A polymer that allows insulin to be delivered through the skin has shown positive results in preclinical studies and could one day offer an alternative to injections for diabetes.
The system could also be used for other protein- or peptide-based therapeutics that are too large to currently be delivered through the skin.
The skin-permeable polymer, described in Nature, exploits pH changes through different layers of the skin to non-invasively enhance its permeability while maintaining its integrity.
In combination with insulin, the polyzwitterion poly[2-(N-oxide-N,N– dimethylamino)ethyl methacrylate] (OP) polymer was able to quickly lower blood glucose levels within the normal range in diabetic mice and minipigs, producing results comparable to injection.
This occurred without damage to the skin and it did not adversely affect blood counts, biochemical parameters, or liver and kidney function.
“OP represents a promising non-invasive transdermal insulin delivery system, offering an ideal alternative to hypodermic injections for diabetes management,” reported Qiuyu Wei, PhD, from Zhejiang University in China, and co-workers.
While drug delivery through the skin is widely used for small molecules, those that are larger, such as proteins and peptides, present a greater challenge.
Methods to enhance the skin’s permeability—such as microneedles that pierce the stratum corneum to access dermal tissue, ultrasound, and jet injection that creates transient channels on the skin surface—compromise skin integrity, are inconvenient, and raise safety and infection concerns.
To investigate alternatives, the team designed a polymer that could transition from a polycation that binds to the surface stratum corneum of the skin to a polyzwitterion in its deeper layers.
The design of the highly water-soluble polyzwitterion OP was inspired by the skin’s characteristic gradient that moves from around pH5 to neutral as it traverses the sebum layer and surface of the stratum corneum to the deeper layers of the stratum corneum and viable epidermis.
The researchers report that insulin conjugated to OP efficiently penetrated the stratum corneum, viable epidermis, and dermis of the skin to enter the circulation of diabetic mice and minipigs.
OP facilitated the transport of insulin through the skin into systemic circulation and its accumulation in key glucose-regulating tissues that included the liver and skeletal muscles. Its use lowered blood glucose levels to the normal range within one or two hours, akin to that seen with injected insulin, and maintained normal levels for up to 12 hours.
“In summary, we present a non-invasive transdermal insulin delivery system that achieves in vivo hypoglycemic efficacy comparable to subcutaneous injections for diabetes treatment, resulting from the efficient skin permeation of OP,” the researchers reported.
“The OP conjugation is versatile for transdermal delivery of biomacromolecules such as peptides, proteins and nucleic acids, with broad therapeutic applications, warranting further investigation in future studies.”
