Design and statistical optimization of glipizide loaded lipospheres using response surface methodology

Design and statistical optimization of glipizide loaded lipospheres using response surface methodology A 32 factorial design was employed to produce glipizide lipospheres by the emulsification phase separation technique using paraffin wax and stearic acid as retardants. The effect of critical formulation variables, namely levels of paraffin wax (X1) and proportion of stearic acid in the wax (X2) on geometric mean diameter (dg), percent encapsulation efficiency (% EE), release at the end of 12 h (rel12) and time taken for 50% of drug release (t50), were evaluated using the F-test. Mathematical models containing only the significant terms were generated for each response parameter using the multiple linear regression analysis (MLRA) and analysis of variance (ANOVA). Both formulation variables studied exerted a significant influence (p < 0.05) on the response parameters. Numerical optimization using the desirability approach was employed to develop an optimized formulation by setting constraints on the dependent and independent variables. The experimental values of dg, % EE, rel12 and t50 values for the optimized formulation were found to be 57.54 ± 1.38 μm, 86.28 ± 1.32%, 77.23 ± 2.78% and 5.60 ± 0.32 h, respectively, which were in close agreement with those predicted by the mathematical models. The drug release from lipospheres followed first-order kinetics and was characterized by the Higuchi diffusion model. The optimized liposphere formulation developed was found to produce sustained anti-diabetic activity following oral administration in rats. Dizaj i statistička optimizacija liposfera s glipizidom pomoću metodologije odgovora površine 32 faktorijalni dizajn je primijenjen za pripravu liposfera s glipizidom metodom separacije pomoću emulzija koristeći parafinski vosak i stearinsku kiselinu kao tvari za usporavanje. Pomoću F-testa praćen je učinak kritičnih varijabli tijekom formuliranja, tj. količina parafinskog voska (X1) i udio stearinske kiseline (X2) na srednji promjer liposfera (dg), postotak inkapsulirane ljekovite tvari (% EE), oslobađanje ljekovite tvari nakon 12 h (rel12) te vrijeme potrebno za oslobađanje 50% ljekovite tvari (t50). Za svaki parametar su pomoću multiple linearne regresijske analize (MLRA) i analize varijabli (ANOVA) načinjeni matematički modeli koji sadrže samo značajne varijable. Proučavanje varijabli na oba načina ukazalo je na njihov značajan utjecaj (p < 0,05) na parametre liposfera. Postavljanjem ograničenja na zavisne i nezavisne varijable provedena je numerička optimizacija na principu poželjnosti. Eksperimentalne vrijednosti dg, % EE, rel12 i t50 optimiziranih formulacija bile su 57,54 ± 1,38 μm, 86,28 ± 1,32%, 77,23 ± 2,78% i 5,60 ± 0,32 h. Dobivene eksperimentalne vrijednosti bile su vrlo slične vrijednostima predviđenim matematič kim modelima. Oslobađanje glipizida iz liposfera slijedio je kinetiku prvog reda i karakteriziran je Higuchijevim difuzijskim modelom. Optimizirane liposfere su nakon peroralne primjene na štakorima pokazale produljeni antidijabetički učinak.

[1]  Roger L. Black,et al.  Goodman and Gilman's The Pharmacological Basis of Therapeutics , 1991 .

[2]  R. Fassihi,et al.  Role of surfactant and pH on dissolution properties of fenofibrate and glipizide—A technical note , 2006, AAPS PharmSciTech.

[3]  N. Peppas,et al.  Mechanisms of solute release from porous hydrophilic polymers , 1983 .

[4]  T. Higuchi.  MECHANISM OF SUSTAINED-ACTION MEDICATION. THEORETICAL ANALYSIS OF RATE OF RELEASE OF SOLID DRUGS DISPERSED IN SOLID MATRICES. , 1963, Journal of pharmaceutical sciences.

[5]  G. Ertan,et al.  Extended release lipophilic indomethacin microspheres: formulation factors and mathematical equations fitted drug release rates. , 2003, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[6]  P. Sinko.  Martin's Physical Pharmacy and Pharmaceutical Sciences , 2005 .

[7]  Martin H. Abramson,et al.  Complete Drug Reference , 1996 .

[8]  M. Efentakis,et al.  Release of Furosemide from Multiple-Unit and Single-Unit Preparations Containing Different Viscosity Grades of Sodium Alginate , 2001, Pharmaceutical development and technology.

[9]  C. Goodman.  United States Pharmacopeial Convention , 1988 .

[10]  A. Hirschfelder.  THE UNITED STATES PHARMACOPEIAL CONVENTION , 1930 .

[11]  M. Srinath,et al.  Development of three layered buccal compact containing metoprolol tartrate by statistical optimization technique. , 2005, International journal of pharmaceutics.

[12]  Response Surface Methodology , 1998 .

[13]  S. Garg,et al.  Development and evaluation of osmotically controlled oral drug delivery system of glipizide. , 2004, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[14]  R. Fassihi,et al.  Development of a controlled release low dose class II drug-Glipizide. , 2006, International journal of pharmaceutics.

[15]  C. M. Adeyeye,et al.  Development and Evaluation of Sustained-Release Ibuprofen–Wax Microspheres. II. In Vitro Dissolution Studies , 1994, Pharmaceutical Research.

[16]  C. Thies.  A SURVEY OF MICROENCAPSULATION PROCESSES , 1996 .

[17]  J. Varshosaz, M. Keihanfar,et al.  Development and evaluation of sustained-release propranolol wax microspheres , 2001, Journal of microencapsulation.

[18]  K. Chowdary,et al.  Design and in vitro and in vivo evaluation of mucoadhesive microcapsules of glipizide for oral controlled release: A technical note , 2003, AAPS PharmSciTech.

[19]  J. Hardman,et al.  Insulin, oral hypoglycemic agents and the pharmacology of the endocrine pancreas , 2001 .

[20]  Jayvadan K. Patel,et al.  Formulation and evaluation of mucoadhesive glipizide microspheres , 2005, AAPS PharmSciTech.

[21]  I El-Gibaly,et al.  Effect of hexacosanol on the characteristics of novel sustained-release allopurinol solid lipospheres (SLS): factorial design application and product evaluation. , 2005, International journal of pharmaceutics.

[22]  C. M. Adeyeye,et al.  Development and Evaluation of Sustained-Release Ibuprofen-Wax Microspheres. I. Effect of Formulation Variables on Physical Characteristics , 1991, Pharmaceutical Research.

[23]  Simon Benita,et al.  Microencapsulation : methods and industrial applications , 1996 .

[24]  N. Mani,et al.  Microencapsulation of a hydrophilic drug into a hydrophobic matrix using a salting-out procedure. I: Development and optimization of the process using factorial design , 2004, Journal of microencapsulation.

[25]  Vincent Li.  Influence of Drug Properties and Routes of Drug Administration on the Design of Sustained and Controlled Release Systems , 1987 .