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

Adeline Siew, PhD

 Ilaris (canakinumab), a selective, fully human, monoclonal antibody that inhibits interleukin-1 beta (IL-1 beta), has been approved in the EU for symptomatic pain relief in patients suffering from gouty arthritis whose condition cannot be managed with current treatments. Approval was supported by data from two Phase III trials, which demonstrated that patients treated with Ilaris experienced significantly greater pain relief compared to the injectable steroid triamcinolone acetonide. Adverse events were mainly mild to moderate, with infections of the upper respiratory tract and nasopharyngitis being the most frequent. 

 Ilaris, developed by Novartis, is administered in a single, subcutaneous injection of 150 mg. This is the first biologic approved by the European Commission for a gouty arthritis indication. The EC also granted an additional year of data exclusivity to Novartis based on the significant clinical benefit over existing treatments demonstrated for Ilaris. 

 "The approval of Ilaris for acute gouty arthritis attacks in patients without appropriate treatment options provides new hope for those debilitated by this excruciating condition," said David Epstein, division head of Novartis, in a 

. "Ilaris targets interleukin-1 beta, a key player in gouty arthritis inflammation. Our vision is to realize the potential of Ilaris wherever IL-1 beta plays a key role and available treatment options don't give patients the help they need." 

 Gouty arthritis, commonly known as gout, is a serious, chronic and progressive inflammatory disease affecting 1 to 4% of adults. Gouty arthritis attacks occur when the body produces a strong inflammatory response to uric acid crystals forming in the affected joints of the toe, foot, ankle, or knee. This disease is associated with a high prevalence of comorbidities, including hypertension, kidney disease, diabetes, dyslipidemia and cardiovascular disease, which can consequently lead to contraindications for existing therapies and complications for disease management. 

 Ilaris, the only approved fully human monoclonal antibody targeting IL-1 beta, is being investigated in a number of rare inflammatory conditions, including systemic juvenile idiopathic arthritis (SJIA), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), colchicine-resistant familial Mediterranean fever (FMF), and cardiovascular disease. The agent has been approved in more than 60 countries, including in the EU, US, Switzerland and Japan for the treatment of cryopyrin-associated periodic syndromes (CAPS). 

Articles

Ilaris (canakinumab), a selective, fully human, monoclonal antibody that inhibits interleukin-1 beta (IL-1 beta), has been approved in the EU for symptomatic pain relief in patients suffering from gouty arthritis whose condition cannot be managed with current treatments.

First Biologic Approved in the EU for Gouty Arthritis

 AstraZeneca's three patents protecting Crestor (rosuvastatin) have been ruled invalid by the Federal Court of Australia. The patents include a formulation patent expiring in 2020, a patent related to the use of rosuvastatin for the treatment of heterozygous familial hypercholesterolemia, which will expire in 2021, and a patent for treating hypercholesterolaemia with an expiry date of 2020. These patents were challenged by Apotex, Watson Pharma, and Ascent Pharma. 

 AstraZeneca has expressed disappointment in the court’s ruling on the validity of these three patents. The company is, however, committed to defending its intellectual property protecting Crestor in Australia. This decision is being carefully reviewed while AstraZeneca continues to evaluate all legal options at this stage, which could include filing an appeal and seeking to maintain existing preliminary injunctions. 

 from the company has stated that the decision of the Federal Court only applies in Australia and will have no impact on the validity of Crestor patents in other countries. It also does not affect AstraZeneca’s financial guidance for 2013, which will, in accordance with normal practice, be reviewed in conjunction with the announcement of the company's first quarter financial results on Apr. 25, 2013. 

 Sales of Crestor in Australia amounted to approximately $350 million in 2012. 

AstraZeneca's three patents protecting Crestor (rosuvastatin) have been ruled invalid by the Federal Court of Australia.

AstraZeneca's Crestor Patents Ruled Invalid in Australia

 spoke to Robert Langer, professor at the Massachusetts Institute of Technology and founder of BIND Biosciences; Stephen Zale, vice-president of development at BIND Biosciences; and Yanli Zhao, assistant professor and national research foundation fellow at Nanyang Technological University, Singapore, about engineering nanoparticles with optimal properties for use in cancer therapies.

Nanoparticles have significantly changed the scientific landscape of disease treatment, prevention, and diagnosis, generating a new wave of nanoscale drug-delivery strategies. From solubility/bioavailability enhancement (1, 2) and targeted drug delivery (3, 4) to controlled/sustained release (5, 6) and protection of labile molecules (e.g., proteins, peptides, and DNA) from enzymatic degradation (7, 8), these structures can be manufactured, controlled, and manipulated to take on novel properties and functions that have opened new doors in the biomedical arena. 

 Sciepro/Science Photo Library/Getty Images 

While nanoparticles may vary in size ranging from 10 nm to 1000 nm, nanomedicines are typically less than 200 nm (9). Nanoparticles made from natural or synthetic polymers have gained popularity because of their stability and ease of surface modification. They can be engineered to achieve controlled drug release as well as specific localization at disease sites by modification of the polymer characteristics and surface chemistry. For example, it has been well established that nanoparticles accumulate preferentially at tumor and inflammatory sites due to the enhanced permeability and retention effect (EPR) of the vasculature (9–11). At the target site, the biodegrable polymeric nanoparticles can act as a local drug depot that provides continuous release of the encapsulated therapeutic agent.  

These advantages offered by nano-particles for targeted drug delivery are a result of their small size and the use of biodegradable materials. The small size enables the nanoparticles to overcome biological barriers (e.g., gastro-intestinal epithelium, tumor vasculatures, and endothelium of inflammatory sites) and achieve cellular uptake while the use of biodegradable materials allows for sustained drug release at the target site (9–11).  

Advances in the development of nanoparticles have seen these systems being translated into clinically useful medicines, particularly in the treatment of cancer. Examples of nanoparticle-based medicines approved by FDA and EMA as cancer therapies include Doxil and Myocet (liposomal formulations of doxorubicin), DepoCyt (liposomal cytarabine), Dauno-Xome (liposomal daunorubicin), Abraxane (an albumin-bound formulation of paclitaxel), and Genexol-PM (a polymeric-micelle formulation of paclitaxel).  

A number of nanoparticle-based formulations are in clinical development as potential treatments for cancer. NanoCarrier's nanoplatin (NC-6004), which consists of cisplatin incorporated into micellar nanoparticles composed of polyethylene glycol (PEG) and polyglutamic acid block copolymers, is undergoing Phase II evaluation in patients with advanced or metastatic pancreatic cancer (12). Preclinical results showed that nanoplatin accumulated in cancer cells and had significantly lower nephro-toxicity and neurotoxicity (13). In a Phase I study conducted in the UK, the formulation was well tolerated in patients with solid tumors, providing sustained and prolonged release with minimal nephrotoxicity and no significant myelosuppression, ototoxicity, emesis, or neurotoxicity (14). 

Cerulean's CRLX101 consists of the topoisomerase-1 inhibitor, campto-thecin, covalently conjugated to a PEG-β-cyclodextrin copolymer that self assembles into nanoparticles of approximately 30 nm in diameter (15). Unlike camptothecin, these nanoparticles have a long circulation half-life, enabling them to accumulate in the tumors. Following uptake of CRLX101 into tumor cells, the active camptothecin is gradually released from the nanoparticles, providing a sustained concentration of the drug in tumors. It has been observed that this sustained concentration of camptothecin at the tumor site results in the inhibition of HIF-1 alpha, a hypoxia-induced transcription factor known to regulate cancer cell survival, metastasis and drug resistance. Studies have demonstrated that CRLX101 nanoparticles augment camptothecin efficacy by facilitating localization and retention at the target tissue, increasing intracellular drug deposition, providing a sustained supply of active camptothecin, and prolonging drug activity at the target site (16). CRLX101 is in Phase II evaluation for the treatment of various tumor types (15).  

Nippon Kayaku's NK105, a nanoparticle-based formulation of paclitaxel incorporated into block copolymers of PEG-polyaspartate, was developed to enhance the antitumor activity of paclitaxel while reducing adverse effects such as neurotoxicity, myelosuppression, and allergic reactions (17). NK105 is currently in Phase III development and studies are being conducted to investigate if NK105 can improve progression-free survival in patients with metastatic or recurrent breast cancer.  

Other examples of molecular-targeted nanoparticle-based cancer therapeutics in clinical development include BIND Biosciences' BIND-014 (Phase I), Calando's CALAA-01 (Phase I), Mebiopharm's MBP-426 (Phase I/II), and SynerGene's SGT53-01 (Phase I). 

 spoke to Robert Langer, professor at the Massachusetts Institute of Technology (MIT) and founder of BIND Biosciences; Stephen Zale, vice-president of development at BIND Biosciences; and Yanli Zhao, assistant professor and national research foundation fellow at Nanyang Technological University (NTU), Singapore, about engineering nanoparticles with optimal properties for use as cancer therapies. 

What are the key considerations when designing nanoparticles for the delivery of cancer therapeutics? How do you engineer these nanoparticles to achieve targeted delivery? 

This is a complicated question because the effects of many characteristics on how nanoparticles behave in the human body are interdependent on one another. Broadly speaking though, for nanoparticles to be effective, they must be able to circulate in the bloodstream, extravasate into diseased tissues, and release their therapeutic payload at a rate that provides high concentrations at the target site.  

We use particles based on copolymers of polylactic acid (PLA) or copolylactic/glycolic acid (PLGA) and PEG, and attach targeting ligands to the end of the PEG chain. We have developed a particle-manufacturing process that encapsulates the drug payload in the PLA/PLGA core of the particle and orients the PEG and the targeting ligand toward the surface of the particle. PEG gives the particle a water-like corona, which disguises the particle from the systems in the body that would otherwise remove them from the bloodstream within minutes after administration. As a result, our nanoparticles display circulation half-lives of nearly 24 hours and are able to concentrate drugs in tumors at levels typically 10 times greater than when the same dose is given as a solution. 

We have used a broad range of targeting ligands, including antibodies, antibody fragments, aptamers, peptides, and small molecules. We have studied a range of targets including, for example, well-established and clinically validated tumor targets such as the prostate-specific membrane antigen (PSMA) and human epidermal growth factor receptor 2 (HER2), and have discovered our own targets and ligands in areas such as cardiovascular disease. At BIND, rapid clinical translation is important, and therefore, the focus is on validated targets in areas of unmet clinical need such as cancer, and primarily using peptide and small-molecule ligands for targeting.  

There are many antigens or receptors expressed by cancer cells or the surrounding tissue that can be targeted by peptide and small-molecule ligands, which are inherently more stable and less complex than macromolecular ligands such as antibodies and aptamers. For examle, while our initial studies employed an aptamer that targets PSMA, BIND switched to a PSMA-binding small molecule in BIND-014, which enabled them to quickly move into clinical development with a simple, pharmaceutically stable, and well-characterized targeted particle. This PSMA-targeted particle can be manufactured reproducibly at large scale and has been shown to be nontoxic in animal studies. 

Nanoparticles tend to aggregate as a result of their large surface-to-volume ratio in biological media. When nanoparticles agglo-merate, they not only lose their intended functionality, but are quickly recognized and effectively removed by the mononuclear phagocytic cells in the reticuloendothelial system (RES) of the liver and spleen. This sequestration is often increased by the surface coating of nanoparticles with a corona of proteins that leads to opsonization and enhanced phagocytosis by the RES.  

A strategy to maintain good dispersion of drug-loaded nanoparticles in biological media is by surface modifications with PEG polymers. PEG has been known to prevent protein adsorption (opsonization) on the nanoparticle surfaces, enhance circulation time, reduce nonspecific RES uptake, and facilitate preferential accumulation at tumor sites through the EPR effect. Passive targeting in itself, however, is often not enough to eradicate the side effects of cytotoxic drugs and divert the anticancer therapy away from healthy cells to selectively target cancer cells.  

To further enhance the targeting ability of drug-loaded nanoparticles, these systems must also be coupled with targeting agents that can actively bind to over-expressed antigens or receptors on the surface of cancer cells. Drug-loaded nanoparticles can be engineered to recognize and bind to cancer cells through ligand-receptor interactions and the bound nanoparticles are internalized before the loaded drug is released inside the cells. Finally, there is another concern that these drug-delivery systems should release the loaded drug rapidly upon accumulating at tumor sites and after being taken up by cancer cells. 

Designing nanoparticles for selective targeting

Could you describe your research on nanoparticles as targeted drug delivery systems in the treatment of cancer?  

The idea of employing targeted nanoparticles to bring cancer drugs to the site of disease and increase their safety and effectiveness has been around for several decades, but until recently the solution has been elusive. A major obstacle has been the inability to achieve the optimal interplay of particle characteristics that confer targeting of diseased cells, evasion of particle clearance mechanisms, and controlled release of the encapsulated drug payload.  

In the mid 2000s, Omid Farokhzad at Harvard Medical School and I developed a new approach for targeting of drug-loaded polymeric nanoparticles to disease sites, including cancer cells and diseased vasculature. The technology is based on a novel self-assembly process which allows formation of nanoparticle libraries consisting of hundreds or even thousands of distinct nanoparticle formulations. We developed methods to screen these particles to identify the ones with the optimal properties for diseased-tissue targeting and avoidance of off-target tissues. Importantly, the particles we developed are composed of biocompatible and biodegradable polymers that are commonly used in other pharmaceutical products such as biodegradable microspheres and PEGylated proteins. 

 BIND is now using this platform to develop targeted nanoparticles called Accurins to treat cancer and other diseases. The company has set about developing Accurins for clinical evaluation. The most advanced of these nanoparticles is BIND-014, an Accurin targeted to a cell-surface receptor expressed in all major solid tumor types. BIND-014 contains the chemotherapeutic agent docetaxel, which is a blockbuster drug in its own right, with approvals in five solid tumor indications, including breast, lung, and prostate. BIND-014 has just completed a Phase I clinical trial and is advancing into Phase II. The early results for BIND-014 are very promising. We have seen that the drug behaves very differently from conventional docetaxel, including showing signs of activity at relatively low doses and in tumors where docetaxel is not normally used.  

 Our multifunctional meso-porous silica nanoparticles for cancer-targeted and controlled drug delivery have three components—the mesoporous silica nanoparticle core, the amino-β-cyclodextrin, the PEG polymers functionalized with an adamantane (Ad) unit at one end and a folate (FA) unit at the other end (Ad-PEG-FA) (18). The surface of mesoporous silica nanoparticles is firstly functionalized with amino-β-cyclodextrin rings bridged by cleavable disulfide bonds, blocking drugs inside the mesopores of the nanoparticles. The Ad-PEG-FA polymers are immobilized onto the nanoparticle surface through strong  -cyclodextrin/adamantane complexation. The multifunctional nanoparticles can be efficiently trapped by folate-receptor-rich cancer cells through receptor-mediated endocytosis, where they then rapidly release the loaded anticancer drug inside the cell when triggered by the acidic pH and intracellular glutathione.  

Several functions are built onto the multifunctional nanoparticles to deliver drugs in an optimal fashion. These functions include:  

PEGylated coating on the nanoparticle surface to enhance long-term stability of the nanoparticles under physiological conditions 

Active cancer targeting by the folate ligands attached onto the nanoparticle surface

pH-triggered drug release to allow drug released within acidic intracellular compartments such as endosome and lysosome (pH 5.0–5.5) 

Positively charged nanoparticle surface under acidic conditions to facilitate the transfer of the nanoparticles from endosome to cytoplasm 

Glutathione-induced cleavage of the disulfide bonds to further enhance the drug release in the cytoplasm of cancer cells. 

The engineering of these functions onto the single nanoparticle entities significantly enhances the efficacy of anticancer drug delivery to cancer cells, while reducing the cytotoxic effects on healthy cells. 

 experiments demonstrate that doxorubicin-loaded multifunctional mesoporous silica nanoparticles could effectively release doxorubicin to tumor sites resulting in significant inhibition of the tumor growth. 

8.  S. Hauptstein and A. Bernkop-Schnurch, 

10.   A.Z. Wang, R. Langer, and O.C. Farokhzad, 

11.  A. Swami et al., "Nanoparticles for targeted and temporally controlled drug delivery," in 

Multifunctional Nanoparticles for Drug Delivery Applications, 

S. Svenson and R.K. Prud'homme, Eds. (Springer, US, 2012), pp. 9-29.  

www.nanocarrier.co.jp/en/research/pipeline

Engineering nanoparticles with optimal properties for use in cancer therapies.

Nanoparticles: Facilitating Targeted Drug Delivery in Cancer Therapy

Poor solubility remains a major challenge in formulation development. As the number of new chemical entities that are poorly soluble keeps increasing, formulation scientists are faced with the important task of addressing these solubility issues so that more compounds can be translated into clinically useful medicines. A popular approach to this problem is to use polymers as solubilizing excipients. 

 brought together a panel of industry experts for a special forum to discuss solubilizing polymers and the related formulation strategies for poorly soluble drugs. Participants include Michael Morgen, PhD, director of new technology at Bend Research; Brian Koblinski, strategic marketing manager at Dow Wolff Cellulosics; and Firouz Asgarzadeh, PhD, director of technical services, North America, pharma polymers & services at Evonik Corporation. 

Chemical classes and physicochemical properties

 Various polymers/copolymers can be used in solubility enhancement. What would you identify as key chemical classes for these excipients and the related properties that contribute to their function as a solubilizer? In what formulation types are they used?  

 Cellulosics, poly(vinylpyrrolidone) (PVP) and its copolymers, acrylates, and poly(ethylene oxide) (PEO) and its copolymers are some of the key classes of polymers that have been investigated as solubilizing excipients for oral formulations. Effective solubilizing polymers tend to be amphiphilic in nature, meaning they have both hydrophobic and hydrophilic sites that enable them to interact favorably with low-solubility (i.e., hydrophobic) compounds and yet disperse and dissolve in aqueous environments such as the gastrointestinal (GI) tract. The specific interactions of the polymer with itself, the API, and the aqueous medium can result in a range of solubilizing structures, including micelles, colloids, and ionic complexes. 

Solubilizing polymers are used in many types of formulations, depending on the route of administration, dose, API properties, and specific delivery challenges associated with the particular development program. For oral delivery, solid amorphous dispersions can be an enabling formulation approach for improving the bioavailability of Biopharmaceutics Classification System (BCS) Class II and IV compounds. Two common processes for making such dispersions are spray-drying and hot-melt extrusion (HME). Spray-drying can be used to form a monolithic dispersion particle or alternatively, the dispersion can be deposited onto a solid support to increase surface area and dissolution rate. Two-phase physical mixtures of polymer and crystalline API in a solid dosage form can be used to solubilize the API. For early scoping studies, liquid solutions of polymer (e.g., PEO) and the API may be valuable. In each case, the choice of formulation type and the manufacturing process will depend on the requirements of the specific drug-development program.  

 Cellulose-based polymers, such as hypromellose (HPMC) and hydroxypropyl methyl cellulose acetate succinate (HPMCAS, also known as hypromellose acetate succinate) have high utility in solid dispersions. Their safety and low drug reactivity make them an ideal candidate for most drugs. Spray-dried dispersions (SDDs) and HME are the most common technologies for solubilization used with cellulosic polymers. Cellulosic polymers maintain stable solid dispersions, inhibit API crystallization, and can promote supersaturation of the drug. Options in viscosity and substitution levels both with HPMC and HPMCAS help a formulator to optimize performance in solubility enhancement as well as in material processibility, which includes postprocessing SDDs and HME formulations into traditional dosage forms such as tablets and capsules. 

 The chemical structure and physicochemical properties of APIs and polymers play a major role in the formation of polymer-API solid solutions. Poly(meth)acrylates, cellulosic polymers and PVP are extensively used in solid dispersion formulation development. Each class of polymers contains specific chemical bonds that can interact with specific groups on APIs. HME, SDD, and coprecipitation techniques transform poorly-soluble crystalline drugs into an amorphous, metastable, higher-state-of-energy structure dispersed in a polymer matrix that is more easily solubilized, leading to enhanced solubility. Strong hydrogen bonding and ionic interactions between the amorphous API and the polymer would inhibit or retard the recrystallization of the API even with polymers that have low glass-transition temperatures (Tg's). Because there is a myriad of API structures with different physicochemical characteristics, there is not one class of polymers that would be considered better solubilizers than others. It is essential to select appropriate polymers for screening studies based on a good understanding of both the polymer and drug structures and the possible interactions they may have. 

 What factors determine the type of pharma polymer to use in a given formulation to improve solubility? Can you provide a specific example to illustrate the decision points used in a challenging formulation, including any relevant data?  

 When selecting solubilizing polymers, the performance, stability, and manufacturability of the associated formulation must all be considered. The chemical and physical properties of the solubilizing polymer affect all three of these attributes; hence, it is often necessary to balance polymer properties to achieve the optimum solubilized formulation. Usually, the properties of the API and the requirements of the development program (e.g., dose) will result in greater emphasis on one or two of these three formulation attributes. 

Ideally, the solubilizing polymer will interact with the API to sustain elevated API concentrations in the GI tract in one or more high-activity species (e.g., freely dissolved drug, micelles, and colloids). For APIs that are particularly prone to precipitation into a low-energy form, significant polymer/API interaction is especially important. For many APIs, polymers that have a substantial hydrophobic interaction with the API are preferred. HPMCAS is one of the more broadly useful dispersion polymers for forming and sustaining high-energy species in aqueous media with BCS Class II and IV compounds. 

Both the chemical and physical stability of solubilized formulations are important. Of the two, chemical stability tends to be more API-specific. Solid-state physical stability is usually an important consideration for solubilized formulations, especially when the drug is in the amorphous state. A key driver for good solid-state physical stability of amorphous forms, such as polymeric dispersions, is low molecular mobility, which can be achieved by choosing a dispersion polymer that has a high Tg. A number of common solubilization polymers, such as PVP and its copolymers and cellulosics, have high Tg in their dry state. Water, however, can plasticize materials and reduce the Tg. Polymers with low-moisture uptake as a function of humidity, such as HPMCAS, often impart better physical stability to amorphous drug forms in the solid state under ambient storage conditions than the more hygroscopic polymers. A high Tg is less important for physical stability when the API and polymer are miscible, which is often the goal for HME formulations. 

Manufacturability is an important consideration when selecting solubilization polymers. For spray drying, high solubility and low viscosity in the volatile organic solvents used during processing are important. HME processing requirements are somewhat different, requiring good thermal stability, especially when formulating drugs with high melting temperature (Tm). In addition, the miscibility of the API and polymer is often desirable in HME processing to achieve a single dispersion phase. 

 The chemical structure of the API as well as the technology used to achieve improved solubility impact polymer choice. SDD and HME are two common technologies used to create solid dispersions to improve solubility. Each technique has its own set of polymer parameters best suited for use in the technology, yet the overall goals for both methods are to render the drug amorphous, inhibit drug crystallization, and to maximize drug load in the formulation.  

Characteristics of polymers best suited for spray drying include the ability to form a sprayable polymer-drug solution. Polymers that result in low-solution viscosity will facilitate higher concentrations of drug and polymer in the solution, thereby reducing solvent usage and increasing formulation versatility.  

To be suitable for HME, a pharmaceutical polymer must be melt processable at conditions that do not degrade the formulation components. Polymers with low Tg as well as a broad thermal-processing window are well suited for HME; however, the Tg must be high enough to prevent recrystallization at storage conditions. The polymer must also have good crystal nucleation inhibition to maintain the API at supersaturated levels upon dissolution. Due to a relatively higher polymer content in many HME formulations, polymer safety during processing (i.e., no toxic degradation products) and in the final formulation is also critical. 

 Polymers used for solid-dispersion formation should have reasonably high Tg's to allow the stabilization of the amorphous API structure 

molecular motion restriction (i.e., the glassy state) at storage conditions that are usually below the finished product Tg. Polymers with lower Tg's have been shown to form stable solid solutions when strong hydrogen bonding or ionic interactions are formed between the polymer and the active. The strong hydrogen bonding and ionic interactions contribute to  the formation and stabilization of solid solutions firstly, by breaking the crystal lattice of poorly-soluble, highly crystalline drugs, and secondly, by delaying the recrystallization as the molecularly dispersed API would prefer to stay bound to the polymer.  

Another consideration when using melt extrusion for preparation of solid dispersions is that the polymer Tg should be sufficiently low to allow acceptable processing temperatures minimizing polymer and/or drug degradation. The cationic amino methacrylate copolymer (Eudragit E, Evonik) forms solutions with the anionic drug ibuprofen due to strong hydrogen bonding and ionic interactions at extrusion temperatures as low as 60 °C. Although the Tg's of ibuprofen/Eudragit E solid solution extrudates are as low as 10 °C to 20 °C, they remain amorphous and stable at room temperatures due to the strong hydrogen bonding and ionic interactions. API melting during melt extrusion is not a requirement but helps with solid-solution formation. Solid solutions of drugs with melting point as high as 250 °C to 300 °C is possible when such strong interactions can be formed between polymers and the drug as is the case for sugar and water (solute/solvent) where sugar is not needed to melt in order to be dissolved in water. 

Can predictive modeling be used in excipient selection of a solubilizing polymer? If so, can you explain the modeling and the related variables used in the model?  

 A range of predictive physical models are helpful in selecting solubilizing polymers. Such models are most valuable when used in conjunction with measured physical properties of the API, the polymer, and/or the formulation. In particular, we often use models to estimate oral absorption based on key parameters, such as API dose, solubility and supersaturation values, API partition coefficient into bile salts, and API dissolution and precipitation rates. Several of these parameters depend on the choice of polymer. In particular, the time profile of the API supersaturation level is often heavily influenced by the choice of polymer and can dramatically affect absorption and bioavailability. These parameters are typically measured 

and then used in predictive models. An important caveat is that it is notoriously difficult to accurately predict certain 

 parameters, such as API precipitation rate based on 

 measurements. Other types of models that are sometimes employed include solubility parameter approaches to predict interactions between APIs and polymers, including estimates of API solubility in a polymer matrix. Although such predictions can be useful, it is sometimes faster and more accurate to make the measurements than to do the calculations. 

 Predictive modeling can be used to calculate polymer–API interactions that may occur. In addition, tools, such as solubility parameters, can be used to establish API solubility in the selected polymer. Hansen solubility parameters are often used in this regard as a screening tool for drug-polymer compatibility, however, they should only be used as a guide in conjunction with preformulation data. 

 In a conventional empirical formulation development approach, various qualitative and quantitative combinations of drug and polymers are melted, spray-dried, or film-casted from organic solvents in numerous experiments to identify appropriate solid solution/dispersion formulations. Such empirical development methodologies are time-consuming and require significant amount of drug as well as costly analyses. Predictive tools to identify solvents for polymers based upon solubility parameters and molecular interactions (e.g., hydrogen bonding and ionic interactions) have been used for several decades in paint, polymer, and organic-chemistry industries. These predictive tools afford faster systematic screening of formulations and processing conditions at the early stages of solid-dispersion product development, independent of the preparation technology used.  

One such tool developed by Evonik is MemFis (Melt-Extrusion Modeling and Formulation-Information System). The MemFis model uses well-established polymer and organic-chemistry group contribution theories to estimate Hansen solubility parameters of drug molecules and polymers. In MemFis, the calculations of more than 50 chemical group contributions and the effects of polar (i.e., dipole moments) as well as 40 different hydrogen-bonding interactions on solubility parameters are considered. MemFis enables the selection of initial solid-solution/dispersion formulations and melt-extrusion processing conditions without API consumption. It reduces the number of experiments by bringing quality into formulation development in a systematic rather than empirical approach targeting appropriate experiments. Other analytical tools, such as Raman mapping, differential scanning calorimetry, and atomic force microscopy, can allow early detection of solid-solution formation or any recrystallization effects. 

 Quality by design (QbD) is an overarching consideration in drug development. With respect to solubility enhancement, what are the critical quality attributes and/or critical process parameters important in excipient selection? 

 Recently, pharmaceutical companies, excipient providers, and CRDMOs (contract research/development/manufacturing organizations) have launched significant initiatives to bring QbD principles to the selection and design of the polymer, the formulation, and the process space. With respect to the polymer, critical quality attributes might include molecular-weight distribution and chemistry attributes, such as the ratio and sequence of different monomeric units and/or the number and substitution pattern of hydrophobic groups on the polymer backbone. There are instances in which relatively small differences in chemistry can significantly affect the performance of the polymer and the formulation. In some cases, the impurity profile of the polymer can also be critical to the performance. 

Typically, a number of critical parameters on the process side will influence the choice of excipients. Depending on the process, solvents, and solution temperatures may be selected based on solubility of API or its compatibility with the solvent, which can in turn influence the choice of the polymer. Likewise, process- time–temperature profiles can be critical process parameters, particularly for the choice of HME excipients, to ensure adequate mixing for complete dispersal and dissolution of the API into the heated polymer matrix if a solid solution is desired. 

 Selecting the right excipient with control of the critical quality attributes is crucial to a robust formulation. A QbD approach to drug development helps the final drug product to have the desired therapeutic effect on a consistent basis. In solubility enhancement, excipients play the role of stabilizing the drug and keeping it in the desired state to achieve the maximum drug release and concentration sustainment. A QbD study with an excipient, for example HPMCAS, will look at characteristics of the polymer, such as acetyl and succinyl substitution using a design of experiment study to cover the experimental space to find the enhanced substitution levels for solubilization of the specific drug. Through studies done at Dow, we have found some drugs, such as phenytoin, are very sensitive to changes in polymer substitution levels and, therefore, require tight control around the enhanced values for consistent performance. Other less sensitive drugs can tolerate a wider range of substitution values while maintaining performance. A QbD program, in cooperation with the excipient manufacturer, can help formulators develop a robust and therapeutically efficient drug product. 

 When selecting excipients for solubility enhancement, excipient physicochemical properties such as morphological characteristics, aqueous/pH solubility, molecular weight, crystalline structure, porosity, density, and viscosity are amongst the critical quality attributes (CQAs) that should be evaluated. The impact of selected CQAs based upon the risk-assessment survey on the properties of the final product should be studied and well understood. Excipients in a solubility-enhanced formulation should not be considered as fillers or part of the binding matrix anymore because they contribute to the performance of API that otherwise does not have any absorption and bioavailability. The critical process parameters (CPPs) are process specific attributes. For solubility-enhancement applications,  melt extrusion and spray drying are the most commonly used technologies. The CPPs for melt extrusion are the screw speed, extrusion temperature, feed rate, glass-transition temperature of the drug-polymer mixture, and melt viscosity. For spray drying however, parameters such as spray rate, percent solids content, size, and scale of the spray dryer, nozzle size and temperature in the expansion chamber should be considered.  

Pharmaceutical Technology brought together a panel of industry experts for a special forum to discuss solubilizing polymers and the related formulation strategies for poorly soluble drugs.

Advancing Polymers for Solubility Enhancement

This article provides an overview of I Holland's tableting science anti-stick research (TSAR) project, which the company is conducting in collaboration with the University of Nottingham in the United Kingdom. The TSAR project seeks to understand why certain formulations stick to tablet tooling, a major problem often encountered by tablet manufacturers.

Problems during tablet manufacturing often result in process downtime and higher operating costs. Some of these problems can be minimized or eliminated with proper maintenance and storage of tablet tooling. 

 spoke to experts at I Holland about the causes of common problems such as tablet weight variation, hardness or breakage issues, capping, picking, and sticking, as well as a seven-step process for tool care. 

I Holland representatives also discussed the company's research collaboration with Nottingham University's School of Pharmacy in the United Kingdom, which seeks to understand why certain formulations stick to tablet tooling, a major problem that is often encountered by tablet manufacturers. The aim of this joint project is to develop a predictive tool that will enable the identification of the best coating solution for formulation-sticking issues without the need of carrying out full-scale trial-and-error experiments with several anti-stick coatings. 

 Tableting science is part of I Holland's core service offering. It encompasses many aspects of our R&D capability, including work with academic and technical partners on scientific research projects that help us to improve our understanding of why a punch or die performs well. For example, for years many tooling manufacturers have polished punches to an optimum mirror finish because they know it helps the punch to perform more effectively, but no one really understood why this was the case. Punch and die manufacturers are essentially engineering companies and often have a reluctance to become involved in wider tableting issues.  

Our investment in tableting science will help tablet manufacturers to reduce expenditures that can be associated with poor tooling performance further down the line by eliminating many issues before the punch or die hits production. For example, 'sticking' is a major tablet-production issue that we are trying to tackle through our work with the University of Nottingham on the tableting science anti-stick research (TSAR) project. We hope to deliver a predictive tool that will remove the need to undertake expensive coating trials to determine the best coating solution. 

What are the common problems encountered in tablet manufacturing?  

 There are many common problems encountered in tablet manufacturing. Some of the most common of these are listed below. Each of these problem areas may have several potential causes, but brief overviews of the main ones are summarized below:  

 The most likely cause of this problem is the extensive variation in punch working lengths, which can often be due to worn punches or sticking/picking that can cause granules to build up on the punch face and result in nonuniform punch lengths.

Picking refers to when a compressed granule adheres to the detail (i.e., embossing) on the punch face. This problem could be due to inappropriate embossing design, worn tip faces, insufficient compaction force, or granulation issues such as excessive moisture or insufficient lubricant.

Sticking is defined as general granule adherence to the punch-tip surface. The same causes as for picking may apply. Additionally, inappropriate tablet profile may have an impact on inadequate tablet hardness and density.

Capping is the laminar separation of the tablet body or cup and is often caused by air entrapment in the body of the tablet.

 This problem could be attributed to poor embossing design (i.e., too small or too shallow), worn punch faces due to abrasive formulation, or excessive polishing.

These issues are often caused by uneven punch lengths across a set, incorrect binding agents in the formulation, or capping due to air entrapment. 

Other tooling related problems exist such as:  

 Punch and die manufacturers should be able to provide training on these issues and how to solve them (1). 

What are the solutions to these problems?  

 Depending on the exact causes of each of the problems previously described, there are several potential solutions. As a guide, following a simple seven-step process for tool care and maintenance can help to minimize the potential occurrence of most tableting and tooling issues (2). The seven-step process is a logically planned and professional approach to tooling maintenance and storage as summarized below:  

When tooling is removed from the tablet press, it should be thoroughly cleaned and dried to remove any oil or product residue, especially from difficult-to-reach areas such as embossing and keyways. 

 Punches and dies should be visually inspected under magnification for signs of damage, wear, or corrosion, and to validate the cleaning process. This assessment will establish whether the production process is running well or not, thereby giving clues to problems with the tablet press or tooling itself and if any tooling maintenance is required. 

 Light surface wear, corrosion, and damage on tooling can be repaired and polished to a useable condition. Worn tips can result in poor quality tablets and inferior embossing definition that can lead to picking and sticking. Repair should be carried out by well-trained and experienced maintenance technicians to ensure that the tooling does not exceed tolerance limits. 

 Measuring is essential after repair to ensure that critical tooling dimensions have been maintained within an acceptable working tolerance. Measuring should be carried out at regular intervals even if repair has not been necessary, to check for natural wear during the compaction process. The essential measurement is the critical working length of the punch as it controls tablet thickness, weight, and dosage.

 Controlled, light polishing on a frequent basis will ensure that tools are maintained to a smooth finish, thereby helping to maximize tooling life and reduce problems such as sticking and capping. 

 Lubrication is important to protect, preserve, and aid smooth operation of the tooling. A range of oils and greases can be recommended for different applications, such as preservatives, or for lubrication purposes.

Tooling storage and transportation should be specifically designed to maximize security and safe handling to minimize damage and deterioration. 

Could you tell us more about the TSAR project, for which you are collaborating with the University of Nottingham?  

Since the launch of our PharmaCote range of punch and die coatings more than five years ago, I Holland has been increasingly called on to solve sticking issues within the pharmaceutical sector as tablet manufacturers realize that these problems can be eliminated without reducing product yield and investing in expensive magnesium stearate systems. The traditional way of troubleshooting a sticking problem would have been to supply a customer with a test set of tools containing many different punch and die coatings. A full compression trial would be carried out at the customer's site to ascertain the coating that would most effectively solve the sticking problem. This approach involves a significant investment for the customer in the tooling as well as in time. 

The aim of the TSAR project is to develop a predictive tool that will allow us to identify which punch and die coating is most likely to solve these sticking issues, thus removing the need to carry out full-scale compression trials with all of the anti-stick coatings. The development of the predictive tool will not commence until we have gathered sufficient interaction data from many different excipients and active ingredients. This work is currently in progress as we are testing several samples supplied by our customers. 

We aim to use newly developed multivariant analysis techniques linked to nanoscale surface chemistry and morphology techniques such as atomic force microscopy (AFM), time-of-flight secondary ion mass spectroscopy (ToFSIMS), Raman spectroscopy, contact angle measurements, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and laser profilometry. Once the data are gathered, we will use a principle component analysis tool to allow us to group the different excipients/active ingredients. Only after this process, will we be able to start the development of the predictive tool. 

We are currently halfway through the two-year project and have spent the first year solely gathering data from various products supplied to us by different customers. The most utilized piece of equipment to date has been the AFM, which allows us to quantitatively map, at the nanoscale, adhesion on PharmaCote coated tablet punches using single drug/excipient particles. The low adhesion force measurements (nN) gathered within the AFM indicates the level of Van der Waals forces that are present. We are also changing the humidity and temperature within the testing environment to gather data on capillary forces that are present. Only when all the ingredients of the formulation are tested in this analytical way, do we move the formulation into a production environment and compress tablets using the same PharmaCote coated tooling.  

This 'real world' checking allows the results of the analytical testing to be verified in a production environment and gives the customer the reassurance that they are purchasing the optimum solution for their specific problem. It cannot be stressed enough how each sticking problem is unique and can vary significantly from site to site, press to press, and product to product, which makes laboratory compression testing vital. 

1.  Eurostandard Educational Collection 2010 Edition. 

The tableting science anti-research (TSAR) project seeks to understand why certain formulations stick to tablet tooling.

Tackling Common Problems in Tableting and Tooling

Belgium drug developer Ablynx and UK-based Spirogen have entered into a research collaboration to discover and develop novel anticancer drug conjugates combining Spirogen's proprietary cytotoxic drugs, pyrrolobenzodiazepines (PBDs), and the company's associated linker technology, with nanobodies generated using Ablynx's proprietary technology platform.

Under the terms of the collaboration, Ablynx will provide access to its novel nanobodies against a specific undisclosed cancer target and Spirogen will provide access to its proprietary PBDs and conjugation technologies. The collaboration is expected to last for up to one year initially. Both companies have agreed to contribute their resources towards the collaboration. 

Once this feasibility phase is completed, Ablynx will have the option to either in-license Spirogen's technology or, in collaboration with Spirogen, move development forward with a third party. No further terms have been disclosed. 

 "We are very pleased to be working with Spirogen to discover and develop novel cancer therapeutics based on both companies' proprietary technologies. Our nanobodies have the potential to selectively and efficiently deliver Spirogen's PBD drugs to the site of the tumour. We are very excited about combining our unique and powerful technology with Spirogen's novel cytotoxic agents to search for breakthrough opportunities in oncology," Dr Andreas Menrad, Chief Scientific Officer of Ablynx, said in a 

 "The collaboration with Ablynx is designed to evaluate the potential of a Nanobody to act as the targeting molecule for the PBD warhead, which is released once it is inside the cancer cell. These warheads have the potential to be extremely potent without distorting the DNA helix thus avoiding mechanisms that lead to tumours becoming resistant to other anti-cancer drugs," commented Dr Chris Martin, Chief Executive Officer of Spirogen in the same statement. 

Ablynx's nanobody platform consists of antibody-derived therapeutic proteins that have unique structural and functional properties of naturally-occurring heavy-chain antibodies. The nanobody technology was originally developed after it was discovered that camelidae (camels and llamas) possess fully functional antibodies despite the lack of light chains. These heavy-chain antibodies contain a single variable domain (VHH) and two constant domains (CH2 and CH3). The VHH domain can be cloned and isolated to form a perfectly stable polypeptide harbouring the full antigen-binding capacity of the original heavy-chain antibody. 

Antibody drug conjugates are highly targeted drug constructs with monoclonal antibodies specific to particular types of tumour cells attached to potent cytotoxic agents. These antibodies bind to specific receptors or antigens present on the surface of the tumor cells where the cytotoxic agent is then released. This selective killing of tumor cells minimizes the impact on normal, healthy tissues and significantly reduces the side effects associated with chemotherapy treatments. The principle can also be applied beyond antibodies, with the possibility of linking anticancer agents to antibody fragments, peptides, vitamins and hormones. 