An in-vitro test for the duration of action of insulin suspensions

Graham, David; Pomeroy, A R

doi:10.1111/j.2042-7158.1984.tb04418.x

Cited by 18 publications

(5 citation statements)

References 2 publications

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“…Insulin, a 5808-Da, 51 amino acid, dual-chain hormone that is secreted and stored in pancreatic b-cells, is therapeutically important for the treatment of diabetes, a chronic disease that requires supplemental insulin delivery in the form of either solution or microcrystalline suspension formulations of insulin (1,2). The crystal morphology influences the pharmacokinetics, governed by the dissolution of the microcrystals and insulin monomer absorption into the bloodstream (3). The pharmacokinetics of microcrystalline insulin suspensions is controlled by the rate of dissociation of insulin from the crystal lattice, dependent on the cohesive energy between insulin molecules, crystal morphology, the dissolution rates of different crystal faces, and the degree of disorder at the crystal-solution interface (4).…”

Section: Introductionmentioning

confidence: 99%

Insulin Particle Formation in Supersaturated Aqueous Solutions of Poly(Ethylene Glycol)

Bromberg¹,

Rashba-Step²,

Scott³

2005

Biophysical Journal

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Protein microspheres are of particular utility in the field of drug delivery. A novel, completely aqueous, process of microsphere fabrication has been devised based on controlled phase separation of protein from water-soluble polymers such as polyethylene glycols. The fabrication process results in the formation of spherical microparticles with narrow particle size distributions. Cooling of preheated human insulin-poly(ethylene glycol)-water solutions results in the facile formation of insulin particles. To map out the supersaturation conditions conducive to particle nucleation and growth, we determined the temperature- and concentration-dependent boundaries of an equilibrium liquid-solid phase separation. The kinetics of formation of microspheres were followed by dynamic and continuous-angle static light scattering techniques. The presence of PEG at a pH that was close to the protein's isoelectric point resulted in rapid nucleation and growth. The time elapsed from the moment of creation of a supersaturated solution and the detection of a solid phase in the system (the induction period, t(ind)) ranged from tens to several hundreds of seconds. The dependence of t(ind) on supersaturation could be described within the framework of classical nucleation theory, with the time needed for the formation of a critical nucleus (size <10 nm) being much longer than the time of the onset of particle growth. The growth was limited by cluster diffusion kinetics. The interfacial energies of the insulin particles were determined to be 3.2-3.4 and 2.2 mJ/m(2) at equilibrium temperatures of 25 and 37 degrees C, respectively. The insulin particles formed as a result of the process were monodisperse and uniformly spherical, in clear distinction to previously reported processes of microcrystalline insulin particle formation.

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Section: Introductionmentioning

confidence: 99%

Insulin Particle Formation in Supersaturated Aqueous Solutions of Poly(Ethylene Glycol)

Bromberg¹,

Rashba-Step²,

Scott³

2005

Biophysical Journal

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“…Crystalline bovine ultralente insulin-which differs from human and porcine insulins by two residues in the A-chain-is reputed to provide optimal pharmacokinetics with a relatively constant plasma insulin concentration, mimicking that present in nondiabetic individuals. However, it remains unclear how the pharmacokinetics, governed by the dissolution of the microcrystals and insulin monomer absorption into the bloodstream, is related to factors such as the conformation of individual insulin molecules, hexamer packing in the solid state, and crystal morphology (Graham and Pomeroy, 1984). Furthermore, little is known about the role of the aforementioned sequence differences on crystal dissociation or growth.…”

Section: Introductionmentioning

confidence: 99%

Structural and Morphological Characterization of Ultralente Insulin Crystals by Atomic Force Microscopy: Evidence of Hydrophobically Driven Assembly

Yip

DeFelippis

Frank

et al. 1998

Biophysical Journal

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Although x-ray crystal structures exist for many forms of insulin, the hormone involved in glucose metabolism and used in the treatment of diabetes, x-ray structural characterization of therapeutically important long-acting crystalline ultralente insulin forms has been elusive because of small crystal size and poor diffraction characteristics. We describe tapping-mode atomic force microscopy (TMAFM) studies, performed directly in crystallization liquor, of ultralente crystals prepared from bovine, human, and porcine insulins. Lattice images obtained from direct imaging of crystal planes are consistent with R3 space group symmetry for each insulin type, but the morphology of the human and porcine crystals observed by AFM differs substantially from that of the bovine insulin crystals. Human and porcine ultralente crystals exhibited large, molecularly flat (001) faces consisting of hexagonal arrays of close packed hexamers. In contrast, bovine ultralente crystals predominantly exhibited faces with cylindrical features assignable to close-packed stacks of insulin hexamers laying in-plane, consistent with the packing motif of the (010) and (011) planes. This behavior is attributed to a twofold increase in the hydrophobic character of the upper and lower surfaces of the donut-shaped insulin hexamer in bovine insulin compared to its human and porcine counterparts that results from minor sequence differences between these insulins. The increased hydrophobicity of these surfaces can promote hexamer-hexamer stacking in precrystalline aggregates or enhance attachment of single hexamers along the c axis at the crystal surface during crystal growth. Both events lead to enhanced growth of ¿hk0¿ planes instead of (001). The insulin hexamers on the (010) and (110) faces are exposed "edge-on" to the aqueous medium, such that solvent access to the center of the hexamer and to solvent channels is reduced compared to the (001) surface, consistent with the slower dissolution and reputed unique basal activity of bovine ultralente insulin. These observations demonstrate that subtle variations in amino acid sequence can dramatically affect the interfacial structure of crystalline proteins.

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“…Release due to dissolution of particulate drug systems can be regulated e.g. by the morphology, size and composition 5, 13. Using the templating approach one can in principle control the release kinetics by adjusting the size of the protein particles.…”

Section: Resultsmentioning

confidence: 99%

“…These requirements can be achieved by protein formulation into particulate systems,3 e.g., by means of conventional techniques including protein crystallization4, 5 and protein embedding into polymers or lipid matrices 6–12. For example, release rate of protein microcrystals can be regulated by the crystalline nature and crystal morphology, size and composition 5, 13. It is, however, complicated to control size and dispersity of protein microcrystals to achieve well defined release profile.…”

Section: Introductionmentioning

confidence: 99%

Current awareness in geriatric psychiatry

2008

Int J Geriat Psychiatry

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Formulation of therapeutic proteins into particulate forms is a main strategy for site‐specific and prolonged protein delivery as well as for protection against degradation. Precise control over protein particle size, dispersity, purity, as well as mild preparation conditions and minimal processing steps are highly desirable. It is, however, hard to fit all these criteria with conventional preparation techniques. Here a one‐step hard‐templating synthesis of microparticles composed of functional, non‐denatured protein is reported. The method is based on filling porous CaCO3 microtemplates with the protein near to its isoelectric point (pI) followed by pH‐ or EDTA‐mediated dissolution of the tempplates. In principle, a wide variety of proteins can be converted into microparticles using this approach. The main requirement is an overlap of the protein insolubility and a template solubility for a certain parameter (here pH or EDTA). Here the formulation of insulin particles is studied in detail and it is shown that particles consisting of high molecular weight protein (catalase) can also be prepared. In this context, the synthesis of CaCO3 templates with controlled size, the mechanism of the protein microparticle formation and mechanical properties of the microparticles are discussed. For the first time, the fabrication of mesoporous monodispersed CaCO3 microtemplates with identical porocity but tuned diameter from 3 to 20 μm is demonstrated. The protein particle diameter can be adjusted by choosing the appropriate template size that is critical for successful pulmonary delivery of insulin. As a first step towards insulin delivery, the in vitro release of insulin at physiological conditions is studied.

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An in-vitro test for the duration of action of insulin suspensions

Cited by 18 publications

References 2 publications

Insulin Particle Formation in Supersaturated Aqueous Solutions of Poly(Ethylene Glycol)

Insulin Particle Formation in Supersaturated Aqueous Solutions of Poly(Ethylene Glycol)

Structural and Morphological Characterization of Ultralente Insulin Crystals by Atomic Force Microscopy: Evidence of Hydrophobically Driven Assembly

Current awareness in geriatric psychiatry

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