What is microneedle
Microneedles are delicate clusters of fine needles made by micro-manufacturing technology. The length is 1-150μm, which is enough to penetrate the stratum corneum or active epidermis of human skin, but does not touch the nerves, has no pain, and has continuous promotion of drug transdermal delivery. Microneedle technology has the comprehensive characteristics of subcutaneous injection and ordinary transdermal patches. Its advantages include: 1. It can deliver macromolecules through the stratum corneum, and is suitable for the transdermal delivery of peptides, proteins and other macromolecular drugs, and even drug-loaded nanoparticles; 2. Compared with the painful subcutaneous injection, the microneedle is almost non-invasive and painless, and has good patient compliance; 3. The dosage is stable and controllable; 4. The bioavailability is high, which is equivalent to subcutaneous injection. The limitation of the microneedle is that it is only suitable for short-term administration and not suitable for large-dose administration. The high concentration in the skin may cause allergic reactions. Microneedles deliver drugs to the junction of active skin and dermis, where immune response cells are located. Therefore, microneedle administration is limited to compounds and prescriptions that are not immunologically active. But for vaccines, microneedles just promote the immune response.
According to the internal structure of microneedles, microneedles are divided into solid microneedles and hollow microneedles. Different types of microneedles have different administration methods. The solid microneedle can be administered by piercing and then pasting, that is, the microneedle patch acts on the skin to create micron-sized holes in the stratum corneum, and then the drug-containing transdermal patch is applied; it can also be wrapped first and then pasted. The mode of administration is to apply the drug to the skin after wrapping the drug on the microneedle. There is no drug reservoir in this mode of administration, and the drug is directly released to the targeted cells or infected tissues. The height of the solid microneedle for transdermal drug delivery is often less than 500 pm, and it does not touch the nerves in the deep layers of the skin, and the patient does not feel pain. Hollow microneedle is actually a kind of microsyringe, which is filled with a drug solution. Driven by the pressure of the liquid flow, the drug diffuses into the human skin through the cavity. Compared with solid microneedles, hollow microneedles are more complicated in design and preparation.
There are many types of materials for making microneedles, such as stainless steel, titanium, silicon, glass, maltose, polylactic acid glycolic acid (PLGA), etc. Among them, polymers have been studied as microneedle substrates. The polymer microneedles prepared by PLGA have a length of 700μm, a width of 200μm, a tip diameter of 25μm, an insertion strength (IF) of 0.06N, and a breaking strength (FF) of 0.20N/needle. Another important use of microneedles is transdermal immunization. Soluble polymer microneedles containing recombinant CN54 HIVgp140 and TLR4 agonist adjuvant MPLA can induce antigen-specific immunity, which is expected to realize HIV transdermal immunity. Compared with subcutaneous injection, microneedle immunization can significantly increase the IgA response level in blood and mucosa. The mechanism of microneedle penetration enhancement is fundamentally different from other physical penetration enhancement methods. Although iontophoresis, electroporation, ultrasonic introduction, pressure wave introduction and other methods can disrupt the orderly arrangement of skin stratum corneum lipids, increase the permeability of the skin stratum corneum. However, the microneedle directly forms an actual channel perpendicular to the skin on the stratum corneum, and its length, shape, model drug dosage, and administration method have a huge impact on the percutaneous penetration of the drug.
Microneedle length
The length of the microneedle should be able to penetrate into the skin to achieve a therapeutic effect, without touching the nerve tissue to avoid pain. Use microneedles with needle lengths of 300pm, 550pm, 700pm, and 900pm to treat freshly isolated human skins, and then dye them with trypan blue. Blue spots were seen on the back side of the skin treated with microneedles with needle lengths of 550μm, 700μm, and 900μm, but not seen on the skin treated with the 300μm microneedle array. With waterfall blue, dextran waterfall blue, and fluorescein isothiocyanate-dextran for transdermal administration, it was found that the last three types of longer microneedles can greatly increase the penetration rate, but the 300μm microneedles cannot. There is no significant difference in the transdermal delivery rate of the first three types of microneedles, so when the length of the microneedle is long enough to penetrate the skin, the penetration depth is no longer important; if the needle is too short to penetrate the skin, the transdermal delivery rate cannot improve.
Microneedle shape
Podophytoxin was used to study the penetration enhancing ability of three needle-shaped microneedles, including triangular, trapezoidal and spear-shaped. The permeation promotion ability is strengthened in order of triangle, trapezoid and spear shape. The transdermal absorption of drugs is related to the cross-sectional area of the microneedles: the larger the cross-sectional area, the greater the resistance; the shallower the effective depth of the microneedle penetration into the skin, the smaller the pore size and the smaller the drug permeability.
Drug molecular weight
Four biological macromolecular model drugs insulin (ISL), lysozyme (LSZ), ovalbumin (OVB), human serum albumin (HSA) were used to study the transdermal penetration enhancement effect of microneedle arrays. Their molecular weights are respectively 5.73kDa, 14.6kDa, 43.0kDa, 66.27kDa. The molecular weight of biomacromolecule drugs is inversely proportional to the transdermal penetration rate, that is, the micro-targeting small molecule drugs have a significant effect on promoting penetration. There are some problems that need to be solved for microneedle transdermal delivery, such as, the small size and special shape of microneedles may break during the process of inserting into the skin. Although the materials used to prepare the microneedles are all biocompatible metals, silicon, and biodegradable polymers, these materials may cause adverse reactions if they stay in the skin for a long time. How to ensure that the drug-coated microneedles will not fall off when inserted into the skin? How to ensure that the hollow microneedles will not be blocked? As the above problems are solved, the application of microneedles for transdermal drug delivery will become more widespread.