Microneedle-based intradermal versus subcutaneous administration of regular human insulin or insulin lispro: pharmacokinetics and postprandial glycemic excursions in patients with type 1 diabetes.

BACKGROUND: This study assessed pharmacokinetics (PK) and pharmacodynamic postprandial glycemia (PPG) in patients with type 1 diabetes mellitus (T1DM) after a standardized liquid meal following insulin lispro (IL) or regular human insulin (RHI) given by microneedle-based intradermal (ID) versus subcutaneous (SC) delivery. RESEARCH DESIGN AND METHODS: In this randomized, open-label, five-way crossover study, 29 T1DM patients received IL and RHI (0.125 U/kg) at 2 min and 17 min premeal, respectively, by both the SC and ID routes and also received RHI by the ID route at 2 min premeal. Blood glucose was stabilized at 120 mg/dL prior to a standardized 82-g carbohydrate liquid meal. ID delivery used a 34-gauge 1.5-mm steel microneedle, and SC delivery used a 31-gauge 8-mm syringe needle. RESULTS: The 90-min PPG (blood glucose area under the curve for 0-1.5 h) for ID RHI was 14% lower than SC RHI at -17 min (P < 0.0001) and 11% lower than ID RHI at -2 min (P = 0.0006). PPG did not differ between ID RHI and SC IL, both at -2 min (P = 0.8345). ID IL PPG was lower than SC, both at -2 min, but not significantly (P = 0.10). Both ID IL and ID RHI PK data showed significantly faster uptake and time to maximum concentration, higher maximum concentration, and shorter systemic circulating duration versus SC dosing. ID IL and RHI delivery was generally well tolerated. CONCLUSIONS: PPG with RHI administered ID via microneedle was improved versus SC delivery when dosed 17 min premeal. ID RHI provided similar control of PPG as SC IL immediately premeal. Further studies of ID insulin delivery via steel microneedles are warranted.

Intradermal microneedle delivery of insulin lispro achieves faster insulin absorption and insulin action than subcutaneous injection.

BACKGROUND: This study compared insulin lispro (IL) pharmacokinetics (PK) and pharmacodynamics (PD) delivered via microneedle intradermal (ID) injection with subcutaneous (SC) injection under euglycemic glucose clamp conditions. METHODS: Ten healthy male volunteers were administered 10 international units (IU) of IL at 3 microneedle lengths (1.25, 1.50, or 1.75 mm) in a randomized, crossover fashion on Days 1-3 followed by a repetitive ID 1.5-mm microneedle dose (Day 4) and an SC dose (Day 5). RESULTS: Microneedle ID delivery resulted in more rapid absorption of IL, with decreased time to maximum insulin concentration (ID vs. SC: 36.0-46.4 vs. 64.3 min, P < 0.05) and higher fractional availability at early postinjection times. ID produced more rapid effects on glucose uptake with shorter times to maximal and early half-maximal glucose infusion rates (GIRs) (ID vs. SC: time to maximum GIR, 106-112 vs. 130 min, P < 0.05; early half-maximal GIR, 29-35 vs. 42 min), increased early GIR area under the curve (AUC), and faster offset of insulin action (shorter time to late half-maximal GIR: 271-287 vs. 309 min). Relative total insulin bioavailability (AUC to 360 min and AUC to infinite measurement) did not significantly differ between administration routes. ID PK/PD parameters showed some variation as a function of needle length. Delivery of ID IL was generally well tolerated, although transient, localized wheal formation and redness were observed at injection sites. CONCLUSIONS: Microneedle ID insulin lispro delivery enables more rapid onset and offset of metabolic effect than SC therapy and is safe and well tolerated; further study for insulin therapy is warranted.

Microneedle-based intradermal delivery enables rapid lymphatic uptake and distribution of protein drugs.

PURPOSE: The purpose of this research was to examine the pharmacokinetics (PK) of drug uptake for microneedle-based intradermal (ID) delivery of several classes of protein drugs compared to standard subcutaneous (SC) administration. METHODS: Systemic absorption kinetics of various proteins were analyzed following microneedle-based ID delivery and standard injection methods in the swine model. Comparative PK data were determined using standard non-compartmental techniques based on blood serum levels. RESULTS: Delivery of proteins using microneedles resulted in faster systemic availability, measured via t(max,) and increased maximal drug concentration, C(max,) over SC delivery for all proteins tested. Some agents also exhibited increased bioavailability for the ID route. Imaging studies using reporter dyes showed rapid lymphatic-mediated uptake. CONCLUSIONS: Microneedle delivery is applicable to a wide variety of protein drugs and is capable of effective parenteral administration of therapeutic drug dosages. This delivery route alters absorption kinetics via targeting a tissue bed better perfused with lymphatic and blood vessels than the SC space. Microneedle delivery may afford various advantages, including a robust method to increase the absorption rate and bioavailability of proteins that have been challenging to deliver at therapeutic levels or with physiologically relevant profiles.

Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system.

The advantages of intradermal (ID) vaccine administration have been well documented but difficulties in performing ID vaccination using existing techniques and equipment have limited it's clinical application. In the present study, a new ID injection technique and associated microinjection system is described and evaluated in a swine and Human models. Clinical investigation models included: injection site imaging (X-ray and 3D ultrasound echography), histological examination of injection sites, fluid injection volume accuracy measurement, subject' perceived pain and local skin reactivity were specifically developed. These evaluations showed that microinjection system can make the practice of ID vaccination easy to perform, reliable and safe, thus setting the stage for broader clinical application of ID vaccine delivery.

Preclinical evaluation of microneedle technology for intradermal delivery of influenza vaccines.

Recent clinical studies have suggested that, for certain strains of influenza virus, intradermal (i.d.) delivery may enable protective immune responses using a lower dose of vaccine than required by intramuscular (i.m.) injection. Here, we describe the first preclinical use of microneedle technology for i.d. administration of three different types of influenza vaccines: (i) a whole inactivated influenza virus, (ii) a trivalent split-virion human vaccine, and (iii) a plasmid DNA encoding the influenza virus hemagglutinin. In a rat model, i.d. delivery of the whole inactivated virus provided up to 100-fold dose sparing compared to i.m. injection. In addition, i.d. delivery of the trivalent human vaccine enabled at least 10-fold dose sparing for the H1N1 strain and elicited levels of response across the dose range similar to those of i.m. injection for the H3N2 and B strains. Furthermore, at least fivefold dose sparing from i.d. delivery was evident in animals treated with multiple doses of DNA plasmid vaccine, although such effects were not apparent after the first immunization. Altogether, the results demonstrate that microneedle-based i.d. delivery elicits antibody responses that are at least as strong as via i.m. injection and that, in many cases, dose sparing can be achieved by this new immunization method.

Intranasal administration of dry powder anthrax vaccine provides protection against lethal aerosol spore challenge.

The use of an aerosolizable form of anthrax as a biological weapon is considered to be among the most serious bioterror threats. Intranasal (IN) delivery of a dry powder anthrax vaccine could provide an effective and non-invasive administration alternative to traditional intramuscular (IM) or subcutaneous (SC) injection. We evaluated a dry powder vaccine based on the recombinant Protective Antigen (rPA) of Bacillus anthracis for vaccination against anthrax via IN immunization in a rabbit model. rPA powders were formulated and administered IN using a prototype powder delivery device. We compared serum IgG and toxin neutralizing antibody (TNA) titers of rabbits immunized IN with 10 microg rPA of a powder formulation with those immunized with the same dose of liquid rPA vaccine, delivered either IN or by IM injection. In addition, each group was tested for survival after aerosol spore challenge. Our results showed that IN vaccination with rPA powders elicited serum PA-specific IgG and TNA titers that were equivalent to those raised by liquid rPA administered IN. Serum PA-specific IgG and TNA titers after IN delivery were lower than for IM injection, however, after aerosol spore challenge, rabbits immunized IN with powders displayed 100% protection versus 63% for the group immunized IN with the liquid vaccine and 86% for the group immunized by IM injection. The results suggest that an IN powder vaccine based on rPA is at least as protective as a liquid delivered by IM injection.

Microneedle-based intradermal delivery of the anthrax recombinant protective antigen vaccine.

The recombinant protective antigen (rPA) of Bacillus anthracis is a promising anthrax vaccine. We compared serum immunoglobulin G levels and toxin-neutralizing antibody titers in rabbits following delivery of various doses of vaccine by microneedle-based intradermal (i.d.) delivery or intramuscular (i.m.) injection using conventional needles. Intradermal delivery required less antigen to induce levels of antibody similar to those produced via i.m. injection during the first 2 weeks following primary and booster inoculation. This dose-sparing effect was less evident at the later stages of the immune response. Rabbits immunized i.d. with 10 mug of rPA displayed 100% protection from aerosol spore challenge, while i.m. injection of the same dose provided slightly lower protection (71%). Groups immunized with lower antigen doses were partially protected (13 to 29%) regardless of the mode of administration. Overall, our results suggest rPA formulated with aluminum adjuvant and administered to the skin by a microneedle-based device is as efficacious as i.m. vaccination.

Anthrax vaccine powder formulations for nasal mucosal delivery.

Anthrax remains a serious threat worldwide as a bioterror agent. A second-generation anthrax vaccine currently under clinical evaluation consists of a recombinant Protective Antigen (rPA) of Bacillus anthracis. We have previously demonstrated that complete protection against inhalational anthrax can be achieved in a rabbit model, by intranasal delivery of a powder rPA formulation. Here we describe the preformulation and formulation development of such powder formulations. The physical stability of rPA was studied in solution as a function of pH and temperature using circular dichroism (CD), and UV-visible absorption and fluorescence spectroscopies. Extensive aggregation of rPA was observed at physiological temperatures. An empirical phase diagram, constructed using a combination of CD and fluorescence data, suggests that rPA is most thermally stable within the pH range of 6-8. To identify potential stabilizers, a library of GRAS excipients was screened using an aggregation sensitive turbidity assay, CD, and fluorescence. Based on these stability profiles, spray freeze-dried (SFD) formulations were prepared at pH 7-8 using trehalose as stabilizer and a CpG-containing oligonucleotide adjuvant. SFD formulations displayed substantial improvement in storage stability over liquid formulations. In combination with noninvasive intranasal delivery, such powder formulations may offer an attractive approach for mass biodefense immunization.

Protective immunization against inhalational anthrax: a comparison of minimally invasive delivery platforms.

A new anthrax vaccine under clinical investigation is based on recombinant Bacillus anthracis protective antigen (rPA). Here, we investigated microneedle-based cutaneous and nasal mucosal delivery of rPA in mice and rabbits. In mice, intradermal (id) delivery achieved up to 90% seroconversion after a single dose, compared with 20% after intramuscular (im) injection. Intranasal (inl) delivery of a liquid formulation required 3 doses to achieve responses that were comparable with those achieved via the id or im routes. In rabbits, id delivery provided complete protection against aerosol challenge with anthrax spores; in addition, novel powder formulations administered inl provided complete protection, whereas a liquid formulation provided only partial protection. These results demonstrate, for the first time, that cutaneous or nasal mucosal administration of rPA provides complete protection against inhalational anthrax in rabbits. The novel vaccine/device combinations described here have the potential to improve the efficacy of rPA and other biodefense vaccines.

Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery.

Skin is an attractive target for delivery of genetic therapies and vaccines. However, new approaches are needed to access this tissue more effectively. Here, we describe a new delivery technology based on arrays of structurally precise, micron-scale silicon projections, which we term microenhancer arrays (MEAs). In a human clinical study, these devices effectively breached the skin barrier, allowing direct access to the epidermis with minimal associated discomfort and skin irritation. In a mouse model, MEA-based delivery enabled topical gene transfer resulting in reporter gene activity up to 2,800-fold above topical controls. MEA-based delivery enabled topical immunization with naked plasmid DNA, inducing stronger and less variable immune responses than via needle-based injections, and reduced the number of immunizations required for full seroconversion. Together, the results provide the first in vivo use of microfabricated devices to breach the skin barrier and deliver vaccines topically, suggesting significant clinical and practical advantages over existing technologies.