SPECIAL FEATURE – Bioavailability & Solubility: New Approaches to Enhance Drug Performance
Among all newly discovered chemical entities, about 40% are lipophilic and fail to reach the market due to their poor water solubility.1 And the future pipeline is estimated to comprise 90% poorly soluble compounds, according to Bryan Wiesner, Director, External Development and Outsourcing, AbbVie.
Solubility issues complicate drug delivery, but there is an array of techniques available to enhance solubility and improve the bioavailability of these drugs. This annual Drug Development & Delivery report highlights many of those techniques, how to determine the right technique for your compound, and how some pharmaceutical companies are realizing faster time to market as a result.
Hot-melt extrusion (HME) is a proven, enabling technology for enhancing the bioavailability and solubility of solid oral doses, including potents. AbbVie was an early adopter of HME technology for formulation development and dosage form for several reasons:
-As a solvent-free technology, it is environmentally friendly;
-Once developed, it is an extremely robust and reliable process;
-Continuous processing makes it a more economical method of manufacturing;
-It is accepted by regulators globally; and
-It has applications for abuse deterrence and taste masking.
“HME, an amorphous dispersion technology, uses pharmaceutical-grade polymers to formulate insoluble or poorly soluble drug molecules,” says Mr. Wiesner. “This dissolves and distributes the API through a specialized matrix, using heat and shear energy, to form a solid solution of known potency and uniformity. This improves efficacy and drug delivery efficiency. The extrudate can be subsequently formed into tablets, multilayer tablets, and capsules, even with advanced profiles like dual API in a single dose or API coatings on a core.”
HME has been used to improve drug performance and patient compliance by reformulating drugs as controlled or modified release to reduce daily dose requirements, or, for example, to avoid the need for refrigeration or substantially reduce daily pill burden rates, says Mr. Wiesner.
The challenges facing the successful formulation of poorly soluble, lipophilic active pharmaceutical ingredients (APIs) can be complex and multifactorial. Perhaps the most critical barriers to overcome in a successful formulation are enhanced drug permeation and increased bioavailability of the active. While there are approaches capable of improving drug dissolution, there are relatively few that can improve drug permeability, claims Dr. Donald Kelemen, Head of Corporate Business Development, ABITEC Corp. Rarer still are excipients that improve dissolution and permeability, are part of normal human physiology, and are capable of negating the food effect and protecting the API from degradation in the GI tract. “Functional lipid excipients can provide for all of these benefits,” says John K. Tillotson, RPh, PhD, Pharmaceutical Technical Business Director, ABITEC Corp. “By dissolving the API in a lipid-based preconcentrate, an oil-in-water emulsion can be generated in the GI tract with the active ingredient molecularly dissolved or dispersed in the lipid phase of a micellar system.” Depending upon composition, these micelles can offer several functional advantages, including serving as a protective environment for the API, instilling permeation enhancement for polar actives through reversible tight junction modulation, and as a substrate for mitigating the impact of Pglycoprotein efflux.
ABITEC develops lipid-based excipients to enhance bioavailability of poorly water soluble and poorly permeable molecules for the pharmaceutical industry. The excipients are manufactured in accordance with strict cGMP and applicable IPEC (International Pharmaceutical Excipient Council) guidelines in ISO-certified facilities. Recently, ABITEC has expanded its manufacturing capabilities to provide greater flexibility to serve our customers throughout development from preclinical to commercialization.
“ABITEC supports the needs of the formulators by developing and providing applications research, investing in manufacturing agility, and innovating to develop new product lines that meet the changing demands of our customers,” says Dr. Tillotson. “Through research partnerships with major universities, we develop new applications papers and guidance on solubility, phase behavior, and permeability of functional lipid formulations that are available to formulators and provide a starting point for formulation development.”
With the increasing number of new chemical entities that may belong to BCS Class II and IV, a formulator rarely gets the opportunity to develop a simple oral solution. The high number of poorly soluble compounds in the industry is leading to the growing need for developing enabling technologies. Understanding the chemical and preformulation property of the API is the first step toward identifying a suitable enabling technique to enhance solubility or bioavailability. Underlying variables and their relationship to product performance and manufacturing needs are also important considerations. A systematic approach for handling formulation issues is required.
A primary driving factor for determining the best formulation approach is to assess the dose/solubility ratio, explains Amol Matharu, PhD, Senior Director, Pharmaceutical Development, AMRI. The maximum absorbable dose is directly related to the solubility, absorption rate, GI volume, and GI transit time. Physiology of the GI tract also plays an important role. For example, the pH change during GI transit can induce precipitation of weakly basic compounds (pKa > 6) and increase solubility for acidic ones (pKa < 5). An experienced and qualified lab should be used to design the biorelevant tests, such as dissolution conditions, to better estimate in vivo product performance.
Identifying the conditions limiting oral absorption is critical to elaborate the mitigating strategies. For a dissolution rate-limited system, where the compound is not fully dissolved in the absorption window (dissolution time is greater than transit time), mitigation strategies include salts, a polymorphic form, particle size reduction, surfactants, polymers, amorphous API, and complexation. In a solubility-limited absorption, where there is incomplete exposure of the drug (absorbed dose is less than total dose), the problems can be mitigated using lipids, a prodrug, solid dispersion, and solid state forms. Finally, for permeability-limited absorption, where there is poor absorption, the main strategies involve using prodrugs or permeability enhancers.
Based on needs and the API properties, some of the enabling techniques utilized include lipid-based drug delivery systems, solid dispersions, nanoparticles, long-acting injectables, and solid oral controlled release formulations. Several examples from AMRI’s experience: A poorly soluble API at preclinical development was formulated as an oral solution in Capmul/Labrasol for a tox study and a PK study; and a micronized API in capsule was developed for a Phase I clinical study. In another case, to improve bioavailability of a poorly soluble drug, a high-energy solid was evaluated in which API was dispersed in polymers through spray drying. As illustrated in Table 1, dissolution of API was modified by modulating drug:polymer ratio. A blend-in-capsule formulation was developed using the high-energy solid for a Phase I clinical study. In the third case, when cosolvents, lipids, surfactants, and complexation techniques alone failed to improve the solubility of an API, a combination approach was used to improve the solubility 80,000 fold, giving an oral solution drug product using a measured balance of various excipients serving defined roles — for example, a mix of dimethylacetamide, Labrasol, and Tween 20 or Tween 80. The formulation was physically and chemically stable and ready for dosing in the preclinical study. In another project, suitable drug exposure was maintained by formulating a long-acting injectable suspension. Careful modulation of the zeta potential and mixing parameters yielded an elegant flocculated drug product utilizing a rugged, reproducible, and scaleable manufacturing process.
Not all solubility problems necessarily involve BCS class II and IV compounds. For instance, one project involved developing a controlled-release tablet for an API that is highly unstable and water soluble. While various matrix-forming agents were evaluated, none were effective to achieve a target release period of 24 hours. “Exploiting the chemical properties of the API, acid-derivatized complexing agents were utilized to slow the release and achieve a stable product with a desirable dissolution profile,” says Dr. Matharu.
As a specialty CDMO, Ascendia focuses on creating formulation solutions for poorly water-soluble molecules. Some of the newer approaches the company offers include nanoemulsions and solid-lipid nanoparticles. “The goal with nanoemulsions is to dissolve and stabilize the drug in a suitable oil vehicle, and then produce oil-in-water nanoemulsions using either a high-shear homogenization or a micro-fluidization process,” explains Jingjun “Jim” Huang, CEO of Ascendia.
Minimizing the amount of co-surfactants and co-solvents required for long-term physical stability is a key strategy. With solid-lipid nanoparticles, the surface area advantage of nanoparticles is extended by having the drug homogeneously dispersed in a lipid carrier before nanonization. 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. Solid lipid nanoparticles are especially useful for long-acting injectable formulations of poorly soluble drugs, he says.
“Many emerging pharmaceutical companies have promising compounds that require novel delivery science to achieve their bioavailability targets,” says Dr. Huang. “Ascendia helps clients determine the best formulation approach by investigating multiple options. While we have capabilities in spray-drying, hot-melt extrusion, ball-milling, micro-fluidics, and homogenization, it is not always obvious which technical approach will optimize a drug’s performance. Ascendia accelerates development time by conducting formulation comparisons and selection in parallel.”
Combinations of excipients and approaches can lead to new intellectual property for a drug’s formulation. For example, for one client, Ascendia developed a nanoemulsion formulation of a drug that has only 3ng/ml water solubility. This 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, drug solubility was achieved in the 30-100mg/ml range—a 1 million-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,” Dr. Huang says.
BASF: Excipient/API Combinations That Expedite Drug Development
Solubility of new chemical entities has been a key issue in drug molecule development. As discovery of more insoluble compounds continues, the industry is adopting more innovative formulation technologies to overcome the solubility and bioavailability challenges to make them commercially viable and FDA compliant. These new approaches are opening doors to more than 80% of NCEs in the pipeline that would otherwise have a modest chance of succeeding, says Shaukat Ali, PhD, Technical Support Manager, BASF. These include solid and liquid dispersion technologies for the development of tablets and soft gels, solvent-free temperature-controlled hot-melt extrusion and shear stress-driven Kinetisol® solvent-based spray drying and electro-spraying technologies. Lipid-based liquid dispersion formulation technology, such as self-emulsifying and micro-emulsifying drug delivery systems, is also employed for the more insoluble NCEs to speed up development cycles.
BASF offers a range of excipients for developing oral solid and liquid dosages. The basic screening of excipients is key to the selection of the appropriate formulation technologies or platforms. BASF also provides medium to high throughput API screening services for customers with a range of excipient choices that provides them the flexibility to design the appropriate solid or liquid formulation dosage.
“Excipients play an important role in formulation and drug delivery, but their role is sometimes limited in certain dosage forms because of regulatory restrictions,” says Dr. Ali. However, many excipients are multifunctional and can give formulators options. For example, Kollidon® VA64 is a film former–a dry binder–used in both direct compression and roller compaction, and also acts as a solubilizer in the melt extrusion of poorly soluble compounds. Kollicoat® IR, a graft copolymer of polyethylene glycol and polyvinyl alcohol, is used as an instant-release coating polymer as well as a wet binder.
“Excipients like Kollidon VA64 and Kollicoat IR are available commercially and have been used in oral solid, liquid, and topical formulations,” says Dr. Ali. “Novel excipients, such as Soluplus®, address the specific requirements of APIs where standard excipients are not as effective.”
He continues: “Our technical and processing know-how and the understanding of excipient chemistries and functionalities enable formulators to efficiently identify the optimal API/excipient combination that expedites drug development,” says Dr. Ali. “For instance, to identify the appropriate polymers or solubilizers for solid or liquid dispersions, screening a broad range of excipients from our portfolio is important to select the ideal candidates for an optimal formulation.”
Capsugel helps customers formulate and advance challenging compounds in many ways. Its core approach to product development accounts for three interconnected themes: Upfront rational formulation design that is based on science, the needs of the molecule, and the needs of the finished dosage form. “This approach translates to greater speed to clinic and market, while our focus on rational design is well suited to meet the market’s demand for more specialized products for specific patient population groups,” says Hywel Williams, PhD, Principal Scientist, Research and Development, Capsugel.
Capsugel’s range of enabling technology addresses slow dissolution rate and/or low solubility (often linked to low oral bioavailability) or to modulate the pharmacokinetic profile of a compound. “We have strategically invested to support client programs from early development through clinical testing and into commercial manufacturing,” says Dr. Williams. “Having a vertically integrated offering can also minimize program complexity and risk by avoiding potentially problematic technology transfers during scale-up.”
Ensuring that a client’s compound is sufficiently bioavailable via the oral route has many dimensions–and is sometimes not limited to addressing dissolution rate or low solubility–requiring that other biopharmaceutical aspects be considered. For example, achieving high bioavailability combined with low variability and minimal local toxicity may require one or more of the following approaches:
-Transient increases in intestinal permeability, e.g., for compounds that are large/ionizable/efflux transporter substrates;
-Recruitment of the bile salt/phospholipid conduit to boost absorption in the fasted-state to mitigate food-effects;
-Targeting of a specific gut segment to exploit a compound absorption window;
-Bypass a specific gut segment to minimize local irritation or compound degradation, or to maximize local compound effects in lower GI segments; and/or
-Access the lymphatic system to reduce first-pass metabolism.
“Our product development teams have encountered myriad combinations of compound characteristics and drug delivery challenges,” he says. “This experience is proving crucial in addressing the obstacles associated with increasingly complex molecules and specialized applications.”
In addition to broadening its understanding of formulation, biopharmaceutics, and processes, Capsugel is investing to expand the formulation and processing space of its core technologies to meet the wider requirements of customers. These include lipophilic salts for increased dose loading using lipid-based formulation approaches, and spray dried dispersion “Hot Process” technology for compounds with low organic solvent solubility.
As the cost of drug development rises, and as companies look to develop drugs for smaller populations, there is pressure to do more with less, to make decisions with the minimum of data and without delay, and to try to manage the inevitable risks. This often means relying on well-known and predictable approaches. But drug companies look to new technologies to provide patent protection, protect the value of their investment in the long term, or to widen the net where standard technologies have been tried and unsuccessful.
Catalent has assembled a range of enabling technologies to support these developments. Platform screening protocols help quickly and inexpensively collect data to determine which approaches are most suitable and which molecules have inherent issues that need to be resolved. “To enhance collaborative scientific development between Catalent, its customers, and partners, we have created a new Science and Technology function to accelerate the development of drug products through the use of advanced formulation and drug delivery technologies,” explains Stephen Tindal, Director, Science and Technology at Catalent.
To help companies at the early stage of formulation development, a platform screening protocol called the OptiForm® Solution Suite combines preliminary formulation development with a molecule preformulation screen. This provides customers with a “toolkit” for improving the bioavailability of poorly soluble drugs using a range of bioavailability-enhancing technologies, including the OptiForm API salt form, particle engineering, lipid-based formulations, and amorphous dispersion.
At the pre-formulation stage, Catalent’s OptiForm API solid form optimization includes salt form screening to optimize solubility and stability, as well as polymorph screening to optimize the crystalline form. Originally developed by GlaxoSmithKline, Catalent has refined OptiForm API screening to help more customers speed the development and optimization of their drug molecules. It offers a high throughput platform for salt, crystal-form, and co-crystal screening, and has been applied to more than 500 compounds, spanning from early-stage lead compounds through launched products.
“Our platform screening protocols use minimal amounts of API, are completed quickly, thus saving money,” claims Mr. Tindal. Using OptiForm Solution Suite, customers receive a summary of study results, recommendations, and risk assessment for each dose form option to yield better bioavailability. These include operational considerations, regulatory approval risks, and patient specific considerations. A dedicated scientific advisor works with the customer to review all the data and make recommendations for the customer’s team. At the end, the customer receives materials for use in animal pharmacokinetic studies, which can include lipid solutions and/or suspensions, milled solid dispersions, and micronized/milled salt form.
As an example of how Catalent worked with a client to improve bioavailability, consider the case of Trio Medicines Ltd. The company was progressing a prodrug API with poor bioavailability through Phase 1. The formulation was sub-optimal. The molecule was classified as BCS Class II. The challenges were limited molecule characterization, fast turnaround, and limited budget. Trio was looking to increase the Area Under Curve (AUC) by three to five times and improve the formulation’s robustness. Catalent data revealed that the molecule should be classified as a Developability Classification System (DCS) IIa (i.e. limited by rate of dissolution rather than absolute solubility) with some stability issues (not uncommon for a prodrug). In this study, three of the four candidate formulations showed improved AUC potential. Trio would like to increase AUC further, and is considering its options before deciding on the best formulation with which to proceed.
Dow: Developing Amorphous Solid Dispersion & Manufacturing Technology for an API
In order to improve the performance of a poorly soluble API, it is imperative to formulate a dosage form in a way that enables the API to readily enter solution and be absorbed by the body. Excipients play vital roles in providing functionality to the final drug product to achieve this goal. “For example, through stabilizing the compound in a high energy state for an amorphous solid dispersion, imparting hydrophilicity to the dosage form to promote dissolution, and maintaining dissolved drug in solution to allow for absorption, the API performance can be enhanced,” says Elizabeth J. Tocce, Associate Research Scientist, Dow.
Dow Food, Pharma and Medical has introduced a line of excipients to enable formulations of poorly soluble drugs to meet their end targets through not only final dosage form performance but also improved use in manufacturing technologies. The AFFINISOL™ polymers are cellulosic derivatives designed specifically for hot-melt extrusion and spray drying applications. “The AFFINISOL portfolio includes a novel grade of hypromellose, AFFINISOL HPMC HME, that has advantageous thermal properties for hot-melt extrusion and improved solubility in organic solvents for spray drying applications,” explains Kevin P. O’Donnell, Associate Research Scientist, Dow.
In addition to the novel hypromellose, there is also AFFINISOL HPMCAS, which is offered in three standard acetate/succinate substitution grades. “HPMCAS, with custom acetate and succinate substitutions tailored to an API to ensure the optimal performance, is supported through a scalable cGMP market development plant,” says William W. Porter III, Associate Research Scientist, Dow.
Additionally, Dow Food, Pharma and Medical has technology capabilities and expertise to further assist formulators in developing a robust drug product. In-house high throughput screening techniques can enable rapid identification of the ideal polymer(s) and drug loading to formulate a stable solid dispersion with optimum performance. Once identified, a formulation can be translated to the desired manufacturing technology. For example, a formulation selected for hot-melt extrusion can be further developed at the laboratory scale for process parameter selection, which is confirmed through scale up when needed.
Evonik recently launched EUDRATEC® PEP technology, 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 meet targeted therapeutic needs. Dr. Firouz Asgarzadeh, Director of Technical Services, Formulation and Application Services, Health Care, Evonik Corp., says that Evonik’s EUDRAGIT® polymers have been used to facilitate the delivery of the active ingredients to a predetermined area of the GI tract, as well as for all types of controlled drug release profiles.
“Functional excipients like EUDRAGIT polymers have revolutionized the concept of excipient use in the pharmaceutical Industry. They allow for the successful development of products with improved bioavailability, targeting, and/or patient compliance,” says Dr. Asgarzadeh.
Additionally, to support customers in minimizing the number of screening experiments and in the selection of the appropriate combinations of pharmaceutically approved polymers with actives to form solid dispersions, Evonik has developed a sophisticated platform called MemFis® (Melt Extrusion Modeling and Formulation Information System). “MemFis uses solubility parameter calculations and hydrogen bond formation probabilities to screen approximately 30 different polymers in combination with the API to identify the best initial approach for formulating a solid dispersion.”
When screening solid dispersion formulations, MemFis allows the selection of the most effective formulations with a minimal number of experiments (typically 3-5) instead of random mixing and matching of hundreds of polymer-drug combinations in an empirical approach.
Evonik has also invested in hot-melt extrusion and spray drying equipment in several of its technical centers to help clients with feasibility studies and formulation development based on MemFis results. “The objective is to offer clients a “first time right” approach to formulation development, enabling shortened development times as compared to conventional random screening methods with a myriad of trial experiments outside of the appropriate design space. This systematic approach saves money and significantly reduces time to market.”
Evonik has applied MemFis to numerous customer projects. In one recent study, MemFis was used for a company developing a generic version of an existing commercial HME drug product. “The results from MemFis directed us to a polymer that was not utilized in the original brand product formulation,” explains Dr. Asgarzadeh. “Both the initial in vitro dissolution and stability studies exhibited better performance of the “super generic” version relative to the branded product. The client is continuing further clinical studies with Evonik’s new formulation proposal.”
Under a recently formed collaboration with Medimetrics, Evonik offers a combination of controlled delivery options, in vivo delivery measurements via wireless communications, and data interpretation with a single-use capsule that is swallowed, called Intellicap®. This service conducts site absorption studies to precisely identify where the drug is best absorbed along the GI tract. Based on the results from these studies, the targeted development of oral controlled release formulations with increased bioavailability can proceed more rapidly, says Dr. Asgarzadeh.
The indisputable fact before the pharmaceutical industry is that a majority of emerging APIs suffer from bioavailability issues attributed to poor solubility, dissolution rate, intestinal permeability, and food effect. A growing number of these compounds are peptides and macromolecules with upward inclination for molecular size, LogP value, and sensitivity to pH and ionization, which may also become substrates for intestinal transporters and enzymatic degradation in the GI tract, explains Jasmine Musakhanian, Scientific & Marketing Director, Gattefossé.
“Hydroalcoholic solvents may improve the drug solubility in the dose but are likely to fail in maintaining the drug in a solubilized state in vivo,” she says. “Traditional approaches like drug micronization or salt formation may offer tangible but limited value for a small number of drugs. As each API presents its own unique set of challenges, early consideration to the science, timing, and choice of technology becomes critical.”
Among the fully developed and in- creasingly popular approaches to bioavailability enhancement is the lipid formulation approach, which is seconded by polymer-based solid dispersion technologies. “Lipid-based formulations are leading the way for bioavailability enhancement because of their unique ability to simultaneously improve intrinsic solubility, enhance solubilization and supersaturation of API in vivo, and to protect the API against precipitation or binding to enzymes in the GI tract,” says Ms. Musakhanian. “Unlike solid dispersion approaches that require extensive kinetic stability studies, lipid formulations are much easier to develop in soft or hard gelatin capsules. Easy to manufacture and readily scalable, they offer significant savings in development time.”
An important and often overlooked benefit of lipid formulations is mitigation of the food effects associated with more than 80% of poorly soluble drugs. Food effect can lead to significant issues during clinical development and post market safety and patient compliance, requiring drug label warnings of intake with meals or on an empty stomach. Gattefossé specializes in lipid excipients and formulations for addressing drug solubility and bioavailability in oral, topical, and other routes of administration.
Gattefossé offers Preclinical Guidelines for early drug development stages, detailing the appropriate excipient dose per animal model. “Our customers can also tap into our Oral Bioavailability Guidelines where we provide step-by-step approaches to identifying and selecting the most promising combination of drug with excipient(s), how to determine stability and miscibility of excipient mixtures, their particle size dispersion, and in vitro lipolysis assays to help predict the in vivo performance of prototype formulations,” says Ms. Musakhanian.
Gattefossé has worked with global organizations toward the development of predictive tools such as lipolysis (lipid digestion) testing that can help predict the potential in vivo behavior of the lipid formulation in humans. “This in vitro test brings to the fore significant time and cost savings associated with animal testing, which incidentally is not always predictive of bioavailability in humans,” she says.
iCeutica: Accelerate Development of New Chemical Entities
Mechanical particle size reduction of the drug substance is a well-known method of increasing the surface area, thereby increasing the dissolution rate of a poorly soluble compound. Jet milling is the most common and widely available method of particle size reduction, but it is limited to reducing average particle size to 3-10 micron, and the powder is typically difficult to work with due to high static and low bulk density. Wet media milling can yield submicron drug particles, which are stabilized with excipients in an aqueous suspension. The drawback to this technique, says Dr. Maura Murphy, Senior Director of Pharmaeutical R&D, iCeutica, is that the water must be removed by a lengthy granulation process. There are some marketed compounds utilizing this technique, including sirolimus (Rapamune®) and aprepitant (Emend®).
It is also possible to produce submicron drug particles utilizing a dry media milling process, which removes the difficulties of the wet media milling process while achieving similar benefits. iCeutica’s SoluMatrix Fine Particle Technology™ is an attritor milling process utilizing ball media and inert GRAS excipients to grind the active to a submicron particle size. Through this low-energy milling process, the excipients that help grind the drug substance remain at 2-10 micron, while the active is reduced to an average of 200-800nm. The excipients also serve to stabilize the drug substance particle size. “In contrast to high energy milling processes such as jet milling, the attritor milled powder has much less static and has moderate bulk density, allowing for much easier handling,” she says. The attritor milling process does not typically alter the drug substance crystal structure, ensuring the product remains thermodynamically stable. This technology has been utilized to optimize absorption in marketed compounds such as diclofenac (Zorvolex®) and meloxicam (Vivlodex®). iCeutica offers development services utilizing the SoluMatrix technology to improve the dissolution rate of compounds for partner companies. iCeutica can conduct rapid feasibility studies, as well as complete dosage form development, clinical study management, and GMP manufacturing up to 150kg scale.
“Improvement of the dissolution rate can enhance drug performance of poorly soluble compounds by improving oral bioavailability, reducing the pharmacokinetic variability, and reducing or removing food effects,” says Dr. Murphy. “A faster dissolution rate can also reduce the time to reach pharmacodynamics effects for compounds with extended Tmax.”
Nanoparticulate technology is transforming the industry’s ability to successfully formulate poorly soluble APIs. Nanoparticulate formulations of poorly dissolving APIs can provide faster drug absorption and higher bioavailability by increasing the API’s dissolution rate. Amorphous nanoparticle dispersions can increase the absorption rate of API while simultaneously stabilizing the amorphous state of the API and its higher solubility.
Metrics Contract Services offers the ability to manufacture spray-dried material or to micronize the API through jet milling, both of which improving solubility and bioavailability and augment Metrics scientists’ knowledge of formulating amorphous materials and nanoparticles. The resulting material will be formulated as a capsule or a tablet.
When it comes to developing challenging compounds, it helps if the scientists know whether the client has performed preliminary solubility studies, any kind of simple animal PK studies, or even what the critical quality attributes are, such as modified release or the need to deliver the drug in the small intestine, explains Michael DeHart, PhD, Developmental Scientist II, Metrics Contract Services. “Such information allows us to move projects forward expeditiously without duplicating efforts.”
Also challenging is the sheer number of excipients on the market, as well as the different grades available. “Scientists at Metrics Contract Services work closely with our vendors’ sales teams and technical support personnel to ensure that we are choosing the optimal excipients from the beginning in order to expedite development,” says Dr. DeHart.
One client brought Metrics a prodrug known to be susceptible to acid degradation and general hydrolysis, which meant it had to be protected from stomach acid. In addition, exposure time to fluid in the small intestine needed to be minimal. “We took a two-pronged approach to resolving these issues,” explains Dr. DeHart. “First, we knew an enteric coat was essential to provide acid protection. Second, we incorporated muco-adhesive polymers into the core tablet, which helped it adhere to the walls of the small intestine. This allowed the prodrug to permeate across the small intestine, where it then was hydrolyzed to the API. Despite the daunting challenge of preventing hydrolysis throughout transit in the stomach and small intestine, animal studies confirmed that we were able to provide bioavailability of the molecule of interest.”
Two major factors in determining the success of a drug are the delivery form and bioavailability. Both of these topics are addressed by MilliporeSigma’s Actives and Formulation R&D activities.
“The interaction of new technologies and excipients, as well as new formulation approaches, create an increasingly complex scenario,” says Andrew Bulpin, Head of Process Solutions Strategic Marketing & Innovation at MilliporeSigma. “A gap in support exists when working with customers to establish formulation techniques and excipients within their R&D platforms using their model APIs. Thus, MilliporeSigma offers pharmaceutical developers support through counseling, hands-on training, and formulation development at our “Formulation Center” at the Darmstadt site, and within our global service network and collaboration centers (M Lab™ Collaboration Centers).”
As a manufacturer of excipients, MilliporeSigma finds the right excipients to boost solubility of APIs, Mr. Bulpin explains. “Poor solubility of small molecules as well as biomolecules is multi-factorial and a one-size-fits-all approach is not applicable. Thus, providing a comprehensive toolbox of products and addressing different solubility technologies and solutions is a must.”
However, many of MilliporeSigma’s customers are reluctant to use novel excipients, given the regulatory implications. To this end, the company formulates these compounds with proven technologies and excipients, ensuring a smooth path through the registration and approval process, he says. “Our offering of more than 400 Emprove® excipients is focused on exactly that.”
Excipients’ impact on API bioavailability requires that scientists determine if the API can be formulated with standard formulation technologies or if nonconventional formulation approaches need to be employed. “MilliporeSigma is working with advanced excipients (Parteck® product portfolio) and formulations that support oral or alternative administration routes that meet the innovator’s desire and increase the patient’s comfort,” says Mr. Bulpin. “We do this by considering modified release approaches and the use of tablets, capsules, or patches instead.”
Particle Sciences: A Range of Solubilization Approaches Ensures a Right Fit
As formulation scientists know, solubility is one of the key physicochemical parameters a formulator needs to understand and manipulate in order to develop viable formulations. Particle Sciences (PSI) has a number of solubilization approaches ranging from in silico design, to nanoparticulate suspensions, to solid solutions, to lipid-based systems such as LyoCells® (PSI proprietary reverse cubic and hexagonal phase nanoparticulate delivery system). API characteristics will determine which technology is best to use. For instance, a heat stable highly potent compound with a positive logP naturally drives towards hot-melt extrusion. “A relatively labile molecule with good lipid solubility may be a good candidate for LyoCells, and a classic BCS II molecule should always be evaluated for its amenability to be formulated as nanoparticulate suspensions,” says Robert W. Lee, PhD, Vice President of Pharmaceutical Development Services, PSI.
Recently, one of PSI’s clients had a need to deliver a BCS II API across the blood brain barrier (BBB). “The API was crystalline so we nanomilled it in order to increase its rate of dissolution,” explains Mark Mitchnick, MD, CEO, Particle Sciences/CMO-Lubrizol LifeSciences. “We then developed a nasal dry powder dosage form to facilitate delivery across the BBB. To minimize potential delivery into the lungs, we spray dried the nanoparticulate suspension in the presence of a larger, inert carrier to produce a mean particle size on the order of 20m and also eliminated fine particles. This approach worked very well and provided the highest in vivo API concentrations into the brain in a primate study.”
A well-informed formulation effort starts with preformulation data, including extensive solubility and excipient compatibility data. PSI uses DOSE™, a proprietary solubility evaluation approach based on Hansen Solubility Parameters. “This data helps guide our selection of excipients and matrix components in the case of emulsions, solid lipid nanoparticles, polymeric micro/nanoparticles, and solid solution approaches,” says Joey Glassco, MBA, Global Market Manager, Drug-Eluting Devices & Pharmaceutical Services, Lubrizol LifeSciences – Particle Sciences. “This can also guide nanomilling when targeting vehicles with the lowest solubility. Based on the physicochemical characteristics of the API, we assess which drug delivery methods will provide the biological performance and match the desired target product profile.”
In all of these methods, the excipients play a key 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. As part of Lubrizol Life-Sciences, PSI has access to a variety of polymers that play a key role in the solubility of APIs such as thermoplastic polyurethane-based technologies. “These relationships help speed our development whether the polymer is used or not,” says Dr. Lee. “Sometimes even knowing what raw material won’t work in a particular application helps to point us in the right direction more quickly.”
And with the backing of its parent company, Lubrizol, a Berkshire Hathaway Company, PSI is proceeding into commercial manufacturing by breaking ground on modular commercial clean room space. “The versatile design of our facility is conducive for the manufacturing of low-volume, high-value complex products, such as nanoemulsions, polymeric nanoparticles, solid lipid nanoparticles, and PLGA micro and nanoparticles,” says Ms. Glassco. The facility will be commercial-ready in the third quarter of 2017 and the first product will follow shortly.
Increasing solubility is only one part of improving bioavailability of drugs. In order to increase flux of the drug through a biological membrane, the permeability of the API through the membrane has to be taken into account. Creating amorphous solid dispersions that increase kinetic solubility of low-soluble compounds without decreasing their effective permeability is one way to achieve higher bioavailability.
Pion Inc. provides a comprehensive suite of physicochemical characterization services that help formulation scientists develop the most-effective formulation in terms of its ability to get absorbed through oral or other routes of administration. These include: ionization constants (pKa) measurements, lipophilicity (logD/logP), solubility and permeability in buffers and biorelevant media, in situ dissolution of pre-formulations in buffers and biorelevant media, and flux measurements. Additionally, Pion Inc. provides instruments and services that help pharmaceutical companies answer key questions about the absorption potential of their drugs from the early stages of formulation until the final stages of drug product development.
Excipients, formulations, and drug delivery platforms are often intended to modify the rate and extent of absorption with the goal of improving bioavailability. Understanding the effect of excipients and formulations on physicochemical properties of API is critical for developing a successful drug product.
In one example, a client provided five different formulations in an attempt to select the most promising one for further development, explains Konstantin Tsinman, Chief Scientific Officer, Pion Inc. “Two formulations showed similar improvements in solubility and dissolution while only one of these two demonstrated superior flux. It was later confirmed by the client that the formulation selected based on flux measurements performed the best in dogs.”
Quotient Clinical: Rapid Formulation Development Optimizes Solubility
While industry has done a tremendous job of developing excipients, formulations, and drug delivery techniques to improve solubility, the question remains: Which is right for my program?
“There are many reasons as to why a particular technology might be selected, including molecule properties and therapeutic indication, but eventually a prototype formulation must be developed and tested in some way,” says John McDermott, Executive Director, Drug Product Optimization, Quotient Clinical. “Initially, laboratory analysis and preclinical studies are used, but these methods are notoriously poor at predicting drug behavior in humans. Often, performance remains sub-optimal when the formulation is dosed to human subjects, and the development program is further disrupted while additional cycles of formulation development and clinical evaluation are performed.”
Mr. McDermott says that Quotient Clinical has developed an innovative approach to identify and overcome these challenges, which enables formulations to be designed, manufactured, and clinically evaluated rapidly within a single organization. “Drug product can be manufactured within 7 days of dosing, removing stability package generation from the critical path to obtain clinical data on product performance,” he says. Integrated GMP manufacturing with clinical testing allows clinical data from one study period to be used in order to select the product to be manufactured for evaluation in the next period. This rapid formulation development and clinical testing (RapidFACT®) approach permits biotech and pharma to select and optimize solubility enhancing formulation technology such as spray dried dispersions, lipidic, and nano-crystalline systems in human subjects, quickly, he says.
In one example, a client completed a Phase 1 clinical trial using an oral suspension of a spray-dried dispersion, but transition to a solid oral dosage form was needed for further development. “In this case, the sponsor had observed a lack of correlation between the in vitro and preclinical models, so drug product selection was impossible without supporting clinical data,” explains Mr. McDermott. “A Rapid-FACT program was designed to develop a range of tablet prototypes based around the core spray dried dispersion. Performance was compared in a rapid and flexible manner in human subjects.
This RapidFACT program evaluated a range of solid oral dose options in the absence of a predictive in vitro or preclinical model, and identified a suitable product for further clinical development in less than 8 months. Mr. McDermott adds: “RapidFACT therefore delivered significant time savings, with a total of 10 formulations evaluated on the basis of human PK data in a clinical phase lasting less than 10 weeks.”
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1. Manikandan, P., et. al., Improving Solubility and Bioavailability of Poorly Water Soluble Drugs by Solid Dispersion Technique – A Review, Int. J. Pharm. Sci. Rev. Res., 23(1), Nov – Dec 2013; no 42, 220-227, http://globalresearchonline.net/journalcontents/v23-1/42.pdf.
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