Skip to main content

Advertisement

SpringerLink
Log in

Cubic Liquid Crystalline Gels Based on Glycerol Monooleate for Intra-articular Injection

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

In situ gels containing sinomenine hydrochloride (SMH) for intra-articular (IA) administration to treat rheumatoid arthritis (RA) were designed and investigated in this study. Glycerol monooleate (GMO) was used due to the potential to generate viscous crystalline phase structures upon water absorption. The gels were evaluated using different parameters: syringeability, gelation, viscosity, and drug release. And, polarized light microscopy (PLM), small-angle X-ray scattering investigation (SAXS), and rheological studies were used to analyze their internal structures. In vitro drug release studies were performed by the dialysis membrane diffusion method. The syringeability, viscosity, gelation time, and water for gelation of the obtained preparation met the requirements of IA injection. PLM, SAXS, and rheological analysis showed that all samples had transformed from flowable isotropic solution phases to the inverse cubic (V2) phases upon excess water. And, the gels were found to be able to maintain the drug release for more than 1 week. Results showed that in situ gels based on GMO liquid crystalline could provide a sustained system for SMH. Due to its sustained release, the in situ cubic gels were suitable for IA injection to treat RA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. I
Fig. II
Fig. III
Fig. IV

Similar content being viewed by others

References

  1. Tirtaatmadja V, Boger DV, Fraser JRE. The dynamic and steady shear properties of synovial fluid and of the components making up synovial fluid. Rheol Acta. 1984;23(3):311–21.

    Article  CAS  Google Scholar 

  2. Chen D, Li H, Liang L, et al. Clinical features and independent predictors in the further development of rheumatoid arthritis in undifferentiated arthritis. Rheumatol Int. 2013;33(11):2827.

    Article  CAS  PubMed  Google Scholar 

  3. Park JH, Park EK, Koo DW, et al. Compliance and persistence with oral bisphosphonates for the treatment of osteoporosis in female patients with rheumatoid arthritis. BMC Musculoskelet Disord. 2017;18(1):152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wu H, Wang K, Wang H, et al. Novel self-assembled tacrolimus nanoparticles cross-linking thermosensitive hydrogels for local rheumatoid arthritis therapy. Colloids & Surfaces B Biointerfaces. 2016;149:97–104.

    Article  Google Scholar 

  5. Li X, Li P, Liu C, et al. Sinomenine hydrochloride inhibits breast cancer metastasis by attenuating inflammation-related epithelial-mesenchymal transition and cancer stemness. Oncotarget. 2017;8(8):13560–74.

  6. Liu L, Buchner E, Beitze D, Schmidt-Weber CB, Kaever V, Emmrich F, et al. Amelioration of rat experimental arthritides by treatment with the alkaloid sinomenine. Int J Immunopharmacol. 1996;18(10):529–43.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang MF, Zhao Y, Jiang KY, et al. Comparative pharmacokinetics study of sinomenine in rats after oral administration of sinomenine monomer and Sinomenium acutum extract. Molecules. 2014;19(8):12065–77.

    Article  PubMed  Google Scholar 

  8. Xu M, Liu L, Qi C, Deng B, Cai X. Sinomenine versus NSAIDs for the treatment of rheumatoid arthritis: a systematic review and meta-analysis. Planta Med. 2008;74(12):1423–9.

    Article  CAS  PubMed  Google Scholar 

  9. Qian S, Chen Y, Gui S, et al. Enhanced penetration of sinomenine fomulations following skin pretreatment with a polymer microneedle patch. Lat Am J Pharm. 2014;33(3):464–9.

    CAS  Google Scholar 

  10. Zhao Z, Xiao J, Wang J, et al. Anti-inflammatory effects of novel sinomenine derivatives. Int Immunopharmacol. 2015;29(2):354–60.

    Article  CAS  PubMed  Google Scholar 

  11. Wu X, Chen Y, Gui S, et al. Sinomenine hydrochloride-loaded dissolving microneedles enhanced its absorption in rabbits. Pharm Dev Technol. 2015;21(7):1.

  12. Gerwin N, Hops C, Lucke A. Intraarticular drug delivery in osteoarthritis. Adv Drug Deliv Rev. 2006;58:226–42.

    Article  CAS  PubMed  Google Scholar 

  13. Réeff J, Oprenyeszk F, Franck T, et al. Development and evaluation in vitro and in vivo of injectable hydrolipidic gels with sustained-release properties for the management of articular pathologies such as osteoarthritis. Int J Pharm. 2015;490(1–2):74.

    Article  PubMed  Google Scholar 

  14. Costa-Balogh FO, Sparr E, Simões Sousa JJ, et al. Drug release from lipid liquid crystalline phases: relation with phase behavior. Drug Dev Ind Pharm. 2010;36:470–81.

    Article  CAS  PubMed  Google Scholar 

  15. Zhai J, Tran N, Sarkar S, et al. Self-assembled lyotropic liquid crystalline phase behavior of monoolein-capric acid-phospholipid nanoparticulate systems. Langmuir the Acs Journal of Surfaces & Colloids. 2571;33(10):2017.

    Google Scholar 

  16. Freag MS, Elnaggar Yosra SR, Abdelmonsif DA, et al. Stealth, biocompatible monoolein-based lyotropic liquid crystalline nanoparticles for enhanced aloe-emodin delivery to breast cancer cells: in vitro and in vivo studies. Int J Nanomedicine. 2016;11:4799–818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen Y, Ma P, Gui S. Cubic and hexagonal liquid crystals as drug delivery systems. Biomed Res Int. 2014;2014(1):815981.

    PubMed  PubMed Central  Google Scholar 

  18. Patil SS. Exploring microstructural changes in structural analogues of ibuprofen-hosted in situ gelling system and its influence on pharmaceutical performance. AAPS PharmSciTech. 2015;16(5):1153–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rappolt M, Gregorio GM, Almgren M, et al. Non-equilibrium formation of the cubic Pn3m phase in a monoolein/water system. Europhys Lett. 2006;75:267–73.

    Article  CAS  Google Scholar 

  20. Chen Y, Liang X, Ma P, et al. Phytantriol-based in situ liquid crystals with long-term release for intra-articular administration. AAPS PharmSciTech. 2015;16(4):846–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang Y, Zhang K, Guo T, et al. Transdermal baicalin delivery using diethylene glycol monoethyl ether-mediated cubic phase gel. Int J Pharm. 2015;479(1):219–26.

    Article  CAS  PubMed  Google Scholar 

  22. Pan X, Han K, Peng X, et al. Nanostructured cubosomes as advanced drug delivery system. Curr Pharm Des. 2013;19(35):6290.

    Article  CAS  PubMed  Google Scholar 

  23. Shi X, Peng T, Huang Y, et al. Comparative studies on glycerol monooleate- and phytantriol-based cubosomes containing oridonin in vitro and in vivo. Pharm Dev Technol. 2017;22(3):322–9

    Article  CAS  PubMed  Google Scholar 

  24. Barauskas J, Cervin C, Jankunec M, et al. Interactions of lipid-based liquid crystalline nanoparticles with model and cell membranes. Int J Pharm. 2010;391(1–2):284.

    Article  CAS  PubMed  Google Scholar 

  25. Zabara A, Mezzenga R. Controlling molecular transport and sustained drug release in lipid-based liquid crystalline mesophases. J Control Release. 2014;188(6):31.

    Article  CAS  PubMed  Google Scholar 

  26. Ali MA, Kataoka N, Ranneh AH, et al. Enhancing the solubility and oral bioavailability of poorly water- soluble drugs using monoolein cubosomes. Chem Pharm Bull. 2017;42(65):42–8.

  27. Borgheti-Cardoso LN, Depieri LV, Diniz H, et al. Self-assembling gelling formulation based on a crystalline-phase liquid as a non-viral vector for siRNA delivery. Eur J Pharm Sci. 2014;58(16):72–82.

    Article  CAS  PubMed  Google Scholar 

  28. Carvalho FC, Campos ML, Peccinini RG, et al. Nasal administration of liquid crystal precursor mucoadhesive vehicle as an alternative antiretroviral therapy. European Journal of Pharmaceutics & Biopharmaceutics Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik EV. 2013;84(1):219.

    Article  CAS  Google Scholar 

  29. Menanteau F, Hughes J P, Sifon C, et al. The Atacama Cosmology Telescope: ACT-CL J0102-4915 “El Gordo,” a massive merging cluster at redshift 0.87. Astrophys J. 2011;748(748):7.

  30. Burckbuchler V, Mekhloufi G, Giteau AP, et al. Rheological and syringeability properties of highly concentrated human polyclonal immunoglobulin solutions. European Journal of Pharmaceutics & Biopharmaceutics Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E V. 2010;76(3):351.

    CAS  Google Scholar 

  31. Yuan Y, Cui Y, Zhang L, et al. Thermosensitive and mucoadhesive in situ gel based on poloxamer as new carrier for rectal administration of nimesulide. Int J Pharm. 2012;430(1–2):114–9.

    Article  CAS  PubMed  Google Scholar 

  32. Akbar S, Anwar A, Ayish A, et al. Phytantriol based smart nano-carriers for drug delivery applications[J]. Eur J Pharm Sci. 2017;101:31–42.

  33. Muller F, Salonen A, Glatter O. Phase behavior of Phytantriol/water bicontinuous cubic Pn3m cubosomes stabilized by Laponite disc-like particles. J Colloid Interface Sci. 2010;342(2):392–8.

    Article  CAS  PubMed  Google Scholar 

  34. Fong W, Hanley T, Boyd BJ. Stimuli responsive liquid crystals provide ‘on-demand’ drug delivery in vitro and in vivo. J Control Release. 2009;135(3):218–26.

    Article  CAS  PubMed  Google Scholar 

  35. Libster D, Aserin A, Wachtel E, et al. An H II, liquid crystal-based delivery system for cyclosporin A: physical characterization. Journal of Colloid & Interface Science. 2007;308(2):514.

    Article  CAS  Google Scholar 

  36. Chang CM, Bodmeier R. Low viscosity monoglyceride-based drug delivery systems transforming into a highly viscous cubic phase. Int J Pharm. 1998;173(1–2):51–60.

    Article  CAS  Google Scholar 

  37. Szlęk J. PhEq-bootstrap: open-source software for the simulation of f2 distribution in cases of large variability in dissolution profiles. Dissolution Technologies. 2013;20(1):13–7.

    Article  Google Scholar 

  38. Polli JE, Rekhi GS, Augsburger LL, Shah VP. Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J Pharm Sci. 1997;86(6):690–700.

    Article  CAS  PubMed  Google Scholar 

  39. Shah VP, Tsong Y, Sathe P, Liu JP. In vitro dissolution profile comparison-statistics and analysis of the similarity factor f2. Pharm Res. 1998;15:889–96.

    Article  CAS  PubMed  Google Scholar 

  40. Réeff J, Gaignaux A, Goole J, et al. New sustained-release intraarticular gel formulations based on monolein for local treatment of arthritic diseases. Drug Dev Ind Pharm. 2013;39:1731–41.

    Article  PubMed  Google Scholar 

  41. Han K, Pan X, Chen M, et al. Phytantriol-based inverted type bicontinuous cubic phase for vascular embolization and drug sustained release. Eur J Pharm Sci. 2010;41(5):692–9.

    Article  PubMed  Google Scholar 

  42. Neustadt DH. Intra-articular injections for osteoarthritis of the knee. Cleve Clin J Med. 2006;73(10):897–911.

    Article  PubMed  Google Scholar 

  43. Réeff J, Gaignaux A, Goole J, et al. Characterization and optimization of GMO-based gels with long term release for intraarticular administration. Int J Pharm. 2013;451(1–2):95–103.

    Article  PubMed  Google Scholar 

  44. Chaiyana W, Rades T, Okonogi S. Characterization and in vitro permeation study of microemulsions and liquid crystalline systems containing the anticholinesterase alkaloidal extract from Tabernaemontana divaricata. Int J Pharm. 2013;452(1–2):201.

    Article  CAS  PubMed  Google Scholar 

  45. Borgheti-Cardoso LN, Depieri LV, Kooijmans SAA, et al. An in situ, gelling liquid crystalline system based on monoglycerides and polyethylenimine for local delivery of siRNAs. European Journal of Pharmaceutical Sciences Official Journal of the European Federation for Pharmaceutical Sciences. 2015;74:103–17.

    Article  CAS  PubMed  Google Scholar 

  46. Fam H, Bryant JT, Kontopoulou M. Rheological properties of synovial fluids. Biorheology. 2007;44:59–74.

    CAS  PubMed  Google Scholar 

  47. Mei L, Xie Y, Huang X, et al. An injectable in situ gel with cubic and hexagonal nanostructures for local treatment of chronic periodontitis. Drug Delivery. 2017;24(1):1148–58.

    Article  CAS  PubMed  Google Scholar 

  48. Nuki G, Ferguson J. Studies on the nature and significance of macromolecular complexes in the rheology of synovial fluid from normal and diseased human joints. Rheol Acta. 1971;10(1):8–14.

    Article  CAS  Google Scholar 

  49. Lim DG, Jeong WW, Kim NA, et al. Effect of the glyceryl monooleate-based lyotropic phases on skin permeation using invitro, diffusion and skin imaging. Asian Journal of Pharmaceutical Sciences. 2014;9(6):324–9.

    Article  Google Scholar 

  50. Lee J, Kellaway IW. Buccal permeation of [d-Ala 2, d-Leu 5] enkephalin from liquid crystalline phases of glyceryl monooleate. Int J Pharm. 2000;195(1):35–8.

    Article  CAS  PubMed  Google Scholar 

  51. Marilisa G, Lara M, Vitória LB, Collett JH, et al. In vitro drug release mechanism and drug loading studies of cubic phase gels. Int J Pharm. 2005;293(1–2):241.

    Google Scholar 

  52. Rizwan SB, Hanley T, Boyd BJ, et al. Liquid crystalline systems of phytantriol and glyceryl monooleate containing a hydrophilic protein: characterisation, swelling and release kinetics. J Pharm Sci. 2009;98(11):4191.

    Article  CAS  PubMed  Google Scholar 

  53. Yaghmur A, Rappolt M, Larsen SW. In situ, forming drug delivery systems based on lyotropic liquid crystalline phases: structural characterization and release properties. Journal of Drug Delivery Science & Technology. 2013;23(4):325–32.

    Article  CAS  Google Scholar 

  54. Negrini R, Mezzenga R. PH-responsive lyotropic liquid crystals for controlled drug delivery. Langmuir. 2011;27:5296–303.

    Article  CAS  PubMed  Google Scholar 

  55. Ahmed AR, Dashevsky A, Bodmeier R. Drug release from and sterilization of in situ cubic phase forming monoglyceride drug delivery systems. Eur J Pharm Biopharm. 2010;75(3):375–80.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGEMENTS

The authors acknowledge the financial support from the National Natural Science Foundation of China (No. 81274099), Anhui Provincial Natural Science Foundation (No. 1408085QH183), and Exploratory Research Projects of Anhui University of Chinese Medicine (No. 2016ts066).

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province, 230012, China

    Qian Li, Jiaojiao Cao, Zhengguang Li & Xiaoqin Chu

Authors
  1. Qian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiaojiao Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengguang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoqin Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaoqin Chu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Q., Cao, J., Li, Z. et al. Cubic Liquid Crystalline Gels Based on Glycerol Monooleate for Intra-articular Injection. AAPS PharmSciTech 19, 858–865 (2018). https://doi.org/10.1208/s12249-017-0894-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-017-0894-y

KEY WORDS

Search

Navigation