Challenges in drug development and delivery

John Fraher of Eurand and Gerd Paulus of Swiss BioAnalytics talk to NGP about common problems in developing successful pharmaceutical products.

“Line extensions that hinge on new or unique formulations are a key component of lifecycle management”
-John Fraher, Eurand

Why does drug insolubility poses significant challenges during drug development? What can companies do to counteract this?
John Fraher. In order for a drug to be an effective oral treatment, it must be able to dissolve and be absorbed by the bloodstream. Permeable yet poorly soluble class II compounds can present challenges such as lack of or reduced levels of absorption or slow solubilisation kinetics which cause a delay in a drug’s onset of action and reduced bioavailability. It may be possible to compensate for low solubility by elevating drug dosage to increase the absorption amount without leading to safety concerns but in many cases the drug must be developed in an injectible dosage form.

Eurand’s proven Biorise technology addresses poor solubility through a novel proprietary process. Biorise breaks down a crystalline drug into nanocrystal and/or amorphous (noncrystalline) form of the drug that is then stabilised in a carrier system to maintain the drug in its activated state. This approach creates a greater surface area to volume ratio that increases the intrinsic solubility and dissolution rate of poorly water-soluble drugs, thereby enhancing the rate and extent of absorption.

Gerd Paulus. Insolubility poses problems in formulation development, and in dissolution and release testing. Insoluble drugs cannot be developed as parenteral drugs. Furthermore the absolute bioavailability will be low leading to high dosages and therefore higher cost of goods.

Companies can try to enhance the solubility by following three major routes. First developments in the formulation can focus on an enhancement of the resorption by using vehicles as PEG400 or using excipients influencing the permeability like ethoxylated fatty acid derivatives, such as Gelucir. A very specific approach is the development of liquid dispersions. Secondly modification of the API could be considered such as the change of the counter ion or the usage of a polymorphism. For the latter example the future release specifications have to be kept in mind. Finally the development of a soluble pro-drug would be an option. 

The effectiveness of a pharmaceutical product can be adversely impacted by patient non-compliance. How common is this problem? What can be done to help alleviate it?
GP. It is a common problem that depends on the severity of the illness, the progression of the disease, the dosage form, the subjective impression of the patient and the doctor-patient relationship. An obvious example is the non-compliance in the antibiotics treatment – taking the drug less than the prescribed seven days. Due to this non-compliance a high rate of resistant bacterial tribes has emerged. Another experience from the past can be found in the area of oral contraceptives, the anti-baby pill, whereby including placebo tablets to achieve a daily regimen decreased the rate of this non-compliance.

By changing the dosage form or formulation, compliance can be enhanced, such as by changing from three times a day formulation to a once daily modified release formulation.

JF. Patient compliance is fundamental to the successful medical management of the vast majority of diagnosed disorders. It is estimated that 40 percent of patients are considered as non-compliant. Three key drivers of patient non-adherence are poor taste, difficulty in administration or swallowing, and the inconvenience of multiple doses per day. The extent of the problems can be reduced through the application of sophisticated technologies. Eurand has a range of technologies within its platforms that can be used to address all three issues.

Poor taste and difficulty in administration and swallowing can be addressed through the application of AdvaTab and Microcaps technologies. AdvaTab is an advanced orally disintegrating tablet technology that enables rapid disintegration in the mouth without water. Microcaps is a versatile and precise microencapsulation technique that coats individual drug particles with a polymeric membrane that provides an immediate or customised release profile with complete taste and odor masking. Used together, AdvaTab and Microcaps create a convenient, patient-friendly orally disintegrating tablet with effective taste masking and a pleasant mouth-feel. 

Multiple dosing per day can often be dealt with through the development of once-a-day dosage forms. Eurand’s customised release platform contains a number of technologies that can provide for the development of customised release multi-particulate or monolithic (tablet) once-a-day dosage forms.

What techniques or tools can pharmaceutical companies use to turn drug candidates into easy to administer, successful pharmaceutical products?
JF. The oral route of administration for drugs remains the most popular delivery vehicle for patients. Techniques aimed at convenient oral dosing and administration, when applied to prescription and over-the-counter (OTC) drug candidates, can produce effective products.

Eurand continues to develop a portfolio of successfully commercialised products with its partners due in large to the breadth and depth of its technology platforms. Our successes include partnering with Cephalon to develop Amrix (Cyclobenzaprine Hydrochloride Extended-Release Capsules) the first and only once-a-day muscle relaxer, partnering with Chattem to commercialise UNISOM SleepMelts, and our most recent success – the FDA approval of orally disintegrating tablets, Lamictal ODT (lamotrigine), soon to be launched by GlaxoSmithKline.

GP. The development of an easy to administer dosage form, such as tablets or capsules, should be the main goal. To avoid surprises the strict follow up and implementation of ‘developability’ concepts from early development should be considered. For example the physico-chemical parameters of a drug candidate should determine the decision for further development – there could be a caveat to develop a BCS class four compound.

What is the best way to promote innovative and effective life cycle management that can prolong the market life of products?
GP. Among multiple options three should be highlighted here, the label extension, a patient centric approach and a strong brand. Marketed drugs can be explored in neighboring indication fields. This strategy can be observed in the field of oncology. Generally only efficacy studies are needed, as all safety data are available.

An example for a strong brand name is Aspirin. Despite heavy competition from generic products sales figures continue to be high. This situation has been supported by following the patient centric approach by the introduction of new comfortable formulations, such as granulates, and the creation of combination products.

JF. An interesting industry trend that is developing is the pursuit of the life cycle management strategies at large pharmaceutical companies, an area once inhabited only by the likes of specialty pharmaceutical companies. Line extensions that hinge on new or unique formulations are a key component of life cycle management. Incorporating custom release profiles, improved solubility or advanced taste-masking techniques within a portfolio of existing drug candidates may optimise market share for our pharmaceutical partners, or create an opportunity to expand into emerging geographies.

Innovative and effective life cycle management strategies need to include core elements such as identifying new clinical indications or creating line extensions that incorporate drug delivery technologies, with the goal of creating additional clinical benefits for current drug candidates or addressing patient groups that are currently not addressed by present therapeutic treatments. Additionally, enhancing the intellectual property around the molecule to defend against generic entry is a key element of lifecycle management.  New formulation patents as well as technology patents may serve to maintain a drug’s share in the marketplace.

John Fraher has been Chief Commercial Officer of Eurand since August 2006, President of Eurand Incorporated since April 1999, and was Vice President of Eurand Incorporated from 1995 to April 1999.  Previously, Fraher was Production Manager at American Home Products Corporation’s affiliate, Fort Dodge Laboratories, located in Ireland, and has worked at Sterling Drug in Ireland.

In June 2005, Gerd Paulus was appointed General Manager of Swiss BioAnalytics AG.
He has worked for pharmaceutical companies in quality control at Bristol Myers and R&D at Ciba-Geigy. As the holder of executive positions in business units and country organisations, Paulus gained in-depth expertise of the general management, as well as experience in the global pharmaceutical industry.