SPECIAL FEATURE - Improving Bioavailability & Solubility: A Top-Down Versus Bottom-Up Approach

Nanocrystals will account for 60% of a $136 billion nanotechnology-enabled drug delivery market by 2021. Nanocrystals are ground in special mills producing nano-sized drugs, which are applicable intravenously as nanosuspensions. This procedure enhances the surface-to-volume ratio and thus the solubility and bioavailability of most insoluble pharmaceuticals.¹

According to Smruti Chaudhari, PhD, Development Scientist I, Metrics Contract Services, two principles can be used to produce nanoparticles: Top-down approaches like milling or ultra-homogenization, and bottom-up approaches such as precipitation. Metrics uses the top-down approach of micronization to reduce an API’s particle size to enhance solubility.

Also using a top-down scalable approach of nanomilling is Particle Sciences, Inc., as it carries minimal regulatory risks. Inayet Ellis, PhD, Scientific Affairs Manager, Gattefossé USA, says that a bottom-up approach to particle modification may be worth exploring if the solubility of an API is limited in lipids. “It depends on the API and process capabilities. A top-down approach, by which larger particles are made into finer ones, can have limitations during the process as the finer particles tend to agglomerate. A bottom-up approach may require careful selection of a solvent and maintaining at the saturated level.”

Shaukat Ali, PhD, Technical Support Manager, BASF Pharma Solutions, agrees that a bottom-up approach is more relevant as more NCEs turn out to be poorly soluble. The first step requires high throughput screening of APIs to identify appropriate polymer/solubilizer candidates. Screening studies are critical to provide the understanding of structure-function relationship, and whether this information can be applied to identify the appropriate technology and/or excipients for development.

“The top-down approach is widely used in the industry based on its proven benefits in manufacturing scale,” summarizes Dr. Jessica Mueller-Albers, Evonik Health Care Scientific Communications. “However, we see a value in further developing bottom-up technologies in order to stay as flexible as possible to select the right technology meeting the requirements of the drug.”

In this annual feature,Drug Development & Deliveryspeaks with several innovative companies about their science, techniques, and technologies aimed at addressing the current challenges, issues, and opportunities in bioavailability and solubility

Ascendia Pharmaceuticals:Achieving Significant Results in Nanoemulsion Solubility

Ascendia Pharmaceuticals is a specialtyCDMO that creates formulation solutionsfor poorly water-soluble molecules.Some of the newer approaches Ascendiaoffers include nanoemulsions and solid lipidnanoparticles. The goal with nanoemulsionsis to dissolve and stabilize thedrug in a suitable oil vehicle, and then produceoil-in-water nanoemulsions using eithera high-shear homogenization or amicro-fluidization process. Minimizing theamount of co-surfactants and co-solvents requiredfor long-term physical stability is akey strategy. With solid-lipid nanoparticles,the surface area advantage that nanoparticleshave in improving drug dissolution isextended by having the drug homogeneouslydispersed in a lipid carrier prior tonanonization, explains Jingjun “Jim”Huang, PhD, CEO of Ascendia. Solid-lipidnanoparticles are especially useful forlong-acting injectable formulations ofpoorly soluble drugs.

An alternative is to coat a drug nanocrystal with a lipidic material prior to final dosage form preparation. Both nanoemulsions and nanoparticles can be administered orally or via injection.

“There continues to be a demand for innovative technologies to address poor drug solubility as many emerging pharmaceutical companies have promising compounds that require novel delivery science to achieve their bioavailability targets,” says Dr. Huang. Ascendia helps clients quickly determine the best formulation approach by investigating multiple options in parallel. Capabilities include spray-drying, hot-melt extrusion, ball-milling, micro-fluidics, and homogenization. Ascendia also has the capability to transition an optimized formulation into cGMP manufacture of clinical materials for animal PK, toxicology, or first-in-man studies.

For example, for one client, Ascendia developed a nanoemulsion formulation of a drug that has only 3ng/ml water solubility. Dr. Huang explains that the drug exhibited significant dose proportionality and food-effect issues. Ascendia experimented with a matrix of oils and surfactants to develop several prototype formulations. “In the oil phase of the nanoemulsion, we achieved drug solubility in the 30-100 mg/ml range — a 1,000,000-fold improvement.”

Multiple formulations achieved good chemical stability, physical stability, and water dispersibility. All of the formulations produced nanoemulsions with droplets sizes less than 1μm, and ranged from as small as 20nm to ~ 700nm. This feasibility study yielded a viable oral formulation for the client that is now being tested clinically to determine the improvement in dosing kinetics and the elimination of the food-effect.

BASF: Innovative Polymers Tackle Modern Formulation Challenges

With the recent surge in poorly soluble APIs, BASF continues to introduce unique polymers, such as one derived from vinylpyrrolidone and acrylic acid monomers, for insoluble molecules. With its greater solubility at low and high pH, it significantly increases the solubility and bioavailability of weakly alkaline drugs, says Shaukat Ali, PhD, Technical Support Manager, BASF Pharma Solutions, BASF Corp. “Polymers like this create potential for the next generation of NCEs and as they continue to be characterized as brick dust or insoluble with high melting points, the industry is taking a more pragmatic approach to adapt non-conventional technologies in drug development. This requires the use of new polymers, excipients or solubilizers that have never been used before due to regulatory challenges.”

Additionally, formulation technologies such as solid amorphous dispersions offer opportunities for highly crystalline APIs to increase solubility and enhance bioavailability, especially those requiring medium/high doses. Spray drying and hot-melt extrusion technologies amongst others have also been widely used for improving bioavailability. That said, these technologies are highly dependent on the functionalities of polymers and solubilizers in oral dosage forms, says Dr. Ali.

He also points out that nanocrystal and nanotechnologies have been used as alternative approaches to solid dispersions for improving solubility and bioavailability, but do bring some challenges of their own. In some cases, precipitation of drugs in liquid suspension/solutions occur due to its inability to maintain supersaturation, causing lower bioavailability.

With the availability of excipients and polymers with greater solubilization capabilities, the solubility of APIs can be improved exponentially and supersaturation can be maintained over longer periods. As a result, the industry is looking to select high functionality excipient/polymers. “The pharma industry’s interest in new excipients has fueled the development of novel polymers and solubilizers to tackle unmet formulation needs,” says Dr. Ali.

Soluplus^®, a polymer designed for hot-melt extrusion technology is an example. Molecules with a higher melting temperature and difficult to formulate have been used with Soluplus in amorphous solid dispersions for improving solubility and bioavailability. “With its unique characteristics of higher lipophilicity and crystalline inhibitory properties, Soluplus has been used both in conventional and nonconventional formulations for improving solubility, loading, and stability by maintaining APIs in supersaturation over an extended period,” he says.

Copovidone and cellulosic excipients have been used in solid dispersions technologies, including spray drying, hot-melt extrusion and electro spinning/spraying. “As the interest in continuous manufacturing continues to grow, the twin screw extruder (TSE) will likely occupy more space in conventional granulation technology to offer an added benefit for many of the poorly soluble drugs requiring low to medium doses, and alleviate the stability challenges with amorphous solid dispersions.”

Evonik: Functional Polymers & Formulation Technology EnhanceBioavailability

From a technical standpoint, the solubility and permeability of many new chemical entities are key issues for the development of new drug formulations. As a result, the industry is in urgent need of new approaches to drug development and specifically to tailored drug delivery.

“In oral drug delivery, we see an increasing interest in excipients and new formulation techniques to enhance drug solubility and bioavailability,” says Dr. Jessica Mueller-Albers, Evonik Health Care Scientific Communications. “The industry is adopting more innovative formulation technologies, which appropriately target the improvement of the transcellular and paracellular uptake of both small molecules and biologics. This often requires the use of new types of excipients, like permeation enhancers, enzyme inhibitors, and polymers with advanced functionalities. An example is Evonik’s proprietary drug delivery technology EUDRATEC^®PEP, which enables the peroral administration of peptide drugs.” EUDRATEC PEP technology is a versatile formulation toolbox where challenging actives (peptides, proteins, BCS II, III and IV compounds) and functional ingredients are combined in a modular way to enhance bioavailability.

For solubility enhancement, solid dispersions are still one of the most important technologies used today and will continue to play a significant role in the future. “If you have a BCS class IV API with poor solubility and poor permeation, increasing the solubility alone may not solve all your problems, but delivering the now soluble drug to the right area of the GI tract may be able to boost bioavailability,” says Dr. Mueller-Albers. “Many scientific research groups are working on the development of new excipients that inhibit enzymatic degradation or improve permeation of biological barriers. However, dissemination of these new entities is often limited by undiscovered toxicology and cost-extensive scalability.”

Functional excipients like Evonik’s EUDRAGIT^®polymers can help with significant increase in bioavailability by delivering the active to the appropriate area of the GI tract where absorption is the highest. Dr. Mueller-Albers says that with the increasing development activities of nanoparticles for oral drug delivery, there is a strong need for carrier formulations that enable the preparation of solid dosage forms and protect the nanoparticles from early degradation or drug leaching in the GIT. By co-spray drying EUDRAGIT polymers together with the nanoparticles, they can be embedded in a polymer that fulfills these requirements.

For example, the recently launched EUDRAGIT FS 100 polymer was specifically designed to enhance drug solubility at the same time as targeting the colon to treat localized diseases, such as colon cancer and irritable bowel syndrome with delivery site-specific APIs. The polymer is suitable for processing via melt extrusion and spray drying.

Gattefossé USA: Lipid-Based Formulations Prove Versatile

While there are multiple existing and emerging strategies to enhance the solubility and bioavailability of poorly soluble drugs, there is also a general lack of clarity on the benefits of these technologies for one or another category of molecules. No single technology can be a solution to all challenges, and in reality, the drug development scientist may resort to two or more approaches to optimize solubility and oral bioavailability based on the API characteristics, process limitations/manufacturability, and safety of the components needed for developing the intended dose. Among the technology choices, lipid-based drug delivery systems (oily solutions, SEDDS, SMEDDS) have emerged as versatile and efficient in enhancing the solubility and bioavailability of BCS II molecules, and more recently, in the optimization of oral bioavailability for various peptides.

“In the realm of lipid-based formulations, the preferred approach is to design formulations capable of forming micro/nanoemulsionsin vivo,” says Inayet Ellis, PhD, Scientific Affairs Manager, Gattefossé USA, Paramus, NJ. “Commonly referred to as SEDDS or SMEDDS, these are anhydrous systems of glycerides and nonionic medium-to-high HLB lipid excipients, and they demonstrate great dilution capacity upon mixing with gastric fluids, reducing the risk of API precipitation in the GI tract.”

As a pioneer of lipid excipients, Gattefossé aims to improve solubility and bioavailability simultaneously. With most drug actives, solubility enhancement is a start but doesn’t always translate into improved exposurein vivo. “The Gattefossé Technical Center of Excellence assists clients with excipient selection and formulation development that will improve solubility and create a stable and consistent dose with potentially good bioavailability,” says Dr. Ellis. “Scientists provide support in solubility screening,in vitrolipolysis testing to predictin vivoperformance, animal dosing, and formulation development.”

Metrics Contract Services: Micronization & Amorphous Solid Dispersion Approaches to Formulation

Recent advances in combinatorial chemistry have led to the discovery of many new drugs. These drugs have either low solubility or low bioavailability or both, and they present special challenges to formulators. There are two ways to increase solubility: Chemical modification or formulation approaches. Chemical modifications include taking a pro-drug approach or using the salt form of the drug.

“There is a certain level of complexity involved in using a salt form to increase solubility due to the need to develop salt form synthesis and purification methods,” says Smruti Chaudhari, PhD, Development Scientist I, Metrics Contract Services. “Formulation methods such as micronization, amorphous solid dispersion, nanocrystals, and nanoparticle are more popular in the field of solubility enhancement.”

Metrics Contract Services offers formulation approaches like micronization and amorphous solid dispersion. Micronization is a simple top-down approach, in which the particle size of the API is reduced, which leads to an increased surface area and eventually solubility enhancement. Although these concepts have shown positive results for many drugs, there are some APIs that need further formulation to increase solubility, says Dr. Chaudhari.

Most of the APIs available in the market are crystalline in nature, which have poor solubility. Such crystalline APIs can be converted into an amorphous form, which has higher solubility through the formation of amorphous solid dispersions using spray-drying technology.

Nanocrystal is an up-and-coming technology that offers advantages in improving solubility and bioavailability of poorly soluble APIs. Nanocrystals are basically crystalline particles in the size range of 2nm to 1,000nm.

“Due to crystalline characteristics, they offer better stability as compared to their amorphous counterparts,” says Dr. Chaudhari. They can be administered as a dispersion in the liquid medium or in the solid state. Nanocrystals can be prepared by bead milling, high-pressure homogenization, and precipitation. One of the main advantages of this technology is that it allows formulating tablets or capsules with a high drug load. This technology uses surfactants as stabilizers, which may result in enhanced side effects or adverse effects.

Apart from these methods, target-specific and site-specific drug delivery is gaining momentum where the drug can be released in an area of optimal absorption. Dr. Chaudhari says: “Metrics has experience in optimizing drug delivery to the small intestine using enteric-coated multiparticulate systems, or tablets and capsules. This technology is beneficial, particularly for acid-sensitive drugs.”

Another characteristic of nanocrystals is that they are 100 percent drug with no carrier. Nanocrystals work to improve solubility through the increase of surface area beyond that provided by just micronization. “This is especially helpful in improving solubility of drugs for which solubility is limited by dissolution rate,” says Dr. Chaudhari. “Amorphous nanoparticles are even more advantageous in improving solubility but they come with the challenge of requiring stability to prevent conversion to the crystalline forms.”

Particle Sciences, Inc.: Nanomilling Is Reliable, Scalable, & Well-Suited for Sterile Products

Particle Sciences (PSI) routinely uses a variety of nanotechnology-based drug delivery technologies, including polymeric nanoparticles, solid-lipid nanoparticles, nanoemulsions, and nanoparticulate suspensions (i.e., nanocrystals).

“We frequently evaluate nanocrystals produced using a high energy media milling process (i.e., nanomilling) for water-insoluble APIs,” says Robert W. Lee, Executive Vice President, Pharmaceutical Development Services, PSI. “Nanomilling has been used in marketed products and there continues to be a lot of interest in nanocrystals. Most of our programs are intended for parenteral administration and we consider this to be a go-to technology for sterile products.”

When it comes to sterile products, most of the nanocrystal formulations are not amenable to terminal sterilization so PSI offers aseptic nanomilling using a proprietary high-energy milling system that was designed specifically to better accommodate aseptic processing. Dr. Lee says: “There are several technologies for formulating BCS II APIs for oral administration, but we feel the true value of nanomilling is for the development of parenteral dosage forms. The capability of providing aseptic nanomilling may allow our clients to offer better products to their patients.”

PSI uses the top-down approach of nanomilling because it’s proven scalable and the regulatory risks are minimal as the technology has been used in several marketed products, says Dr. Lee.

Aside from these considerations, nanomilling is typically done in an aqueous vehicle. This contrasts with a bottom-up approach, such as controlled precipitation, in which the API is solubilized in a water-miscible organic solvent then mixed with water as the anti-solvent. “In the case of a bottom-up process, one is always presented at the end of the nanoparticle formation with organic solvent in the mixture,” says Mark Mitchnick, MD, CEO, Particle Sciences, Inc. and Chief Medical Officer, Lubrizol Life-Sciences. “This may require downstream processing to remove the organic co-solvent.”

Another consideration is that the concentration of the API in controlled precipitation may be very low – on the order of single-digit percentages in most cases. “In contrast, with nanomilling we can achieve concentrations up to 50% API. Nanomilling leads to a more efficient process requiring fewer unit operations to produce the final drug product. It facilitates scale-up and eventual commercialization.”

For most drug delivery systems, excipients play a facilitating role. To increase the range of materials at its disposal, PSI maintains strategic relationships with a variety of excipient suppliers, such as with PLGA for use in polymeric nano- and micro-particulate formulations. Additionally, as part of Lubrizol LifeSciences, PSI can access a variety of polymers that can be matched with the solubility of APIs such as thermoplastic polyurethane-based technologies. “These relationships help speed our clients’ development programs,” says Joey Glassco, Global Market Manager, Drug Eluting Devices & Pharmaceutical Services, PSI. PSI is also seeing more clients interested in functional excipients, such as some that serve as permeation enhancers for mucosal delivery.

Quotient Sciences: Using the Human System to Understand & Resolve Bioavailability

Sub-optimal bioavailability isn’t always a function of poor solubility. Broader corrective drug delivery strategies may be required to achieve desired pharmacokinetic (PK) profiles. As demonstrated through the Biopharmaceutics Classification System (BCS), permeability of the molecule may also be a barrier to achieving the desired systemic exposure, requiring strategies to increase absorption and/or inhibit efflux membrane transporters. Additional strategies would also be required if rate-limiting factors such as gut-wall metabolism or molecule lability in the gastrointestinal lumen were observed. Thus, it is imperative that the fundamental factors causing poor or variable bioavailability are fully understood or strongly hypothesized before formulation strategies are defined, advises Peter Scholes, Chief Scientific Officer, Quotient Sciences.

“Poor solubility is arguably the area that has the greatest potential for success for formulation scientists, given continued research to identify technologies to improve oral bioavailability and realize the therapeutic potential of new drugs (or improve the posology of old ones),” he says. “New drug delivery technology companies continue to emerge, focusing on novel ways to address either kinetic or thermodynamic limitations inherent in drug substance properties. Promising preclinical and clinical data attributed to some of these innovations are now coming into the public domain.”

Even with these additional tools, key challenges for the formulation scientist are technology selection, achieving the target product profile, and optimizing the system to meet the uniquein vivodelivery needs of each molecule in humans. “Surrogate tools remain sub-optimal in predicting clinical performance of enabled formulation systems,” says Dr. Scholes. “Nonclinical PK data is widely acknowledged and reported as having poor correlation with corresponding human bioavailability, even to the point of questioning the ethics of continuing to use this practice to assess candidate formulation systems to take into human screening.”

There have been significant advances, however, in the use ofin vitroandin silicomethods as characterization and predictive tools to aid technology selection. As an example, physiologically based pharmacokinetic (PBPK) modelling is widely used to explore the potential for formulation factors to influence oral bioavailability by developing models with existing datasets and then running PK simulations based on formulation variables such as drug particle size, he explains.

Quotient Sciences advocates the use of the “human system” to understand and resolve bioavailability risks and challenges. The integration of real-time adaptive GMP manufacturing and clinical testing is the established principle behind the science of Translational Pharmaceutics^®, which enables both the manufacture of drug products within a week of dosing and the ability to modify compositions in response to emerging clinical data. This adaptive platform consequently reduces the timeframe and cost barriers to evaluating multiple formulation technologies in the clinical setting to provide definitive data on technology selection.

“This is highly advantageous when addressing solubility issues,” says Dr. Scholes. “For example, arising PK data have recently been used to screen different spray dried polymer dispersions, identify optimum drug:excipient ratios and compare different solubilization technologies head-to-head (e.g. particle size reduction, lipidic and amorphous systems) in the strive to overcome sub-optimal bioavailability.”

Thermo Fisher Scientific: Predictive Platform Provides Formulation & Product Development Pathway

Patheon, a part of Thermo Fisher Scientific, uses a differentiated approach to solubility enhancement called Quadrant 2^®. This is a predictivein silicoplatform that provides a strategic pathway through the formulation development landscape, explains Sanjay Konagurthu, PhD, Sr. Director, Global Science and Technologies, Pharma Services, Patheon, part of Thermo Fisher Scientific. “The landscape consists of several solubility enhancement technologies plus additional components related to the materials and processes needed for an individual technology. The Quadrant 2 strategy is an agnostic approach towards achieving the molecule’s target product profile and improved bioavailability. It is specifically designed to reduce the amount of experimental work typically performed in preformulation and early clinical development projects and laying a robust pathway to commercialization,” he says.

Quadrant 2 analyzes the molecular structure and physicochemical characteristics of a compound to provide input for thein silicoplatform that selects the most promising solubility enhancement technologies, such as size reduction (micronization and nanomilling), amorphous solid dispersions (spray drying, hot-melt extrusion and coated multiparticulates), lipid-based approaches, complexes, etc. “This approach contrasts sharply with empirical trial-and-error methods,” says Dr. Konagurthu. “Our algorithms have been developed based on Thermo Fisher Scientific’s comprehensive understanding of multiple proven solubility enhancement technologies, materials science, and molecular modeling. Using this toolbox, timelines can be shortened, and compounds advanced to the clinic using a solubility enhancement technology suitable for clinical trials and commercialization.”

Selection of the proper excipients early in a development program is critical to successfully formulating and manufacturing a drug product. Quadrant 2 includes excipient selection algorithms that provide a scientific basis for formulation design.Insilicopredictions involving quantum mechanical and molecular dynamics modeling, combined with statistical analysis, are used to select appropriate excipients.

Thermo Fisher Scientific supports developing and commercializing these technologies through a network of worldwide manufacturing sites. Comprehensive services provide solutions at every stage, including API manufacturing, drug product for clinical trials, and commercial manufacturing, including packaging, labeling, and distribution).

Reference

1. Kwaśniewski, Michał, Nanotechnology for Drug Delivery: Global Market for Nanocrystals, Pharmaceutical Research Reports, https://pharmaceuticals.report/?pharma_reports=nanotechnologyfor-drug-delivery-global-market-for-nanocrystals, Posted on January 9, 2018.

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