Formulating low dose naltrexone into a cream

The opioid receptor antagonist naltrexone has been on the periphery of my autism research career for as long as I can remember. As unusual as it might sound, some of the early interpretations for example, on why installation of a gluten- and casein-free (GFCF) diet seemed to correlate with changes to behavioural presentation for some on the autism spectrum, relied heavily on the notion of opioid-excess [1] as a function of the proposed bioactivity of gluten and casein derived peptide species. This allied with a body of evidence more directly linking administration of naltrexone as affecting some peripheral facets observed in cases of autism [2] touched upon in a recent post (see here).

No, not that type of cream... @ Herrick @ Wikipedia 

This line of thought of excess opioid activity being related to cases of autism has not been without its critics down the years [3]. Certainly I'd be the first to admit that a degree of naivety existed in terms of appreciating the complexity of autism (sorry, the autisms) in those early times. That being said, I'm not yet ready to consign the opioid-excess theory to the scientific trash-heap just yet, as one of the other parts of the theory - abnormal gut permeability (leaky gut) - enjoys some well deserved research attention (see here and see here).

The connection made between autism, opioid-excess and naltrexone has also evolved as time as gone on. Accepting the anti-opioid power of naltrexone, there has at the same time been a shift in our understanding of naltrexone as also being an immunomodulating agent. I can't readily provide you with the full picture of how naltrexone affects immune function because there is still more to be done on this topic. What I can say is that (i) opioids can have effects on immune function [4] and (ii) anti-opioid drugs such as naltrexone also seem to have some effects on immune function [5].

On the back of this very long introduction, I'm talking today about an interesting piece of work [6] which I had a very, very small part in, looking at the formulation of low doses of the drug naltrexone into a cream and some of the chemistry behind it. You'll note the addition of the words 'low dose' to naltrexone indicating an increasing body of evidence discussing, well, low doses of naltrexone (LDN), for all manner of health issues including Crohn's disease [7], fibromyalgia [8] and multiple sclerosis [9]. Indeed, I've mentioned this topic in an earlier blog post (see here).

So what did we do and why did we do it?

Well discussions about this project began some years back. Quite a few of the medications suggested for tackling facets of autism and other developmental conditions generally tend to rely on the oral route of administration i.e. swallowing pills. Whilst this is a good way of getting the active part of a drug into the body, there are a few issues surrounding this method including having the ability and desire to want to swallow a tablet or capsule and sticking to a regime of tablet swallowing often over quite a long period of time. Little things that people take for granted such as drinking water when swallowing a tablet might not necessarily be so implied for everyone. And then there are the various biological processes that any orally administered medication needs to go through before producing a therapeutic effect, even the possibility of an effect from those trillions of bacteria in our gut which call us home... In short, oral drug delivery is not necessarily always the best drug delivery route for everyone.

As it happens, there are lots of other ways of getting medication into the body such as through the skin (transdermal) or under the tongue (sublingual) (and erm, other routes) provided you can formulate your medicine appropriately. We had quite a few discussions about what medicines were out there and how we could formulate them into something a little more versatile when it comes to administration. Naltrexone was an obvious candidate because it has quite a nice chemical structure and also, as I've discussed, there is growing interest in its usefulness for various different conditions not just for cases of autism.

It was then a case of making a cream containing naltrexone which our collaborators are pretty good at doing based on their other work formulating things like transdermal patches [10]. Our part (the Royal 'We') involved testing said cream using our Q-ToF mass spectrometer for how well the cream performed in terms of releasing naltrexone and its metabolite 6-β-naltrexol. In short, it did pretty well: "It was concluded that the cream may be an effective formulation for the sustained transdermal delivery of LDN".

On this occasion, we stopped short of actually testing the cream on real people with real conditions in terms of things like safety and effectiveness simply because clinical trials are a whole other ballgame. That being said, I'd like to think there might be other groups who would be willing to have a look at our formulation and perhaps take up the research gauntlet too (hint, hint).

Music to close. Something lively I think, so how about Icona Pop and 'I Love It' (with a parental advisory for some of the lyrics...)

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[1] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[2] Elchaar GM. et al. Efficacy and safety of naltrexone use in pediatric patients with autistic disorder. Ann Pharmacother. 2006 Jun;40(6):1086-95.

[3] Cass H. et al. Absence of urinary opioid peptides in children with autism. Arch Dis Child. 2008 Sep;93(9):745-50.

[4] Zhang EY. et al. Depletion and recovery of lymphoid subsets following morphine administration. Br J Pharmacol. 2011 Dec;164(7):1829-44.

[5] Boyadjieva NI. & Sarkar DK. Opioid-like activity of naltrexone on natural killer cell cytolytic activity and cytokine production in splenocytes: effects of alcohol. J Interferon Cytokine Res. 2010 Jan;30(1):15-22.

[6] Dodou K. et al. Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay. Pharm Dev Technol. 2014 May 2.

[7] Smith JP. et al. Low-dose naltrexone therapy improves active Crohn's disease. Am J Gastroenterol. 2007 Apr;102(4):820-8.

[8] Younger J. et al. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38.

[9] Sharafaddinzadeh N. et al. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010 Aug;16(8):964-9.

[10] Ho KY. et al. Effect of drug-polymer binary mixtures on the in-vitro release of ibuprofen from transdermal drug-in-adhesive layers. Drug Discov Ther. 2008 Oct;2(5):277-81.

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Dodou K, Armstrong A, Kelly I, Wilkinson S, Carr K, Shattock P, & Whiteley P (2014). Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay. Pharmaceutical development and technology PMID: 24785567