At what point in the drug development process should the drug delivery method be chosen?
Dr. Nitin Swarnakar, Scientist III Global Technical Marketing (Pharma Solutions), BASF Corporation: The drug development process involves rigorous in vitro and in vivo studies to understand pharmacodynamics and pharmacokinetic properties of lead compounds. Overall, knowledge of biopharmaceutical properties of the compound such as potency, selectivity, Biopharmaceutical Classifi cation System (BCS), ADME (absorption, distribution, metabolism and excretion) and physiochemical properties are required to defi ne the drug delivery method early in development. For example, a BCS class I API with a good safety profi le drug can be delivered orally by instant release mechanisms while BCS class I APIs with a low therapeutic window would require a controlled (sustained or modifi ed) release profi le. BASF has instant and modifi ed release excipients such as binders, matrices and fi llers, disintegrants, and polymers to help customers achieve their drug delivery needs. APIs that are BCS class III and IV are diffi cult-todeliver because of their poor permeability and need special novel drug delivery strategies such as self-emulsifying drug delivery systems, amorphous solid dispersions, etc. BASF off ers solubilization technologies to help its customers achieve therapeutic and commercial value of their fi nished products.
For generic pharma companies, the drug delivery method depends on their drug application fi ling strategy such as 505(j), 505(b1), 505(b2) etc. For 505(j), the drug delivery method is predefi ned by the innovator product. Other fi ling strategies can leverage diff erent drug delivery systems to modify formulations of existing drugs in order to improve safety, effi cacy and patient compliance. Many pharmaceutical companies have collaborated with BASF to improve their drug delivery technologies via providing inactive and “functional” excipients such as Kolliphor® ELP, Kolliphor® RH 40, Soluplus and Kollidon® VA 64. The overall goal of a formulator is to define the delivery method as early as possible, in order to develop a product with maximum therapeutic value and good safety profile for the patient.
Ronak Savla, PharmD, Ph.D., Global Scientific Affairs Manager, Catalent: At Catalent, we recommend that the drug delivery method be chosen as early as possible to avoid time delays and reduce costs. To reach this decision point, drug developers should complete sufficiently thorough physicochemical and pharmacokinetic characterization and parallel formulation screening. Capturing these data will allow developers to fully elucidate and address the biopharmaceutical challenges such as poor solubility, poor permeability, high metabolism, and short half-life. The Developability Classification System (DCS) and in silico physiologically-based pharmacokinetic (PBPK) modelling are some of the tools used in early development. The dose of the final drug product is the biggest unknown that affects formulation and drug delivery method. Using a range of doses as recommended in the refined DCS process is one approach to assess the influence of low, medium, and high doses on choice of drug delivery method.
True L. Rogers, RPh, PhD. Senior Research Scientist and Mark L. Dreibelbis, PhD. Associate Research Scientist, DuPont Nutrition and Biosciences Pharma Solutions: The drug delivery method should be decided quite early in the process, once the target patient population is known. Different patient populations (i.e. pediatric, non-ambulatory, etc.) or disease states may require different dosage forms. Of course, understanding API physicochemical properties, pharmacokinetic parameters, and therapeutic windows are all critical in selecting a delivery method. For example, there are different formulation and drug delivery aspects for an API with a short half-life, low solubility, and/or high logP that must be considered as early in the development process as possible.
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Paul Spencer, Head of Pharmaceutical Polymers and Services, Evonik: It is always best to consider oral and parenteral drug delivery methods early in the drug development process. For complex parenteral formulations, such as extended-release microparticles, liposomes and nanoparticles, drug delivery options should be considered as an integral companion of the drug discovery process. It is advantageous to focus on proven drug delivery technologies where required drug properties are known to help guide drug candidate screening and potentially influence drug molecule design. For complex oral formulations, such as those for drugs with poor aqueous solubility, poor permeability, short half-lives or narrow therapeutic windows, the drug delivery approach can maximize bioavailability and efficacy. For those drugs with poor water solubility, techniques such as amorphous solid dispersions are now commonly used to improve oral bioavailability. Modified release formulations are also now widely used to improve patient compliance and reduce side effects. Early communication between drug discovery scientists and formulators can ensure the final dosage form is not only feasible, but aid in evaluations of the IP landscape. Overall, the early consideration of drug delivery options will help to minimize risk and accelerate product development times.
Hibreniguss Terefe, Ph.D., V. P. Research and Development, ExxPharma Therapeutics LLC: Selection of appropriate drug delivery methods that would enhance bioavailability and provide sufficient exposure to advance a molecule to First-in-Human (FIH) and beyond should, preferably, take place at early development stage.
The first step in improving the performance and developability of a hit molecule is lead optimization by modifying the molecular structure of the drug substance, salt selection and selection of more soluble and stable polymorphs. Despite all the efforts made during lead optimization to improve bioavailability, the trend of New Chemical Entities (NCEs) towards poorly soluble and or poorly permeable molecules is persistent. Employing formulation and drug delivery strategies to enhance API performance at early development stages would be a complementary tool to more efficiently advance drug molecules in the product development process. Investing in cost-effective drug delivery methods that take into consideration the limited availability of a drug substance during early development and utilize easily scalable processes would help accelerate development timelines and pay dividends down the development path.
As more companies strive to develop drugs that are “patient-centric” what drug delivery technologies or attributes seem to be most in favor?
Swarnakar: Patient compliance is central to the success of any drug treatment. A good example of patient-centric technology that could help achieve maximum compliance would be a small oral tablet with good palatability and no side effects that could be administrated once per day.
It is well known that once or twice daily doses are acceptable for high patient adherence rate, but the adherence drops drastically with three or more doses per day. In the latter case, the dosage form with sustained release polymer such as Kollidon® SR can significantly reduce the frequency of administration and can improve safety and efficacy of a drug, making it more “patient-centric”. Similarly, a therapeutic outcome can be improved by enhancing bioavailability of the drug using various drug delivery technologies such as modifying the drug release profile, changing dose concentration, form and routes of administration via various dosage forms.
Taste masking using water soluble (e.g., polyvinylpyrrolidone and hydroxypropyl methylcellulose) and insoluble polymers (e.g., polyvinyl acetate and copolymers of methyl methacrylate) can also be a consideration. BASF recently introduced Kollicoat® Smartseal (methyl methacrylate and diethylaminoethyl methacrylate) which is suitable for taste-masking and moisture protection. It is a film-forming polymer designed to provide minimal/no drug release in the oral cavity and complete dissolution in the gastrointestinal tract.
Savla: The choice of drug delivery technologies should take both drug and patient factors into consideration. There is no single drug delivery technology that can be applied to all drugs or all patients. Multiparticulates or granules have garnered favor recently because they can be made into age-appropriate dosage forms. Multiparticulates can be administered as themselves for patients who have difficulty swallowing. They can also be filled into capsules. Multiparticulates with different coatings and release rates can be combined into a single dosage unit to enable both immediate release and modified release of drug. Another patient-centric dosage form is orally disintegrating tablets. Recent advancements in orally disintegrating tablets allow for taste-masking of bitter drugs and delivery of larger doses. A drug delivery technology can be patient-centric by addressing drug factors. An example would be potential mitigation of food effects by lipid-based drug delivery systems. Improving bioavailability of drugs can also reduce pharmacokinetic variability. These approaches that address shortcomings of drugs result in better efficacy and safety for patients.
Rogers and Dreibelbis: There are many options available for drug administration, such as implantable drug delivery systems, injectable, topical, inhalation, or buccal systems to name a few. However, any time an oral solid dosage form is a viable delivery route, it is almost universally chosen due to maximal patient acceptance. Furthermore, extended release drug delivery systems which reduce the frequency of administration and maintain systemic concentration within the therapeutic window for an extended time period will increase compliance and maximize therapeutic outcome.
Spencer: The future will rely upon the use of multiple drug delivery approaches that provide the formulation versatility that will be required for treatments that are patient-centric. These formulation solutions will be provided not only through progressive improvements to proven drug delivery methods, but also new and innovative approaches including additive manufacturing, the use of new materials, biological tools and digitalization. The properties of new drug substances identified for new modalities will also influence the drug delivery methods that are chosen for each project. At Evonik, we are experiencing significant interest in the delivery of nucleic acids such as mRNA with our lipid nanoparticle platforms largely due to their long history of proven performance and regulatory acceptance. We are also experiencing interest in delivery systems that can directly interact within the inside and outside of cells.
Terefe: Patient-centric drug delivery technologies need to address several factors including bioavailability, palatability, drug administration convenience and reliability, dosage frequency minimization, appropriate dose banding, minimization of food effect, selection of nontoxic excipients, and process robustness.
Flexible patient-centric drug delivery technologies that consider developmental physiology and morbidity related differences of target population segments would be of a great value in addressing diverse patient needs and consequently, improving drug therapy, compliance and cost of drug therapy.
For example, addressing the need of pediatric and geriatric patients is of great interest. Conventional drug delivery systems, especially oral solid dosage forms, are designed with the average adult population in mind. One of the most obvious difference between adult and pediatric drug therapy is the complexity of dose adjustment and calculations used for different sub-populations within the overall pediatric population. Due to their continuing anatomical and physiological development, pediatric patients require age and body weight related dosing and administration regimen. Moreover, younger pediatric patients require different oral drug delivery systems than other subsets of the population, typically, liquid oral dosage forms are preferable.
Due to their impaired physiological, visual, motoric functions and swallowing capabilities; geriatric patients struggle in appropriately administering conventional oral dosage forms which may lead to suboptimal drug therapy and non-compliance. Designing convenient to administer and easy to swallow dosage forms would benefit geriatric patients.
According to FDA Guidance for Industry - Q8 Pharmaceutical Development, “In all cases, the product should be designed to meet patients’ needs and the intended product performance”.
Solubility has become a major issue is drug delivery. What are some best practices drug developers can follow to help them achieve a good solubility profile for a drug in development?
Swarnakar: Poorly soluble APIs have become a major challenge for the pharmaceutical industry as it limits the full potential of an API. More than 40% of APIs in currently marketed products and 70% of new chemical entities in the discovery pipeline are considered poorly soluble. Solubilization strategies such as: micronization, hot melt extrusion, spray drying and lipid-based drug delivery systems (LBDDS) have been shown to be highly effective at improving solubility and bioavailabilty.
Selecting the right solubilization strategies for these APIs often involves trial and error. These trials can be minimized by partnering with solubilization experts such as BASF, which has access to industryleading tools e.g. high-throughput screening robots for rapid screening of suitable surfactant or polymer.
Savla: It is important to recognize that solubility is not a single number and that decisions cannot be made based on a single measurement or prediction. Solubility is influenced by both molecular descriptors of drug molecules (molecular size, shape, LogP, and hydrogen-bonding ability) and experimental conditions (solvent/ buffer composition, pH, time, and temperature). Therefore, developers should measure solubility in a variety of media and buffers. Of the various choices, solubility measurement in biorelevant media are most likely to closely mimic in vivo conditions. Solubility measurements in both fasting state, simulated intestinal fluid, and fed state simulated intestinal fluid can reveal potential for food effects. It is also wise to measure solubility across a pH range. In silico solubility predictions have garnered increasing interest over the past several years. However, the precision of this model may not be sufficient to warrant the use of predictions as basis for development decisions.
Rogers and Dreibelbis: Formulators need an intimate understanding of the drug compound’s physicochemical characteristics and where it fits in the Biopharmaceutics Classification System. The approach for formulating a waxy or lipophilic compound will be different from that of a rapidly crystallizing compound. Likewise, it is important to understand how readily a compound will be absorbed. Classic approaches such as co-crystals, particle size reduction, and formulation with surfactants have been practiced for decades, but relatively newer approaches such as amorphous solid dispersions have risen to prominence. Solubility-enhancing excipients coupled with process technologies such as melt extrusion and spray drying have enabled improved bioavailability to achieve desired therapeutic outcomes.
Spencer: Drug solubility has been, and will continue to be, a major issue. However, a number of technical solutions have been developed over recent decades that provide significant versatility. Such solutions should be assessed on a case-by-case basis given the diverse range of factors that can affect performance, IP and accessibility. At Evonik, we offer a variety of technical solutions to enhance the solubility and bioavailability of oral and parenterally administered drugs. For parenterals, we use our lipid-based and polymeric-based nanoparticle technologies to improve drug solubility and enhance drug exposure. For oral administration, we start with a structured development approach that takes into account the properties of the drug candidate. By selecting the best solubility enhancing technology and polymer systems through in silico and miniaturized screening tools including stability testing, we can improve the overall reliability of the formulation concept during the early stages of development. This enables faster commercialization times, lowers development cost and reduces regulatory risk.
Terefe: Good understanding of the physicochemical properties of drug substances is key in employing the most appropriate bioavailability enhancement technology for a given molecule.
With the advance of drug discovery technologies, drug substances are becoming increasingly complex and highly poorly soluble.
In a broader sense, poor aqueous solubility could be dissolution rate or solubility limited. In general, solubility of the former type of molecules is addressed by conventional particle size reduction technologies such as milling and micronization while the latter is addressed by formulation technologies that employ solubility enhancing excipients such as surfactants, cosolvents and emulsifiers etc.
A closer look into the molecular and solid-state property provides more understanding and helps a rational selection of drug delivery systems that would effectively solve solubility problems. Accordingly, poor aqueous solubility could be solid-state-limited also known as “brickdust”, solvation-limited also colloquially called “grease-ball” or both.
Currently, the most popular solubilization technologies that are used to solve these issues are Amorphous Solid Dispersions (ASDs) or lipid-based formulations such as Self-Emulsifying Drug-Delivery Systems (SEDDS) and Self-Micro Emulsifying Drug-Delivery Systems (SMEDDS) with different real or perceived limitations. Therefore, there is a need for innovative solubilization technology platforms that would address solubility issues irrespective of the drug substance physicochemical properties.
Are drug delivery issues becoming more complex? Do these issues require more than one approach/technology to solve these challenges? How do suppliers to the industry help solve these problems?
Swarnakar: Yes, drug delivery issues are becoming more complex due to intellectual property requirements, patient-centric and evergreen technologies. Innovative companies often require unique technologies which are difficult to reverse engineer such as holt-melt extrusion- and self-emulsifying drug delivery-based products. This increases the life-span of the product even after patent expiration and is often referred to as ever green technology. At the same time, generic companies are trying to increase profitability by making superior generic formulations with improved safety and efficacy -(via 505(b2) and via 505(b1) pathways). Excipient companies are contributing in solving the problems by manufacturing unique “functional excipients” such as Soluplus®, Kollidon® VA 64, Kollicoat® Smartseal, Kolliphor® ELP, poloxamers and Kolliphor® RH 40 which ultimately help develop products leading to better patient compliance.
Savla: As medicinal chemists are able to design compounds that bind to “undruggable” targets, formulators will need to work more closely with them to address potential biopharmaceutical challenges. Drug delivery issues can be addressed by medicinal chemistry and by formulation science. The decisions made by medicinal chemists can affect downstream drug delivery decisions. The newer classes of compounds are larger and more lipophilic to bind with the allosteric binding pockets of proteins. At Catalent, we recommend a parallel formulation screening approach to choose the optimal approach to improving solubility. There are no steadfast rules or a priori strategies to choose a delivery technology without the need for prototype formulations. Because API supply can be limited at early stages, narrowing the range of formulations based on chemical characteristics of the drug molecule and use of material sparing strategies should be used.
Rogers and Dreibelbis: More and more APIs in development pipelines are poorly soluble, but have concomitant narrow therapeutic indices, such as compounds used to treat cancer, HIV, pain, neurological conditions, diabetes, and cardiovascular conditions. Consequently, formulators are faced with the challenge to simultaneously solubilize the API, while avoiding spikes in systemic levels above toxic concentration. In the literature, there has been a rise in the prevalence of lipidic compounds with the aforementioned issues, but also requiring unique formulation approaches due to not being a solid processable powder at room temperature. Suppliers to the industry offer complementary skill sets such as polymer expertise to aid formulators in solving these unique drug delivery challenges.
Spencer: It is true that drug delivery challenges are becoming more complex. That is why Evonik chooses to focus on complex parenterals and solid oral dosage forms. We recognize that today’s advanced medical discoveries and new modalities are driving this complexity, which is reflected in the increasing number of approved biological drugs, the promise of nucleic acid-based systems, the recent surge in highly potent drugs, and early achievements in immunotherapy and regenerative medicine. Multidiscipline teams consisting of material scientists, formulators, manufacturing engineers, practitioners, and others will be required to solve these complex drug product development challenges. Industry suppliers not only need to understand these trends, they also need to continue to advance new and existing drug delivery technologies to better meet tomorrow’s patient and drug product requirements.
Terefe: Advances in combinatorial chemistry, high throughput screening, molecular targeting, development of drugs based on pharmacogenomics, targeting of complex biological sites and modes of actions and poly-pharmacology are helping the pharma industry to develop a vast library of promising molecules. However, these drug discovery technology advances have shifted the physicochemical properties of the molecules out of the traditional “Rule of Five” chemical space. New chemical entities have become more complex and the need for multidisciplinary and sophisticated solutions to advance these molecules to the market has become more crucial.
Drug candidate molecules fail due to several reasons such as lack of efficacy, toxicity and poor absorption, distribution, metabolism and elimination (ADME) properties during preclinical and clinical development stages. Absorption limitation attributed to poor aqueous solubility and/or permeability is one of the prominent reasons for the failure of many candidate molecules in early development stage. Advancing such molecules to First-in-Human (FIH) and beyond requires engagement of pharmaceutical scientists in search of appropriate drug delivery technologies that would solve drug absorption issues as early as possible.
Some molecules are prone to first pass effect. For such molecules transmucosal and transdermal delivery systems may be the way to go. Molecules that have short half-life or are labile to gastric pH require modified release dosage forms.
Availability of approved/pharmacopeial excipients that could be used for solubility enhancement are very limited. Excipient quality specifications, most of the time, are very broad and cause quality impacting lot to lot variabilities. Excipient suppliers can help by increasing the library of approved excipients, tightening their specifications and improving their manufacturing processes to minimize lot-to-lot variabilities. Co-processed excipients also facilitate less expensive and expediated formulation selection.
Moving forward, as drug developers continue to work on new products, what advice would you give them in regards to drug delivery technologies, choices, and best practices?
Savla: The best advice would consist of: understand your molecule (physicochemistry, solid state properties, and biopharmaceutics); view drug development as an integrated approach (every decision has potential to impact patient outcomes); conduct necessary studies to avoid future delays and re-work; and work with external partners when you do not have the internal equipment or expertise.
Rogers and Dreibelbis: Since drug delivery is so critical to therapeutic success, it is critical for formulators and suppliers to work closely together from as early as possible in the development process. Partnering with suppliers early on to understand the challenges for a specific API or drug delivery system allows the problems to be approached from multiple perspectives for maximal success.
Spencer: Now, and even more so in the future, formulators will rely on multiple drug delivery technologies for formulation solutions that can be evaluated on a case-by case basis. The market preference for safe and established excipients will continue for both oral and parenteral dosage forms. New materials will only be introduced if they deliver significant advantages over existing materials, have attained a strong safety record, and can be efficiently scaled-up. Also trending is use of sustainable materials and the use of non-animal -derived materials. Lastly, drug developers will continue to depend on CDMO service providers for formulatiTerefe: Having multiple and flexible drug delivery technologies in their toolbox and having good understanding of the physicochemical properties of the drug substance and giving drug delivery technologies as much importance as lead optimization, salt and polymorph selection at early development stage will help enhance API performance early on and minimize lead attrition.on feasibility studies, process development and scale up support, and manufacturing of clinical and commercial drug products.
Terefe: Having multiple and flexible drug delivery technologies in their toolbox and having good understanding of the physicochemical properties of the drug substance and giving drug delivery technologies as much importance as lead optimization, salt and polymorph selection at early development stage will help enhance API performance early on and minimize lead attrition.