Septia Nurmala
Swallowing four different tablets three times a day may not sound like a pleasant experience. Neither does injecting medication every day. A new drug delivery system gives hope to bypass these issues by taking advantage of the skin’s physical and chemical properties, and the mass application is imminent.
Figure created by Septia Nurmala with BioRender.com.
Microneedles (MNs) are one type of drug delivery device containing micro-sized needles uniformly arranged and attached to a membrane, popularly known as patch. The drugs are incorporated into the needles and penetrate the skin deep enough to deliver it systemically. The patch where the needles are attached to acts as a backing layer to hold the needles in place, ensuring the dose is uniformly transported.
This device holds some key advantages over conventional drug delivery methods, with the most prominent feature being comfortability. The needles are usually less than 1 mm in height, an ideal size to cross the stratum corneum barrier of the skin without activating the pain fibers. The usefulness of this feature translates to chronic illnesses patients, such as insulin-dependent diabetes mellitus patients who require a daily insulin injection to manage their blood glucose levels. A clinical trial investigating the tolerability of conventional insulin injection versus insulin microneedle found that half of the participants experienced painless puncture with the microneedle, with 35% favoring the latter technique to be used in the future.
Insulin is one of the few substances benefited from this delivery system. With an area of less than 0.2 cm2, the choice of drugs incorporated into the needle array are limited. Only biological products (such as proteins and hormones) and high potency chemical-based products are viable because of the small amount they need to have an effect in the body, thus matching the finite area of the device. With very little surface available, microneedle’s beneficial feature does not leave much of an impact for the delivery of infectious drugs. This is because the treatment of infectious disease requires a certain dose that is usually around hundred milligrams to be delivered to create a Minimum Inhibitory Concentration (MIC)—a condition where the growth of 90% of the microorganism is inhibited with the lowest antimicrobial concentration, in order to prevent disease relapse that could lead to antimicrobial resistance (AMR). The aforementioned challenge inspired the researchers to conduct a study on the communicable disease drug delivery.
In a recent paper published in European Journal of Pharmaceutics and Biopharmaceutics, researchers developed a microneedle that can be used to transport drugs to treat tuberculosis. “The idea is to be able to transport high-dose drugs through microneedles. The small size of the microneedles is exclusively reserved for only high potent drugs—the kind of drugs that require only small doses to achieve therapeutic concentration. And we’d like to challenge the concept,” said Dr Anjani, one of the researchers behind the study.
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis that primarily infects lungs and, when left untreated, can cause serious damage to other organs. As dangerous as it is for individuals, M tuberculosis also poses a threat to global public health due to the bacteria’s capability to mutate and escape treatment, creating a highly resistant strain. To overcome this, clinical treatment of tuberculosis relies on using multi-drug regimens to combat the pathogen. Clinically used drugs for tuberculosis treatment consist of four different antibiotics: isoniazid, rifampicin, ethambutol, and pyrazinamide. These pills have to be taken three times a day for a 6-month period. The treatment has to be restarted ad nauseam when the patient misses a dose, creating inconvenience among patients. Because of this, Dr Anjani and colleagues tried to manufacture a new type of microneedle device called hydrogel-forming microneedle to transport the tablets directly through the skin.
Hydrogel-forming microneedles
There are various types of microneedles being developed, with the popular ones including solid, coated, dissolving, and hollow microneedles. Each type has its own distinct features as well as advantages and disadvantages. Solid MN works by puncturing the skin followed by the application of different patches containing the drugs. This two-step application process discourages patients from using it. Coated MN removes the hassle presented by solid MN, but its use is limited to potent drugs due to the finite surface area. Dissolving MN is preferred for controlled drug release following the degradation of the needle inside the skin, but the storage requirement hinders the clinical use of it. Hollow MN uses electricity to transport drugs, but the equipment associated with it somewhat reduces the convenience.
A group of researchers manufactured a new type of MN called hydrogel-forming microneedles. This MN is prepared by mixing hydrophobic and hydrophilic polymers in their aqueous form. When combined, the two polymers interact with each other forming a crosslink that changes the initial properties of each polymer and provides the microneedles with mechanical strength. What is interesting about this MN is the needles are devoid of drugs, instead the needles’ role is to take up the interstitial fluid from the skin to allow diffusion of the molecules. The molecules are contained within a reservoir, attached to the upper side of the patch–allowing the freedom in concentration and shape design of the pills.
The first step the researchers did was designing the microneedle film. There were 3 films created with different formulas as well as temperature and crosslinking time–which are the two critical steps during the crosslinking process. Reaction time is essential because the longer the reaction occurs, the higher the crosslinking degree will be, but the ability of the film to absorb will lessen. To test this theory, each of the films were analyzed for its swelling capacity. Higher swelling percentage indicates better solute absorbance from the drug reservoir to the film. The first formulation showed to have the highest swelling percentage, and subsequently will lead to more molecules getting administered into the skin.
Afterwards, the researchers constructed the needle arrays using the same solution used to manufacture the films. The solution was poured into a mould and dried to create a complete piece of microneedles. The mechanical resistance of the arrays was tested by measuring the reduced length of the needles before and after the compression with equal force. The ability of the needles to puncture the skin was also measured by using a non-adhesive tape as the stratum corneum model. The three models gave similar results; the deeper the layer tape, the fewer holes the needles were able to create, indicating the strong mechanical resistance alongside their ability to prevent the activation of the nerve fibers.
The challenge when designing hydrogel-forming MN is the construction of the reservoir, often in the form of tablets. Conventional tablets tend to need a lot of water to dissolve and get absorbed, but this is impossible when the device used to transport has limited space. The researchers then created a rapidly dissolving tablet made from a mixture of excipients that enhance the active substance’s solubility. When tested with permeation study—a type of study investigating how well the microneedle and the reservoir transport the drug using porcine skin as the model, the team concluded each reservoir has a different optimum enhancer type, concentration, and preparation method needed to dissolve the tablet completely in a short time frame.
“We have shown the versatility of this system for every drug, regardless of their potency. With a few modifications—either during the manufacturing process or by adding the right excipients, the needs of the active ingredients can be met,” Anjani said. “This preliminary study aids the optimization process needed should the pharmaceutical industry be interested in continuing to the pharmacokinetic phase to study the fate of this drug delivery system inside the living organism.”
The team remains optimistic that this drug delivery system is close to being commercialized, even if the Food and Drug Administration (FDA) declared otherwise following a Complete Response Letter (CRL) given to a pharma company seeking the approval of microneedle system for migraine treatment in 2020. “Mass application will occur maybe in about 5 years from now, with the COVID-19 vaccination underway and some companies finished with developing influenza vaccine patches, these can speed up the application process. Not to mention a few FDA-approved microneedles for cosmetic use,” Anjani added. Indeed, who is not interested in swapping their painful jabs with painless patch delivery?
References:
Anjani, Q. K. et al. (2021) ‘Versatility of hydrogel-forming microneedles in in vitro transdermal delivery of tuberculosis drugs’, European Journal of Pharmaceutics and Biopharmaceutics. Elsevier B.V., 158, pp. 294–312. doi: 10.1016/j.ejpb.2020.12.003.
Waghule, T. et al. (2019) ‘Microneedles: A smart approach and increasing potential for transdermal drug delivery system’, Biomedicine and Pharmacotherapy. Elsevier Masson SAS, pp. 1249–1258. doi: 10.1016/j.biopha.2018.10.078.