Methylphenidate Formulations

In 2001, Celgene obtained FDA approval to re-launch the single enantiomer dexmethyl-phenidate d-threo 2, formerly Dexedrine ) for ADHD under the brand name Focalin , and subsequently sold the product to Novartis, d-threo Methylphenidate has a 2.2 h 

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Lopez F, Silva R, Pestreich L, et al Comparative efficacy of two once daily methylphenidate formulations (Ritalin LA and Concerta) and placebo in children with attention-deficit hyperactivity disorder across the school day. Paediatr Drugs 5 545-555, 2003... 

Initial response to short-acting stimulant formulations (e.g., methylphenidate and dextroamphetamine) is seen within 30 minutes and can last for 4 to 6 hours.13,14 This short duration of effect frequently requires that short-acting stimulant formulations be dosed at least twice daily, thus increasing the chance of missed doses and non-compliance. Further, patients using any stimulant formulation but especially shortacting formulations can experience a rebound effect of ADHD symptoms as the stimulant wears off.14... 

Atomoxetine is the most recent addition to the ADHD armamentarium in both children and adults. In clinical studies, atomoxetine has demonstrated superior efficacy over placebo and equivalent efficacy when compared with a suboptimal immediate-release methylphenidate dose.17 20 However, it is not clear whether atomoxetine is superior to typical methylphenidate doses or other stimulant formulations. Atomoxetine may be used as a second- or third-line medication for ADHD. 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

Hubbard, J.W., Srinivas, N.R., Quinn, D., and Midha, K.K. (1989) Enantioselective aspects of the disposition of dl-threo-methylphenidate after the administration of a sustained-release formulation to children with attention deficit disorder. / Pharm Set 78 944-947. 

Methylphenidate hydrochloride, a piperidine derivative structurally similar to amphetamine, is a commonly prescribed stimulant for the treatment of ADHD in children age 6 years and older. It is a racemic mixture of d,l methyl a-phenyl-2-piperidineacetate hydrochloride. The drug is available in immediate-release, extended-release, and controlled-release formulations. It is hepatically metabolized to an inactive metabolite and excreted by the kidneys. 

In school-age children and adolescents with ADHD, treatment with immediate-release methylphenidate typically consists of administration once a day in the morning or in divided morning and noon doses. Doses can then be titrated upward on a weekly basis until improvement of target symptoms is achieved. Some patients take a third dose (typically 50% of other doses) in the late afternoon to manage symptoms in the early evening hours or to minimize rebound symptoms. Extended-release and controlled-release formulations have longer durations of action and are often preferred because less frequent dosing is needed. 

Dextroamphetamine, the d-isomer of amphetamine, is available in immediate-release and extended-release formulations. It is functionally more potent than methylphenidate and may be associated with a greater risk of growth retardation and abuse. 

Gonzalez MA, Pentkis HS, Anderi N, et al Methylphenidate bioavailability from two extended-release formulations. Int J Clin Pharmacol Ther 40 175-184, 2002... 

Pentikis HS, Simmons RD, Benedict ME, et al Methylphenidate bioavailability in adults when an extended-release multiparticulate formulation is administered sprinkled on food or as an intact capsule. J Am Acad Child Adolesc Psychiatry 41 443-449, 2002... 

Strattera (package insert). Indianapolis, IN, Eli Lilly and Co, 2005 Swanson JM, Volkow ND Pharmacokinetic and pharmacodynamic properties of stimulants implications for the design of new treatments for ADHD. Behav Brain Res 130 73-78, 2002 Swanson J, Gupta S, Lam A, et al Development of a new once-daily formulation of methylphenidate for the treatment of attention-deficit/hyperac-tivity disorder proof of concept and proof of product studies. Arch Gen Psychiatry 60 204-211, 2003... 

More recently, a new oral, osmotic, extended-release formulation of methylphenidate (Concerta), with both an immediate and continuous release component, has been approved by the FDA (72). When taken once daily, it results in plasma levels similar to those achieved with a three-times-a-day schedule of the immediate-release formulation. In addition, serum concentrations appear to fluctuate less. The additional cost, however, is significant. 

MPH is most often taken in pill form. It is available in prescribed quantities of 5-, 10-, and 20-mg tablets. A sustained or delayed release 20-mg tablet is also available. In 2001, the FDA approved Concerta, a longer acting MPH tablet that is taken once a day. Besides its long lasting action, Concerta has another benefit Abusers sometimes grind MPH tablets into a powder and snort it up their noses, but Concerta is formulated so that it cannot be ground into a powder. According to the DEA, methylphenidate abusers also dissolve the immediate-release MPH tablets in water and then inject the mixture. 

Methylphenidate is marketed in the United States under the prescription names Concerta, Metadate, Methylin, and Ritalin (26). It is available in immediate and sustained-release formulations for the treatment of attention deficit/hyperactivity disorder (ADHD) and the symptomatic management of narcolepsy (a disorder characterized by excessive daytime sleepiness). 

Methylphenidate is readily absorbed and produces peak plasma levels in approximately 2 hr (immediate-release formulation). The duration of action is 3-6 hr for the immediate-release and 8 hr for the sustained-release formulation. Approximately 90% of methylphenidate is excreted in the urine as metabolites (80% is ritalinic acid) and the remainder as unchanged drug (26,36). 

There are also sustained-release forms of methylphenidate. The effects of Ritalin SR (sustained release) last from 4 to 6 hours. A newer formulation called Concerta , which arrived on the market in 2002, lasts up to 12 hours and needs to be taken only once daily. 

Consider adjusting dose or switching to another formulation of d,l-methylphenidate or to another agent... 

For the expert, can combine immediate release formulation with a sustained release formulation of d,l-methylphenidate for ADHD... 

Immediate release formulations (Ritalin, Methylin, generic methylphenidate) have 2-4 hour durations of clinical action... 

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