Finding the Right Formula
Like other sectors of the drug discovery and development process, drug formulation and drug delivery research has been challenged with finding effective and economical routes to bringing a drug to its target. In a recent survey, Drug Discovery & Development asked contract research organizations (CROs) to identify trends in drug formulation and drug delivery. The responding CROs provide a range of services that meet the changing scientific and business needs of the market.
The looming “patent cliff” and tough economic conditions have changed the way drug companies approach research. Peter Thornton, senior vice president, head of product, technology and business development, Elan Drug Technologies, Dublin, Ireland, reports that more than two-thirds of products approved by the U.S. Food and Drug Administration (FDA) are for optimized or reformulated products.
Investors are less willing to gamble on drugs in discovery or preclinical phases, instead seeking compounds that are closer to clinical trials. Those companies that can generate early formulation data on molecules not only speed their research, but can improve the attractiveness of their offerings to potential investors.
The ability to provide integrated services to customers is becoming critical for management of timelines, according to WuXi AppTec Co., Ltd, Shanghai, China, which specializes in solid, oral dosage forms. The ability to generate critical preformulation data on drug molecules at an early stage enables decisions on the further development of drug candidates.
Technology has aided drug research in discovery, preclinical, and development phases, the respondents say. Thanks to advances in formulation techniques and new analytical methods, drugs that previously were difficult to formulate are now being taken into development, according to Charles River, Wilmington, Mass. The company offers formulation discovery and development activities for a range of dosage forms including preformulation investigations and screening, formulation development and validations, stability assessments, compatibility studies, and analytical chemistry services.
Generic and offshore competition, lower research productivity, and trimmed R&D budgets have provided sufficient incentive for drug and biotech companies to seek alternative routes for research efforts. Outsourcing can not only reduce fixed costs, but also buy expertise that may not be available internally.
“Increasing generic competition, declining R&D productivity, and rising drug development costs have pharmaceutical companies turning to CRO partners more now than in the past,“ says Linda M. Batykefer, marketing manager, ChemImage Corporation, Pittsburgh, Pa. “As the FDA pushes for quality by design (QbD) and process analytical technology, CRO companies will prove to be a valuable resource to pharmaceutical companies, guiding the creation of innovative solutions that satisfy these regulatory initiatives.”
Besides business decisions, scientific strategies play a vital role, not only in deciding to use a CRO, but selecting the best CRO for the task. The charts on pages 31-38 provide a snapshot of the services offered by the CROs that responded to the survey. Additional services can be found on www.dddmag.com.
The “fail early” theme holds true for drug formulation as researchers look to eliminate ineffective or unsafe compounds as soon as possible. Strategies include starting formulation studies earlier and re-examining dosing.
“There appears to be a push in pre-clinical testing to raise the amounts of drug dosed,” says David Barnes, CEO, Velesco Pharmaceutical Services, Plymouth, Mich. “More questions are being asked as to why the ‘maximum feasible dose’ cannot be raised. Velesco has invested considerable time and effort to develop better formulation systems for drugs in pre-clinical testing in order to help clients avoid such challenges from the regulatory authorities and to provide strong scientific evidence to support any ‘maximum feasible dose’ argument.” The company is developing a niche specialization in formulating benign, high drug loading products for use in pre-clinical studies.
Solubility was cited as a key scientific challenge as drug candidates become more and more insoluble.
“A large fraction of APIs under development are water insoluble or sparingly soluble. This is no longer as formidable a challenge as it used to be,” says Robert Lee, PhD, vice president, pharmaceutical development, Particle Sciences, Inc. (PSI), Bethlehem, Pa. “However, if the low solubility is coupled with hydrolytic or enzymatic lability, it can be very challenging to develop viable formulations. Additionally, if an API is highly potent and requires targeting, these constraints exacerbate the problem. Fortunately, these issues also represent opportunities for those able to overcome these hurdles.” PSI specializes in nano-based and rational solubility systems design approaches to formulation, with experience in topical and mucosal product development.
The Biological Test Center in Irvine, Calif., which focuses on drug dosage formulations, reports that due to the insolubility of certain compounds, nanotechnology is moving to the forefront. For both commercial and experimental ophthalmic compounds, the company has seen an increase in testing of implantable drug coated or controlled-release delivery devices.
“The days when a simple salt of a molecule would provide all of the solubility and stability required appear to be behind us,” says Velasco’s Barnes. “This actually provides a great opportunity for formulators to save an otherwise good drug molecule from oblivion. There is also the added benefit of patent life extension to be gained by companies who invest in formulating these challenging compounds.”
No surprise, safety is a top concern. “The focus seems to be on new drug delivery methods that have fewer side effects and make administration to the patient easier,” says Batykefer. “Researchers are now looking at local or systemic delivery methods such as nasal, inhalation, and transdermal as alternatives to more traditional ones. As these administration routes present new challenges in drug design, development, and characterization, we will likely see many advancements made in this area.”
Companies also are looking at formulation as a way to alter toxicology profiles, change bioavailability, or deliver drugs to particular sites, according to Charles River. Time release formulations, depot formulations, formulations that are used with special devices to administer the drug, and use of nanoparticles to change the distribution of drugs in cells and tissues are becoming more and more complex.
“Drivers of the drug delivery market include customized oral drug delivery, depot injectable delivery, localized delivery of certain therapeutic agents or methods in which patient compliance is improved resulting in reduced health care costs,” says Elan Drug Technologies’ Thornton. In 40 years in the drug delivery business, the company has brought 36 client drugs to market, offering bioavailability enhancement technologies and customized oral drug technologies.
Some challenges appear in the formulation stage. BioConvergence LLC, Bloomington, Ind. notes molecules in the development pipeline are becoming more sensitive to the stresses of formulation and storage conditions, especially as the presence of biotech molecules increases. Company scientists have worked on both small and large molecules, sterile injectable formulations, lyophilized products, oral and topical formulations, and potent and cytotoxic products.
Stason Pharmaceuticals, Irvine, Calif., focuses on products requiring high containment manufacturing, cytotoxic products as well as products that are difficult to manufacture.
A key trend, according to the company, is that the FDA has increased its scrutiny of the active pharmaceutical ingredients (API) particle size and their impact on the finished product solubility and has mandated testing for residual solvents in finished products. Statson offerings include solubility and stability evaluations, prototype development, comprehensive screening of raw materials and excipients, formulation optimization, and finalization.
With the ongoing shift toward proteins and large molecules, MPI Research, Inc., Mattawan, Mich., has increased its expertise, says Alan Breau, PhD Vice President Bioanalytical/Analytical. “In order to respond to this trend MPI has added PhD-level protein chemists to its formulations staff. We recognize the unique formulation and handling challenges required in the preparation of protein versus small molecule dose formulations.” The company develops and validates methodologies for small and large molecules in a wide variety of biomatrices.
Whether in partnership or on a contractual basis with a drug formulation company, drug companies seek both lab assistance and also expertise in new research arenas.