María Florencia Cafisi – Analytical Development Chief
In October, we join to the awareness campaigns on ADHD by sharing this article that briefly describes the characteristics of transdermal system containing methylphenidate that has been recently developed by Amarin Technologies for the treatment of this condition.
Pharmacological treatment of ADHD by the use of transdermal delivery systems offers advantages over oral dosage forms. Through careful selection of the excipients and a special packaging design, Amarin Technologies has developed a transdermal system that shows a drug release comparable to the innovation product with adequate quality and security.
ADHD is a neurodevelopmental disorder that affects around 3-5% of the school-age pediatric population worldwide and is associated with difficulties in academic performance and alterations in the child’s behavior and socialization patterns. Although it is usually diagnosed at an early age, this condition prevails in adults in 60-70% of cases. The main synthons of ADHD are impulsiveness, hyperactivity and/or attention deficit.
The purpose of ADHD treatment is to improve the patient`s quality of life. In accordance with the Diagnostic and Statistical Manual of Mental disorders (DSM-IV) and, based on clinical practice guidance, the pharmacological treatment of ADHD is recommended as part of the comprehensive multimodal approach, which also includes family support, school community a advice and psychological assistance.
Methylphenidate is one of the most frequently prescribed drugs for the ADHD treatment, both in oral pharmaceutical forms (immediate or modified release) and transdermal patches. Clinical studies show that the efficacy of both pharmaceutical forms is similar.
The methylphenidate transdermal patches are used once a day during 9 hours, and the drug’s half-life is between 3 and 4 hours since product removal from skin. When comparing both routes of administration, the main advantages of transdermal systems are longer therapeutic action and better compliance of the pharmacological treatment in comparison with oral forms, which is important considering that the target population is pediatrics. In children suffering from this condition, the patch shows a special benefit in terms of easy application and this therapy is widely accepted by both the kids and their families. Besides, the transdermal route of administration avoids first-pass metabolism, limiting hepatic and gastric side effects. Cutaneous absorption reduces plasma levels peaks and valleys, which also means benefits lowering the incidence of other side effects. Although some undesired local secondary effects have been reported (such as allergic contact dermatitis, pigmentation changes, sensitization reactions, etc.), they are generally mild, limited to the application area and in most times, are not permanent and revert when the use of the patch is interrupted.
The methylphenidate patch shows a lag-time of about 2 hours in the first use prior to detect plasma levels of the drug, however this period is reduced in case of repeated applications. The maximum plasma concentration of methylphenidate is reached after 8 -10 hours since the patch is adhered to skin and it has a long duration of action (about 10 – 12 hours for a period of use of 9 hours a day). With adequate medical follow-up, it is possible to design the treatment scheme that better fits the patient routine; for instance, in case of school-age children or adolescents, it is desirable to achieve the maximum therapeutic effect when they are at school and thus reducing the synthons associated with low academic performance, behavior disorders, and difficulties interpersonal relationships.
During the development of the new product, the evaluation of the adhesive properties was considered critic for Amarin, in particular the release liner peel, peel adhesion and shear. The excipient selection using different experimental designs allowed to achieve a quali-quantitative composition with no difficulties in detaching the release liner prior to use. The prototype showed no signs of cold flow, and there were not residues of adhesive matrix neither on the release liner nor on the inside of the pouch and no glue sticks on the skin as oozing. The adhesiveness was challenged by wearing tests, in vitro peel adhesion tests and finally by adhesion assessment during the pharmacokinetic clinical trial. This is mainly related with the drug release, because the patch should be adhered to the skin for 9 hours to guarantee pharmacological effect as expected.
Knowing that the methylphenidate molecule is sensitive to humidity, a special package was design, considering intellectual properties restrictions, that prevents product chemical degradation caused by moisture, reducing the impact on impurity formation and the potential drug content decrease. This was investigated through stability studies during formulation development and it was important to define the product shelf life.
Other significant advantage of Amarin`s formulation is its smaller size and lower drug content in comparison with the innovator product. This means that the residual drug content of the prototype is lower. As methylphenidate is a psychostimulant, the lower concentration and the lower residual drug content reduce risks if the patient or thirds parties are accidentally exposed to the patch and also discourages its potential abuse or misuse.
In conclusion, during the development of this methylphenidate transdermal delivery system, we focused on adhesive properties optimization, packaging design that assures product’s shelf-life and a similar or better in vivo performance in comparison with the marketed product. Once again, Amarin Technologies has achieved, with this new development of a methylphenidate transdermal patch, an advantageous pharmaceutical product that may be in an alternative for ADHD treatment. The development of this project has encompassed formulation and analytical method development and abbreviated methods validation, RLD characterization, impurity profile assessment, stability study at climatic zones II and IVb according to ICH guidance and pilot clinical pharmacokinetic study predicting bioequivalence vs RLD and Adhesion study. All these tasks have been carried out within the framework of the Good Manufacturing Practices and in compliance with regulatory expectations proposed by well-known Agencies.
In the month of the awareness about ADHD, through our daily work, we reinforce our commitment to contribute trough science and technology to improve the quality of life of the patients suffering from this condition, offering transdermal products as an alternative for therapeutic treatment.
Evaluating elevated release liner adhesion of a transdermal drug delivery system (TDDS): A study of Daytrana™ methylphenidate transdermal system; March 2011, Drug Development and Industrial Pharmacy 37(10):1217-24. Anna M Wokovich, Meiyu Shen, William Doub, Stella Machado
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