Can you tell us about some of the latest technologies for controlled release? What are their benefits?
Dr. Thomas Dürig, Sr. R&D Director, Ashland: Among the promising new oral controlled release technologies are bioavailability enhancing technologies coupled with extended release technologies. An example of these are gastro resident systems which enable the extended delivery of drugs with limited colonic absorption. While older hydrophilic matrix based technologies such as Accuform™ have been in the market for several years, newer technologies are in development that bind to the mucosal membranes and have ability to also repel gastric contents, thus allowing for extended gastric residence. Another promising bioavailability enhancing technological development is the coupling of enabling technologies such as amorphous dispersions with modified release formulation techniques such as matrix tablets, thus enabling the extended delivery of poorly soluble drugs. This can now be readily achieved with the aid of appropriate hot melt extrusion technologies. Existing advances have also been made in manufacturing and process technologies, for instance in the use of 3D printing to engineer devices with complex architecture for precise drug release modulation.
Shaukut Ali, PhD, BASF: 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 design 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.
Kyle Kyburz, PhD, Senior Research Chemical Engineer, Bend Research, a division of Capsugel Dosage Form Solutions: Oral controlled release dosage forms provide tunable platforms to modify and adjust critical drug release characteristics – such as the time scale of release, reduction of Cmax, and GI site targeting (such as gastro-retentive or colonic delivery) – with the potential of reducing dosing frequency to increase patient compliance. While some new technologies exist, evolution of proven oral solid technologies remains the mainstay. When considering controlled release, formulation scientists should select a dosage form and technology based on the specific characteristics of the drug substance – including solubility, pharmacokinetics and drug loading – and the desired release profile. For example, these may include hydrophilic or lipophilic matrix tablets, typically for first-order release; osmotic systems for zero-order or consistent release; gastroretentive tablets for targeting the upper GI; and multiparticulates (MP) such as lipid, spray-layered, extrusion/spheronized and mini-tablets for tailored release profiles including delayed, pulsed or multiphase. Additionally, specialized approaches for fixed-dose combinations or dual release profiles can be achieved by implementing variably coated MPs, bi/tri layered tablets, and capsule-in-capsule technology.
MP systems hold distinct drug release advantages, specifically being highly-tunable and versatile platforms that can be coated with multiple drug and polymeric layers, and blended at encapsulation, to afford targeted release rates with consistent GI transit and absorption characteristics. MPs are also amenable to combinations of controlled release and solubilization technologies, which is a challenging combination. Spray Layered dispersions can be applied by spraying a solution of drug and polymer to an amorphous form, or a micronized or nanomilled form. MPs tend to provide flexibility for pediatrics, including flexible dosing from six months of age forward, and are suitable for taste-masking, palatability and controlled release, in the form of sachets, capsules, or capsules that can be opened and the contents sprinkled into liquids or soft foods.
At Capsugel, one newer technology focus is lipid MPs created by a melt-spray-congeal, which uses a continuous process spinning-disk to produce smooth, tunable (often 200-400um) microspheres. These can be used as-is or fluid-bed coated for immediate and modified release and/ or taste-masking.
Additionally, osmotically controlled systems such as EOP, PPOP, SCT and AMT have the advantage of consistent drug release over a variety of physiologically relevant conditions, including fed and fasted states, and do not dose-dump in the presence of alcohol. SCT and PPOP technology can further be combined with solubilized forms for improved absorption across the entire GI tract.
Shrikant N. Khot, Ph.D., Sr. R&D Manager, Dow Pharma & Food Solutions: Whether it is for immediate release or for controlled release applications, there is an overarching need to improve manufacturing efficiencies without sacrificing the quality of the end product.
For the multiparticulate market, Dow has developed a new ethylcellulose grade, ETHOCEL™ HP, with a particle size distribution which has been optimized for use with high productivity dry powder coating processes. These processes are capable of offering drug release profiles similar to traditional fluid bed coatings in a fraction of the time and without the use of expensive solvents and solvent handling requirements.
Additionally, in traditional matrix modified release, Dow recently introduced METHOCEL™ DC2, a pure hypromellose designed to offer similar controlled release performance of hypromellose, but with improved powder flow properties, thus helping streamline tablet manufacture and helping avoid costly and time-consuming granulation processing steps.
Jasmine Musakhanian, Scientific and Marketing Director – Pharmaceutical Division, Gattefosse: Among processing technologies, melt extrusion, melt congealing, and spray atomization may be the biggest accelerators for the development of novel and sophisticated compositions for developing controlled release (CR) drug delivery systems. Also on the development list are solid lipid nanoparticles (SLN/NLC), orally administered floating particles, and muco-adhesive formulations. Meanwhile, devices such as implants, topical patches, and vaginal rings are among the technologies that are amenable to CR delivery.
Whether administered orally as a tablet or delivered by a patch on the skin, the goal of a CR formulation is to offer a predictable, constant plasma concentration of the drug, over a fixed period of time. Controlling the drug release rate is beneficial for improving the drug efficacy, safety, and simultaneously reducing its undesirable side effects. Moreover, it is desirable for improving acceptance and patient compliance.
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?
Dürig: Formulators face challenges in the rate controlled oral delivery of high dose drugs. Both highly soluble and low solubility high dose drugs represent a tremendous challenge as these drugs typically necessitate the use of large amounts of excipients to modulate their release or render them soluble, which combined with a large amount of drugs then leads to large, difficult to swallow dosage forms. Fixed dose combination drugs are also very challenging as again the combination of drugs may represent a considerable payload, but also in this case two distinctly different release profiles may have to be reliably achieved. Lastly drugs with poor bioavailability such as limited colonic absorption, low water solubility or peptides and proteins which have virtually no permeability in the GIT represent major challenges. Pediatric and geriatric treatments in oral liquid form also are challenging.
The best candidates are drugs that can be administered orally at effective doses of 1-250mg with a dose/ solubility ratio of 1-100ml and no ionization in the physiological pH range. They should have at least 30% colonic absorption, a half- life of 2 to 10 hours.
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 (e.g. Kollicoat® SR30D, a 30% dispersion) 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.
Kyburz: Controlled release (CR) drug products can be difficult to formulate due to drug substance challenges, including very low solubility, lack of colonic absorption, high dose, gastric fluid degradation and/or rapid clearance rates. Additionally, treatments for elderly and pediatric patients, where swallowing is difficult, can be challenging, as drug loading, inability to crush, excipient amount and dosage size are constraining. Use of enabled technologies, such as amorphous or nano-sized particles, can help, as can flexible multiphase CR options afforded by MPs and multilayer tablets. Products requiring high drug loading and low solubility are particularly difficult to formulate without being large. Geriatric and pediatric populations have difficulty swallowing large, monolithic CR dosage forms, whereas MPs (particles, pellets, beads, granules/mini-tablets) are more flexible, since the final dosage forms can vary from capsules and tablets to orally dissolving tablets, sachets and sprinkle capsules. Drugdrug incompatibility can be a concern for some fixed-dose CR or IR/CR combination products – multi-layer tablets, or more independent, isolated MP products are approaches to maintain stability while providing drug release flexibility.
One important treatment that has become urgently critical due to the epidemic levels of death and abuse is controlled release, abuse deterrent delivery of prescription opioids. These are challenging due to U.S. Drug Enforcement Administration handling requirements and the drug delivery technologies required to prevent accidental overdose or intentional abuse, such as extraction, crushing and snorting for immediate release delivery.
Khot: Liquid dosage forms are gaining popularity with geriatric and pediatric applications, but have traditionally been difficult to formulate into CR dosage forms. Ion exchange resins have successfully been used to impart CR performance into oral liquids and syrups.
In tablets, the complexity and robustness of the final formulation is API dependent. For certain APIs it’s critical to understand how the excipient attributes play a role in final formulation. A science-driven approach, based on a comprehensive understanding of the excipient characteristics is needed to develop a robust tablet formulation.
Musakhanian: Studies confirm that a large proportion of patients do not take drugs as prescribed. As such, CR delivery is ideal for treatments that require chronic and multiple daily doses, notably when patient compliance or lack thereof critically compromises the efficacy of the therapy. Examples include chronic administration of blood pressure, glaucoma, and pain management medicines.
Whereas drug candidates that are absorbed in the gut by diffusion mechanisms, and which have acceptable solubility and short half-life are generally good candidates for CR development. Water soluble but poorly absorbed potent drugs which rely on carrier mediated transport mechanisms for absorption are deemed to be poor candidates for CR.
Meanwhile, drugs requiring high administration doses, having poor solubility, and very long half-life which have historically been dismissed, may now face new opportunities – thanks to emerging developments and new formulation technologies.
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?
Dürig: Controlled release technologies have huge potential to add value to existing and more mature therapies. However today’s regulatory and third party payer environment discourages the traditional, life cycle extension plays. In order to gain regulatory approval and adoption in third party payer formularies, a controlled release dosage form needs to demonstrate patient benefit that the marketed, conventional dosage form cannot provide. Increasingly these benefits are not just convenience of reduced dosing frequency, but improved therapeutic and economic patient outcomes. An example is the wide spread adoption of controlled release metformin HCl as the standard treatment for type II diabetes. In contrast to the conventional immediate release metformin, the controlled release version allows not just for reduced dosing but also significantly reduced gastric side effects and better compliance and glycemic control. Additionally recent advances in this therapy have led to the adoption of manufacturing technologies that allow for tablet size reduction, an important aspect of metformin controlled release therapy in the largely middle aged and older patient population. The Metsmall brand of metformin HCl marketed by Dr Reddy’s is an example of this innovative approach. Further examples of older therapies that can be enhanced with advanced controlled release technologies are opioid analgesics which have been increasingly reformulated as controlled release dosage forms for both enhanced pain management but also improved abuse deterrence.
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.
Kyburz: An increasing number of new drug applications are following the FDA NDA 505(b)2 pathway, due to the relatively short development times and economic incentives (3-7 years dependent upon reformulation complexity). Products pursuing the 505(b)2 pathway include new indications and improvements to existing products’ bioavailability. These often include solubility enhancement technologies; reduced Cmax and more consistent drug levels in the blood plasma resulting in reduced side effects; dosing convenience and therefore improved patient compliance; and new fixed dose combinations, among others. Controlled release technologies play a critical role in formulating an improved product via 505(b)2 pathway and plays a continuing role in life cycle management (LCM), including CR versions for pediatric and geriatric patient populations. Additionally, there is an increasing number of products being developed as CR for initial filing, rather than for LCM.
Khot: Yes. Controlled release technologies continue to be the preferred life-cycle management (LCM) approach by pharmaceutical companies, as they provide tangible benefits like improving patient compliance. There is also a clear interest in the industry to try unique polymers and technologies as a way to achieve performance-driven differentiation in the market and to produce high quality drug products costs-effectively.
For instance, we have seen customers who encounter IVIVC issues with their formulations find ways to breathe new life into them through the use of alternative technologies, such as osmotic pumps, which provide zero order release profiles independently of digestive state.
What are some regulatory requirements manufacturers have to be aware of when formulating new controlled release products?
Ali: Abuse deterrent formulations (ADFs) or tamper resistant formulations (TRFs) have been a subject of continued debate in the industry and the agency has set forth a guideline for opioids and other controlled substance formulations. With the new landscape in ADF, the industry is using novel formulation technologies to derive 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 injecting. For non-opioids, and conventional drugs, the industry has been using the commercially available and approved excipients including cellulosic and vinyl acetate and gums due to their abilities to control and deliver drugs, and hence, alleviate the dose dumping and systemic toxicity.
Kyburz: During development of a modified release product, it is important to show robust formulation and operational process ranges through implementation of Quality by Design (QbD) principles as outlined in ICH guidelines: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. For both commercial immediate and controlled release products, the FDA recently redefined process validation to focus on a lifecycle approach with distinct design, qualification and continuous verification phases. The aim is to understand the source and risk of material and process variations via in-depth process development and process qualification, and appropriate control strategies based on statistical scientific evidence. These are especially critical for modified release dosage forms where raw materials and manufacturing variables have high impact. For products that are post-approval, the FDA SUPAC-MR guidelines streamline changes to the formulation, manufacturing process, and/or batch size for modified release dosage forms. While all SUPAC guidances are older than ICH and PV, it’s expected these rules will be updated to be consistent with current development and validation philosophies.
Another regulatory requirement is demonstration of drug release robustness to substantial amounts of ethanol. Certain CR technologies are intrinsically more robust – such as osmotic tablets, some matrix tablets, some MPs – but this factor must be designed into all CR dosage forms prior to key studies.
An additional focus of regulatory agencies is to require, or incentivize, pediatric drug formulation evaluations alongside conventional dosage forms intended for adults, including controlled release. For pediatric formulations, there is a heightened need for palatability, swallowability, ease of preparation and administration, and appropriateness for a wide range of pediatric ages.
Khot: Quality by Design (QbD) was previously viewed as optional, but it is now an absolute requirement. Formulators need to work closely with raw material suppliers to understand the sources of variability that could impact their product. The Dow-Colorcon Alliance offers a full library of QbD samples for matrix modified release, as well as technical support for other controlled release technologies.
Musakhanian: Many of the currently referenced oral CR dosage forms consist predominantly of polymers that serve as drug stabilizers and or sustained release matrices. The approach has its limitations. The high percentage of polymer needed to diminish the drug release is not amenable to high drug dosing. More importantly, the polymers may be subject of rapid hydration in the gastrointestinal tract due to pH, presence of alcohol, or food, leading to untimely burst release or dose dumping. Such risks may have grave consequences for potent drugs with narrow therapeutic index.
FDA continues to issue guidance documents aimed at ensuring drug safety and efficacy. With respect to controlled release dosage forms, the FDA may require additional studies. These include scientific evidence that the product performance does indeed match the claims being made. More importantly the innovator must demonstrate that the integrity of the dose in alcoholic and at times in acidic media is preserved. Since alcoholic beverage consumption may lead to a more rapid release of the drug impacting its safety and efficacy, a bioavailability study of the drug product when administered with alcohol may be needed.
Another concern with CR dosage forms is the potential variation in therapeutic response among patients. In a warning issued in September 2015, the FDA strongly cautions the health authorities about the dangers of administering the opioid analgesic Tramadol HCL to children aged 17 and younger.
Can you tell us about some new technologies that will debut in the next five years that will make the development of controlled released products easier and more efficient?
Dürig: New techniques to achieve gastro retention will increasingly facilitate the development of controlled release products for BCS class III drugs.
Novel highly functional polymers are under development that will facilitate more efficient development of controlled release matrix systems due to their ability to accommodate drugs with a wide range of characteristics and improved in vivo robustness, thus facilitating easier in vivo-in vitro correlation .
Finally adoption of GMP grade 3-D printing technologies has the potential to revolutionize controlled release device development. This technology allows the rapid development of novel device architectures and geometries that can enable novel drug delivery benefits.
Ali: The agency is focused on setting the standards for developing controlled release formulations − especially abuse deterrent formulations (ADF) to safeguard the patients, and public at-large. This is extremely critical as more opioids and pain killers going off patent are being developed. In this endeavor, the hydrogel are becoming more common, and the trend will continue because of the available range of excipients possessing the ability to hydrogel and control the release of drugs. For instance, polymers such as high molecular weight polyethylene oxides and polyethylene glycols will continue to play an important role. In other cases, polymers having the abilities for thermo-gelling 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 celluluse, polyacrylic acid, serum albumin among others, will contribute significantly to new innovative drug delivery technologies such as the nanotechnologies for controlled delivery of biologics for oral, injectable and topical products.
Kyburz: The recent emergence of continuous processing for oral solid immediate release products is expected to be quickly adopted for certain controlled release dosage forms, such as matrix tablets, with additional processing technologies to follow, including functional coating and coupled extrusion. Along with the many benefits of continuous processing, adhering to regulatory guidelines such as QbD becomes easier with the implementation of real-time process monitoring of the operational space utilizing process analytical techniques (PATs) and potential reduction of the scale-up API and resource burdens during development and manufacture.
New encapsulation technologies will likely see expanded use in enabling the oral delivery of sensitive molecules, including proteins, peptides, and live biological products. Microbiome and live biotherapeutics, such as using a living microorganism that is applicable in the prevention, treatment, and cure of a disease, represents exciting new fields. An oral controlled release/delivery of microbial flora to ileum and colon for disease treatment is an unmet medical need and has significant challenges. One focus of current research is delayed release capsule technology to provide enteric protection and site delivery for targeted release applications such as fecal microbiota transplantation (FMT) to treat relapsing clostridium difficile infection. The use of oral DRcap®-in-DRcap® technology obviates the need for invasive procedures for administration and significantly reducing cost.
The new enTRinsic™ drug delivery technology platform offers full enteric protection without the use of functional coatings. This utilizes cellulosic enteric derivatives and a standard single capsule manufacturing processes. Thus, biomolecules (proteins and peptides) and live organisms (bacteria and viruses) that require gastric protection can be formulated with common encapsulation equipment and avoid heat and moisture liability from functional coating and drying. Such sensitive applications have previously relied on non-oral delivery mechanisms.
Khot: We continue to see a higher need for productivity enhancement in the development of solid oral dosage forms. Excipient offerings which allow faster, streamlined processing with fewer steps help our customers see reduction in costs without sacrificing quality or performance. Another market trend we see is the environmental push towards more sustainable operations. New technologies combined with new excipient offerings could help reduce or eliminate the use of solvents.
In addition, most new chemical entities have poor bioavailability and thus are more difficult to formulate into CR dosage forms. Improving solubility with solid dispersions manufactured via spray drying, employing lower molecular weight polymers for their spray-ability, does not impart controlled release. Additional formulation steps are required to impart the desired release performance. On the other hand, hot melt extrusion is also gaining popularity for its ability to continuously produce solubilized products, but high molecular weight controlled release polymers are very challenging to process via HME. We believe that new developments, such as the extrudable HPMC grades available from Dow, will continue to emerge in this area, enabling both solubilization and controlled release performance in fewer processing steps.
Musakhanian: Technology-driven changes such as new devices and continuous process technologies are expected to dramatically accelerate. Solvent free technologies such as extrusion and spray congealing, atomization and granulation will facilitate the development of novel dosage forms with safe and stable combinations of enhanced, immediate, and extended delivery systems.
Launching of new excipients is time consuming and costly and quite expectedly new raw materials are subject of rigorous scrutiny for safety and functional attributes. Therefore, innovative use of existing well known excipients is the safest and shortest path to development of new CR dosage forms. For these reasons, at Gattefossé we focus on the novel applications of well characterized and fully understood excipients.
As indicated previously (in question 4) polymeric matrices are susceptible to rapid disintegration in alcoholic media, leading to dose dumping. In contrast, lipid excipients are insoluble in ethanol and offer a pH independent modulation of the drug release. In addition to being safe alternative to polymers, due to their low melting point and low melt viscosities, lipids do not require solvents during granulation, extrusion or other matrix preparations.
A great example of lipid matrix for CR is that of an azithromycin oral suspension prescribed as antibiotic for pediatrics. Azithromycin is characterized for its very rapid absorption, extensive distribution into tissues, and serum half-life of ~68 hours which make it an ideal candidate for a single dose controlled release therapy. The formulation consists primarily of microspheres obtained by melt congealing of the drug with two different lipid excipients: a hydrophobic excipient to provide a waterinsoluble matrix and a hydrophilic surfactive lipid within the matrix serving as pore former.
Another trend in CR development relates to amorphous solid dispersions which are increasingly used for addressing solubility limitations of BCS Class II and IV drugs. For poorly soluble drugs that have short half-life however, it may be beneficial if not crucial to enhance drug dissolution reducing the drug release rate in the gastrointestinal tract. For example, CR tablets of carbamazepine and itraconazole have been successfully developed with a hydrophobic excipient like Compritol® combined with high MW polyvinylpyrrolidones (PVP) to produce extrudates prior to compression. In this example, Compritol® created an insoluble matrix exhibiting near zero order release while also serving as binder / processing aid by reducing the undesirably high melt viscosity of PVP.
Used alone or in combination with polymers, lipid excipients therefore have key roles to play in the development of future CR dosage forms.