Topical semi-solid preparations include creams, ointments, gels and other dosage forms, which contain various excipients such as emulsifiers, preservatives, thickeners or emollient agents, etc. They can be single-phase system, or multiple system consisting of continuous phase and disperse phase thanks to its complex design of formulation and manufacturing process. Rheology properties are critical quality attributes of topical semi-solid preparations, which can comprehensively reflect the difference in microstructure such as the substance distribution and aggregation state of the product, and is related to other attributes such as in vitro release, in vitro penetration, stability and cutaneous sense. It is one of the most effective means to evaluate the quality equivalence between generic drugs and innovator drugs. After reviewing domestic, foreign literature and relative policies, this paper described the research status and test methods of rheology, analyzed the possible factors affecting rheological properties, discussed the quality differences reflected in rheological data, in order to guide pharmaceutical manufacturers to improve their formulations and processes and provide help for the development and quality equivalence research of such preparations.

1.Simões A, Miranda M, Cardoso C, et al. Rheology by design: a regulatory tutorial for analytical method validation[J]. Pharmaceutics, 2020, 12(9): 820. DOI: 10.3390/pharmaceutics12090820.

2.罗婷婷, 庾莉菊, 宁保明, 等. 外用半固体制剂质量研究与体外评价技术进展[J]. 药物分析杂志, 2022, 42(5): 748-760. [Luo TT, Yu LJ, Ning BM, et al. Progress in applications of quality research and in vitro evaluation technology in topical semi-solid preparations[J]. Chinese Journal of Pharmaceutical Analysis, 2022, 42(5): 748-760.] DOI: 10.16155/j.0254-1793.2022.05.02.

3.武余波, 黄乐乐, 卢望丁, 等.皮肤局部外用制剂Q3等同性研究技术要点解析[J]. 中国医药工业杂志, 2022, 53(5): 601-610. [Wu YB, Huang LL, Lu WD, et al. Analysis of technical points on topical dermatologic drugs for Q3 equivalence study[J]. Chinese Journal of Pharmaceuticals, 2022, 53(5): 601-610. ] DOI: 10.16522/j.cnki.cjph.2022.05.002.

4.李克, 毕宏煜, 蔡沅璇, 等. 基于CiteSpace的国内外亚硫酸盐及其添加剂安全性研究文献计量分析[J]. 医药导报, 2024, 43(5): 735-744. [Li K, Bi HY, Cai YX, et al. Bibliometric analysis of domestic and foreign literature on safety of sulfite and its additives based on CiteSpace[J]. Herald of Medicine, 2024, 43(5): 735-744. ] DOI: 10.3870/j.issn.1004-0781.2024.05.011.

5.伍清芳, 刘可欣, 杨诗雯, 等. 基于CiteSpace的国内外家庭药师实践进展[J]. 医药导报, 2024, 43 (1): 68-77. [Wu QF, Liu KX, Yang SW, et al. Practice advances of family pharmacist in domestic and aboard based on CiteSpace [J]. Herald of Medicine, 2024, 43(1): 68-77.] DOI: 10.3870/j.issn.1004-0781.2024.01.012.

6.新注册分类的皮肤外用仿制药的技术评价要求(征求意见稿) [EB/OL]. (2018-07-11) [2024-06-15]. https://www.cde.org.cn/main/news/viewInfoCommon/bec4520b9d49718ce022c1e96fb6a450.

7.皮肤外用化学仿制药研究技术指导原则(试行) [EB/OL]. (2021-03-16)[2024-06-15]. https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=d54a8e1825219f083ce47ae116f88d34.

8.Physicochemical and Structural Characterization of Topical Drug Products Submitted in ANDAs[EB/OL]. (2022-10)[2024-06-15]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/physicochemical-and-structural-q3-characterization-topical-drug-products-submitted-andas.

9.Draft Guidance on Acyclovir[EB/OL]. (2020-10-24) [2024-06-15]. https:// www.accessdata.fda.gov/drugsatfda_docs/psg/Acyclovir_topical%20cream_RLD%2021478_RV12-16.pdf.

10.European Medicines Agency. Draft Guideline on Quality and Equivalence of Topical Products[EB/OL]. (2020-10-24) [2024-06-15]. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-and-equivalence-topical-products_en.pdf#.

11.Ili T, Panteli I, Savi S. The implications of regulatory framework for topical semisolid drug products: from critical quality and performance attributes towards establishing bioequivalence[J]. Pharmaceutics, 2021, 13(5): 710. DOI: 10.3390/pharmaceutics13050710.

12.USP 44[S]. 2021: 1911.

13.Mihaela G, Mircea H, Dumitru L, et al. Flow and thixotropic parameters for rheological characterization of hydrogels[J]. Molecules, 2016, 21(6): 786. DOI: 10.3390/molecules21060786.

14.Nunes A, Marto J, Martins AM, et al. Investigations of olive oil industry by-products extracts with potential skin benefits in topical formulations[J]. Pharmaceutics, 2021, 13(4): 465. DOI: 10.3390/pharmaceutics13040465.

15.胡国和, 虎晓东, 徐自冲, 等. 触变性及触变剂研究进展[J]. 应用化工, 2023, 52(10): 2940-2944. [Hu GH, Hu XD, Xu ZC, et al. Research progress of thixotropy and thixotropic agent[J]. Applied Chemical Industry, 2023, 52(10): 2940-2944.] DOI: 10.3969/j.issn.1671-3206. 2023.10.041.

16.Inoue Y, Furuya K, Matumoto M, et al. A comparison of the physicochemical properties and a sensory test of Acyclovir creams[J]. Int J Pharm, 2012, 436(1-2): 265-271. DOI: 10.1016/j.ijpharm.2012.06.023.

17.Toker OS, Karasu S, Yilmaz MT, et al. Three interval thixotropy test (3ITT) in food applications: a novel technique to determine structural regeneration of mayonnaise under different shear conditions[J]. Food Research International, 2015, 70: 125-133. DOI: 10.1016/j.foodres.2015.02.002.

18.Mezger TG. The Rheology Handbook. 4th ed[M]. Vincentz Network GmbH & Co. KG: Hanover, Germany, 2010: 59.

19.Cristiano MC, Froiio F, Mancuso A, et al. The rheolaser master and kinexus rotational rheometer to evaluate the influence of topical drug delivery systems on rheological features of topical poloxamer gel[J]. Molecules, 2020, 25(8): 1979. DOI: 10.3390/molecules25081979.

20.Víctor MS, María PV, Matilde MS, et al. Assessment of the inter-batch variability of microstructure parameters in topical semisolids and impact on the demonstration of equivalence[J]. Pharmaceutics, 2019, 11(10): 503. DOI: 10.3390/pharmaceutics11100503.

21.Eccleston GM. Structure and rheology of cetomacrogol creams: the influence of alcohol chain length and homologue composition[J]. J Pharm  Pharmacol, 2011, 29(1): 157-162. DOI: 10.1111/j.2042-7158.1977.tb11274.x.

22.Sanz T, Salvador A, Hernández MJ. Creep-recovery and oscillatory rheology of flour-based systems[J]. Advances in Food Rheology and Its Applications, 2017: 277-295. DOI: 10.1016/B978-0-08-100431-9.00011-5.

23.Shah VP, Yacobi A, Flavian ŞR, et al. A science based approach to topical drug classification system (TCS) [J]. Int J Pharm, 2015, 491(1-2): 21-25.DOI: 10.1016/j.ijpharm.2015.06.011.

24.田洁. 皮肤外用半固体制剂体外透皮吸收对比试验常见问题分析[J]. 中国新药杂志, 2016, 25(18): 2113-2115. [Tian J. Main problems and analysis of the in vitro transdermal absorption comparative test of skin's external semisolid preparations[J]. Chinese Journal of New Drugs, 2016, 25(18): 2113-2115.] https://d.wanfangdata.com.cn/periodical/ChlQZXJpb2RpY2FsQ0hJTmV3UzIwMjQwNzA0Eg96Z3h5enoyMDE2MTgwMTYaCDV5Z21xZnhz.

25.侯景孝, 隋万林. 凡士林基质的流变学性质对水杨酸体外释放的影响[J]. 中国药学杂志, 1985, (10): 600-602. [Hou JX, Sui WL. Effect of the rheological properties of petroleum jelly matrix on the in vitro release of salicylic acid[J].  Chinese Pharmaceutical Journal,  1985, (10): 600-602.] http://journal11.magtechjournal.com/Jwk_zgyxzz/CN/Y1985/V20/I10/600.

26.Miron DS, Rădulescu FS, Voicu VA, et al. Rheological and invitro release measurements of manufactured acyclovir 5% creams: confirming sensitivity of the invitro release[J]. Pharm Dev Technol, 2021, 26(7): 779-787. DOI: 10.1080/10837450.2021.1945625.

27.刘琳琳, 严佳, 周欣. 自制复方特比萘酚软膏渗透促进剂的研究[J]. 药学实践杂志, 2021, 39(1): 58-61, 72. [Liu LL, Yan J, Zhou X. Penetration enhancer for pharmacy prepared compound terbinafine ointment[J]. Journal of Pharmaceutical Practice, 2021, 39(1): 58-61, 72. ] DOI: 10.12206/j.issn.1006-0111.202008062.

28.Li C, Liu C, Liu J, et al.  Correlation between rheological properties, in vitro release, and percutaneous permeation of tetrahydropalmatine[J]. AAPS PharmSciTech, 12(3): 1002-1010. DOI: 10.1208/s12249-011-9664-4.

29.秦云, 涂家生, 孙春萌. 乳化剂乳化性能及其关键质量属性研究进展[J]. 药学研究, 2022, 41(4): 236-241. [Qin Y, Tu JS, Sun CM. Research progress on emulsifying properties and critical quality attributes of emulsifiers[J]. Journal of Pharmaceutical Research, 2022, 41(4): 236-241.] DOI: 10.13506/j.cnki.jpr.2022.04.007.

30.李荣苗, 管咏梅, 王森, 等. 烷基糖苷类乳化剂及其复配对乳膏微观结构与物理稳定性的影响[J]. 中成药, 2016, 38(1): 62-67. [Li RM, Guan YM, Wang S, et al. Effects of alkyl polyglycoside emulsifier and complex formulation on cream microstructure and physical stability[J]. Chinese Traditional Patent Medicine, 2016, 38(1): 62-67.] DOI: 10.3969/j.issn.1001-1528.2016.01.013.

31.Pénzes T, Csóka I, Erős I. Rheological analysis of the structural properties effecting the percutaneous absorption and stability in pharmaceutical organogels[J]. Rheol Acta, 2004, 43: 457-463.DOI:10.3969/j.issn.1001-1528.2016.01.013.

32.Dong YX, Qu HO, Pavurala N, et al. Formulation characteristics and in vitro release testing of cyclosporine ophthalmic ointments [J]. Int J Pharm, 2018, 544(1): 254-264. DOI: 10.1016/j.ijpharm.2018.04.042.

33.Bao QY, Newman B, Wang Y, et al. In vitro and ex vivo correlation of drug release from ophthalmic ointments[J]. J Control Release, 2018, 276: 93-101. DOI: 10.1016/j.jconrel.2018.03.003.

34.范冉冉, 王增明, 张慧, 等. 紫杉醇温敏凝胶的制备、体外表征及其药代动力学研究[J]. 药学学报, 2022, 57(7): 2197-2205. [Fan RR, Wang ZM, Zhang H, et al. Preparation, in vitro characterization and pharmacokinetics of paclitaxel thermosensitive gel[J]. Acta Pharmaceutica Sinica, 2022, 57(7): 2197-2205.] DOI: 10.16438/j.0513-4870.2021-1578.

35.陈丽梅, 王森, 朱卫丰, 等. 冷却速率对新生皂类乳膏基质流变学特性和物理稳定性的影响[J]. 江西中医药大学学报, 2016, 28(2): 74-77. [Chen LM, Wang S, Zhu WF, et al. The effect of cooling rate on newborn soaps cream base rheological properties and physical stability[J]. Journal of Jiangxi College of Traditional Chinese Medicine, 2016, 28(2): 74-77.] DOI: CNKI:SUN:XYXB.0.2016-02-030.

36.中国药典2020年版. 四部[S]. 2020: 11.

37.王英舟, 余瑞锋, 肖晶晶, 等. 黄芩苷微乳凝胶的稳定性和流变学考察[J]. 中国现代应用药学, 2022, 39(15): 1967-1973. [Wang YZ, Yu RF, Xiao JJ, et al. Stability and rheological characteristics of baicalin loaded in microemulsion-based gel[J]. Chinese Journal of Modern Applied Pharmacy, 2022, 39(15): 1967-1973. ] DOI: 10.13748/j.cnki.issn1007-7693.2022.15.008.

38.孙婉婷, 钟欣, 任元海, 等. 高温、高湿和光照对特殊医用配方食品流变特性的影响[J]. 食品科技, 2020, 45(2): 98-103. [Sun WT, Zhong X, Ren YH, et al. Influence of high temperature, high humidity and light on rheological properties of special medical formula foods[J]. Food Science and Technology, 2020, 45(2): 98-103.] DOI: 10.13684/j.cnki.spkj.2020.02.017.

39.郭涤亮, 徐萍蔚, 王亚敏. 皮肤局部外用仿制药质量等同性评价的一般考虑[J]. 中国新药杂志, 2018, 27(18): 2116-2120. [Guo DL, Xu PW, Wang YM. Considerations on quality equivalence evaluation of generic topical dermatologic drugs[J]. Chinese Journal of New Drugs, 2018, 27(18): 2116-2120.] DOI: CNKI:SUN:ZXYZ.0.2018-18-006.

40.Hirose R, Sugano K. Effect of food viscosity on drug dissolution[J]. Pharm Res, 2024, 41(1): 105-112.DOI:10.1007/s11095-023-03620-y.

41.Al-Khamis K, Davis SS, Hadgraft J, et al. The determination of thermodynamic activity by gas chromatography head space analysis and its use in studying release rates of drugs from topical preparations[J]. Int J Pharm, 1982, 10(1): 25-28.DOI: 10.1016/0378-5173(82)90059-X.

42.Davis SS, Khanderia M. Viscoelastic properties of pharmaceutical semi-solids: characterization of the plastibases for bioavailability studies[J]. J Pharm Pharmacol, 1972, 24(Suppl): 176-177. DOI: 10.1002/jps.2600580404.

43.Dong L, Liu C, Cun D, et al. The effect of rheological behavior and microstructure of the emulgels on the release and permeation profiles of Terpinen-4-ol[J]. Eur J Pharm Sci, 2015, 78: 140-150.DOI: 10.1016/j.ejps.2015.07.003.

44.Dewan M, Bhowmick B, Sarkar G, et al. Effect of methyl cellulose on gelation behavior and drug release from poloxamer based ophthalmic formulations[J]. Int J Biol Macromol, 2015, 72: 706-710. DOI: 10.1016/j.ijbiomac.2014.09.021.

45.Bain MK, Bhowmik M, Maity D, et al. Control of thermo reversible gelation of methylcellulose using polyethylene glycol and sodium chloride for sustained delivery of ophthalmic drug[J]. J Appl Polym Sci, 2010, 118(2): 631-637. DOI: 10.1002/app.32350.

46.楼观涛, 王楷峰, 马权,等. 普乐安治疗良性前列腺增生症用药依从性对疗效的影响[J]. 浙江医学, 2024, 46(1): 20-23. [Lou GT, Wang KF, Ma Q, et al. Influence of medication compliance on curative effect of Pule'an in the treatment of benign prostatic hyperplasia[J]. Zhejiang Medical Journal, 2024, 46(1): 20-23.] DOI: 10.12056/j.issn.1006-2785.2024.46.1.2023-641.

47.Radebe NW, Fengler C, Klein CO, et al. Rheo-IR: a combined setup for correlating chemical changes via FTIR spectroscopy and rheological properties in a strain-controlled rheometer[J]. J Rheol, 2021, 65(4): 681-693. DOI: 10.1122/8.0000251.