Attention DeficitHyperactivity Disorder

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Attention-deficit/hyperactivity disorder (ADHD) is a common neurobeha-vioral disorder that is often recognized in early childhood, and can persist into adulthood. The principal characteristics of ADHD are inattention, hyper-activity, and impulsivity. In the United States, between 3% and 6% of school-aged children meet accepted diagnostic criteria for ADHD (183). Over 60% of children with a diagnosis of ADHD continue to exhibit ADHD symptoms through their adult life (184).

Methylphenidate (MPH), a psychostimulant medication, has been used for the last 50 years to treat children with ADHD, and is the most widely prescribed medication in child psychiatry (185). Immediate release formulations of MPH are short-acting and patients are typically dosed 3-4 times per day to achieve and maintain adequate ADHD symptom control. Consequently, children with ADHD require one or more doses during school hours. Beyond issues of storage and handling, adherence to a multiple dose regimen is problematic in this patient population.

To overcome the challenges of short-acting MPH with multiple-daily-dose regimens, long-acting, stimulant formulations were introduced decades ago for use in treating ADHD. However, these first-generation formulations sustained release MPH formulations were not well accepted in clinical practice due to slower onset of action, variable response, and overall reduced efficacy compared to IR formulations (186). It was hypothesized that the therapeutic failure of initial SR MPH formulations was caused by the inability of a zero-order drug release design to maintain efficacy throughout the day.

Recently, a number of second generation formulations have been developed to overcome the shortcomings of earlier SR products and optimize therapeutic outcomes for ADHD patients. The technology of these

Table 3 Advanced Formulation Strategies: Examples of Drug Products Used to Treat CNS Diseases and General Approaches to Enhance CNS Drug Delivery

CNS Disease

Product(s)

Description

Attention deficit

Concerta®

Extended-release formulations of

hyperactivity disorder

Metadate

methylphenidate (MPH) providing

Adderall XR®

once-a-day therapy

Daytrana®

Transdermal delivery system of MPH approved for use in children

Parkinson's disease

Neupro®

Transdermal delivery system of rotigitine for patients in early stages of disease

Pain

Actiq®

Oral formulations designed to provide

Bema™

buccal delivery of fentanyl for patients

Fentanyl

with breakthough pain

DepoDur®

Extended release liposome formulation of morphine sulfate. Epidermal administration after surgery provides pain relief for up to 48 h

Epilepsy

Cerebyx®

Injectable formulation of fosphenytoin (a phosphate ester prodrug of phenytoin) produces fewer adverse reactions that other phenytoin salts

Diastat®

Diazepam rectal gel used provides at home treatment of breakthrough seizures

CNS Tumors

Depocyte®

Depot liposomal formulation of cytarabine used as an intrathecal treatment of neoplastic and lymphomatous meningitis

Gliadel®

Wafer formulation containing carmustine that provides localized delivery of chemotherapy directly to tumor site. Wafers are implanted are removal of malignant glioma, releasing high concentrations of drug targeting microscopic tumor cells that sometimes remain after surgery

Abbreviations: MPH, methylphenidate.

Abbreviations: MPH, methylphenidate.

new "once daily" ER formulations is based on the strategy of delivering an initial burst dose of MPH in addition to providing an extended release of drug. The burst dose provides an initial bolus delivery of MPH that is expected to achieve peak plasma concentrations and have rapid onset of efficacy within 2 h of dosing. This is followed by an extended, controlled delivery of MPH that is designed to achieve higher plasma concentrations during later times and maintain efficacy for an extended period of time (187). While these new MPH products share the same therapeutic goal, they utilize various formulation technologies, as describe below.

Concerta® as is a once-daily MPH medication that provides effective treatment for ADHD patients throughout the day (188). The formulation is based on the ALZA's OROS® Tri-Layer Technology (Fig. 4). Drug is delivered via a dual process of aqueous dissolution of the drug overcoat and osmotic delivery of the core drug. When the tablet is ingested, 22% of the dose is released by dissolution of the drug overcoat layer. Upon dissolution of the overcoat, an osmotic gradient is establishing across the rate controlling membrane, providing controlled drug delivery for approximately 10 h (189,190). Clinical studies have demonstrated comparable plasma exposure for 12 h following single dose administration of Concerta compared with IR MPH administered three times daily (Fig. 5) (185).

Like Concerta, Metadate CD® is a once daily formulation of MPH. The product formulation is based on Diffucaps® technology (Fig. 6), which provides a modified release profile of MPH for optimal therapeutic results (191). The biphasic drug release profile is created by layering MPH onto sugar sphere, followed by a rate-controlling, polymer membrane, yielding beads less than 1 mm in diameter. Metadate CD is a hard gelatin capsule containing MPH in both rapid release and continuous release beads such

OROS® Tri-layer Delivery orifice

OROS® Tri-layer Delivery orifice

Drug compartment #2

Drug compartment #2

Figure 4 OROS -Trilayer Technology. Drug is delivered via a dual process of aqueous dissolution of the drug overcoat and osmotic delivery of the core drug. Upon dissolution of the overcoat, an osmotic gradient is establishing across the rate controlling membrane, providing controlled drug delivery for approximately 10 h. Source: From Ref. 189.

Figure 5 The Diffucaps™ system for drug delivery. Drug release profiles are created by layering active drug onto a neutral core such as sugar spheres, crystals or granules followed by a rate-controlling, functional membrane. By incorporating beads of differing drug release profiles into hard gelatin capsules, combination release profiles can be achieved. Source: Reprinted from Ref. 185 with permission.

Figure 5 The Diffucaps™ system for drug delivery. Drug release profiles are created by layering active drug onto a neutral core such as sugar spheres, crystals or granules followed by a rate-controlling, functional membrane. By incorporating beads of differing drug release profiles into hard gelatin capsules, combination release profiles can be achieved. Source: Reprinted from Ref. 185 with permission.

that 30% of the dose is rapidly released and 70% of the dose is continuously released. With this biphasic delivery, Metadate CD capsules provide school-day-long control of symptoms associated with ADHD with a single morning dose (192).

Formulation Design
Figure 6 Pharmacokinetic profiles comparing an OROS-methylpheni-date formulation administered with a high-fat breakfast and without (fasting) food, and TID (3 times daily)—immediate release methyl-phenidate administered in the fasting state. Source: Reprinted with permission from Eurand.

Adderall XR® is yet another extended release formulation for MPH. Unlike most MPH products that contain the hydrochloride salt of MPH (including those described above), Adderall XR contain equal amounts of four amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccha-rate, racemic amphetamine aspartate monohydrate, and racemic amphetamine sulfate. These salts provide a 3:1 ratio of d-amphetamine to l-amphetamine. The once-daily capsule formulation two types of drug-containing beads designed to give a double-pulsed delivery of amphetamine. Immediate-release beads release the first half of the dose upon ingestion, and the delayed-release beads begin to release the second half of the dose 4 hours later (193,194).

A methylphenidate transdermal patch (Daytrana®) has been approved by the US FDA for use in children aged 6-12 years. This delivery system permits sustained absorption of MPH through the skin and into the bloodstream. After morning application to the hip, the formulation is designed to MPH continuously throughout the day; the patch is removed after 9 h and its effects continue for 3h thereafter (195). In well controlled trials in children with ADHD, patients administered MTS patches showed significantly greater improvements in their ADHD symptoms than placebo recipients (196).

ADHD was once considered to be a condition that children outgrew before reaching their teens. Current data indicate that up to 80% of children with ADHD continue to experience symptoms into their teen years, and up to 65% of children with ADHD have symptoms well into adulthood. A single morning dose of second generation MPH SR products provide symptomatic coverage in children throughout the day. However, adolescents and adults with ADHD may require symptom control that extends beyond the 12 h provided by existing formulations.

To better meet adult-patient needs for prolonged ADHD symptom control with once-daily dosing, an enhanced extended-release amphetamine formulation has been designed to provide coverage for up to 16 h (194). The formulation is composed of a single morning capsule containing three types of beads. The first two type of beads are similar to those found is Adderall XR, and provide a double-pulsed delivery of mixed amphetamine salts. The third bead provides an additional extended-release dose of amphetamine during the later part of the day. Clinical studies have demonstrated similar a dose-augmentation strategy consisting of Adderall XR supplemented by administration of IR MPH 8 h later.

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