of the gastrointestinal (GI) tract affecting more than one million people in Europe and more than 500 000 people in the US. Janus kinase (JAK) enzymes play a key role in the signaling of several cytokines involved in autoimmune diseases. JAK inhibitors have the potential to become effective treatment options because of their immune-modulating effects. 

GLPG0634 is an orally-available, novel Janus kinase (JAK) inhibitor with selectivity for JAK1 developed by Galapagos. By inhibiting JAK1, GLPG0634 blocks signaling for several key pro-inflammatory cytokines such as interleukin 6 (IL-6). 

"Galapagos and AbbVie are moving forward with GLPG0634, expanding the scope of the development program into inflammatory bowel disease. The innovative Phase II program in Crohn's disease is designed to move rapidly into Phase III when successful," said Onno van de Stolpe, CEO of Galapagos, in a 

. "Galapagos is in a strong financial position to fund the Crohn's program, in addition to the Phase IIb program with GLPG0634 in RA and our other proprietary clinical and preclinical programs. Our pipeline continues to mature in stage and scope, now that we have three Phase II molecules in five inflammatory indications, all with readouts by mid 2015 or earlier." 

"AbbVie supports the start of this innovative study in Crohn's disease with GLPG0634. Our experience within gastroenterology, combined with a novel alternative treatment for this disease may provide a greater benefit to patients in the future," said Scott Brun, MD, vice president, pharmaceutical development, AbbVie. 

AbbVie and Galapagos have extended their collaboration on the clinical development of GLPG0634 to include Crohn's disease.

AbbVie and Galapagos Extend GLPG0634 Collaboration

  that three of its cancer compounds— moxetumomab pasudotox, olaparib and selumetinib—will be moving forward to Phase III clinical development. Oncology is one of the company’s core therapy areas and accelerating the development of a number of new molecular entities in its pipeline is a strategic priority. 

The first patient has been enrolled in a Phase III trial evaluating moxetumomab pasudotox in adult patients with hairy cell leukaemia who have not responded to or relapsed after standard therapy. The trial is sponsored by the Cancer Therapy Evaluation Program (CTEP), a program within the Division of Cancer Treatment and Diagnosis at the US National Cancer Institute. Moxetumomab pasudotox is a CD22 immunotoxin composed of a binding portion of an anti-CD22 antibody fused to a toxin. After binding to CD22, the molecule is internalised, processed and will release its modified protein toxin that inhibits protein translation, causing tumour cell death. 

 “This is further evidence of AstraZeneca’s commitment to invest in distinctive science in our core therapy areas and to accelerate our Phase III pipeline,” said Dr. Bahija Jallal, executive vice president of MedImmune, which is AstraZeneca’s global biologics research and development arm. “We believe that targeted therapies, which address the underlying mechanisms of disease, are the future of personalised healthcare to help meet the unmet needs in treating cancer patients. MedImmune’s partnership with the National Cancer Institute is an example of our focus on innovative technologies designed to target cancer cells in more effective ways.” 

AstraZeneca also plans to begin Phase III evaluation of olaparib during the second half of 2013 based on Phase II data which demonstrated the agent’s potential as a maintenance treatment for platinum-sensitive relapsed ovarian cancer patients carrying BRCA gene mutations. Olaparib is a potential first-in-class oral poly ADP ribose polymerase (PARP) inhibitor that exploits DNA repair pathway deficiencies to preferentially kill cancer cells. 

Results from the Phase II trial will be presented at the American Society of Clinical Oncology (ASCO) Congress in Chicago on 31 May to 4 June. This study evaluated the efficacy of olaparib maintenance therapy compared with placebo in high grade platinum-sensitive relapsed serous ovarian cancer patients. The pre-planned subgroup analysis retrospectively evaluated patients with confirmed gBRCA mutation status and tBRCA mutation status from archival tumour samples. 

The company will also present findings from a selumetinib study for the treatment of advanced uveal (eye) melanoma. This randomised trial, sponsored by the National Cancer Institute, compared selumetinib with temozolomide (chemotherapy) in patients with metastatic uveal melanoma. Results from an AstraZeneca-sponsored study will also be presented. This randomised study evaluated selumetinib in combination with dacarbazine as a first-line treatment for advanced cutaneous melanoma patients harboring a mutation of the BRAF gene. 

Selumetinib is planned to progress into Phase III evaluation for non small cell lung cancer patients during the second half of this year. The study will investigate selumetinib in combination with docetaxel as a second-line therapy for patients with KRAS mutation-positive and metastatic non small cell lung cancer. 

 “As one of our three core therapy areas, we are committed to investing in innovative science in oncology to address areas of high unmet medical need,” said Menelas Pangalos, executive vice president of Innovative Medicines and Early Development at AstraZeneca. “The progress we are making with olaparib and selumetinib, combined with our broader early phase portfolio across small molecules and biologics, puts us in a strong position to deliver our pipeline of targeted cancer medicines.” 

AstraZeneca announced that three of its cancer compounds-moxetumomab pasudotox, olaparib and selumetinib-will be moving forward to Phase III clinical development. Oncology is one of the company's core therapy areas and accelerating the development of a number of new molecular entities in its pipeline is a strategic priority.