Controlled Release Roundtable

Can you tell us about some of the latest technologies for controlled release? What are their benefits?

John Tillotson, RPh, PhD, Pharmaceutical Technical Business Director (Americas), ABITEC Corporation: The latest technologies in controlled release are formulated not only to provide specific release characteristics, but also include one or more other functionalities, such as increased solubility, increased permeability, site-specific release, bio-adhesion, etc. A good example of this type of controlled release technology is solid lipid nanoparticles (SLN). By altering the lipid composition of the SLN varying release profiles can be obtained. Additionally, as required, SLN particles can be layered with functional coatings allowing for further control and specificity of formulation release characteristics. With regard to additional functionalities, SLN can provide for enhanced solubility of active pharmaceutical ingredients (API) by transporting the API in a dissolved form within the oil phase of an oil in water emulsion. Additionally, depending on the composition of the SLN, permeation enhancement of certain API’s is possible. If longer chain lipids are incorporated in the SLN, then tissue targeting may be possible through the lymphatic system. API release from SLN’s can be controlled by multiple mechanisms including melting, pore former incorporation, functional coatings, digestive emulsification, and auto-emulsification. SLN’s also offer multiple routes of administration, including per-oral, pulmonary, nasal, topical, injectable, and intra-follicular.

Shaukat Ali, PhD, Technical Support Manager, BASF Corporation: Controlled release has been a subject of continued interest in the industry with particular focus on creating a better and smarter dosage that (i) meets the therapeutic index by maintaining the desired plasma concentrations for extended periods, (ii) avoids drug toxicity and (iii) makes patient compliance less burdensome. These can be achieved by selecting appropriate excipients and technologies that are compatible and yield desired release profiles. This can be done by drug layering. For instance, pulsatile release polymeric excipients control the selective delivery when and where it is desired. It offers a unique advantage because timely release is controlled by coating the drug with polymers having sustained and/or enteric modified release characteristics. While drug layering and pulsatile release is effective in releasing the drugs through polymeric barrier layers around APIs, in colon drug delivery, for example, the drug layering may require multiple coatings with different polymers to destine the release at a specific pH and site in the GI tract. In such cases, polymers with enteric or reverse enteric modified characteristic are often required to mitigate the pH effects, while allowing the controlled release for periods of 10-12 hours and beyond. This poses a challenge as the polymers get dissolved before the drug reaches the desired site in colon or large intestine. Thus, the targeted delivery remains challenging, but it offers significant benefits as to avoid the multiple dosing and reduce the pill burden for treatment of same therapeutic indications.

Jonathan Cape, PhD, Scientist, Capsugel’s Bend Facility: We are observing and experiencing a number of recent industry trends in modified and controlled release formulations that are driven by increasingly challenging API characteristics, regulatory guidelines, and the increasing move towards specialized or patient-centric medicines. One key trend is an expansion of pediatric formulations (also termed “age appropriate dosage forms”) either as part of a parallel formulation to complement adult formulations in development, or as a follow-on indication for an approved product. Regulatory requirements and incentives, such as market exclusivity expansions of 6-24 months, are driving this trend. Pediatric studies are required for application submissions entailing NME, new indication, new dosage form or regimen (Pediatric Research Equity Act).

According to regulatory guidelines, controlled release dosage forms or combination products for adults should also be made available for pediatric patients when appropriate.

Pediatric formulations have their own special set of technical challenges including the need for dosage-form and dose flexibility, populationspecific excipient safety, and, importantly ease of patient dosing and therefore compliance. High palatability – inclusive of taste and odor masking as well as mouthfeel – is critical for pediatric populations.

Orally dosed multiparticulates, although largely a mature technology set, continue to fill a key role in this area and offer innovative formulation pathways to the evolving performance needs of pediatric applications inclusive of controlled release drug products.

We see a continued move towards oral solid dosage forms for pediatrics vs. liquids/suspensions and, in particular, for various multiparticulate (including mini-tab) processing approaches. Part of the move towards multiparticulates for pediatric formulations is due to their being highly suitable for modified or controlled release formulations, and the ease with which they can be taste-masked. High-performance coatings for taste-masking (reverse enterics) are becoming the norm and several ready-made commercial coating systems are present in the market place to address this need. Use of these coating systems with robust MP IR- or CR-core platforms in an encapsulated sprinkle-cap form is now offered as a first line formulation approach by many CDMOs. We are also finding increased application for lipid multiparticulates which can be readily tailored achieve controlled release delivery and high palatability (taste-masking and mouth-feel) to pediatric dosage forms without the need for functional coatings.

Another observation is the need for more than one enabling technology to be used for particularly challenging compounds and/ or target product profiles. It has been extensively reported that between 60-90% of the drug product pipeline has poor dissolution rate or solubility. We are increasingly combining solubility enhancing technologies and controlled or targeted delivery technologies to achieve the required BA and pharmacokinetics.

Additionally, there are new technologies enabling the oral delivery of some biomolecules. For example, a number of biomolecules including some vaccines, peptides, LBP’s, require enteric protection for oral delivery but cannot withstand the high temperatures associated with traditional pan or fluid bed coating processes. Intrinsically enteric capsule technologies, which incorporate enteric polymer into the capsule shell, obviate the need for coating and can enable oral delivery of sensitive biomolecules.

Mathias Bayru, Group Product Manager, Advanced Delivery Technologies, Catalent Pharma Solutions: There are, as always, new and niche technologies but none have proven commercial viability or have become as relevant as established controlled release technologies. We have seen an increasing demand for controlled release solutions, for example for pediatric medications, to improve the patient experience and/or patient outcomes, and/ or to extend a product’s marketed life. We are also seeing the rise of the super generics, where companies take generic APIs and approve them for the first time in a controlled release format. We do not see really “groundbreaking” new technologies; nevertheless, Catalent has developed an advanced program for controlled release, which combines a scientific development approach based on the measurement of pharmacokinetic (PK)/pharmacodynamic (PD) data to optimize the therapeutic outcome, with a dose form that is optimized to be patient-friendly.

Nick Grasman, Lead Market Manager, Dow Pharma Solutions (The Dow Chemical Company): One technology that I am particularly excited by is dry powder layering of controlled release films. This technology has the potential to transform this segment of the market by eliminating residual solvent concerns in final drug products while simultaneously enhancing production throughput by up to 70%. With specially micronized controlled release polymers, such as ethylcellulose, now being available, all the pieces are in place for conversion from solvent based to dry powder application.

Andrew Bulpin, Head of Process Solutions Strategic Marketing & Innovation, MilliporeSigma: Parenteral polymer based particulate systems are gaining significant interest mostly for small molecules and hormones, but a lot of work on protein systems is seen as well, triggering an increase of research on new polymer systems. In the solid space, the use of new polymer systems for controlled release are showing promise, such as PVA, PLGA/PEG, and Hydroxyethylmetacrylate copolymers. These are also suitable for the upcoming 3D printing technology, allowing highly personalized medicines without the need to bring the API into a solution. We are also seeing a combination of novel technologies such as micro needles for sub cutaneous delivery and controlled release through e.g. PVA.

David Elder, Consultant, David P Elder Consultancy: Long acting parenteral formulations, using solid drug nano-particulate technology, have the potential for once monthly or even longer administration of key drugs. This type of formulation offers great promise for those chronic diseases where patient adherence (or compliance) is detrimental to treatment outcomes. Such approaches have been used historically in schizophrenia, contraception, and more recently in HIV therapies. Several anti-retroviral drugs are currently in Phase III clinical development using long acting injectable formulations, including long acting cabotegravir (an integrase inhibitor) and long acting rilpivirine (a second-generation non-nucleoside reverse transcriptase inhibitor). These long acting injectable regimens have been greeted enthusiastically by HIV patients, academic and scientific communities.

Inayet Ellis, PhD, Scientific Affairs Manager, Gattefossé USA: Before answering the question, we must define the term “controlled release.” Some workers in the field use it interchangeably with “sustained or extended-release”, while others define the term as release of drug over certain times and/or certain locations. The dosage form itself can be intended for oral, injectable or topical/ transdermal administration. My responses are specifically for oral sustained/extended release technologies.

The latest technologies, particularly in light of the current opioid epidemic, incorporate abuse deterrent mechanisms (aversion, physical barriers, and embedded antagonists) into sustained release dosage forms. This is particularly important as controlled release opioid formulations have high drug load which can lead to overdose if abused. This important and latest developing special class of sustained release technologies is based on physical/chemical/ sensorial barriers that limit the drug release with chewing, crushing, grinding and solvent extracting with the use of robust matrix systems such as lipid based matrices.

Are there dosage forms or treatments that are difficult to formulate into a controlled release form? What types of products make for the best controlled release candidates?

Ali: Polymeric excipients are the key components in the design and development of a controlled release dosage. With the advent of new polymers and a better understanding of formulation technologies, the industry is aiming for targeted delivery to avoid side effects, and using safe and pharmaceutically accepted polymers to yield certain release profiles. These polymers possess unique characteristics ranging from pH dependent to independent solubility, (e.g. enteric and reverse enteric polymers), bearing functional groups that are prone to self-healing and semipermeable in nature. All these characteristics aid in the design of a dosage for effective delivery of an API. For instance, polyvinyl acetate polymer) has been effectively used to deliver the drugs in a controlled manner while maintaining the semipermeable characteristics without any dose dumping.

Such flexibility is highly warranted when selecting the polymers for achieving the desired therapeutic index, avoiding toxicity and maintaining zero order plasma concentration of drug.

Cape: Traditional challenges for controlled release dosage forms are high drug loading and fixed dose combinations. The relatively high polymer/excipient content that can be required to achieve controlled, dual or tailored release profiles can lead to large and difficult to swallow dosage forms.

Drugs with poor bioavailability such as limited permeability, low water solubility, or peptides and proteins - which have virtually no permeability in the GI tract – also represent major challenges. Controlled release formulations of opioids and certain stimulants can represent formulation challenges in achieving both the target release profiles and (increasingly required) abuse deterrence mechanisms.

Liquids/solutions/suspensions for pediatric formulations are a challenge – hence the move towards orally dosed solids, and particularly multiparticulates as discussed above.

Bitter actives and the requirement for taste-masking can be an additional challenge. A specific example is oral multiparticulate suspensions that require taste-masked coatings over a separately formulated inner core (e.g., IR release, extended release). The choice between a solvent-based or aqueous-based coating system is more frequently being skewed toward the latter, driven by concerns for patient safety (e.g., residual solvents). Although multiple commercialized aqueous coating systems to target pH, CR and barrier coat properties are available, options at many CDMOs also include the custom formulation aqueous dispersions across a range of compendial water-insoluble polymers. A certain degree of up front process development is required when coating from aqueous dispersion to ensure a well-coalesced and continuous final coating. Subsequent curing processes may also be used to facilitate film coalescence and phase equilibration, furthering the effectiveness of the desired coating. The best candidate indications for this type of formulation approach include populations with difficulty swallowing or wherein process complexity or regulatory concerns with solvents make it more efficient and cost effective to coat from an aqueous dispersion.

Bayru: A major challenge is the formulation of a controlled release form for children. Physiological changes happen from birth through adolescence, leading to differences in pharmacokinetics and pharmacodynamics, so developing suitable medicines can be challenging, requiring different formulations, dosage forms, strengths, or different routes of administration.

PK/PD variations are caused by the physical, metabolic, and physiological processes inherent in growth, and demonstrate that children are not ‘small adults’. Several important factors drive these changes, for example, variation in gastric pH, especially in the first three years of a child’s life, and can affect drug exposure.

Drug permeation through the gastrointestinal (GI) tract changes too, as variation in factors such as lumen diameter, cell junction, and cell maturity (shuttle capability) reduce absorption values in children. If API permeability is lower, then a drug’s Biopharmaceutics Classification System may change too, from (BCS) class I (adults) to BCS III (children), or from BCS II (adult) to BCS IV (children), inferring a change on formulation and bioavailability enhancement requirements.

Finally, differences related to total body water, plasma protein binding, metabolic enzymes, first-pass effect, glomerular filtration, renal secretion, and renal absorption lead to differences in clearance between adults and children.

API solubility is a challenge too. Controlled release generally controls the point of API release, or limits dissolution over time. If the amount of drug that can theoretically be dissolved and absorbed during GI passage is already close to its maximum for an immediate release form, then a controlled release form may reduce the maximum dose that can be absorbed.

Grasman: Increased demand for patient compliance in pediatric and geriatric populations is leading more formulations to consider liquid and transdermal routes of administration. These have traditionally not been areas where controlled release technologies are employed, but functional excipients such as ion exchange resins and silicone based adhesive layers offer the means to provide improved patient compliance through reduced dosing schedules.

Bulpin: There are difficult treatments such as some cancer indications with a high risk that a therapy stop is required (e.g. removal of implant) or in case of severe side effects (fast in and fast out of drug). In general, APIs of low stability and the need for high dosages are difficult to formulate as a controlled release form. Ph sensitive APIs are also challenging due to the hydrolysis process and large molecules are difficult to formulate for sustained release but not impossible. The best candidates are small and relatively small stable and highly active APIs, such as hormones, or hormone-like peptides.

Gwenaël Servant, Ph.D., Managing Director, Servier: Any drug substance intended for formulation in a controlled-release format must have an appropriate dissolution rate and stability within the relevant body systems. Very rapid dissolution cannot typically be overcome through the use of controlled release technologies (coating, loading of porous particles, etc.). On the other hand, very slow dissolution rates eliminate the need for controlled release formulations. In addition, stability in the gastrointestinal tract (oral), nose (intranasal), lungs (inhalation) or bloodstream (parenteral) must be suitable for the route of administration. Some drug substances are not appropriate for sustained or controlled release because they degrade too rapidly.

Elder: Historically, drugs that were too soluble proved to be very challenging to deliver in a controlled fashion. Indeed, many of these drugs were often re-formulated using less soluble versions of the drug substance, e.g. less soluble salts. Unfortunately, nowadays as a result of high-throughput and combinatorial chemistry the challenge of very soluble drugs is often of academic interest only. The principal problems are high doses linked with poor solubility. Because controlled release dosage forms need high levels of matrix forming polymers (typically > 30%) in addition to other conventional excipients, they already have a significant adverse impact on the size of the dosage form. Oftentimes additional formulation effort is required to improve the solubility of the drug. For instance, it isn’t uncommon for drugs to have solubulities < 10μg/mL and therefore intrinsically too insoluble to be available without formulation intervention. Geriatric and pediatric patients will struggle to swallow drug products that are too large. Classical “workarounds” such as dividing or crushing the drug product are contraindicated as this will often destroy the release controlling mechanism of the product. The best candidates are therefore drugs showing low-moderate solubility with low-moderate doses.

Ellis: The most difficult in developing a sustained release formulation is for a highly soluble and non-potent active ingredient that requires a high drug load. Highly soluble actives generally have faster dissolution kinetics than poorly soluble substances do and the high drug load necessarily leads to a larger tablet or capsule which can be difficult to swallow. Actives with a very short half-life and high therapeutic index would make an excellent candidate for controlled release dosage form.

Are advanced controlled release technologies breathing new life into some older products on the market? Is examining a product for new controlled release capabilities a way to extend a products shelf life?

Tillotson: The relatively recent advancements in the area of nanoparticle-based drug delivery systems are showing tremendous promise and applications across broad spectrums of drug classes and therapeutic indications. Considerable focus is directed towards the formulation and delivery of new and existing oncology drugs and the non-viral delivery of nucleic acids for gene-based therapies. For example, paclitaxel is a critically important chemotherapeutic drug with a broad spectrum of actively against solid tumors. However, the therapeutic efficacy and patient compliance are severely impacted as a result of the associated high toxicity which is in itself directly related to drug’s very poor aqueous solubility and limited biodistribution. Next generation paclitaxel containing nanoparticles formulated with specific classes of lipids, lipid-polymer combinations and/or surface PEGylation with tumor-targeting ligands have shown greater colloidal stability, improved systemic circulation and reduced cytotoxicity. Efficient gene therapy is mainly dependent on the ability of the highly labile genetic material (RNA, plasmid DNA, oligonucleotides) to reach the intended therapeutic target. For this purpose, nanoparticles also offer a broad range of design options with biodegradable materials for efficient targeted drug delivery.

Ali: OROS® technology, which delivers an immediate release and a controlled release mechanism of a drug through a tiny laser drilled hole, has been used in over 17 marketed drugs. The OROS® patent, set to expire in July 2017, with pediatric exclusivity until January 2018, has generated tremendous interest in the industry for use in both generic and innovative drugs as well. Polyvinyl acetate based excipients such as Kollicoat® SR30D and Kollidon® SR have been used in controlled and sustained release drugs due to their profile and ease of use in coated and matrix tablets, respectively. Requiring no laser drilling in the tablets, as required in OROS®, these excipients carry a pore forming ingredient such as Povidone K30 (Kollidon® 30), that controls the release via a diffusion process, thereby avoiding dose dumping. The unique properties of these polymers offer further advantages such as the ability to adjust release profiles in bioequivalent media by incorporating other hydrophilic polymers compatible to a drug and/or polymer in formulation dosages.

Cape: Controlled release continues to be the preferred life cycle management strategy. Controlled and tailored release has the potential to add value to existing and mature therapies, though regulators have started to discourage this more traditional form of life cycle management and require that a proven benefit (economic/ health outcomes) over the original drug be demonstrated.

Examining the potential benefits of reformulating to a CR/MR release profile can be a good way to identify potential 505(b)2 product opportunities or to better suit a follow on indication. We have seen an increasing number of 505(b)2 strategies following either improved BA or pharmacokinetics through enhanced solubility and/or controlled release approaches. Feasibility assessment for these efforts might involve combining current pharmacokinetic and pharmacodynamic (PK/PD) knowledge of a product with biomodeling approaches to offer predictions for whether a CR reformulation is a viable approach, or can offer any PK/PD advantages. This approach can help parameterize in vitro release targets and other dosage form characteristics during early development.

New functionalities may also be introduced into a current product by switching to a CR/MR formulation such as abuse resistance and reducing the likelihood of dose dumping. Investigating CR/MR formulations may also be appropriate for new indications to reduce the number of doses or produce release profiles that target the therapeutic window of a specific patient population. All of these may be compelling reasons to re-investigate CR/MR formulations for a current product, or, simply make CR/MR a parallel formulation leg in early stage product development.

Bayru: Of course, advanced controlled release technologies are often used for life-cycle management to extend patent and market protection, but more and more it is used to improve patient experience and outcomes. This is often the best way to improve patient adherence, and provide better treatment.

Grasman: Life cycle management via development of a controlledrelease formulation, while still occurring, seems to be more market driven than it may have been in the past. Market drivers for controlledrelease technologies still exist, particularly in areas where patient compliance has been challenging. Advanced delivery systems like osmotic pump tablets and transdermal patches offer formulators a great deal of flexibility.

Bulpin: Yes, reformulating older APIs can help to create new sustained release injectable formulations with more optimized release. This can help to increase patient comfort and compliance.

Servant: Effective lifecycle management continues to be increasingly important as the pharmaceutical industry faces growing pricing pressures and becomes ever more competitive. Switching from a traditional formulation to a controlled-release format can provide tremendous advantages to a product nearing the end of its lifetime. For instance, controlled release products have a reduced dosing frequency, which can be very attractive to many patients. In addition, patient medication adherence has been shown to be higher with controlled release products, which can be a selling point for governments and payers. In some cases, reformulating as a controlled release product can even enable entry into new markets.

Elder: Controlled release has always been part of life cycle management within the pharmaceutical industry. After the drug has been established on the market it is a logical extension to then launch a product with superior performance; either decreasing the dosing interval to improve compliance or reducing Cmax mediated sideeffects by “blunting Cmax” or addressing other deficiencies that can be mitigated by a more controlled delivery of the drug to the patient. Although these approaches can be patented and extend product exclusivity, the main driver does appear to be patient-focused.

Ellis: Definitely. A good example is Azithromycin: a wide spectrum antibiotic first made in early 80s. With advanced melt –spray–congeal process technologies, and utilizing right carriers/excipients such as glyceryl behenate (Compritol 888 ATO®), a novel high dose sustained release formulation of Azithromycin was developed for single-dose therapy- Zmax®

Hence, we can say sustained release is not only a way to extent a product’s shelf-life, but also a way of improving patients’ lives.

What are some regulatory requirements manufacturers have to be aware of when formulating new controlled release products?

Tillotson: Most specifically, when formulating an already existing therapy into a new controlled release therapy, the manufacturer has to be specifically aware of how the new release profile and any additional functionalities, especially those that will increase bioavailability or change the route of administration, will alter the bio-exposure to the active, as dosing adjustments will likely be necessary to match therapeutic plasma levels.

Ali: Abuse deterrent formulations (ADFs) or tamper resistant formulations (TRFs) have been a subject of continued debate in the industry and the FDA has set forth a guideline for opioids and the other controlled substance formulations. With the new landscape in ADF, the industry is using novel formulation technologies to derive the dosages that meet the current challenges for the abuse. The formulation technologies such as hot met extrusion and lipid based formulations have been used to prevent and alleviate the once readily available extractable drugs to difficult-to-extract drugs for sniffing, snorting, and directly inject. In other areas for non-opioids, and conventional drugs, the industry has been using the commercially available and approved excipients including cellulosic and vinylacetate and gums due to their abilities to control and deliver drugs, and hence, alleviate the dose dumping and systemic toxicity.

Grasman: Scrutiny of new controlled release products remains very high and applicants should be prepared to defend specification limits for all ingredients used in the formulation. Quality by Design (QbD) plays an important role as it provides strong, scientifically based justification of the impact that excipient variability could introduce to the final drug product. In many cases, the impact of excipient variability is negligible causing it to be ignored by developers, but without the QbD justification applicants may be forced to accept restrictive limits that challenge product availability.

Bulpin: For injectables, manufacturers need to be aware of QbD and batch to batch reproducibility in excipients. For oral solid forms there are no specific requirements in terms of controlled release. The FDA is also starting to consider whether some of the controlled release polymers for injectables have to be treated like APIs using ICH Q7.

Elder: Despite its age and the fact that it is a “US only” guidance, the Scale Up and Post-Approval Changes (SUPAC) MR guidelines are still viewed favorably in the US and other territories. They provide guidance for the scale-up and transfer of controlled release products into production environments. Reproducible dissolution profiles remains one of the biggest challenges and this can be significantly affected by manufacturing site as well as subtle changes in the performance of release controlling excipients (see next Q&A). Global regulatory agencies will always request details of the development of the dissolution method and the specification, and its clinical relevance. In addition the influence of alcohol on the in vitro release profile is often requested as alcohol can initiate “burst release” of some controlled release products, which potentially can have safety implications, i.e. drug overdosing.

Ellis: I think manufacturers need to be aware of a recent FDA guideline on abuse-deterrent opioids. Although dose dumping test requirements are still in progress, there might be expectations from regulatory bodies to perform in-vitro tests like release profiles in presence of alcohol and in various physiological conditions. Also, use of GRAS excipients not only gives flexibility in process and formulation, but also has regulatory approvals worldwide.

Has the globalization of the pharmaceutical industry affected the development of controlled release products?

Ali: Globalization has helped the industry to align the drug development processes by harmonization of the guidelines and cGMP standards. By building the inventories of the right quality raw materials in the supply chain and acquiring through the suppliers and maintaining them under the ICH storage conditions, the industry is more flexible and efficient than ever before in technical transfer, scale up and manufacturing of the drug products. The streamline in material supply, storage and manufacturing facilities built to comply with the agency’s requirements, have eased up the pressure on the industry to commercialize and efficiently market the drugs worldwide. This applies to all dosage forms including controlled release products. The advent of new innovative excipients and the continued trend on the development of safer drugs with fewer side effects have fueled the surge in design and development of controlled release products ranging from taste-masking, gastroretentive to modified and delayed/sustained release drugs. It has also brought some challenges because of recent regulatory requirements for development and marketing of opioids and other controlled substances by the FDA. This is extremely critical as more opioids and pain killers go off patent and are developed within the US.

Cape: As has been extensively reported, the world’s population is gaining access to medicines overall and this includes higher value drugs such as controlled release formulations. The category of oral solid modified release dosage forms continues to grow at a much higher rate than overall oral solid dosage forms in most major markets around the globe.

The development of orphan applications is now incented and international patient groups can be necessary to conduct clinical trials. Specialized formulations for pediatric and elderly populations are increasingly developed due to a combination of regulatory requirements, incentives, branding, and patient compliance.

Controlled release is now incorporated routinely into NDA’s versus its historic use in life cycle management strategies. An obvious driver is reduced dosing regimen associated with CR forms and therefore increased compliance. An additional driver for novel drug delivery technology can be intellectual property and an additional barrier to patent challenges.

Another trend worth citing is the trend towards utilizing CDMOs for development and commercial manufacturing services on a global scale. This trend tends to be more pronounced when the design and development (and manufacture) of specialized dosage forms requiring one or more enabling technology.

Bayru: Efficient controlled release development needs a lot of resources, expertise and capabilities. Globalization and specialization has led to more companies having enough resources and knowledge to work on controlled release forms for new drug applications (NDAs), or for the purposes of life-cycle management. However, for a majority of pharma companies, controlled release development could still be challenging. This is where the extensive expertise and global capabilities of a Contract Development and Manufacturing Organization (CDMO) such as Catalent could help a company develop the right formulation with the right dose form.

Grasman: Globalization has impacted the pace of market acceptance for introduction of new excipient grades. The last few years have seen a significant growth in the number of available excipients that are designed to remove cost from production processes by eliminating costly and time consuming steps such as wet granulation. The global nature of the industry has allowed these innovations to find their way into commercialized products more quickly than they have in the past.

Elder: Excipients are now commonly globally sourced. It is well known that the chemical heterogeneity of release controlling excipients has the ability to significantly influence the release behavior of certain drug products. The in vitro release properties of these products are significantly influenced by the source of those release controlling excipients. Some companies will often ‘dual source’ these key excipients to ensure that they have a reliable supply chain. However, this can significantly impact on product robustness. Several studies have showed that controlled release products that used different batches of HPMC sourced from different areas of the world, e.g. China, U.S. and Japan did show different release profiles. This is common across most drugs irrespective of solubility.

Ellis: Globalization has created more stringent requirements for specialty excipients that impart controlled release properties to dosage forms; excipients must meet pharmacopeia specifications for Europe, Asia and the Americas. In addition, these markets can have different safety quality standards for such excipients, so that an excipient that is accepted by one market, may not be by another. These situations can force formulators to seek excipients that can be used in all markets, and it is critical for the formulator to understand where the drug will be used, for example, only the Americas, or globally.

What do you see as the future for controlled release products? Will more become available? Will the expansion of products into under-served markets result in the demand for controlled release products?

Tillotson: The future of controlled release products will be focused on the formulation of multimodal functionality, which extends the utility of the formulation beyond obtaining a certain API release profile. Examples of extended functionalities include but are not limited to site specific release, increased API solubility, increased API permeability, API protection from degradation, alternate routes of administration, and tissue targeting. Lipid nanoparticle delivery systems have extended well beyond the delivery of single small molecule drugs. In fact, the applications of lipid nanoparticle has moved across many areas of targeted drug delivery including combinatorial drug delivery, viable new platforms for non-invasive vaccine delivery and are currently the leading technology for non-viral delivery systems which has expanded the clinical potential of next-generation genetic drugs. Lipid-based nanoparticles are currently under evaluation in numerous clinical trials across a broad spectrum of therapeutic indications and hold great promise for the future of targeted and controlled-release drug delivery.

Ali: The industry is moving in the direction of launching more controlled release drugs for better patient compliance and to avoid adverse effects at large. In this regard, polymeric excipients, which have hydrogel forming capabilities, are becoming more common. This trend will continue as more drugs for delayed, extended, controlled and pulsatile release profiles are developed. As the market continues to expand for the controlled release products, polymeric excipients with thermo-gelling abilities will play an important role in controlling the release of small and large molecules. For instance, Poloxamer 407 (Kolliphor® P407) and other gelling enhancing excipients such as Poloxamer 188, hyaluronic acid, hydroxypropyl methyl cellulose, polyacrylic acid, serum albumin among others, will markedly contribute on the new innovative drug delivery technologies such as nanoparticulates for controlled delivery for biologics for oral, injectable and topical products.

Cape: We foresee a continued trend towards increased use of CR products going forward, driven by many factors as cited previously – global demand for more effective therapeutics, pediatrics/geriatric populations and their specialized needs for palatability and ease of administration/swallowing, fixed dose combinations, drug-device combinations, etc.

Continued innovation in CR/MR products will also be driven by the need to address the diverse array of industry-wide technology gaps, including formulating to address combination problem statements such as MR and bioavailability enhancement, combination therapies with multiple actives, or reaching stringent performance specifications for today’s taste-masked products. In all these examples specific project circumstances continue to necessitate using combinations of established CR/MR formulation approaches with other enabling technologies. There is also a trend to broaden the range of applicability of innovative approaches of platform technologies by testing the bounds of their composition and processing windows.

Flexible dosing is also an area of interest sure to see innovative solutions coming to market. Devices to that can reliably count and dose fixed amounts multiparticulates in combination in-situ encapsulation technologies might enable easy dose titration in clinical settings.

Bayru: In industry, we see more and more scientific understanding of controlled release technologies and of related excipients. However, industry still seeks to apply “20th century controlled release technology” to more complex formulation and patient challenges.

We envisage that the next generation of controlled release products will be more intelligently formulated to better control the API release based on conditions in the body. In other words, the controlled release products of the future will be able to detect the right environment and right moment of API release by themselves, and will be able to start release accordingly.

Will more become available? Yes, the trend in the direction of controlled release products is obvious, as it enables products with better outcome and/or better patient experience. Development and formulation programs, such as OptiDose CR, will help the pharmaceutical industry make controlled release products more accessible.

Will the expansion of products into under-served markets result in the demand for controlled release products? Yes. When the underserved countries see the benefit of controlled release, they will ask for more controlled release products, and programs like OptiDose CR will help them to develop more them faster, and more efficiently.

Grasman: Controlled Release products will continue to serve a critical role in human health. Poor patient compliance with pharmaceutical therapies introduces significant amounts of undue cost into the healthcare system. As patient access to the healthcare system expands, we can expect these hidden costs to become more visible and help drive development of controlled release formulations.

Servent: The future for controlled release products is quite bright. The number of NCEs with poor solubility and bioavailability continues to increase, and often times controlled/sustained release delivery systems can help overcome these physicochemical properties. Lifecycle management will also continue to be crucial for pharma companies; controlled- and other types of sustained-release formulations provide numerous options. As the industry continues to move away from blockbusters to targeted therapies, controlled release mechanisms will be of greater importance because they can be designed to meet the needs of specific patient populations. In addition, the continued push for more patient-friendly dosage forms will drive greater demand for controlled-release formulations as they have been shown to improve patient adherence in a number of different patient groups. Finally, it is worth noting that as particle engineering, coating and polymer design technologies continue to advance at an accelerated pace, more effective solutions for controlled release drug formulations will be developed and lead to expansion of this important drug delivery approach.

Elder: “Pill Burden” is a significant issue in the elderly. Geriatric patients are often treated for multiple chronic long term disorders and this can result in taking significant numbers of different types of medicines. As the population in general ages, this issue will become even more prevalent. This can be addressed in part by fixed dose combinations (FDC) for drugs with similar dosing intervals; however, many older drugs are still dosed twice or three times daily. These drugs could be re-formulated into once daily dosage forms as part of the “pill burden” initiatives.

Ellis: With advances in process technologies such as melt extrusion and printing, there will be more robust sustained release formulations to meet next century demand, which will be personalized medicines. Perhaps, the formulators have to design the sustained release formulations for pharmacy shelves’ that can be 3D printed by pharmacists based on patient needs. Advances in sustained release technologies perhaps can also take the good old medicines to a more safe/effective mode.

  • <<
  • >>

Join the Discussion