New Routes in Dosing

Among new options, Catalent adds controlled-release and quick-dissolve formats.
Controlled-release and fast-dissolve technologies have expanded the possibilities of solid-dose delivery. Orally disintegrating tablets (ODT) have experienced significant market growth as they promote patient compliance and differentiation in life-cycle management.
 
With controlled release tablet technology—where dosing may be sustained at timed intervals or delayed for specific points in the body—and with advanced ODT formulations, drugs can be configured for improved clinical performance.
Fast-dissolve formulations are a growing segment, with drugs commercialized in pain, cough/cold, allergy, and gastro-tract ailment treatments.
 
Zydis Fast-Dissolve ODT technology from Catalent Pharma Solutions (www.
catalent.com) has a track record in products including Claritin RediTabs (loratadine), Zyprexa Zydis (olanxzapine), and Zofran Zydis wafers (ondansetron).
 
Catalent has expanded capabilities in ODT and in compressed tablet technology this year.
The company acquired from Pantec AG (Switzerland) exclusive worldwide development rights to the Lyopan fast-dissolve technology for healthcare products. For manufacturing of compressed controlled-release tablets, Catalent has an exclusive agreement with Sanwa Kagaku Kenkyusho Co. to develop, manufacture, and market Sanwa’s OSDrC Optidose delivery technology in all markets outside of Japan, Korea, China, and Taiwan. OSDrC Optidose rotary tableting machines use a unique variable double-punch technology that places active ingredient cores in virtually any variety of sizes, shapes, and positions within a tablet.
 
As with Zydis, the Lyopan technology employs a continuous sequential form-fill-freeze process in which doses deposited in blisters are lyophilized. The resulting highly porous tablets allow for rapid water or saliva penetration and disintegration.
 
“Zydis fast-dissolve is the recognized leader in palatability and rapid dispersion, which may be as little as 3 seconds. [These properties have supported] patient adherence and create the strong patient preference that has led to continuing market success for prescription and OTC Zydis products,” says Susan Barker, director, market development and innovation.
“By comparison, orally disintegrating tablets produced by direct compression may have dispersion times of up to 30 seconds and even longer,” Barker says.
“Of course, the actual dispersion time depends on the drug and the formulation, but we expect Lyopan technology to produce dispersion times comparable to Zydis,” she adds.
Lyopan’s formulation and first processing step differs from Zydis’s. The different technology has the potential to offer improved treatments over a wider range of drugs. The Zydis process uses a liquid suspension or solution dosed into a blister that is then cryogenically frozen and lyophilized.
 
“Lyopan technology utilizes dry powder dosing, followed by the addition of liquid to bind the dose form prior to freezing. After this the downstream processes are very similar to the Zydis process,” Barker explains.
“For Zydis products, the fast dispersion time relies on the fast-melt properties of the matrix formers, usually gelatin and mannitol, along with its highly porous structure due to the freeze-drying process.
 
“The Lyopan formulations are based on a powder blend comprised of the API, highly soluble sugars, and superdisintegrants. These components are dosed into the blister pocket and subsequently wetted with an aqueous solution containing binding and wetting agents. The fast-disintegration properties of Lyopan are therefore achieved through the use of highly soluble sugars, superdisintegrants, and the porous structure imparted by the freeze-drying process, Barker says.
 
“Lyopan offers additional options for taste masking and the ability to formulate higher doses of drug in a lyophilized dose form. For over-the-counter products in particular, Lyopan technology will allow our clients to offer a larger number of products as lyophilized fast-dissolve. For example, we anticipate that a fast-dissolve APAP (acetaminophen) or ibuprofen might be possible using Lyopan technology,” Barker says
Because it utilizes dry dosing, Lyopan enables coating of the API. “This means we can provide modified release capability. For example, enteric coating to help our clients deliver better treatments for their patients,” she says.
 
Lyophilized ODTs are also promising for delivery of certain biologicals. Zydis fast dissolve is used in ALK-Abello’s Grazax, a purified grass pollen vaccine for treatment of allergic rhinitis.
“Zydis has proven compatibility with proteins and peptides resulting in room-temperature stable products. The Lyopan technology can be considered complementary to Zydis in the area of proteins and peptides. It may be particularly useful for more labile molecules, since the contact time with aqueous media is reduced from hours with Zydis technology to minutes with Lyopan technology,” Barker says.
 
Catalent is installing a Lyopan production line at its Swindon, UK, facility for GMP manufacturing in about 12 to 18 months. The equipment comprises standard blister forming/sealing capability with proven powder dosing technology that has been configured and optimized for the Lyopan process.
 
 “The Lyopan technology is based on a patented process developed by Pantec an affiliate of Rohrer AG, the equipment manufacturer, so the process was developed with manufacturability in mind,” Barker says.
 
ONE-STEP DRY TABLETING
OSDrC Optidose is a fully developed one-step manufacturing process commercially proven by Sanwa in Japan for a cardio drug. Catalent is currently installing a rotary tableting machine with 54 double punches at its Winchester, KY, plant for producing OSDrC Optidose tablets. Customer product development trials will commence in January 2012, says Steve Hamlen, group product manager, modified release technologies, Catalent.
 
The one-step process eliminates the need to separately manufacture API cores. In a dual-punch structure, center and outer punches in the upper and lower punches compress the powder independently. The punch processes encases the API core or cores between the bottom and side and top layers. Punches can be switched out for changing the number, shape, and alignment of cores, and to alter the thickness of the coating.
 
“OSDrC Optidose technology can produce pulsatile tablets, bi-layer tablets, multi-core tablets, dividable tablets, delayed release tablets and direct compression orally dissolving tablets with better quality and release control design than standard tableting technology,” Hamlen says.
 
Using OSDrC Optidose, agents with poor compressibility that normally require capsules can be rendered as tablets. The hard-to-compress powders are formed into cores encased in the tablet’s powder coating. 
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