The performance of a drug can often be optimized by controlling the rate and extent of its release in the body. As controlled-release (CR) drug-delivery systems continue to play an important role in the treatment of diseases, Pharmaceutical Technology brought together a panel of industry experts to discuss the challenges involved when developing CR formulations and the advances made in this field. Participating in the roundtable were Randy Wald, senior research fellow at Bend Research, part of Capsugel’s Dosage Form Solutions Business Unit; Ali Rajabi-Siahboomi, PhD, vice-president and chief scientific officer, Colorcon; Leah Appel, PhD, managing partner, Green Ridge Consulting; Ninad Deshpanday, PhD, president of R&D, and Vinod Gupta, PhD, vice-president of pharmaceutical development, both at Kemwell; Anshul Gupte, PhD, Michael DeHart, PhD, and Joe Cobb, CPIP, all three from Metrics; and Anil Kane, PhD, MBA, executive director and global head of formulation sciences at Patheon.
PharmTech: What do you see as the top three challenges in the development of CR formulations?
Wald (Bend Research):The three main challenges in the development of CR formulations include: the intersection of market expectations for once-daily dosing and the prevalence of lower-solubility, higher-dose compounds for the development of oral solid CR products; the development of CR dosage forms that impart abuse resistance; and the increasing need for pediatric CR dosage forms.
Many compounds do not have sufficient colonic absorption for conventional CR formulations. Absorption technologies such as nanoparticles, amorphous-drug, and lipid-formulation technologies are needed to provide sufficient driving force for adequate absorption, especially in the lower part of the gastrointestinal (GI) tract. These absorption technologies have matured over the past two decades for immediate-release (IR) dosage forms, but substantial research is required to couple them with the processing technologies needed for CR capsules and tablets. This research requires a fundamental understanding of the in-vivo absorption and biotransformation using the ‘high-energy’ formulations as well as an understanding of the process-engineering fundamentals required for manufacturing with capsules (e.g., based on lipids and/or multiparticulates); tablets (e.g., based on gel matrix, osmotic, or compressed multiparticulates); and sachets or other bulk oral solid presentations. One additional challenge of coupling enabling technologies with CR technologies is achieving adequate drug loading and the desired dosage form size. The use of absorption-enabling technologies that also have intrinsic modified-release properties is, therefore, desirable. Two examples include the use of amorphous solid dispersions using enteric or controlled-release polymers and lipid-based systems—both of which can be used in monolithic and multiparticulate dose forms.
The second challenge involves the development of CR dosage forms that impart abuse resistance, an increasingly important and legislated requirement for opioids and other controlled substances. Designing an effective approach for deterring abuse requires understanding the typical approach an abuser may use to extract the drug inappropriately. The approaches have been novel and vary greatly using physical, chemical, and pharmacological approaches. Formulation scientists and dosage-form solution providers have devised an array of approaches that facilitate meeting target pharmacokinetic profiles while providing abuse resistance (e.g., waxy excipients, high melting point and viscosity modifiers, and others).
The third challenge surrounds the urgent and increasing need for pediatric CR dosage forms. This is a challenge because fewer excipients are deemed acceptable for pediatric use by regulatory agencies and/or have precedence of use for pediatric formulations than for adult formulations. Dosage forms for infants and very young children are especially challenging because these patients may not be able to swallow a solid-dosage capsule or tablet, and/or concern for dose dumping is of crucial importance. In these situations, sachets, sprinkles, and other suspendable dosage-form intermediates are preferred, although texture and taste constraints must be overcome. Generally, multiparticulates (e.g., 100- to 300-µm micropellets or lipid multiparticulates, coated or uncoated) offer the most viable path forward when designed properly for the target patient population. Nevertheless, the challenges remain high for designing pediatric formulations that meet target pharmacokinetic profiles, which has driven our development of a multiparticulate platform that includes multiple bead-layering approaches, mini-tablets, lipid multiparticulates, and specialized capsules for delivery.
Rajabi-Siahboomi (Colorcon):The top challenge for the development of CR formulations is in the area of biopharmaceutics, namely, establishing desired release profiles for new chemical entities, and for generics, matching the originator release profile in-vivo (i.e., bioequivalence). One of the other challenges for CR dosage forms is the risk management of dose dumping under different GI tract conditions. Most CR formulations contain a higher concentration of the drug within the dosage form compared to a single dose of an IR formulation; the risk of dose dumping from CR dosage forms is, therefore, higher. It is the responsibility of the formulators and drug manufacturers to have an indepth understanding of the potential risks involved and have strategies to mitigate them.
Maintaining the quality and consistency of CR dosage forms from batch-to-batch during manufacturing is also key. This can be a critical challenge for generic companies, whereby competitive pressures may lead to use of lower-grade (lower-cost) raw materials, which could result in quality issues and batch-to-batch variability of CR drug products. Colorcon, through the Controlled Release Alliance with Dow Pharma and Food Solutions, helps manufacturers to optimize their process and minimize any risks, leading to predictable outcomes and greater manufacturing efficiency. There has been a specific focus on quality-by-design (QbD) initiatives for the robust design of products and manufacturing processes of hydrophilic matrices, given that these are still the most widely marketed dosage form for CR products.
Appel (Green Ridge): The delivery of a CR high-dose drug formulation has always been a challenge due to the relatively large amount of excipients generally needed to provide a specific delivery profile. This issue, combined with the currently large percentage of poorly soluble drugs, is especially problematic in the development of CR dosage forms. Technologies to address poor solubility also tend to require a significant amount of excipients, making CR formulations of high-dose poorly-soluble compounds significantly challenging.
CR formulations continue to take longer and cost more to develop than IR formulations. Generally, several prototypes spanning a range of release profiles are taken into initial clinical trials, and there may be several iterations needed to obtain the desired pharmacokinetic profile. This issue continues to hamper development efforts.
Deshpanday (Kemwell): In spite of the many advances in controlled-release research, establishing in-vitro-in-vivo correlation (IVIVC) is still one of the biggest challenges. Other challenges include the selection of biocompatible and biodegradable materials with desired controlled-release properties to achieve therapeutic concentrations at the target site and designing CR delivery systems for biologic drugs, bearing in mind their susceptibility to degradation.
Gupte (Metrics): The challenges for CR formulations can be divided into four categories:
- Drug related—APIs with short half-life and the need for high-dose delivery
- Process related—Often need solvent-handling capabilities because most polymers need to be solubilized in organic solvents before coating the CR formulations (i.e., tablets, capsules, granules)
- Formulation related—Increased complexity of patient-to-patient variability and IVIVC in the formulations
- Regulatory—Enhanced scrutiny and requirements of CR formulations.
Kane (Patheon): The top three challenges when developing CR formulations include understanding the target release rate, the target extent of release (i.e., total dose and fraction of dose released over the targeted time), and the mechanism of CR formulation that will meet the rate and extent of release over the targeted time period.
The development of CR formulations is usually undertaken as a lifecycle management strategy. At this stage of the development program, the pharmacokinetic parameters such as peak concentration (Cmax), time to peak concentration (Tmax), half-life (T1/2), area under the curve (AUC), and the absorption, distribution, metabolism, and excretion (ADME) profile of an IR dosage form of the drug are well defined. The dosing interval required to obtain the required plasma levels of the drug that result in a therapeutic effect should be well understood. These data are crucial in defining the range of dose required to be administered over a defined period of time. For example, clinicians would define that a 100-mg dose is required to be released over a 12-hour period with approximately 20-40% in the first 2 hours, 40-60% in the next 4 hours, and more than 80% released between 8 and 12 hours to achieve the clinical effect.
The plasma levels that may cause undesirable side effects would also be known. It is, therefore, important to ensure that the drug is released from the dosage form in a controlled rate and not to an extent that it causes side effects.
Several principles of controlling the release of the drug are used to formulate the dosage form—erosion, diffusion, and release based on concentration gradient through osmosis among others. The choice of the formulation design strategy is based on the target release rate and extent as well as properties of the drug molecule.
Advances in CR drug delivery
PharmTech: What would you identify as the most significant advances in CR drug delivery over the past 10 years?
Rajabi-Siahboomi (Colorcon): Probably the most significant advances have been around collective fundamental understanding of CR dosage forms amongst medical professions, pharmaceutical scientists, manufacturers, and regulators. Realizing the potential clinical advantages of CR products has refined the treatment approach to certain conditions such as cardiovascular and central nervous system diseases. In addition, these learnings have helped formulation scientists to design CR dosage forms in a way that are most closely related to the therapeutic challenges and needs of disease conditions.
Through review of clinical needs and drug physicochemical properties, different CR platform technologies, such as hydrophilic matrices, multiparticulate reservoir-type systems, and push-pull osmotic pumps, have been commonly used to effectively deliver drugs over time. These approaches have enhanced patient experience and compliance, as well as enabling challenging drugs (e.g., drugs with side effects due to high Cmax) to be formulated and successfully marketed.
Improved understanding has also led to the development of more complex formulations, such as fixed-dose combinations (FDC), in which two or more drugs with the same or different release profiles are formulated into one dosage form. FDCs offer several advantages, such as increased patient compliance for chronic diseases (e.g., better disease management of diabetes and hypertension due to the synergistic effect of two or more drugs), patient convenience (e.g., in the treatment of AIDS and cardiovascular diseases), reduced cost to the patient (one co-pay), and an opportunity for lifecycle management of marketed drug products.
Gupta (Kemwell): The success of oral, parenteral, ocular, and topical routes has been established through several marketed CR systems such as osmotic CR tablets, coated granules/beads/particulates for release over time, poly(lactic-co-glycolic acid) microparticles, liposomes, matrix or reservoir transdermal delivery, iontophoresis patches, and ocular inserts. During the past few years, significant advances have been made in the area of targeted drug-delivery systems, in which drugs are targeted to specific organs and tissues. Examples include dendrimers, polymeric nanoparticles, solid lipid nanoparticles, nanoemulsions, and vesicular systems such as liposomes and virosomes. Another advancing field is the combination of regenerative medicines and tissue/genetic engineering including the use of DNA or siRNA in CR systems for regeneration of bone, cartilage, and osteochondral interface.
DeHart (Metrics): Significant advances include advances in polymer chemistry, specifically pH-dependent and pH-independent release from polymer systems and the availability of specific grades of the polymers; advances in in-vitro and in-vivo models to understand the release mechanism of the API from the formulation; the co-delivery of IR and CR systems; advancement in engineering of manufacturing equipment to support scale up of CR formulations; and the development of targeted delivery systems or delivery of medications directly to the affected area as opposed to systemic delivery.
Kane (Patheon): Targeted drug delivery has been made possible by use of novel polymers, formulation, and analytical techniques, such as imaging to control the level of coating to obtain the required performance of the dosage form. Advances in polymer systems to control drug delivery and techniques to identify critical material properties that can impact drug product quality and dosage form performance have resulted in the development of better controlled systems.
There has been significant progress in the importance of understanding the API properties and its influence in development of dosage forms. The concept of risk assessment and use of QbD principles have helped in developing robust drug formulations for controlled release. The use of medical devices to administer CR formulations has also increased due to advances in technology in the transdermal, topical, ocular, and parenteral routes of administration.
Wald (Bend Research): One big change in the past 10 years has been the increased number of FDC products that employ various combinations of IR and CR technologies. These products often require once-daily dosing and have introduced a new set of challenges, ranging from clinical and regulatory challenges to the direct chemistry and formulation/process challenges. Naturally, FDC products that include one or more CR profiles provide the biggest challenges. Nevertheless, a significant number of products have progressed to the market and offer important advances in the controlled-release arena using monolithic (e.g., bilayer tablets with active coatings) and multiparticulate (e.g., blends of coated pellets in capsules) approaches.
Further areas that have matured are pulsatile-release approaches and chronotherapeutic delivery. Concerta (methylphenidate extended-release tablets) represents a good example in which drug delivery is designed for known daily cyclic needs of the patient. The extension of this concept sets the stage for the personalized medicine genre, an area that appears poised for substantial growth, and enabling technologies integrated into the pharmaceutical development area.
Nanotechnology and personalized medicines
PharmTech: How are the advent of nanotechnology and the paradigm shift towards personalized medicines changing the way novel CR technologies are developed?
Appel (Green Ridge): Nanotechnologies (e.g., nanoparticles, nanorobots) are enabling the development of new drug-delivery approaches in many areas. For example, the development of high surface area mesoporous silica substrates, which offer the ability to provide bioavailability enhancement and deliver a high drug payload, may have broad utility in the development of oral CR formulations of poorly soluble compounds.
Nanorobots can either be MEMS based (microelectromechanical systems) or biochemically based (e.g., DNA nanobots) and can offer the ability to deliver specific, complex release profiles, and/or target specific cells. This technology may enable customization of dose regimens for a specific patient and disease state.
Deshpanday (Kemwell): Developing drug-delivery techniques that help minimize toxicity and improve efficacy offer great benefits to patients and open up new markets for pharmaceutical companies. Nanotechnology offers both diagnostic and therapeutic advantages. The assimilation of biomarkers into delivery systems focuses on tailored therapy for a patient based on gene sequencing, metabolites, and proteins. Prognostic biomarkers can be used for predicting the pathway of a disease as well as deciding the therapeutic approach and dose for a patient. Activatable CR systems are based on the concept of activating the specific biomarker once the drug reaches the therapeutic site. This approach decreases the toxicity associated with potent drugs. The three technologies can be utilized together for efficient diagnostic, therapeutic, and specific delivery. Nanotechnology has already been adopted in several fields such as gene delivery, imaging, and diagnostics.
Wald (Bend Research): The impact of nanotechnology is probably felt more in the parenteral area for targeted delivery. Nevertheless, the use of submicron- or nanometer-sized drug crystals has also affected oral CR dosage forms. In reality, nanotechnology is being used in IR and CR dosage forms but is not recognized per se because the nanoparticles are formed in situ rather than as part of the packaged dosage form. For example, colloidal, nanometer-sized species are formed in situ in many amorphous, lipid, and occasionally salt drug forms, as they pass through the GI tract and the components interact with the GI fluids, dissolved buffer, bile salts, and lipoproteins. Research in nanotechnology remains strong and the likelihood of a nanotechnology being reduced to practice in commercial-scale oral CR pharmaceuticals seems eminent.
The use of companion diagnostics and genomics to drive personalized medicine into pharmaceutical dosage-form development would also appear imminent. It can be argued that the increase of the orphan drug market—where subpopulations and treatment modalities are identified from genomics, diagnostics, and specific biomarkers—is a broader-scale form of personalized medicine. In these cases, CR dosage forms may be the enabling technology given that the range of active molecules offers less latitude for design (e.g., half-life, solubility). At an individual level, the use of personalized flexible doses, dosing regimens, and combinations of drugs has gained momentum in the treatment of cardiovascular disease and diabetes. Since the concept of personalized medicine implies compliance, the new paradigm requires flexible dosage forms amenable to assurance of dosing. Likely examples include CR dosage forms integrated with electronics and personalized dispensing devices that enable customized dosing.
Lastly, while not personalized medicine per se, there has been a shifting paradigm in drug-development clinical trials that can be considered near personalized medicine. It involves custom manufacturing (e.g., to achieve the desired dose or drug release rate) by a compounding pharmacist or a contract research organization (CRO) that has a closely integrated small-/miniature-scale manufacturing facility. The former—commonly called extemporaneous preparation or manufacture—has recently been used to prepare some CR dosage forms, bypassing the costs and time associated with the manufacture of bulk clinical-trial material (CTM), extended stability, and providing dosing customization based on quick bioanalysis or biomarker feedback. As an example, Quotient Biosciences has been a pioneer in small-/miniature-scale manufacturing as a combined contract development manufacturing organization/contract manufacturing organization (CDMO/CMO) in the same facility focused on customized dosing and evaluation of dosage-form performance.
PharmTech: What future innovations in CR drug delivery do you expect to see in the next five to 10 years?
Kane (Patheon): I believe there will be a lot more work in pharmacokinetic modeling and simulation techniques to predict the drug-release performance in the development phase of CR formulations. We will also see the use of advanced medical devices to administer drugs for controlled delivery via transdermal, subcutaneous, ocular, and parenteral routes.
Wald (Bend Research): Several areas continue to receive investment, and further innovation is expected over the coming years. These areas can be broadly classed into public health, large molecules, and the manufacturing of finished dosage forms.
Public health. Two public health areas for oral CR innovation are pediatric and abuse-deterrent CR dosage forms. Direct financial incentives exist for innovation in both areas. The need for abuse-deterrent formulations has been prominently discussed in the United States medical and media arenas, which includes not only direct opioid extraction abuse, but also ethanol-retardant technologies. There are a number of abuse-resistant formulation approaches available today, and these approaches will continue to be refined and expanded.
Pediatric studies are now required for product approval and are crucially important because dosing challenges, flexibility, GI transit, and ADME are often different for pediatric patients than for adults. Similarly, the need for innovation to better serve the growing geriatric population is strong. Examples include FDC products, easier-to-swallow dose units, and devices to assist with compliance and compliance monitoring.
Large molecules. Despite significant efforts over the past decades, oral delivery of high molecular-weight molecules, peptides, and proteins using immediate-release or modified-/delayed-release approaches remains an ongoing challenge. This problem is exacerbated by a growing percentage of molecules in this category and the growing importance of such molecules to the pharmaceutical industry. While exceptions exist, this area remains almost entirely an unmet need. Innovation in new materials and associated dosage forms is an ongoing area of research to address this need. While early in development, orally delivered microelectronics and devices show promise to assist in the protection, absorption, and controlled-release delivery of pharmaceuticals.
Manufacturing. Two areas in the manufacturing arena that require innovation to meet increasing economic and environmental health and safety (EH&S) drivers are continuous manufacturing processes and improved and new approaches for containing high-potency actives. While there is opportunity for synergy in these two areas—since continuous unit operations often have smaller control volumes and, thus, smaller containment volumes—these research areas generally are independent. Continuous processing has advanced further for IR and straightforward CR dosage forms (e.g., hydrophilic gel-matrix CR tablets), but continuous-processing and containment innovations are still required in key controlled-release unit operations such as fluid-bed coating and functional tablet pan coating.
Rajabi-Siahboomi (Colorcon): One possible outcome of the QbD initiative is to be able to use continuous processing in the manufacture of CR formulations. While there is interest and some successes, the continuous or semi-continuous processing/manufacturing requires innovation not only in the platform technologies, but also in the processing equipment. A potential area for future innovation is research into complex release profiles for one or more drugs with biologically responsive delivery platforms in combination with biomarkers. Although oral drug delivery is the most desired route of administration, some of the new molecules are only available through injection or implant. Of course, innovations in these areas are also something to watch for.
Appel (Green Ridge): There are significant advances being made in targeted drug delivery to deliver drugs to specific cell types (e.g., tumors) and minimize systemic exposure. It is probable that some of these approaches will be demonstrated clinically and become commercially viable. Another area that is poised for significant advancement is the use of drug/device combinations. One example is the combination of a specific drug and a more sophisticated micropump (similar to those currently used for insulin delivery) for more complex delivery profiles. This approach would enable facile clinical evaluation of different dosing regimens and may ultimately lead to the customization of delivery profiles for a specific patient and disease state.
Deshpanday (Kemwell): Although there continues to be significant innovation in the development of CR drug-delivery technologies, we can expect to see efforts focused on converting these ideas from concept to practical use. Examples include customized/personalized delivery technologies for diseases affecting daily life of patients and conditions requiring frequent dose adjustment depending on stage of the disease (e.g., Parkinson’s and Alzheimer’s), chrono-pharmacokinetic delivery systems, use of newer and better controlled-release polymers, and improved targeting leading to site-specific controlled-release delivery of pharmaceuticals and biologics.
Cobb (Metrics): Continued research in polymer chemistry would mean that polymers of the future would be able to respond better to the circadian cycles of different individuals, thereby, resulting in appropriate dose of the API being released over time to maintain an appropriate API concentration in the patient.
About the Author
Adeline Siew, PhD, is the scientific editor for Pharmaceutical Technology.