Cyclobenzaprine ER: partnering for success in lifecycle management

Patients’ unmet needs due to inconvenient dosing and significant side effects with existing therapies led to the collaboration to develop Amrix®, the first and only once-daily skeletal muscle relaxant available in the U.S.

“The development and commercialization of cyclobenzaprine ER is another successful example of the application of drug delivery technology to improving patients’ lives”
-Troy M. Harmon, MS, MBA, VP Business Development, Eurand Inc.

Muscle relaxants are commonly prescribed as an adjunct to rest and physical therapy for acute, painful musculoskeletal conditions. They are a unique group of drugs that have different mechanisms of action. These drugs do not act directly on the muscles; instead they act centrally, typically by blocking nerve impulses or pain sensations in the brain. Drugs available for prescription for muscle relaxation include anti-spasmolytics such as cyclobenzaprine (Flexeril®), carisoprodol (Soma®), and metaxolone (Skelaxin®), some of which have been on the market for many years. Cyclobenzapine remains a leading prescribed muscle relaxant in the U.S. and is available as a generic. An inherent problem, however, for these immediate-release formulations is that they are required to be dosed three to four times daily, a very inconvenient dosing regimen. Additionally, all of these drugs have significant sedation as a common side effect, which decreases their acceptability.

Extended Release Formulation
In an effort to address these issues, Eurand collaborated on a development program with ECR Pharmaceuticals to create a once-daily dosage form of cyclobenzaprine. It was envisioned that such a product would provide the efficacy of immediate-release cyclobenzaprine, but with a much more convenient once-daily dosing regimen, and perhaps with less of the limiting side-effects of the drug (drowsiness, dry mouth, and dizziness). Eurand developed a novel multiparticulate formulation of cyclobenzaprine, produced clinical materials, and ECR conducted two multi-center, randomized, double-blind, placebo-controlled Phase III studies with the product. Results of patient ratings on the product’s helpfulness in reducing muscle spasm are shown in Table 1.

The cyclobenzaprine ER product demonstrated statistically significant differences in patient’s rating of medication helpfulness versus placebo at day 4, and essentially equivalent helpfulness ratings versus the immediate-release reference product. Plasma levels achieved for the cyclobenzaprine ER product versus the immediate-release dosage form are shown in Figure 1. Cyclobenzaprine ER maintains a consistent plasma level over the 24-hour post-dosing period, without the peaks and troughs associated with t.i.d. administration of the immediate-release product.

In addition to the compliance advantage of once-daily administration, the cyclobenzaprine ER product demonstrated less daytime drowsiness than the immediate-release product dosed three times a day as shown in Table 2.

Technology in the Product
The technology used to develop cyclobenzaprine ER was Eurand’s Diffucaps® technology. Diffucaps is a technology for creating small layered particles with tailored drug-release properties. Customized drug-release profiles are created by first layering active drug onto a neutral core (such as cellulose spheres) followed by the application of one or more rate-controlling, functional membranes. As shown in Figure 2, these particles (also known as beads) can have an outer layer that must erode before drug release initiates. This enables the development of products with delayed release of drug. Following erosion of the outer layer, an inner, sustained-release polymer can further control a steady release of drug for a set time.

Eurand has developed formulation technology that combines the customized drug release offered by Diffucaps with technologies that enhance the solubility of insoluble drugs in the gastrointestinal tract. The drug layering process can be conducted either from aqueous or solvent-based drug solutions, which increases the flexibility of the technology to work with a wide variety of compounds.

Customized Release Diffucaps® Technology
Diffucaps beads are small, approximately 1 mm or less in diameter, and are filled into capsules to create the final dosage form. Beads of differing drug-release profiles can be easily combined in a single capsule. This gives a remarkable level of control to create complex release profiles. Diffucaps beads of different drugs can be combined to make convenient single-dose units for combination drug therapies as well. Thus, the Diffucaps system offers significant flexibility by enabling the combination of different types of release profiles into one dosage form. As a result, Eurand can combine sustained-release, pulsatile-release, and immediate-release profiles, depending on the specific needs of the product. In addition, different dose-proportional strengths of a product can be easily manufactured by filling capsules with varying amounts of the Diffucaps beads.

For the cyclobenzaprine ER product, Eurand custom formulated a bead by spraying a solution of cyclobenzaprine onto an intert core followed by the application of multiple polymer layers to achieve the desired release profile. Eurand developed two strengths of the product, 15 mg and 30 mg. The same bead is contained in both product strengths; the higher strength simply contains twice the number of beads as the lower strength.

Cyclobenzaprine ER – Commercialization of Amrix®
ECR’s NDA for the cyclobenzaprine ER product was approved by the FDA in 2007. However, instead of launching the product themselves, ECR sold rights to the product to Cephalon in August 2007. The tradename selected for the product was Amrix®, and Cephalon began promotion of the product in November 2007 (Figure 3).

Despite the limited time to promote and sell the product in 2007, Cephalon achieved $8.4 million in 2007 revenues (source: IMS Health). In 2008, Cephalon expanded the sales force promoting Amrix, and weekly prescriptions steadily increased as shown in Figure 4, with sales for the year reaching $73.6 million. Eurand is the exclusive supplier of cyclobenzaprine ER to Cephalon.

Amrix is the first and only once-daily skeletal muscle relaxant available in the US. With the approval and launch of Amrix, physicians have the option to prescribe a more convenient dosing regimen for patients. Patients now have a more convenient option for administration of the market-leading muscle relaxant cyclobenzaprine, and may also benefit from a lower incidence of somnolence that has been associated with the immediate-release formulation of the drug. The development and commercialization of cyclobenzaprine ER is another successful example of the application of drug delivery technology to improving patients’ lives.

“Despite the limited time to promote and sell Amrix® in 2007, Cephalon achieved $8.4 million in 2007 revenues”
-Source: IMS Health

Troy Harmon is currently Vice President, Business Development for Eurand. Mr. Harmon joined Eurand in 2002, and his responsibilities include business development, marketing, and licensing efforts for Eurand in North America. Prior to joining Eurand, Mr. Harmon was Director, Business Development at Delsys Pharmaceutical in Princeton, NJ, where he was responsible for marketing and partnering the company’s electrostatic powder deposition technologies worldwide. In addition, Mr. Harmon has served as Director, Business and Product Development at FEI Technologies, a company specializing in implantable drug delivery systems, and as Sr. Scientist at Summit Technology, an innovator in laser vision correction procedures. Mr. Harmon earned his BS from the University of Kentucky, where he was elected to Phi Beta Kappa and received the University’s first prize for undergraduate academic research. He earned his MS in Physical Chemistry from Cornell University and his MBA from Villanova University.

About Eurand (NASDAQ: EURX)
Eurand is a global specialty pharmaceutical company that develops, manufactures and commercializes enhanced pharmaceutical and biopharmaceutical products based on its proprietary drug formulation technologies. Eurand has had five partnered products approved by the FDA since 2001 and has a pipeline of product candidates in development for itself and collaboration partners.

Eurand has a strong track record of developing products using its innovative drug formulation technologies. With integrated manufacturing and R&D facilities in the U.S. and Europe, the Company has four primary technology platforms:

• Customized Drug Release
• Bioavailability Enhancement
• Taste Masking / Orally Disintegrating Tablets (ODTs)
• Drug Conjugation

These platforms include nine distinct technologies and are covered by more than 300 patents. Eurand uses these technologies to develop and expand the Company’s own internal pipeline and to partner with pharmaceutical and biopharmaceutical companies to develop their products. For more information, feel free to visit our website at www.eurand.com.