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Nasal powders of thalidomide for local treatment of nose bleeding in persons affected by hereditary hemorrhagic telangiectasia

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ABSTRACT

In this work nasal powder formulations of thalidomide were designed and studied to be used by persons affected by hereditary hemorrhagic telangiectasia as a complementary anti-epistaxis therapy, with the goal of sustaining the effect obtained with thalidomide oral treatment after its discontinuation for adverse effects. Three nasal powders were prepared using as carriers β-CD or its more hydrophilic derivatives such as hydropropyl-β-CD and sulphobutylether-β-CD and tested with respect to technological and biopharmaceutical features after emission with active and passive nasal powder devices. For all formulated powders, improved dissolution rate was found compared to that of the raw material, making thalidomide promptly available in the nasal environment at a concentration favouring an accumulation in the mucosa. The very limited transmucosal transport measured in vitro suggests a low likelihood of significant systemic absorption. The topical action on bleeding could benefit from the poor absorption and from the fact that about 2–3% of the thalidomide applied on the nasal mucosa was accumulated within the tissue, particularly with the β-CD nasal powder.

No MeSH data available.


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DSC thermograms of (a) thalidomide raw material, (b) β-CD nasal powder, (c) HP-β-CD nasal powder and (d) SBE-β-CD nasal powder.
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fig0010: DSC thermograms of (a) thalidomide raw material, (b) β-CD nasal powder, (c) HP-β-CD nasal powder and (d) SBE-β-CD nasal powder.

Mentions: In order to verify whether a complex was formed during the kneading process, the powders were studied by differential scanning calorimetry in comparison with crystalline thalidomide (THAL) raw material (Fig. 2). The THAL raw material thermogram showed a sharp endothermic peak at 276 °C corresponding to the drug melting point. The thermograms of the thalidomide/CD powders showed a broad endothermic band around 100 °C, corresponding to the release of water from the cyclodextrin cavity. The melting peak of thalidomide was still present, although much smaller and shifted to lower temperatures, likely due to an interaction of the two compounds in the mixture. In fact, the enthalpy of fusion for the pure drug was −158 J g−1, whereas it was −44.32 J g−1, −21.92 J g−1 and −133.94 J g−1 respectively for THAL/β-CD, THAL/HP-β-CD and THAL/SBE-β-CD. This last value should not be considered as fully reliable, being affected by the degradation peak of SBE-β-cyclodextrin that superposed to the THAL melting peak.


Nasal powders of thalidomide for local treatment of nose bleeding in persons affected by hereditary hemorrhagic telangiectasia
DSC thermograms of (a) thalidomide raw material, (b) β-CD nasal powder, (c) HP-β-CD nasal powder and (d) SBE-β-CD nasal powder.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120990&req=5

fig0010: DSC thermograms of (a) thalidomide raw material, (b) β-CD nasal powder, (c) HP-β-CD nasal powder and (d) SBE-β-CD nasal powder.
Mentions: In order to verify whether a complex was formed during the kneading process, the powders were studied by differential scanning calorimetry in comparison with crystalline thalidomide (THAL) raw material (Fig. 2). The THAL raw material thermogram showed a sharp endothermic peak at 276 °C corresponding to the drug melting point. The thermograms of the thalidomide/CD powders showed a broad endothermic band around 100 °C, corresponding to the release of water from the cyclodextrin cavity. The melting peak of thalidomide was still present, although much smaller and shifted to lower temperatures, likely due to an interaction of the two compounds in the mixture. In fact, the enthalpy of fusion for the pure drug was −158 J g−1, whereas it was −44.32 J g−1, −21.92 J g−1 and −133.94 J g−1 respectively for THAL/β-CD, THAL/HP-β-CD and THAL/SBE-β-CD. This last value should not be considered as fully reliable, being affected by the degradation peak of SBE-β-cyclodextrin that superposed to the THAL melting peak.

View Article: PubMed Central - PubMed

ABSTRACT

In this work nasal powder formulations of thalidomide were designed and studied to be used by persons affected by hereditary hemorrhagic telangiectasia as a complementary anti-epistaxis therapy, with the goal of sustaining the effect obtained with thalidomide oral treatment after its discontinuation for adverse effects. Three nasal powders were prepared using as carriers β-CD or its more hydrophilic derivatives such as hydropropyl-β-CD and sulphobutylether-β-CD and tested with respect to technological and biopharmaceutical features after emission with active and passive nasal powder devices. For all formulated powders, improved dissolution rate was found compared to that of the raw material, making thalidomide promptly available in the nasal environment at a concentration favouring an accumulation in the mucosa. The very limited transmucosal transport measured in vitro suggests a low likelihood of significant systemic absorption. The topical action on bleeding could benefit from the poor absorption and from the fact that about 2–3% of the thalidomide applied on the nasal mucosa was accumulated within the tissue, particularly with the β-CD nasal powder.

No MeSH data available.


Related in: MedlinePlus