A study of factors controlling dissolution kinetics of zinc complexed protein suspensions in various ionic species.
The presence of bound and unbound zinc in the crystal matrix of protein suspensions helps physically stabilize the crystal and limits the dissolution of the drug. In case of zinc insulin suspensions, dissolution can be promoted by complexation of zinc with an ionic species for which the zinc has a greater affinity, these complexing ions having either formulation and/or physiological relevance. The purpose of this work was to use ligand-complexed formulations of insulin suspensions to gain an understanding of these products' dissolution performance and to establish a fundamental understanding of the rate-limiting steps in zinc insulin dissolution. Our group has suggested that the critical factors to zinc insulin dissolution are: (1) chemical complexation (zinc with ionic species); and (2) drug transport (insulin diffusion and solubility). Dissolution studies conducted using different ionic species (acetate, phosphate, citrate and EDTA) in a spin-filter device demonstrated a rank order correlation for different sources of zinc insulin; it was observed that human zinc insulin dissolved faster than bovine insulin, these differences attributed to their binding properties and the respective affinities to the various ionic species used. Also, as the amount of crystallinity increased in a formulation, a rank order increase in dissolution times was observed. The project also identified a sensitive and reproducible dissolution testing methodology. Overall, this study demonstrated that: (1) the complexation rate-limiting step was more significant in the dissolution of zinc insulin than the diffusion rate-limiting step; and (2) that dissolution kinetics depended primarily on the source and solid state differences and the binding affinities of the zinc insulin.
Prabhu
S
S
College of Pharmacy, Western University of Health Sciences, 309 E, 2nd Street, Pomona, CA 91766, USA. sprabhu@westernu.edu
Jacknowitz
A I
AI
Stout
P J
PJ
D000085:Acetates / Q000737:chemistry; D000818:Animals; D002417:Cattle; D002626:Chemistry, Pharmaceutical; D019343:Citric Acid / Q000737:chemistry; D004058:Diffusion; D004492:Edetic Acid / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry*; D049528:Insulin, Long-Acting / Q000737:chemistry*; D008956:Models, Chemical; D010710:Phosphates / Q000737:chemistry; D012995:Solubility
D000085:Acetates; D007004:Hypoglycemic Agents; D049528:Insulin, Long-Acting; D010710:Phosphates; D019343:Citric Acid; D004492:Edetic Acid