Marika Nespi, Justin Ly, Yuchen Fan, Shu Chen, Liling Liu, Yimin Gu, Steven Castleberry
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In this study, we evaluated the impact of different vehicles on the performance of a model SDD in in-vitro and in-vivo settings, to mitigate the risks associated with its administration in liquid form. A poorly water-soluble compound (GEN-A) was selected to screen various SDDs and generate the SDD model at 30% drug load with HPMCAS-MF polymer carrier. The SDD was suspended in selected aqueous vehicles after a careful vehicle components screening, that included suspending agents (HPC-SL), solubilizers (PEG400, Propylene glycol), surfactants (Vitamin E TPGS, SLS, Tween 80, Poloxamer 188), and complexing agents (HP-ꞵ-CD, SBE-ꞵ-CD). The suspensions were characterized for stability, dose-ability and dissolution in biorelevant media, prior administration in pre-clinical species. The SDD dissolution profile revealed that the drug's supersaturation level was positively impacted by the presence of a surfactant (SLS) and a complexing agent (SBE-ꞵ-CD) with respect to a suspending agents (HPC-SL) in the vehicle. Similarly, the pharmacokinetics profiles of the drug following the administration of the SDD in a vehicle with a complexing agent (SBE-ꞵ-CD) achieved greater exposure compare to the SDD in a vehicle with a suspending agent (HPC-SL). These findings confirm a synergistic effect between the SDD and the vehicles, suggesting that this combination could be leveraged to maximize the advantages of the amorphous approach.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Vehicle Effect on In-Vitro and In-Vivo Performance of Spray Dry Dispersions.\",\"authors\":\"Marika Nespi, Justin Ly, Yuchen Fan, Shu Chen, Liling Liu, Yimin Gu, Steven Castleberry\",\"doi\":\"10.1016/j.xphs.2024.10.043\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>In early drug development, amorphous spray-dried dispersions (SDDs) applied to enhance the bioavailability of poorly water-soluble compounds are typically administered to preclinical species via oral gavage in the form of suspensions. The liquid formulations are usually prepared on the same day of dosing to minimize the exposure of the amorphous material to the aqueous vehicle, thereby reducing the risk of crystallization. Dose-ability (e.g. syringeability) of the suspensions is also a critical factor for the administration, particularly when high doses, thus concentrations, are required for toxicology studies. As a result, it is standard practice during early formulation screening to assess the stability and the maximum feasible concentration of SDDs in various vehicles. In this study, we evaluated the impact of different vehicles on the performance of a model SDD in in-vitro and in-vivo settings, to mitigate the risks associated with its administration in liquid form. A poorly water-soluble compound (GEN-A) was selected to screen various SDDs and generate the SDD model at 30% drug load with HPMCAS-MF polymer carrier. The SDD was suspended in selected aqueous vehicles after a careful vehicle components screening, that included suspending agents (HPC-SL), solubilizers (PEG400, Propylene glycol), surfactants (Vitamin E TPGS, SLS, Tween 80, Poloxamer 188), and complexing agents (HP-ꞵ-CD, SBE-ꞵ-CD). The suspensions were characterized for stability, dose-ability and dissolution in biorelevant media, prior administration in pre-clinical species. The SDD dissolution profile revealed that the drug's supersaturation level was positively impacted by the presence of a surfactant (SLS) and a complexing agent (SBE-ꞵ-CD) with respect to a suspending agents (HPC-SL) in the vehicle. Similarly, the pharmacokinetics profiles of the drug following the administration of the SDD in a vehicle with a complexing agent (SBE-ꞵ-CD) achieved greater exposure compare to the SDD in a vehicle with a suspending agent (HPC-SL). 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Vehicle Effect on In-Vitro and In-Vivo Performance of Spray Dry Dispersions.
In early drug development, amorphous spray-dried dispersions (SDDs) applied to enhance the bioavailability of poorly water-soluble compounds are typically administered to preclinical species via oral gavage in the form of suspensions. The liquid formulations are usually prepared on the same day of dosing to minimize the exposure of the amorphous material to the aqueous vehicle, thereby reducing the risk of crystallization. Dose-ability (e.g. syringeability) of the suspensions is also a critical factor for the administration, particularly when high doses, thus concentrations, are required for toxicology studies. As a result, it is standard practice during early formulation screening to assess the stability and the maximum feasible concentration of SDDs in various vehicles. In this study, we evaluated the impact of different vehicles on the performance of a model SDD in in-vitro and in-vivo settings, to mitigate the risks associated with its administration in liquid form. A poorly water-soluble compound (GEN-A) was selected to screen various SDDs and generate the SDD model at 30% drug load with HPMCAS-MF polymer carrier. The SDD was suspended in selected aqueous vehicles after a careful vehicle components screening, that included suspending agents (HPC-SL), solubilizers (PEG400, Propylene glycol), surfactants (Vitamin E TPGS, SLS, Tween 80, Poloxamer 188), and complexing agents (HP-ꞵ-CD, SBE-ꞵ-CD). The suspensions were characterized for stability, dose-ability and dissolution in biorelevant media, prior administration in pre-clinical species. The SDD dissolution profile revealed that the drug's supersaturation level was positively impacted by the presence of a surfactant (SLS) and a complexing agent (SBE-ꞵ-CD) with respect to a suspending agents (HPC-SL) in the vehicle. Similarly, the pharmacokinetics profiles of the drug following the administration of the SDD in a vehicle with a complexing agent (SBE-ꞵ-CD) achieved greater exposure compare to the SDD in a vehicle with a suspending agent (HPC-SL). These findings confirm a synergistic effect between the SDD and the vehicles, suggesting that this combination could be leveraged to maximize the advantages of the amorphous approach.
期刊介绍:
The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.