Design of Hyaluronic Acids Hydrogels as a Long-term Implant and Those Application for Endometriosis Therapy

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Endometriosis is a disease caused by algomenorrhea, coital pain, and agenesis. According to a lot of epidemiological surveys, it is thought that 5-10% of reproductive-age women infected the endometriosis. This disease often forms cysts in ovary. Oral administration and hypodermic injection of danazol and GnRH analogues have been tried to cure the endometriosis. However, those drugs cause adverse effects such as liver dysfunction, agenesis, dropsy, headache, and so on. From this perspective, local release of danazol at uterus is expected to improve the side effects. Here, we report on hydrophobically modified hyalumnic acid (HA) for injectable hydrogels and local release of danazol. Biodegradable properties of HA at uterus may lead to controlled release of danazol without causing inflammations. Stearoyl HA (StHA) and glutaryl HA (GlHA) were synthesized and evaluated in terms of danazol loading, enzymatic degradation, danazol release, and those effects on a model rat.Viscosity of StHA in … More the presence of 100 unit/ml hyaluronidase (HAase) was not changed at 160 min after adding the HAase. Viscosities of GlHA and HA under the same condition were decreased to 50 % of the initial value at 161 and 120 min after adding the HAase, respectively. These results suggest that chemical modification of HA by stearoyl and glutaryl groups suppressed the accessibility of HAase to the HA backbone. Especially, longer alkyl chains of StHA was effective for suppressing the accessibility of HAase to the HA backbone. The introduced hydrophobic groups contribute to the increased solubility of danazol. GlHA seemed to be more hydrophobic domains because of its high DS. In both systems, the concentration of danazol in plasma was below 10 hg/ml through the experimental period. This value is below 1/20 of the concentration of danazol in plasma via oral administration.Concentration of danazol in the cysts was also measured. In both StHA and GlHA systems, the concentrations of danazol in the cysts are about 10 μg/g(at 1st week). At 2 nd week, it decreased to 1μg/g in the StHA system, while it remained 8 μg/g in the GlHA system. These results indicate that almost all the danazol in the StHA system was disappeared from cysts by the 2 nd week. From these results, it is suggested that burst release of danazol increased the concentration of danazol in cysts by the 1 st week. On the other hand, the low concentration at 2 nd week in StHA system is presumably due to slow release of danazol in relation to slower degradation of StHA than that of GlHA. The effect of local injecting the danazol solubilized StHA system on cysts was observed by microscopic image. Atrophy of whole cells was observed after injecting at 4 th weeks, although such an atrophy of cells without injection was not observed. Taking the result of danazol concentration in plasma and cysts into account, the released danazol was absorbed directly in cysts without inhibiting hypothalamo-hypophysial functions. Less