The development of new medicines is a highly regulated process focused on demonstrating efficacy and safety of new products. Although such qualities always will remain the primary focus of drug development, the biopharmaceutical industry gradually has adopted additional design aspects. New approaches can help meet patients’ divergent needs to improve their lives in meaningful ways.
Often referred to as “patient-centered†or “patient-focused†drug-product design, such considerations are expected by many experts to become an increasingly dominant part of future drug development. Patient centricity presents in many different ways, all generally relating to convenience and safety of administration, patient compliance with treatment, and general patient engagement. No single or universal solution applies to all disease conditions and all patients. Each patient group, condition, and treatment paradigm requires a different patient-centered approach to maximize compliance, safety, and treatment outcomes.
A number of technological advances contribute to patient-centered development, including creative drug-product formulation, smart delivery devices, and connectivity with monitoring systems through dedicated apps or purpose-built controllers such as those used in closed-loop systems for diabetes mellitus treatment (1, 2). Although all such advances increasingly are integrated into singular complex systems, my focus herein is on patient-centricity features that rely on creative formulation.
How Formulation Fits In
Drug-product formulation is the process by which an active drug is converted into a safe and convenient form with specific combinations of additives (excipients) and optimization of parameters such as pH and osmolarity. The fundamental principles of formulation are well established and practiced, with small degrees of variability among product-development groups in big pharmaceutical, small biotechnology, or contract manufacturing companies. Formulation development is an integral part of drug-product development, no matter what the drug-substance modality is, and it must align closely with the final container and drug-delivery method to address potential incompatibilities between active ingredients and materials of construction.
In addition to well-established formulation approaches, certain (often proprietary) technologies can provide further benefits to formulated drug products. Such advantages include improved stability during storage or use, reduced drug-product viscosity, tunable rates of active-ingredient release from an injection site, and the ability to deliver large volumes without causing unacceptable discomfort to patients. Such benefits can enable a patient-centered product design for certain types of drugs. Creative formulation technologies thus are becoming a fundamental part of patient-focused development efforts, and their importance is likely to increase over time in a competitive industry putting ever stronger emphasis on patients’ wants and needs.
Injectable Alternatives: A key patient-centered product concept is liquid formulation for relatively convenient subcutaneous or intramuscular injections (rather than intravenous injection or infusion). A number of smart delivery devices for such liquid products are available — including prefilled syringes and pens, autoinjectors, and programmable infusion pumps. Many of those are intended for self-administration, so that either a patient or home caregiver can administer required doses easily without help from a healthcare professional. Ease of use has been shown to improve treatment compliance and outcomes significantly (3–5). Convenience (and in turn, compliance) improves further with flexibility in temperature during storage and use, such as the ability to store and use products at ambient temperatures without refrigeration.
Despite availability of a wide range of advanced delivery options, product developers often find that the stability of their active ingredients is not sufficient to work with such technologies. Many drug substances, particularly complex biological molecules, simply are not stable enough in liquid solutions at all; they must be formulated in lyophilized powders that can be inconvenient for patients or caregivers to use. In other cases, even when a liquid formulation is possible, product stability requires cold-chain protection. And because of the relatively small dose volumes required for subcutaneous or intramuscular administration, active ingredients often must be present at very high concentrations, which can lead to unacceptably high viscosities that prevent easy administration. That often makes a less convenient intravenous delivery route the only viable option.
Clinical Administration: Despite the trend toward self-administration, intravenous infusion or injection remains the best and sometimes the only option for many therapeutic areas (e.g., certain oncology and infection-disease treatments) in hospital settings. However, even in these cases, creative formulation can improve the safety and convenience of use for healthcare professionals — with a similarly positive effect on treatment outcomes. This is particularly true for often-lifesaving drugs that come as lyophilized powders requiring complex reconstitution procedures for administration to patients.
Dosage preparation adds to the workload of healthcare professionals and can cause unnecessary delays for patients receiving urgent treatments. In addition, complex reconstitution processes can incur errors and safety risks, with patients sometimes receiving the incorrect drug or dose. Stable liquid formulations in the form of ready-to-use liquid concentrates — and ideally, ready-to-use liquid premixes formulated directly in suitable intravenous bags — provide a relatively convenient, safe, and effective treatment option for products that must be administered in a clinical setting.
To that end, the US Food & Drug Administration (FDA) and the International Medication Safety Network (IMSN) hosted a meeting for international drug regulators in June 2018 to discuss medication safety issues related to pharmaceutical labeling, packaging, and pharmacovigilance. The meeting included discussions on ensuring the availability of ready-to-use products such as prefilled syringes and premixed intravenous solutions for the purpose of decreasing nursing/pharmacy workloads and errors.
Successful Examples
The above challenges show where creative formulation technologies can facilitate highly desirable patient-centered product concepts. That can enable product-concept updating, such as a switch from lyophilized to liquid composition or from a refrigeration-stable to an ambient-stable formulation. The requisite technologies might be based on unique combinations of excipients for improvements in stability or other critical product attributes (e.g., viscosity). If the stabilizing or viscosity-reducing effect is sufficiently unique and novel, then it lends itself to patent protection, which provides exclusivity for the improved products and thus increases the innovation incentive (which ultimately benefits patients) as well as staving off potential competition (which benefits innovators).
Arecor Therapeutics has developed an innovative and proprietary formulation technology platform to address different aspects of stability of therapeutic products, ranging from small molecules to complex biological constructs. Arecor leverages that technology, which is protected by an extensive patent portfolio of 33 patent families (e.g., 6–8) to develop highly differentiated, patient-centered product concepts through codevelopment programs with bio/pharmaceutical companies. Current projects involve some challenging ready-to-use and ready-to-administer formats and highly concentrated products. In addition, the company is developing an internal proprietary portfolio of differentiated product formats based on approved active ingredients.
Creative formulation approaches that can be used to enable patient-centered solutions do not always relate to product stability, however. For example, Halozyme Therapeutics has been successful in applying its proprietary Enhanze technology for subcutaneous delivery of large injection volumes to enable convenient delivery of high-dose products that otherwise would have to be delivered intravenously. Another company with a creative technology for improving patient convenience is Alkermes. Using controlled-release and long-acting technologies, the company is improving product concepts that reduce the frequency of administration, leading to increased patient compliance.
The patient-focused approach to product development may be a relatively new concept, but it is certain to remain a key aspect of drug development in the future. As an increasing number of novel product formats emerge — such as complex protein constructs, mRNA drugs, viral vectors, and products based on mixing two or more active ingredients — challenges are likely to increase in addressing their required quality attributes for patient-centered product formats.
Note that not only new development candidates are of interest in this field. A number of existing products can benefit from a smart reformulation to create more convenient product concepts. Whether differentiating follow-on products or extending the patent life of marketed drugs, a high degree of innovation will be needed. That creates a significant opportunity for technology partners such as Arecor to provide innovative solutions in drug delivery and product formulation.
References
1 Scott C. Drug Delivery: Partnerships Are Key As Medical and Digital Worlds Converge. BioProcess Int. eBook 24 November 2020; https://lne.e92.mwp.accessdomain.com/manufacturing/fill-finish/ebook-drug-delivery-partnerships-are-key-as-medical-and-digital-worlds-converge.
2 Cengiz E, et al. Moving Toward the Ideal Insulin for Insulin Pumps. Exp. Rev. Med. Devices 13, 2016: 57–69; https://doi.org/10.1586/17434440.2016.1109442.
3 Dashiell-Aje E, et al. Patient Evaluation of Satisfaction and Outcomes with an Autoinjector for Self-Administration of Subcutaneous Belimumab in Patients with Systemic Lupus Erythematosus. Patient 11, 2018: 119–129; https://doi.org/10.1007/s40271-017-0276-2.
4 Quero C, et al. Safety of Switching from Intravenous to Subcutaneous Rituximab During First-Line Treatment of Patients with Non-Hodgkin Lymphoma: The Spanish Population of the MabTella Study. Brit. J. Haematol. 188, 2020: 661–673; https://doi.org/10.1111/bjh.16227.
5 De Costera I, et al. Assessment of Preparation Time with Fully-Liquid Versus Non-Fully Liquid Paediatric Hexavalent Vaccines: A Time and Motion Study. Vaccine 33, 2015: 3976–3982; http://dx.doi.org/10.1016/j.vaccine.2015.06.030.
6 Jezek J. WO/2009/133408: Protein Formulation. World Intellectual Property Organization: Geneva, Switzerland, 5 November 2009: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009133408.
7 Gerring D, et al. WO/2018/060735/A1: Novel Formulations. World Intellectual Property Organization: Geneva, Switzerland, 5 April 2018: http://patentscope.wipo.int/search/en/WO2018060735.
8 Jezek J, et al. WO/2019/122935: Novel Composition. World Intellectual Property Organization: Geneva, Switzerland, 27 June 2019: http://patentscope.wipo.int/search/en/WO2019122935.
Jan Jezek, PhD, is chief scientific officer of Arecor Limited, Chesterford Research Park, Little Chesterford, CB10 1XL, United Kingdom; 44-1223-426-060; jan.jezek@arecor.com; https://arecor.com.
Enhanze is a registered trademark of Halozyme Therapeutics.