Bill Longcore /Science Photo Library
Recently, the pharmaceutical industry has experienced expirations on patents of some major blockbuster drugs, resulting in losses worth billions of pounds. This situation is set to continue with more blockbuster drugs losing patents in the coming years. The industry is responding by increasingly adopting various new drug delivery systems to enhance their product efficacy, patient compliance and extend patent lives through innovative repositioning and reformulations of existing drugs. This has resulted in significant growth of the drug delivery market over the past few years.1–3
The drug delivery sector has focused on the development of formulation technologies for life-cycle management and improvement of therapeutic outcomes rather than launching new chemical entities (NCEs). Such formulation technologies involve complex dosage forms such as transdermal, transmucosal and also novel formulations for oral delivery. The number of reformulated products using such technologies reached about triple that of NCEs in 2009 (75 versus 26).4
However, there are a few cases where such sophisticated technologies have been used for the launch of NCEs. An example of a recent NCE that has been originally formulated to a transdermal patch is rotigotine (Neupro, UCB) for the treatment of Parkinson’s disease and restless leg syndrome. Rotigotine is the first and only drug formulated rather than reformulated into a transdermal dosage form.
The regular introduction of NCEs is nevertheless currently weak, and such innovation is at an all-time low. Also, the increased demand for a greater number of complex clinical trials is increasing time to market. Hence the emergence of repatentability, achieved by the introduction of controlled release formulations of existing immediate release products is an attractive financial option for pharmaceutical companies. The funding for pharmaceutical research has doubled in the past 20 years and, as a result, the research in the field of novel controlled release drug delivery systems has continuously grown over the years. Formulation scientists have developed various novel controlled release formulations. In this first of two articles, we are going to focus on novel formulations for oral delivery.
Controlled release formulations
Controlled drug release and subsequent biodegradation are important for developing successful formulations. Potential release mechanisms involve:
• Desorption of surface-bound and adsorbed drugs
• Diffusion through the carrier matrix
• Diffusion (in the case of nanocapsules) through the carrier wall
• Carrier matrix erosion
• A combined erosion and diffusion process
The mode of delivery can be the difference between a drug’s success and failure because the choice of a drug is often influenced by the way the medicine is administered. Sustained (or continuous) release of a drug involves polymers that release the drug at a controlled rate due to diffusion out of the polymer or by degradation of the polymer over time.
Pulsatile release is often the preferred method of drug delivery since it closely mimics the way the body naturally produces hormones such as insulin. It is achieved by using drug-carrying polymers that respond to specific stimuli (eg, exposure to light, changes in pH or temperature).
OROS
One of the most widely commercialised controlled release technologies is the Osmotically controlled Release Oral delivery System (OROS), developed by Alza (Johnson & Johnson). These systems are made up of a tablet core containing a water-soluble drug and osmotic agents such as sodium chloride, sugars, hydrophilic polymers, etc. The tablet core is coated with a semi-permeable polymer such as cellulose acetate, which is permeable to water but not to the drug. Within the gastrointestinal tract, aqueous fluid enters the OROS tablet through this membrane and pushes the drug out through a delivery orifice at a constant controlled release rate.5
Poorly soluble drugs can be incompletely released. Alza Corporation has developed the OROS push-pull technology, where tablets are made up of multiple drug layers with a push layer — a water-swellable polymer — at the bottom. The swollen layer pushes solution from the upper drug layers out of the system through the delivery orifice.6
L-OROS, developed for highly water insoluble drugs (eg, hormones, steroids) and liquid drugs, consists of a liquid-filled softgel coated with multiple layers, such as an osmotic push layer and a semipermeable layer. The internal osmotic layer pushes against the drug compartment and forces the liquid drug formulation from the delivery orifice present in the outer layers of a coated capsule. Glucotrol XL (glipizide extended release, Pfizer) and Procardia XL (nifedipine extended release, Pfizer) are classic examples of OROS tablets.6
OCAS
Astellas Pharma (Tokyo) has developed a dosage form that incorporates a highly water-retaining polymer that drags and retains water during transit in the GI tract, which then uses the drug-releasing media in the colon — where there is little surrounding fluid — to facilitate release and absorption. This Oral Controlled Absorption System (OCAS) technology has been applied to tamsulosin and branded as Alna OCAS, Omnic OCAS, Flomaxtra XL, Urolosin OCAS and Praf T. These reformulated products not only show higher night-time maintenance of plasma concentrations but also no change of their pharmacokinetic profiles by food.5
TIMERx
TIMERx controlled release tablet formulation forms a hydrophilic matrix in aqueous media and controls the drug release for 24 hours. Its advantages include cost-effectiveness, ease of manufacture, good patient compliance, and suitability to a wide variety of actives with different drug loading and solubility. Different release profiles can be achieved through the adjustment of the two constituent polysaccharides (xanthan gum and locust bean gum) that slow water penetration into the dosage form and thereby control release of the drug.
SODAS, IPDAS and CODAS
Elan has developed a spectrum of technologies designed according to the need of the drug, such as Spheroidal Oral Drug Absorption System (SODAS), Intestinal Protective Drug Absorption System (IPDAS) and Chronotherapeutic Oral Drug Absorption System (CODAS).
Ritalin LA and Focalin XR, controlled release formulations of the central nervous system stimulants to treat attention deficit-hyperactivity disorder (ADHD) in children, use the SODAS technology, where a combination of immediate and controlled release beads are incorporated within the system to obtain a pulsatile release profile.7
Bilayer, trilayer and dual release tablet technology can also give different release profiles of one or more drugs. This technology is also useful for controlled release and abuse-resistant systems. Madopar DR is a trilayered gastro-retentive matrix tablet of levo-dopa for the treatment of Parkinson’s disease. The outer layers release l-dopa in high concentration for quick action and the inner sustained release layer is made up of a hydrophilic water-swellable polymer that increases the gastric retention of the tablet and allows the maintenance dose to be released slowly for up to six hours.
Naprelan demonstrates a controlled release profile of naproxen using IPDAS technology that compresses high density multiparticulate beads into tablet formulations. The tablets disintegrate into dispersion of beads throughout the GI tract to prevent dose dumping of the GI-irritant drug. Minitablets are filled into capsules, thereby benefiting from the properties of both tablets and multiparticulate dosage forms.
The CODAS drug delivery system is tailored to allow drug release according to circadian patterns of the disease. Research has shown that certain diseases are affected by the rhythmic changes of the human body (eg, heart attacks appear to be more likely to occur during the early morning hours than in the evening). Verelan PM, a sustained release formulation of verapamil hydrochloride, which is taken at bedtime, gives a higher drug release during the early morning hours. These chronotherapeutic systems allow maximal health benefits with optimal patient compliance.8
Stomach and colon
Drugs targeting the stomach and the colon are also approaches that are being exploited in modern research. Colonic delivery has attracted interest primarily to treat local conditions such as Crohn’s disease, ulcerative colitis and colorectal cancer. Encap has used the ENCODE technology for the targeted delivery of capsules to the colon. The ENCODE Phloral system is triggered by both the pH and the microbes in the colon to deliver the drug accurately and consistently.9
Cosmo has developed a Multi Matrix MMX technology that is a pH-resistant acrylic co-polymer that delays release until it reaches the pH of the desired location of the intestine, allowing for controlled release over the length of the colon. This has been used in the dosage form to deliver budesonide to the colon in the treatment of mild to moderate ulcerative colitis.
Alizyme’s Colal delivery system has been effective at delivering prednisolone topically to the colon to treat ulcerative colitis at an efficacy similar to that of standard oral prednisolone but without the debilitating side effects usually associated with steroids. This is achieved via the use of a coating that is only broken down by the microbes residing in the colon.8
Conclusion
Despite all advancements made within the field of oral drug delivery, many technologies have come and gone, but what is clear is that new systems are still emerging. However, it appears that their longevity is questionable based on recent trends.
Reformulated products require five years to demonstrate any pharmaceutical or clinical evidence, and must be exclusively marketed for at least 10 years. Therefore, the industry only has five years between showing evidence and launching the product into the market. When the exclusivity expires, there is a likely tendency of generics companies copying the technology quickly.
Consequently, the best strategy to secure more valuable next-generation reformulated products is an early marriage between an NCE and a drug delivery system through a partnership between a pharmaceutical company and a drug delivery company. This approach will lead to a synergistic innovation in both arenas that supersedes an advance made in either in isolation.5
References
1 Sastry SV, Nyshadham JR, Fix JA. Recent technological advances in oral drug delivery — a review. Pharmaceutical Sciences and Technology Today 2000;3:138–45.
2 Oral drug delivery market — controlled and sustained release to be major revenue benerators. Available at: www.marketresearch.com (accessed 11 April 2012).
3 Das NG, Das SK. Controlled-release of oral dosage forms. Pharmaceutical Technology 2003;10–6.
4 Rekhi GS. Advances in solid dose oral drug delivery. Available at: www.ondrugdelivery.com (accessed 11 April 2012).
5 Wang H, Park J. A possible approach for the desire to innovate. Available at: www.ondrugdelivery.com(accessed 11 April 2012).
6 Ghosh T, Ghosh A. Drug delivery through osmotic systems — an overview. Journal of Applied Pharmaceutical Science 2011;1:38–49.
7 Rekhi GS. Advances in solid dose drug delivery. Available at: www.ondrugdelivery.com (accesssed 11 April 2012).
8 Kalantzi LE, Karavas E, Koutris EX et al. Recent advances in oral pulsatile drug delivery. Recent Patents On Drug Delivery And Formulation. 2009;3:49–63.
9 Norman G. Liquid-fill hard two-piece capsules: the answer to many product development issues. Available at: www.ondrugdelivery.com (accessed 11 April 2012).
