Journal of pharmaceutical sciences
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The current study presents a new approach to tackle high-dose lung delivery using a prototype multibreath Orbital® dry powder inhaler (DPI). One of the key device components is the "puck" (aerosol sample chamber) with precision-engineered outlet orifice(s) that control the dosing rate. The influence of puck orifice geometry and number of orifices on the performance of mannitol aerosols were studied. ⋯ The puck-emptying rate linearly related to the orifice hole length (R(2) > 0.95). Mass median aerodynamic diameters of the emitted aerosol ranged from 4.03 to 4.62 μm and fine particle fraction (≤6.4 μm) were 50%-66%. Laser diffraction suggested that the aerosol performance and emptying rates were not dependent on breath number, showing consistent size distribution profiles.
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Intractable cancer-related pain complicated by a neuropathic component due to nerve impingement is poorly alleviated even by escalating doses of a strong opioid analgesic. To address this unmet medical need, we developed sustained-release, bioerodable, hydromorphone (potent strong opioid)- and ketamine (analgesic adjuvant)-loaded microparticles for intrathecal (i.t.) coadministration. Drug-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared using a water-in-oil-in-water method with evaporation. ⋯ Possible explanations include inadequate release of ketamine and/or hydromorphone into the spinal fluid, and/or insufficient ketamine loading to prevent development of analgesic tolerance to the released hydromorphone. As sub-analgesic doses of i.t. ketamine at 24-48 h intervals restored analgesia on each occasion, insufficient ketamine loading appears problematic. We will investigate these issues in future work.
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This study was designed to assess the analgesic efficacy and systemic exposure of oxycodone administered topically in a novel tocopheryl phosphate mixture (TPM) gel formulation, to the inflamed hindpaws in a rat model of inflammatory pain. Unilateral hindpaw inflammation was induced in male Sprague-Dawley rats by intraplantar (i.pl.) injection of Freund's complete adjuvant (FCA). Mechanical hyperalgesia and hindpaw inflammation were assessed by measuring paw pressure thresholds and hindpaw volume, respectively, just prior to i.pl. ⋯ Systemic oxycodone exposure was insignificant after topical dosing. The in vitro cumulative skin permeation of oxycodone was linearly related to the amount applied. Topical TPM/oxycodone gel formulations have the potential to alleviate moderate to severe inflammatory pain conditions with minimal systemic exposure, thereby avoiding central nervous system (CNS)-mediated adverse effects associated with oral administration of opioid analgesics.
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Human chromosome 7 open reading frame 24 has been identified as a tumor-related protein, and later it was shown to be γ-glutamylcyclotransferase (GGCT). This protein is upregulated in various types of cancer and is proved to be associated with cellular proliferation. RNA interference is an effective method to achieve highly specific gene regulation. ⋯ Transfection of anti-GGCT siRNA-loaded PEG-HA-NP could achieve effective GGCT downregulation and induce the subsequent cell cytotoxicity against MCF-7/ADR cells. Systemic administration of PEG-HA-NP at 0.35 mg/kg siRNA could retard the tumor growth and induce necrosis of tumor tissue while showing no obvious toxicity to normal tissues. Therefore, systemic administration of anti-GGCT-loaded PEG-HA-NP was proved to be a promising strategy for drug-resistant MCF-7 breast cancer therapy.