Controlled Release Technologies: an Evolving Role in Drug Development

Formulation

Controlled Release Technologies: An Evolving Role in Drug Development

Delivering on the promise of better treatments, controlled release Jeff Browne, Rao Tatapudy and Steve Hamlen at technologies have evolved to provide improved therapeutic profiles, Catalent Pharma Solutions increased patient compliance and enhanced bioavailability. Controlled release technologies – superiority of a drug, but also to pharmacokinetic (pK) profiles in the as well as their applications – have ensure that payers reimburse it. following ways: experienced a surge in innovation in recent years. This article will These market dynamics are ●● Extended (long-acting) release discuss the drivers that have driving companies to integrate oral (ER): decreased dosing frequency led to this, as well as how these controlled release formulations and compared with immediate technologies are being applied in technologies earlier in the drug release (IR) formulations. Specific the pharmaceutical prescription development process with a focus amount of drug released at and over-the-counter (OTC) market on developing better treatments. specific time intervals to deliver on the promise of better This represents a shift from the ●● Delayed release: drug released treatments. The discussion will traditional industry use of these at specific targeted points in focus on three main benefits that technologies largely as a life cycle the body, based on pH or other controlled release has delivered: management approach, as shown in characteristics improved therapeutic profiles, Figure 1. In a January 2012 survey of ●● Pulsed release: short term and patient compliance and 281 professionals involved in drug long term combined release (IR enhanced bioavailability. development and formulation, plus ER) in one dosage form over one-third (39 per cent) Drivers of Controlled reported that their company Technology innovations have Release Evolution typically decides which drug recently been introduced that delivery route to launch with prior expand controlled release Two key factors are driving this to ‘first in human’ clinical trials (1). capabilities. An example is OSDrC® increased focus on oral controlled OPTIDOSETM which enables the release drug delivery. First, Improved Therapeutic Profiles design of dividable, multi-layer, innovation has slowed in the single or multi-core tablets with branded pharmaceutical industry Controlled release solution a practically endless variety of over the past decade leading to providers have a broad portfolio core numbers, shapes, sizes and significant generic erosion and of technologies, as well as placement within the tablet. The pressure on innovator company significant scientific formulation flexible core capability provides revenues and profit margins. At the and manufacturing expertise in new alternatives in controlled same time, the level of competition applying them to address current release designs for drug formulators, has increased. industry challenges. Table 1 developers and marketers in a high Keywords Companies of all illustrates how numerous product quality, one-step manufacturing sizes are under attributes have been affected by processes. This new technology Controlled release pressure to controlled release technologies expands tableting capabilities in Patient compliance differentiate their across multiple therapeutic areas for many areas including fixed dose products – not both prescription and OTC products. combination tablets, thin film Orally disintegrating tablet only to convince dry-coated tablets and loosely Softgel technology regulators and Traditional controlled release compressed beadlets encased Hot melt extrusion clinicians of the formulations alter the drug in tablets.

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Line extensions Dosing convenience Historical role of controlled release: a life cycle management focus

Preclinical Phase 1 Phase 2 Phase 3 Commercial Image: Catalent

Dose form and controlled release technology Product optimisation Line extensions Bioavailability solutions Dose improvements and Figure 1: Controlled Enhanced therapeutic profiles differentiation release technologies Patient adherence improvements are playing an evolving role in drug Evolved role of controlled release: integrated into development process and throughout product life cycle development A better treatment focus

Patient Compliance of two oral methods for the approved treatments with delivery of selegiline, a treatment supporting clinical trials were all Controlled release formulations for Parkinson’s disease: a standard with subcutaneous injections. for oral drug delivery can address pill and a Zydis® fast-dissolve several factors that represent ODT formulation that achieved This was the first approved and barriers to patient compliance, pre-gastric absorption. The results registered disease-modifying allergy through modification of drug showed a 98.5 per cent compliance immunotherapy tablet (AIT) for the pharmacokinetic (pK) profiles to rate with the ODT formulation treatment of grass pollen allergic deliver drug when it is needed, compared with 81 per cent for rhino conjunctivitis, and patients to pill burden reduction through the standard oral treatment in US benefit from having an approved extended release and combination Medicare patients (see Figure 2, oral therapy as an alternative to medications, to targeted drug page 66) (2). injections. Parenteral therapy release delivery of drug where it presented challenges to patient is needed in the body. A summary Patient compliance can also be compliance, whether injected at the of how patient compliance factors addressed by altering the route of physician site of care or – in some can be addressed by controlled administration from an injection countries – self-injected at home. release and proprietary OSDrC® to an oral tablet. As an example, Not surprisingly, patient preference OPTIDOSETM technologies is shown Catalent formulated ALK-Abello’s studies indicated that over 80 per in Table 2 (page 68). Grazax®, a standardised allergen cent of patients highly preferred a extract of pollen from Timothy grass non-injection treatment alternative. Orally disintegrating tablet (ODT) (Phleum pratense), with its Zydis® formulations dissolve in the ODT technology as a once-daily, The oral formulation helped mouth, without the need for water, oral medication for chronic grass improve medication persistence – therefore eliminating the need pollen allergy sufferers. Previously continuation of the treatment for the for patients to swallow pills. ODT applications have continued to Table 1: Patient compliance factors addressed by controlled release formulations expand as dysphagia (difficulty in Efficacy Safety/tolerability Payer value Dosage/administration Indications/populations swallowing), patient compliance Increased Targeted drug delivery Increased patient compliance Less frequent dose regimen Entire labelled patient and consumer convenience issues bioavailability (for example once versus population Controlled drug plasma Reduction in patient twice daily) have gained prominence. Faster onset of action profile (pK) pill burden Elderly patient segment Orally disintegrating tablets – Targeted drug delivery Reduction in first pass Extended and flexible dosing disperses in mouth without Paediatric patient segment A recent study of longitudinal metabolism through – lower cost to treat with water in usually less than patient records at Catalent Sustained drug the liver increased convenience three seconds ‘On the go’ lifestyle patient plasma profile (pK) segment supports the theory that drug Poly-therapy with a Tablets, pills, capsules delivery can improve patient Controlled drug single dose plasma profile (pK) Orally dissolving powder – compliance. The one-year study to match specific loose free-flowing powder compared the compliance rates treatment needs granules

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Zydis® fast-dissolve formulation has highest patient compliance for Medicare Parkinson’s optimal and, in some cases, disease market, based on 12 month longitudinal patient record analysis. Per cent clinically-meaningful plasma concentrations, and results in many 100 2010 Selegiline market size: $19.3 million One per cent increase in compliance = $200,000 development programmes being 95 98.5 Value added to healthcare system either discontinued or progressing

90 with non-competitive product profiles and dosing schedules. 85 87.9

80 81 Improving a drug’s solubility is Compliance one of the most effective means 75 to improve bioavailability. The 70 formulation of these drugs in solubility-enhancing lipid-based 65 Zelapar® Zydis® Eldepryl® Selegiline HCL systems in a softgel delivery form Zelapar®, age: total, gender: total, pay type: Medicare is the most common approach to enhance both solubility

Figure 2: Zydis® prescribed duration – a particularly an injection, Grazax® can be and bioavailability. fast-dissolve challenging issue for individuals administered at home – or patient compliance improvement receiving specific immunotherapy wherever the patient happens to Softgel (soft gelatin) technology compared with which, unlike other treatments for be – a feature that makes allergy is an established method of traditional tablet allergic rhino conjunctivitis, does immunotherapy more convenient encapsulating a liquid or semi-solid, formulations not produce immediate relief and less expensive for the patient. oral drug formulation in a soft, Source: SDI Health Patient Data, 2011 of symptoms that can be easily dissolvable or erodible matrix. The perceived by the patient. In fact, a Bioavailability softgel process was patented by recent German study found that Robert Pauli Scherer in 1933. Softgel medication persistence – as measured In a January 2012 survey polling technology improves solubility, by filling at least one prescription drug development professionals on permeability and bioavailability annually for the length of the three- the leading problems facing them for a wide range of poorly water- year study – was significantly greater in current development projects, soluble drugs. In addition to with Grazax® than with subcutaneous 41 per cent of respondents cited their direct pharmacological immunotherapy. Moreover, the ODT bioavailability, with solubility (35 benefits, softgels enhance dose dosage form made adherence easier per cent) and dissolution (31 per uniformity and stability, and for children and the elderly, whilst cent) following closely behind (1). enhance compliance through ease also eliminating the issue of ‘needle This finding is consistent with of swallowing and taste-masking. phobia’, which is estimated to affect many public sources, estimating Softgels are compatible with a wide approximately six per cent of the that approximately 40 per cent of range of lipid-based formulations, general population. new investigational drugs suffer and are capable of targeted dose- from poor water-soluble properties. release modification through the Additionally, instead of visiting Poor solubility/bioavailability application of modified release film- the doctor’s office to receive prevents drugs from achieving coatings. More recently, Vegicaps®, a novel capsule technology, allows for higher temperature encapsulation of lipids that subsequently set In a January 2012 survey polling as semi-solid matrices at room drug development professionals temperature. This technology is particularly useful for controlled on the leading problems facing release matrix formulations them in current development containing poorly water-soluble active ingredients. © W h i t e B o x A g n c y - S a l d P r v projects, 41 per cent of respondents cited bioavailability, Another advanced – but still-emerging – formulation with solubility (35 per cent) and technology to consider is hot dissolution (31 per cent) melt extrusion (HME). Although well-known in the plastics following closely behind and materials industries, HME

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Table 2: Controlled release applications can impact therapeutic profiles across many product attributes Conclusion FAST, Factors impacting patient compliance: Controlled release solutions: The global pharmaceutical Complicated dosing regimen Optimise drug pK profile by ‘dialing a dose’ industry is currently facing High pill burden Reduce pill burden through less frequent dosing and single pill poly-therapy Slow onset of action unprecedented challenges due Target drug delivery to specific parts of the body (lower side effect/ Doesn’t work long enough increased safety potential) to lack of innovation, increased Side effects EFFECTIVE competition, and heightened Have to take with other medicines/food Optimise dosing regimen to match patient lifestyle and disease Low bioavailability (efficacy) requirements regulatory and payer pressures. Social stigma for certain diseases Combine IR and ER drug release profiles in a single pill These dynamics have increased the need to maximise product is only beginning to realise extruded. HME is a continuous differentiation – not only as its full potential among process and consumes no solvent. part of life cycle management INSIGHT pharmaceutical formulators. strategies, but also early in the HME provides advantages similar Poor bioavailability is a growing development process. This has to those of softgel, namely, it problem for development-stage led to innovative applications of increases a drug’s solubility pharmaceuticals. Several promising controlled release technologies and bioavailability. Additionally, technologies now allow drug to address the unmet needs of HME offers greater flexibility for developers to overcome this serious patients, physicians and payers. controlled or modified release, as challenge and realise their products’ Delivering on the promise of the extrudate is further processed full potential. Bioavailability issues better treatments, controlled into tablets. With HME, the active are not solved by formulation and release technologies have ingredient and excipients are delivery technologies alone, but by evolved to improve therapeutic combined and heated into a combining these approaches with profiles, increase patient solid dispersion matrix, and then proven expertise. compliance and enhance bioavailability. MAGAZINES To be taken quarterly Jeff Browne, PhD, is Technical Director, Pharmaceutical Softgels at Catalent Pharma Solutions. After receiving his PhD in Industrial & Physical Pharmacy from Purdue University The need for better treatments (West Lafayette, IN) in 1979, he spent the first 11 years of his career working for The has also sparked innovation in 5 Upjohn Company in Kalamazoo, MI. While at Upjohn, he held various positions in solution providers, as in the case of pharmaceutical manufacturing & technical services and drug delivery R&D, with a focus the recent introduction of OSDrC® on topical, transdermal, inhalation and oral liquid dosage forms. For the next four years, OPTIDOSETM technology for he was Director, US Technical Affairs for The Mentholatum Co (a division of Rhoto Pharmaceutical Co) optimised dosing, expanding the ! Select remedy based on requirement: located in Buffalo, NY. Since joining Catalent Pharma Solutions (formally RP Scherer and Cardinal Health industry’s capabilities for controlled European Biopharmaceutical Review executives Pharmaceutical Technologies & Services) in 1994, Jeff has held a variety of positions. He is the current Chair release. It is likely that controlled of the Dane O Kildsig Center for Pharmaceutical Processing Research, an industrial university cooperative European Pharmaceutical Contractor release solution providers and research centre, and serves on several American Association of Pharmaceutical Scientists (AAPS) Focus Innovations in Pharmaceutical Technology pharmaceutical companies will also Pharmaceutical Manufacturing and Packing Sourcer Groups including the Steering Committee for Lipid-Based Drug Delivery and the Strategic Planning International Clinical Trials Committee for the Manufacturing, Science and Engineering Focus Group. Email: [email protected] innovate their business models as true development partnerships Unparalleled analysis targeting key Rao Tatapudy, R Ph, PhD, is Vice President of Scientific Affairs, Innovation and Growth, at and risk-sharing structures evolve Ingredients: Catalent Pharma Solutions and is responsible for global R&D and technology platforms. from what was traditionally ‘fee and decision-makers across the pharmaceutical industry He has 27 years of pharmaceutical experience. Previously he was at Pfizer, where he for service’. was New Product Leader and Director of New Product and Process Development with responsibility for global manufacturing services. Prior to Pfizer, Rao spent 21 years with References Wyeth Pharmaceuticals in various departments including brand, toxicology, generic, life 1. January 2012, Pharmaceutical cycle, technical operations and product supply (TO&PS). Rao holds a PhD and MSc in Industrial Pharmacy Technology Survey of 281 from St John’s University (Queens, NY) and is a registered pharmacist in the state of New York. professionals involved in drug Email: [email protected] development and controlled release technologies Steve Hamlen is Group Product Manager for Modified Release Technologies at Catalent Pharma Solutions, leading teams in the launch of new controlled release 2. Twelve-month longitudinal technologies to help pharmaceutical and consumer health care companies address patient records analysis unmet needs and develop better treatments through drug delivery. He has 19 years’ conducted by SDI Health, For repeat prescriptions, visit www.samedanltd.com experience in the life sciences industry, including various product form development a division of IMS Health, and marketing roles at Hoffmann-La Roche and Johnson & Johnson. Steve has a BSc in January, 2011. Study in Chemical Engineering and an MBA from Lehigh University (Bethlehem, PA). included 1,520 US patients Email: [email protected] prescribed Zelapar, Eldepryl, or generic selegiline European Biopharmaceutical Review epc 68 Innovations in Pharmaceutical Technology Issue 41 European Pharmaceutical Contractor

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