Skip to main content
SpringerLink
Log in

Design, optimization, and evaluation of ezetimibe solid supersaturatable self-nanoemulsifying drug delivery for enhanced solubility and dissolution

  • Original Article
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

Abstract

This study was intended to develop a solid supersaturatable self-nanoemulsifying drug-delivery system (solid S-SNEDDS) to improve the solubility and dissolution of a poorly water-soluble drug ezetimibe. Self-nanoemulsifying drug delivery system (SNEDDS) preconcentrate was systematically optimized by a central composite design (α = 1.682). The optimized SNEDDS preconcentrate consisted of Captex 355 (30 % w/w), Cremophor RH40 (40 % w/w) and Imwitor 988 (30 % w/w). Saturation solubility of ezetimibe in the optimized SNEDDS preconcentrate was found to be 90.62 mg/ml. HPMC-E5 (5 % w/w) and ezetimibe (90 % saturation solubility level) were added to the SNEDDS preconcentrate to form a supersaturatable SNEDDS (liquid S-SNEDDS). Dilution of liquid S-SNEDDS resulted in a nanoemulsion having a mean droplet size of 27.3 nm. TEM studies of diluted liquid S-SNEDDS confirmed uniform shape and size of the droplets. The liquid formulation was adsorbed onto microcrystalline cellulose and talc to form a solid S-SNEDDS. In vitro supersaturation test of solid S-SNEDDS showed a higher ezetimibe concentration (that retarded precipitation of ezetimibe at least up to 60 min) in comparison to the solid-SNEDDS (without HPMC-E5). PXRD studies of the precipitates collected from the in vitro supersaturation test, revealed the presence of amorphous ezetimibe. DSC and SEM results indicated that the presence of ezetimibe in an amorphous and molecular dispersed state within the solid S-SNEDDS. In vitro release (in 15 min) of ezetimibe from solid S-SNEDDS improved by 1.17, 1.69, and 13.21-fold as compared with solid-SNEDDS, commercial product, and the free drug (powder), respectively.

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. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Bali V, Ali M, Ali J (2010) Novel nanoemulsion for minimizing variations in bioavailability of ezetimibe. J Drug Target 18:506–519

    Article  CAS  PubMed  Google Scholar 

  • Bali V, Ali M, Ali J (2011) Nanocarrier for the enhanced bioavailability of a cardiovascular agent: in vitro, pharmacodynamic, pharmacokinetic and stability assessment. Int J Pharm 403:46–56

    Article  CAS  PubMed  Google Scholar 

  • Bandyopadhyay S, Katare O, Singh B (2014) Development of optimized supersaturable self-nanoemulsifying systems of ezetimibe: effect of polymers and efflux transporters. Expert Opin Drug Deliv 11:479–492

    Article  CAS  PubMed  Google Scholar 

  • Basalious EB, Shawky N, Badr-Eldin SM (2010) SNEDDS containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I: development and optimization. Int J Pharm 391:203–211

    Article  CAS  PubMed  Google Scholar 

  • Brouwers J, Brewster ME, Augustijns P (2009) Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci 98:2549–2572

    Article  CAS  PubMed  Google Scholar 

  • Carr RL (1965) Evaluating flow properties of solids, chemical engineering. Chem Eng 18:163–168

    Google Scholar 

  • Dabhi MR, Limbani MD, Sheth NR (2011) Preparation and in vivo evaluation of self-nanoemulsifying drug delivery system (SNEDDS) containing ezetimibe. Curr Nanosci 7:616–627

    Article  CAS  Google Scholar 

  • Dash RN, Habibuddin M, Humaira T, Patel AA (2014) Application of quality by design for the optimization of an HPLC method to determine ezetimibe in a supersaturable self-nanoemulsifying formulation. J Liquid Chromatogr Related Technol 38:874–885

    Article  Google Scholar 

  • Dash RN, Habibuddin M, Humaira T, Ramesh D (2015a) Design, optimization and evaluation of glipizide solid self-nanoemulsifying drug delivery for enhanced solubility and dissolution. Saudi Pharm J 23:528–540

    Article  PubMed  PubMed Central  Google Scholar 

  • Dash RN, Mohammed H, Humaira T, Reddy AV (2015b) Solid supersaturatable self-nanoemulsifying drug delivery systems for improved dissolution, absorption and pharmacodynamic effects of glipizide. J Drug Deliv Sci Technol 28:28–36

    Article  CAS  Google Scholar 

  • Derringer G, Suich R (1980) Simultaneous Optimization of Several Response Variables. J Qual Technol 12:214–220

    Google Scholar 

  • Dixit RP, Nagarsenker MS (2008) Self-nanoemulsifying granules of ezetimibe: design, optimization and evaluation. Eur J Pharm Sci 35:183–192

    Article  CAS  PubMed  Google Scholar 

  • Gao P, Akrami A, Alvarez F, Hu J, Li L, Ma C, Surapaneni S (2009) Characterization and optimization of AMG 517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption. J Pharm Sci 98:516–528

    Article  CAS  PubMed  Google Scholar 

  • Grove M, Mullertz A, Pedersen GP, Nielsen JL (2007) Bioavailability of seocalcitol III. Administration of lipid-based formulations to minipigs in the fasted and fed state. Eur J Pharm Sci 31:8–15

    Article  CAS  PubMed  Google Scholar 

  • Gulsun T, Gursoy RN, Oner L (2011) Design and characterization of nanocrystal formulations containing ezetimibe. Chem Pharm Bull (Tokyo) 59:41–45

    Article  CAS  Google Scholar 

  • Gursoy RN, Benita S (2004) Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 58:173–182

    Article  PubMed  Google Scholar 

  • Hu X, Lin C, Chen D, Zhang J, Liu Z, Wu W, Song H (2012) Sirolimus solid self-microemulsifying pellets: formulation development, characterization and bioavailability evaluation. Int J Pharm 438:123–133

    Article  CAS  PubMed  Google Scholar 

  • International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, Draft Step 4 (2003) Stability testing of new drug substances and products Q1A (R2). ICH, Geneva

    Google Scholar 

  • Khanfar M, Sheikh Salem M, Hawari R (2013) Formulation factors affecting the release of ezetimibe from different liquisolid compacts. Pharm Dev Technol 18:417–427

    Article  CAS  PubMed  Google Scholar 

  • Kiekens F, Eelen S, Verheyden L, Daems T, Martens J, Van Den Mooter G (2012) Use of ordered mesoporous silica to enhance the oral bioavailability of ezetimibe in dogs. J Pharm Sci 101:1136–1144

    Article  CAS  PubMed  Google Scholar 

  • Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB (2005) Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet 44:467–494

    Article  CAS  PubMed  Google Scholar 

  • Lestari Maria LAD, Ardiana F, Indrayanto G (2009) Ezetimibe. In: Brittain HG (ed) Profiles of drug substances, excipients and related methodology, 1st edn. Academic Press, London, pp 104–105

    Google Scholar 

  • Lundstedt T, Seifert E, Abramo L, Thelin B, Nystrom A, Pettersen J, Bergman R (1998) Experimental design and optimization. Chemom Intell Lab Syst 42:3–40

    Article  CAS  Google Scholar 

  • Mohsin K, Long MA, Pouton CW (2009) Design of lipid-based formulations for oral administration of poorly water-soluble drugs: precipitation of drug after dispersion of formulations in aqueous solution. J Pharm Sci 98:3582–3595

    Article  CAS  PubMed  Google Scholar 

  • Montgomery DC (2013) Design and analysis of experiments. Wiley, Hoboken

    Google Scholar 

  • Nazzal S, Khan MA (2002) Response surface methodology for the optimization of ubiquinone self-nanoemulsified drug delivery system. AAPS PharmSciTech 3:23–31

    Article  PubMed Central  Google Scholar 

  • Pandya V, Patel J (2011) Formulation and evaluations of ezetimibe nanoparticles prepared by controlled nanoprecipitation and transformation into solid dosage. Acta Pharm Sci 53:477–488

    CAS  Google Scholar 

  • Parmar KR, Shar SR, Sheth NR (2011) Studies in dissolution enhancement of ezetimibe by solid dispersions in combination with a surface adsorbent. Dissolution Technol 8:55–61

    Article  Google Scholar 

  • Patel R, Bhimani D, Patel J, Patel D (2008) Solid-state characterization and dissolution properties of ezetimibe–cyclodextrins inclusion complexes. J Incl Phenomena Macrocycl Chem 60:241–251

    Article  CAS  Google Scholar 

  • Pouton CW (2000) Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems. Eur J Pharm Sci 11(Suppl 2):S93–98

    Article  CAS  PubMed  Google Scholar 

  • Pouton CW, Porter CJ (2008) Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Adv Drug Deliv Rev 60:625–637

    Article  CAS  PubMed  Google Scholar 

  • Pund S, Shete Y, Jagadale S (2014) Multivariate analysis of physicochemical characteristics of lipid based nanoemulsifying cilostazol–quality by design. Colloids Surf B Biointerfaces 115:29–36

    Article  CAS  PubMed  Google Scholar 

  • Rahman MA, Iqbal Z, Hussain A (2012) Formulation optimization and in vitro characterization of sertraline loaded self-nanoemulsifying drug delivery system (SNEDDS) for oral administration. J Pharm Investig 42:191–202

    Article  CAS  Google Scholar 

  • Sancheti PP, Karekar P, Vyas VM, Shah M, Pore YV (2009) Preparation and physicochemical characterization of surfactant based solid dispersions of ezetimibe. Pharmazie 64:227–231

    CAS  PubMed  Google Scholar 

  • Strickley RG (2007) Currently marketed oral lipid-based dosage forms: Drug products and excipients. In: Hauss DJ (ed) Oral lipid-based formulations: enhancing the bioavailability of poorly water-soluable drugs, 1st edn. Informa Healthcare, New York, pp 1–31

    Google Scholar 

  • Sweetman SC (2009) Martindale: the complete drug reference. Pharmaceutical Press, London

    Google Scholar 

  • Tang B, Cheng G, Gu JC, Xu CH (2008) Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms. Drug Discov Today 13:606–612

    Article  CAS  PubMed  Google Scholar 

  • Thomas N, Holm R, Müllertz A, Rades T (2012) In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS). J Control Release 160:25–32

    Article  CAS  PubMed  Google Scholar 

  • Wei Y, Ye X, Shang X, Peng X, Bao Q, Liu M, Gup M, Li F (2012) Enhanced oral bioavailability of silybin by a supersaturatable self-emulsifying drug delivery system (S-SEDDS). Colloids Surf A 396:22–28

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This article does not contain any studies with human and animal subjects performed by any of the authors. Authors are thankful to Abitec Corp., Janesville, USA; BASF SE, Ludwigshafen, Germany; Gattefosse Corp., Saint-Priest, France, and Sasol olefins and surfactants, GmbH, Germany for providing excipients used during this study. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Author information

Authors and Affiliations

  1. Alliance Institute of Advanced Pharmaceutical & Health Sciences, Plot No. 64, Survey No. 145, Sardar Patel Nagar, Kukatpally, Hyderabad, Telangana, 500072, India

    Rajendra Narayan Dash

  2. Adept Pharma and Bioscience Excellence Private Limited, Corporate Office: 10-3-561/3/A/102, Vijayanagar Colony, Hyderabad, Telangana, 500057, India

    Habibuddin Mohammed & Touseef Humaira

Authors
  1. Rajendra Narayan Dash
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Habibuddin Mohammed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Touseef Humaira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Habibuddin Mohammed.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 580 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dash, R.N., Mohammed, H. & Humaira, T. Design, optimization, and evaluation of ezetimibe solid supersaturatable self-nanoemulsifying drug delivery for enhanced solubility and dissolution. Journal of Pharmaceutical Investigation 46, 153–168 (2016). https://doi.org/10.1007/s40005-015-0225-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-015-0225-9

Keywords

Search

Navigation