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Simple Summary Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes massive financial losses in pig production worldwide. Vaccination is still the most cost-effective tool to handle PRRSV infection. PRRSV induces apoptosis in different organs. Angiotensin II (Ang II) participates in the inflammatory response, cell proliferation, migration, and apoptosis. The objective of the current study was to assess the concentration of Ang II in the serum of piglets following immunization against PRRSV through intradermal (ID) or intramuscular (IM) vaccination with a commercial PRRS modified live virus (MLV) vaccine. The results indicated differences in viremia of tested piglets at 7 weeks of age, while piglets at 10 weeks of age were all found qRT-PCR positive for PRRSV. Moreover, significant differences were noticed in Ang II in 7-week-old piglets. In conclusion, our study provides evidence that ID vaccination induces less tissue damage, based on the lower measurements of Ang II in the serum of ID vaccinated piglets. The Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) induces apoptosis in different organs. Angiotensin II (Ang II) is the main effector of the renin-angiotensin system and participates in apoptosis. Thus, this study aimed to investigate changes in piglet serum Ang II levels following intradermal (ID) and intramuscular (IM) vaccination with a commercial PRRS modified live virus (MLV) vaccine. The trial was conducted in a commercial pig farm, including 104 piglets which were randomly allocated to four groups: Group A-Porcilis PRRS ID, Group B-Porcilis PRRS IM, Group C-Diluvac ID and Group D-Diluvac IM. The study piglets were either vaccinated or injected at 2 weeks of age and they were tested by qRT-PCR for PRRSV and by ELISA for Ang II. The results indicated differences in viremia of tested piglets at 7 weeks of age, while piglets at 10 weeks of age were all found qRT-PCR positive for PRRSV. In addition, significant differences were noticed in Ang II in 7-week-old piglets. In conclusion, the present study provides evidence that ID vaccination induces less tissue damage, based on the lower measurements of Ang II in the serum of ID vaccinated piglets.

Objective: Fear of dental procedures is a common barrier to effective dental care. A promising technique to overcome dental anxiety is needle-free jet injection, which involves delivering local anaesthetic as a high-speed jet capable of penetrating the oral mucosa without a needle. Previous efforts have used loud, uncontrolled injectors designed for transdermal delivery that have failed to achieve significant uptake in dental practice. Methods: In this work, we present and validate a controllable jet injection device driven by a silent electric motor for the delivery of dental local anaesthetic. The injector includes a novel tubular attachment at its distal end, which allows the delivery to be performed comfortably throughout the mouth. The expected pressure loss resulting from the use of this attachment is analysed. This analysis predicted that a 75 mm long tubular attachment of 0.53 mm radius would result in negligible pressure loss. To validate delivery in human tissue, the injection system was used to perform 18 injections into the mouths of two Thiel-embalmed human cadavers. These injections were visualised using cone-beam computed tomography (CBCT). Results: Benchtop testing of the prototype injector verified the expected pressure loss along the attachment. The CBCT scans demonstrated that the fluid was successfully delivered to the desired locations, adjacent to the root apex of the teeth, at every injection site. Conclusion: These outcomes validate the performance of this novel needle-free injector, demonstrating its potential as a tool to reduce dental anxiety. Clinical and Translational Impact Statement— Our controllable jet injection device overcomes key limitations associated with previous attempts to deliver dental local anaesthetic needle-free. This could greatly reduce barriers to effective dental care.

The work reported here focuses on an evaluation of a novel heat stable formulation of a uterotonic peptide drug oxytocin involving stability testing under elevated temperatures and toxicokinetic response generated by sublingual (SL) administration in rabbits. The formulation was thermotolerant, maintaining the potency of oxytocin in the form of a fast-dissolving tablet at the end of 2-year storage at 30 °C/65% relative humidity with less than 5% loss in oxytocin content based on analytical high performance liquid chromatography (HPLC). The toxicokinetic results in rabbits showed that the fast-dissolving tablet was safe without any reactogenicity or toxicity associated with SL administration or the excipients present in the formulation. The SL route elicited rapid absorption of oxytocin in plasma within 5 min of administration although lower than intramuscular (IM) administration. IM resulted in area under the curve (AUC) values approximately 5 times higher than SL oxytocin. However, due to the limitations encountered during SL administration in an anesthetized rabbit model, the relevance of heat stable oxytocin formulation that has the flexibility to be adapted in different formats may warrant a human clinical study to determine whether therapeutically relevant plasma levels for treating postpartum hemorrhage can be generated via alternate non-injectable routes of administration.

Needle-free liquid jet injectors are medical devices used to administer pharmaceutical solutions through the skin. Jet injectors generate a high-speed stream of liquid medication that can puncture the skin and deliver the drug to the underlying tissues. In this work, we investigated the feasibility of using liquid jet injectors to administer nanosuspensions, assessing the impact of the jet injection on their pharmaceutical and physicochemical properties. For this purpose, the model drug diclofenac was used to prepare a set of nanosuspensions, stabilized by poloxamer 188, and equilibrated at different pHs. The hydrodynamic diameter and morphology of the nanocrystals were analyzed before and after the jet injection across porcine skin in vitro, together with the solubility and release kinetics of diclofenac in a simulated subcutaneous environment. The efficacy of the jet injection (i.e., the amount of drug delivered across the skin) was evaluated for the nanosuspension and for a solution, which was used as a control. Finally, the nanosuspension was administered to rats by jet injector, and the plasma profile of diclofenac was evaluated and compared to the one obtained by jet injecting a solution with an equal concentration. The nanosuspension features were maintained after the jet injection in vitro, suggesting that no structural changes occur upon high-speed impact with the skin. Accordingly, in vivo studies demonstrated the feasibility of jet injecting a nanosuspension, reaching relevant plasma concentration of the drug. Overall, needle-free jet injectors proved to be a suitable alternative to conventional syringes for the administration of nanosuspensions.

Needle-free injections are mainly used for administering human or mammalian vaccines or drugs. However, poultry vaccines, in ovo injections to embryos, subcutaneous injections to chickens, and intramuscular injections are administered using needle injections. This article presents a new needle-free in ovo injection device method that uses push-pull solenoids to eject liquid jets, mainly for embryonic eggs of chickens. Furthermore, our study investigated the suitable jet pressures for using this method and the post-injection hatching rates in 18-day-old embryonic eggs. Using this method, we could deliver the liquid to the allantoic and amniotic cavities or the muscle tissue through the egg membrane of the air chamber using a jet pressure of ~6–7 MPa or ~8 MPa. After injecting 0.25 mL of 0.9% saline into 18-day-old Lohmann breed layer embryonic eggs and specific pathogen-free (SPF) embryonic eggs at a jet pressure of ~7 MPa, we observed hatching rates of 98.3% and 85.7%, respectively. This study’s electromagnetic needle-free in ovo injection device can apply vaccine or nutrient solution injection for embryo eggs and serve as a reference for future studies on needle-free in ovo injection automation systems, jet pressure control, and injection pretreatment processes.

Drug delivery using oral route is the most popular, convenient, safest and least expensive approach. It includes oral transmucosal delivery of bioactive compounds as the mucosal cavity offers an intriguing approach for systemic drug distribution. Owing to the dense vascular architecture and high blood flow, oral mucosal layers are easily permeable and can be an ideal site for drug administration. Recently, the transmucosal route is being investigated for other therapeutic candidates such as vaccines for their efficient delivery. Vaccines have the potential to trigger immune reactions and can act as both prophylactic and therapeutic conduit to a variety of diseases. Administration of vaccines using transmucosal route offers multiple advantages, the most important one being the needle-free (non-invasive) delivery. Development of needle-free devices are the most recent and pioneering breakthrough in the delivery of drugs and vaccines, enabling patients to avoid needles, reducing anxiety, pain and fear as well as improving compliance. Oral, nasal and aerosol vaccination is a novel immunization approach that utilizes a nanocarrier to administer the vaccine. Nanocarriers improve the bioavailability and serve as adjuvants to elicit a stronger immune response, resulting in increased effectiveness of vaccination. Drugs and vaccines with lower penetration abilities can also be delivered transmucosally while maintaining their biological function. The development of micro/nanocarriers for transmucosal delivery of macromolecules, vaccines and other substances is currently drawing much attention and a number of studies were performed recently. This comprehensive review is aimed to summarize the most recent investigations on needle-free and non-invasive approaches for the delivery of vaccines using oral transmucosal route, their strengths and associated challenges. The oral transmucosal vaccine delivery by nanocarriers is the most upcoming advancement in efficient vaccine delivery and this review would help further research and trials in this field.

Swift vaccination is necessary as a response to disease outbreaks and pandemics, otherwise, the species under attack is at risk of a high fatality rate or even mass extinction. Statistics suggest that at least 16 billion injections are administered worldwide every year. Such a high rate of needle/syringe injection administration worldwide is alarming due to the risk of needle-stick injuries, disease spread due to cross-contamination and the reuse of needles, and the misuse of needles. In addition, there are production, handling, and disposal costs. Needle phobia is an additional issue faced by many recipients of injections with needles. In addition to a detailed literature review highlighting the need for needle-free injection systems, a compressed air-driven needle-free jet injection system with a hydro-pneumatic mechanism was designed and developed by employing an axiomatic design approach. The proposed injection system has higher flexibility, uninterrupted force generation, and provides the possibility of delivering repeated injections at different tissue depths from the dermis to the muscle (depending on the drug delivery requirements) by controlling the inlet compressed air pressure. The designed needle-free jet injector consists of two primary circuits: the pneumatic and the hydraulic circuit. The pneumatic circuit is responsible for driving, pressurizing, and repeatability. The hydraulic circuit precisely injects and contains the liquid jet, allowing us to control the volume of the liquid jet at elevated pressure by offering flexibility in the dose volume per injection. Finally, in this paper we report on the successful design and working model of an air-driven needle-free jet injector for 0.2–0.5 mL drug delivery by ex vivo experimental validation.

Each individual's skin has its own features, such as strength, elasticity, or permeability to drugs, which limits the effectiveness of one-size-fits-all approaches typically found in medical treatments. Therefore, understanding the transport mechanisms of substances across the skin is instrumental for the development of novel minimal invasive transdermal therapies. However, the large difference between transport timescales and length scales of disparate molecules needed for medical therapies makes it difficult to address fundamental questions. Thus, this lack of fundamental knowledge has limited the efficacy of bioengineering equipment and medical treatments. In this article, we provide an overview of the most important microfluidics-related transport phenomena through the skin and versatile tools to study them. Moreover, we provide a summary of challenges and opportunities faced by advanced transdermal delivery methods, such as needle-free jet injectors, microneedles, and tattooing, which could pave the way to the implementation of better therapies and new methods.

Facial seborrheic dermatitis (FSD) is a common facial inflammatory dermatitis. Needle-free transdermal jet injection (NTJI) is a non-invasive injection of drug solution by using a high-pressure liquid injection instrument. To explore a safer, more tolerable, and convenient medical way using NTJI in the treatment of FSD, the patients were treated with vitamin B6, glycyrrhizin compound, metronidazole, and hyaluronic acid sequentially using NTJI every 2 weeks, and only those treated for more than three times were included. A VISIA facial imaging system for the evaluation of erythema, superficial lipid level, and roughness of skin surface and a CK analyzer for biophysical parameters, including the stratum corneum hydration, facial surface lipid, and trans-epidermal water loss, were applied. Erythema was significantly reduced after every treatment (weeks 2, 4, and 6; P < 0.05), whereas superficial lipid level was not improved significantly until week 6 (P < 0.05), and roughness of the skin surface was not improved significantly during the whole treatment. The stratum corneum hydration of lesional skin was significantly increased after three times of treatment (P < 0.05). No observable adverse effect, such as marked erythema, blistering, or atrophy, was observed. Sequential transdermal delivery of small molecular weight drugs (vitamin B6, glycyrrhizin compound, metronidazole, and hyaluronic acid) using NTJI is a safe, low-toxicity, and take-home drug-free therapy for the treatment of FSD.

Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; however, oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free administration. Using methods developed previously, we produced a robust FDT that maintained oxytocin stability at 40 °C, 75% relative humidity for 12 months. This formulation contains 9% sucrose, 1.5% (hydroxypropyl)methyl cellulose, 9% mannitol, 4% dextran, 1% carbomer, 1% sodium taurocholate, and 100 IU oxytocin. An in vitro study showed a > 30% reduction in tissue transepithelial electrical resistance after treatment with the oxytocin FDT, implying an increase in the permeability of the mucosal tissue to oxytocin. Anesthetized Yucatan miniature swine were administered a SL FDT, and blood was periodically collected for a pharmacokinetic study. Higher plasma concentrations were seen when larger SL doses were given. The maximum concentrations for SL and intramuscular doses in anesthetized pigs were 207 and 612 pg/mL, respectively. Whether the levels attained will be sufficient to elicit beneficial results in humans is yet to be determined. This study demonstrates the feasibility of our approach for developing a heat-stable oxytocin tablet that can be administered successfully via the SL route. Electronic supplementary material The online version of this article (10.1007/s13346-017-0471-7) contains supplementary material, which is available to authorized users.

This thesis describes the development of improved formulations and alternative delivery strategies for polio vaccination. A new generation of IPV should not only be affordable and safe to produce, but preferably should also induce mucosal immunity, remain stable at unrefrigerated conditions, and be easy to administer. This is also important with regard to stockpiling and outbreak management in the period towards and beyond polio eradication. Solid dosage forms that have improved thermostability, like biodegradable Bioneedles comprising lyophilized IPV or polymer-based oral films, would be favorable to reach remote areas in developing countries for which proper logistics are not available. Replacing the currently used polio vaccines with a thermostable vaccine may yield significant cost savings. Furthermore, vaccination via mucosal routes showed to have important advantages over conventional intramuscular vaccination using needle and syringes.

Introduction: With the increasing number of vaccines and vaccine-preventable diseases, the pressure to generate multi-valent and multi-pathogen vaccines grows. Combining individual established vaccines to generate single-shot formulations represents an established path, with significant ensuing public health and cost benefits. Poxvirus-based vector systems have the capacity for large recombinant payloads and have been widely used as platforms for the development of recombinant vaccines encoding multiple antigens, with considerable clinical trials activity and a number of registered and licensed products. Areas covered: Herein we discuss design strategies, production processes, safety issues, regulatory hurdles and clinical trial activities, as well as pertinent new technologies such as systems vaccinology and needle-free delivery. Literature searches used PubMed, Google Scholar and clinical trials registries,with a focus on the recombinant vaccinia-based systems, Modified Vaccinia Ankara and the recently developed Sementis Copenhagen Vector. Expert commentary: Vaccinia-based platforms show considerable promise for the development of multi-valent and multi-pathogen vaccines, especially with recent developments in vector technologies and manufacturing processes. New methodologies for defining immune correlates and human challenge models may also facilitate bringing such vaccines to market. Refereed/Peer-reviewed

The limited durability of pertussis vaccine-induced protection requires novel approaches to reactivate immunity and limit pertussis resurgence in older children and adults. We propose that periodic boosters could be delivered using a novel epicutaneous delivery system (Viaskin®) to deliver optimized pertussis antigens such as genetically-detoxified pertussis toxin (rPT). To best mimic the human situation in which vaccine-induced memory cells persist, whereas antibodies wane, we developed a novel adoptive transfer murine model of pertussis immunity. This allowed demonstrating that a single application of Viaskin® delivering rPT and/or pertactin and filamentous hemagglutinin effectively reactivates vaccine-induced pertussis immunity and protects against Bordetella pertussis challenge. Recalling pertussis immunity without needles nor adjuvant may considerably facilitate the acceptance and application of periodic boosters.

The threat posed by the 2009 pandemic H1N1 virus emphasized the need for new influenza A virus vaccines inducing a broad cross-protective immune response for use in both humans and pigs. An effective and broad influenza vaccine for pigs would greatly benefit the pork industry and contribute to public health by diminishing the risk of emerging highly pathogenic reassortants. Current inactivated protein vaccines against swine influenza produce only short-lived immunity and have no efficacy against heterologous strains. DNA vaccines are a potential alternative with advantages such as the induction of cellular and humoral immunity, inherent safety and rapid production time. We have previously developed a DNA vaccine encoding selected influenza proteins of pandemic origin and demonstrated broad protective immune responses in ferrets and pigs. In this study, we evaluated our DNA vaccine expressed by next-generation vectors. These new vectors can improve gene expression, but they are also efficiently produced on large scales and comply with regulatory guidelines by avoiding antibiotic resistance genes. In addition, a new needle-free delivery of the vaccine, convenient for mass vaccinations, was compared with intradermal needle injection followed by electroporation. We report that when our DNA vaccine is expressed by the new vectors and delivered to the skin with the needle-free device in the rabbit model, it can elicit an antibody response with the same titers as a conventional vector with intradermal electroporation. The needle-free delivery is already in use for traditional protein vaccines in pigs but should be considered as a practical alternative for the mass administration of broadly protective influenza DNA vaccines.

Highlights • We compared MMR vaccine administration by disposable-syringe jet injector (DSJI) and needle and syringe (N-S). • The study was conducted in 340 toddlers who had received a measles vaccine at 9 months. • On day 35, seropositivity for all three viruses was more than 97% in both the groups. • Reactogenicity by both methods was comparable. • MMR vaccination via DSJI is as immunogenic and safe as vaccination by N-S., Background We conducted a randomized, non-inferiority, clinical study of MMR vaccine by a disposable-syringe jet injector (DSJI) in toddlers in India in comparison with the conventional administration. Methods MMR vaccine was administered subcutaneously by DSJI or needle-syringe (N-S) to toddlers (15–18 months) who had received a measles vaccine at 9 months. Seropositivity to measles, mumps, and rubella serum IgG antibodies was assessed 35 days after vaccination. Non-inferiority was concluded if the upper limit of the 95% CI for the difference in the percent of seropositive between groups was less than 10%. Solicited reactions were collected for 14 days after vaccination by using structured diaries. Results In each study group, 170 subjects received MMR vaccine. On day 35, seropositivity for measles was 97.5% [95% CI (93.8%, 99.3%)] in the DSJI group and 98.7% [95% CI (95.5%, 99.8%)] in the N-S group; for mumps, 98.8% [95% CI (95.6%, 99.8%)] and 98.7% [95% CI (95.5%, 99.8%)]; and for rubella, 98.8% [95% CI (95.6%, 99.8%)] and 100% [95% CI (97.7%, 100.0%)]; none of the differences were significant. The day 35 post-vaccination GMTs in DSJI and N-S groups were measles: 5.48 IU/ml [95% CI (3.71, 8.11)] and 5.94 IU/ml [95% CI (3.92, 9.01)], mumps: 3.83 ISR [95% CI (3.53, 4.14)] and 3.66 ISR [95% CI (3.39, 3.95)] and rubella: 95.27 IU/ml [95% CI (70.39, 128.95)] and 107.06 IU/ml [95% CI (79.02, 145.06)]; none of the differences were significant. The DSJI group reported 173 solicited local reactions and the N-S group reported 112; most were mild grade. Of the total of 156 solicited systemic adverse events, most were mild, and incidence between the two groups was similar. Conclusions MMR vaccination via DSJI is as immunogenic as vaccination by N-S. Safety profile of DSJI method is similar to N-S except for injection site reactions which are more with DSJI and are well-tolerated. Registration US National Institutes of Health clinical trials identifier – NCT02253407. Clinical trial registry of India identifier – CTRI/2013/05/003702

Vaccination faces many challenges nowadays, and among them the use of adjuvant molecules and needle-free administration are some of the most demanding. The combination of transcutaneous vaccination and nanomedicine through a rationally designed new-formulation could be the solution to this problem. This study focuses on this rational design. For this purpose, new hyaluronic acid nanocapsules (HA-NCs) have been developed. This new formulation has an oily nucleus with immunoadjuvant properties (due to &alpha, tocopherol) and a shell made of hyaluronic acid (HA) and decorated with ovalbumin (OVA) as the model antigen. The resulting nanocapsules are smaller than 100 nm, have a negative superficial charge and have a population that is homogeneously distributed. The systems show high colloidal stability in storage and physiological conditions and high OVA association without losing their integrity. The elevated interaction of the novel formulation with the immune system was demonstrated through complement activation and macrophage viability studies. Ex vivo studies using a pig skin model show the ability of these novel nanocapsules to penetrate and retain OVA in higher quantities in skin when compared to this antigen in the control solution. Due to these findings, HA-NCs are an interesting platform for needle-free vaccination.

For global eradication of poliomyelitis, inactivated poliovirus vaccine (IPV) needs to become available in all countries. Using fractional-doses (reduced-doses) may impact affordability and optimize the utilization of the production capacity. Intradermal administration has the potential to lower the dose without reducing immunogenicity. A needle-free jet injector may be a reliable way to administer vaccines intradermally. The primary objective of this randomized controlled trial was to compare the immunogenicity and tolerability of fractional-dose intradermal IPV (Netherlands Vaccine Institute, NVI) booster vaccination administered with a jet injector (PharmaJet) to full-dose and fractional-dose intramuscular vaccination with a needle and syringe. Immunogenicity was assessed by comparing the differences in the post-vaccination log2 geometric mean concentrations of neutralizing antibodies (GMC) between the study groups. A total of 125 Dutch adult volunteers with a well-documented vaccination history were randomized to one of four groups: full-dose intramuscular needle (IM-NS-0.5), full-dose intramuscular jet injector (IM-JI-0.5), 1/5th dose intramuscular needle (IM-NS-0.1), 1/5th dose intradermal jet injector (ID-JI-0.1). Vaccination with the JI was less painful (87% no pain) than vaccination with a NS (60% no pain), but caused more transient erythema (JI 85%, NS 24%) and swelling (JI 50%, NS 5%). Intradermal vaccination caused less vaccination site soreness (ID 16%, IM 52%). At baseline all subjects had seroprotective antibody concentrations. After 28 days, GMC were slightly lower in the ID-JI-0.1 group than in the reference group (IM-NS-0.5). The differences were not statistically significant, but the stringent non-inferiority criterion (i.e. a difference of 1 serum dilution in the microneutralization assay) was not met. After one year, differences in GMC were no longer apparent. In contrast, intramuscular vaccination with a fractional dose administered with a needle (IM-NS-0.1) was statistically inferior to full-dose intramuscular vaccination. This shows that intradermal but not intramuscular delivery of fractional-dose IPV may be sufficient for routine polio vaccination.

In the Netherlands, children receive within the National Vaccination Program, 14 injections against 12 diseases. This number will only increase in the future. Since needles and syringes have several drawbacks, such as needle stick injuries and needle fear, alternatives have been assessed to deliver vaccines. The aim of the thesis was to identify and evaluate methods suitable for minimally invasive delivery of vaccines in order to become more flexible in complex pediatric immunization programs. Access to these delivery methods would facilitateincorporation of new vaccines in the program. Three alternatives are assessed in this thesis: -Bioneedles for s.c delivery -Elastic vesicles for topical application -Liquid jet injector for i.d delivery

The skin has evolved to resist the penetration of foreign substances and particles. Effective topical drug delivery into and/or through the skin is hindered by these epidermal barriers. A range of physical enhancement methods has been developed to selectively overcome this barrier. This review discusses recent advances in physical drug delivery by broadly separating the techniques into two main areas; indirect and direct approaches. Indirect approaches consist of electrical, vibrational or laser instrumentation that creates pores in the skin followed by application of the drug. Direct approaches consist of mechanical disruption of the epidermis using techniques such as microdermabrasion, biolistic injectors and microneedles. Although, in general, physical techniques are yet to be established in a clinical setting, the potential gains of enhancing delivery of compounds through the skin is of great significance and will no doubt continue to receive much attention. Refereed/Peer-reviewed

Protein and peptide based therapeutics are typically administered by injection due to their poor uptake when administered via enteral routes of drug administration. Unfortunately, chronic administration of these drugs through multiple injections presents certain patient related problems and it is difficult to mimic the normal physiological release patterns via this mode of drug administration. A need therefore exists to non-invasively deliver these drugs by means of alternative ways such as via the oral, pulmonary, nasal, transdermal and buccal administration routes. Although some attempts of needle free peptide and protein drug delivery have progressed to the clinical stage, relatively limited success has been achieved in terms of commercially available products. Despite the low frequency of clinical breakthroughs with noninvasive protein drug delivery this far, it remains an active research area with renewed interest not only due to its improved therapeutic potential, but also due to the attractive commercial outcomes it offers. It is the aim of this review article to reflect on the main strategies investigated to overcome the barriers against effective systemic protein drug delivery in different routes of drug administration. Approaches based on chemical modifications and pharmaceutical technologies are discussed with reference to examples of drugs and devices that have shown potential, while attempts that have failed are also briefly outlined http://benthamscience.com/journals/protein-and-peptide-letters/ http://dx.doi.org/10.2174/0929866521666140807112148

Despite progress in the management of chronic pain, acute pain remains an issue for many postoperative patients. Although patient-controlled analgesia (PCA) has demonstrated efficacy and patient satisfaction, current techniques using intravenous (IV) administration present limitations, including the risk of programming errors and the potential to limit patient mobility due to pumps, lines, and tubing. The patient-controlled fentanyl hydrochloride (HCl) iontophoretic transdermal system (fentanyl ITS) was designed to address these concerns. Fentanyl ITS is an innovative, needle-free, self-contained drug-delivery system that uses iontophoretic technology to deliver fentanyl through the skin by application of a low-intensity electrical field. The results of several clinical studies are presented in this review. In three phase 3 placebo-controlled trials, fentanyl ITS was shown to be superior to placebo for the treatment of postoperative pain following major abdominal, orthopedic, and thoracic surgery. The results of one active-comparator phase 3 trial demonstrated comparable safety and efficacy with a standard morphine IV PCA dosing regimen, without significant difference in the side effect profile. Fentanyl ITS represents a safe, easy to use, non-invasive, and convenient alternative to current acute postoperative pain management modalities.

Objective: Efficacy of eutectic mixture of local anesthetic (EMLA) cream and the needle-free injection of local anesthesia for reducing pain associated with fine-needle aspiration biopsy (FNAB) of thyroid nodules has been previously reported. However, there has not been a direct comparison of the analgesic efficacy of these methods. The aim of this study was to compare the analgesic efficacy of EMLA cream and needle-free injection of lidocaine for FNAB-associated pain. Materials and Methods: A total of 138 patients having their first ultrasonography-guided thyroid nodule biopsy were randomly assigned to receive either EMLA cream (n=68) or needle-free injection of lidocaine (n=70) before FNAB of thyroid nodules. Four needle passes for biopsy of each nodule were performed. Patients rated pain associated with the procedure according to a 100-mm visual analog scale (VAS), an 11-point numeric rating scale (NRS), and 4-category verbal rating scale (VRS). Results: There were no significant differences between groups in age, sex, thyroid volume, nodule size, or nodule site. Significant differences between groups were noted in ratings of all three pain scales. When the effectiveness of EMLA was compared with that of needle-free injection of lidocaine, the mean VAS score was 23.4±20.5 mm versus 12.7±15.5 mm (p=0.001), and the mean NRS score was 2.8±2.1 points versus 1.6±1.7 points (p