Over the past year can you tell us about one critical issue that has most affected new drug delivery efforts?
Satish Shetty, Director of Product Development, Cambrex: In 2020, the most critical issue has become the COVID-19 pandemic situation. This has affected new drug delivery eff orts in two ways:
- a disruption in the supply chain impacting availability of active pharmaceutical ingredients (APIs) due to sourcing and globalization issues
- a shift in focus from existing or new development programs to COVID-centric programs (vaccines and treatments)
The global API market is estimated to reach USD 245.2 billion by 2024 from USD 182.2 billion in 2019. Chinese and Indian manufacturers account for more than 50% of all APIs used worldwide, which could grow as the market grows. During the spring of 2020, as COVID lockdowns first started happening, we saw fractures in the supply chain based on shipping and trade challenges. This glimpse into the “what if” of losing access to certain APIs made the large reliance on Asia a deep concern because the adequate supply of APIs is the backbone for developing drug delivery systems.
Indeed, the pandemic has served as a wake-up call to counter the dominance of India and China in the world supply of APIs. Western governments need to take initiative and encourage domestic production of active pharmaceutical ingredients.
Susan Banbury, Head of Zydis Formulation, Catalent: The biggest drug delivery challenge encountered over the last year is that of overcoming bioavailability issues. This may be due to very low solubility of the active pharmaceutical ingredient (API) and consequent dissolution rate limited absorption. In such cases, formulation and processing eff orts focus on improving the API’s solubility, for example through excipient choice or pH modification, or increasing its surface area via micronization. These techniques can present their own formulation challenges - micronized API may have increased cohesive force, leading to poor bulk powder flow or agglomeration in suspension, which can lead to manufacturing and quality issues. These are typically overcome by using an appropriate surfactant or flow enhancing excipient.
Poor bioavailability can also occur where the API degrades in the GI tract prior to absorption or when heavily metabolized in the liver. For some of these APIs, orally disintegrating tablet (ODT) formulations may be used in delivery to the oral mucosa, facilitating pre-gastric absorption, allowing the API to transport through the oral mucosal tissue into the blood stream, and avoiding potential degradation in the GI tract or first pass hepatic metabolism. This delivery method is subject to several physicochemical factors such as solubility, molecular weight, and lipophilicity as well as dose.
Tom Tice, Senior Director, Global Technical Marketing for Parenteral Drug Delivery, Evonik: Ocular delivery poses a unique set of significant drug delivery challenges. Although there are many topical ocular products, the main challenge is to identify bioabsorbable materials and dosage forms that can reliably deliver drug over months to the back of the eye. Part of the challenge lies in understanding the biology of the eye and identifying bioabsorbable excipients that are biocompatible in the vitreous environment. Albeit, there are two lactide/glycolide ocular products on the market. The first is an intravitreally administered implant that releases dexamethasone for one month for the treatment of uveitis, macular edema and diabetic macular edema. The second product is an intracamerally administered implant that releases bimatoprost for four months to treat glaucoma. This is a micro-implant of less than one millimeter in length that comprises an excipient blend of three lactide/glycolide polymers and a PEG polymer. Other lactide/glycolide products are presently in clinical development that may further address some of the challenges involved in delivering drug to the back of the eye.
What is your view on combination devices/wearables? Will these devices grow in popularity? Why?
Shetty: There is a significant growth in patient administration of drug therapies for different disease states like rheumatoid arthritis, psoriasis, diabetics, chronic pain management, long term management of asthma and mental health diseases. With the patient in control of staying on track with treatments, there have been a variety of hurdles to compliance. Mechanical complexity, physical dexterity and needle phobias are some of the most common challenges that cause patients to get off track with dosing, which negatively impacts treatments.
A wearable device is a hands-free device that adheres to the body and administers medication over an extended period. These devices have been developed to provide therapeutic value to patients (and assurance of compliance to the treating physician) by easing administration, reducing pain, and preventing missed doses. The advantages are significant, with proven increases in compliance and efficacy of treatment paths.
We expect that user studies will help to evolve this sector. Improvements in designs will focus on comfort, simplicity, and ease of use.
Tice: In the bioabsorbable medical device space, there are several device/drug combination products using lactide/glycolide polymers. The drugs that are released from these devices include antibiotics, an anti-inflammatory and an antiproliferative drug. In all cases, the products are registered as a medical device. Interestingly, the polymers to achieve device performance are different than the drug-release polymers that are coated with drug on the device surface. Although I expect to see further growth in device/drug combination products, this growth will still be hindered by higher costs and longer development times when a combination product is required to be developed and approved as a drug product rather than a medical device.
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Looking at oral solid dosage products – what technologies are companies using to “modernize” them? Are technologies such as taste-masking, size, and shape, critical to ensuring patient compliance and subsequent drug delivery?
Shetty: The modernization of oral solid dosage products has followed the trajectory of the industry. And increased focus on quality and efficacy is now complemented by a greater focus on working to ensure patient compliance in taking prescribed medicines. In fact, patient compliance has become a much more extensively studied and documented topic in today’s industry because without compliance, treatment paths cannot be clinically successful.
Solid dosage forms like tablets and capsules have been extensively reviewed by drug developers to determine how size and shape of solid doses can either help or hinder patient compliance. Guidance has been drafted by the US FDA for solid dosage size and shape requirements based on studies investigating different patient swallowing ability profiles by age, as well as general patient preferences. Variable tablet and capsule size, shape, surface, and color trials have been done to see what patients respond to best. In these studies, gelatin capsules were found easier to swallow than tablets, and coated tablets were found easier than uncoated normal tablets. The preferred color was white both for tablets and capsules, and the most disliked colors were purple tablets and brown capsules.
Another important factor of solid dosage compliance is the taste. Various methods are employed to create patient-friendly taste profiles, including:
- Taste masking by way of granulation
- Masking via microencapsulation
- Use of Ion-exchange resins by complexation
- Taste covering by way of adsorption
- Taste protection by means of gelatin
Banbury: Many pharma companies are attracted to ODTs as an option that appeals to patients over traditional tablets and capsules. ODTs offer patients oral delivery where difficulty in swallowing a solid tablet is overcome by fast disintegration in a small volume of saliva. The ability to take ODT medications without water also offers increased convenience, especially for treatment of acute conditions. This is particularly true of those with very fast oral dispersion times, such as lyophilized ODTs and can be especially beneficial for pediatric or populations where potential choking hazards associated with conventional solid oral products is increased. Whereas the large size of conventional tablets and capsules can be daunting to many patients, the very fast disintegration of lyophilized tablets facilitates administration regardless of tablet size. The use of mini-tabs or dry granule formulations similarly aim to address swallowability by size reduction, whereas elongated shapes may offer some swallowing benefit for larger solid dosages.
Taste-masking is also important for patient compliance, particularly where the API is immediately available to taste as soon as the dosage is placed in the mouth. Again, this is particularly important for pediatric populations for whom taste will be a key factor in compliance, and for consumer health products, where organoleptic properties are likely to influence repeat purchase. Several formulation techniques can be utilized to mask the taste. It may be that the addition of a sweetener and an appropriate flavor are sufficient to provide a palatable dosage form. However, where the API taste is particularly unpleasant or presents an unacceptable sensation such as numbing or burning, then more advanced masking techniques are necessary.
Dr. Jessica Mueller-Albers, Strategic Marketing Director, Oral Drug Delivery, Evonik: Companies using polymethacrylates to modernize their oral solid dosage forms mainly focus on two areas. The first is to optimize bioavailability to increase drug performance while decreasing any undesired side and food effects. This can be achieved either through solubility enhancing technologies such as amorphous solid dispersions, or through modifying the drug release to optimize absorption. Modifying the drug release can be challenging as every drug has its specific target area in the GI tract. Therefore, advanced formulation technologies can often be required to target the desired region of the duodenum, jejunum or colon. The second area of focus is around patient adherence, where formulators are seeking solutions for taste masking and swallowability, or to reduce the pill burden through improved bioavailability and sustained release medications. Reducing the size of the final oral dosage form and improving or neutralizing taste can be especially important for dedicated patient groups such as pediatrics. Over the last few years, authorities have placed a stronger focus on the swallowability of oral dosage forms to boost patient adherence. This can be positively influenced by applying a smooth coating on the surface to avoid stickiness in the mouth.
Is there a “road map” or “step-wise” approach to formulate products to incorporate ideal drug delivery profiles? What is your advice to pharma companies?
Shetty: The best “road map” for product formulation is based on simplicity and structure from early in the process. The primary cause for drug failure in the development phase is poor pharmacokinetic and ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties rather than unsatisfactory efficacy. By working ADMET profiling assays into the process and prioritizing the drug candidates by their biopharmaceutical properties, companies can expedite development and reach the market to meet the unmet needs of patient faster.
Longer range, a company can leverage different delivery systems to extend the life cycle of a product.
Stephen Carino, Manager, Early Development, Catalent: Generally, a good understanding of the anticipated delivery route and the physicochemical properties of the drug candidate are necessary first steps in designing a formulation that delivers the desired pharmacokinetic (PK) profile. For oral solid drug candidates, the formulation path can be assessed via the developability classification system (DCS), originally proposed by Butler and Dressman in 2010. Using the DCS, simple solubility in fasted-state simulated intestinal fluid along with permeability data can be used to establish if the drug candidate will require a simple formulation or an enabling technology such as lipid-based or amorphous solid dispersion formulations to achieve the targeted pharmacokinetic profile.. Additionally, the DCS can provide guidance on the need for permeation enhancers in the formulation. All these assessments assume that the drug candidate exhibits a well-behaved solid form (i.e., stable crystal-form, chemically stable, acceptable hygroscopicity, etc.) which implies that it can be prepared reproducibly. Once initial formulations have been prepared, initial data from animal PK studies can be used to develop a physiologically-based model which can further help understand if any of the formulation is able to achieve the desired exposure or needs to be redesigned.
Tice: For complex parenterals that are based on lactide glycolide polymers such as injectable microparticles and implants, there is a general road map to formulate new products. The first step is to select the route of administration for systemic or local delivery, and to then select the desired duration of drug release. The route, duration of drug release, and drug pharmacokinetics data are then used to estimate drug dose. Using this dose estimate and considering the physicochemical properties of the drug, a formulation expert for the target drug delivery technology can then estimate the total dose and determine if the total mass, including a vehicle if necessary, is acceptable for the desired route of administration. If it is not, then the target duration of drug release can be decreased, or the drug properties optimized, for instance, through the use of an alternate salt. The next step is to perform a feasibility study to demonstrate the ability to make formulation preparations. Based on the characterization results of these preparations, including in vitro and in vivo performance testing, lactide/glycolide excipients can then be tailored or tuned through polymer synthesis to achieve the ideal drug delivery profile.
Based upon these results, excipient, composition and process-tuning can be further performed to optimize the release profile. Bottomline, dose and drug properties are the key elements in the road map to maximize product development outcomes.
Mueller-Albers: Understanding your formulation challenges such as solubility, stability and the absorption window is the key to starting a successful development campaign. A structured development approach is recommended for technologies where no one-size-fits-all solution is available, such as for the solubility enhancement of poorly soluble drugs. This structured development approach comprises in silico and miniaturized screenings, and the selection of the best technology before starting into lab-scale feasibility trials and development programs. The engineering of a dedicated release profile and enabling the targeting of a drug to a specific region within the GI tract requires extensive knowledge of the different excipients, formulations and technologies that are available. Asking the formulation experts can reduce development times and project risk as they should have a strong record in matching target profiles with all different types of drugs.
In the next few years what do you see as some drug delivery challenges and what advice would you give drug developers regarding drug delivery technologies, choices, and best practices?
Shetty: Development of new drug molecules is expensive and time consuming. To bring a new drug through discovery, clinical testing, development, and regulatory approval can take around a decade with costs well over $120 million. Still, the industry is continuously innovating to try to bring the timeline and cost down without impacting (and even increasing) quality of drug products.
New technologies are being explored, including beaded, liposomal, and targeted drug delivery systems. Approaches are being explored for new skin, buccal and nasal membrane delivery methods. And there is strong growth in biologics and biosimilars, with a rapid increase in blended small and large molecule therapies making their way into the market. Of course, controlled drug delivery has long been pursued in the industry, but this still has challenges to overcome from dosedumping, erratic dissolution, and food effects.
My advice is to make it a standard best practice to respond quickly to the ever-changing demands of the global community and develop the personnel resources and equipment to meet the evolving needs.
Carino: Many drug candidates coming out of discovery are lipophilic and exhibit poor water solubility. At the basic level, certain solubility and bioavailability issues can be addressed by salt formation and by cocrystallization. These two crystal engineering approaches, which both involve the addition of small molecule coformers, have proven to be viable solutions for drug candidates. Cocrystallization, in particular, has garnered increased interest after the FDA relaxed its guidance in 2018. However, drug molecules that are extremely insoluble will require enabling formulation technology for development. Enabling approaches such as amorphous solid dispersions, lipid-based formulations and nanoparticulate technology are being pursued, sometimes in parallel, to fast-track the development of these poorly soluble compounds. During early development, these technologies also facilitate ascending doses for toxicological studies which otherwise would not be accessible in the case of the crystalline solid. As these approaches are fairly involved, it is necessary to assess physicochemical properties of the drug candidates early on so resources can be focused on finding the appropriate enabling technologies.
Tice: In terms of choices and best practices, a key emerging drug delivery challenge is to identify, select and apply the best formulation approaches, excipients and manufacturing technologies to develop products that meet desired target product profiles. For success, it is imperative that you have broad knowledge of drug delivery principles and delivery formulation options. Furthermore, you should understand what formulation and manufacturing strategies are needed to take a product development program from feasibility through scale-up and launch. Risk can be reduced if safe, well-characterized materials and proven process technologies are selected. For example, consider extended-release complex parenterals such as microparticles, implants, in situ forming dosage forms, and nanoparticles, where there over 60 products on the market. These products rely on the long safety record and tunable properties of bioabsorbable lactide/glycolide polymers. Furthermore, these products are made using proven manufacturing processes that can be efficiently scaled up to commercial quantities. Most pharmaceutical companies use a variety of dosage forms for a product line. Many of these dosage forms are relatively straightforward and can therefore be developed in-house. However complex parenterals are different. Their chemical and physical properties are unique, with many critical material attributes that need to be understood. Furthermore, their development requires a unique set of formulation competencies, including the ability to develop and perform product-by-process manufacturing. Consequently, complex parenterals are most often developed with the help of CDMO partners.
Mueller-Albers: For complex oral dosage forms, drug product developers should leverage expert knowledge on bioavailability enhancement and modified release strategies early in the development process. This can quickly identify the best formulation options and optimize the pathway to the development of a successful clinical program.