MPH Part 3: Retardation

The description of the degradation of MPH by CES1A has been moved to the article Drug duration of action in ADHD.

• 13. Immediate release methylphenidate
• 14. Sustained release MPH, sustained release techniques
  • 14.1. Ingestion with / without food
  • 14.2. Retardation forms with MPH
    • 14.2.1. Tablets / capsules
      • 14.2.1.1. Medikinet retardation system
      • 14.2.1.2. OROS - Oral system with osmotic release
      • 14.2.1.3. MAS-XR (SODAS) - mixture of pellets with immediate and delayed action
      • 14.2.1.4. MPH-CD, Diffucaps
      • 14.2.1.5. MPH-SR, wax matrix
      • 14.2.1.6. MPH-MLR, MLRTM, multilayer composite beads
        • 14.2.1.6.1. 40 % IR / 60 % ER
        • 14.2.1.6.2. 20 % IR / 80 % ER
        • 14.2.1.6.3. 40 Or 50 % IR / 50 or 60 % ER
      • 14.2.1.7. MPH-ERCT
      • 14.2.1.8. MPH XR-ODT
      • 14.2.1.9. DR/ER-MPH
      • 14.2.1.10. Novo-MPH ER-C
      • 14.2.1.11. Matrix technology
      • 14.2.1.12. “Lumpy gravy” technology
    • 14.2.2. Transdermal delivery via patch
      • 14.2.2.1. MTS
    • 14.2.3. Suspension
      • 14.2.3.1. MEROS: ER-Suspension

13. Immediate release methylphenidate¶

Immediate release (“normal”) MPH has a typical duration of action of between 2.5 and 4 hours. However, it can also be as short as 1 hour.¹ The individual duration of action remains the same over the entire lifespan.
The advantage of the short duration of action is better controllability, because sometimes a little earlier or a little later, sometimes a little less or a little more can be taken and the daily coverage can be regulated more easily. The disadvantage is that greater cooperation and discipline is required from the person with ADHD. With ADHD in general and with children with ADHD in particular, this reliability is not always given. If you only realize that you need to take a refill because you have just “exploded” again for no adequate reason, or because you have been staring into space for a long time, a large part of the achievable normalization of life has been missed. In addition, the frequent use of medication throughout the day more clearly conveys the feeling of being affected by a Disorder. In comparison, medication with a long delay (10-14 hours), which only has to be taken once in the morning, has a much stronger effect on the feeling of normalization.

For dosing, an immediate release form is preferable, provided that it is taken reliably, as immediate release tablets can be divided into finer units and the shorter duration of action allows better adjustment of the dose level.

14. Sustained release MPH, sustained release techniques¶

Sustained-release preparations cause a modified/slowed release of the active ingredient compared to dosage forms with unchanged release of the active ingredient. The prolonged release is achieved by a special composition and/or a special manufacturing process.²
In contrast to depot dosage forms, prolonged-release dosage forms are understood to be perorally administered dosage forms in the narrower sense. However, both terms are often used synonymously. However, drugs that are absorbed with a delay due to their pharmacokinetic properties (and not their release mechanisms) or, in the case of prodrugs, are only converted into their actual active form by the organism are not prolonged-release drugs.³

Depending on the preparation, sustained release MPH works for between 4 and 12 hours by slowly releasing its active ingredients into the body.
The advantage is that the person with ADHD does not have to remember to take their medication again; the disadvantage is the lack of fine control over the quantity, as the capsules only contain the prescribed dosages and cannot be divided like tablets, and that once the effect has worn off, if there are still a few hours of day left to live, the duration of effect of a capsule may last too long, which can then cause sleep problems.
Immediate releases may help to reduce dysphoria and/or hyperactivity during rebound when the effects of sustained releases wear off.⁴
Each person with ADHD has to find out for themselves what suits them better.

The combination of sustained release preparations (as a standard for the day) with immediate release tablets (for a quicker start in the morning, for supplementation later in the afternoon or evening and for fine control in the case of increased loads) is permitted.⁴

In principle, daily coverage should be aimed for. With immediate release MPH, 3 to 4 single doses are required, with half-day release preparations 1 to 2 doses⁵

For the individual sustained release / immediate release MPH preparations, see below.

14.1. Ingestion with / without food¶

Some preparations (e.g. Medikinet Adult and Medikinet retard) require a food base for ingestion. Otherwise Medikinet has an immediate release effect (twice as strong and half as long).

Eating before taking other long-acting preparations can also influence the duration of the effect. When taken on an empty stomach, there is an increased risk that the drug without acid-dependent sustained release has already migrated so deeply into the intestine by the time the effect of the sustained release components is supposed to start that complete absorption of the active ingredient is no longer guaranteed.⁶ The bioavailability of Ritalin LA (whose retardation is not acid-dependent) is said to be around eleven percent higher when taken after a meal than when taken on an empty stomach, meaning that Ritalin LA and Ritalin Adult should also be taken with or after a meal.⁷

14.2. Retardation forms with MPH¶

14.2.1. Tablets / capsules¶

14.2.1.1. Medikinet retardation system¶

Medikinet®; Medikinet® CR; Medikinet® EM; Medikinet® MR; Medikinet® XL

Countries:⁸
Europe: Austria, Belgium, Cyprus, Denmark, Estonia, Finland, France, Germany, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom.
Israel
Korea
South America: Argentina, El Salvador, Guatemala, Honduras

In Germany: Medikinet retard and Medikinet adult

We have not yet found a detailed technical description of Medikinet’s retardation system.

Medikinet retard

• 50 % IR pellets
• 50 % enteric-coated ER pellets

Medikinet Adult and Medikinet sustained release require a food base for ingestion because the sustained release portion is encased in an acid-resistant membrane and relies on slowed passage through the stomach into the intestine (by means of solid food). If it is transported too quickly into the alkaline region of the duodenum, the sustained release portion can be released prematurely⁹, which leads to an excessive and shortened effect.

• Dose dumping problems possible with stomach pH above 5.5⁶
  • Active ingredient is released too quickly, resulting in increased effects and side effects
  • e.g. through
    • Proton pump inhibitors (such as pantoprazole, omeprazole)
    • H2 antagonists (such as ranitidine, famotidine) less likely)
    • Antacids

14.2.1.2. OROS - Oral system with osmotic release¶

Preparation: Concerta (with outer coating, all-day retardant)

Concerta extended release; Concerta® LP

Countries:⁸
Africa: Botswana, Brazil, Egypt, Namibia, Nicaragua, South Africa
Asia: Bahrain, China, Hong Kong, Indonesia, Israel, Japan, Jordan, Republic of Korea, Kuwait, Lebanon, Malaysia, Oman, Philippines, Qatar, Saudi Arabia, Singapore, Taiwan, United Arab Emirates, Yemen
Australia
New Zealand
Europe: Austria, Belgium, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Iceland, Ireland, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom
North America: Bahamas, Barbados, Canada, Cayman Islands, Dominican Republic, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Trinidad and Tobago, USA.
South America: Argentina, Aruba, Bolivia, Chile, Colombia, Costa Rica, Ecuador, Panama, Paraguay, Peru, Uruguay, Venezuela.

OROS (Osmotic Release Oral System) was the first retardation system developed for MPH.¹⁰ It is also known as the “pulse and leak” mechanism¹

In the OROS system, the first release of the active ingredient (22%) is immediate from the capsule coating (pulses).
The semi-permeable membrane of the capsule’s outer wall surrounds a three-layer core, which contains two active ingredient layers and an osmotically active pressure layer. If water penetrates the membrane, the osmotic pressure layer gradually expands and pushes the 78% of the MPH in the core out of the capsule through a laser-drilled hole (leak). After complete MPH release, the capsule remains intact and is excreted in the stool. OROS-MPH tablets must therefore be swallowed whole and must not be opened, crushed, divided or chewed.¹⁰
There is a concentration gradient between the two inner active ingredient compartments, which also modifies the release rate of the active ingredient. OROS-MPH exhibits an initial concentration peak after approximately 1 hour and a gently increasing plasma concentration profile, which is thought to minimize the development of “acute tolerance” and maintain full efficacy throughout the day¹¹
“Acute tolerance” was an idea put forward by Swanson, who assumed that an optimal effect would be achieved by a steady increase in MPH levels throughout the day, with tolerance breaking down overnight and the brain starting from zero again the following day.¹² Consequences of this idea were the strongly back-loaded distribution of Concerta (22 / 78).
However, the results of Swanson et al. could not be reproduced and are not consistent with the experience of clinical practice.¹ People with ADHD who dose themselves appropriately (in consultation with their doctor) use either

• an initial dose and several relatively smaller subsequent doses throughout the day (in our experience the most common form of administration, which indicates the need for a constant level)
• a single high dose (rather rare in our experience)
• a low starting dose and high subsequent doses throughout the day (very rare constellation.¹ We have been told about a person with ADHD taking this regimen)

By design, one sixth of the dose of Concerta remains in the capsule and is not bioavailable. Therefore, an 18 mg capsule actually only delivers 15 mg MPH, a 36 mg capsule only delivers 30 mg, etc¹

The half-life (“t1/2”) of MPH in healthy adults is approximately between 3.3 to 4 hours. Despite the lower Cmax, the relative bioavailability of OROS-MPH was comparable to IR-MPH administered three times daily every 4 hours.¹⁰¹³

Advantages:

• Very long duration of action of up to 12 hours
• no dependence on food intake¹³

Disadvantages:

• poorer dosing than with two doses of half-day sustained-release MPH in succession, where the dosage can be selected differently (second dose usually 1/2 to 2/3 of the first dose)

14.2.1.3. MAS-XR (SODAS) - mixture of pellets with immediate and delayed action¶

Preparations: Ritalin LA, Ritalin LP, Ritalin Adult (EU, USA), Focalin XR (Switzerland, USA), Miacalcic
Chile

SODAS® technology (Spheroidal Oral Drug Absorption System)

Capsule contains two different types of pellets¹¹

• Pellets that release the active ingredient immediately (active ingredient content 40 or 50 %)
• Pellets with enteric polymer coating that becomes permeable to liquid approx. four hours after ingestion. The liquid then dissolves the active ingredient and releases it (active ingredient content 60 or 50 %)

At 50 % IR / 50 % ER:¹⁰⁵

• two peak values
  • Cmax1 after approx. 2 hours
  • Cmax2 approx. 3.5 to 4.5 hours later
• Half-life
  • for children with ADHD approx. 2.4 hours
  • in healthy adult men approx. 3.3 hours (like IR-MPH)
• Cmax
  • 2-fold higher in children with ADHD than in healthy adults (20 mg MPH-LA)
  • presumably due to body weight and volume of distribution

Advantages:

• no food intake required for ingestion
• As retardation is not achieved by coating the capsule shell, the capsule can be opened (e.g. taken in muesli)
• slightly slower release than OROS (Medikinet)¹⁴
• Release independent of gastric pH; no dose dumping risk as with OROS (Medikinet, Concerta)⁶

Available dosage strengths:

• 10, 20, 30, 40 mg

Food intake:¹⁰

• As with other formulations with pellet technology
  • can be swallowed whole, opened and sprinkled on applesauce
  • Spoonful of applesauce did not alter pharmacokinetics in healthy adults
  • high-fat food when ingested
    • unchanged: AUC, Cmax1, Tmax2
    • reduced: Cmax2 by 23 %
    • delayed: Tmax1 by one hour

FOCALIN XR® is the only pure D-MPH preparation with extended release (D-MPH-ER).¹⁰

Pharmacokinetic profile in healthy adults:

• First peak after about 1.5 to 2 hours
• Second peak after 5.5 to 6.5 hours
  • Slightly lower than IR-d-MPH
• Slightly longer Tmax2 than IR-d-MPH
  • Indicates lower peak and trough fluctuations with d-MPH-ER
• Low point of the MPH plasma concentration between the two peaks
• Half-life in healthy adults approx. 3 hours

20 mg d-MPH-ER once daily was shown to be bioequivalent to

• two doses of IR-d-MPH, 10 mg each, 4 hours apart
• one dose of MPH-LA 40 mg

Available dosage strengths:

• 5, 10, 15, 20, 25, 30, 35, 40 mg
• in healthy adults dose-proportionally from 5 to 40 mg
• 2 to 3 doses / day required⁵

Food intake:

• not examined
• probably like Ritalin-LA / Ritalin Adult

14.2.1.4. MPH-CD, Diffucaps¶

Preparations:
Equasym Depot®, Equasym Retard®, Equasym XR®, Quasym LP®, Metadate CD®, Metadate ER®

Countries:⁸
Europe: Denmark, Finland, France, Germany, Ireland, the Netherlands, Norway, Sweden, Switzerland and the United Kingdom.
South Korea
USA

Bead technology, Diffucaps®

MPH CD gelatine capsules¹⁰

• 30 % IR pellets
• 70 % ER pellets

According to Pheil et al, Metadate CD is said to use a system related to MAS-XR, in which one capsule contains two different types of pellets consisting of sugar spheres mixed with active ingredient and without (IR) or with (ER) a release retardant coating.⁵

Pharmacokinetic profile:⁵¹⁰

• Two peak values
• Sharp, initial incline
• First peak after about 1.5 hours (similar to immediate release MPH)
• Continued resorption
• Second peak (Cmax) approx. 3 hours later

25% to 35% of children with ADHD in a multiple-dose pharmacokinetic study showed a single-peak profile.

Half-life in healthy adults approx. 5.6 to 6.4 hours.
Compared to IR-MPH administered twice daily at 4-hour intervals, both Cmax and AUC were slightly lower with MPH-CD administered once daily at a similar total daily dose of 20 mg

Dosage strengths:

• 10, 20, 30, 40, 50, 60 mg

Children:

• Linear dose proportionality between 20 mg and 40 mg
  Healthy adults
• Linear dose proportionality between 10 mg and 60 mg

MPH-CD capsules can either be swallowed whole or opened and sprinkled on applesauce without affecting bioavailability if the person with ADHD has difficulty swallowing.
Food intake by adults with ADHD

• delayed Tmax by 1 hour
• increased Cmax by 30 %
• increased AUC by 17 %

14.2.1.5. MPH-SR, wax matrix¶

Preparation: Ritalin SR®¹⁵
USA, Canada

MPH-SR was one of the first retardation techniques.
MPH-SR uses tablets with a wax-based matrix.¹⁶

Duration of action of up to 8 hours probably only theoretical.
In practice, no effect in the first 2 hours, then 4 hours of effectiveness, after that no more effect¹
Efficacy may be lower than with multiple doses of immediate release MPH.
The flat drug release profile of MPH-SR (zero order) may be responsible for the poorer effect of MPH-SR compared to MPH-IR according to some studies and for the development of acute MPH tolerance within the day, leading to a poorer effect in the afternoon.¹¹¹⁷

14.2.1.6. MPH-MLR, MLRTM, multilayer composite beads¶

14.2.1.6.1. 40 % IR / 60 % ER¶

Preparation: APTENSIO XR® (USA), Biphentin®

MPH-MLR (MLRTM) uses multilayer composite beads:⁵

• outer IR layer, approx. 40 % MPH
• inner layer with sustained release, approx. 60 % MPH

Dosage strengths:

• 10, 15, 20, 30, 40, 50, 60 mg

Food:

• as whole capsules
• as a sprinkle on applesauce

Pharmacokinetics:¹⁰

• fast initial release, comparable to IR-MPH
  • Cmax 1 approx. 2 hours after ingestion
• consequences of small but noticeable decrease in MPH release during midday
  • moderate decrease in plasma concentration in hours 4 to 6
• second controlled release of MPH during the rest of the day
  • gradual increase to attenuated second peak (Cmax 2) in hours 7 to 8 hours after ingestion
• gradual decrease in MPH levels during dinner and bedtime
• Duration of action approx. 10 to 12 hours

Half-life

• approx. 5 hours (healthy adults, fasting)

Food:
high-fat breakfast

• increased Cmax by approx. 28 %
• increased AUC by approx. 19
• reduced the second peak
• delayed the Tmax by 1 hour

14.2.1.6.2. 20 % IR / 80 % ER¶

Preparation: ADHANSIA XR®

Multilayer bead technology such as MPH-MLR

• outer IR layer approx. 20 % MPH
• inner layer with controlled release approx. 80 % MPH

Pharmacokinetics:¹⁰

• first peak after approx. 1.5 hours
• second tip after approx. 12 hours
• after adjustment to body weight, age-independent pharnacokinetics

Half-life:

• for adults approx. 7 hours
• approx. 5 hours for young people
• for children approx. 4 to 7 hours

Floating equilibrium/steady state

• in healthy adults, fasting, 100 mg: from day 3
  then
  • first Cmax increased by 22
  • second Cmax similar to 20 mg IR-MPH 3 x daily every 4 hours
  • AUCcum 50 % higher than with IR MPH

Dosage strengths:

• 25, 35, 45, 55, 70, 85 mg
• Take as a whole capsule or sprinkled on applesauce

Food:
High-fat meal caused

• Cmax unchanged
• AUC unchanged
• Tmax1 like Tmax2 delayed by one hour (compared to fasting)

14.2.1.6.3. 40 Or 50 % IR / 50 or 60 % ER¶

Biphentin®
Canada

Capsule contains pellets consisting of two layers and a core.

• Capsule shell is provided with a dissolution-delaying coating
• The outer layer of the capsule contains the immediately releasing active ingredient (active ingredient content 40 or 50 %)
• Outer capsule and inner capsule are separated by a membrane
• The inner layer of the capsule contains an active ingredient that can only slowly overcome the surrounding membrane (active ingredient content 60 or 50 %)
• there is a capsule core inside the inner capsule layer

14.2.1.7. MPH-ERCT¶

Preparation: QUILLICHEW ER® (USA)

MPH-ERCT are cherry-flavored chewable tablets.⁵

Retard distribution:

• 30 % IR MPH, uncoated microparticles
• 70 % ER MPH, coated microparticles

Active ingredient distribution:¹⁰
MPH comes from

• 15 % MPH hydrochloride salt
• 85 % MPH ionically bound to sulfonate groups of sodium polystyrene sulfonate particles

Dosage strengths:

• 20, 30, 40 mg

Pharmacokinetics:

• in healthy adults, fasting, 40 mg:
  • Peak after about 5 hours
  • Half-life 5.2 hours
  • Duration of action approx. 12 hours
• in children and adolescents with ADHD
  • not examined

Bioavailability of a 40 mg single dose of MPH-ERCT

• equalizes two IR-MPH chewable tablets of 20 mg each 6 hours apart up to Cmax
  • Cmax at MPH-ERCT compared to the second peak of IR-MPH by 20 %
• Duration of action 12 hours

Food:
A high-fat meal resulted in a 40 mg single dose:

• Tmax unchanged
• Cmax increased by 20
• AUC increased by 4

14.2.1.8. MPH XR-ODT¶

Preparation: COTEMPLA XR-ODT® (USA, 2017)

Once-daily, orally disintegrating tablet⁵

• 25 % IR-MPH
• 75 % ER-MPH

Retardation technique:
Ion exchange resin technology in which MPH is ionically bound to the sulfonate of polysterene sulfonate microparticles. To produce MPH-loaded microparticles, MPH salts are dissociated in solution and the positively charged MPH replaces the Na+ of the resin. These microparticles are either uncoated (IR) or coated (ER) and are then pressed into tablets.¹⁰

Dosage strengths:

• 8.6; 17.3; 25.9 mg
• corresponds to 10, 20, 30 mg MPH hydrochloride
• do not chew or crush
• remove from blister with dry hands

Pharmacokinetics:

• healthy adults, fasting. 51.8 mg MPH XR-ODT
  • broad peak
  • Maximum after 5 hours
  • consequences of apparent first-order elimination phase
  • Duration of action approx. 12 hours
• for children
  • Cmax 2-fold higher than in adults
• for adolescents
  • Cmax as for adults
• according to body weight
  • no differences between the age groups.

Half-life: 4 hours

Food:
High-fat meal:

• Tmax shortened by 30 minutes
• Cmax reduced by 24
• AUC increased by 16

14.2.1.9. DR/ER-MPH¶

Preparation: JORNAY PM™ (USA)

DELEXIS® drug delivery platform

Special feature: Take in the evening.

Uniform microspheres consisting of a core with two functional layers.¹⁰¹⁸

• outer layer with delayed release (DR layer)
  • hydrophobic, hygroscopic, pH-dependent polymers
  • are said to have a therapeutic effect on waking up
• inner ER layer
  • hydrophobic, soluble polymers
  • should maintain effectiveness for the rest of the day
• Core with IR-MPH

Dosage strengths.

• 20, 40, 60, 80, 100 mg
• Dose proportionality between the 20 and 100 mg dose

Pharmacokinetics:

• Start of MPH release approx. 8 to 10 hours after ingestion
  • barely relevant release of less than 5% of the total active ingredient during the night
  • long-lasting effect from early morning to late afternoon or evening¹⁸
• single peak
  • in healthy adults 14 to 16 hours after ingestion
  • in children and adolescents with ADHD 16 to 18 hours after ingestion
• then prolonged, controlled release throughout the day
  • Release takes place in the large intestine because the coated capsule travels through the digestive tract for several hours before starting to take effect
  • more than 50 % of MPH release occurs after peak concentrations are reached
• almost constant after adjustment to dose and body weight, independent of age
• Steady state is reached with the second dose.
• prolonged elimination phase and 25 % lower bioavailability compared to IR-MPH
• due to absorption by the large intestine, which is less resorbable
• part of the released MPH is not absorbed but excreted in the stool
• Due to the properties of the multiple polymers in the DR and ER layers of DR/ER-MPH micropellets, the initial dissolution and subsequent absorption of MPH is not dependent on a single factor, such as pH, gastrointestinal tract fluctuations or site of release. Therefore, DR/ER-MPH is less susceptible to the influence of individual triggers, resulting in reduced fluctuations in absorption and thus less (subjective) differences in effect between patients and in individual patients over the duration of intake.
• Duration of effect increased with increasing dose¹⁸
• Responder rate up to 97 %¹⁸
• Remission rate up to 87 %¹⁸
• Sleep problems were the most common side effect and were present in 97% of the people with ADHD by the end of the 6-week trial¹⁸
• In a retrospective cohort of patients 16 years and older, the mean initial dose of DR/ER-MPH was 53.6 mg/day and the mean optimized dose after more than 3 months of treatment was 81.9 mg/day. More than half of these patients optimized to a dose of 100 mg/day. Due to absorption in the lower gastrointestinal tract, DR/ER-MPH has a reduced bioavailability compared to other MPH preparations. In adults, the relative bioavailability of DR/ER-MPH is 73.9% compared to MPH-IR. The optimized doses of DR/ER-MPH ranged from 1.8 to 4.3 times that of previous long-acting stimulants and 4.7 to 6.0 times that of previous short-acting stimulants ¹⁸

Half-life in healthy adults, fasting: approx. 5.9 to 6.5 hours

Food:

• DR/ER-MPH capsules can be swallowed whole or opened and sprinkled on applesauce
• High-fat meal in the evening with intake caused
  • AUC unchanged
  • Cmax reduced by 11 % to 14 %
  • Tmax delayed by approx. 2.5 hours
• Low-fat or high-fat breakfast
  • no influence on pharmacokinetics
  • probably because DR/ER-MPH microspheres are already present in the colon

14.2.1.10. Novo-MPH ER-C¶

MPH Novo-MPH ER-C tablets were first approved in Canada in 2010¹⁹ and are considered bioequivalent to OROS-MPH there.²⁰

Preparation: Teva-Methylphenidate ER-C (Canada)

We have not yet found any information on the mechanism of action of Novo-MPH ER-C.

14.2.1.11. Matrix technology¶

Preparation:

• Kinecteen® (D/A/CH) / Rubicrono® (Spain) / Xaggitin® (United Kingdom)

Slowly eroding matrix tablet. Swells on contact with liquid and forms a translucent gel. MPH is released in a controlled manner when the gel layer breaks down.²¹

Dosages:

• 18, 27, 36, 45, 54 mg (Kinecteen)

We have not yet found any further information on the mechanism of action of Kinecteen.

Preparation:

• Metadate ER tablets

The matrix release system works by forming a water channel through the tablet. The active ingredient is released through the channel and the thickness of the matrix layer in the tablet determines the release rate.²²
The tablets are not divisible, as a break increases the surface area of the tablet, which changes the release rate. The tablets must be swallowed whole⁵

Dosages:

• 20-mg

Pharmacokinetics:

• Maximum after 4 to 5 hours

14.2.1.12. “Lumpy gravy” technology¶

Preparations:

• Metadate ER®
• Methylin ER®

“Lumpy gravy” is a good linear release mechanism and was one of the first working technologies for the prolonged release of methylphenidate¹

The MPH is mixed with treated cellulose and wax to hold the tablets together.
When the tablets come into contact with the stomach acid, they float up, similar to lumps in a sauce. The physical action of the stomach breaks up the lumps and releases the MPH.
The tablets can be divided into pieces in order to fine-tune the dose, despite the sustained release.¹

Typical duration of action approx. 6 hours.
This is better than the 2.5 to 4 hours of the immediate release MPH, but too short for a school or work day, where at least 8 hours are required.¹

14.2.2. Transdermal delivery via patch¶

14.2.2.1. MTS¶

Preparation: DAYTRANA® (USA)

DOT Matrix® technology

MTS delivers racemic MPH transdermally via a diffusion-based patch¹⁰
The plaster consists of a carrier film made of apolyester/ethylene acetate laminate, which carries an MPH-containing multipolymer adhesive layer.
Apply to intact skin.
Continuous MPH delivery depending on patch size and wearing time.
Transdermal administration reduces first-pass metabolism.
Duration of action up to 9 hours

Dosage strengths:

• 10 mg (12.5 cm²)
• 15 mg (18.75 cm²)
• 20 mg (25 cm²)
• 30 mg (37.5 cm²)

Dose proportionality:

• For children with ADHD from 10 mg to 30 mg
  • Cmax of l-MPH dose-proportional
  • AUC slightly disproportionate
• 12.5 cm² patch shown over 9 hours
  • 2-hour delay in d-MPH absorption
  • Peak plasma concentration after 10 hours
  • Half-life approx. 4 to 5 hours
• Accumulation through long-term use
  • Equilibrium is probably reached after about 14 days
  • compared to single dose
    • AUC increased by 64 % and 76 % respectively
    • Cmax increased by 69 % and 100 % respectively
  • systemic exposure in children 1.4 to 1.6 times higher with systemic OROS-MPH
  • systemic exposure in adolescents, on the other hand, is similar for both formulations

14.2.3. Suspension¶

14.2.3.1. MEROS: ER-Suspension¶

Preparation: QUILLIVANT XR® (USA)

MEROS: LiquiXR® technology

Powder in bottles with 300, 600 or 750 mg. Becomes a suspension with 5 mg/ml MPH after the addition of water.¹⁰ The suspension is stable for 4 months at room temperature and must be shaken for 10 seconds before each use.⁵

MEROS contains two types of microparticles:

• solid particles with ion exchange resin, which form a complex with MPH through ion binding
  • release 20 % of the MPH as immediately effective
• Particles are coated with a layer of an aqueous, pH-independent polymer of different thicknesses
  • release 80 % of the MPH with a delay

Pharmacokinetic profile:

• rapid initial increase in MPH concentration
• then gradual, prolonged release

In healthy adults, a single dose of 60 mg, administered on an empty stomach:

• maximum d-MPH concentration after 5 hours
• Half-life 5.65 hours
• bioequivalent to two 30 mg doses of oral solution of IR-MPH 6 hours apart
• Onset of the effect within 45 minutes

In children and adolescents with ADHD

• Single dose of 20 or 60 mg:
  • maximum d-MPH concentration after 2 to 4 hours
• Single dose of 60 mg:
  • Cmax in children approx. 2 times higher than in adults
  • Cmax in adolescents comparable to adults

Dose proportionality:

• Cmax and AUC similar after adjustment for body weight

Food intake:

• high-fat breakfast:
  • shortened Tmax by 1 hour
  • increased Cmax by 28 %
  • increased AUC by 19