Hybrid insulin cocrystals for controlled release delivery

Abstract

The ability to tailor the release profile of a drug by manipulating its formulation matrix offers important therapeutic advantages. We show here that human insulin can be cocrystallized at preselected ratios with the fully active lipophilically modified insulin derivative octanoyl-N(epsilon)-LysB29-human insulin (C8-HI). The cocrystal is analogous to the NPH (neutral protamine Hagedorn) crystalline complex formed with human insulin, which is commonly used as the long-acting insulin component of diabetes therapy. The in vitro and in vivo release rates of the cocrystal can be controlled by adjusting the relative proportions of the two insulin components. We identified a cocrystal composition comprising 75% C8-HI and 25% human insulin that exhibits near-ideal basal pharmacodynamics in somatostatin-treated beagle dogs. The dependence of release rate on cocrystal ratio provides a robust mechanism for modulating insulin pharmacodynamics. These findings show that a crystalline protein matrix may accommodate a chemical modification that alters the dissolution rate of the crystal in a therapeutically useful way, yet that is structurally innocuous enough to preserve the pharmaceutical integrity of the original microcrystalline entity and the pharmacological activity of the parent molecule.

Novel Long-Acting Crystal Formulation of Human Growth Hormone

“…In general, the high intrinsic solubility of proteins makes crystallizationbased long-acting biopharmaceuticals seem counterintuitive. Even co-crystallization of insulin with lipophilically modified insulin derivatives did not extend insulin release beyond 1 day (14). Yet several therapeutic proteins would benefit from much longer release profile.…”

The role of co-crystals in pharmaceutical design

“…Insulin has poor oral bioavailability and is commonly injected. Human insulin has been co-crystallised with a lipophilically modified, closely related insulin analogue octanoyl-N -LysB29-human insulin (68). The lipophilic formulation was designed to provide a slow release profile compatible with an improved physiological insulin profile.…”

Designing a Cocrystal of γ‐Amino Butyric Acid

“…A recently suggested alternative to the common inorganic salts is the preparation of cocrystals [1] or organic salts, some of which have been shown to improve therapeutic utility while reducing side effects. [2][3][4] Candidates for cocrystal formation with a particular structural motif for achieving desired physical properties [5,6] are chosen on the basis of their ability to utilize known intermolecular interactions in forming those crystals. Because hydrogen bonds are among the strongest and most preferentially directional intermolecular interactions, they have been the leading candidates for the interactions to be utilized in forming cocrystals, [7][8][9][10] although other interactions have also been suggested.…”