It is sometimes amazing what people do to get insoluble drugs into laboratory animals. While a slightly crazy formulation may be the best option for early animal studies, if you get married to it, the divorce could get messy.

We formulators like to gripe about not getting enough attention. In a previous newsletter article we have made the case for re-formulating oral solids before getting too far down the development path. This article focuses on delivery-challenged drugs, especially poorly soluble molecules, and some of the traps we have seen people fall into.

There are many ways to get a poorly soluble drug into an animal. A whole range of surfactants and other solubilizers can be used, and if administered via a central vein, surprisingly high levels of solvents can be tolerated. The problem occurs when the development team with limited formulation expertise and funding is lured into a false sense of security by a formulation that is more ideal for laboratory animals than for development. While we have done a good business in emergency re-formulations, we would rather help our clients do it right the first time. Here are some of the common traps:

Using the Wrong Excipients.

The FDA approves drug products, not excipients, so any excipient that can be shown to be safe in the drug product is theoretically acceptable. The reality, however, is that using an excipient that has not previously been used at that level for that route of administration carries a huge risk of adverse events and increased regulatory scrutiny. Unless there is a proven need to use a non-approved excipient, doing so will almost always lead to costly re-formulation and repetition of toxicology and/or clinical studies downstream.

Using Too Many Excipients.

I have often seen formulators throw an excipient into a formulation because they think it might help or because it was in another formulation. This is not altogether a bad idea for early stage development, as it is easier to take something out than to add something in downstream. However, each excipient will need to be purchased, received, and tested as well as being justified in the development history report. The risk of interaction and batch failures due to excipient variability increases as more are used. It may not hurt to go into Phase 1 with a complicated formulation, but be prepared to justify or simplify before getting too far along.

Formulating for Those Really Skilled in the Art. A common problem we see with difficult drugs is that the formulation and/or process is so touchy that five Ph.D.s need to be in the room to prepare the drug product. Those of us who have done clinical and commercial manufacturing know how different the clean room is from the laboratory and how many things can go wrong during batch manufacture. Unless some robustness is built in to both the formulation and the process, batch failures are all but inevitable.

Neglecting Scalability.

I used to have a cartoon pasted above my desk of scientists scaling up a process using a 30-foot high Erlenmeyer flask. I don’t remember the caption, but the point is well taken regardless. If a drug can be solubilized really well in 10-mL of a formulation using a probe sonicator, make sure it can also be solubilized using a homogenizer or Microfluidizer or some other piece of equipment that is available at commercial scale. Better yet, see if there is a way to do it with a blade mixer. The simpler the process and the more common the process equipment, the more likely the formulation is to succeed in the long term.

Using Proprietary Technologies.

I have had success on many occasions in formulating poorly soluble drugs with cyclodextrins. On as many occasions I have been asked to reformulate away from cyclodextrins after sponsors have heard the terms of licensing agreements. Unfortunately, many of the “sexier” formulation technologies are covered by patents, and their use entails substantial long-term costs in the form of licensing fees and royalty payments. Although this may not seem like a big deal in pre-clinical or early clinical development, the promise of formulation royalties, which often amount to 15-20% of sales, will substantially devalue your drug product asset to potential buyers.

These are a few of the most common traps I have seen young companies fall into in formulating their nascent drug products. PharmaDirections is here to do emergency reformulation work if you need it, but a little extra effort early on will let everyone sleep better later.

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Bruce Rehlaender, Ph.D., Principal, Formulation Development at PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, CMC and regulatory affairs. We design and direct preclinical programs for biotech firms.

Bruce Rehlaender, Ph.D., Principal, Formulation Development at http://www.PharmaDirections.com, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We design and direct preclinical programs for biotech.

Author Bio: Bruce Rehlaender, Ph.D., Principal, Formulation Development at PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, CMC and regulatory affairs. We design and direct preclinical programs for biotech firms.

Category: Medicines and Remedies
Keywords: Pharmaceutical Consulting, Project Management, Formulation Development, Preclinical, CMC