9 minute read
COVER STORY
TAKING ORALLY DISPERSIBLE DOSAGES TO THE NEXT LEVEL In November 2019, it was heartening to read a New York Times article 1 about the eff orts of Cipla, an Indian drug manufacturer, to potentially save the lives of children living mostly in Africa. The simple switch of a combination HIV medication ritonavir–lopinavir–abacavir–lamivudine (Quadrimune) dosage into a strawberry-fl avored, sprinklestyle form palatable for babies and toddlers, signifi cantly improved compliance versus traditional tablets or an unpleasantly bitter syrup.
Over the last 20 years, formulations with a pleasant patient experience have grown into a signifi cant portion of marketed medicines. Adhering to the regimen is as important a factor as the effi cacy of a given medication. Development of patient-centric dosage forms addresses the psychological hurdle in the adherence portion of the effi cacy equation. Developing a positive consumption experience for the patient includes characteristics such as taste, mouthfeel, tablet robustness, shape, size and presentation. Such properties are critical for patient-centric or more aptly, patient-preferred platforms which encourage drug regimen adherence and reduce missed dosages of less desirable forms. A formulator must be mindful of these properties when designing an Orally Dispersible Dosage form (ODD). Other practical considerations for manufacturing need to be considered; for example, formula stability, compressibility, friability, fl ow and blending.
SPI Pharma, along with academia and industry, have taken the approach of looking at this adherence challenge from the patient’s perspective to better understand the psychological obstacles and provide meaningful solutions in the ODD segment.
PRODUCTS The increasing demand for patient-preferred forms such as ODTs has led formulators to focus on specially designed excipients, such as co-processed platforms that allow drugs to be formulated quickly, often with only the addition of a lubricant and fl avours/sweeteners. SPI Pharma was a pioneer in this area with the introduction of Pharmaburst 500, a product which enables high drug loading in an ODT while retaining fast disintegration. Compendial excipients such as mannitol can also be tailored for these uses. Mannitol has long been associated with ODDs due to its desirable sweetness, smooth texture, cooling sensation, and inertness. SPI Pharma’s Precious Gems Collection of mannitol allows signifi cantly increased compressibility whilst still retaining its compendial status, pleasing palatability and fast disintegration. The high compressibility of such excipients is critical for direct compression processing, especially when a formula contains a signifi cant portion of a poorly compressible drug. Furthermore, some drugs such as taste-masked versions or multi-particulate systems (MUPS) can cause segregation during processing due to higher particle size and/or density properties. SPI Pharma has addressed this with Mannogem XL Ruby, developing a high compressibility granular mannitol grade with similarly matched properties to overcome such issues. PHYSIOLOGICAL SIMULATION Traditionally, oral disintegration testing has been measured by the USP Disintegration Test. However, this rather one-dimensional test has little in common with the actual physiological conditions that occur in the mouth after an ODT is administered. There are various methods designed to better simulate such conditions. An example can be found in our recent work with the University of London which outlined a simulated mechanical tongue and oral cavity. The authors concluded that this “model could have the potential to be implemented as a decisionsupport tool during the early stages of the drug design process to improve acceptability and further understand ODT disintegration behavior” 2 .
SPI Pharma explores the advancements that are helping make drug dosage forms more patient-centric.
Schematic of oral cavity model (OCM) (side view/sagittal plane). On the left is the initial position and on the right is full compression. This image is adapted from the original image included in citation.
TASTE-MASKING One of the main challenges for any formulation of ODTs is masking unpleasant drug taste. There exist a range of techniques to achieve this. Traditionally, these have consisted of applying barriers or WAYNE CAMARCO Global Head of Technical Development Wayne Camarco joined SPI Pharma in 2019 as Global Head of Technical Development. Wayne brings broad-based excipient and API experience in the areas of formulation development and technical service. He has worked in a variety of technical, sales and business development roles at ACG Capsules, Juniper Pharma (Catalent UK), Ashland Specialty Ingredients in US and Rhodia in US & France. second disintegration.
pH-sensitive polymer coatings to drug particles or complexing the drug with other materials. However, these techniques tend to add signifi cant bulk and increase mean particle size which limits the drug loading per dosage and can cause content uniformity issues. To improve this situation, we have developed an innovative aqueous coacervation technique that can add a minimal coating loading (<10%) while retaining good taste-masking properties. This Actimask technology has been applied successfully to acetaminophen and ibuprofen for eff ective taste-masking with minimal (approx. 8%) coating load.
STICKPACKS Stickpacks are gaining popularity in nutraceutical and pharmaceutical applications, partly for patient convenience, but they also enable formulators to utilise higher and more fl exible drug dosages than ODTs. To be eff ective, such formulas need good fl owability to both fi ll the package and subsequently pour- delivering a pleasant patient experience. Products such as Pharmasperse 416 - a granulated, preformulated fl owable platform - can simplify development of these formulations. Flowable formulations can also fi nd utility in larger sachet type packs or in applications where the fi nished formula may be sprinkled onto a foodstuff . This can increase palatability, especially in the case of bitter-tasting drugs, and allow easier administration to children or the elderly.
DRUG DELIVERY ODD formulas theoretically off er faster drug delivery by eliminating the stomach disintegration lag of traditional swallowed tablets. Depending on the drug properties, this can also open drug delivery via the oral cavity as an option with advantages such as fast drug uptake and potentially longer retention within the body (by avoiding hepatic fi rst pass (1)NY Times ref: https://www.
metabolism).
FUTURE As patient awareness of available dosage options and changing regulatory emphasis grow, the demand for more patient-centric formats will intensify. The FDA has emphasised a shift away from syrups/suspensions due to concerns that include dosing accuracy, portability and the Paediatric Investigation Plan requirement for new drug applications, all of which are driving manufacturers to consider all available solutions. With our long history of developing innovative patientcentric solutions, SPI Pharma has developed expertise in this area. Currently we are working on a directly compressible, sublingual platform with sub 10
The collective goal in pharmaceuticals is to make sick people well - requiring the right medicine be delivered in the right quantity throughout the prescribed timeframe. By building on current and future technology advances, we can improve the patient experience and make a diff erence in patients’ lives.
REFERENCES nytimes.com/2019/11/29/health/ AIDS-drugs-children.html (2) University of London ref: Desai, N; Redfearn, A; MacLeod, G; Tuleu, C; Hanson, B; Orlu, M; (2020) How Do Orodispersible Tablets Behave in an In Vitro Oral Cavity Model: A Pilot Study. Pharmaceutics, 12 (7), Article 651. 10.3390/pharmaceutics 12070651.
Author’s Bio:
stability of liquids, as well as GRAEME MACLEOD Global Head of Research and Development Graeme is a pharmacist and attained his PhD in Pharmaceutical Technology from the University of Manchester, England. His 25 years of industrial experience were gained in a number of positions within Industry in the fi elds of formulation development and drug delivery and Senior Technical Positions within Pharmaceutical Solid Form equipment and excipient companies. Graeme joined SPI Pharma in June 2017. His areas of experience include oral dose form technologies and processes, novel soft capsule technologies, and drug formulation.
EPM speaks to Acino to learn about the world of contract manufacturing.
Quick questions with Yuliyana Manolova, business development manager, Contract Manufacturing, Acino.
Choosing the right partner to manufacture your product is key for customers. What would you say is the most important attribute?
It has to be a combination of attributes. Many contract manufacturing organisations (CMOs) have the technical capabilities to manufacture a product, but this alone is not enough. There are many other factors which defi ne how well the transfer will go and whether the parties can work smoothly together.
I once attended a manufacturing conference that was very technical, and the hosts had prepared a live poll asking which factor represented the greatest risk in new partnerships. There were over 200 people present in the room and the answer with the highest number of votes was “Cultural and organisational fi t”. People are the driving force behind every successful project or company, and just as important are the technical capabilities and the technical know-how. Without solid expertise, scientifi c knowledge, a solid understanding of your customer’s needs and equally high-quality standards, it can be diffi cult to achieve great results.
What changes have occurred for Acino Contract Manufacturing over the last six to 12 months?
The last 12 months have been very dynamic for Acino Contract Manufacturing. In addition to the transfer activities at our Swiss and Estonian plants, we also implemented a new marketing and sales strategy, as it is important to fi nd new ways of introducing our high-quality services to potential customers. Again, producing high-quality products in state-of-the-art facilities is not enough; we have to ensure people are aware of what we can off er. Our eff orts paid off and we received great feedback: so we know that we are on the right track.
Covid-19 has enforced a diff erent way of working with customers. How has Acino responded to this change?
We are lucky to be living in a digitalised world that allows us to continue working with our clients during the pandemic. From a CMO perspective, I would not say that there is a new way of working with customers, but rather that there were some temporary challenges we needed to address. There were active pharmaceutical ingredient (API) and excipient delivery delays, and sometimes-revised ordered quantities which had to be clearly communicated. There were also delays in launches due to the market uncertainty. We remained fl exible and supported our clients during these diffi cult times. The experience allowed us to strengthen our partnerships and to gain trust as a reliable company.
What new solutions are Acino off ering that perhaps incorporates a digital solution?
As a result of the pandemic we could not schedule face-to-face meetings with our clients and organise site tours. This was a big challenge for us as we have a lot of projects in the pipeline. External visitors are still not allowed in our facilities for safety reasons and we had to fi nd a way to help new partners visualise where their products could be produced. We introduced LIVE 360 degrees sessions with excellent
audio connection that allow the participants to have full visibility in our facilities and interact freely with our colleagues in the production sites. As a result of this successful implementation we also used the technology to conduct our fi rst virtual on-site audit. It was conducted by one of our biggest customers and we successfully passed it. Exciting success story.
What is the roadmap for the next 12 months for Acino Contract Manufacturing and its customers?
There are a lot of new transfer projects we have recently started, and we are hiring new colleagues in the Quality Assurance, Quality Control, and Manufacturing, Science and Technology teams to support these activities. We are investing in technology and capacity increase and have started a project to assess the upgrade of our Liesberg bulk manufacturing plant to handle high potency products. It is an exciting time to be part of Acino and our management is leading us through remarkable growth despite the diffi cult Covid-19 context.
