Transdermal Drug Delivery and Microneedle Technology

When science and nature combine in just the right amounts, the results can be astounding. Take transdermal drug delivery, which is expected to grow substantially in the next decade, with microneedle-based delivery devices expected to reach annual sales of 485 million units by 2030.

That figure is no surprise to those involved with transdermal drug delivery, which is one of those perfect blends of technology and medicine. The benefits of transdermal delivery over other methods are numerous—it provides a vastly superior experience for the patient in a large number of cases.

One reason for the expected market growth is advances in microneedle technology, including the use of liquid silicone rubber (LSR), which provides smaller, stronger polymers that are more stable and, thus, last longer through more uses. Details on engineering and manufacturing advances are outlined later in this article.

Perhaps the most promising devices being introduced today are those involving microneedles, which are divided into four types.

1. Hollow. These infuse a drug through the bores with adequate flow
2. Solid. These puncture holes in the skin to increase permeability where a drug can then be delivered
3. Coated. These are coated with a drug-containing dispersion
4. Polymer. These are made from special polymers the offer dissolving, non-dissolving, or hydrogel-forming options

Transdermal devices using microneedles solve a long-standing medical problem: the skin’s anatomical peculiarities make it difficult to cross. The skin’s major barrier consists of the stratum corneum, the outermost layer. However, the layer underneath, the viable epidermis, also plays a protective role.  According to research published in Pharmaceutics, only compounds that are able to get through the stratum corneum and diffuse through both layers of the epidermis have the potential to reach circulation and achieve systemic effects.

One obvious benefit of transdermal microneedle delivery is that it reduces the need for hypodermic injections. Although they’re effective, hypodermic needles can cause discomfort, bruising, and even hypersensitivity at the injection site. For patients receiving an occasional vaccine, this is a minor inconvenience; the effects are much more serious for patients requiring daily or weekly injections. A transdermal patch is virtually pain free and can be self-administered, resulting in improved medication compliance.

Another benefit is improved drug delivery, especially over an extended period. Orally-administered drugs must travel through the metabolic system of the liver, which eliminates a substantial amount before widespread distribution. Less drug is needed when administered through a transdermal device. In addition, a transdermal patch can deliver an even flow of the active ingredient over an extended period, ranging from 24 hours to seven days. Many oral medications do not absorb well in the gastrointestinal tract, resulting in low bioavailability. The bioavailability of a patch is also fairly low, but placed correctly, it can avoid first-pass metabolism and partial elimination.

Microneedle patches also permit site-specific dosing. For example, placing the patch on or near an injured appendage to reduce inflammation, rather than having the drug circulate throughout the entire body. Studies have shown that changes in the absorption and distribution of drugs administered via patches are quite different from those take orally.

Patches provide a different way to control a drug’s pharmacokinetics. Taking a pill once a day is relatively easy to remember. However, to reduce side effects or offset a metabolism issue, patients sometimes need to take a pill multiple times a day at precise intervals. This is inconvenient for patients and especially difficult to manage overnight. Patches allow for exact control of both dose and time. Twice the size of a patch means twice the dosage. When you need to stop dosing, you remove the patch.

Finally, there is evidence that transdermal microneedle methods are more effective than hypodermics for immunization. Certain cells in the epidermis and dermis (Langerhans and dermal dendritic, respectively) are part of the skin’s unique immune system. Because these cells are designed to initiate immune responses to protect the body, less vaccine is needed to initiate a defense response when administered via a transdermal patch than intramuscularly.

Large strides have been made in recent years in the design and manufacturing of microneedles, in part due to materials advances. Specifically, silicone has become an excellent materials option because of its haptic properties. In addition, silicone does not cause skin irritation, is biocompatible, and is compliant with medical industry regulations.

Liquid Silicone Rubber (LSR) technology has proven particularly suitable for transdermal drug delivery, providing small, strong polymers that are stable and long wearing. Microfabrication of needles requires the incorporation of parts weighed in micrograms or nanograms, and LSR allows complex, high-precision components to be produced in large volumes in these dimensions with relative ease and precise accuracy.

Keep in mind that transdermal administration is not appropriate for all types of drugs. The optimal physicochemical properties of the drug and its biological properties must be considered, along with the pharmacokinetic and pharmacodynamic properties of the drug. The most important requirement is the need for controlled delivery, such as short half-life, adverse effect associated with another route, or a complex oral or IV dose regime.

The parameters for ideal candidates can be divided into physicochemical properties, biological characteristics, and polymer variables.

1. The drug should have a molecular weight less than approximately 1000 Daltons.
2. The drug should have affinity for both lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin.
3. The drug should have a low melting point
4. Since the skin has a pH of 4.2 to 5.6, solutions within this pH range are used to avoid damage to the skin. However, for a number of drugs, there may also be significant transdermal absorption at pH values at which the unionized form of the drug is predominant.

1. The drug should be potent with a daily dose of the order of a few mg/day
2. The half-life of the drug should be short
3. The drug should be non-irritating and non-allergic
4. Drugs that degrade in the GI tract or are inactivated by hepatic first-pass effect are suitable candidates for transdermal delivery

Advances in transdermal drug delivery technology have been rapid because of sophisticated polymer science that allows incorporation of polymers in transdermal systems in adequate quantity. The release rate from transdermal systems can be tailored by varying polymer composition. Selection of a polymeric membrane is important in designing a variety of membrane-permeation controlled transdermal systems.

1. The polymer should be chemically nonreactive or an inert drug carrier
2. The polymer must not decompose on storage or during life span
3. Molecular weight, physical characteristic, and chemical functionality of the polymer must allow the diffusion of the drug substance at a desirable rate
4. The polymer and its decomposed product should be nontoxic. It should be biocompatible with skin
5. The polymer must be easy to manufacture and fabricate into desired products. It should allow incorporation of large amounts of active agent 

Silicone elastomer blend networks, sugar siloxanes, amphiphilic resin linear polymers, and silicone hybrid pressure sensitive adhesives are showing promise for potential performance advantages and improved drug delivery efficacy.

Early on, transdermal delivery systems were used mainly for delivery of small, lipophilic, low-dose drugs. More recently, delivery systems began using chemical enhancers, non-cavitational ultrasound, and iontophoresis to enhance the efficacy of transdermal patches. Today, the ability of iontophoresis to control delivery rates in real time is providing added functionality in a number of instances.

At the same time, microneedles combined with thermal ablation are progressing through clinical trials for delivery of macromolecules and vaccines, including insulin, parathyroid hormone, and influenza. With these enhancement strategies, transdermal delivery is poised to significantly impact drug delivery choices.

Both chemical enhancers and the newest physical enhancers (ultrasound, thermal ablation, and microneedles) have begun expanding transdermal delivery of macromolecules and vaccines. These scientific and technological advances enable targeted disruption of the stratum corneum while protecting deeper tissues, positioning all types of transdermal drug delivery to have a widespread impact on medicine.

For a recommendation on the best design or material for liquid silicone rubber applications contact your local Trelleborg Sealing Solutions marketing company.