MODIFIED RELEASE - Getting the Right Formula: Using Modified-Release Formulations to Address Complex Challenges in Drug Development

INTRODUCTION

Simple, immediate release (IR), once-a-day (QD) formula­tions are desired not only by the patient for rapid onset and im­proved compliance, but also by the pharmaceutical industry due to ease of development and cost benefits. However, many small molecules in today’s pipelines have sub-optimal properties for QD IR formulations. Challenges, including poor solubility or per­meability, can lead to reduced absorption (input in the body) or high clearance (output from the body) that causes a short dura­tion of therapeutic effect. This results in more frequent dosing reg­imens, which may not be suitable for patient compliance. Another challenge comes from the significant peaks and troughs in circu­lating drug concentrations. Using IR formulations, the drug im­mediately enters the bloodstream, and if dosing is not optimized, this could lead to side effects for the patient and variation in ther­apeutic efficacy.

For IR formulations that require more than once-a-day dos­ing, a modified release (MR) formulation, which delivers the drug to the lower GI tract over a sustained period, can be a better choice to achieve the desired therapeutic effects. The following will discuss the opportunities and challenges when transitioning from an IR to MR formulation. It will review the therapeutic ben­efits and challenges associated with MR formulations, GI physi­ology environments and API physicochemical properties, technology choices, and how drug developers can achieve trans­lation success.

MR FORMULATIONS CAN OFFER ADDED THERAPEUTIC BENEFITS

MR formulations are a common alternative for drug devel­opers looking to overcome the challenges of IR formulations, in­cluding requirements to dose multiple times a day, large peak-to-trough ratios associated with Cmax driven adverse events (AEs), and limited therapeutic efficacy. Fundamentally, MR allows for more control over the rate and location of drug release in the GI tract and may provide added therapeutic benefits, such as:

• The maintenance of drug plasma levels, wherein a prolonged period of release extends drug plasma levels, reducing the dosing frequency requirements
• Attenuation of peak-to-trough ratios, leading to lower peak-related adverse effects and improved therapeutic efficacy; and
• Targeted delivery, or the specific release of a drug at a partic­ular site in the GI tract, whether to target GI disease or reduce the impact of delivering a drug to non-absorptive regions.

MR technologies have traditionally been adopted for life cycle management strategies, the extension of drug product patents, and continued market exclusivity. However, MR is increasingly being used to develop new chemical entities and deliver an opti­mal formulation at launch.

THE DEVIL’S IN THE DEVELOPMENT: COMMON MR FORMULATION CHALLENGES

Navigating MR formulation develop­ment can be challenging when it comes to anticipating regional absorption of the GI tract — this is not normally a consideration when producing IR dosage forms. Accord­ingly, the development team will typically need to conduct multiple cycles of formu­lation development, in vitro screening, and preclinical and clinical studies to find the balance of drug release rate and dose to achieve the target plasma concentration profile for the MR formulation to succeed as a QD formulation.

For example, a sustained-release for­mulation that transits to the GI tract while continuously releasing the drug must also be sufficiently absorbed in the lower GI tract to maintain a therapeutic effect. As most drugs will have reduced absorption in the lower GI tract, the dose of the MR formulation will likely need to be higher than the total daily IR dose to give the same daily exposure.

Another challenge when developing an MR formulation is the disconnect be­tween formulation performance in preclin­ical species and man. Grass and Sinko (2002) and Musther et al (2013) have shown that animal bioavailability often doesn’t predict human bioavailability for IR formulations. The same is true for MR formulations, given the differences in the GI tract physiology between preclinical species and man and the challenge of defining the correct release rate and dose to give the target plasma concentration profile.

While in vitro dissolution is used to develop MR formulations with specific re­lease rate profiles, it is assumed in vitro dissolution is equivalent to in vivo dissolu­tion in the GI tract. In practice, we have found this is often not the case. In vitro to in vivo correlation is not fully known until an MR formulation has been dosed in the clinic The chances of optimizing an MR formulation in a canine or a primate and having the desired concentration and time profile for that MR formulation later to translate seamlessly into first-in-human studies and achieve a QD profile, without further optimization (release rate and dose), is limited and unlikely.

HOW GI PHYSIOLOGY ENVIRONMENTS & API PHYSICOCHEMICAL PROPERTIES AFFECT MR FORMULATIONS

Successful MR development requires considering the multiple GI environments and different anatomical regions the for­mulation will encounter. With an MR for­mulation, drug developers must also be mindful the drug is released slower in the GI tract or to targeted regions than IR for­mulations.

GI physiology changes from the stom­ach to the colon, reflecting the change in function of the various regions. The upper GI tract, for example, has villi and mi­crovilli to increase the surface area to op­timize the absorption of nutrients, whereas the colon does not. The tight junctions (the tiny, fluid-filled gaps between the GI tract cells) become tighter as moving down the GI tract, this reduction in surface area and increase in tight junction permeability can lead to a reduction in the drug’s perme­ability.

Transfer across the GI tract cells and reduced absorption is often referred to as an absorption gradient, or the ability to cross cells. The function of the lower GI tract is to absorb water, so the fluid volume available in the lower GI tract is reduced when compared to the upper GI tract, which may also affect the drug dissolving and overall absorption.

The pH of the GI tract fluid will also vary and may impact the solubility of the drug and the polymers controlling release from the formulation, or the dissolving of the formulation coating controlling re­lease.

It has been well documented trans­porters may assist the drug in transferring across the GI tract cells or may remove the drug from the body via efflux transporters. Expression of transporters down the GI tract has been documented to vary and can impact the overall plasma concentra­tion time profile of the MR formulation. Likewise, the GI tract cells express enzymes that break down the drug to help the body eliminate it. These enzymes have also been shown to have regional expression in the GI tract, which can impact overall ex­posure.^1,2

Finally, the properties of the API must be addressed, as they will heavily impact how the drug behaves when administered. For example, a highly soluble API will gen­erally have a much quicker release rate and may require a greater percentage of the polymer in the MR formulation to con­trol the release. Basic compounds with higher solubility in the stomach may be subject to a gastric burst effect and must be assessed to ensure the required peak-to-trough ratio is achieved. Some APIs are unstable at low pH; in such cases, an en­teric coating may be necessary to protect the drug from chemical breakdown in the stomach. Due to the absorption gradient, drugs with low permeability will be a greater challenge when developing MR formulations.

CHOOSING THE BEST MR FORMULATION TECHNOLOGY

A clear target product profile (TPP) can be essential to help guide the devel­opment of an MR formulation and ensure the desired characteristics are achieved. The TPP is based on the drug product re­quirements that include the intended clin­ical use, dosage strength(s), drug release characteristics, stability, and other product quality criteria.

There are different MR technologies that can be considered depending on the goals of the therapy. Figure 1 provides an overview of the common types of MR forms and their benefits.

• Sustained or extended-release tech­nologies allow the MR formulation to release the drug over an extended pe­riod (e.g., 100 % release over 12 hours). These technologies can prolong absorption and reduce the peak-to-trough ratio, leading to higher drug lev­els at the end of the dosing frequency.
• Delayed release technologies use pH or time-dependent coating systems to allow a drug to reach an intended site in the GI tract before release for more targeted delivery.
• Biphasic/pulsatile release technologies allow both instantaneous and ex­tended-release, reducing the need for repeat dosing.
• Additionally, some drugs are only ab­sorbed in the upper GI tract. In this sce­nario, gastro-retentive formulations are required to target this region. These for­mulations are designed to have a longer residency time in the stomach, during which they release drug, which, on gastric emptying, is delivered to the upper GI tract to target the absorption window. Gastro-retentive formulations are required to be dosed in the fed state with a moderate to high-fat meal to maximize the chance of achieving the desired stomach retention.

CHOOSING THE BEST PROVIDER TO ACHIEVE TRANSLATION SUCCESS

Choosing a contract research, manu­facturing, and development (CRO/CDMO) provider with the right expertise in MR for­mulation development can be pivotal in adding speed and efficacy to drug devel­opment. However, traditional formulation development and clinical research/testing services often rely on successfully testing several formulations developed in vitro within a preclinical in vivo model before entering human clinical testing. As there are complex biological differences be­tween in vitro and in vivo models com­pared to human clinical testing, approximately 40%-50% of candidates fail due to not meeting the TPP.

The integration of services for rapid formulation development, drug product manufacturing, and clinical testing, such as those offered through Quotient Sci­ences’ Translational Pharmaceutics® plat­form, allows for different iterations of MR formulations to be manufactured and tested within a clinical study, all within the same organization and under the same program of work. This model allows for­mulation optimization to be achieved using clinical PK data, removing the re­liance on non-predictive in vitro and pre­clinical models.

Additionally, bracketing the upper and lower limits of critical formulation pa­rameters, such as dose and polymers or controlling release rate, in a “design space” can allow for manufacturing CMC regulatory batches on the extremes of those parameters for greater flexibility in testing. Small batches of typically 300 units can be GMP manufactured just before clinical dosing. In these cases, stability re­quirements are reduced to cover the clinical dosing only, generally 7 to 35 days, as op­posed to 6 months in traditional formulation development.

REFERENCES

1. Paine et al., 1997:2. Pang et al, 2003.
2. The Regional-Specific Relative and Absolute Expression of Gut Transporters in Adult Caucasians: A Meta-Analysis, Matthew D. Harwood, Mian Zhang, Shri­ram M. Pathak and Sibylle Neuhoff.

Dr. Vanessa Zann is an Executive Drug Development Consultant at Quotient Sciences with over 2 decades of industry experience providing biopharmaceutics support to discovery, development, and clinical programs. Since joining Quotient Sciences in 2012, she has led the implementation of modelling and simulation and has been heavily involved in pharmaceutical sciences’ in vitro characterization strategy, as well as designing clinical studies and providing scientific support through clinical study delivery. Prior to joining Quotient Sciences, she worked at AstraZeneca as a permeability expert in the Pharmaceutical Development department. Here, she led the global Caco-2 facility for the development and was responsible for liaising with discovery scientists to ensure the selection of new chemical entities (NCEs) with appropriate biopharmaceutical properties. She introduced the intravenous (IV) microtracer technique and provided biopharmaceutical support to both discovery and development programs. She completed postdoctoral research in buccal transport mechanisms at Cardiff University, and earned her PhD in Pharmaceutical Sciences and a Bachelor of Science in Applied and Human Biology, both from Aston University.