There are several ways in which pharmacological treatments for ADHD can be delivered:
Immediate-release tablets or capsules are the most widely used drug-delivery systems. They are designed to undergo disintegration in the stomach into smaller granules and subsequent dissolution in the fluids of the gastrointestinal tract.1
Figure: Immediate release. Reproduced with kind permission from Gupta A et al. AAPS PharmSciTech 2009; 10: 495-499.1
Extended-release formulations are designed to produce slow, uniform absorption of the drug.2
Commonly used extended-release formulations of ADHD medications are described below.
Multiple bead system
The multiple bead system consists of a water-soluble gelatin capsule that dissolves quickly once swallowed, releasing drug-containing beads of two different dissolution rates.3-6 Multiple bead formulations release a steady level of drug into the bloodstream, allowing for once-daily dosing.3-6
Once-daily dosing has practical advantages, particularly in young patients. Furthermore, the potential for stimulant abuse may be lower for extended-release formulations compared with immediate-release formulations.7
Figure: The multiple bead system for delivery of ADHD medication.4-6 Reproduced with kind permission from Stahl SM and Mignon L. Stahl’s Illustrated Attention Deficit Hyperactivity Disorder. New York, NY; Cambridge University Press, 2009.7
Osmotic-controlled release oral delivery system
Methylphenidate is also available as an osmotic-controlled release oral delivery system formulation. The outer layer of the capsule is coated with methylphenidate, which quickly releases once the pill is ingested.8,9
The inner layers are set up along an osmotic gradient; the first compartment, with a small amount of the drug, releases via simple diffusion, but the second compartment, with a higher amount of the drug, releases as a result of the osmotic pressure created when water reacts with the third compartment.8
The osmotic-controlled release oral delivery system was designed to provide a longer duration of effect than the previous multiple bead system (Ritalin SR®).9
Figure: The osmotic-controlled release oral delivery system for delivery of ADHD medication. Reproduced with kind permission from Stahl SM and Mignon L. Stahl’s Illustrated Attention Deficit Hyperactivity Disorder. New York, NY; Cambridge University Press, 2009.7
Prodrugs are pharmacologically inactive molecules that are converted into one or more active metabolites through a natural metabolic process.10,11
These molecules are designed to enhance the attributes of the active drug, such as enhanced solubility, increased/enhanced absorption and distribution, and prolonged systemic availability.10,11
Lisdexamfetamine dimesylate (LDX)
The prodrug is a formulation that is not active until it is metabolised by the body. LDX is one such drug; lysine is covalently linked to amfetamine and the drug only becomes active after lysine is cleaved by enzymes in the bloodstream.12,13
More specifically, the hydrolysis of LDX is thought to result from aminopeptidase-like activity in the red blood cell cytosol.14
Figure: Prodrug LDX for the treatment of ADHD. Figure developed using multiple sources.12-17
The lisdexamfetamine prodrug becomes active only after it has been absorbed by the intestinal tract and has been converted to dextroamphetamine and l-lysine.7
- Gupta A, Hunt RL, Shah RB, et al. Disintegration of highly soluble immediate release tablets: a surrogate for dissolution. AAPS PharmSciTech 2009; 10: 495-499.
- Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and elimation. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 12th edition. New York, NY: McGraw-Hill Medical, 2011, p21.
- Maldonado R. Comparison of the pharmacokinetics and clinical efficacy of new extended-release formulations of methylphenidate. Expert Opin Drug Metab Toxicol 2013; 9: 1001-1014.
- Novartis Pharmaceuticals Corporation. Ritalin LA US Prescribing Information. Last updated April 2018.
- Shire Pharmaceuticals Ltd. Equasym XL Summary of Product Characteristics. Last updated June 2018.
- Flynn Pharma Ltd. Medikinet XL Summary of Product Characteristics. Last updated March 2017.
- Stahl SM, Mignon L. Stahl’s Illustrated Attention Deficit Hyperactivity Disorder. New York, NY; Cambridge University Press, 2009.
- Conley R, Gupta SK, Sathyan G. Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form. Curr Med Res Opin 2006; 22: 1879-1892.
- Modi NB, Lindemulder B, Gupta SK. Single- and multiple-dose pharmacokinetics of an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl) formulation. J Clin Pharmacol 2000; 40: 379-388.
- Stanczak A, Ferra A. Prodrugs and soft drugs. Pharmacol Rep 2006; 58: 599-613.
- Ettmayer P, Amidon GL, Clement B, et al. Lessons learned from marketed and investigational prodrugs. J Med Chem 2004; 47: 2393-2404.
- Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat 2010; 6: 317-327.
- Shire Pharmaceuticals Ltd. Elvanse Summary of Product Characteristics. Last updated April 2018.
- Sharman J, Pennick M. Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells. Neuropsychiatr Dis Treat 2014; 10: 2275-2280.
- Floor E, Meng L. Amphetamine releases dopamine from synaptic vesicles by dual mechanisms. Neurosci Lett 1996; 215: 53-56.
- Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 2006; 6: 6.
- Heal DJ, Cheetham SC, Smith SL. The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology 2009; 57: 608-618.