Scientists have developed a new system that can provide a controlled and sustained release of parkinsonian medications, thus enabling better management of Parkinson’s disease.
The mechanisms behind this delivery system were described in the study, “Multi-Drug-Loaded Microcapsules with Controlled Release for Management of Parkinson’s Disease,” published in the journal Small.
Parkinson’s is characterized by the loss of neurons that produce the neurotransmitter dopamine — a chemical messenger that is essential for muscle control. Levodopa (LD), which is a precursor to dopamine, has long been one of the gold standards for Parkinson’s treatment and can be taken orally up to six times per day.
However, as the disease progresses, patients typically need to gradually increase their levodopa dosage, resulting in a condition known as levodopa-induced dyskinesia. Dyskinesia is characterized by uncontrollable involuntary movements.
Additionally, patients also experience the emergence of off periods, or periods where symptoms return before another dose can be taken.
Administering levodopa in combination with both carbidopa and entacapone (sold by Novartis as Stalevo) has been shown to lessen symptoms and the number of “off” periods. Carbidopa helps prevent the breakdown of levodopa before it can reach the brain and take effect, while entacopone helps the levodopa and carbidopa work better by allowing more of it to reach the brain.
Researchers have attempted both to tackle levodopa-induced dyskinesia and improve patients’ compliance with their prescribed medication regimen.
Now, researchers at Nanyang Technological University (NTU), in Singapore, have developed a slow-release pill that delivers dopaminergic medication over a period of 24 hours.
“We hope that by reducing dosage to just once-a-day would greatly improve patient compliance, lower the pill burden of these patients, while alleviating the ‘off’ periods that these patients experience,” Joachim Loo, PhD, associate professor at NTU and founder of the university-incubated start-up LiberaTx, said in a press release.
The team previously engineered micro-capsules that allow slow, continuous, and controlled medication delivery. In this study, the NTU scientists sought to develop a multi-drug delivery system, specific to Parkinson’s, to provide sustained and controlled release of the triple dopaminergic medicines — levodopa or LD, carbidopa or CD, and entacapone or ENT.
“We engineered our micro-capsules to float in the stomach, thereby allowing for a slow but continuous delivery of drugs into the upper intestine for improved absorption,” Loo said. “This is key in maintaining the drugs’ concentration in the blood.”
To make the micro-capsules, the researchers used two biocompatible and biodegradable polymers approved by the U.S. Food and Drug Administration: poly-L-Lactic acid (PLLA) and polycaprolactone (PCL). These capsules were then loaded with LC, CD, and ENT, both in their hollow cavity and in their outer shell, at a ratio similar to commercial tablets.
The scientists evaluated several parameters in both the hollow and coated micro-capsules, such as the PLLA/PCL ratio — which can influence how the compounds are released — spray-coating of the capsules, and the medicines’ amount and localization.
The morphology of the micro-capsules — the relationships between their structures — was observed with scanning electron microscopy (SEM). Raman mapping was used to observe the polymer and medicine distribution within the micro-capsules.
Drug release profiles from various formulations were analyzed in simulated gastric and intestinal fluid for up to 24 hours. Then, the capsules’ floating capabilities and degradation capacity also were investigated.
Recent pharmacokinetics studies — those that study the movement of a compound into, through, and out of the body — have shown that these new micro-encapsulation formulations have longer half-lives and mean residence times, or how much time each molecule spends in the body, with enhanced bioavailability.
The researchers believe that multiple-drug encapsulation of LD, CD, and ENT could be further evaluated through studies in live animals and compared against commercially available formulations.
“This new drug formulation by the NTU team has the potential to enable oral delivery of levodopa in a steady sustained manner over 24 hours that will prolong the effectiveness of levodopa in [Parkinson’s] patients experiencing ‘wearing-off’ effects of levodopa,” said Louis Tan, deputy director of research at the National Neuroscience Institute, Singapore.
The new proprietary technology has been filed as a patent through NTUitive, NTU’s innovation and enterprise company, and is now being commercialized through LiberaTx. The start-up is planning clinical trials in Singapore and possibly in other territories to test the efficacy of the new system.
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