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Could the small molecules such as amino acids improve aqueous solubility and stabilize amorphous systems containing Griseofulvin?
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-12-05 , DOI: 10.1016/j.ejps.2019.105178 Maria Terezinha França 1 , Tatyane Martins Marcos 1 , Rafael Nicolay Pereira 1 , Hellen Karine Stulzer 1
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-12-05 , DOI: 10.1016/j.ejps.2019.105178 Maria Terezinha França 1 , Tatyane Martins Marcos 1 , Rafael Nicolay Pereira 1 , Hellen Karine Stulzer 1
Affiliation
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Griseofulvin (GSF) is an antifungal drug that has low aqueous solubility and low oral bioavailability. Amorphous systems are capable to promote rapid drug dissolution, usually affording concentrations above drug solubility in the gastrointestinal tract (supersaturation) in order to promote better absorption. Thus, the aim of this work was to evaluate the ability of amino acids, as hydrophilic carriers, to improve drug kinetic solubilization and to stabilize GSF supersaturated solutions, as well as to stabilize GSF amorphous systems at solid-state. The effect of 5 amino acids on GSF precipitation behavior was investigated by solvent shift method. Amorphous systems were developed by ball milling (GSF + amino acid 1:1 M ratio) and Quench Cooling (to obtain GSF QC) techniques. The samples were characterized by solid-state techniques, submitted to in vitro kinetic solubility studies and evaluated under stability tests. Aspartic acid, methionine, valine and tryptophan demonstrated similar anti-precipitant abilities in phosphate buffer pH 6.5. However, in FaSSIF biorelevant medium, tryptophan was only one able to slow down the drug precipitation. The characterization of milled samples showed that an amorphous system was obtained just using the combination of the drug with tryptophan (GSF-TRYP BM). At the higher dose tested (0.850 mmol L-1) during in vitro kinetic solubility studies, this amorphous system increased the AUC in FaSSGF (88.6%) and FaSSIF (58.2%) media when compared to GSF QC. Thus, the ability of this amino acid to inhibit GSF precipitation appears to be dependent on its concentration in solution and could be optimized. During the stability study, TRYP inhibited GSF recrystallization in the solid-state for a period of 12 months, whereas GSF QC recrystallized in 1 week.
中文翻译：
氨基酸等小分子能否改善水溶性并稳定含有灰黄霉素的无定形系统？
灰黄霉素（GSF）是一种抗真菌药物，具有低水溶性和低口服生物利用度。非晶态系统能够促进药物快速溶解，通常提供高于药物在胃肠道中溶解度的浓度（过饱和），以促进更好的吸收。因此，这项工作的目的是评估氨基酸（作为亲水性载体）改善药物动力学增溶作用和稳定GSF过饱和溶液以及将GSF非晶态系统稳定在固态的能力。通过溶剂转移法研究了5种氨基酸对GSF沉淀行为的影响。通过球磨（GSF +氨基酸1：1 M比例）和淬火冷却（以获得GSF QC）技术开发了无定形系统。样品通过固态技术进行了表征，进行了体外动力学溶解度研究，并在稳定性测试下进行了评估。天冬氨酸，蛋氨酸，缬氨酸和色氨酸在磷酸盐缓冲液pH 6.5中显示出相似的抗沉淀能力。然而，在FaSSIF生物相关培养基中，色氨酸只是一种能够减慢药物沉淀的物质。研磨样品的特征表明，仅使用药物与色氨酸（GSF-TRYP BM）的组合即可获得无定形系统。在体外动力学溶解度研究中，以更高的测试剂量（0.850 mmol L-1）进行测试时，与GSF QC相比，该无定形系统增加了FaSSGF（88.6％）和FaSSIF（58.2％）培养基中的AUC。因此，该氨基酸抑制GSF沉淀的能力似乎取决于其在溶液中的浓度，可以对其进行优化。在稳定性研究中，
更新日期：2019-12-05
中文翻译：
氨基酸等小分子能否改善水溶性并稳定含有灰黄霉素的无定形系统？
灰黄霉素（GSF）是一种抗真菌药物，具有低水溶性和低口服生物利用度。非晶态系统能够促进药物快速溶解，通常提供高于药物在胃肠道中溶解度的浓度（过饱和），以促进更好的吸收。因此，这项工作的目的是评估氨基酸（作为亲水性载体）改善药物动力学增溶作用和稳定GSF过饱和溶液以及将GSF非晶态系统稳定在固态的能力。通过溶剂转移法研究了5种氨基酸对GSF沉淀行为的影响。通过球磨（GSF +氨基酸1：1 M比例）和淬火冷却（以获得GSF QC）技术开发了无定形系统。样品通过固态技术进行了表征，进行了体外动力学溶解度研究，并在稳定性测试下进行了评估。天冬氨酸，蛋氨酸，缬氨酸和色氨酸在磷酸盐缓冲液pH 6.5中显示出相似的抗沉淀能力。然而，在FaSSIF生物相关培养基中，色氨酸只是一种能够减慢药物沉淀的物质。研磨样品的特征表明，仅使用药物与色氨酸（GSF-TRYP BM）的组合即可获得无定形系统。在体外动力学溶解度研究中，以更高的测试剂量（0.850 mmol L-1）进行测试时，与GSF QC相比，该无定形系统增加了FaSSGF（88.6％）和FaSSIF（58.2％）培养基中的AUC。因此，该氨基酸抑制GSF沉淀的能力似乎取决于其在溶液中的浓度，可以对其进行优化。在稳定性研究中，
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