The 505(b)(2) regulatory pathway is an increasingly popular method of getting drug approval – and one which we are quite familiar with at LGM. This pathway allows a pharma company to improve an existing drug, for example, by changing the dosage form. One of the main trends we see with 505(b)(2) filings is clients working to modify the delivery route from injectable to oral products.
Improving Drug Delivery with the 505(b)(2) Pathway
There are many reasons why companies tend to shy away from injectables, the drug delivery mechanism by which one or more drugs in liquid form are administered via syringe into a muscle or fat. Most notably, the injectable form is challenging – both in terms of administration and weak patient adherence.
Shifting the product from injectable to oral dosage resolves the two key challenges of injectables: delivery is less painful, and self-administration is simple.
There are three primary types of oral systems; oral solids, oral liquids and semi-solids. The oral solid (OSDF) is the most popular form, with the drug formulated into a pill, tablet, or capsule and administered by mouth.
A second oral form is liquid – where one or more drugs are delivered through a homogenous liquid form.
Some oral liquid forms can be taken as directed – such as the syrup – where others require dilution or shaking, such as suspensions or emulsions. The final oral delivery method is semi-solid in which the active pharmaceutical ingredient(s) are delivered through a liquid form that retains its shape, such as a paste or a chew.
Another popular form of drug delivery gaining traction as an alternative to injectables is the transdermal route. This delivery mechanism is painless, and the drugs are absorbed through the skin. It is typically administered via patch, microneedles, or lasers. The key driver of transdermal delivery is that it creates a path allowing an API to the bloodstream at a constant rate, overcoming the ‘peaks and valleys’ more common with tablets and other OSDFs.
What Are the Challenges of 505(b)(2) Projects?
While these 505(b)(2) projects are certainly gaining traction, they are not without their challenges. If your team is working on this type of project, there are few factors to bear in mind. One key challenge with a novel delivery system project is that it often demands a different solid for the API.
In many cases, the commonly used API may not be suitable for your new drug delivery system. You may require a different API salt form, which can potentially result in lost time and higher costs. Remember, not only would you need new stability data, but you would need to factor in extra time for production, an updated DMF, and finding the correct manufacturer at your project scale.
Selecting the Right Development and Manufacturing Partner Makes a Difference.
Finding the right manufacturer who can provide both the regular API and also develop the proper form or API salt for the project is vital. You’ll need to ensure they have the capabilities based on the number of synthesis steps, the process duration and scale, and the complexity of the chemistry involved. It is absolutely critical to know your API manufacturer, thoroughly understand their capabilities, and maintain a good relationship with them.
The existing route of synthesis is often a source of delay when shifting from a research to production footing. If early process development work didn’t take other salt forms of the API into consideration, or if the general synthesis route is inefficient, you risk losing valuable time. Likewise, if your chosen manufacturer uses a route of synthesis that doesn’t result in the final API form you need, more time could be lost.
As mentioned above, much of this comes down to relationship-building. When you know your manufacturer and their capabilities, you inevitably save yourself time and money. In one case, LGM Pharma saved a client a year’s worth of work due to our access to the only manufacturer that could offer them the API form that they needed – right off the shelf.
Bioavailability has become a principal challenge in the world of drug delivery and drug development, since highly insoluble compounds suffer from poor bioavailability. The last few decades have seen the majority of new drug APIs swing from ‘solidly soluble’ to ‘largely insoluble.’ One study suggested about 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline suffer from poor water-solubility.
The Rise of Solid Form Screening & Bioavailability-Enhancing Formulations
This issue with insolubility and low bioavailability resulting in sub-optimal drug delivery has been a top cause of most drug failures. To overcome this challenge, companies are developing new drug delivery technologies that can better formulate insoluble drugs.
Typically, companies will use specific techniques such as solid-form screening and bioavailability-enhancing formulations to achieve a more soluble form. Solid-form screening identifies a more soluble form – such as a salt – and is vital for improving bioavailability. Crystallization is a similar procedure and the most widely used technique to isolate and purify the API because it can be done at scale. Many companies have successfully used these techniques and others to turn marketed insoluble drugs into more soluble forms.
A Successful 505(b)(2): Saving Drug Developers Time & Money and Improving Patient Care
If you are a drug-maker pursuing the 505(b)(2) pathway or a novel drug delivery system, it is common to encounter challenges with your API. Whether the issue is the incorrect form or insolubility, you can overcome these challenges with the right partners on your side.
Companies who successfully navigate through a change in drug delivery technique stand to gain marketing exclusivity and patent protection. More importantly, the drug is ultimately more effective and safer for patients.