International Journal of Pharmaceutics 225 (2001) 31 – 39 Polymethyacrylate based microparticulates of insulin for oral delivery: Preparation and in vitro dissolution stability in the presence of enzyme inhibitors Vikas Agarwal, Indra K. Reddy, Mansoor A. Khan * Department of Pharmaceutical Sciences, Texas Tech Uniersity HSC, School of Pharmacy, 1300 Coulter, Suite 400, Amarillo, TX 79106, USA Received 29 September 2000; received in revised form 24 January 2001; accepted 17 May 2001 Abstract The purpose of this investigation was to (a) evaluate the coprecipitation technique for preparing microparticulates of insulin, (b) study the effect of variables such as addition of salts in the precipitating medium and ratio of polymeric solution to volume of precipitating medium on the dissolution and encapsulation efficiency of insulin microparticu- lates, and (c) evaluate the in-vitro enzymatic dissolution stability of insulin microparticulates in the presence of chicken ovomucoid (CkOVM) and duck ovomucoid (DkOVM) as inhibitors. Insulin dissolved in 0.01 N HCl was mixed with alcohol USP to get a final concentration of 32% v/v. Eudragit L100, a representative polymethyacrylate polymer, was then dissolved in this solution which was transferred to a beaker containing cold water with homogenization to obtain microparticulates. Dissolution studies were carried out in pH 6.8 phosphate buffer using a 100-ml conversion kit in a standard dissolution assembly. Dissolution stability of microparticulates was evaluated in the presence of 0.5 M trypsin and 0.l M chymotrypsin at various ratios of CkOVM and DkOVM. The results indicated that insulin microparticulates could be prepared using the coprecipitation technique with high encapsulation efficiency by proper selection of experimental conditions and amount of polymer. Presence of salts in the precipitating medium decreased the dissolution of insulin from the microparticulates. As the ratio of precipitating medium with respect to the polymeric solution was increased, the encapsulation efficiency increased. In dissolution stability experiments, insulin was not detected in the presence of enzymes alone. When CkOVM and DkOVM were incorporated, the stability of insulin increased significantly in a concentration dependent fashion. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Insulin; Microparticulates; Coprecipitates; Inhibitors; Chicken ovomucoid; Duck ovomucoid; Dissolution stability www.elsevier.com/locate/ijpharm 1. Introduction Oral delivery of therapeutic proteins is limited due to barriers such as enzymatic degradation in the gastrointestinal tract, low epithelial permeabil- ity and instability under formulation conditions * Corresponding author. Tel.: +1-806-356-4000x285; fax: +1-806-356-4034. E-mail address: khan@cortex.ama.ttuhsc.edu (M.A. Khan). 0378-5173/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S0378-5173(01)00740-2