{"title":"氨基酸酯类萘普生盐的特性及其在局部皮肤制剂中的应用。","authors":"Ewelina Kopciuch , Ewa Janus , Paula Ossowicz-Rupniewska , Anna Nowak , Wiktoria Duchnik , Łukasz Kucharski , Urszula Adamiak-Giera , Zofia Lendzion-Bieluń","doi":"10.1016/j.ejpb.2024.114505","DOIUrl":null,"url":null,"abstract":"<div><div>In the study, the modification of naproxen (NAP) with esters of four amino acids (AAs): glycine (GlyOiPr), L-proline (ProOiPr), L-leucine (LeuOiPr), and L-serine (SerOiPr) <em>iso</em>propyl ester was performed to improve water solubility and enhance the permeation of the drug through the skin in comparison to the parent NAP. The NAP derivatives were prepared using the equimolar ratio of the components. In-depth NMR and FTIR analysis revealed that the salts formed with the proton transfer from the carboxylic group of NAP to the amine group of the appropriate AA ester. The NAP salts exhibited improved solubility in water and PBS solution (pH 7.4) when compared to parent NAP. The values of the partition coefficient (log P<sub>O/W</sub>) for prepared salts were lower than for NAP, however, the salts maintained hydrophobic character determined by the positive values of log P. The <em>In vitro</em> permeation through the pig skin performed in Franz diffusion cells showed that all NAP salts exhibited a higher cumulative mass of permeated NAP (Q<sub>24h</sub>) than the parent acid. The highest permeation value was noted for [ProOiPr][NAP], with a pseudo-steady state flux (J<sub>ss</sub>) 32.5 µg NAP cm<sup>−2</sup>h<sup>−1</sup>, and Q<sub>24h</sub> = 246.4 µg NAP cm<sup>−2</sup>, it was 2.5 % of the applied dose. Moreover, topical preparations with [ProOiPr][NAP] and NAP were prepared based on two vehicles − Celugel® and Pentravan®- approved in pharmacy recipes. The permeation experiments through the Strat-M® showed, that both the J<sub>ss</sub> and Q<sub>24h</sub> of permeated drug from preparations containing [ProOiPr][NAP], were statistically several times greater than from the respective preparations with the unmodified acid. Additionally, preparations with [ProOiPr][NAP] provided significantly improved permeation of NAP than two commercial preparations, one of which contained naproxen as the acid and the other – as the sodium salt.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"204 ","pages":"Article 114505"},"PeriodicalIF":4.4000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Characterization of naproxen salts with amino acid esters and their application in topical skin preparations\",\"authors\":\"Ewelina Kopciuch , Ewa Janus , Paula Ossowicz-Rupniewska , Anna Nowak , Wiktoria Duchnik , Łukasz Kucharski , Urszula Adamiak-Giera , Zofia Lendzion-Bieluń\",\"doi\":\"10.1016/j.ejpb.2024.114505\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>In the study, the modification of naproxen (NAP) with esters of four amino acids (AAs): glycine (GlyOiPr), L-proline (ProOiPr), L-leucine (LeuOiPr), and L-serine (SerOiPr) <em>iso</em>propyl ester was performed to improve water solubility and enhance the permeation of the drug through the skin in comparison to the parent NAP. The NAP derivatives were prepared using the equimolar ratio of the components. In-depth NMR and FTIR analysis revealed that the salts formed with the proton transfer from the carboxylic group of NAP to the amine group of the appropriate AA ester. The NAP salts exhibited improved solubility in water and PBS solution (pH 7.4) when compared to parent NAP. The values of the partition coefficient (log P<sub>O/W</sub>) for prepared salts were lower than for NAP, however, the salts maintained hydrophobic character determined by the positive values of log P. The <em>In vitro</em> permeation through the pig skin performed in Franz diffusion cells showed that all NAP salts exhibited a higher cumulative mass of permeated NAP (Q<sub>24h</sub>) than the parent acid. The highest permeation value was noted for [ProOiPr][NAP], with a pseudo-steady state flux (J<sub>ss</sub>) 32.5 µg NAP cm<sup>−2</sup>h<sup>−1</sup>, and Q<sub>24h</sub> = 246.4 µg NAP cm<sup>−2</sup>, it was 2.5 % of the applied dose. Moreover, topical preparations with [ProOiPr][NAP] and NAP were prepared based on two vehicles − Celugel® and Pentravan®- approved in pharmacy recipes. The permeation experiments through the Strat-M® showed, that both the J<sub>ss</sub> and Q<sub>24h</sub> of permeated drug from preparations containing [ProOiPr][NAP], were statistically several times greater than from the respective preparations with the unmodified acid. Additionally, preparations with [ProOiPr][NAP] provided significantly improved permeation of NAP than two commercial preparations, one of which contained naproxen as the acid and the other – as the sodium salt.</div></div>\",\"PeriodicalId\":12024,\"journal\":{\"name\":\"European Journal of Pharmaceutics and Biopharmaceutics\",\"volume\":\"204 \",\"pages\":\"Article 114505\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Pharmaceutics and Biopharmaceutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S093964112400331X\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Pharmaceutics and Biopharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S093964112400331X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
摘要
本研究用甘氨酸(GlyOiPr)、L-脯氨酸(ProOiPr)、L-亮氨酸(LeuOiPr)和 L-丝氨酸(SerOiPr)四种氨基酸(AAs)的异丙基酯对萘普生(NAP)进行了改性,以提高其水溶性,并增强药物在皮肤中的渗透性。NAP 衍生物的制备采用了各组分的等摩尔比。深入的核磁共振和傅立叶变换红外分析表明,这些盐是通过质子从 NAP 的羧基转移到适当 AA 酯的胺基上形成的。与母体 NAP 相比,NAP 盐在水和 PBS 溶液(pH 值为 7.4)中的溶解度有所提高。所制备盐类的分配系数(log PO/W)值低于 NAP,但盐类仍具有疏水性,这由 log P 的正值决定。渗透值最高的是[ProOiPr][NAP],其假稳态通量(Jss)为 32.5 µg NAP cm-2/h-1,Q24h = 246.4 µg NAP cm-2,是施用剂量的 2.5%。此外,还利用两种载体--Celugel® 和 Pentravan®--制备了[ProOiPr][NAP]和 NAP 的局部制剂,这两种载体已被批准用于药剂配方。通过 Strat-M® 进行的渗透实验表明,含有[ProOiPr][NAP]的制剂渗透药物的 Jss 和 Q24h 都比含有未改性酸的制剂高出数倍。此外,与两种商用制剂相比,含有[ProOiPr][NAP]的制剂对萘普生的渗透率明显提高,其中一种制剂含有萘普生酸,另一种制剂含有萘普生钠盐。
Characterization of naproxen salts with amino acid esters and their application in topical skin preparations
In the study, the modification of naproxen (NAP) with esters of four amino acids (AAs): glycine (GlyOiPr), L-proline (ProOiPr), L-leucine (LeuOiPr), and L-serine (SerOiPr) isopropyl ester was performed to improve water solubility and enhance the permeation of the drug through the skin in comparison to the parent NAP. The NAP derivatives were prepared using the equimolar ratio of the components. In-depth NMR and FTIR analysis revealed that the salts formed with the proton transfer from the carboxylic group of NAP to the amine group of the appropriate AA ester. The NAP salts exhibited improved solubility in water and PBS solution (pH 7.4) when compared to parent NAP. The values of the partition coefficient (log PO/W) for prepared salts were lower than for NAP, however, the salts maintained hydrophobic character determined by the positive values of log P. The In vitro permeation through the pig skin performed in Franz diffusion cells showed that all NAP salts exhibited a higher cumulative mass of permeated NAP (Q24h) than the parent acid. The highest permeation value was noted for [ProOiPr][NAP], with a pseudo-steady state flux (Jss) 32.5 µg NAP cm−2h−1, and Q24h = 246.4 µg NAP cm−2, it was 2.5 % of the applied dose. Moreover, topical preparations with [ProOiPr][NAP] and NAP were prepared based on two vehicles − Celugel® and Pentravan®- approved in pharmacy recipes. The permeation experiments through the Strat-M® showed, that both the Jss and Q24h of permeated drug from preparations containing [ProOiPr][NAP], were statistically several times greater than from the respective preparations with the unmodified acid. Additionally, preparations with [ProOiPr][NAP] provided significantly improved permeation of NAP than two commercial preparations, one of which contained naproxen as the acid and the other – as the sodium salt.
期刊介绍:
The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics.
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