Dr. Suniket Fulzele is an experienced drug delivery and formulation development scientist. He joined CIMA Labs, a Cephalon Company, in 2010 and is involved in developing immediate- and modified-release oral solid dosage forms. Prior to this, Dr. Fulzele worked at Nektar Therapeutics and Aradigm Corporation. He earned his PhD in Pharmaceutics from Nagpur University, India, followed by post-doctoral research at Florida A&M University. He has published over 100 peer-reviewed research articles, abstracts, and patents.
Dr. Derek Moe is currently Vice President, Drug Delivery Technologies at CIMA Labs, a Cephalon Company. Dr. Moe came to CIMA in 2001 from the formulation group at Pfizer Global Research and Development in La Jolla, CA (previously Agouron). He began his career as a Formulator at Syntex, Inc. in Palo Alto, CA. Dr. Moe earned his PhD in Pharmaceutics from the University of Minnesota and his BA in Chemistry and Math from St. Olaf College.
Dr. Ehab Hamed started as a Formulation Scientist at CIMA Labs nearly 10 years ago and is currently the Director of the Formulations Department at CIMA. In this role, he is responsible for all internal and partnered new drug product formulation development, including prototype design, CTM manufacturing, process scale up to pilot and commercial scale, as well as commercial products transfer between sites. He also provides technical leadership role in IP strategy/litigation, technology/product valuation, and regulatory filings. He has numerous patent applications, book chapters, and published articles to his credit. He is a pharmacist by training and earned his PhD in Industrial Pharmacy from the University of Cincinnati.
Drug Delivery is often challenged to provide new technologies that offer significant clinical and financial value in addition to research and innovation niche. The innovation designs may involve modifying formulation compositions and manufacturing technologies to achieve new product performance end points. Orally disintegrating tablets (ODTs) offer improved patient compliance as they enable oral administration without water or chewing. The US FDA defines an ODT as "a solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue."1 The 2008 FDA guidance recommends a disintegration time of 30 seconds or less based on US Pharmacopeia disintegration test method and maximum tablet weight of 500 mg. ODTs are preferred by multiple patients groups with swallowing difficulties, including geriatrics, pediatrics, dysphagic, and bed ridden. ODTs also offer potential for product line extension for first-to-market product and marketing differentiation for Over the Counter Products (OTCs).
The ODT market is expected to exceed $13 billion by 2015, which is more than double its value in 2009.2 The increase may be attributed to three main driving factors:
â€¢ Increased generic competition and the need for product differentiation.
â€¢ Expected increase in the number of prescription products switch to OTCs.
â€¢ The 2007 introduction of the European regulation on medicinal products for pediatrics.
This new regulation mandates that all newly developed products (including new indication, new route, and new dosage forms of existing molecules that are still IP protected) to have a pediatric formulation. The European medicinal a gency's Committee for Medicinal Products for Human Use describe ODT as having "great promise for children."3 The committee also acknowledges that taste will be a challenge for these ODTs because a limited quantity of flavor and/or sweetener will be allowed in these dosage forms, and the need for alternative taste-masking techniques like particle coating will be needed.3
Tablet compression and lyophilization remain the two most popular industrial approaches to manufacture ODTs. The compressed ODT involves conventional tableting with achieved rapid disintegration using super-disintegrants in combination with lower compression forces and/or the use of water-soluble excipients. Direct compression is often the technique of choice. Some of the patented compressed ODT technologies include Flashtab, Advatab, Orasolv, Durasolv, Wowtab, and Ziplets. The lyophilized ODT employs the process of lyophilization in which solvent is removed from a frozen drug solution or suspension containing structure forming excipients. The lyophilization manufacturing process produces wafer with greater porosity, allowing for shorter disintegration times than compressed ODTs. The patented lyophilized ODT technologies include Zydis, Lyoc, and Quicksolv. The advantages and disadvantages of both (compressed and lyophilized ODTs) have been extensively reviewed in literature.4-7 Other techniques to manufacture ODTs include spray drying, molding, thin films, melt granulation, extrusion, and sugar floss.8 The following article reviews the lyophilized wafer technology, specifically Lyoc, that offered the world's first ODT, ODA Lyoc (sodium saccharinate and flamenol) in 1968.
Lyoc technology is an oral solid porous dosage form that immediately dissolves in the mouth without the need for water (Figure 1). The technology is suitable for a variety of actives with different physicochemical properties and can be tailored to incorporate drug particles with different functional coatings, including taste-masked, extendedrelease, and modified-release coating. There are currently seven commercialized ODT products utilizing Lyoc technology, including Spasfon-lyoc (phloroglucinol), Para-lyoc (paracetamol), Proxa-lyoc (piroxicam), and Loperamide-lyoc (loperamide).
Lyoc utilizes a unique manufacturing process based on an innovative nonpolluting, nonpolluting, environment-friendly, freezedrying technology that yields high purity and safe products as it operates in the absence of organic solvents. The typical Lyoc manufacturing steps (Figure 2) include:
â€¢ Preparation of a suspension, solution, or emulsion containing active ingredients.
â€¢ Distribution of this liquid homogenous preparation in preformed blisters (Figure 3).
â€¢ Very low temperature freezing (preferably below -40Â°C). At this stage, the active molecules are immobilized; their properties remain unaltered as the rate of chemical reactions is nearly nil at this low temperature.
â€¢ Sublimation or water elimination: this is typically carried out at low temperature and low pressure. Under particular conditions, the ice is directly converted into the vapor phase. The lyophilization step is depicted in Figure 4.
â€¢ The finished product is a porous solid capable of very rapid disintegration (Figure 1). The active ingredients remain in a dispersed state within the mass.
â€¢ Sealing the blister with top foil.
MANUFACTURING CHALLENGES FOR LYOPHILIZED ODTs
Two main challenges face the development of lyophilized ODTs; the rarity of industrial-scale manufacturer with the appropriate know-how and the difficulty in incorporating drug particles with functional coat into the product.
To the authors' knowledge, there are currently only two companies that are approved to manufacture lyophilized wafers on industrial scale in Europe and US, Catalent Pharma Solutions and Cephalon. The uniqueness of the manufacturing process has limited the number of contract manufacturing organizations (CMOs) that offer the technology. With the expected increase in the number of ODT products, commercial incentives could lead to an increase in the number of CMOs that provide the technology. However, given the inherent complexity in the formulation design and manufacturing process development, a long learning curve is expected before any new company masters the manufacturing process development. Lyoc technology offered by Cephalon has been used to commercialize ODTs since the late 1960s. The manufacturing facility is approved by the EMEA and other regulatory authorities. The accumulated know-how has streamlined the development process to allow the fast production (three batches per day for each freeze dryer) of robust lyophilized wafers that can be packaged in push-through foils, a feature that is not affordable by many compressed tablets ODT technologies due to the production of soft tablets that are much more friable.
Incorporation of Drug Particles With Functional Coat
The difficulty in incorporating coated drug particles into a lyophilized wafer has limited the spread of the technology as a large percentage of orally administered drugs have bitter, unwanted taste, which may require particle coating for taste-masking. This difficulty also limited the use of lyophilized ODTs to provide extendedrelease or delayed-release features. The difficulty stems from the following two factors: (1) the need to reduce "drug leakage" from the coated drug particle during manufacturing, and (2) ensuring the drug suspension can sustain the freeze drying process and still yield a highly porous and robust dosage form.
Reducing Drug Leakage During Manufacturing
As previously described, the Lyoc manufacturing process includes suspending the drug particles in an aqueous system before dosing into preformed wells. During scale-up to manufacturing scale, the duration of time needed to prepare, dose the suspension into wells, and freeze is significantly longer than what is typically employed during prototype development. This could lead to failure during scale-up if the formulation component, particularly the taste-masked component and the solution used are not appropriately optimized. Batchto- batch variability in suspension preparation and dosing time during routine commercial manufacturing must be factored in during prototype development. Therefore, one of the lyophilized ODTs critical quality attribute (CQA) that must be tested and confirmed during prototype development is the prevention of drug leakage in the manufacturing solution for an extended period of time (preferably at least 6 hours). The developed formulation must allow immediate drug release in the stomach, which is typically assessed through drug dissolution using pharmacopeia methods. The balance between these two CQAs (limited drug leakage and fast dissolution) can be achieved through the careful selection of the taste-masking agent(s) and the lyophilization solution's physical and chemical properties and the understanding of the manufacturing-scale limitations early during prototype development. Ionic strength, pH dependent solubility, osmotic pressure, viscosity, and coated drug particle size can be successfully optimized to protect the particles during production. Figure 5 shows the release profiles of extendedrelease phenylephrine HCl-coated beads before and after lyophilization. Extendedrelease drug particles offer a bigger challenge compared to taste-masked particles as even minor drug leakage during manufacturing could lead to the product failing the dissolution requirement. As seen in the figure, the developed Lyoc formulation was able to maintain the drugrelease profile from the coated drug particles unchanged after exposing them to suspension in water, dosing, freezing, and drying as Lyoc.
Ensuring the Drug Suspension Can Sustain the Manufacturing Process
During scale up, shorter freeze-drying cycles are mandated for obvious costreduction rationale. For all lyophilization processes, the drying steps are the longest and are typically the focus of process optimization to shorten the production cycle. To achieve this, drying processes are "pushed" to higher shelf/product temperature. The formulation must be designed to have high product collapse temperature (preferably above -5Â°C), which is achieved through the use of high level of bulking agents like mannitol and glycine. Mannitol is an obvious excipient of choice for any ODT owing to its slight sugary taste and cooling sensation that improves the palatability of the product. However, with the introduction of other excipients to minimize drug leakage from the coated particles, a decrease in product collapse temperature can be expected due to the formation of a glassy phase during freezing. For decades, Lyoc formulations have been successfully designed with the aforementioned balance in mind. The optimized Lyoc formulations are designed to sustain primary and secondary drying in less than 6 hours without melt back or collapse.
FUTURE TRENDS FOR LYOC
In addition to its application in manufacturing ODTs, Lyoc technology can also be used to prepare buccal wafers and improve drug solubility/bioavailability. Buccal wafers can be designed to offer oral disintegrating attributes for patient compliance and/or product differentiation or it can be used to prepare the dosage forms for buccal delivery. For drug solubility/bioavailability enhancement, Lyoc technology can be used in conjunction with other formulation/excipients approach to enhance drug solubility. For example, the drug can be formulated into a microemulsion that can be converted into a "selfmicroemulsifying system" upon lyophilization. Figure 6 presents the dissolution profiles of a Lyoc meloxicam micro-emulsifying formulation compared to the marketed product MobicÂ®. Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) that is practically insoluble in water. The poor solubility is a limiting factor for gastrointestinal absorption and subsequent onset of action, which restricts the use of meloxicam for acute indications. As seen in the Figure 6, meloxicam Lyocs shortened the time needed to release more than 80% of the dose from 75 to 80 minutes for the commercial product to about 10 minutes. The fast meloxicam dissolution was maintained following prolonged storage.
Lyoc offers innovative and wide-ranging possibilities to pharmaceutical formulation development. The technology has evolved to allow the incorporation of coated particles, which widens the technology application to include more efficient taste-masking, delayed-release, and extended-release dosage forms. Combining the pharmacological and therapeutic advantages aside from pharmacoeconomics, Lyoc brings a strong differentiation to product lines. It allows optimizing new products, extending existing ranges, and even strengthening the patent protection of older products.
The authors would like to acknowledge and thank Lisa Hillman for her help in data compilation.
1. Food and Drug Administration. Guidance for Industry: Orally Disintegrating Tablets. Rockville, MD, 2008.
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6. Nayak AK, Manna K. Current developments in orally disintegrating tablet technology. J Pharm Edu Res. 2011;2:21-34.
7. Shukla D, et al. Mouth dissolving tablets part 1: an overview of formulation technology. Sci Pharm. 2009;77:309-326.
8. McLaughlin R, et al. Orally disintegrating tablets: the effect of recent FDA guidance on ODT technologies and applications. Pharm Technol. September 2009 (supplement).