Method to Increase the Systemically Delivered Amount of Drug from Dissolving Microneedles

Abstract

To increase the absorbed amount of a drug from dissolving microneedles (DMs), three DM array chips were prepared in which (1) the drug was localized at the acral portion of DMs, (2) the drug was loaded in each whole DM, and (3) the drug was loaded in DMs and the chip. Fluorescein free form (FL) and its sodium salt (FLNa) were used as model drugs. The DM array chip had 15-mm diameter with 225 DMs, each 500-µm long with a 300-µm diameter base. The respective FLNa contents in the three chips were (1) Key words systemic delivery; dissolving microneedle; percutaneous absorption; rat Transdermal drug delivery systems (TDDS) are attractive drug delivery systems (DDS) for the systemic delivery of drugs with high safety. 1) However, TDDS products of drugs are only nine compounds such as nicotine, fentanyl, and hormones. The main reason is the poor permeability of drugs through the human skin. Moreover, most drugs do not permeate through the skin at therapeutically relevant rates. Consequently, a therapeutic drug concentration is not maintained in systemic circulation. To increase the permeability of the drug through the skin, several methods such as chemical enhancers, electric fields, ultrasound, and thermal methods have been attempted.2-6) Nevertheless, those technologies have not been applied to drugs as TDDS, because they often show skinrelated side-effects, skin damage, etc. To overcome the limitations of those technologies, microneedles (MNs) are being studied 7) : small needles by which microconduits are formed on the skin surface and through which drugs are absorbed into the skin. Human skin comprises three layers. The outermost one is the stratum corneum that is dead tissue with thickness of 10-15 µm. The stratum corneum has a strong primary barrier function against exogenous compounds, including drugs. MNs physically destroy the stratum corneum. Consequently, the drug permeates through the skin. MNs do not cause pain. Now, MNs of four kinds are used [8][9][10] : (1) extremely small needles through which the drug solution can be injected into the skin; (2) metallic and/or silastic MNs onto which surface drug is coated; (3) metallic and/or silastic MNs by which microconduits are made on the skin, after which a drug solution or cream is applied following removal of the microneedle; and (4) dissolving microneedles (DMs).11) DMs are made of watersoluble biopolymers such as chondroitin sulfate, hyaluronic acid and dextran, in which drug molecules are formulated as a solid dispersion or suspension.12) An important advantage of DMs over other MNs is that DMs have high biocompatibility, because the base polymer is made of water-soluble biopolymers and is more compatible with the human body than metal and silastic MNs. We have been studying on DMs for use as a delivery system for hydrophilic drugs such as peptide protein drugs. Results of those studies have improved the bioavailability (BA) of macromolecular drugs having poor permeability through the skin, for example 91.3-97.7% for insulin in mice 13) and of 81.5-102.3...

Microneedle Integrated Transdermal Patch for Fast Onset and Sustained Delivery of Lidocaine

“…37 Integration of high loading efficiency backing layer to the microneedle shafts does not require any ancillary equipments as has been reported previously. 26 Fabrication of the whole integrated patch system can be achieved within 1-2 minutes, thus commercial scaling up and production of these 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 23 microneedles is feasible. With more than 1.5 billion people around the world suffering from chronic pain and the pain management market projected to grow to about USD$60 billion by 2015, this microneedle integrated transdermal patch can possibly serve as a viable source for the transdermal delivery of lidocaine with a faster rate of pain relief as compared to the commercially available patch and creams.…”

“…25 Drug amounts in the range of 1-3 mg have been encapsulated at the maximum using polymeric microneedles. Ito et al recently demonstrated the attachment of drug loaded chip fabricated by pouring a drug-polymer glue in the molds of a tabletting machine, to a microneedle array fabricated by conventional mold based process to achieve a drug encapsulationof 12 mg. 26 5…”

Noninvasive vaccination against infectious diseases

“…In general, non-dissolvable microneedles are made of inorganic materials, such as metal, silicon, glass, and ceramics, while dissolvable microneedles are made from water-soluble biopolymers, such as sulfate dextran and chondroitin, in which the drugs are applied as a suspension that dissolves into the skin. 167 In fact, the eye may also be a target organ for microneedle application. 168 This technology can be applied to the delivery of DNA, viral capsid subunits, and inactivated and live attenuated vaccines.…”

Sinomenine hydrochloride-loaded dissolving microneedles enhanced its absorption in rabbits

“…Compared to the SH-G group, the cumulative permeation quantity and rate of SH from the SH-DM were 3.36-and 3.32-fold at 48 h, respectively. The results indicated that the cumulative permeation quantity of SH was Dissolving microneedles enhanced its absorption 3 significantly enhanced in SH-DM formulation which successfully broke and penetrated through the stratum corneum 56,57 .…”