We describe, for the first time, hydrogel-forming microneedle arrays prepared from "super swelling" polymeric compositions. We produced a microneedle formulation with enhanced swelling capabilities ...from aqueous blends containing 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000 and 3% w/w Na2CO3 and utilised a drug reservoir of a lyophilised wafer-like design. These microneedle-lyophilised wafer compositions were robust and effectively penetrated skin, swelling extensively, but being removed intact. In in vitro delivery experiments across excised neonatal porcine skin, approximately 44 mg of the model high dose small molecule drug ibuprofen sodium was delivered in 24 h, equating to 37% of the loading in the lyophilised reservoir. The super swelling microneedles delivered approximately 1.24 mg of the model protein ovalbumin over 24 h, equivalent to a delivery efficiency of approximately 49%. The integrated microneedle-lyophilised wafer delivery system produced a progressive increase in plasma concentrations of ibuprofen sodium in rats over 6 h, with a maximal concentration of approximately 179 mu g/ml achieved in this time. The plasma concentration had fallen to 71 plus or minus 6.7 mu g/ml by 24 h. Ovalbumin levels peaked in rat plasma after only 1 hour at 42.36 plus or minus 17.01 ng/ml. Ovalbumin plasma levels then remained almost constant up to 6 h, dropping somewhat at 24 h, when 23.61 plus or minus 4.84 ng/ml was detected. This work represents a significant advancement on conventional microneedle systems, which are presently only suitable for bolus delivery of very potent drugs and vaccines. Once fully developed, such technology may greatly expand the range of drugs that can be delivered transdermally, to the benefit of patients and industry. Accordingly, we are currently progressing towards clinical evaluations with a range of candidate molecules.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This chapter discusses the various microneedle (MN) approaches that have been explored to enhance photodynamic therapy (PDT) and charts the advancements that have been made in the area. The most ...commonly used approaches for MN‐mediated PDT are, skin pre‐treatment using MNs, and, photosensitiser delivery using MNS containing the photosensitising agent itself, with each discussed in the chapter. PDT has progressed considerably from the early application of sunlight and haemato‐porphyrin derivative, to the use of Photofrin and to second generation preformed photosensitisers and topical application of the prodrug 5‐aminolevulinic acid (ALA), which leads to in situ synthesis of the endogenous photosensitiser, protoporphyrin IX (PpIX). ALA and its methyl ester are not specifically photosensitisers but rather precursors of the endogenously produced photosensitising molecule, PpIX. While most studies investigating MNs incorporating the active agent within the device are dissolving systems, other MN forms have also been explored for MN‐assisted PDT.
Microneedle Technology Singh, Thakur Raghu Raj; Donnelly, Ryan F
Novel Delivery Systems for Transdermal and Intradermal Drug Delivery,
2015, 2015-07-15
Book Chapter
Microneedles (MNs) are minimally invasive devices consisting of numerous micron‐sized projections amassed on a baseplate, designed to enhance transdermal drug delivery. When applied to the skin, the ...needles puncture the outermost layer, the stratum corneum, forming aqueous conduits through which drugs can diffuse to the dermal microcirculation. With an average length of 50–900 μm, MNs are short enough to avoid stimulation of dermal nerves and do not induce bleeding, yet gain access to the skin's rich microcirculation for drug delivery. MNs have been extensively investigated for drug and vaccine delivery, demonstrating their efficacy at increasing the number of compounds amenable to delivery through the skin. This chapter discusses the materials and fabrication methods involved in MN production, alongside the different types of MN arrays and their delivery capabilities. The field has expanded to consider novel applications of MNs including minimally invasive patient monitoring, ocular delivery and enhanced administration of cosmeceuticals. Patient usage and effects on the skin are also considered in terms of safety, efficacy and acceptability. The next steps in MN development are to focus on the scale‐up of manufacturing processes, a challenge considering the number of small‐scale methods detailed in the literature. Regulatory guidance is awaited to direct this, alongside provision of clearer patient instruction for safe and effective use of MN devices. MNs have tremendous potential to yield real benefits for patients and industry and with continued research in the key areas highlighted, this will begin to be realised over the next number of years.
BACKGROUND Blunt aortic injury is a major cause of death from blunt trauma. Evolution of diagnostic techniques and methods of operative repair have altered the management and posed new questions in ...recent years.
METHODS This study was a prospectively conducted multicenter trial involving 50 trauma centers in North America under the direction of the Multi-institutional Trial Committee of the American Association for the Surgery of Trauma.
RESULTS There were 274 blunt aortic injury cases studied over 2.5 years, of which 81% were caused by automobile crashes. Chest computed tomography and transesophageal echocardiography were applied in 88 and 30 cases, respectively, and were 75 and 80% diagnostic, respectively. Two hundred seven stable patients underwent planned thoracotomy and repair. Clamp and sew technique was used in 73 (35%) and bypass techniques in 134 (65%). Overall mortality was 31%, with 63% of deaths being attributable to aortic rupture; mortality was not affected by method of repair. Paraplegia occurred postoperatively in 8.7%. Logistic regression analysis demonstrated clamp and sew (p = 0.002) and aortic cross clamp time of > or = to30 minutes (p=0.01) to be associated with development of postoperative paraplegia.
CONCLUSIONS Rupture after hospital admission remains a major problem. Although newer diagnostic techniques are being applied, at this time aortography remains the diagnostic standard. Aortic cross clamp time beyond 30 minutes was associated with paraplegia; bypass techniques, which provide distal aortic perfusion, produced significantly lower paraplegia rates than the clamp and sew approach.
Considerable heterogeneity in the amount of surface antigen can regularly be demonstrated by cytofluorometric analysis among genetically identical cells in a tumor clone. We have used monoclonal ...idiotype-specific antibodies to investigate the patterns of change in amounts of an idiotypic tumor antigen and how such changes affect the immune escape of malignant B cells expressing this antigen. By the use of fluorescence-activated cell sorting, we separated cells expressing either very large or very small amounts of the idiotypic target antigen and then analyzed these subpopulations of tumor cells at various times after isolation for expression of idiotype. We found that the differences in amount of antigen expression were not heritable, and that over a period of about 7 days of continuous growth in vitro, the fluorescence-activated cell sorted populations gradually came to express normal amounts of idiotype. The mechanisms regulating the quantity of surface idiotype were independent of those affecting the amounts of other membrane-associated molecules such as H-2 antigen. Furthermore, these nonheritable intraclonal differences in amounts of antigen expression were unrelated to stages of the cell cycle but clearly did affect the susceptibility of the cells from immune lysis. Thus, tumor cells expressing the lowest amount of surface idiotype were much more resistant to the lytic effects of antiidiotypic antibody and complement but had the same cell cycle distribution as did unseparated cells. These results demonstrate that nonheritable, non-cell cycle-related heterogeneity in amount of tumor antigen expression can significantly determine which cells in a cloned malignant cell population preferentially escape monoclonal tumor-specific antibody therapy.
Studies of the urinary excretion of a number of metabolites by normal adults and by persons suffering from chronic formation of calcium oxalate calculi have been made. The normal subjects excreted ...significantly less xanthurenic acid and 4-pyridoxic acid and more citric acid than the patients.
Following administration of tryptophan, there was a marked rise in the excretion of oxalate. In all but two of the subjects, ingestion of vitamin B6 was followed by a decrease in urinary oxalate.
Studies of the urinary excretion of a number of metabolites by normal adults and by persons suffering from chronic formation of calcium oxalate calculi have been made. The normal subjects excreted ...significantly less xanthurenic acid and 4-pyridoxic acid and more citric acid than the patients.
Following administration of tryptophan, there was a marked rise in the excretion of oxalate. In all but two of the subjects, ingestion of vitamin B6 was followed by a decrease in urinary oxalate.
PDF
