Needle-free Administration Research Articles

Lower-Sized Chitosan Nanocapsules for Transcutaneous Antigen Delivery.

Transcutaneous vaccination has several advantages including having a noninvasive route and needle-free administration; nonetheless developing an effective transdermal formulation has not been an easy task because skin physiology, particularly the stratum corneum, does not allow antigen penetration. Size is a crucial parameter for successful active molecule administration through the skin. Here we report a new core-shell structure rationally developed for transcutaneous antigen delivery. The resulting multifunctional carrier has an oily core with immune adjuvant properties and a polymeric corona made of chitosan. This system has a size of around 100 nm and a positive zeta potential. The new formulation is stable in storage and physiological conditions. Ovalbumin (OVA) was used as the antigen model and the developed nanocapsules show high association efficiency (75%). Chitosan nanocapsules have high interaction with the immune system which was demonstrated by complement activation and also did not affect cell viability in the macrophage cell line. Finally, ex vivo studies using a pig skin model show that OVA associated to the chitosan nanocapsules developed in this study penetrated and were retained better than OVA in solution. Thus, the physicochemical properties and their adequate characteristics make this carrier an excellent platform for transcutaneous antigen delivery.

The effect of needle-free administration of local anesthetic on the behavior and physiology of castrated pigs

Abstract Pigs are routinely castrated in many countries without giving pain relief, which is an animal welfare concern. The objectives of this study were to evaluate the stress caused by administering local anesthetic (LA) using a needle-free injection system and evaluate if there are any benefits of administering LA immediately before castration on postoperative pain. At 3 days of age, piglets were allocated to 1 of 4 treatment groups. Treatments included sham castration (CON), surgical castration (CAS), castration plus LA administered immediately before castration using a conventional needle and syringe (NED), and castration plus LA administered immediately before castration using a needle-free injection system (NF). In experiment 1, behavior and stress vocalizations were recorded during administration of treatments, and blood samples were collected from all piglets before and 30, 60, 120, and 180 minutes post-treatment to measure complete blood cell counts and cortisol concentrations. In experiment 2, behavior was recorded in the farrowing crate for 180 minutes post-treatment using 1-minute scan sampling (n = 9 pigs/treatment). Change in the percentage of stress vocalizations in response to processing differed among treatments ( P = 0.004) with CAS, NED, and NF pigs producing more stress vocalizations than CON. Over the entire processing period, tail movement and the sum of the behavioral scores during processing were greater ( P ≤ 0.01) for CAS, NED, and NF compared with CON pigs. During the administration of LA, NF pigs tended to have lower tail flicking ( P = 0.062) and sum of behavior scores ( P = 0.056) than NED pigs. Cortisol concentrations were elevated ( P P = 0.01) time lying without contact compared with CON pigs, and NED ( P = 0.074) and NF ( P = 0.032) pigs spent less time lying without contact compared with CAS pigs; however, there was no effect of treatment on other behaviors measured. These results suggest that administering LA using a needle-free injection may cause less stress; however, administering LA immediately before castration did not appear to reduce postoperative pain. More research is needed to find effective practical methods of pain relief for piglets during castration.

Needle-Free Jet Lidocaine Administration for Preinjection Anesthesia in Trigger Finger Injection: A Randomized Controlled Trial

To evaluate the efficacy of needle-free jet lidocaine (J-tip) administration for pain reduction in trigger finger corticosteroid injection compared with simultaneous lidocaine injection with corticosteroid. A prospective randomized clinical trial was performed in which patients received either 0.25 mL of 2% lidocaine administered by J-tip just prior to 0.5 mL of corticosteroid injection by needle or 0.5 mL of 1% lidocaine and 0.5 mL of corticosteroid administered simultaneously through a needle for the treatment of trigger finger. Both the expected painpreinjection and the actual pain experienced postinjection were measured with a visualanalog scale (VAS). Pain catastrophizing scale (PCS) scores were recorded before injection. The use of the J-tip demonstrated a lower mean actual pain, 3.3 VAS, compared with the control group, 4.6 VAS. Both study groups anticipated more pain than they actually experienced. The PCS did not correlate to pre- or post-injection scores. Needle-free jet administration of lidocaine reduces the pain associated with trigger finger injection. Patients anticipate more pain than they experience with trigger finger injection. Therapeutic I.

Rhamnogalacturonan-I Based Microcapsules for Targeted Drug Release.

Drug targeting to the colon via the oral administration route for local treatment of e.g. inflammatory bowel disease and colonic cancer has several advantages such as needle-free administration and low infection risk. A new source for delivery is plant-polysaccharide based delivery platforms such as Rhamnogalacturonan-I (RG-I). In the gastro-intestinal tract the RG-I is only degraded by the action of the colonic microflora. For assessment of potential drug delivery properties, RG-I based microcapsules (~1 μm in diameter) were prepared by an interfacial poly-addition reaction. The cross-linked capsules were loaded with a fluorescent dye (model drug). The capsules showed negligible and very little in vitro release when subjected to media simulating gastric and intestinal fluids, respectively. However, upon exposure to a cocktail of commercial RG-I cleaving enzymes, ~ 9 times higher release was observed, demonstrating that the capsules can be opened by enzymatic degradation. The combined results suggest a potential platform for targeted drug delivery in the terminal gastro-intestinal tract.

Responses of primary human nasal epithelial cells to EDIII-DENV stimulation: the first step to intranasal dengue vaccination.

BackgroundAbout half of the world’s population are living in the endemic area of dengue viruses implying that a rapid-mass vaccination may be required. In addition, a major target of dengue vaccine are children, thus, a needle-free administration is more attractive. These problems may be overcome by the alternative route of vaccination such as topical, oral and intranasal vaccination. Here, we investigated the possibility to deliver a dengue immunogen intranasally, a painless route of vaccination. The tested immunogen was the domain III of dengue serotype-3 E protein (EDIII-D3) loaded into trimethyl chitosan nanoparticles (EDIII-D3 TMC NPs). The primary human nasal epithelial cells, HNEpCs, were used as an in vitro model for nasal responses.ResultsAt tested concentrations, EDIII-D3 TMC NPs not only exerted no detectable toxicity toward HNEpC cultures but also efficiently delivered EDIII-D3 immunogens into HNEpCs. Moreover, HNEpCs quickly and strongly produced proinflammatory cytokines (IL-1β, IL-6, TNF-α), type-I IFN, the growth factors (GM-CSF, IL-7), the chemokines (MCP-1, MIP-1β, IL-8), Th1-related cytokines (IL-2, IL-12p70, IL-17, IFN-γ) and Th2-related cytokine (IL-4) in response to EDIII-D3 TMC NPs treatment.ConclusionsA potential mucosal delivery system for dengue immunogens was revealed and found to stimulate a strong local innate antiviral response which possibly leading to a systemic adaptive immunity.

A polyvalent influenza DNA vaccine applied by needle-free intradermal delivery induces cross-reactive humoral and cellular immune responses in pigs

BackgroundPigs are natural hosts for influenza A viruses, and the infection is widely prevalent in swine herds throughout the world. Current commercial influenza vaccines for pigs induce a narrow immune response and are not very effective against antigenically diverse viruses. To control influenza in pigs, the development of more effective swine influenza vaccines inducing broader cross-protective immune responses is needed. Previously, we have shown that a polyvalent influenza DNA vaccine using vectors containing antibiotic resistance genes induced a broadly protective immune response in pigs and ferrets using intradermal injection followed by electroporation. However, this vaccination approach is not practical in large swine herds, and DNA vaccine vectors containing antibiotic resistance genes are undesirable. ObjectivesTo investigate the immunogenicity of an optimized version of our preceding polyvalent DNA vaccine, characterized by a next-generation expression vector without antibiotic resistance markers and delivered by a convenient needle-free intradermal application approach. MethodsThe humoral and cellular immune responses induced by three different doses of the optimized DNA vaccine were evaluated in groups of five to six pigs. The DNA vaccine consisted of six selected influenza genes of pandemic origin, including internally expressed matrix and nucleoprotein and externally expressed hemagglutinin and neuraminidase. ResultsNeedle-free vaccination of growing pigs with the optimized DNA vaccine resulted in specific, dose-dependent immunity down to the lowest dose (200μg DNA/vaccination). Both the antibody-mediated and the recall lymphocyte immune responses demonstrated high reactivity against vaccine-specific strains and cross-reactivity to vaccine-heterologous strains. ConclusionThe results suggest that polyvalent DNA influenza vaccination may provide a strong tool for broad protection against swine influenza strains threatening animal as well as public health. In addition, the needle-free administration technique used for this DNA vaccine will provide an easy and practical approach for the large-scale vaccination of swine.

Fentanyl Iontophoretic Transdermal System: A Review in Acute Postoperative Pain.

Fentanyl iontophoretic transdermal system (ITS) [Ionsys(®)] is indicated for the management of acute postoperative pain in adults requiring opioid analgesia in the hospital setting. This article reviews the clinical use of fentanyl ITS for postoperative pain management, and summarizes the pharmacology of fentanyl and the characteristics of the two-component fentanyl ITS (Ionsys(®)) device. In well-designed, multicentre clinical trials, fentanyl ITS was an effective and generally well tolerated method for managing acute postoperative pain in inpatients who had undergone major abdominal, thoracic or orthopaedic surgery. Overall, fentanyl ITS provided equivalent analgesic efficacy to that with morphine patient-controlled intravenous analgesia (PCIA), but was perceived to be more convenient/easier to use than morphine PCIA by patients, nurses and physical therapists. Patients receiving fentanyl ITS also had a greater ability to mobilize after surgery than patients receiving morphine PCIA. In addition, relative to morphine PCIA, fentanyl ITS offers advantages in terms of the noninvasive administrative route (i.e. transdermal needle-free administration), pre-programmed delivery (no risk of programming errors/incorrect dosing) and improved tolerability with regard to the overall incidence of opioid-related adverse events (ORAEs) and some individual ORAEs. Hence, fentanyl ITS is a useful option for the management of acute postoperative pain in adults requiring opioid analgesia in the hospital setting.

Pharmacodynamics and clinical efficacy of fentanyl iontophoretic transdermal system for post-operative pain in hospitalized patients

Introduction: The fentanyl iontophoretic transdermal system (ITS) is a patient-controlled transdermal system allowing needle-free administration of on-demand doses of Fentanyl of 40 µg over a 10-min period up to 80 doses or over a 24-h period. It is indicated in opioid naïve patients for the treatment of acute postoperative pain in the hospitalized patients for up to 72 h.Areas covered: It has been demonstrated to be effective and safe in randomized trials and to provide comparable analgesia versus morphine intravenous (i.v.) patient-controlled analgesia (PCA) with adverse events similar between groups.Expert opinion: Fentanyl ITS has shown high patient satisfaction rates, and was described by patients and investigators as easy and convenient to use. These properties make this technology interesting when considering perioperative pain management. In the present health care environment additional data are required to establish the cost-benefit ratio of this technology in optimizing patient’s recovery from surgery.

Orotracheal administration of contrast agents: a new protocol for brain tumor targeting.

The development of new non-invasive diagnostic and therapeutic approaches is of paramount importance in order to improve the outcome of patients with glioblastoma (GBM). In this work we investigated a completely non-invasive pre-clinical protocol to effectively target and detect brain tumors through the orotracheal route, using ultra-small nanoparticles (USRPs) and MRI. A mouse model of GBM was developed. In vivo MRI acquisitions were performed before and after intravenous or orotracheal administration of the nanoparticles to identify and segment the tumor. The accumulation of the nanoparticles in neoplastic lesions was assessed ex vivo through fluorescence microscopy. Before the administration of contrast agents, MR images allowed the identification of the presence of abnormal brain tissue in 73% of animals. After orotracheal or intravenous administration of USRPs, in all the mice an excellent co-localization of the position of the tumor with MRI and histology was observed. The elimination time of the USRPs from the tumor after the orotracheal administration was approximately 70% longer compared with intravenous injection. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify and longitudinally monitor the development of GBMs. The absence of ionizing radiation and high resolution of MRI, along with the complete non-invasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge, this is the first time that the advantages of a needle-free orotracheal administration route have been demonstrated for the investigation of the pathomorphological changes due to GBMs.

Enhancement of Mucosal Immunogenicity of Viral Vectored Vaccines by the NKT Cell Agonist Alpha-Galactosylceramide as Adjuvant.

Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (α-GalCer), a synthetic glycolipid agonist of natural killer T (NKT) cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including α-GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with α-GalCer adjuvant. These results support the utility of α-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors.

Comparing safety of abrasion and tape-stripping as skin preparation in allergen-specific epicutaneous immunotherapy

Comparing safety of abrasion and tape-stripping as skin preparation in allergen-specific epicutaneous immunotherapy

The Ocular Conjunctiva as a Mucosal Immunization Route: A Profile of the Immune Response to the Model Antigen Tetanus Toxoid

BackgroundIn a quest for a needle-free vaccine administration strategy, we evaluated the ocular conjunctiva as an alternative mucosal immunization route by profiling and comparing the local and systemic immune responses to the subcutaneous or conjunctival administration of tetanus toxoid (TTd), a model antigen.Materials and methodsBALB/c and C57BL/6 mice were immunized either subcutaneously with TTd alone or via the conjunctiva with TTd alone, TTd mixed with 2% glycerol or TTd with merthiolate-inactivated whole-cell B. pertussis (wBP) as adjuvants. Mice were immunized on days 0, 7 and 14 via both routes, and an evaluation of the local and systemic immune responses was performed two weeks after the last immunization. Four weeks after the last immunization, the mice were challenged with a lethal dose (2 × LD50) of tetanus toxin.ResultsThe conjunctival application of TTd in BALB/c mice induced TTd-specific secretory IgA production and skewed the TTd-specific immune response toward a Th1/Th17 profile, as determined by the stimulation of IFNγ and IL-17A secretion and/or the concurrent pronounced reduction of IL-4 secretion, irrespective of the adjuvant. In conjunctivaly immunized C57BL/6 mice, only TTd administered with wBP promoted the establishment of a mixed Th1/Th17 TTd-specific immune response, whereas TTd alone or TTd in conjunction with glycerol initiated a dominant Th1 response against TTd. Immunization via the conjunctiva with TTd plus wBP adjuvant resulted in a 33% survival rate of challenged mice compared to a 0% survival rate in non-immunized animals (p<0.05).ConclusionConjunctival immunization with TTd alone or with various adjuvants induced TTd-specific local and systemic immune responses, predominantly of the Th1 type. The strongest immune responses developed in mice that received TTd together with wBP, which implies that this alternative route might tailor the immune response to fight intracellular bacteria or viruses more effectively.

Characterization and optimization of bilosomes for oral vaccine delivery

Oral vaccines offer significant benefits due to the ease of administration, better patient compliance and non-invasive, needle-free administration. However, this route is marred by the harsh gastro intestinal environment which is detrimental to many vaccine formats. To address this, a range of delivery systems have been considered including bilosomes; these are bilayer vesicles constructed from non-ionic surfactants combined with the inclusion of bile salts which can stabilize the vesicles in the gastro intestinal tract by preventing membrane destabilization. The aim of this study was to investigate the effect of formulation parameters on bilosome carriers using Design of Experiments to select an appropriate formulation to assess in vivo. Bilosomes were constructed from monopalmitoylglycerol, cholesterol, dicetyl phosphate and sodium deoxycholate at different blends ratios. The optimized bilosome formulation was identified and the potential of this formulation as an oral vaccine delivery system were assessed in biodistribution and vaccine efficacy studies. Results showed that the larger bilosomes vesicles (~6 µm versus 2 µm in diameter) increased uptake within the Peyer’s patches and were able to reduce median temperature differential change and promote a reduction in viral cell load in an influenza challenge study.

O004 Using type III interferon to improve the efficacy of vaccine and oncolytic viral vectors

Introduction Vaccines based on replicating viral vectors that express foreign antigens can generate superior durable antibody and memory CD8 T cell responses compared to inactivated virus or recombinant protein, with the added benefit of potential needle-free intranasal administration. Despite these significant advantages, safety concerns related to viral vectors as vaccine platforms can be an issue with this approach. Replicating viral vectors are perceived as less safe alternatives compared to other immunization modalities, especially in the context of intranasal administration, where the potential exists for systemic virus spread from the lung. The type III interferons (IL-29, IL-28A, IL-28B; also known as IFN-lambda1, 2, and 3) play a critical role in protecting epithelial cells in the lung and gut from virus infection, and can also stimulate adaptive immunity. We therefore examined the ability of this cytokine family to improve the safety and efficacy of a viral vector by limiting its systemic spread and vector-associated pathological effects after intranasal delivery. Methods Vesicular stomatitis virus (VSV) based vectors are promising candidates for use as vaccines and oncolytic agents. We generated recombinant VSV vectors expressing mouse IL-28A either from the fifth position or the more highly expressing first position of the viral genome, and measured virus replication in cell culture and mice. Results We found that IL-28A is properly expressed, secreted, and active when produced by VSV-infected cells. In cell culture, expression of IL-28A from VSV attenuated virus replication in type III IFN-sensitive cells, but not in type III IFN-resistant cells. Following intranasal inoculation in mice, spread of the VSV.IL28A vector from the lung to the lymph nodes, spleen, blood, liver, and brain was significantly reduced compared to recombinant wild-type VSV. Despite this attenuation, the VSV.mIL28A vector generated virus-specific CD8 T cell and antibody responses in mice that were comparable to wild-type VSV. Conclusion These studies demonstrate the ability of the type III interferon cytokine family to improve the safety and efficacy of a clinically promising viral vaccine vector. These results may potentially also inform the enhancement of VSV oncolytic activity by increasing selectivity of the virus for type III IFN-resistant tumor cells.

Eliciting mucosal and systemic CD8+ T-cell responses via pulmonary vaccination with synthetic nanoparticles (113.21)

Abstract Mucosal vaccines offer needle-free administration and can stimulate immune responses systemically and at mucosal sites. “Vectorless” vaccines based on antigens packaged in synthetic nanoparticles (NPs) offer potential advantages in manufacturing, enhanced safety, and lack of anti-vector immune responses. To this end, we tested the ability of lipid NPs encapsulating ovalbumin or SIV-gag epitopes with Toll-like receptor agonists to stimulate mucosal immunity following pulmonary vaccination in mice. CD11c+B220+MHC-II+CD205+ DCs and CD11c+MHC-IIloF4/80+CD11b+ macrophages were the major cell types acquiring antigen in the lungs. Following prime and boost, a dramatic expansion of endogenous antigen-specific CD8+ T-cells to ~15% of CD8+ cells in blood was observed-twice the level seen with soluble antigen vaccines and 3 times the level achieved by s.c. immunization. Antigen-specific T-cell expansion was detected in the local lung tissue (~60% of CD8 cells), as well as in the gut and vaginal tract (~40% CD8 cells). These T-cells produced effector cytokines, and lasting CD127hi KLRG1lo effector memory cells were detected at 11wks after priming in both systemic and mucosal compartments. ELISA analysis of serum, fecal pellets and vaginal washes demonstrated that humoral responses were also stimulated. This data provides evidence that mucosal delivery of synthetic NPs can safely and effectively stimulate CD8+ T cells at sites relevant for protection against mucosal pathogens such as HIV.

Vaccine delivery carriers: Insights and future perspectives

Vaccination is undoubtedly the most effective health intervention for disease prevention and eradication. Nevertheless, currently there is still a need for improving immunization coverage worldwide. A promising strategy to achieve this goal nowadays relies on the use of delivery carriers capable of inducing an effective immune response and providing improved stability, safety and cost effectiveness. This article focuses on analyzing the critical aspects in the design of these carriers, and reviewing the state of the art of currently marketed formulations and those in advanced clinical development. These vaccine delivery carriers include emulsions, liposomes and polymeric particulate carriers. Finally, particular attention is given to the evolution in the design of polymeric nanocarriers, which have been receiving increasing attention and hold promise to generate novel platforms for needle-free administration and single-dose vaccination.

“IDEAL” vaccines for resource poor settings

In developing countries, immunization delivery would be more efficient, safer and economical if all vaccines could elicit long-term protection following needle-free administration of just a single dose and without need for a cold chain, and if immunization left an indelible (e.g., serologic) marker that would identify immunized persons. A few existing vaccines (e.g., yellow fever, measles) confer long-term protection following a single dose. To accomplish the same with less immunogenic live vaccines and with non-living antigens, potent (parenteral and mucosal) adjuvants are required. Emerging knowledge of how the innate immune system modulates adaptive immune responses is guiding development of modern adjuvants that can markedly enhance immune responses to vaccines by selective stimulation of components of the innate immune system. Needle-free immunization can be accomplished by administering vaccines via mucosal (oral or nasal) or transcutaneous routes or by parenteral injection using needle-free injection devices. Technologies such as vitrification (treatment with trehalose followed by drying) render vaccines resistant to temperature extremes. Ideally, immunization would lead to a biomarker such as a specific vaccine-derived antibody that allows differentiation of successfully immunized persons from susceptibles.

Development and Testing of Solid Dose Formulations Containing Polysialic Acid Insulin Conjugate: Next Generation of Long-Acting Insulin

The need for lifelong, daily insulin injections can have a dramatic effect on patient compliance, can be painful, and runs the risk of local infections. Furthermore, needle-stick injuries are common, and the issue of needle disposal is troublesome. Injecting a long-acting insulin analog with needle-free administration would be a significant improvement for diabetic subjects, but is not currently feasible. To achieve a constant, reliable delivery of a novel, long-acting insulin analog, Lipoxen's SuliXen (polysialylated insulin) in a solid dosage form capable of being delivered without a needle has been developed. The aim of this study was to evaluate the feasibility of Lipoxen's SuliXen delivery with the Glide solid dose injector, Glide SDI. A formulation containing 14 kDa polysialic acid (PSA)-recombinant human insulin conjugate was manufactured at Lipoxen PLC and transferred to Glide Pharma. The PSA-insulin conjugate solution was incorporated into different excipients at Glide Pharma (excipients 1 and 2), and formulations were manufactured containing implants with doses of 0.3 and 1.0 IU of insulin, respectively. Two different polymeric excipients were investigated for their suitable release profiles. The physicomechanical properties of the formulations were characterized in terms of solid dosage form strength (via three-point bend and compression) and disintegration time at 37 degrees C. A preclinical efficacy study was performed in a nondiabetic rat model (Sprague-Dawley). The study demonstrated successful incorporation of PSA-insulin conjugate into formulations compatible for use with the solid dose injector. Physicochemical characterization indicated that each formulation produced was physically robust. For excipient 1, the compressive stress and three-point-bend-test values recorded for the 0.3 IU formulation were 106.99 +/- 14.3 MPa and 30.6 +/- 1.4 N (force in newtons), respectively. Corresponding values for the 1.0 IU dose were 53.10 +/- 10.2 MPa and 16.66 +/- 1.0 N. For excipient 2, the compressive stress and three-point-bend-test values recorded for the 0.3 IU dose were 53.10 +/- 10.2 MPa and 7.64 +/- 0.9 N, respectively, whereas the corresponding values recorded for the 1.0 IU dose were 41.61 +/- 7.4 MPa and 13.18 +/- 1.3 N. Each formulation successfully penetrated a laboratory substrate, achieving 100% penetration in each case. In vivo analysis demonstrated that PSA-insulin conjugate shows prolongation of activity (at least two-fold more compared to insulin) for more than 5 hours in the rat model. Even though additional work may be required, for example, to develop several fixed dose formulations, the preliminary results show that solid dosage forms incorporating PSA-insulin conjugate maintained the prolongation of PSA-insulin conjugate activity in the rat model. Convenient and easy to use, the solid dose injector will not only ensure diabetic patient compliance and trust but also provide cost-effective solutions for safe, reliable, and controlled needle-free injection of PSA-insulin conjugate.

Topical Delivery of Interferon Alpha by Biphasic Vesicles: Evidence for a Novel Nanopathway across the Stratum Corneum

Noninvasive delivery of macromolecules across intact skin is challenging but would allow for needle-free administration of many pharmaceuticals. Biphasic vesicles, a novel lipid-based topical delivery system, have been shown to deliver macromolecules into the skin. Investigation of the delivery mechanism of interferon alpha (IFN alpha), as a model protein, by biphasic vesicles could improve understanding of molecular transport through the stratum corneum and allow for the design of more effective delivery systems. The interaction of biphasic vesicles with human skin and isolated stratum corneum membrane was investigated by confocal microscopy, differential scanning calorimetry (DSC) and small- and wide-angle X-ray scattering (SAXS and WAXS). Confocal microscopy revealed that biphasic vesicles delivered IFN alpha intercellularly, to a depth of 70 microm, well below the stratum corneum and into the viable epidermis. DSC and SAXS/WAXS data suggest that the interaction of biphasic vesicles with SC lipids resulted in the formation of a three-dimensional cubic Pn3m polymorphic phase by the molecular rearrangement of intercellular lipids. This cubic phase could be an intercellular permeation nanopathway that may explain the increased delivery of IFN alpha by biphasic vesicles. Liposomes and submicrometer emulsion (the individual building blocks of biphasic vesicles) separately and methylcellulose gel, an alternative topical vehicle, did not induce a cubic phase and delivered low amounts of IFN alpha below the stratum corneum. Molecular modeling of the cubic Pn3m phase and lamellar-to-cubic phase transitions provides a plausible mechanism for transport of IFN alpha. It is hypothesized that induction of a Pn3m cubic phase in stratum corneum lipids could make dermal and transdermal delivery of other macromolecules also possible.

Needle‐Free Subcutaneous Sumatriptan (Sumavel™ DosePro™): Bioequivalence and Ease of Use

Subcutaneous (s.c.) injection of sumatriptan is currently associated with needle aversion in some patients, and sharps disposal issues. To investigate whether a needle-free system can deliver s.c. sumatriptan. If so, to examine whether needle-free administration is bioequivalent to a 26-gauge needle-based auto-injector. Lastly, to assess the needle-free system for clinical acceptability and ease of use during migraine attacks. Two clinical trials. Study A: Pharmacokinetics and bioequivalence was studied in normal adult volunteers (n = 57 total), directly comparing needle-free (Sumavel DosePro) with needle-based (Imitrex STATdose System) administration of 6 mg s.c. sumatriptan. An incomplete, randomized, partial factorial, crossover design was used. Each subject received 2 administrations of each product, at 2 of the 3 anatomical sites (abdomen, thigh or arm). There were appropriate "washout" periods between each. Pharmacokinetic sampling was at standard time points, and tests for bioequivalence then followed. Study B: The term "ease of use" was used for clinical acceptability and utility of the needle-free system when it was assessed among 52 outpatients treating migraine attacks. Instructional materials were used as would be provided after ordinary prescription. The primary endpoint was successful use of the needle-free system to administer sumatriptan at the first attempt, including appropriate injection site selection. Second and subsequent uses of the needle-free system were also documented. For administration sites in the thigh and the abdomen, but not the arm, the needle-free and needle-based systems were bioequivalent (for all pharmacokinetic endpoints the mean ratios between the 2 devices were always between 90.1% and 115%). Among outpatients treating a migraine attack with the needle-free system, 51 of 52 on first attempt used the needle-free system successfully when treating a migraine attack. Sumavel DosePro needle-free delivery system is a new presentation of s.c. sumatriptan that delivers drug effectively, is bioequivalent to the existing needle auto-injector when used at the thigh or abdomen, and is easy to use.