Notes

Suffers from in modern home care associated with children with life-limiting problems.
Naloxone (NAL) is administered parenterally or intranasally for treating opioid overdose. The short duration of action of NAL calls for frequent re-dosing which may be eliminated by the development of a transdermal system. This study aimed to assess the effect of microneedles on improving the skin permeation of NAL hydrochloride. In vitro permeation of NAL across intact and microneedle-treated (Dr. Pen™ Ultima A6) porcine skin was evaluated. The effect of microneedle length and application duration, and donor concentration on NAL permeation were investigated. In-vitro in-vivo correlation of the permeation results was done to predict the plasma concentration kinetics of NAL in patients. In vitro passive permeation of NAL after 6 h was observed to be 8.25±1.06 µg/cm2. A 56- and 37-fold enhancement was observed with 500 and 250 µm needles applied for 1 min, respectively. Application of 500 µm MNs for 2 min significantly reduced the lag time to ~ 8 min and increasing the donor concentration for the same treatment group doubled the permeation (p less then 0.05). Modeling simulations demonstrated the attainment of pharmacokinetic profile of NAL comparable to those obtained with the FDA-approved intramuscular and intranasal devices. Microneedle-mediated transdermal delivery holds potential for rapid and sustained NAL delivery for opioid overdose treatment.The main objective of the study was to determine if rodent housing conditions, specifically housing climate, could impact the in vivo performance of poly(lactide-co-glycolide) (PLGA) microspheres through temperature modification of the subcutaneous space. Vivitrol®, a once monthly naltrexone injectable suspension, was chosen as a model PLGA microparticle formulation for this study. Two lots of Vivitrol were used to ascertain any potential differences that may exist between the batches and if in vitro characterization techniques could delineate any variation(s). The pharmacokinetics of the naltrexone-PLGA microparticles were determined in the rodent model under two different housing climates (20 vs. 25 °C). The results demonstrate that such difference in housing temperature resulted in a change in subcutaneous temperature but actually within a narrow range (36.31-36.77 °C) and thus minimally influenced the in vivo performance of subcutaneously injected microparticles. The shake-flask method was used to characterize the in vitro release at 35, 36, and 37 °C and demonstrated significant differences in the in vitro release profiles across this range of temperatures. Minimal differences in the in vitro characterization of the two lots were found. While these results did not provide statistical significance, the local in vivo temperature may be a parameter that should be considered when evaluating microparticle performance. The IVIVCs demonstrate that in vitro release at 37 °C may not accurately represent the in vivo conditions (i.e., subcutaneous space in rodents), and in certain instances lower in vitro release temperatures may more accurately represent the in vivo microenvironment and provide better correlations. Future studies will determine the extent temperature and specifically co-housing, may have on the relative impact of the in vivo performance of injectable polymeric microparticles based upon the significant differences observed in the in vitro release profiles across the range of 35-37 °C.The aim of the present work was to develop novel meshes of poly (n-butyl cyanoacrylate) (PBCA) nanofibers for potential applications in drug delivery and tissue engineering taking into account the successful application of PBCA in other medical uses. Electrospinning was applied to solutions of PBCA, 103 and 106 Da. 5-fluorouracil was chosen as model drug for the delivery study because of its effectiveness against cancer, while human gingival fibroblasts (HFIB-G) to confirm the biocompatibility of drug-free PBCA meshes and their potential for tissue engineering. PBCA was able to be electrospun in a wide range of molecular weights, producing fibers free of defects with diameters between 380 nm and 6 μm. Meshes of PBCA (105-106 Da) showed high flexibility with Younǵs modulus and maximal tension values in the range of 0.3-1.6 MPa and 0.03-0.13 MPa respectively. Results from the drug delivery study suggested that 5-fluorouracil was homogeneously loaded into PBCA meshes. Its release was extremely slow, initially 20% in 7 days and the rest gradually (until 96 days) in physiological medium at 37 °C. HFIB-G were well attached and proliferated over PBCA nanofibers during 23 days. Results suggested that PBCA meshes serve as excellent frameworks for cell adhesion/proliferation, and for drug delivery extended periods.A commonly used approach to enhance the dissolution of drugs with pH-dependent solubility is the incorporation of pH modifiers. The aim of this study was to evaluate the duration and extent of pH modifying effect on the micro-environmental pH in HPMC matrix by applying two mechanistic approaches regarding hydrodynamic stress on the tested formulation (i.e. static dissolution apparatuses (USP2) and dynamic approaches including the Advanced gastric simulator (AGS) and the Intestinal model for simulation of peristaltic action (IMSPA)). Moreover, the aim of our research was also the preparation of sustained-release matrix systems with improved - enhanced drug dissolution. In our study, the occurrence of a pH gradient in the gel layer of the HPMC tablets was observed during simulation of their passage along different compartments of the GIT. The pH gradient was affected by the media composition and duration of tablet exposure to the surrounding media. BSO inhibitor Both dissolution methods were also used to evaluate the influence of the mechanical stress on the drug release kinetics. Micro-environmental pH (pHM) was evaluated, using two methods the cryostatic method with a surface pH electrode, and with the incorporation of a pH sensitive dye (methyl orange) into the matrix tablets. Our study demonstrates a significantly higher dissolution rate due to mechanical stress during the bio-relevant simulation of GIT transit of the mechanically sensitive HPMC tablets with poorly soluble drugs. A considerably higher release rate was also observed from tablets with the weakly basic drugs dipyridamole and propranolol hydrochloride containing pH modifier in case of mechanically bio-relevant dissolution models compared to the USP2 apparatus. For the assessment of the pHM, the incorporation of a pH indicator dye in the HPMC tablet proved to be more suitable, while the cryostatic method was found to be useful only for a rough pHM estimation.
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