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Results suggest that the two-layered dissolving microneedles are useful as an immediate-release transdermal DDS for peptide/protein drugs.

Advances in transplantation technology have brought about great benefits to patients suffering from organ failure, but the problem still remains of complications induced by steroids used for post-transplant immunosuppression. Among the side-effects caused by steroids, non-traumatic osteonecrosis of the femoral head (ONF) constitutes a serious problem. The same protocol for steroid administration induces ONF in some patients, but not in others, indicating the presence of individual difference in steroid sensitivity. We hypothesized that this difference might be mediated by the drug-transport protein, P-glycoprotein (P-gp), and investigated the relationship between single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1, MDR1) encoding P-gp and ONF. Subjects comprised 136 patients receiving kidney transplantation. Thirty patients developed post-transplant ONF. Genomic DNA was extracted from peripheral blood, and genotypes of ABCB1 C3435T (exon 26) and G2677T/A (exon 21) were determined by direct sequencing. Multivariate analyses based on clinical information were performed to determine the relationship between ABCB1 genotypes and ONF. The dose/concentration (D/C) ratios of tacrolimus were also determined to estimate the activity of P-gp in patients with different genotypes of ABCB1 C3435T (CC, CT, TT), and in those who did and did not develop ONF. The ABCB1 3435TT genotype showed a significantly lower incidence of ONF (adjusted odds ratio = 0.10, P = 0.034). The D/C ratio in the 3435TT genotype was significantly higher than that in the 3435CC genotype. The D/C ratio in patients developing ONF was significantly higher than in those patients who did not develop ONF. The results suggest increased activity of P-gp in patients with the 3435TT genotype and in those who did not develop ONF. The ABCB1 2677 homozygous variant type also showed a lower incidence of ONF (adjusted odds ratio = 0.26, P = 0.056). The 3435T and 3435C alleles were in linkage disequilibrium with the 2677T and the 2677G alleles, respectively, in the study population. An assessment of C3435T and G2677T/A polymorphisms preceding steroid treatment could be useful for predicting the resistance to ONF development.

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Erythropoietin (EPO) loaded microneedles were prepared using thread-forming polymer as a base for the percutaneous administration of EPO. The used polymers were dextrin, chondroitin sulfate and albumin. Under room temperature, EPO solution was added to high concentration of polymer solution and microneedles were prepared by forming thread with polypropylene tips. The mean weight of microneedle was 0.59 +/- 0.01 mg and length and basal diameter were 3.24 +/- 0.16 and 0.55 +/- 0.03 mm, respectively. Four microneedles were percutaneously (pc) administered to mice at the EPO dose levels of 100 IU/kg. After administration, blood samples were collected for 24 h and serum EPO levels were measured. Dextrin EPO microneedles were administered both pc and subcutaneously (sc) to mice. Serum EPO levels vs. time profiles showed Cmax of 138.6 +/- 16.1 and 146.5 +/- 8.0 mIU/ml, respectively. Tmax were 7.5 h. The values of bioavailability (BA) of EPO were 82.1 and 99.4%, respectively. By decreasing the dose from 100 to 50 and 25 IU/kg, dose-dependent serum EPO levels vs. time profiles were not clearly obtained. When chondroitin sulfate and albumin were used as the microneedle base, the serum EPO levels vs. time profiles showed almost the same pattern. Cmax of chondroitin sulfate and albumin microneedles were 96.3 +/- 8.8 and 132.2 +/- 18.9 mIU/ml, respectively. AUCs were 835.1 and 1098.7 mIU h/ml. Tmax were 8 and 6.8 h. These results suggest the usefulness of microneedles for the percutaneous administration of EPO.

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