Different ways to enhance the permeability, lipophilicity, and bioavailability of the antidiabetic drug, Metformin: Review Article

Document Type : Review Article


1 Department of Pharmaceutics, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

2 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.



Metformin is a drug that needs improvement in its bioavailability and absorption. This  can be acheived by using different drug delivery systems, making prodrugs, and changing the drug release environment. Drug delivery systems are used for various reasons, for example, targeted drug delivery, protecting the drugs from destruction by enzymes, and enhancing the drug's absorption, permeability, and bioavailability. According to the studies and surveys, the permeability, absorption, and bioavailability of metformin can be improved in many ways, like making prodrugs and using carriers. Prodrugs and lipid-based carriers like nanostructured lipid carriers and lipid-based polymers are the best methods that can help the medical system to reduce the dose of metformin usage in patients and reduce the side effects. 
Please cite this article as: Salar Masoomzadeh, Maryam Maghsoodi. Different ways to enhance the permeability, lipophilicity, and bioavailability of the antidiabetic drug, Metformin: Review Article. Trends in Pharmaceutical Sciences. 2022;8(2):69-74 .doi: 10.30476/TIPS.2022.93380.1125


1.    Huttunen KM, Rautio J, Leppänen J, Vepsäläinen J, Keski-Rahkonen P. Determination of metformin and its prodrugs in human and rat blood by hydrophilic interaction liquid chromatography. Journal of pharmaceutical and biomedical analysis. 2009;50(3):469-74.
2.    Sun X, Du S, Sun Y, Li H, Yu C, Guo J, et al. Solubility Measurement and Data Correlation of Metformin Hydrochloride in Four Aqueous Binary Solvents and Three Pure Solvents from 283.15 to 323.15 K. Journal of Chemical & Engineering Data. 2021;66(8):3282-92.
3.    Seifarth C, Schehler B, Schneider H. Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Experimental and clinical endocrinology & diabetes. 2013;121(01):27-31.
4.    Malin SK, Kashyap SR. Effects of metformin on weight loss: potential mechanisms. Current Opinion in Endocrinology, Diabetes and Obesity. 2014;21(5):323-9.
5.    He H, Zhao Z, Chen J, Ni Y, Zhong J, Yan Z, et al. Metformin-based treatment for obesity-related hypertension: a randomized, double-blind, placebo-controlled trial. Journal of Hypertension. 2012;30(7):1430-9.
6.    Anurag P, Anuradha C. Metformin improves lipid metabolism and attenuates lipid peroxidation in high fructose‐fed rats. Diabetes, Obesity and Metabolism. 2002;4(1):36-42.
7.    Zabielski P, Hady HR, Chacinska M, Roszczyc K, Gorski J, Blachnio-Zabielska AU. The effect of high fat diet and metformin treatment on liver lipids accumulation and their impact on insulin action. Scientific reports. 2018;8(1):1-11.
8.    Hajjar J, Habra MA, Naing A. Metformin: an old drug with new potential. Expert opinion on investigational drugs. 2013;22(12):1511-7.
9.    Viktorova AS, Elizarova ES, Romanova RS, Timergalieva VR, Khutoryanskiy VV, Moustafine RI. Interpolymer complexes based on Carbopol® and poly (2-ethyl-2-oxazoline) as carriers for buccal delivery of metformin. Drug development & registration. 2021;10(1):48-55.
10.    Zhou Y, Geng Z, Wang X, Huang Y, Shen L, Wang Y. Meta‐analysis on the efficacy and safety of SGLT2 inhibitors and incretin based agents combination therapy vs. SGLT2i alone or add‐on to metformin in type 2 diabetes. Diabetes/Metabolism Research and Reviews. 2020;36(2):e3223.
11.    Huttunen KM, Leppänen J, Laine K, Vepsäläinen J, Rautio J. Convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of metformin. European Journal of Pharmaceutical Sciences. 2013;49(4):624-8.
12.    Divakar P, Kumar D, Praveen C, Sowmya C, Reddy CS. Formulation and in vitro evaluation of liposomes containing metformin hydrochloride. International Journal of Research in Pharmaceutical and Biomedical Sciences. 2013;4(2):479-85.
13.    Qushawy M. Effect of the Surfactant and Liquid Lipid Type in the Physico-chemical Characteristics of Beeswax-based Nanostructured Lipid Carrier (NLC) of Metformin. Pharmaceutical Nanotechnology. 2021;9(3):200-9.
14.    Ghasemiyeh P, Mohammadi-Samani S. Hydrogels as drug delivery systems; pros and cons. Trends in Pharmaceutical Sciences. 2019;5(1):7-24.
15.    Shukla SK, Kulkarni NS, Chan A, Parvathaneni V, Farrales P, Muth A, et al. Metformin-encapsulated liposome delivery system: an effective treatment approach against breast cancer. Pharmaceutics. 2019;11(11):559.
16.    Han H-K, Amidon GL. Targeted prodrug design to optimize drug delivery. Aaps Pharmsci. 2000;2(1):48-58.
17.    Pavan B, Dalpiaz A, Ciliberti N, Biondi C, Manfredini S, Vertuani S. Progress in drug delivery to the central nervous system by the prodrug approach. Molecules. 2008;13(5):1035-65.
18.    Huttunen KM, Mannila A, Laine K, Kemppainen E, Leppanen J, Vepsalainen J, et al. The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption. Journal of medicinal chemistry. 2009;52(14):4142-8.
19.    Williams HD, Ford L, Lim S, Han S, Baumann J, Sullivan H, et al. Transformation of biopharmaceutical classification system class I and III drugs into ionic liquids and lipophilic salts for enhanced developability using lipid formulations. Journal of pharmaceutical sciences. 2018;107(1):203-16.
20.    Farag MM, Abd El Malak NS, Yehia SA, Ahmed MA. Sonocomplexation as an effective tool to enhance the antitumorigenic effect of metformin: Preparation, in vitro characterization, molecular dynamic simulation & MiaPaCa-2 cell line hypoxia evaluation. Journal of Drug Delivery Science and Technology. 2020;59:101968.
21.    Iqbal MA, Md S, Sahni JK, Baboota S, Dang S, Ali J. Nanostructured lipid carriers system: recent advances in drug delivery. Journal of drug targeting. 2012;20(10):813-30.
22.    Torchilin VP. Nanoparticulates as drug carriers: Imperial college press; 2006.
23.    Callender SP, Mathews JA, Kobernyk K, Wettig SD. Microemulsion utility in pharmaceuticals: Implications for multi-drug delivery. International journal of pharmaceutics. 2017;526(1-2):425-42.
24.    Vyas A, Kumar Sonker A, Gidwani B. Carrier-based drug delivery system for treatment of acne. The scientific world journal. 2014;2014.
25.    Li Y, Song J, Tian N, Cai J, Huang M, Xing Q, et al. Improving oral bioavailability of metformin hydrochloride using water-in-oil microemulsions and analysis of phase behavior after dilution. International journal of pharmaceutics. 2014;473(1-2):316-25.
26.    Nayak AK, Pal D, Santra K. Development of calcium pectinate-tamarind seed polysaccharide mucoadhesive beads containing metformin HCl. Carbohydrate polymers. 2014;101:220-30.
27.    Sahu AK, Verma A. Development and statistical optimization of chitosan and eudragit based gastroretentive controlled release multiparticulate system for bioavailability enhancement of metformin HCl. Journal of Pharmaceutical Investigation. 2016;46(3):239-52. 
28.    Sander C, Nielsen HM, Jacobsen J. Buccal delivery of metformin: TR146 cell culture model evaluating the use of bioadhesive chitosan discs for drug permeability enhancement. International journal of pharmaceutics. 2013;458(2):254-61.
29.    Desai D, Wong B, Huang Y, Ye Q, Tang D, Guo H, et al. Surfactant-mediated dissolution of metformin hydrochloride tablets: wetting effects versus ion pairs diffusivity. Journal of Pharmaceutical Sciences. 2014;103(3):920-6.
30.    Desai D, Wong B, Huang Y, Tang D, Hemenway J, Paruchuri S, et al. Influence of dissolution media pH and USP1 basket speed on erosion and disintegration characteristics of immediate release metformin hydrochloride tablets. Pharmaceutical development and technology. 2015;20(5):540-5.