Development and bioavailability assessment of ramipril nanoemulsion formulation.

The objective of our investigation was to design a thermodynamically stable and dilutable nanoemulsion formulation of Ramipril, with minimum surfactant concentration that could improve its solubility, stability and oral bioavailability. Formulations were taken from the o/w nanoemulsion region of phase diagrams, which were subjected to thermodynamic stability and dispersibility tests. The composition of optimized formulation was Sefsol 218 (20% w/w), Tween 80 (18% w/w), Carbitol (18% w/w) and standard buffer solution pH 5 (44% w/w) as oil, surfactant, cosurfactant and aqueous phase, respectively, containing 5 mg of ramipril showing drug release (95%), droplet size (80.9 nm), polydispersity (0.271), viscosity (10.68 cP), and infinite dilution capability. In vitro drug release of the nanoemulsion formulations was highly significant (p<0.01) as compared to marketed capsule formulation and drug suspension. The relative bioavailability of ramipril nanoemulsion to that of conventional capsule form was found to be 229.62% whereas to that of drug suspension was 539.49%. The present study revealed that ramipril nanoemulsion could be used as a liquid formulation for pediatric and geriatric patients and can be formulated as self-nanoemulsifying drug delivery system (SNEDDS) as a unit dosage form.

[1]  R. Schwendener,et al.  Lipophilic 1-β-d-arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model , 2005, Journal of Cancer Research and Clinical Oncology.

[2]  N. Yata,et al.  Enhancement of bioavailability of a hydrophobic amine antimalarial by formulation with oleic acid in a soft gelatin capsule. , 1978, Journal of pharmaceutical sciences.

[3]  S. Yuk,et al.  Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. , 2004, International journal of pharmaceutics.

[4]  A. Cohen,et al.  Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril , 2004, European Journal of Clinical Pharmacology.

[5]  B. Aungst.  Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism. , 1993, Journal of pharmaceutical sciences.

[6]  S. Yusuf,et al.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. , 2000 .

[7]  M. Maurin,et al.  Improved oral bioavailability of the hypocholesterolemic DMP 565 in dogs following oral dosing in oil and glycol solutions. , 1997, Biopharmaceutics & drug disposition.

[8]  A. Serajuddin,et al.  Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions. , 2005, International journal of pharmaceutics.

[9]  R. Murthy,et al.  Microemulsions: a potential drug delivery system. , 2006, Current drug delivery.

[10]  M. Lawrence,et al.  Light-scattering investigations on dilute nonionic oil-in-water microemulsions , 2000, AAPS PharmSci.

[11]  C K Kim,et al.  Preparation and evaluation of biphenyl dimethyl dicarboxylate microemulsions for oral delivery. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[12]  K. Kawakami,et al.  Microemulsion formulation for enhanced absorption of poorly soluble drugs. II. In vivo study. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[13]  S. Yusuf,et al.  Ramipril and the development of diabetes. , 2001, JAMA.

[14]  D. Attwood,et al.  A study on factors influencing the droplet size in nonionic oil-in-water microemulsions , 1992 .

[15]  E. Perrier,et al.  Nano-emulsion formulation using spontaneous emulsification: solvent, oil and surfactant optimisation. , 2004, International journal of pharmaceutics.

[16]  Steven W. Booth,et al.  An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy , 1995 .

[17]  M. Williams,et al.  Development and validation of a liquid chromatographic method for the determination of the related substances of ramipril in Altace capsules. , 2000, Journal of pharmaceutical and biomedical analysis.

[18]  D. Levitt,et al.  Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat , 2006, BMC clinical pharmacology.

[19]  Colin W. Pouton,et al.  Formulation of self-emulsifying drug delivery systems , 1997 .

[20]  T. Needham,et al.  Oral Delivery of a Renin Inhibitor Compound Using Emulsion Formulations , 1992, Pharmaceutical Research.

[21]  J. Swarbrick,et al.  Encyclopedia of Pharmaceutical Technology , 2006 .

[22]  G. Edwards,et al.  Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine , 1998 .

[23]  J. Crison,et al.  A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability , 1995, Pharmaceutical Research.

[24]  D. Craig,et al.  An investigation into the physico-chemical properties of self-emulsifying systems using low frequency dielectric spectroscopy, surface tension measurements and particle size analysis , 1993 .

[25]  M. Abounassif,et al.  A stability-indicating LC method for the simultaneous determination of ramipril and hydrochlorothiazide in dosage forms. , 2001, Journal of pharmaceutical and biomedical analysis.

[26]  Koji Takahashi,et al.  Microemulsion formulation for enhanced absorption of poorly soluble drugs. I. Prescription design. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[27]  K. Palin,et al.  The oral absorption of cefoxitin from oil and emulsion vehicles in rats , 1986 .

[28]  Colin W. Pouton,et al.  Self-Emulsifying Drug Delivery Systems: Formulation and Biopharmaceutic Evaluation of an Investigational Lipophilic Compound , 2004, Pharmaceutical Research.

[29]  M. Carvajal,et al.  Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs , 1994 .

[30]  M. Khan,et al.  Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. , 2001, International journal of pharmaceutics.

[31]  K. Shinoda,et al.  Organized surfactant systems: microemulsions , 1987 .

[32]  J. Klimeš,et al.  Stability of ramipril in the solvents of different pH. , 2005, Journal of pharmaceutical and biomedical analysis.

[33]  F. Jané,et al.  Influence of renal function on the pharmacokinetics of ramipril (HOE 498). , 1987, The American journal of cardiology.

[34]  M. Lawrence,et al.  Microemulsion-based media as novel drug delivery systems , 2000 .

[35]  Valentino J. Stella,et al.  Systemic bioavailability of penclomedine (NSC-338720) from oil-in-water emulsions administered intraduodenally to rats , 1992 .

[36]  M. Ghosh.  Fundamentals of experimental pharmacology , 2007, Indian Journal of Pharmacology.

[37]  P. Constantinides,et al.  Lipid Microemulsions for Improving Drug Dissolution and Oral Absorption: Physical and Biopharmaceutical Aspects , 1995, Pharmaceutical Research.

[38]  A. Serajuddin,et al.  Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions. , 1988, Journal of pharmaceutical sciences.