Efficacy and safety of DFN-11 (sumatriptan injection, 3 mg) in adults with episodic migraine: a multicenter, randomized, double-blind, placebo-controlled study.

BackgroundIn a previous randomized, double-blind, proof-of-concept study in rapidly escalating migraine, a 3 mg dose of subcutaneous sumatriptan (DFN-11) was associated with fewer and shorter triptan sensations than a 6 mg dose. The primary objective of the study was to assess the efficacy and safety of acute treatment with DFN-11 compared with placebo in episodic migraine.MethodsThis was a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of DFN-11 in the acute treatment of adults with episodic migraine (study RESTOR). The primary endpoint was the proportion of subjects taking DFN-11 who were pain free at 2 h postdose in the double-blind period compared with placebo. Secondary endpoints included earlier postdose timepoints, assessments of pain relief and subjects' freedom from their most bothersome symptom (MBS) (among nausea, photophobia, and phonophobia). Safety and tolerability were assessed.ResultsA total of 392 subjects was screened, 268 (68.4%) were randomized, and 234 (87.3% of those randomized) completed the double-blind treatment period. The proportion of subjects who were pain free at 2 h postdose was significantly greater in the DFN-11 group than in the placebo group (51.0% vs 30.8%, P  =  0.0023). Compared with placebo, significantly higher proportions of subjects treated with DFN-11 were also pain free at 30, 60, and 90 min postdose (P  ≤  0.0195). DFN-11 was significantly superior to placebo for pain relief at 60 min, 90 min, and 2 h postdose (P ≤ 0.0179). At 2 h postdose, DFN-11 was also significantly superior to placebo for freedom from photophobia (P  =  0.0056) and phonophobia (P  =  0.0167). Overall, 33.3% (37/111) who received DFN-11 and 13.4% (16/119) who received placebo experienced at least 1 treatment-emergent adverse event (TEAE), the most common of which were injection site swelling (7.2% vs 0.8%) and pain (7.2% vs 5.9%). Chest discomfort was about half as common in the DFN-11 treatment group as it was in the placebo group (0.9% vs 1.7%).ConclusionsThis study met its primary endpoint, pain freedom at 2 h postdose, with DFN-11 significantly better than placebo, and the incidence of TEAEs and triptan sensations with DFN-11 was low. The 3 mg dose of sumatriptan in DFN-11 appears to be an effective alternative to a 6 mg SC dose of sumatriptan, with good safety and tolerability. ( clinicaltrials.gov : NCT02569853; registered 07 October 2015)

Microneedles for drug delivery: trends and progress

In recent years there has been a surge in the research and development of microneedles, a transdermal delivery system that combines the technology of transdermal patches and hypodermic needles. The needles are in the hundreds of micron length range and therefore allow relatively little or no pain. For example, biodegradable microneedles have been researched in the literature and have several advantages compared to solid or hollow microneedles, as they produce non-sharp waste and can be designed to allow rapid or slow release of drugs. However they also pose a disadvantage as successful insertion into the stratum corneum layer of the skin relies on sufficient mechanical strength of the biodegradable material. This review looks at the various technologies developed in microneedle research and shows the rapidly growing numbers of research papers and patent publications since the first invention of microneedles (using time series statistical analysis). This provides the research and industry communities a valuable synopsis of the trends and progress being made in this field

Transdermal Microneedles for Insulin Delivery

Diabetes is a chronic metabolic disease that occurs when there is a deficiency in the production of insulin by the pancreas or when the body cannot effectively use the insulin it produces. Therefore, the treatment of diabetes aims to control the levels of glucose in the blood, which involves many different approaches, including insulin therapy many times. To date, even though many strategies have been proposed as alternative administration routes for insulin, subcutaneous injections still the most common administration route. To overcome the disadvantages imposed by the daily subcutaneous injections of insulin and to increase patient compliance, this thesis aimed to develop stable coated microneedles for rapid transdermal delivery of insulin. For that, polymeric microneedles made of a biocompatible resin class I were developed using 3D printing technology and studied along with a commercial metallic microneedle. The penetration studies showed that the 3D printed MNs presented superior penetration capacity compared to the metallic microneedles. To apply specific doses of insulin on the microneedles, an Inkjet printing technology was used. The SEM revealed the formation of fine layers on the microneedles without loss of insulin during the coating process. Moreover, Micro-CT showed that the films stayed onto the MNs surfaces during the piercing. In order to address the challenges with insulin instability, different polymers and sugars were used as drug carriers to preserve insulin integrity during the coating process as well as to form uniform coating layers and facilitate rapid release rates. Circular dichroism and Raman spectroscopy demonstrated that most of the carriers maintained the secondary structure of insulin in its native form in the films. Moreover, X-ray diffraction analysis revealed that the insulin-carriers tended to originate amorphous films. The release studies using Franz cell diffusion showed that insulin is quickly released from the coated microneedles within 30 min. Furthermore, the animal studies showed that the coated 3D printed microneedles promoted a similar initial profile release to the SC injections, followed by a more sustained release pattern for all tested insulins (bovine, aspart and glargine)

Iontophoresis of Biological Macromolecular Drugs

Over the last few decades, biological macromolecular drugs (e.g., peptides, proteins, and nucleic acids) have become a significant therapeutic modality for the treatment of various diseases. These drugs are considered superior to small-molecule drugs because of their high specificity and favorable safety profiles. However, such drugs are limited by their low oral bioavailability and short half-lives. Biological macromolecular drugs are typically administrated via invasive methods, e.g., intravenous or subcutaneous injections, which can be painful and induce needle phobia. Noninvasive transdermal delivery is an alternative administration route for the local and systemic delivery of biological macromolecular drugs. However, a challenge with the noninvasive transdermal delivery of biological macromolecular drugs is the outermost layer of the skin, known as the stratum corneum, which is a physical barrier that restricts the entry of extraneous macromolecules. Iontophoresis (IP) relies on the application of a low level of electricity for transdermal drug delivery, in order to facilitate the skin permeation of hydrophilic and charged molecules. The IP of several biological macromolecular drugs has recently been investigated. Herein, we review the IP-mediated noninvasive transdermal delivery of biological macromolecular drugs, their routes of skin permeation, their underlying mechanisms, and their advance applications

Microneedles for Drug Delivery via the Gastrointestinal Tract

Both patients and physicians prefer the oral route of drug delivery. The gastrointestinal (GI) tract, though, limits the bioavailability of certain therapeutics because of its protease and bacteria-rich environment as well as general pH variability from pH 1 to 7. These extreme environments make oral delivery particularly challenging for the biologic class of therapeutics. Here, we demonstrate proof-of-concept experiments in swine that microneedle-based delivery has the capacity for improved bioavailability of a biologically active macromolecule. Moreover, we show that microneedle-containing devices can be passed and excreted from the GI tract safely. These findings strongly support the success of implementation of microneedle technology for use in the GI tract.National Institutes of Health (U.S.) (Grant EB000244)National Institutes of Health (U.S.) (Grant T32DK7191-38-S1

Lipid nanocarriers and 3D printed hollow microneedles as strategies to promote drug delivery via the skin

The skin represents an interesting site for the administration of active pharmaceutical ingredients. It offers several advantages over the most conventionally used routes of administration such as the oral and the parental route. Indeed, it bypass the 1st pass metabolism, avoids variables that affect drug absorption in the gastrointestinal tract (i.e. pH, enzymatic activity and drug-food interactions), it is a convenient and non-invasive means of drug delivery and does not require specialized healthcare staff for drug administration. However, due to the structural properties of the skin, only drugs with selected physicochemical features are suitable to be delivered via this administration route. In order to facilitate skin drug delivery various strategies have been studied over the years such as the use of chemical enhancers, external energy or nanodelivery systems. In this thesis lipid nanocarriers combined with the penetration enhancer Transcutol® P and 3D printed microneedles are employed as strategies to promote drug delivery via the skin. Specifically, Part 1 investigates the combination of the penetration enhancer Transcutol® P with two different lipid nanocarriers, solid lipid nanoparticles (Chapter 1) and phospholipid vesicles (Chapter 2), as tools to promote the skin accumulation of 8-methoxypsoralen (8-MOP). In Part 2, 3D printing is employed as an innovative method for the manufacturing of solid and hollow microneedles (MNs) patches

Bio-functional textiles: Combining pharmaceutical nanocarriers with fibrous materials for innovative dermatological therapies

In the field of pharmaceutical technology, significant attention has been paid on exploiting skin as a drug administration route. Considering the structural and chemical complexity of the skin barrier, many research works focused on developing an innovative way to enhance skin drug permeation. In this context, a new class of materials called bio-functional textiles has been developed. Such materials consist of the combination of advanced pharmaceutical carriers with textile materials. Therefore, they own the possibility of providing a wearable platform for continuous and controlled drug release. Notwithstanding the great potential of these materials, their large-scale application still faces some challenges. The present review provides a state-of-the-art perspective on the bio-functional textile technology analyzing the several issues involved. Firstly, the skin physiology, together with the dermatological delivery strategy, is keenly described in order to provide an overview of the problems tackled by bio-functional textiles technology. Secondly, an overview of the main dermatological nanocarriers is provided; thereafter the application of these nanomaterial to textiles is presented. Finally, the bio-functional textile technology is framed in the context of the dierent dermatological administration strategies; a comparative analysis that also considers how pharmaceutical regulation is conducted

INTRANASAL DELIVERY OF INSULIN BY NANOEMULSION SYSTEM

The main objective of this research was to develop an o/w nanoemulsion dosage form of insulin for intranasal delivery where insulin is loaded into the oil phase of the nanoemulsion for enhanced absorption. When loaded into the lipid droplets (oil phase), insulin can be protected from enzymatic degradation, can permeate through the mucus gel barrier in a comparatively efficient manner and can be absorbed through transcellular permeation along with paracellular route. To incorporate lipophilicity to insulin molecule, several complexes of insulin with various amphiphiles were developed to load it into the oil phase. The cytotoxicity of these amphiphiles and the developed nanoemulsions was tested on the human nasal epithelial cells in vitro. An optimized formulation with high loading of insulin and low in vitro cytotoxicity was developed and characterized. To predict the absorption of insulin through nasal membrane in vivo by the nanoemulsion system, the insulin-loaded nanoemulsion along with controls was tested for the transport across human nasal epithelial cell monolayer in vitro. The nanoemulsion significantly (p \u3c 0.01) enhanced the permeation of insulin by three times as compared to the insulin solution. The in vivo absorption of insulin after intranasal delivery of the insulin-loaded nanoemulsion was evaluated in anesthetized rats. The results show that the maximum plasma concentration (Cmax) and the bioavailability (relative to the subcutaneous delivery) of the insulin-loaded nanoemulsion was 255.9 µU/ml and 68 %, respectively, while the intranasal delivery of the insulin solution resulted only 5.8 µU/ml of Cmax and 5% of relative bioavailability. Intranasal delivery of 3.6 IU/kg insulin in nanoemulsion decreased the plasma glucose level remarkably, achieving a maximum reduction of 70%, and the glucose reduction activity lasted for the whole experimental period of 4 h. These results demonstrate that the nanoemulsion significantly enhanced insulin absorption through intranasal delivery, indicating that the developed nanoemulsion system offers a promising approach for intranasal delivery of insulin

Non-invasive vaccination by nanoparticle-based messenger RNA (mRNA) delivery via the transfollicular route

In search for alternative strategies to replace the traditionally used syringe and needle for vaccine administrations and to overcome related disadvantages, the non-invasive approach using nanoparticles (NPs) via the transfollicular route appeared as a promising method to improve patient compliance. As a cargo for NPs, mRNA gained remarkable attention, carrying genetic information of different antigens, proteins or peptides. Hence, the thesis presents a detailed characterization of the mechanistic behind NP-penetration into hair follicles and NP-cellular internalization. Furthermore, advanced delivery systems for mRNA delivery using pharmaceutical safe excipients were designed and mRNA complexed NPs were explored for their potential to efficiently transfect immune cells. In vitro transfection studies in dendritic cells revealed a high transgene expression rate of approx. 80% for novel developed lipid-polymer nanoparticles (LPNs) when compared to an established polymeric system made of PLGA with a chitosan surface coating (CS-PLGA NPs). Based on such encouraging in vitro results, mRNA encoding the influenza antigen hemagglutinin was loaded onto the LPNs and further characterized for their potential to induce effective immunity in in vivo adoptive transfer experiments using HA-transgenic mouse. However, the lack of the expected immune response in this model indicated several challenges related to transfollicular mRNA-vaccination and consequently demand optimization strategies for this administration site to pursue such non-invasive antigen delivery in the future.Alternative Strategien zum Ersatz von Spritzen und Nadeln bei Vakzinierungen würden die damit verbundenen Nachteile beseitigen und somit die Patienten- Compliance verbessern. Der nicht-invasive Ansatz unter Zuhilfenahme von Nanopartikeln (NPs) über die transfollikuläre Route hat sich als eine vielversprechende Methode dafür gezeigt. Der Benutzung von mRNAs als Cargo für Nanopartikel kam eine beachtliche Aufmerksamkeit zu, da eine solche Technologie erlaubt unterschiedliche genetische Informationen von Antigenen, Proteinen und Peptiden zu transportieren. Diese Arbeit zeigt die Entwicklung optimierter mRNA-Trägersysteme, basierend auf pharmazeutisch sicher einzustufender Hilfsstoffe und beschreibt das Potenzial der mRNA beladenen NPs Immunzellen zu transfizieren. In vitro Transfektionsstudien in dendritischen Zellen zeigten eine hohe Transgen-Expressionsrate von ~80% für ein neuentwickeltes Lipid-Polymer-Hybrid NP-System (LPNs) verglichen mit einem etablierten NP-System bestehend aus PLGA und einer Chitosan Beschichtung (CS-PLGA NPs). Ausgehend von diesen ermutigenden in vitro Ergebnissen wurden die LPNs mit einer mRNA beladen, die für das Influenza-Antigen Hämagglutinin kodiert und anschließend auf ihre Effektivität hin, eine Immunantwort in einem adaptiven Transferexperiment im Mäusemodell zu stimulieren, analysiert. Im Tiermodel konnte keine zufriedenstellende Immunantwort durch die transfollikuläre mRNA-basierte Vakzinierung hervorgerufen werden, was einer weiteren Optimierung dieser Administrationsroute bedarf um einen nicht-invasiven Antigen-Transport zu erlauben