Rosie McLaughlin, Dr Susan Banbury and Cornell Stamoran, of Catalent Pharma Solutions look at how, since the launch of Zydis, orally disintegrating tablets have created a new market niche
Since first launched in 1986, orally disintegrating tablets (ODT) have become an important part of the industry's oral dose form tool kit. Prescription products in ODT form reached global sales of nearly $2 billion in 2006, and ODTs are one of the few oral dose form categories to demonstrate strong volume growth in the market over the past three years. This strong growth reflects the favourable product lifecycle management characteristics that ODTs originally brought to the market, as well as more recently understood advantages arising from physician and patient preferences for ODT, and the use of advanced characteristics of some ODTs to achieve unique clinical outcomes.
Historically, ODTs were primarily employed as bioequivalent line extensions of existing marketed drugs, relying on simple form differentiation and ODT patents to lengthen the life of existing branded products. Today, however, advanced dose form technologies, including ODTs, need to meet a higher standard in order to contribute to market success. Most major pharmaceutical markets are applying tighter standards before providing access to or reimbursing drugs, in order to control the overall cost of pharmaceutical benefits for patients. In this reimbursement-constrained environment, advanced dose forms ultimately need to provide a clear clinical benefit sufficient to persuade a physician to write a prescription, a payer to reimburse the cost, and a patient to actually consume the drug as intended. The most successful products have attributes in each of these areas.
In April 2007, the FDA issued a draft "Guidance for Industry: Orally Disintegrating Tablets" which provides a much needed definition of what constitutes a fast dissolving oral tablet technology. The draft guidance states: "The products are designed to disintegrate or dissolve rapidly on contact with saliva, thus eliminating the need for chewing the tablet, swallowing an intact tablet or taking the tablet with water". The guidance further states that: "ODTs [should] be considered oral preparations that disintegrate rapidly in the oral cavity, with an in-vitro disintegration time of approximately 30 seconds or less..." Some of the ODT technologies used in products on the market today will not meet these standards.
Zydis, the technology from Catalent Pharma Solutions which launched the ODT category in 1986, has a proven track record for regulatory acceptance and successful launch, with 20 products globally spanning a range of applications based on either market segment (OTC, Rx, product line extensions), therapeutic area (CNS, GI, allergy, oral vaccine) or patient population (geriatric, paediatric, veterinary).
Zydis is a freeze-dried ODT with in-vivo dispersion times of typically less than five seconds. These characteristics and the unique manufacturing process provide the following
particular benefits:
- Ease of administration
- Potential for improved patient compliance
- Potential for pre-gastric absorption to provide faster onset and/or improved bioavailability
- Product protection and differentiation.
Ease of administration and compliance go hand-in-hand and are important factors in the effectiveness of any treatment. In one study (Schwarz Pharma 2004) of 679 adults, 40% indicated that they had experienced difficulty in taking their medication. As a result, 14% delayed taking doses, 8% skipped a dose and 4% discontinued use of their medication. In another study, 450 subjects aged 21 to 83 years were given either 40mg famotidine Zydis or 40mg famotidine conventional tablets. Up to 75% of subjects expressed a preference for taking the Zydis formulation compared with a conventional tablet. These studies, as well as refill persistence and compliance information for ODT products, demonstrate how ODTs can significantly improve patient compliance and contribute to effective therapy.
A comparison of the disintegration times of selected ODT products is given in table 1.
The Zydis rapid dispersion characteristics make it ideal for paediatric or elderly populations or for patients where the swallowing reflex is compromised, such as in Parkinson's patients. It also can lend itself to products where dose administration is known to be particularly problematic with human and animal patients and where non-compliance is consistently an issue.
The Zydis dose form has a range of clinical applications. The active ingredient can either be formulated to achieve bioequivalence to an existing dose form, or to target "pre-gastric" uptake.
On contact with saliva in the mouth, the Zydis structure disintegrates instantaneously. Products formulated to contain an insoluble form of the drug produce a fine dispersion in the saliva and are swallowed and absorbed in the normal way, typically resulting in products that are bioequivalent to conventional tablets.
For other applications an alternative clinical approach may be desired, for example, to avoid first pass metabolism. Pre-gastric absorption may improve the rate of onset, improve bioavailability or reduce unwanted side effects by minimising harmful metabolites.
For some active ingredients capable of being absorbed by a pre-gastric route, the use of an ODT can result in the active being absorbed more quickly and reproducibly compared with a standard oral dose form. In these cases, the speed of dispersion is critical, as the amount of drug retained in the oral cavity and available for oral mucosal absorption, rather than swallowed before dispersing, could make a difference to the pharmacokinetic profile.
A good example where this route of administration has been used to commercial and clinical advantage is the Zydis-based selegiline product, Zelepar. The 1.25mg Zydis product provides equivalent therapeutic plasma levels to the 10mg standard oral tablet, while resulting in a reduction in the levels of amphetamine metabolites3. Figure 2 shows the pharmacokinetic profile of selegiline Zydis 10mg and 1.25mg compared to the standard 10mg tablet.
The very fast dispersion times of Zydis formulations clearly distinguish them from alternative ODT products (see table 1). The technology has been granted hundreds of patents worldwide, and requires significant proprietary know-how in formulation development and manufacturing, which helps to provide product protection from generic competition and counterfeiting. Furthermore, Zydis ODT is highly customisable. It can be produced in a variety of colours and shapes, and can also be debossed with logos and product codes. In addition, patented packaging design encompasses a range of child resistant features.
The manufacturing process and intellectual property related to Zydis make ODT products incorporating the technology more difficult to counterfeit, providing additional product integrity protection.
The formulation in its basic form comprises the active pharmaceutical ingredient (API), a polymeric structure former (typically gelatin) to form a glassy amorphous structure that imparts strength and resilience, and a saccharide (typically mannitol) to provide crystallinity, strength and optimal mouth feel. Typically the API is dispersed (as a suspension or solution) in an aqueous solution of gelatin and mannitol.
The dispersion is then dispensed as unit doses into pre-formed blister packs, which travel through a liquid nitrogen filled tunnel to rapidly freeze the product. Once frozen, the product is dried in a lyophilizer, and the ice crystals within the product are sublimed to leave behind a highly porous tablet (Figure 3). This highly porous structure together with the rapid dissolution characteristics of the gelatin and mannitol are responsible for the rapid dispersion of the product.
In addition to the basic structure forming ingredients, other excipients may be included in the formulation, such as sweeteners and flavours. Other taste masking ingredients such as encapsulated API or ion-exchange resins may also be incorporated.
The pH of the formulation can be manipulated by use of pharmaceutically acceptable pH modifiers such as citric acid or sodium hydroxide. The pH of the formulation can be important for taste masking, to optimise product stability or to influence bioavailability. It is also possible to include permeation enhancers within the formulation to improve bioavailability if required.
The formulation during the aqueous phase of processing may be prone to microbial growth, but this can be eliminated either through control of pH or the temperature of the bulk dispersion during mixing and dosing. Once dried the water activity of the product is generally too low to support microbial growth.
For water insoluble APIs, dose strengths up to approximately 400mg per tablet can be achieved. For water soluble APIs, the upper dose strength is in the region of 60mg per tablet. Water soluble components within the formulation may form eutectic mixtures thereby depressing the freezing point and presenting challenges in freezing the product, or may lead to melting during the drying process. These events can be minimised by the addition of crystal forming materials to provide additional structural robustness.
The onset of melting of the frozen product, glass transition temperatures and moisture uptake of the product is determined during formulation development by use of Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA) and Dynamic Vapour Sorption (DVS) evaluation. These data help to determine appropriate freezing, drying and environmental conditions required during processing.
The process comprises four key phases:
Mixing: The initial stage of the process is to produce a homogenous dispersion of the API in an aqueous solution of gelatin and mannitol, to which other formulation ingredients are added as required. For this step of the process conventional pharmaceutical mixers are employed.
The majority of products are mixed at around room temperature (23°C though low temperature mixing (<10°C) may be employed if required, e.g. to ensure aqueous stability of the API, inhibit crystal conversions or eliminate microbial growth. On completion of mixing, the dispersion is transferred to an intermediate storage vessel (ISV), which is connected to the dosing system for the next stage in the process.
Forming, Filling & Freezing: Blister forming, filling and freezing take place as a continuous sequential process. Figure 4 shows a typical form, fill freeze line which was specifically designed for the Zydis process and comprises a blister forming machine coupled to the dosing system, which in turn is coupled to the liquid nitrogen freeze tunnel.
At the front end of the process a ribbon of packaging material is fed into the blister-forming machine, which creates the blister packs by traditional thermo form or cold form processes depending on the packaging material used. The sheets of formed blister packs pass under the dosing nozzles, which dispense an accurate single unit dose of the Zydis dispersion into the blister pockets. The dosing process is fully automatic and dose weights are accurate to +/- 2% of the target dose weight.
The dosing system utilises a bank of up to 40 individual dose pumps enabling a rapid and efficient dosing process. Each of the individual pumps is connected to a dosing manifold, which is fed bulk product from the ISV by a peristaltic pump. The bulk dispersion is continuously recycled from the ISV to the manifold and back, ensuring homogeneity of the mix.
The liquid dosing process ensures good dose uniformity and facilitates containment of the active ingredients. If required, low temperature processing minimizes manufacturing losses of labile products.
Once dosed, the sheets of blister packs are cut into trays, which travel into the freeze tunnel. The freezing temperature and residence time within the tunnel is optimised to achieve the desired structural characteristics important to the finished product, e.g. strength, physical stability and disintegration time. On exiting the freeze tunnel, product is stored frozen in refrigerated cabinets prior to drying.
Drying: the product is dried in large-scale freeze driers (Fig. 1) designed to enable rapid removal of large volumes of vapour while avoiding melting of the product. The drying cycle temperatures and time are optimised with respect to desired finished product characteristics and process efficiency. Typical lyophilisation cycles for the Zydis product are in the region of 6 hours.
Sealing: The sealing process takes place in an environmentally controlled area to ensure minimum moisture pick up prior to sealing. The blister trays are sealed using conventional heat-sealing equipment whose design has been modified to accommodate the blister trays. Once sealed, the individual blister packs are punched out.
The final dosage form is preferably packaged in an aluminium cold form blister that typically enables a shelf life beyond two years at room temperature and is easy to distribute and store.
ODTs will likely continue to be among the fastest volume growth rate oral dose form categories, due to patient self-administration ease, perceived medication adherence advantages, and the potential for improved drug clinical performance or safety pro-files through pre-gastric absorption.
One area of increasing interest for ODT is the delivery of biological products, most of which are delivered via injection today. Zydis is particularly advantaged for this, as lyophilization is already frequently used to produce stable formulations of proteins and peptides . Although there are many barriers to the oral delivery of proteins and peptides, such as instability in stomach acid or poor mucosal permeability, for certain biologics oral delivery using ODTs may contribute greatly to product success.
One example of an ODT-delivered biological molecule is ALK-Abello's Grazax, an oral allergy vaccine for grass pollen allergies using the Zydis technology to help replace traditional parental administration. Patents for delivery of vaccines using the Zydis technology have been granted in the EU and are pending in the US.