ArticleLiterature Review

Devices for intradermal vaccination

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

New insights in vaccine development, the need for safe, economic and efficient vaccine administration and the increasing mechanistic knowledge of immune responses induced by targeting the intradermal layers of the skin have all driven the engineering of devices for intradermal vaccination. In this review we highlight different delivery devices that make the epidermal and dermal layers of the skin accessible for vaccine administration. Depending on the device the desired vaccine can be applied either as a liquid formulation or as solid, powdered vaccine particles. The process of intradermal injection employs micron-sized needles that are inserted 1.5mm perpendicularly into the skin, and which inject approximately 100-200μl of a liquid vaccine formulation into the dermal skin layers. Tattoo devices, on the other hand, can be used to deliver liquid vaccine formulations into the dermal layer of the skin by the use of oscillating needles. Microneedle arrays are made of vaccine-coated solid microneedles or biodegradable microneedles. These are inserted into the dermal layers of the skin where either the vaccine coating is dissolved, or the microneedle itself dissolves in place. Jet-injectors operate by generating a high pressured stream, which flushes the liquid vaccine formulation into the deeper skin layers. Delivery devices using liquid vaccine formulations are advantageous, as established vaccine formulations can be used as provided without the need for reformulation. However, approaches that deliver vaccines in a solid form may also prove to be promising. One such method is the ballistic approach, in which solid vaccine particles or vaccine-coated gold particles are accelerated towards the skin by needle-free devices, so that the particles are deposited in the epidermal and dermal layers of the skin. These various delivery devices are explored in this review with regard to their delivery mechanism and ease of handling, their efficacy in clinical trials and their suitability for practical use.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Currently, most vaccines including inactivated-EV71 are administered intramuscularly (IM) or subcutaneously (SC) by injections with needles and syringes, which possess several inherent drawbacks (pain, medical personnel requirement, needlerelated diseases or injuries, and cold chains for storage and distribution, etc.) [12][13][14]. Besides, injection vaccination primarily delivers antigen to muscle or subcutis regions where neither is particularly rich in immunologically sensitive cells compared to the skin layers [15,16]. To overcome these limitations, development of needle-free, easy-to-use, and efficient vaccination strategies is urgently needed, especially during a pandemic. ...
... To breach skin's barrier imposed primarily by the outermost stratum corneum layer, a range of physical technologies, including iontophoresis, electroporation, liquid/powder jet injections, ultrasound and thermal ablation, have been extensively investigated [15,20,21]. Such approaches, however, employ sophisticated equipment, complex vaccination protocols, and may cause pain similar to standard needle injection. ...
... This should be due to the fact that dissolving MNs inherently target antigen to the epidermis and upper dermis layers, where much more APCs are available compared to muscle or subcutis regions (Fig. 4). Delivered immunogen could effectively contact and stimulate the skin's immunologically sensitive cells, thereby eliciting robust immune responses with a low antigen dose [15,22,50,51]. Additionally, the IgG isotype distributions indicated that, compared to SC injection, MN-1 and IM-10 immunizations developed more balanced cellular and humoral immune responses (Fig. 8C). ...
Article
Recent large outbreaks of hand-foot-and-mouth disease (HFMD) have seriously affected the health of young children. Enterovirus 71 (EV71) is the main causative agent of HFMD. Herein, for the first time, rapidly dissolvable microneedles (MNs) loaded with EV71 virus-like particles (VLPs) were evaluated whether they could induce robust immune responses that confer protection against EV71 infection. The characteristics of prepared MNs including hygroscopy, mechanical strength, insertion capacity, dissolution profile, skin irritation and storage stability were comprehensively assessed. EV71 VLPs remained morphologically stable during fabrication. The MNs made of sodium hyaluronate maintained their insertion ability for at least 3 h even at a high relative humidity of 75%. With the aid of spring-operated applicator, EV71 MNs (approximately 500 μm length) could be readily penetrated into the mouse skin in vivo, and then rapidly dissolved to release encapsulated antigen within 2 min. Additionally, MNs induced slight erythema that disappeared within a few hours. More importantly, mouse immunization and virus challenge studies demonstrated that MNs immunization induced high level of antibody responses conferring full protection against lethal EV71 virus challenge that were comparable to conventional intramuscular injection, but with only 1/10th of the delivered antigen (dose sparing). Consequently, our rapidly dissolving MNs may present as an effective and promising transcutaneous immunization device for HFMD prophylaxis among children.
... La seconde catégorie couvre à la fois l'immunisation épidermique et intradermique par la technologie gene gun et l'EGT (Peachman et al., 2003). L'immunisation balistique (gene gun) Par conséquent, afin de mieux standardiser cette injection, de nouveaux systèmes sont à l'heure actuelle développés tels que des systèmes de microinjection (microaiguilles, liquid jet injectors…) permettant une injection ID perpendiculairement à la peau (e.g Intanza  développé par Sanofi) (Kis et al., 2012 ;Lambert and Laurent, 2008 ;Laurent et al., 2007). ...
... utilise de l'hélium comprimé pour injecter des particules d'or qui sont chargées avec le plasmide. Malgré des résultats prometteurs, cette technique voit son efficacité limitée par la mort des cellules ayant intégré des particules d'or et par la polarisation des réponses CD4 en type Th2(Kis et al., 2012). L'EGT impliquant des impulsions électriques améliore la transfection de l'ADN (cette technique est décrite au point 3.4.3) ...
Thesis
Le cancer est l’une des principales causes de morbidité et de mortalité dans le monde. L’étude de ses mécanismes a mis en évidence des interactions particulières entre la tumeur et l’immunité adaptative. Les cellules cancéreuses suite à leur transformation maligne expriment des antigènes tumoraux reconnus par les LTs. Ce fondement constitue la base des immunothérapies ciblant les antigènes associés aux tumeurs (TAAs). Parmi les TAAs identifiés, la hTERT apparaît comme un antigène universel, par son implication dans le processus d’oncogenèse et sa surexpression dans 80 à 90% des cancers. Les réponses anti-hTERT trouvées chez des individus sains et des patients cancéreux, témoin d’un répertoire T spécifique préexistant et d’une cassure naturelle de la tolérance, ont orienté nos stratégies vaccinales sur ce TAA. Durant ce doctorat, des stratégies d’immunothérapies basées sur différents produits codant une forme inactive de la hTERT ont été développées. Le premier axe a constitué au développement de vaccins ADN thérapeutiques optimisés à la fois dans leur construction (délétions, réarrangements) et dans leur mode de délivrance. Une procédure d’électroporation a été mise au point afin de les délivrer efficacement dans le derme. Deuxièmement, dans l’optique d’augmenter l’immunogénicité de l’ADN par la réalisation de vaccinations hétérologues ou de créer un produit dérivé, un vecteur rougeole recombinant la hTERT a aussi été développé. Au cours de ce projet, l’immunogénicité et la cytotoxicité des réponses induites par la vaccination pour l’ensemble des constructions ont été démontrées in vivo dans des souris conventionnelles ou transgéniques HLA. De plus, un effet anti-tumoral a aussi été démontré pour le premier produit clinique d’Invectys.
... 57 On the contrary muscle quite inefficient to capture antigens 26 and the IM route is therefore inferior to ID route in terms of biological mechanism and action.The molecular mechanisms of Fluzone Ò ID have been recently uncovered also using innovative cutting-edge biotechnologies, such as transcriptomic assays, which have shown a strong signature of adaptive immunity activation following vaccination. 58 In particular, Fluzone Ò ID seems to elicit temporary transcriptional changes in the circulating myeloid compartment. Vaccination upregulates modules linked to NF-kB-driven inflammation, IFN-g response, TNF and CD40 signaling. ...
... Solid-silicon microneedles and solid metal microneedle arrays, hollow-silicon microneedles, polymers-or carbohydrates-based microneedles, macroneedles, patches are other possible devices, which are being currently investigated. [58][59][60] ID devices are used in other fields, such as diabetology (such as SQ-PEN technology, InsuJet TM , Injex23 TM , Injex30 TM , Vision Ò MediJector II TM , or ClickSoft TM for the delivery of insulin), 61,62 immunology/allergology, 63 anaesthesiology (J-Tip Needle-Free Injector, Medajet-XL), 64-65 endocrinology (for the delivery of growth hormones, including for example Bioject Ò Cool Click TM , SeroJet, Antares' Medi-Jector Vision technology), 66 dermatology and cosmetology (for example, MTS ROLLER TM , ScalpRoller TM , DERMAROLLER Ò , MICRO HYALA Ò , or LITE CLEAR Ò , for the treatment of anti-aging, scars, hair-loss, and acne). 67 The Soluvia BD device represents the first FDA-approved delivery system in the field of vaccinology. ...
Article
Full-text available
Influenza is a highly contagious respiratory acute viral disease which imposes a very heavy burden both in terms of epidemiology and costs, in the developed countries as well as in the developing ones. It represents a serious public health concern and vaccination constitutes an important tool to reduce or at least mitigate its burden. Despite the existence of a broad armamentarium against influenza and despite all the efforts and recommendations of international organisms to broaden immunization, influenza vaccination coverage is still far from being optimal. This, taken together with logistic and technical difficulties that can result into vaccine shortage, makes intra-dermal (ID) vaccines, such as Fluzone® ID and Intanza®, particularly attractive. ID vaccines are comparable and, in some cases, superior to intra-muscular/sub-cutaneous vaccines in terms of immunogenicity, safety, reactogenicity, tolerability and cross-protection profiles, as well as in terms of patient preference, acceptance and vaccine selection. Further advances, such as Fluzone® ID with alternative B strains and Quadrivalent Fluzone® ID or the possibility of self-administering the vaccines, make influenza ID vaccines even more valuable.
... One approach is to coat a solution containing the vaccine onto the outer surface of nondissolving microneedles. Non-dissolving microneedles for influenza vaccination are usually made of materials such as stainless steel, titanium, silicon, or glass and manufactured by a chemical etching process, a strong cutting laser, or electropolishing [86]. The coating is applied by dipping a small array of microneedles into a coating solution and then drying by an air or vacuum drying. ...
... Another approach uses (water) dissolving microneedles consisting of vaccines encapsulated in matrices of polymers like CMC, polyvinylpyrrolidone (PVP), polyethylene glycol, or polyvinylalcohol, polysaccharides like dextrin, dextran, or hyaluronic acid, disaccharides like maltose, and monosaccharides like galactose (Figure 2(a)) [86,87]. These microneedles dissolve within minutes once inserted into the skin. ...
Article
Full-text available
Cold-chain requirements, limited stockpiling potential and the lack of potent immune responses are major challenges of parenterally formulated influenza vaccines. Decreased cold chain dependence and stockpiling can be achieved if vaccines are formulated in a dry state using suitable excipients and drying technologies. Furthermore, having the vaccine in a dry state enables the development of non-parenteral patient friendly dosage forms: microneedles for transdermal administration, tablets for oral administration, and powders for epidermal, nasal or pulmonary administration. Furthermore, in comparison to parenteral administration, these administration routes have the potential to elicit an improved immune response. This review highlights the rationale for the development of dried influenza vaccines, as well as processes used for the drying and stabilization of influenza vaccines; it also compares the immunogenicity of dried influenza vaccines administered via non-invasive routes with that of parenterally administered influenza vaccines. Finally, it discusses unmet needs, challenges and future developments in the field of dried influenza vaccines.
... For instance, (i) MicronJet ™ , a hollow MN device made of silicon with a commercial licence for vaccine delivery. MicronJet ™ , which has been developed by NanoPass Technologies, by delivering 20% of the flu vaccine dose has been found to cause a similar or greater effect than the standard vaccine [72], (ii) Fluzone ® , an injection system utilising a MN for the delivery of the seasonal influenza vaccine that obtained Food and Drug Administration (FDA) approval in 2011 [73], (iii) 3M™ Microchannel Skin System, a MN patch consisting of 351 MN/cm 2 (650 m in height) used to pre-treat the skin prior to dermatological applications [74] and (iv) Dermaroller ® , a FDA approved MN system based on 192 titanium MN of 0.5 mm in a cylindrical assembly used for skin care with creams and serums (Fig. 3). 3M also has solid (sMTS) and hollow (hMTS) microstructured transdermal systems using polymeric MN which can be integrated with a glass reservoir for self-administration. hMTS, ranging from 500-900 m in height, have been studied for the delivery of human growth hormone with a bioavailability close to the obtained using a conventional syringe. ...
... Patches of 1,000 MN of 250 m in height were successfully inserted to a depth of 120 m in hairless guinea pig skin, achieving a delivery of 60-70% of the naloxone hydrochloride coated on the sMTS [75]. Other MN devices are still undergoing pre-clinical and clinical studies, such as the Macroflux ® patch from Zosano Pharma, a drug-coated titanium MN patch for the treatment of severe osteoporosis from which positive feedback was given by participants in focus groups [76], the Nanopatch ™ a vaccine-coated MN and the dissolvable MN devices MicroCor ® for the delivery of parathyroid hormone and TheraJect ™ Patch for sumatriptan and vaccine delivery [72]. A clinical study to compare the preference of the h-Patch ™ for the delivery of insulin in diabetic patients was carried out in 2007 but was terminated as the endpoint resulted not to be meaningful [77]. ...
Article
Microneedles (MN) offer a simple, minimally invasive and reduced pain alternative to hypodermic needles for drug delivery, including vaccines. Previous studies investigating the use of MN have highlighted the benefit of this technology to facilitate dermal and transdermal drug delivery. Going forward towards commercialization, it is important to consider the perceptions and acceptability that MN technology will have once available in the market. This review collects the opinions and expectations of different population groups such as children, parents, paediatricians and the general public on various MN systems. In addition, the low pain perception scores, based on a visual analog scale for MN application, should also lead to a greater acceptability of this technology as a means of transdermal drug delivery. This review also highlights the potential challenges associated with the different types of MN together with issues of sterility and biocompatibility which will be important future factors to consider.
... The needle-based delivery system functions as the standard intradermal injection technique that involves the insertion of the tip into the skin and pushing the contents within a plastic 1 ml disposable syringe (Lambert and Laurent, 2008). For avoiding disadvantages of needle-based administrations, vaccine delivery systems facilitated by needle-free injection, liquid jet injectors, ballistic injectors, and microneedle injection have been developed (Giudice and Campbell, 2006;Kis et al., 2012;Hossain et al., 2020). Different delivery methods have different immune efficiency attributed to the priming of immune cells and subsequent immune response. ...
Article
Full-text available
Microneedles have garnered significant interest as transdermal drug delivery route owing to the advantages of nonselective loading capacity, minimal invasiveness, simple operation, and good biocompatibility. A number of therapeutics can be loaded into microneedles, including hydrophilic and hydrophobic small molecular drugs, and macromolecular drugs (proteins, mRNA, peptides, vaccines) for treatment of miscellaneous diseases. Microneedles feature with special benefits for cutaneous diseases owing to the direct transdermal delivery of therapeutics to the skin. This review mainly introduces microneedles fabricated with different technologies and transdermal delivery of various therapeutics for cutaneous diseases, such as psoriasis, atopic dermatitis, skin and soft tissue infection, superficial tumors, axillary hyperhidrosis, and plantar warts.
... Des techniques de vaccination sans aiguille se sont aussi développées (Kersten and Hirschberg, 2007;Kis et al., 2012) incluant l'administration par voie transcutanée (TC) (Lee et al., 2013;Matsuo et al., 2013). Cette voie consiste en l'application topique d'Ag directement sur l'épiderme intacte (y compris la couche cornée) ou prétraité (perturbation chimique ou physique de la couche cornée) (Combadiere and Liard, 2011 (Mahe et al., 2009), sur des explants de peau humaine (Vogt et al., 2006) et chez l'homme au cours d'essais cliniques de vaccination contre la grippe Gonçalves et al., 2019;Vogt et al., 2008) et contre le VIH (Cheeseman et al., 2018;Haidari et al., 2017) (Combadiere and Liard, 2011) Chapitre II : ...
Thesis
Les vaccins doivent d’être plus sûrs et plus immunogènes que leurs ascendants empiriquement développés afin d’éradiquer les maladies infectieuses à l’origine de millions de morts dans le monde chaque année. Pour cela, il nous faut comprendre les interrelations entre les réponses immunitaires innées et adaptatives sous-jacentes à la protection acquise par la vaccination. Au cours d’études cliniques randomisées, de vaccins contre la grippe et contre le VIH, des données issues de dosages immunologiques classiques sont combinées aux profilages moléculaires par cartographie omique grâce à la biologie des systèmes. Ainsi, des signatures moléculaires de l’immunité innée essentielles à la conduite des immunités humorale et cellulaire, sont mises en lumière tout en considérant l’importance des voies d’administration. Alors, les réponses anticorps provoquées par la vaccination, selon les voies intramusculaire et intradermique, reposent sur des molécules issues de la signalisation interféron, du traitement et de la présentation antigénique, dépendent de l’état de développement des cellules B et passent par l’induction de CXCL10 ou d’IL-6. Tandis que les réponses cellulaires T CD8+ après immunisation transcutanée sont engagées par les voies métaboliques. De telles signatures moléculaires, traduites en biomarqueurs d’efficacité vaccinale, nous guident vers un développement rationnel des vaccins et faciliteront leur dépistage lors d’essais cliniques pour répondre plus rapidement aux épidémies. Une meilleure compréhension des origines de l’hétérogénéité interindividuelle des réponses vaccinales permettront d’adapter les formulations afin d’améliorer la protection au sein des populations.
... However, for hypodermic needles, superficial injections into the dermis are only possible through the Mantoux method. This is a difficult and inconsistent injection method and requires highly trained personnel [119,120]. Furthermore, the patient often experiences more pain during this injection [121]. For this reason, almost all needle injections are done in the deeper skin layers, such as the subcutis and muscles. ...
Article
Full-text available
Needle-free jet injectors have been proposed as an alternative to injections with hypodermic needles. Currently, a handful of commercial needle-free jet injectors already exist. However, these injectors are designed for specific injections, typically limited to large injection volumes into the deeper layers beneath the skin. There is growing evidence of advantages when delivering small volumes into the superficial skin layers, namely the epidermis and dermis. Injections such as vaccines and insulin would benefit from delivery into these superficial layers. Furthermore, the same technology for small volume needle-free injections can serve (medical) tattooing as well as other personalized medicine treatments. The research dedicated to needle-free jet injectors actuated by laser energy has increased in the last decade. In this case, the absorption of the optical energy by the liquid results in an explosively growing bubble. This bubble displaces the rest of the liquid, resulting in a fast microfluidic jet which can penetrate the skin. This technique allows for precise control over volumes (pL to μ L) and penetration depths (μ m to mm). Furthermore, these injections can be tuned without changing the device, by varying parameters such as laser power, spot size and filling level of the liquid container. Despite the published research on the working principles and capabilities of individual laser-actuated jet injectors, a thorough overview encompassing all of them is lacking. In this perspective, we will discuss the current status of laser-based jet injectors and contrast their advantages and limitations, as well as their potential and challenges.
... Microneedle patch technology has the potential to overcome the challenges involved in mass vaccination against COVID-19 across the world and has already shown promising achievements in delivering lyophilised or liquid formulation-based vaccines and macromolecules including influenza vaccines and insulin [19][20][21]. Research showed effective delivery of solidstate influenza vaccine into mice skin by microneedles [22], and delivery of macromolecular drugs to deep skin tissues of rats by a minimally invasive system consisting of microneedles and skin electroporation [23]. In particular, microneedles facilitate transdermal delivery of water-soluble and high molecular weight drugs. ...
Article
Full-text available
Microneedle-based microdevices promise to expand the scope for delivery of vaccines and therapeutic agents through the skin and withdrawing biofluids for point-of-care diagnostics – so-called theranostics. Unskilled and painless applications of microneedle patches for blood collection or drug delivery are two of the advantages of microneedle arrays over hypodermic needles. Developing the necessary microneedle fabrication processes has the potential to dramatically impact the health care delivery system by changing the landscape of fluid sampling and subcutaneous drug delivery. Microneedle designs which range from sub-micron to millimetre feature sizes are fabricated using the tools of the microelectronics industry from metals, silicon, and polymers. Various types of subtractive and additive manufacturing processes have been used to manufacture microneedles, but the development of microneedle-based systems using conventional subtractive methods has been constrained by the limitations and high cost of microfabrication technology. Additive manufacturing processes such as 3D printing and two-photon polymerization fabrication are promising transformative technologies developed in recent years. The present article provides an overview of microneedle systems applications, designs, material selection, and manufacturing methods.
... Due to the convenience of intramuscular (IM) injection, the majority of vaccines have been injected into the muscular tissue (3). To overcome some drawbacks of needle-based injection delivery, such as needlestick injuries and sharps waste, needle-free Jet Injectors (PharmaJet, Bioject) were developed to deliver high-speed fine-stream liquid vaccines into the muscular tissue (4)(5)(6)(7). ...
Article
Full-text available
Vaccine delivery technologies are mainly designed to minimally invasively deliver vaccines to target tissues with little or no adjuvant effects. This study presents a prototype laser-based powder delivery (LPD) with inherent adjuvant effects for more immunogenic vaccination without incorporation of external adjuvants. LPD takes advantage of aesthetic ablative fractional laser to generate skin microchannels to support high-efficient vaccine delivery and at the same time creates photothermal stress in microchannel-surrounding tissues to boost vaccination. LPD could significantly enhance pandemic influenza 2009 H1N1 vaccine immunogenicity and protective efficacy as compared to needle-based intradermal delivery in murine models. The ablative fractional laser was found to induce host DNA release, activate NLR family pyrin domain containing 3 (NLRP3) inflammasome, and stimulate interleukin 1β release despite of their dispensability for laser adjuvant effects. Instead, the ablative fractional laser activated MyD88 to mediate its adjuvant effects by potentiation of antigen uptake, maturation, and migration of dendritic cells. LPD also induced minimal local or systemic adverse reactions due to the micro-fractional and sustained vaccine delivery. Our data support the development of self-adjuvanted vaccine delivery technologies by intentional induction of well-controlled tissue stress to alert innate immune systems for more immunogenic vaccination.
... IN influenza vaccination provides an important alternative to needle-based IM vaccination for those who have needle phobia [35]. Needle-free Jet Injectors, such as PharmaJet and Bioject ZetaJet, have been also developed for the IM delivery of inactivated influenza vaccines [36][37][38]. Due to the richness of antigen-presenting cells (APCs) in the skin [39,40], inactivated influenza vaccines are also approved for ID delivery by Intradermal Microinjection Systems and MicronJet600 to save vaccine dose and cost [41,42]. Based on the usage, influenza vaccines can be divided into seasonal, pre-pandemic, and pandemic vaccines [32]. ...
Article
Full-text available
Influenza poses a huge threat to global public health. Influenza vaccines are the most effective and cost-effective means to control influenza. Current influenza vaccines mainly induce neutralizing antibodies against highly variable globular head of hemagglutinin and lack cross-protection. Vaccine adjuvants have been approved to enhance seasonal influenza vaccine efficacy in the elderly and spare influenza vaccine doses. Clinical studies found that MF59 and AS03-adjuvanted influenza vaccines could induce cross-protective immunity against non-vaccine viral strains. In addition to MF59 and AS03 adjuvants, experimental adjuvants, such as Toll-like receptor agonists, saponin-based adjuvants, cholera toxin and heat-labile enterotoxin-based mucosal adjuvants, and physical adjuvants, are also able to broaden influenza vaccine-induced immune responses against non-vaccine strains. This review focuses on introducing the various types of adjuvants capable of assisting current influenza vaccines to induce cross-protective immunity in preclinical and clinical studies. Mechanisms of licensed MF59 and AS03 adjuvants to induce cross-protective immunity are also introduced. Vaccine adjuvants hold a great promise to adjuvant influenza vaccines to induce cross-protective immunity.
... Intradermal injections may potentially reduce the occurrence and intensity of pain associated with injection due to the low presence of pain sensory nerves [15]. However, the total thickness of the dermal tissue is approximately 4 mm and so, the limit of allowed variation in target depths for jet injection is very small [20], and very few devices have been specifically designed for delivering intradermal injections [21][22][23]. ...
Article
Transdermal drug delivery using spring-powered jet injection has been studied for several decades and continues to be highly sought after due to the advent of targeted needle-free techniques, especially for viscous and complex fluids. As such, this paper reports results from numerical simulations to study the role of fluid rheology and cartridge geometry on characteristics such as jet exit velocity, total pressure drop and boundary layer thickness, since these all factor in to jet stability and collimation. The numerical approach involves incompressible steady flow with turbulence modelling based on the system Reynolds number at the orifice (Re = ρdovj/μ). The results are experimentally validated for a given geometry over a wide range of Reynolds numbers (101 < Re < 104), and our results indicate a sharp decrease in dimensionless pressure drop (Eu = 2∆P/ρvj2) for Re < 102) and gradually approaching the inviscid limit at Re ≥ 104. By extending the study to non-Newtonian fluids, whose rheological profile is approximated by the Carreau model, we also elucidated the effect of different rheological parameters. Lastly by studying a range of nozzle geometries such as conical, sigmoid taper and multi-tier tapers, we observe that fluid acceleration suppresses the boundary layer growth, which indicates there may be optimal geometries for creating jets to target specific tissue depths.
... Sous ce terme de nombreux systèmes existent [36] ; les aiguilles peuvent être en silicium, en métal comme le titane ou le nickel [37] , en polymères types poly lactic-co-glycolic acid ou polyacide glycolique [38] , ou encore en composés permettant une dissolution in situ. La géométrie, le type d'espacement des aiguilles, qu'elles soient pleines ou creuses, ont été étudiés afin d'obtenir un bon compromis entre la force mécanique nécessaire et la pénétration cutanée [39] . ...
Article
Résumé La peau limite l’entrée des substances appliquées et régule les pertes en eau par l’intermédiaire de son stratum corneum. La fonction barrière de la peau n’est pas absolue et sa perméabilité est liée aux propriétés physicochimiques des molécules en contact. Les molécules absorbées sont distribuées dans l’organisme après un transfert passif, puis éliminées ou stockées. Dans ce domaine, l’état de la peau est également un facteur primordial et des différences d’absorption sont importantes entre une peau saine et des peaux pathologiques ou présentant des lésions d’origine diverse. L’estimation du pourcentage de substance absorbée est un point particulièrement important pour l’évaluation du risque en cosmétique. En règle générale, cette évaluation est mise en œuvre sur une peau saine, mais le développement des routines de soins, l’usage extensif de promoteurs d’absorption, l’utilisation en vue d’améliorer l’efficacité de produits dits « frontières », enfin l’emploi récurrent de gadgets ou de techniques issues du secteur pharmaceutique, peuvent majorer l’absorption des ingrédients utilisés. Cet article développe l’analyse de l’impact des formulations et des dispositifs utilisés en faveur de la pénétration des actifs, ainsi que les conséquences de l’utilisation de produits dont l’objectif initial est d’améliorer l’état cutané et pour lesquels l’absorption des ingrédients est un élément secondaire.
... Indeed, many existing springand gas-actuated jet injectors operate at a single velocity, usually between 100 and 200 m/s [2]. This does not allow adapting to the broad variety of mechanical properties of skin and soft tissue in the population, thus occasionally resulting in uncontrolled drug delivery into deeper layers and excitation of nerve endings [4,[6][7][8]. ...
Article
Full-text available
Needle-free jet injection enables the delivery of drugs into skin or soft tissue by puncturing them with a high-velocity liquid jet. However, precise and efficient drug delivery requires generating such liquid jets with both a controlled velocity and a high throughput, which remains challenging with current spring- and gas-actuated jet injectors. Here, we propose a depth-controlled and high-throughput injection method by adapting laser-induced forward transfer (LIFT), a high-resolution two-dimensional printing technique, for direct three-dimensional liquid delivery into soft tissues. The velocity of thin liquid jets is laser actuated from 10 to 85 m/s so that doses as small as 10 pL, not achievable with other injectors, are injected at a 1 Hz repetition rate into a 300 μm thick soft gelatin substrate with a 25 μm depth precision and 12 μm lateral resolution. We further investigate the potential of this liquid delivery technique as a direct three-dimensional cell-delivery vehicle and show that depth-controlled particle delivery requires high-delivery efficiency. Our direct three-dimensional liquid delivery system opens up more possibilities for pinpoint drug delivery in soft tissues or tissue-engineered constructs.
... We have demonstrated higher intrinsic immune efficacy of our VREP vaccine via delivery in the skin as compared to the intramuscular (i.m.) route. 16,17 Another way to enhance the potency of DNA vaccination is in the vector itself. For instance, we and others have constructed DNA vectors based on the replicase of alphaviruses such as Semliki Forest virus (SFV), Sindbis virus and Venezuelan equine encephalitis virus (VEE). ...
Article
Full-text available
Cervical cancer develops as a result of infection with high-risk human papillomavirus (HPV) through persistent expression of early proteins E6 and E7. Our group pioneered a recombinant viral vector system based on Semliki Forest virus (SFV) for vaccination against cervical cancer. The most striking benefit of this alphavirus vector-based vaccine platform is its high potency. DNA vaccines on the other hand, have a major advantage with respect to ease of production. In this study, the benefits associated with both SFV-based vaccines and DNA vaccines were combined with the development of a DNA-launched RNA replicon (DREP) vaccine targeting cervical cancer. Using intradermal delivery followed by electroporation, we demonstrated that DREP encoding for E6,7 (DREP-E6,7) induced effective, therapeutic antitumor immunity. While immunizations with a conventional DNA vaccine did not prevent tumor outgrowth, immunization with a 200-fold lower equimolar dose of DREP (0.05 µg of DREP) resulted in approximately 85% of tumor-free mice. To overcome the safety concern of potential malignant transformation at the vaccination site, we evaluated the anti-tumor effect of a DREP vaccine encoding a shuffled version of E7 (DREP-E7sh). DREP-E7sh delayed tumor growth yet not to the same extent as DREP-E6,7. In addition, inclusion of a helper cassette and an ER targeting signal (sigHelp) did not significantly further enhance the suppression of tumor outgrowth in the long term, albeit exhibiting better tumor control early after immunization. Collectively, this study points towards the clinical evaluation of DREP encoding HPV antigens as a potent immunotherapy for patients with HPV16 (pre)-malignancies.
... Several years from past the formulation scientists are striving hard to develop a delivery system that works as needle- free injection (NFI) [18], These NFI devices can improve patient compliance by evoking less pain and stress. Novel inventions regarding NFI includes intradermal layers of the skin, that are being targeted for vaccination with innovative devices [19]. TDDS has been classified as first, second and third generation respectively, first generation includes delivery of low dose lipophilic drugs, second generation involved delivery system that used chemical enhancers, iontophoresis etc for clinical implications. ...
Article
Transdermal drug delivery system (TDDS) provides controlled and continuous input of drugs, especially those with short biological half-life, they are designed to deliver therapeutically effective concentration of drug through patient skin. Normally hypodermic needles are used in clinical practice to deliver medication across the skin, especially vaccines. Injections with hypodermic needles are essential from clinical point of view, but they are painful, they may induce hypersensitivity reactions, bruising or bleeding at the site of injection. So, in order to overcome these drawbacks associated with hypodermic needles in clinical practice, we designed micro needles. Microneedles have been designed as novel drug delivery carrier for Transdermal drug delivery system, they are similar to traditional needles, but they are of the size range from 1 micron to 100 microns in length and 1 micron in diameter. Microneedles are also known as micro scale needles arranged on a Transdermal patch, these are micro structure system composed of micronized array projections coated with a drug or vaccine. They improve patient compliance as self-administration is possible, micro needles are divided into four types: hollow, solid, coated and polymer. Hydrogel forming micro needles with super swelling properties shows enhanced stability and better patient acceptability.
... Adaptors that standardize ID injections offer the advantage to administer various drugs intra-dermally with a single types of standard tuberculin syringe (17,18). Solutions have been launched in the life-science market to perform ID injections perpendicular to the subject's skin (12,16,(19)(20)(21)(22). Perpendicular ID injections are promising new solutions since they allow targeting the dermis more precise and standardized, compared to the Mantoux technique, independent of the user's training experience. ...
Article
Full-text available
PurposeThe force that has to be exerted on the plunger for administering a given amount of fluid in a given time, has an important influence on comfort for the subject and usability for the administrator in intradermal drug delivery. The purpose of this study is to model those forces that are subject-independent, by linking needle and syringe geometry to the force required for ejecting a given fluid at a given ejection rate. Material and Methods We extend the well-known Hagen-Poiseuille formula to predict pressure drop induced by a fluid passing through a cylindrical body. The model investigates the relation between the pressure drop in needles and the theoretic Hagen-Poiseuille prediction and is validated in fifteen needles from 26G up to 33G suited for intradermal drug delivery. We also provide a method to assess forces exerted by operators in real world conditions. ResultsThe model is highly linear in each individual needle with R-square values ranging from 75% up to 99.9%. Ten out of fifteen needles exhibit R-square values above 99%. A proof-of-concept for force assessment is provided by logging forces in operators in real life conditions. Conclusions The force assessment method and the model can be used to pinpoint needle geometry for intradermal injection devices, tuning comfort for subjects and usability for operators.
... CV7201 doses of 80 µg up to 640 µg were tested using intradermal or intramuscular routes of administration with needle-syringe or needle-free injector devices. 16 Three different needle-free injection devices were used: intradermal injector 1 (Tropis; PharmaJet, Golden, CO, USA), a spring-powered intradermal injector; intra dermal injector 2 (Biojector 2000; Bioject Medical Technologies, Tigard, OR, USA), a carbon dioxide gas-powered intradermal injector; and intramuscular injector (Stratis; PharmaJet, Golden, CO, USA), a spring-powered intramuscular injector. The dose range was based on preclinical data, clinical experience with mRNA cancer vaccines, and by limitations imposed by injection volumes of the intradermal injectors (0·1 mL with a final concentration of 0·8 mg/mL) and intramuscular injector (0·5 mL with a final concentration of 0·4 mg/mL). ...
Article
Background: Vaccines based on mRNA coding for antigens have been shown to be safe and immunogenic in preclinical models. We aimed to report results of the first-in-human proof-of-concept clinical trial in healthy adults of a prophylactic mRNA-based vaccine encoding rabies virus glycoprotein (CV7201). Methods: We did an open-label, uncontrolled, prospective, phase 1 clinical trial at one centre in Munich, Germany. Healthy male and female volunteers (aged 18-40 years) with no history of rabies vaccination were sequentially enrolled. They received three doses of CV7201 intradermally or intramuscularly by needle-syringe or one of three needle-free devices. Escalating doses were given to subsequent cohorts, and one cohort received a booster dose after 1 year. The primary endpoint was safety and tolerability. The secondary endpoint was to determine the lowest dose of CV7201 to elicit rabies virus neutralising titres equal to or greater than the WHO-specified protective antibody titre of 0·5 IU/mL. The study is continuing for long-term safety and immunogenicity follow-up. This trial is registered with ClinicalTrials.gov, number NCT02241135. Findings: Between Oct 21, 2013, and Jan 11, 2016, we enrolled and vaccinated 101 participants with 306 doses of mRNA (80-640 μg) by needle-syringe (18 intradermally and 24 intramuscularly) or needle-free devices (46 intradermally and 13 intramuscularly). In the 7 days post vaccination, 60 (94%) of 64 intradermally vaccinated participants and 36 (97%) of 37 intramuscularly vaccinated participants reported solicited injection site reactions, and 50 (78%) of 64 intradermally vaccinated participants and 29 (78%) of 37 intramuscularly vaccinated participants reported solicited systemic adverse events, including ten grade 3 events. One unexpected, possibly related, serious adverse reaction that occurred 7 days after a 640 μg intramuscular dose resolved without sequelae. mRNA vaccination by needle-free intradermal or intramuscular device injection induced virus neutralising antibody titres of 0·5 IU/mL or more across dose levels and schedules in 32 (71%) of 45 participants given 80 μg or 160 μg CV7201 doses intradermally and six (46%) of 13 participants given 200 μg or 400 μg CV7201 doses intramuscularly. 1 year later, eight (57%) of 14 participants boosted with an 80 μg needle-free intradermal dose of CV7201 achieved titres of 0·5 IU/mL or more. Conversely, intradermal or intramuscular needle-syringe injection was ineffective, with only one participant (who received 320 μg intradermally) showing a detectable immune response. Interpretation: This first-ever demonstration in human beings shows that a prophylactic mRNA-based candidate vaccine can induce boostable functional antibodies against a viral antigen when administered with a needle-free device, although not when injected by a needle-syringe. The vaccine was generally safe with a reasonable tolerability profile. Funding: CureVac AG.
... A potential advantage of DNA microseeding is vaccine distribution over a large surface area, which could facilitate the transfection of a broad cell population (Kis et al. 2012). Additional advantages include: (1) natural production of antigen in vivo (as opposed to delivery of purified protein/peptides); (2) no need for specific formulation of the DNA vaccine; ...
Article
Full-text available
Spontaneous canine malignant melanoma provides an excellent pre-clinical model to study DNA vaccines for melanoma immunotherapy. A USDA-approved xenogeneic human tyrosinase (huTYR) plasmid DNA vaccine delivered intramuscularly induces detectable immune responses and has clinical activity in some dogs with melanoma. The objective of this pilot study was to evaluate the feasibility, safety and immunogenicity of huTYR plasmid DNA administered to the skin via microseeding in dogs with spontaneous melanoma. DNA microseeding utilizes a modified tattooing device as an alternate and potentially more potent delivery method for DNA immunization. DNA was delivered to shaved inner thigh skin of six companion dogs with melanoma approximately every 14 days for a planned total of four vaccination time points. An anti-huTYR ELISA was used to test pre- and post-treatment sera. Biopsies of treated skin were obtained for detection of huTYR transgene expression. DNA microseeding was well tolerated with no significant toxicity detected beyond local site irritation, and there were no signs of autoimmunity. huTYR-expressing cells were observed in biopsies of huTYR DNA microseeding sites. Increased humoral anti-huTYR antibodies were seen in two of five evaluable dogs following microseeding compared to baseline. DNA microseeding is well tolerated in companion dogs with melanoma. Further investigation is needed to determine if combining DNA microseeding with other immunotherapy regimens potentiates this delivery platform for cancer immunotherapy.
... The first available ID influenza vaccine, Intanza (Sanofi Pasteur, Lyon, France), also known as IDflu, was licensed in 2009 in Europe. The doses adminstered are 9 μg HA per strain for adults aged 18-59 years and 15 μg HA per strain for adults aged ≥ 60 years 38,39 . Same vaccine is given at a dose of 9 μg HA per strain was licensed in the US for use in adults aged 18-64 years 40 . ...
Article
Full-text available
While some viruses occasionally pop-up and over-powers the immune system and cause deadly diseases Influenza virus is not one among them. In contrast, Influenza infections are much common with clinical manifestations such as common cold however they cannot be over sighted since they can cause uncommon consequences and even death if untreated. In this context prevention of Influenza infection is of primordial issue. Federal governments and pharma and biotech industries spend billions of dollars every year to develop novel yet robust anti flu vaccines but unfortunately we cannot shirp yet due to the fact that the immunity offered by them is temporary thanks to their very high rate of mutability. Currently these influenza vaccines are produced using reassortment genetical method in embyonated eggs. Cell culture based vaccines have also been developed however their efficacy is in par with inactivated influenza vaccines and live attenuated influenza vaccines only. Developing a universal influenza vaccine is the need of the hour and the future influenza vaccines are moving in these direction. With the advent of such universal vaccine influenza pandemics would be certainly a past history.
... The ID immunization using an NF device such as Biojector 2000 (B2000) is reliable, reproducible and does not require substantial technical expertise. In addition to simplifying the procedure of immunization, the NF devices improve the safety profile of the vaccination 13 and enhance the immunogenicity of vaccines 14,15 . ...
Article
Full-text available
The delivery of plasmid DNA to the skin can target distinct subsets of dermal dendritic cells to confer a superior immune response. The needle-free immunization technology offers a reliable, safe and efficient means to administer intradermal (ID) injections. We report here that the ID injection of DNA vectors using an NF device (NF-ID) elicits a superior cell-mediated immune response, at much lesser DNA dosage, comparable in magnitude to the traditional intramuscular immunization. However, the humoral response is significantly impaired, possibly at the stage of B cell isotype switching. We found that the NF-ID administration deposits the DNA primarily on the epidermis resulting in a rapid loss of the DNA as well as the synthesized antigen due to the faster regeneration rate of the skin layers. Therefore, despite the immune-rich nature of the skin, the NF-ID immunization of DNA vectors may be limited by the impaired humoral response. Additional booster injections are required to augment the antibody response. As an alternative and a viable solution, we rescued the IgG response by coadministration of a Toll-like receptor 9 agonist, among other adjuvants examined. Our work has important implication for the optimization of the emerging needle-free technology for ID immunization.
... ID administration is now the standard technique for tuberculin skin testing, which is performed by means of the Mantoux technique and requires skill to create a wheal indicating successful injection. 8 Because of advances in skin immunology and the advantages of ID vaccination (discussed above), novel devices for antigen delivery into the skin have been developed, 9 and accumulating evidence indicates that ID vaccination is effective for both adults and children. 5 However, existing devices were developed by using data on adult skin thickness, 10 and the use of such data could result in suboptimal immune response in children if the needle is too long or too short to reach the SC layer of infants and children. ...
Article
Intradermal (ID) vaccination induces a more potent immune response and requires lower vaccine doses as compared with standard vaccination routes. To deliver ID vaccines effectively and consistently, an ID delivery device has been developed and is commercially available for adults. The clinical application of ID vaccines for infants and children is much anticipated because children receive several vaccines, on multiple occasions, during infancy and childhood. However, experience with ID vaccines is limited and present evidence is sparse and inconsistent. ID delivery devices are not currently available for infants and children, but recent studies have examined skin thickness in this population and reported that it did not differ in proportion to body size in infants, children, and adults. These results are helpful in developing new ID devices and for preparing new vaccines in infants and children.
... [24][25][26] A few such delivery devices exist, such as the liquid jet injector and the intradermal microinjection system. 27 New technology that enhances immunity to vaccines is necessary to improve their clinical efficacy and effectiveness and to reduce influenza-related morbidity and mortality further. Additional investigations and new innovations to optimize immunization are necessary. ...
... corneum, thus increasing their accumulation in the viable epidermis. Such a method might be iontophoresis [4] or dermal injections, using nanoparticle-loaded polymer microneedles [5][6][7]. Once accumulated in the viable layer of the epidermis, NCs will be in contact with keratinocytes, the most abundant cells in this part of the skin. At this point, NCs efficacy and toxicity will depend on their uptake by the cells or their persistence in the extracellular matrix as well as the modalities and release kinetics of the encapsulated molecule in the intracellular or extracellular media. ...
Article
Calcium alginate nanocarriers (CaANCs) were developed as a potential tool for delivery of hydrophobic active molecules such as pharmaceutical and cosmetic active ingredients. In this study, we focused on interactions between CaANCs and keratinocytes in culture and examined toxicity, internalization and drug release. Prior to cellular interactions, cryogenic transmission electron microscopy images showed that CaANCs appear as regular, spherical and dense particles, giving evidence of the surface gelation of CaANCs. Their size, around 200nm, was stable under tested conditions (temperature, culture media, presence of serum and presence of encapsulated dye), and their toxicity on keratinocyte was very low. Flow cytometry assays showed that CaANCs are internalized into keratinocytes by endocytosis with a predominant implication of the caveolae-mediated route. Förster resonance energy transfer (FRET) demonstrated that after a 2h contact, the release of CaANC contents in the cytoplasm of keratinocytes was almost complete. The endocytosis of CaANCs by a lysosome-free pathway, and the rapid release of their contents inside keratinocytes, will allow vectorized molecules to fully exhibit their pharmacological or cosmetic activity.
... Furthermore, the use of a normal syringe for intradermal injection requires signifi cant expertise, and the diffi culties associated with this technique can explain the interlaboratory variations observed. Nevertheless, the construction of microdevices containing microneedles, tattooing-like vaccine instruments, and needleless syringes [ 25 ] is facilitating the use of dermal vaccines with the specifi c idea to target the place where Langerhans cells reside. ...
Chapter
Full-text available
Only a small fraction of any administered drug, including a vaccine, reaches its intended target tissue or cells. Homing vaccines to antigen-presenting cells (APC), where they can do their magic, has been the focus of attention for several decades. Since they are equipped with proper co-stimulatory signals, only professional APC are able to correctly process antigens and stimulate T and B cells to mount specific immune responses. With advances in the fields of modern immunology and nanotechnology, the new vaccine delivery platforms are emerging. APC-targeted vaccine delivery is required to elicit protective immunity, to reduce manufacturing costs, to minimize unanticipated effects of vaccines caused by off-target effects (thus reducing immunosuppressive mechanisms and toxicity), and to dramatically increase immunization efficacy. Indeed, in vivo targeting of APCs may represent the best hope for the generation of strategies leading to a personalized immunization without the need of expensive and complex ex vivo manipulation of patients’ PBMCs. Here, we will review and compare novel approaches on nanoparticle-based-targeted vaccine platforms, evaluating their molecular mechanisms of action, their translation ability, their efficacy, and their cost.
Article
Vaccination is an urgently needed and effective option to address epidemic, cancers, allergies, and other diseases. Nasal administration of vaccines offers many benefits over needle-based injection including high compliance and less risk of infection. Inactivated or attenuated vaccines as convention vaccine present potential risks of pathogenic virulence reversal, the focus of nasal vaccine development has shifted to the use of next-generation (subunit and nucleic acid) vaccines. However, subunit and nucleic acid vaccine intranasally have numerous challenges in development and utilization due to mucociliary clearance, mucosal epithelial tight junction, and enzyme/pH degradation. Nanoplatforms as ideal delivery systems, with the ability to enhance the retention, penetration, and uptake of nasal mucosa, shows great potential in improving immunogenic efficacy of nasal vaccine. This review provides an overview of delivery strategies for overcoming nasal barrier, including mucosal adhesion, mucus penetration, targeting of antigen presenting cells (APCs), enhancement of paracellular transportation. We discuss methods of enhancing antigen immunogenicity by nanoplatforms as immune-modulators or multi-antigen co-delivery. Meanwhile, we describe the application status and development prospect of nanoplatforms for nasal vaccine administration. Development of nanoplatforms for vaccine delivery via nasal route will facilitate large-scale and faster global vaccination, helping to address the threat of epidemics.
Thesis
La vaccination, particulièrement chez les espèces animales, demeure toujours un outil efficace de préventions des maladies infectieuses. Les adjuvants sont des composants généralement indispensables dans la formulation des vaccins de par leurs rôles de vecteurs de l'antigène ainsi que de stimulateurs du système immunitaire. En effet, les antigènes seuls, pour la plupart, ne permette pas d'induire une protection satisfaisantes. Les propriétés uniques du chitosane, polymère naturel biocompatible et biodégradable, offrent un matériau de choix pour l'élaboration de nouvelles générations d'adjuvant tel que des nanoparticules ou des hydrogels.Les travaux de cette thèse ont portés sur l'élaboration d'adjuvants à base de chitosane chez l'animal. La préparation de solutions visqueuses de chitosane (0, 2 = Cp = 0,75 % (w/v)) en association avec différents types d'antigènes à savoir une souche atténuée de bactéries vivantes atténuées, de virus vivants atténués ou inactivités ainsi qu'une protéine recombinante purifié ont permis d'obtenir une réponse immunitaire chez les différentes espèces animales étudiées. Par ailleurs, le chitosane, par l'inspection des animaux durant les essais ainsi que post-mortem, a démontré une bonne innocuité ainsi qu'une résorbabilité satisfaisante. Dans le cadre du développement d'un système de relargage retardé d'antigènes, nous avons débuté l'élaboration d'un système permettant de prélever et d'injecter, via un système classique seringue/aiguille, une solution visqueuse gélifiante en conditions physiologiques (150 mM, 37°C). La diffusion plus lente d'un antigène associé à ce matériau a pour objectif d'améliorer la protection des animaux en stimulant de manière prolongée les différents acteurs du système immunitaire
Book
Cornea is a major barrier for traditional topical drug delivery in the treatment of anterior segment diseasessuch as glaucoma, keratitis and bacterial and viral infections. Cornea is a transparent, avascular and highly innervated tissue [1]. It mainly consists five layers. Corneal epithelium (5-6 layers of columnar cells), bowman’s layer (a homogenous non-cellular layer), stroma (thickest layer of cornea composed of collagen fibers and 90% water), descemet’s membrane (thick membrane separating stroma and endothelium) and endothelium (single cell layer with pinocytotic vesicles). The corneal epithelium layer possesses tight junction cells which limits the entry to small hydrophilic drug molecules following topical administration. Moreover, hydrophilic structure of stroma offers limited entry of lipophilic compounds. Presence of efflux proteins (P-glycoprotein and MRPs) on the corneal epithelium also restricts the entry of xenobiotics to the anterior segment tissues. Precorneal drainage, tears washout and limited contact time are major challenges to the anterior segment drug delivery following topical administration. To be clinically effective topical formulation has to possess a balance between the hydrophilicity and lipophilicity with higher contact time.
Article
DNA vaccines have emerged as innovative approaches that have great potential to overcome the limitations of current conventional vaccines. Plasmid DNA vaccines are often safer than other vaccines {AuQ: Edit OK?} because they carry only antigen genetic information, are more stable and easier to produce, and can stimulate both humoral and cellular immune responses. Although the results of ongoing clinical trials are very promising, some limitations compromise the immunogenicity of these vaccines. Thus, this review describes different strategies that can be explored to improve the immunogenicity of plasmid DNA vaccines, including the optimization of the plasmid vector backbone, the use of different methods for vaccine delivery, the use of alternative administration routes and the inclusion of adjuvants. In combination, these improvements could lead to the successful clinical use of plasmid DNA vaccines.
Article
Full-text available
The current perspective reviews the biopharmaceutical market until end of 2020 and highlights the transforming biopharmaceutical landscape during the recent decade. In particular, the rise of biosimilars and the development of new therapeutic modalities through recent advancement in molecular biology research sustainably change the product scenery. The present manuscript describes opportunities for pharmaceutical technical development, highlighting concepts such as product differentiation to succeed in a competitive product landscape. Product differentiation offers the opportunity for numerous life-cycle options and market exclusivity through incremental improvements in standard of care treatment. In particular, different formulation options and formulation-device combinations are described, focusing on systemic delivery of monoclonal antibody products and patient-centered development. The concept of product differentiation is exemplified in a case study about HER2+ breast cancer therapy, underlining pharmaceutical technical solutions and major improvements for the patient.
Article
Tolerance inducing vaccines have re-appeared in recent years as a mean to re-establish immunological tolerance in the context of autoimmune disease. In the case of multiple sclerosis, several myelin-related peptides have been identified. The use of microneedles (MNs) allows the painless administration of molecules to the epidermal and intradermal space. This approach has been considered particularly promising in the scope of vaccination as the skin represents an immunologically super-active organ. This work explores the preparation of a MN patch that can deliver immunologically active peptides foreseeing the establishment of tolerance in the context of multiple sclerosis. A new MN design was achieved by microfabrication. The patches are composed of a dense MN array containing 33x33 needles with 200 or 125 µm diameter and height around 600 µm. Polymeric MNs composed by poly(vinyl alcohol), poly(vinyl pyrrolidone) and chitosan were successfully obtained, replicating the silicon masters morphology. The polymer MN patches showed to perforate pig skin, reaching more than 400 µm depth of penetration when assessed using agarose as a model for the skin viscoelastic properties. The MNs with 200 µm diameter showed improved mechanical properties in comparison to 125 µm diameter MNs. The presence of chitosan in the MN structure was explored and found not to affect mechanical properties or significantly alter the drug loading or release profile. The immunomodulatory peptide associated with the proteolipid protein PLP139-151 was loaded in 200 µm diameter MN patch and it is released in physiological conditions at therapeutic doses of the peptide, putting forward this strategy to integrate a new tolerance-inducing therapy for multiple sclerosis successfully.
Article
Riassunto La pelle limita l’ingresso delle sostanze applicate e regola le perdite d’acqua attraverso il suo strato corneo. La funzione barriera della pelle non è assoluta e la sua permeabilità è correlata alle proprietà fisicochimiche delle molecole in contatto. Le molecole assorbite vengono distribuite nel corpo dopo un trasferimento passivo, poi vengono eliminate o immagazzinate. In questo contesto, anche lo stato della pelle è un fattore primario e le differenze di assorbimento sono importanti tra pelle sana e pelle patologica o con lesioni di varia origine. La stima della percentuale di sostanza assorbita è un punto particolarmente importante per la valutazione del rischio in cosmetica. In generale, questa valutazione viene effettuata su una pelle sana, ma lo sviluppo delle routine di cura, l’ampio uso di promotori dell’assorbimento, l’uso in vista di migliorare l’efficacia dei cosiddetti prodotti “di frontiera” e, infine, l’utilizzo ricorrente di gadget o tecniche nate dal settore farmaceutico possono aumentare l’assorbimento degli ingredienti utilizzati. Questo articolo sviluppa l’analisi dell’impatto delle formulazioni e dei dispositivi utilizzati a favore della penetrazione dei principi attivi, nonché le conseguenze dell’uso di prodotti il cui obiettivo iniziale è di migliorare le condizioni della pelle e per i quali l’assorbimento degli ingredienti è un elemento secondario.
Chapter
Needle‐free jet injectors are medical devices used for the delivery of liquid medications across the skin as a high‐speed stream of fluid, without the use of a needle. The absence of a needle abolishes the risk of needle‐stick injuries, frequent among healthcare providers, and increases the compliance to injections in needle‐phobic patients. Through the modulation of several parameters of the jet injectors, the liquid medication can be delivered to different sites within or below the skin, thus allowing the use of such devices for both local and systemic therapies in a multitude of disorders. In the present chapter, after a brief historical overview, the functioning principles and the rationale behind the use of needle‐free jet injectors are presented. Moreover, preclinical and clinical studies where jet injectors have been employed for the systemic or local delivery of therapeutics are reviewed. Finally, in the last section, the potential of such devices for the administration of nano‐ and micro‐particulate drug delivery systems is discussed.
Chapter
Since the introduction of smallpox vaccination more than two centuries ago, vaccines have been—and still are—instrumental in the prevention of infectious diseases. Nowadays vaccines form a heterogeneous group of pharmaceutical products that differ in several aspects from other biopharmaceuticals. In this chapter, after a brief introduction we first cover immunological principles that are important for vaccine design. Next, we give an overview of the different vaccine categories and current approaches to vaccine development, illustrated with representative examples. We also describe current trends in the field of vaccines against non-infectious diseases, such as therapeutic vaccines against cancer and other diseases. Moreover, routes of administration relevant to vaccination and pharmaceutical aspects of vaccines are briefly discussed.
Article
Full-text available
Hollow microneedles are an emerging technology for delivering drugs and therapeutics, such as vaccines and insulin, into the skin. Although the benefits of intradermal drug delivery have been known for decades, our understanding of fluid absorption by skin tissue has been limited due to the difficulties in imaging a highly scattering biological material such as skin. Here, we report the first real-time imaging of skin tissue at the microscale during intradermal injections through hollow microneedles, using optical coherence tomography. We show that skin tissue behaves like a deformable porous medium and absorbs fluid by locally expanding rather than rupturing to form a single fluid filled cavity. We measure the strain distribution in a cross section of the tissue to quantify local tissue deformation, and find that the amount of volumetric expansion of the tissue corresponds closely to the volume of fluid injected. Mechanically restricting tissue expansion limits fluid absorption into the tissue. Our experimental findings can provide insights to optimize the delivery of drugs into skin for different therapeutic applications, and to better model fluid flow into biological tissue.
Chapter
This chapter discusses the application of microneedle (MN)‐mediated intradermal delivery of vaccines in detail. It addresses the recurring theme of antigen stability in the MN arrays. The chapter shows that hollow MN delivery platforms should be favoured over their solid counterparts due to the fact that hollow MN assisted vaccination was deemed to have induced both humoral and cellular immune responses with better administration accuracy and precision than solid MNs or indeed commercial vaccine. Owing to superior antigen delivery from the coated MN arrays, the chapter also shows that the coated MN system was better than the "Poke and Patch" methodology and as such demonstrated greater applicability for intradermal vaccination strategies. The chapter explores the status of intradermal delivery using MNs, and considers other strategies or routes which have, or may yet be, explored in vaccine delivery.
Article
Vaccination is the most effective method of preventing the spread of the influenza virus. However, the traditional intramuscular (IM) immunization causes fear, pain, and cross infection. In contrast, needle-free (NF) immunization is quick and easy for medical personnel and painless and safe for patients. In this study, we assessed the safety and protective efficacy of NF intradermal (ID) immunization with the influenza H7N9 split vaccine (AnhuiH7N9/PR8). A preliminary safety evaluation showed that ID immunization with 15 μg of the H7N9 influenza vaccine was not toxic in rats. Moreover, the antigen was metabolized more rapidly after ID than after IM immunization, as determined by in vivo imaging, and ID immunization accelerated the generation of a specific immune response. Additionally, ID immunization with a 20% dose of the H7N9 split vaccine Anhui H7N9/PR8 offered complete protection against lethal challenge by the live H7N9 virus. Taken together, our findings suggest that NF ID immunization with the H7N9 influenza vaccine induces effective protection, has a good safety profile, requires little antigen, and elicits an immune response more rapidly than does IM immunization. This approach may be used to improve the control of influenza H7N9 outbreaks.
Chapter
Gene therapy can be defined as the use of nucleic acids (NAs) as medicines with the aim of correcting a deficient gene expression, introducing new functions in the cell, repairing mutations and modulating the gene expression. Two main classes of vectors, viral and nonviral, have been used for gene delivery in order to avoid the NAs hydrolysis by tissue nucleases and improve their cellular uptake. The ideal gene delivery vector should offer high transfection efficacy, cell specificity and low toxicity. However, the immunogenic and mutagenic side effects of viral vector as well as toxicity and low efficacy of nonviral carriers are limiting their application. In this respect, naked NAs delivery by physical methods could be the safest procedure for gene therapy strategies if the appropriate efficacy can be achieved. These procedures employ physical forces to permit the nucleic acid cross the cell membrane and reach the cell without any carrier agent. Although viral and nonviral chemical methods are widely employed in experimental research and clinical trials, the physical methods of DNA delivery are a strategy in increasing progress. In this chapter, the main physical procedures (microinjection, needle injection, needle-free jet injection, gene gun, electroporation, sonoporation, hydroporation, magnetofection and laser irradiation) for naked nucleic acids delivery are described, emphasizing their use justification, their development, the proposed mechanism of NAs transfer and their clinical use or potential application.
Article
Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are the two major causative agents of hand, foot and mouth disease (HFMD), which erupts in the Asia-Pacific regions. A bivalent vaccine against both EV71 and CVA16 is highly desirable. In the present study, on the bases that an experimental bivalent vaccine comprising of inactivated EV71 and CVA16 induces a balanced protective immunity against both EV71 and CVA16, we compare the immunogenicity and reactogenicity of one fourth of a full dose of an intradermal vaccine administered by needle-free liquid jet injector with a full dose of an intramuscular vaccine administered by needle-syringe in monkeys. The results suggest that intradermal injection of a fractional dose of an inactivated HFMD vaccine elicits similar immunogenicity and reactogenicity to intramuscular inoculation of a full dose of an Al(OH)3-adjuvanted vaccine, regardless of whether monovalent or bivalent vaccines were used. Our results support the use of an intradermal bivalent vaccine strategy for HFMD vaccination in order to satisfy the requirements and reduce the costs.
Chapter
The natural biological function of the skin is to protect the body against harmful infections by hindering the intrusion of foreign pathogens. In terms of protection, the skin serves a dual functionality: the physical barrier provided by the stratum corneum and the immunological barrier stimulated by the antigen-presenting cells (APCs) in the dermis and epidermis. In recent years, several findings have established that stimulating the APCs underneath the stratum corneum can provide several advantages in terms of vaccine administration over conventional methods. Hence, such “intradermal immunization” methods have been investigated worldwide. As a result, some of the intradermal vaccine delivery methods that were developed include the Mantoux technique, ballistic vaccination, epidermal powder immunization (EPI), jet injector, tattoo immunization, and microneedles. This chapter attempts to briefly delineate these methods and describe the state of research regarding these technologies in the present day.
Chapter
This chapter discusses patch and patchless delivery systems and several novel approaches in the transdermal drug delivery (TDD). The TDD poses several advantages over traditional oral routes for the delivery of drugs with high first-pass metabolism, for example, drugs with poor bioavailability. However, assuring that these drugs travel through the skin layers is no easy task. The chapter discusses the utilization of patches for the TDD. It also focuses on patchless transdermal delivery where the aims are to enhance skin permeability by disrupting the microstructure of the SC and/or by employing external forces to drive the drug into the skin layers. The chapter also discusses the transcutaneous immunization via microneedle techniques. The most recent research papers, ongoing clinical trials, and FDA-approved microneedle-based product for transcutaneous immunization are reviewed in the chapter.
Article
Introduction: An intradermal version of Fluzone(®) split-virion inactivated trivalent influenza vaccine, containing 9 µg hemagglutinin per strain of A/H1N1, A/H3N2, and one B lineage virus (Fluzone Intradermal, Sanofi Pasteur), became available in the US during the 2011-2012 influenza season for adults 18-64 years of age. In advance of the 2015-2016 season, Fluzone Intradermal was replaced with Fluzone Intradermal Quadrivalent vaccine, which contains 9 µg hemagglutinin per strain of the two A-strain viruses and both B-strain lineage viruses (Victoria and Yamagata). Areas covered: This literature review summarizes the history and mechanism of intradermal vaccination, discusses the clinical trial results supporting the immunogenicity and safety of Fluzone Intradermal Quadrivalent vaccine, and describes the unique microinjection system used to deliver Fluzone Intradermal Quadrivalent. Expert commentary: Fluzone Intradermal Quadrivalent may boost confidence in influenza vaccination with the addition of a second B-lineage strain. By using an innovative microinjection system, the vaccine is also designed to address some of the logistic challenges faced by healthcare providers administering immunizations.
Article
Full-text available
Heart disease remains the leading cause of mortality and morbidity worldwide, with 22 million new patients diagnosed annually. Essentially, all present therapies have significant cost burden to the healthcare system, yet fail to increase survival rates. One key employed strategy is the genetic reprogramming of cells to increase contractility via gene therapy, which has advanced to Phase IIb Clinical Trials for advanced heart failure patients. It has been argued that the most significant barrier preventing FDA approval are resolving problems with safe, efficient myocardial delivery, whereby direct injection in the infarct and remote tissue areas is not clinically feasible. Here, we aim to: (1) Improve direct cardiac gene delivery through the development of a novel liquid jet device approach (2) Compare the new method against traditional IM injection with two different vector constructions and evaluate outcome (3) Evaluate the host response resulting from both modes of direct cardiac injection, then advance a drug/gene combination with controlled release nanoparticle formulations.
Article
Enterotoxigenic Escherichia coli (ETEC) are a common cause of diarrhea. Extraordinary antigenic diversity has prompted a search for conserved antigens to complement canonical approaches to ETEC vaccine development. EtpA, an immunogenic extracellular ETEC adhesin relatively conserved in the ETEC pathovar, has previously been shown to be a protective antigen following intranasal (i.n.) immunization. These studies were undertaken to explore alternative routes of EtpA vaccination that would permit use of double mutant heat-labile toxin (R192G/L211A) LT (dmLT) adjuvant. Here, oral vaccination with EtpA adjuvanted with dmLT afforded significant protection against small intestinal colonization, and the degree of protection correlated with fecal IgG, IgA, or total fecal antibody responses to EtpA. Sublingual (sl) vaccination yielded compartmentalized mucosal immune responses with significant increases in anti-EtpA fecal IgG and IgA, and mice vaccinated via this route were also protected against colonization. In contrast, while intradermal (ID) vaccination achieved high levels of both serum and fecal antibodies against both EtpA and dmLT, mice vaccinated via the ID route were not protected against subsequent colonization and the avidity of serum IgG and IgA EtpA-specific antibodies was significantly lower after ID immunization compared to other routes. Finally, we demonstrate that antisera from vaccinated mice significantly impairs binding of LT to cognate GM1 receptors and near complete neutralization of toxin delivery by ETEC in vitro. Collectively, these data provide further evidence that EtpA could complement future vaccine strategies, but also suggest that additional effort will be required to optimize its use as a protective immunogen.
Article
DNA vaccination represents a smart and promising approach for cancer immunotherapy. DNA vaccines for cancer immunotherapy are designed to deliver one or several genes encoding tumor antigens, thereby eliciting or augmenting antigen-specific immune responses against antigens that play a central role in tumor initiation, progression and metastasis. Vaccine efficacy can be significantly improved by implementing strategies for enhancing antigen presentation and immunogenicity, such as new delivery systems, addition of molecular adjuvants and immunostimulatory signals, optimized prime-boost strategies or blockade of immune checkpoints. Taken into consideration that innate immune responses are important in the induction and enhancement of antigen-specific adaptive responses, manipulations that integrate these approaches in the vaccine design, can achieve activation of protective adaptive immune responses, thereby overcoming the self-tolerance towards many tumor antigens. Such approaches are employed in a number of clinical trials for DNA cancer immunotherapy and hold promise for prophylactic and therapeutic vaccine development. In this context, strategies that improve immunogenicity and enhance the efficacy of DNA vaccines for cancer immunotherapy are discussed.
Chapter
This chapter reviews how currently available commercial vaccines are formulated and administered to patients and how new vaccines may be administered in the future using novel delivery devices and formulation technologies. Many new vaccine delivery technologies are being evaluated both in the laboratory and the clinic to provide more targeted delivery of vaccines to specific tissues, using either injection (ID, IM, SC) or oral, nasal, or even buccal or aerosol delivery. It has been demonstrated that administration of the vast majority of inactivated or recombinant vaccines by the oral route does not elicit protective immune responses, often due to loss and instability of various vaccine antigens. For devices to deliver drug powders, many different powder/aerosol technologies are available and are classified into three general categories: pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and nebulizers.
Article
Microneedle (MN) offers an attractive, painless and minimally invasive approach for transdermal drug delivery. Polymer microneedles are normally fabricated by using the micromolding method employing a MN mold, which is suitable for mass production due to high production efficiency and repeat-using of the mold. Most of the MN molds are prepared by pouring sylgard polymer over a MN master to make an inverse one after curing, which is limited in optimizing or controlling the MN structures and failing to keep the sharpness of MNs. In this work we describe a fabrication method of MN mold with controlled microstructures, which is meaningful for the fabrication of polymer MNs with different geometries. Laser micro-machining method was employed to drill on the surface of PDMS sheets to obtain MN molds. In the fabrication process, the microstructures of MN molds are precisely controlled by changing laser parameters and imported patterns. The MNs prepared from these molds are sharp enough to penetrate the skin. This scalable MN mold fabrication method is helpful for future applications of MNs.
Chapter
Advances in drug formulation engineering and the development of nanotechnology for drug delivery applications have recently attracted a major attention. The use of polymeric nanoparticles for the application of local and systemic drugs to the skin is one of the important applications of nanotechnology in the pharmaceutical field. The skin provides a natural protective barrier against particle penetration, but there are several reports about the accumulation in hair follicles and interaction with diseased skin. The following chapter will consider the possible potential of using micro- and nanoparticles for dermal and transdermal drug delivery. Their ability to enhance transdermal drug permeation will be discussed, and an improved understanding of their interaction with the skin will also be addressed.
Data
Full-text available
Tattooing is one of a number of DNA delivery methods which results in an efficient expression of an introduced gene in the epidermal and dermal layers of the skin. The tattoo procedure causes many minor mechanical injuries followed by hemorrhage, necrosis, inflammation and regeneration of the skin and thus non-specifically stimulates the immune system. DNA vaccines delivered by tattooing have been shown to induce higher specific humoral and cellular immune responses than intramuscularly injected DNA. In this study, we focused on the comparison of DNA immunization protocols using different routes of administrations of DNA (intradermal tattoo versus intramuscular injection) and molecular adjuvants (cardiotoxin pre-treatment or GM-CSF DNA co-delivery). For this comparison we used the major capsid protein L1 of human papillomavirus type 16 as a model antigen. L1-specific immune responses were detected after three and four immunizations with 50 μg plasmid DNA. Cardiotoxin pretreatment or GM-CSF DNA co-delivery substantially enhanced the efficacy of DNA vaccine delivered intramuscularly by needle injection but had virtually no effect on the intradermal tattoo vaccination. The promoting effect of both adjuvants was more pronounced after three rather than four immunizations. However, three DNA tattoo immunizations without any adjuvant induced significantly higher L1-specific humoral immune responses than three or even four intramuscular DNA injections supported by molecular adjuvants. Tattooing also elicited significantly higher L1-specific cellular immune responses than intramuscularly delivered DNA in combination with adjuvants. In addition, the lymphocytes of mice treated with the tattoo device proliferated more strongly after mitogen stimulation suggesting the presence of inflammatory responses after tattooing. The tattoo delivery of DNA is a cost-effective method that may be used in laboratory conditions when more rapid and more robust immune responses are required.
Article
Full-text available
Needle-free injection devices (NFIDs) have been available for humans since the 1930s. Their implementation in the swine industry has been slow because of the low cost and ease of use of needle-syringe injection. Recently, there has been a renewed interest in needle-free devices in swine due to two main factors: immunology research, indicating that targeting dendritic cells in the skin and the subcutaneous tissues results in improved immune response with minimal antigen doses, and implementation of pork quality assurance standards to minimize needle-site lesions that are the result of broken needles, bacterial contamination, or both. In this article, we review the peer-reviewed and non-peer-reviewed literature on the use of NFIDs in swine.
Article
Full-text available
A two-wafer polysilicon micromolding process has been developed for the fabrication of hollow tubes useful for microfluidic applications. These small tubes can be fabricated with a pointed end, resulting in a micro hypodermic injection needle. Microneedles are desired because they reduce both insertion pain and tissue damage in the patient. Such microneedles may be used for low flow rate, continuous drug delivery, such as the continuous delivery of insulin to a diabetic patient. The needles would be integrated into a short term drug delivery device capable of delivering therapeutics intradermally for about 24 hours. In addition, microneedles can be used for sample collection for biological analysis, delivery of cell or cellular extract based vaccines, and sample handling providing interconnection between the microscopic and macroscopic world. The strength of microneedles was examined analytically, experimentally and by finite element analysis. Metal coatings provide significant increases in the achievable bending moments before failure in the needles. For example, a 10 μ m platinum coating increased the median bending moment of a 160 μ m wide, 110 μ m high microneedle with a 20 μ m wall from 0.25 to 0.43 mNm. In addition, fluid flow in microneedles was studied experimentally. Microneedles 192 μ m wide, 110 μ m high and 7 mm long have flow rates of 0.7 ml/sec under a 138 kPa inlet pressure. This flow capacity exceeds previous microneedle capacities by an order of magnitude.
Article
Full-text available
Swine influenza is a highly contagious viral infection in pigs that significantly impacts the pork industry due to weight loss and secondary infections. There is also the potential of a significant threat to public health, as was seen in 2009 when the pandemic H1N1 influenza virus strain emerged from reassortment events among avian, swine, and human influenza viruses within pigs. As classic and pandemic H1N1 strains now circulate in swine, an effective vaccine may be the best strategy to protect the pork industry and public health. Current inactivated-virus vaccines available for swine influenza protect only against viral strains closely related to the vaccine strain, and egg-based production of these vaccines is insufficient to respond to large outbreaks. DNA vaccines are a promising alternative since they can potentially induce broad-based protection with more efficient production methods. In this study we evaluated the potentials of monovalent and trivalent DNA vaccine constructs to (i) elicit both humoral and gamma interferon (IFN-γ) responses and (ii) protect pigs against viral shedding and lung disease after challenge with pandemic H1N1 or classic swine H1N1 influenza virus. We also compared the efficiency of a needle-free vaccine delivery method to that of a conventional needle/syringe injection. We report that DNA vaccination elicits robust serum antibody and cellular responses after three immunizations and confers significant protection against influenza virus challenge. Needle-free delivery elicited improved antibody responses with the same efficiency as conventional injection and should be considered for development as a practical alternative for vaccine administration.
Article
Full-text available
The skin is known to be a highly immunogenic site for vaccination, but few vaccines in clinical use target skin largely because conventional intradermal injection is difficult and unreliable to perform. Now, a number of new or newly adapted delivery technologies have been shown to administer vaccine to the skin either by non-invasive or minimally invasive methods. Non-invasive methods include high-velocity powder and liquid jet injection, as well as diffusion-based patches in combination with skin abrasion, thermal ablation, ultrasound, electroporation, and chemical enhancers. Minimally invasive methods are generally based on small needles, including solid microneedle patches, hollow microneedle injections, and tattoo guns. The introduction of these advanced delivery technologies can make the skin a site for simple, reliable vaccination that increases vaccine immunogenicity and offers logistical advantages to improve the speed and coverage of vaccination.
Article
Full-text available
Intradermal (ID) vaccination can offer improved immunity and simpler logistics of delivery, but its use in medicine is limited by the need for simple, reliable methods of ID delivery. ID injection by the Mantoux technique requires special training and may not reliably target skin, but is nonetheless used currently for BCG and rabies vaccination. Scarification using a bifurcated needle was extensively used for smallpox eradication, but provides variable and inefficient delivery into the skin. Recently, ID vaccination has been simplified by introduction of a simple-to-use hollow microneedle that has been approved for ID injection of influenza vaccine in Europe. Various designs of hollow microneedles have been studied preclinically and in humans. Vaccines can also be injected into skin using needle-free devices, such as jet injection, which is receiving renewed clinical attention for ID vaccination. Projectile delivery using powder and gold particles (i.e., gene gun) have also been used clinically for ID vaccination. Building off the scarification approach, a number of preclinical studies have examined solid microneedle patches for use with vaccine coated onto metal microneedles, encapsulated within dissolving microneedles or added topically to skin after microneedle pretreatment, as well as adapting tattoo guns for ID vaccination. Finally, technologies designed to increase skin permeability in combination with a vaccine patch have been studied through the use of skin abrasion, ultrasound, electroporation, chemical enhancers, and thermal ablation. The prospects for bringing ID vaccination into more widespread clinical practice are encouraging, given the large number of technologies for ID delivery under development.
Article
Full-text available
Delivery of vaccine antigens to the dermis and/or epidermis of human skin (i.e. intradermal delivery) might be more efficient than injection into the muscle or subcutaneous tissue, thereby reducing the volumes of antigen. This is known as dose-sparing and has been demonstrated in clinical trials with some, but not all, vaccines. Dose-sparing could be beneficial to immunization programmes by potentially reducing the costs of purchase, distribution and storage of vaccines; increasing vaccine availability and effectiveness. The data obtained with intradermal delivery of some vaccines are encouraging and warrant further study and development; however significant gaps in knowledge and operational challenges such as reformulation, optimizing vaccine presentation and development of novel devices to aid intradermal vaccine delivery need to be addressed. Modelling of the costs and potential savings resulting from intradermal delivery should be done to provide realistic expectations of the potential benefits and to support cases for investment. Implementation and uptake of intradermal vaccine delivery requires further research and development, which depends upon collaboration between multiple stakeholders in the field of vaccination.
Article
Full-text available
Mortality due to seasonal and pandemic influenza could be reduced by increasing the speed of influenza vaccine production and distribution. We propose that vaccination can be expedited by (1) immunizing with influenza virus-like particle (VLP) vaccines, which are simpler and faster to manufacture than conventional egg-based inactivated virus vaccines, and (2) administering vaccines using microneedle patches, which should simplify vaccine distribution due to their small package size and possible self-administration. In this study, we coated microneedle patches with influenza VLP vaccine, which was released into skin by dissolution within minutes. Optimizing the coating formulation required balancing factors affecting the coating dose and vaccine antigen stability. Vaccine stability, as measured by an in vitro hemagglutination assay, was increased by formulation with increased concentration of trehalose or other stabilizing carbohydrate compounds and decreased concentration of carboxymethylcellulose (CMC) or other viscosity-enhancing compounds. Coating dose was increased by formulation with increased VLP concentration, increased CMC concentration, and decreased trehalose concentration, as well as increased number of dip coating cycles. Finally, vaccination of mice using microneedles stabilized by trehalose generated strong antibody responses and provided full protection against high-dose lethal challenge infection. In summary, this study provides detailed analysis to guide formulation of microneedle patches coated with influenza VLP vaccine and demonstrates effective vaccination in vivo using this system.
Article
Full-text available
The association of microneedles with electric pulses causing electroporation could result in an efficient and less painful delivery of drugs and DNA into the skin. Hollow conductive microneedles were used for (1) needle-free intradermal injection and (2) electric pulse application in order to achieve electric field in the superficial layers of the skin sufficient for electroporation. Microneedle array was used in combination with a vibratory inserter to disrupt the stratum corneum, thus piercing the skin. Effective injection of proteins into the skin was achieved, resulting in an immune response directed to the model antigen ovalbumin. However, when used both as microneedles to inject and as electrodes to apply the electric pulses, the setup showed several limitations for DNA electrotransfer. This could be due to the distribution of the electric field in the skin as shown by numerical calculations and/or the low dose of DNA injected. Further investigation of these parameters is needed in order to optimize minimally invasive DNA electrotransfer in the skin.
Article
Full-text available
A simple method suitable for self-administration of vaccine would improve mass immunization, particularly during a pandemic outbreak. Influenza virus-like particles (VLPs) have been suggested as promising vaccine candidates against potentially pandemic influenza viruses, as they confer long-lasting immunity but are not infectious. We investigated the immunogenicity and protective efficacy of influenza H5 VLPs containing the hemagglutinin (HA) of A/Vietnam/1203/04 (H5N1) virus delivered into the skin of mice using metal microneedle patches and also studied the response of Langerhans cells in a human skin model. Prime-boost microneedle vaccinations with H5 VLPs elicited higher levels of virus-specific IgG1 and IgG2a antibodies, virus-specific antibody-secreting cells, and cytokine-producing cells up to 8 months after vaccination compared to the same antigen delivered intramuscularly. Both prime-boost microneedle and intramuscular vaccinations with H5 VLPs induced similar hemagglutination inhibition titers and conferred 100% protection against lethal challenge with the wild-type A/Vietnam/1203/04 virus 16 weeks after vaccination. Microneedle delivery of influenza VLPs to viable human skin using microneedles induced the movement of CD207(+) Langerhans cells toward the basement membrane. Microneedle vaccination in the skin with H5 VLPs represents a promising approach for a self-administered vaccine against viruses with pandemic potential.
Book
Mass immunization is the blitzkrieg of vaccination practice. It serves to rapidly protect populations, both because of the high coverage achieved and because of the herd immunity thereby induced. However, as in war, mass immunization campaigns must be conducted intelligently, with careful strategy and strong attention to logistics of supply and deployment. If conducted badly, mass immunization may fail or even be counter-productive. In this volume, some of the most successful practitioners of mass im- nization tell us about its art and science. David Heymann and Bruce Aylward of WHO begin the book with a theoretical and practical overview of mass immunization. Michael Lane, who participated in the successful effort to eradicate smallpox relates how this was done using mass vaccination and other strategies. Application of mass immunization by the US military is c- ered by John Grabenstein and Remington Nevin, who have a large experience in these matters. Karen Noakes and David Salisbury recount the striking s- cesses of mass immunization in the United Kingdom. The global control of the clostridia that produce diphtheria toxin is described by Charles Vitek. Hepa- tis A is decreasing dramatically under the impact of large-scale vaccination, as Francis André illustrates. The French experience with Hepatitis B vac- nation has been mixed, and François Denis and Daniel Levy-Bruhl explain the circumstances. In?uenza vaccination is an annual example of large-scale campaigns, the complexity of which is recounted by Benjamin Schwartz and Pascale Wortley.
Article
The mechanical and transport-enhancing properties of microneedles were examined. Microneedle arrays were inserted into epidermis and transdermal transport of calcein or fluorescein-labeled BSA was determined by spectrofluorimetry. Following this, microneedles were examined to determine if any breakage occurred during insertion and removal. It was observed that the microneedles are mechanically strong, able to increase transdermal transport by more than four orders of magnitude in vitro, and do not cause pain in human subjects.
Article
To overcome the skin's barrier properties that block transdermal delivery of most drugs, arrays of microscopic needles have been microfabricated primarily out of silicon or metal. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, micro-electromechanical masking and etching were adapted to produce beveled- and chisel-tip microneedles and a new fabrication method was developed to produce tapered-cone microneedles using an in situ lens-based lithographic approach. To replicate microfabricated master structures, PDMS micromolds were generated and a novel vacuum-based method was developed to fill the molds with polylactic acid, polyglycolic acid, and their co-polymers. Mechanical testing of the resulting needles measured the force at which needles broke during axial loading and found that this failure force increased with Young's modulus of the material and needle base diameter and decreased with needle length. Failure forces were generally much larger than the forces needed to insert microneedles into skin, indicating that biodegradable polymers can have satisfactory mechanical properties for microneedles. Finally, arrays of polymer microneedles were shown to increase permeability of human cadaver skin to a low-molecular weight tracer, calcein, and a macromolecular protein, bovine serum albumin, by up to three orders of magnitude. Altogether, these results indicate that biodegradable polymer microneedles can be fabricated with an appropriate geometry and sufficient strength to insert into skin, and thereby dramatically increase transdermal transport of molecules.
Article
Needle-free jet injections constitute an important method of drug delivery, especially for insulin and vaccines. This report addresses the mechanisms of interactions of liquid jets with skin. Liquid jets first puncture the skin to form a hole through which the fluid is deposited into skin. Experimental studies showed that the depth of the hole significantly affects drug delivery by jet injections. At a constant jet exit velocity and nozzle diameter, the hole depth increased with increasing jet volume up to an asymptotic value and decreased with increasing values of skin's uniaxial Young's modulus. A theoretical model was developed to predict the hole depth as a function of jet and skin properties. A simplified model was first verified with polyacrylamide gels, a soft material in which the fluid mechanics during hole formation is well understood. Prediction of the hole depth in the skin is a first step in quantitatively predicting drug delivery by jet injection.
Article
An age-related decline in functioning of the innate and adaptive immune systems results in increased susceptibility to infections (e.g. influenza) and decreased responses to vaccination in elderly people. A satellite symposium held during the xixth IAGG World Congress of Gerontology and Aging in Paris, 5–9 July 2009, considered the potential of intradermal vaccination to enhance immune responses in the elderly. The rich supply of capillary blood and lymphatic vessels in the dermis, along with its resident population of dendritic cells, make the skin an attractive site for vaccine delivery. Intanza® 15μg is a purified, inactivated, trivalent, split-virus influenza vaccine containing 15μg haemagglutinin/strain/0.1ml dose that is administered using a novel intradermal microneedle injection system. A randomised, open-label phase III trial in 3695 people aged 60–95 years found that antibody responses to the intradermal influenza vaccine were superior to those for the same vaccine administered intramuscularly. The systemic safety profile of the intradermal vaccine was comparable with that of the intramuscular vaccine, but rates of injection-site reactions were higher with the intradermal vaccine, reflecting the close proximity of injected vaccine to the skin surface. The increased immunogenicity of Intanza® 15μg in the elderly compared with the standard intramuscular influenza vaccine supports the concept of intradermal vaccination to enhance immune responses in elderly people.
Article
A unique biomedical delivery system (biolistics), for micro-sized powder formulation of drugs (typically protein- and/or DNA-based macromolecules) to be effectively and efficiently delivered into human skin or mucosal tissue for the treatment of a scope of diseases, has been proposed. One of the key concerns for designing and evaluating the biolistic system is to warrant that micro-particles are accelerated and penetrated in to the skin with a controllable velocity range and uniform spatial distribution for optimal targeting the cells of interest. In this paper, we numerically interrogate the performance of a prototype biolistic device, designed for a uniform micro-particle acceleration and penetration. Swirling effects on the gas–particle dynamics, the particle acceleration and penetration as well as the device performance are presented and interpreted. Variations of the micro-particle velocity range and spatial distribution with swirl ratios are examined. The ability of the micro-particles penetrating in to a model skin target is demonstrated and discussed.
Article
The stratum corneum provides the first barrier to the percutaneous absorption of drugs as well as regulating water loss. This barrier limits the topical/transdermal delivery of drugs and biological macromolecules. Chemical and physical approaches have been examined to decrease these properties. Tape stripping is commonly used to disrupt the epidermal barrier, to enhance the delivery of drugs and to obtain information about stratum corneum function. Tape stripping results in the production and release of cytokines and co-stimulatory molecules and increases the humoral and cellular immune responses against peptide, protein and DNA antigens by a topical vaccination in vivo. This paper reviews the stripping method, experimental factors and its applications for penetration and topical vaccination.
Article
A novel DNA vaccine against hepatitis B virus was administered intraepidermally by particle-mediated epidermal delivery (PMED) to 16 human subjects who demonstrated absent or non-sustainable responses to conventional hepatitis B vaccination. Eleven subjects received three doses of vaccine at 56-day intervals, and five subjects received only a single vaccination. Each dose of vaccine contained 4 microg of plasmid DNA encoding the hepatitis B surface antigen (HBsAg). The vaccine was safe and well tolerated. Remarkably, the DNA vaccine elicited antibody responses in 12 of the 16 subjects after a licensed subunit vaccine failed to induce a lasting response after >/=3 vaccinations. This study provides evidence in humans for protective immunogenicity of a particle-mediated DNA vaccine in subjects who have responded suboptimally to conventional vaccination.
Article
This paper proposes a method for the creation of hybrid meshes with embedded surfaces for viscous flow simulations as an extension of the multiple marching direction approach (AIAA J. 2007; 45(1):162–167). The multiple marching direction approach enables to place semi-structured elements around singular points, where valid semi-structured elements cannot be placed using conventional hybrid mesh generation methods. This feature is discussed first with a couple of examples. Elements sometimes need to be clustered inside a computational domain to obtain more accurate results. For example, solution features, such as shocks, vortex cores and wake regions, can be extracted during the process of adaptive mesh generation. These features can be represented as surface meshes embedded in a computational domain. Semi-structured elements can be placed around the embedded surface meshes using the multiple marching direction approach with a pretreatment method. Tetrahedral elements can be placed easily instead. A couple of results are presented to demonstrate the capability of the mesh generation method. Copyright © 2008 John Wiley & Sons, Ltd.
Article
A unique form of powdered vaccine and drug delivery has been developed. The principle behind the concept is to accelerate vaccine and drug particles, using a gas flow, so that they attain sufficient velocities to enter the skin and achieve a pharmaceutical effect. This paper presents the Contoured Shock Tube (CST), configured to deliver particles to the skin with a narrow and controlled velocity distribution and uniform spatial distribution. The gas and particle flows of a prototype CST are explored experimentally and compared with Computational Fluid Dynamics (CFD) calculations. Some key steps in converting the prototype into a practical hand-held vaccine and drug delivery system are discussed. The ability of this system to deliver particles to the skin is illustrated by sample penetration data into excised human tissue.
Conference Paper
To overcome skin's barrier properties that block transdermal delivery of most drugs, we and others have microfabricated arrays of microscopic needles, primarily out of silicon or metal. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, we adapted microelectromechanical masking and etching to produce beveled-tip and chisel tip microneedles and developed a new fabrication method to produce tapered-cone microneedles using an in-situ lens-based lithographic approach. To replicate microfabricated master structures, PDMS micromolds were generated and a novel vacuum-based method was developed to fill the molds with polylactic acid, polyglycolic acid and their copolymers. Mechanical testing of the resulting needles measured the force at which needles broke during axial loading and found that this failure force increased with Young's modulus of the material and needle base diameter and decreased with needle length. Failure forces were generally much larger than the forces needed to insert microneedles into skin, indicating that biodegradable polymers can have satisfactory mechanical properties for microneedles. Finally, arrays of polymer microneedles were shown to increase permeability of human cadaver skin to a low-molecular weight tracer, calcein, and a macromolecular protein, bovine serum albumin, by up to three orders of magnitude. Altogether, these results indicate that biodegradable polymer microneedles can be fabricated with an appropriate geometry and sufficient strength to insert into skin, and thereby dramatically increase transdermal transport of molecules.
Article
Vaccination is one of the major achievements of modern medicine. As a result of vaccination, diseases such as polio and measles have been controlled and small pox has been eradicated. However, despite these successes there are still many microbial diseases that cause tremendous suffering because there is no vaccine or the vaccines available are inadequate. In addition, even if vaccines were available for all infectious diseases there is no guarantee that people would use them routinely. One of the major impediments to ensuring vaccine efficacy and compliance is that of delivery. Presently most vaccines are given by intramuscular administration. Unfortunately this is often traumatic, especially in infants. Thus, if it was possible to replace intramuscular immunization by mucosal (oral/intranasal) or transdermal delivery it may be possible to both enhance mucosal immunity as well as improve overall compliance rates. The transdermal route has been used by the pharmaceutical industry for the delivery of various low molecular weight drugs. Some of the approaches used for smaller compounds may also have potential for delivery of either protein or polynucleotide vaccines. However, there is a greater challenge to delivering large molecular weight molecules through the skin due to size, charge and other physicochemical properties. This review will describe the recent advances that have been made in dermal and topical delivery as related to vaccines.
Article
Streptococcus pneumoniae is a leading cause of morbidity and mortality in both the developing and developed world. The T-independent nature of the current polysaccharide vaccine renders it ineffective in elderly adults and children <2 years of age. Although the recently licensed conjugate vaccines are capable of producing T-cell-dependent immunity, they also have their limitations, namely a lack of response in certain populations. Our laboratory has focused on a different approach, DNA vaccination. We have defined a peptide sequence (pep4) that mimics the S. pneumoniae serotype 4 capsular polysaccharide (PPS4) using a monoclonal antibody to PPS4 (mAb4) and phage display library. Pep4 was synthesized, complexed to proteosomes and used to immunize mice. We have shown by ELISA that this peptide mimic is capable of eliciting an anti-PPS4 immune response significantly higher than in negative control mice (P<0.05). A PPS4-DNA vaccine was made by cloning an oligodeoxynucleotide encoding pep4 into the HBcAg vector. Following epidermal immunization with the PPS4-DNA vaccine, mice produced an anti-PPS4 antibody response significantly higher than in mice immunized with an impertinent DNA vector (P<0.05). Our results demonstrate the feasibility of peptide mimicry in DNA vaccine development.
Article
Six hundred and forty-eight tuberculin negative Cardiff schoolchildren were vaccinated. using two 18-needle multiple puncture instruments and the intradermal method in rotation. The multiple puncture instruments did not contain a trigger device for releasing the needles, but incorporated a catch mechanism, which gave an audible click when the end plate was retracted for the needle points to protrude 2 mm. and retained the end plate in the retracted position until it was released. One instrument, on which 1·8 kg. pressure was required to engage the catch, gave a tuberculin conversion rate of 79% to five TU of OT twelve weeks later. For the other instrument, identical to the first except that 3·0 kg. pressure was required, the conversion rate was 86%. The intradermal method gave a tuberculin conversion rate of 93%. Two medical officers working separately obtained substantially similar results with each of the three methods.All the dried BCG vaccines used maintained their potencies for at least 90 minutes after suspension, as judged by the development of tuberculin sensitivity after vaccination.The size and appearance of the two sets of BCG lesions were closely similar in each child vaccinated by multiple puncture, and the same or closely similar for 84% of those vaccinated by the intradermal method, but they varied considerably from one child to another.
Article
Within the context of future multipuncture withdrawal, we managed, in April 2005, a survey on BCG vaccine habits. During April 2005, 636 paediatricians and 192 GP took part in a survey about BCG, practices managed by InfoVac-France, InVS and AFPA. Most of physicians (73.6%) don't use Mantoux test before BCG vaccination in children less than 6 months old, and the Monovax® is the most frequent vaccine used (93.7%). Less than 30% physicians are thinking to be ready to systematically vaccine children after prospected withdrawal of multipuncture vaccination, and almost 1 pediatrician of 5 and one GP of 7 don't want to vaccine anymore. In future, preferred option after Monovax® withdrawal is to vaccinate with BCG only the high risk population for tuberculosis (59%). About 60% physicians think that parents could be opposed to intradermal immunization. More than 2/3 of physicians have not an assistant (except the parents) to contain the children during the intradermal injection (71.6%). It seems not acceptable for 2/3 of physicians to address their patients to colleagues or to specialized structures.
Article
Microneedle arrays are promising devices for the delivery of drugs and vaccines into or the skin. However, little is known about the safety of the microneedles. In this study we obtained insight in the ability of microneedles to disrupt the skin barrier, which was evaluated by transepidermal water loss (TEWL). We also determined the safety in terms of skin irritation (skin redness and blood flow) and pain sensation. We applied microneedle arrays varying in length and shape on the ventral forearms of 18 human volunteers. An effect of needle length was observed, as TEWL and redness values after treatment with solid microneedle arrays of 400 microm were significantly increased compared to 200 microm. The blood flow showed a similar trend. Needle design also had an effect. Assembled microneedle arrays induced higher TEWL values than the solid microneedle arrays, while resulting in less skin irritation. However, for all microneedles the irritation was minimal and lasted less than 2h. In conclusion, the microneedle arrays used in this study are able to overcome the barrier function of the skin in human volunteers, are painless and cause only minimal irritation. This opens the opportunity for dermal and transdermal delivery of drugs and vaccines.
Article
Infusion into skin using hollow microneedles offers an attractive alternative to hypodermic needle injections. However, the fluid mechanics and pain associated with injection into skin using a microneedle have not been studied in detail before. Here, we report on the effect of microneedle insertion depth into skin, partial needle retraction, fluid infusion flow rate and the co-administration of hyaluronidase on infusion pressure during microneedle-based saline infusion, as well as on associated pain in human subjects. Infusion of up to a few hundred microliters of fluid required pressures of a few hundred mmHg, caused little to no pain, and showed weak dependence on infusion parameters. Infusion of larger volumes up to 1 mL required pressures up to a few thousand mmHg, but still usually caused little pain. In general, injection of larger volumes of fluid required larger pressures and application of larger pressures caused more pain, although other experimental parameters also played a significant role. Among the intradermal microneedle groups, microneedle length had little effect; microneedle retraction lowered infusion pressure but increased pain; lower flow rate reduced infusion pressure and kept pain low; and use of hyaluronidase also lowered infusion pressure and kept pain low. We conclude that microneedles offer a simple method to infuse fluid into the skin that can be carried out with little to no pain.
Article
Over the past decade, microneedles have been shown to dramatically increase skin permeability to a broad range of compounds by creating reversible microchannels in the skin. However, in order to achieve sustained transdermal drug delivery, the extent and duration of skin's increased permeability needs to be determined. In this study, we used electrical impedance spectroscopy to perform the first experiments in human subjects to analyze the resealing of skin's barrier properties after insertion of microneedles. Microneedles having a range of geometries were studied in conjunction with the effect of occlusion to test the hypothesis that increasing microneedle length, number, and cross-sectional area together with occlusion leads to an increase in skin resealing time that can exceed one day. Results indicated that in the absence of occlusion, all microneedle treated sites recovered barrier properties within 2 h, while occluded sites resealed more slowly, with resealing windows ranging from 3 to 40 h depending on microneedle geometry. Upon subsequent removal of occlusion, the skin barrier resealed rapidly. Longer microneedles, increased number of needles, and larger cross-sectional area demonstrated slower resealing kinetics indicating that microneedle geometry played a significant role in the barrier resealing process. Overall, this study showed that pre-treatment of skin with microneedles before applying an occlusive transdermal patch can increase skin permeability for more than one day, but nonetheless allow skin to reseal rapidly after patch removal.
Article
We propose pretreatment using microneedles to increase perianal skin permeability for locally targeted delivery of phenylephrine (PE), a drug that increases resting anal sphincter pressure to treat fecal incontinence. Microneedle patches were fabricated by micromolding poly-lactic-acid. Pre-treatment of human cadaver skin with microneedles increased PE delivery across the skin by up to 10-fold in vitro. In vivo delivery was assessed in rats receiving treatment with or without use of microneedles and with or without PE. Resting anal sphincter pressure was then measured over time using water-perfused anorectal manometry. For rats pretreated with microneedles, topical application of 30% PE gel rapidly increased the mean resting anal sphincter pressure from 7±2 cm H(2)O to a peak value of 43±17 cm H(2)O after 1 h, which was significantly greater than rats receiving PE gel without microneedle pretreatment. Additional safety studies showed that topically applied green fluorescent protein-expressing E. coli penetrated skin pierced with 23- and 26-gauge hypodermic needles, but E. coli was not detected in skin pretreated with microneedles, which suggests that microneedle-treated skin may not be especially susceptible to infection. In conclusion, this study demonstrates local transdermal delivery of PE to the anal sphincter muscle using microneedles, which may provide a novel treatment for fecal incontinence.
Article
A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h-DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0 × 1.0 cm, contains 100 microneedle arrays in a 10 × 10 matrix. The mean lengths of DMs were 496.6 ± 2.9 μm for h-DM and 494.5 ± 1.3 μm for d-DM. The diameters of the array basement were 295.9 ± 3.9 μm (d-DM) and 291.7 ± 3.0 μm (h-DM), where ST contents were 31.6 ± 4.5 μg and 24.1 ± 0.9 μg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, Cmax, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6 ± 4.9 ng/ml and 24.6 ± 3.9 ng · h/ml for h-DM and 38.4 ± 2.7 ng/ml and 14.1 ± 1.5 ng · h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7 ± 18.8% for h-DM and 93.6 ± 10.2% for d-DM. Good dose dependency was observed on Cmax and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, −80, 4, 23, and 50°C. At the end of incubation period, they were, respectively, 100.0 ± 0.3%, 97.8 ± 0.2%, 98.8 ± 0.2%, and 100.7 ± 0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy.
Article
Needle-free liquid jet injectors have been developed for the delivery of several drugs including insulin and growth hormone. Here, we assess the ability of liquid jet injectors to deliver polymeric nanoparticles into skin. As a first step, polystyrene particles of several sizes and two shapes were injected into skin using a jet injector. The dispersion area of particles, measured in the cross section of the skin, was found to inversely relate to the particle size and directly proportional to the injection volume. Environmental scanning electron microscopy studies confirmed that particles indeed penetrate into the skin and are generally located around the injection site. Next, poly lactide co-glycolide (PLGA) particles, containing a model solute, coumarin-6, were synthesized and delivered into the skin using the jet injector. PLGA particles were effectively delivered into the skin and released coumarin-6 into the skin.