EXECUTIVE INTERVIEW - EMD Millipore: Enhancing the Bioavailability of Active Pharmaceutical Ingredients

Bioavailability – or ensuring that the right amount of drug gets to the right place in the body at the right time – has increasingly become a key factor to a therapeutic’s success. Nearly 40% of drug candidates fail in clinical trials due to poor bioavailability properties, representing a significant loss of time and resources invested in drug development. Avoiding these failures can help control skyrocketing drug development costs and accelerate the development process, as well as boost pipeline productivity, secure return on investment, and enable more effective life-cycle management. EMD Millipore offers a comprehensive portfolio of products and technologies for enhancing drug bioavailability, including solutions for solubility enhancement, optimized release, and targeted drug delivery. Drug Development & Delivery recently interviewed Steffen Denzinger, Head of Portfolio Development at EMD Millipore, to discuss bioavailability challenges and how EMD Millipore’s formulation portfolio and expertise are helping the pharmaceutical industry achieve maximum efficacy with active pharmaceutical ingredients.

Q: To what extent has bioavailability become more of a challenge for the pharmaceutical industry? Why?

A: A basic definition of bioavailability is that the drug gets to the right place in the body at the right time. In the current, collective pharmaceutical pipeline, 90% of all new active pharmaceutical ingredients are either in BCS class II or IV, which means they are either poorly soluble or poorly soluble and have a bad permeability. As such, the initial challenge is to get enough of the drug substrate into solution, get the PK/PD profile, and target the active in the most suitable way, all in a formulation that ensures ease of use
and patient compliance.

Q: What are the most common causes of bioavailability problems that you have experienced? Has this evolved over the years?

A: Solubility of the API has become more and more of a challenge. In today’s marketed drugs, about 40% of the actives are either BCS class II or IV. Establishing the correct PK/PD profile is more of a challenge today. Furthermore, many drugs have high efficacy but are not very targeted, a classical example being the chemotherapeutic agent cisplatin. Due to its toxicity to healthy cells, dosage and therapy cycles are difficult to adopt to give the best treatment to the patient. If such actives can be targeted in a way that only tumor cells are attacked, major advantages for therapy will be seen. Similarly, the structure of large biological molecules requires adopted strategies to address the same issues as described.

Q: What is your process when a customer comes to EMD Millipore with a bioavailability challenge?

A: First, we need to know as much as possible about the properties of the active related to the bioavailability issue. This can be a challenge as customers may be quite reluctant to disclose the molecular structure – but information about BCS class, solubility, and molecular weight will most definitely be needed as well as information about the intended target. A tablet will need different strategies than an intravenous injection, different again from a nasal delivery or a transdermal patch. There is never a one-size-fits-all approach. Depending on the challenge, the solution can be quite straightforward, such as trying either a specific counter ion in salt screening or use of a carrier system, or an inclusion compound to enhance the solubility. But very often the problem is not straightforward as it may include more issues than just solubility. For example, after the solubility is addressed, stability issues can occur, so this may mean trying several options to find the most suitable. The key to quick success is most definitely information exchange. The more the customer and EMD Millipore work together as partners the better. The advantage of a real partner is to not offer only one technology based on either a strength in a specific chemistry or a specific physical modification method. Rather, the range of options should be as broad as possible in order to find the optimal solution. For this, we have developed roughly 15 to 20 different technologies to address various bioavailability challenges.

Q: With 400 products, how do you quickly assess what is the correct path?

A: We offer ~400 different chemicals and 15 to 20 different technologies ranging from counter ions for salt screening or activated PEGs for conjugation of proteins. We also offer drug carriers, inclusion compounds, specific lipids for liposomal delivery, and specific highly functional binders that allow economic production of dosage forms using some physical measure like micronization or nanomilling. The time required to make an initial recommendation will strongly depend on the complexity of the issues the active is facing. The recommendation may come very quickly, or we may have to go to the lab and try different approaches, such as loading of new drug carrier systems, which will take somewhat longer.

Q: What is the business model? Does EMD Millipore develop formulations to address bioavailability challenges or do you provide counsel only to the customer?

A: We provide counsel to our customers and applications services all the way through to developing the formulation. The need depends very much on the problem our customer is facing. For our new drug carrier systems, a crucial step is the loading of the API, so we offer development of the best loading procedure for our customers so that they can get the biggest benefit for this innovative solution.