From Molecule to Dose Form Bioavailability Toolkit to Fast Track Development Introduction

contents introduction 2 part one: Connecting the 4 Dots in Drug Delivery part two: The Bioavailability 8 Toolbox part three: The Toolbox of 2025 16 part four: Delivering Change 21 from molecule to dose form bioavailability toolkit to fast track development introduction When it comes to drug formulation challenges, there trend and the key to succeed in this competitive is no one-size-fits-all solution. landscape. The leading evidence of this trend includes more direct-to-consumer advertising and a The 3rd annual drug delivery landscape survey* recent patient focused drug development initiative confirms that bioavailability, safety, efficacy by the FDA to gather the patient’s perspective and solubility are the top challenges faced by on their condition and available treatments. formulation scientists. The pharmaceutical and Interestingly, survey data shows that although biopharmaceutical industries have to overcome not the industry has identified the value of patient- only formulation challenges but also the business centric drug design, it has not been very successful challenges of bringing a product successfully to in applying it. For instance, to successfully apply market. The survey participants, a vast majority of patient-centric design, the drug product should be whom are Formulation Scientists and R&D Managers, adapted as per the patient’s preference at earlier indicated that development time, selecting the stages of drug development to avoid high costs at appropriate drug delivery platform, budget and late stages, a practice which is not very common in choosing the right external partner are the top the industry. Also, when asked to rate the significant business challenges. The survey also shows a major factors in drug development, patient adherence, shift in trend towards “patient-centric” drug design. patient dosing convenience, and impact on patient’s Oral delivery of macromolecules was the trend that likely drug regimen received very low scores. will most influence the drug delivery technology in next five years, followed by improving bioavailability There is a definite need for a drug delivery strategy of BCS Class IV drugs. In a nutshell, Formulation that not only overcomes formulation challenges Scientists have a three-fold challenge; designing a but also meets patient demands. Industry pioneers safe, effective and stable dosage form, ensuring it is in formulation technology have developed a broad patient friendly, and bringing it faster to market. range of advanced drug delivery technologies, which are viable tools to solve formulation challenges, The days of “low-hanging fruit” in the drug discovery improve patient compliance, and bring product faster era when most new chemical entities (NCE) were to market. Here is a brief snapshot of the type of highly permeable and soluble (BCS class I) are over. tools available to formulation scientists. As drug discovery teams dig deeper into compound libraries to identify a NCE, the compounds are softgel technology: For last 80+ years, softgel increasingly becoming less soluble and/or permeable technology has enabled more than 50 poorly soluble than previously developed drugs. It is estimated that drugs to be commercialized, making it one of the ~70% of NCEs are class II or IV, either poorly soluble most successful drug delivery vehicles for BCS class in water, have low cell permeability or both. In II compounds. It is also a proven method to deliver addition, in the midst of the technology and business unstable API, low dose, potent compounds, light and challenges, we cannot afford to lose sight of end oxygen sensitive compounds. Softgel technology users, i.e., the patients. has utilized lipid-based drug delivery systems (LBDDS) in which drug is delivered in a solution Traditionally, the target customers were physicians form and maintained in solution upon dispersion but the survey indicates that the industry has into biological fluids until it reaches GI track. LBDDS realized that patient-centric drug design is a major are used to overcome issues created by API that 2 are practically insoluble in water and spontaneously size range. It is suitable for sensitive API as there emulsify in gastric juices. There are a number of is no heat degradation and the process results technologies that can accommodate a wider range in thermodynamically stable crystalline form of drug molecules and excipients. For instance, one of API. The micronization process has a track technology utilizes a plant polysaccharide based record of improving bioavailability of potent and shell which allows encapsulation of fill formulations thermolabile compounds, such as oncology drugs. at higher temperatures, up to ~70° C for semi-solid This technology is also well known in the industry for and highly viscous fill formulations. bringing orphan drugs faster to market by combining expertise in particle size reduction and efficient Additionally, there is a new tool to improve the manufacturing processes. delivery characteristics of macromolecules including peptides and proteins. Macromolecules delivered fast dissolving technology: Ever-increasing through the intravenous route may result in poor demand for fast dissolving and palatable dosage patient compliance for long term treatment. This forms among pediatric and geriatric population new technology improves the bioavailability of has made it a rapidly growing field. Fast dissolve macromolecules by incorporating permeability technologies have been shown to improve patient enhancers which modulate intestinal membrane compliance by providing a convenient dosage form permeability. The enteric coating provides targeted for allergens and large molecules. It is a unique, delivery of API by preventing gastric degradation of freeze-dried dosage form that is palatable, does macromolecules and releases the macromolecule at not require water, and is resistant to microbial the site of absorption. contamination due to low moisture content. Oral fast dissolve tablets can be tailored to meet various solid dispersion system: Solid dispersion technology dose requirements. At present, it covers seventeen has emerged as an effective way to enhance therapeutic areas in Rx and OTC products. dissolution rate of low solubility API. This versatile technology offers multiple advantages such as To summarize, there are a variety of tools to generating stable and processable product that can overcome bioavailability challenges of poorly soluble be further formulated into the desired dosage form. compounds. It is crucial to select a tool that not only Hot melt extrusion is the process of creating API- solves formulation challenges but also delivers an polymer dispersion by applying heat and shear stress agreeable dosage form for patients. Explore further to create an amorphous dispersion. There is no need chapters to learn how Catalent offers commercially for toxic organic solvents, which means no related viable and faster to market solutions. expense or the environmental hazards associated with removing them. Hot melt extrusion technology *The 3rd annual drug delivery landscape survey can accomodate ~90% of drug loading (the ratio was sponsored by Catalent Applied Drug Delivery of the active drug to the total contents of the dose) Institute. For more information, visit www. which provides reduced pill burden and enhances drugdeliveryinstitute.com patient compliance. Hot melt extrusion processes have been proven to increase bioavailability and decrease time-to-market for multiple compounds including an anti-inflammatory drug and to improve product differentiation and brand performance for analgesic products. particle size reduction: Micronization is an established method of improving oral bioavailability of poorly soluble compounds. The drug particles are accelerated utilizing high velocity compressed gas within a chamber to achieve desired particle 3 But a reduction in bioavailability isn’t the only part one problem. Poor solubility is also often associated Connecting the Dots in with unacceptable variability in blood levels of the drug, both within and between patients Drug Delivery – and it increases the risk of food effects. Despite the challenges, oral dosage forms The days of “low-hanging fruit” in drug discovery are (read: convenient and non-invasive) remain the a thing of the past. Drug candidates are increasingly preferred route of administration for traditional made up of complex, poorly soluble molecules – and small molecule drugs, making up around 40 that poses a big challenge: how can we continue to percent of all prescription drugs (1). In essence, produce effective medicines that meet patient needs. to deliver the convenient dosage forms that patients want, we must find ways to enhance the bioavailability of poorly soluble drugs. To do that, we need to connect more than a few dots... Simple Solubility? Improving solubility is simple in theory: we (just!) need to break down the crystal lattice structure before the patient ingests the medicine. In practice though, with the demands of stability and patient acceptability to contend with, it’s a much trickier proposition. Typically, the lattice can be broken down Welcome to the first part of a four-article series by applying heat, shear stress or solvents to the API that will explore the unprecedented challenges and adding suitable excipients. Hot-melt extrusion facing pharmaceutical scientists – in particular, or spray drying to create solid dispersions, self- the ability to offer good bioavailability and patient-

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