The Long and Short of It
Why drug developers should take a fresh look at long-acting dosage forms
Robert W. Lee | | Longer Read
Long-acting drug delivery systems or long-acting medications can take a number of forms – implants, depot injections, long-acting injectables (LAIs), combination products – but they all offer the potential for targeted drug release, lower dosage requirements, and improved patient compliance. A well-designed drug-eluting system can improve the bioavailability, stability, and pharmacokinetics of an API, while also offering potential intellectual property and life-cycle management opportunities.
For example, studies have repeatedly documented high non-adherence rates (around 50 percent) for patients with schizophrenia and bipolar disorder (1); 18 months after treatment initiation, non-adherence can be as high as 74 percent. Non-adherence is associated with increased relapse rates, frequent hospitalizations, greater costs, and higher morbidity, and mortality rates (2). Wouldn’t antipsychotic LAIs be a more practical option?
In fact, the US National Council for Behavioral Health encourages its members to increase and support the safe and effective use of long-acting medications (LAMs); it states that all community mental health providers should provide these as a first-line treatment option to patients. Currently, LAMs are most often used as a strategy to address medication non-adherence; however, research supports the use of LAMs as first tier medications, not just as second or third tier approaches (3).
Treatment for addiction and pain management can similarly benefit from LAIs. Put simply, there is clearly a strong case for the industry to increase its use of long-acting formulations.
My diagnosis of branch retinal vein occlusion (BRVO) can help emphasize the benefits of long-acting formulations (though admittedly my experience is plucked from the world of biopharmaceuticals). First, a little physiology for context: the eye’s retina has one main artery and one main vein; when the branches of the retinal vein become blocked – as in BRVO – blood and fluid spill out into the retina, causing the macula to swell, which affects central vision. Eventually, without blood circulation, nerve cells in the eye can die and more vision can be lost. One part of my treatment consisted of monthly intravitreal (IVT) injections of Lucentis (ranibizumab injection). The first injection into my eye was memorable to say the least! And if there was an option for a longer duration formulation (from a biologic or small molecule), I would be very keen on trying it. For me, even an increase in duration from one to two months would be attractive...
Getting more technical, LAIs also allow the use of advanced drug delivery technologies that circumvent physicochemical limitations of the API, such as chemical instability, solubility challenges, and polymorphic transformation issues. For example, if an API has low aqueous solubility, the formulator could use nanomilling or other nanotechnology-enabled drug delivery systems within the LAI to increase dissolution rate and improve performance. If an API is chemically unstable, it’s possible to encapsulate it or incorporate it in a solid state. Today, many different technologies and techniques are available to help non-viable drug candidates progress into clinical trials and beyond.
From a CDMO perspective, the industry will need strong scientific and technical expertise to help improve long-acting products. Experience in a variety of drug delivery systems is crucial. But by investing in the infrastructure to develop and manufacture complex dosage forms – PLGA microspheres, polymeric depots, bioerodible and biodurable implants, for example – as well as the necessary analytical and physicochemical characterization tools, it is possible to formulate such advanced drug products with confidence.
We are already seeing solutions for increased duration of drug release and improved safety profiles, such as more benign excipients and polymers. And in the future, there is also scope for additional routes of administration, such as topical and mucosal, although both present challenges. Different form factors may also play a role; there are sprays for topical or nasal delivery. And intravaginal rings have proven their worth in providing long-acting contraception – could they be used for other indications?
I believe the industry has a duty to ensure that more patients are offered LAMs as a treatment option. And by satisfying patient needs, we can all look forward to a promising future for long-acting drug dosage forms.
- AS Reece, “Psychosocial and treatment correlates of opiate free success in a clinical review of a naltrexone implant program,” Subst Abuse Treat Prev Policy, 2 (2007).
- Pharmacy Times, “New Frontiers for Pharmacists: Administration of Long-Acting Injectable Antipsychotics,” (2019). Available at bit.ly/3ilr750
- The National Council, “Guide to Long-Acting Medications for Providers and Organizations,” (2019). Available at bit.ly/33wZLVE