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There are several ways in which pharmacological treatments for ADHD can be delivered:

Immediate release

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

Immediate release. Reproduced with kind permission.1

Immediate release

Extended release

Extended-release formulations are designed to produce slow, uniform absorption of the drug.2

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

The multiple bead system for delivery of ADHD medication.4-7 Reproduced with kind permission.7

The multiple bead system for delivery of ADHD medication

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®).8,9

The osmotic-controlled release oral delivery system for delivery of ADHD medication. Reproduced with kind permission.7

The osmotic-controlled release oral delivery system for delivery of ADHD medication

Prodrug

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 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

Prodrug LDX for the treatment of ADHD12-17

prodrug-ldx-for-adhd

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

  1. 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.
  2. Brunton LL, Chabner B, Knollmann BC. Goodman & Gilman’s the pharmacological basis of therapeutics. McGraw-Hill Medical New York, 2011.
  3. 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.
  4. Equasym XL Summary of Product Characteristics. Shire Pharmaceuticals Ltd. Last updated 10 March 2014.
  5. Medikinet XL Summary of Product Characteristics. Flynn Pharma Ltd. Last updated 17 June 2014.
  6. Ritalin LA Summary of Product Characteristics. Novartis Pharmaceuticals Corporation. Last updated 29 June 2015.
  7. Stahl SM, Mignon L. Stahl’s illustrated attention deficit hyperactivity disorder. Cambridge University Press, 2009.
  8. 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.
  9. 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.
  10. Stanczak A, Ferra A. Prodrugs and soft drugs. Pharmacol Rep 2006; 58: 599-613.
  11. Ettmayer P, Amidon GL, Clement B, et al. Lessons learned from marketed and investigational prodrugs. J Med Chem 2004; 47: 2393-2404.
  12. Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat 2010; 6: 317-327.
  13. Elvanse Summary of Product Characteristics. Shire Pharmaceuticals Ltd. Last updated 13 September 2016.
  14. 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.
  15. Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacology 2006; 6: 6.
  16. Floor E, Meng L. Amphetamine releases dopamine from synaptic vesicles by dual mechanisms. Neurosci Lett 1996; 215: 53-56.
  17. Heal DJ, Cheetham SC, Smith SL. The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology 2009; 57: 608-618.
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