What are the main marketplace and technical issues facing companies currently developing controlled release products?
One of the major technical challenges is the delivery of poorlysoluble drugs. Modified release drugs require adequate absorption throughout the gastrointestinal tract (GIT) including the colon, therefore the ideal drug for modified release would be one with good solubility and absorption at all regions of the GIT. If poorly soluble drugs require an enabling technology in addition to modified-release excipients, the drug loading will be low, resulting in a large dosage form or the need for multiple doses.
For poorly soluble drugs, a combination of a solubility-enhancing technology such as hot melt extrusion, as well as controlled release, can result in the desired release profile and bioavailability.
Modified release products can be ideal for pediatric patients, but only limited excipients are approved or suitable for pediatrics. Additionally, children may be unable to swallow whole tablets and capsules. Many pediatric dosage forms such as sprinkles in capsules or minitablets use modified release technology to achieve the desired profile, as well as taste masking to make the dose palatable.
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Another challenge is achieving the desired release profile to maximize efficacy and minimize safety concerns, and to establish in vitro-in vivo correlation (IVIVC). Integration of pharmacokinetic mechanistic models with in vitro and in vivo studies is a valuable approach to predict modified release pharmacokinetic profile and design modified release formulations.
Do you see an increased demand for controlled release products? If so, why?
There is an increasing demand for modified release products, both in the oral and injectable spaces, with most market research studies estimating a 14 percent compound annual growth rate (CAGR) for modified release technologies. Beyond the traditional benefits of lower dosing frequency and improved patient adherence, modified release products may enhance the safety and efficacy of drugs.
Other driving factors for growth in this area include product differentiation, competition, life cycle management, and an increased focus on patient adherence.
An increasing number of products are also utilizing modified release for targeted delivery to specific areas of the colon; as well as using the technology for chronotherapeutic drug delivery, taste masking for pediatric and geriatric formulations, and for abuse deterrence.
Are most controlled release products developed as such? Or, are they reformulated at a later date to extend the product’s shelf life? How do companies approach this situation?
Historically, many drug products with modified release properties were initially launched as immediate release formulations, with modified release formulations introduced later as lifecycle management tools. With an increased emphasis on understanding the patient, building adherence enhancement into the product and increased competition, innovators are pressed to launch a new chemical entity (NCE) with modified release properties. There are therapeutic areas where modified release products are becoming the standard of care, such as injectable depots for antipsychotics for the treatment of schizophrenia.
Companies should evaluate and understand the pharmacokinetics of their NCE early in development and establish whether it is likely to require multiple daily doses. This may be challenging however, as the development of modified release formulations requires a large amount of API, which may not be available during early development.
At Catalent, we use commercially available physiologically-base pharmacokinetic (PBPK) mechanistic simulations to predict modified release pharmacokinetics from in vitro and immediate release data. The model is further used to design modified release formulations while minimizing API consumption.
Are controlled release products a part of the overall industry drive to make treatments more “patient-centric”? If so, can you explain?
As previously mentioned, modified release products are administered less frequently, and there is an inverse correlation between dosing frequency and adherence. Furthermore, modified release products may have smaller peak plasma concentrations (Cmax), which minimizes the side effects of some drugs. Modified release drugs maintain the drug concentration above minimum effective concentration, so they can be more effective.
Modified release products can require large doses and more excipients resulting in large, hard-to-swallow tablets and capsules that cannot be crushed, split, or opened. To overcome this, one approach has been to develop modified release pellets or granules, which can be filled into capsules, sachets or stick packs. Patients can then sprinkle the contents on food for easier administration.
Treatments are also being increasingly tailored to provide timed release to enable presence of adequate plasma levels as needed for the symptomology of certain diseases, such as multiple sclerosis.
What do you see as the future for controlled release products?
Improved PBPK modelling has the potential to expedite the development of modified release products and perhaps shift modified release development from a lifecycle management approach to more of an early development activity. New excipients such as polymers, and technologies - including nanoparticles - are increasingly being tailored for modified release and will accelerate the growth and application of modified release products. For non-oral modified release products, devices will continue to play a major role in the success, but there needs to be integrated development of formulation and device.