Insulin release profile

Figure 5 Modulating insulin release profile from pH/temperature-sensitive beads made of terpolymers of iV-isopropylacrylamide (NIPAAm)/butyl methacrylate (BMA)/acrylic acid (AA) feed mol ratio 85/5/10 and increasing MW. Beads were placed at pH 2.0 and 37°C for 2h and then at pH 7.4 and 37°C for the remainder of the release studies in = 6). (Adapted from Ref. 76.)...

Ramkissoon-Ganorkar C, Liu F, Baudys M, Kim SW. Modulating insulin-release profile from pH/thermosensitive polymeric beads through polymer molecular weight. J Control Release 1999 59 287-298. 

An animal study with streptozotocin-induced diabetic rats was carried out and involved the subcutaneous injection of both microspheres. While Msp B caused a burst effect (hypoglycemia) followed by a quick change in blood glucose and insulin levels, Msp A exhibited relatively sustained blood glucose levels and the release of insulin for 10 days. In vitro and in vivo insulin release profiles were foxmd to be rather consistent (49). 

In an early study by Lin et al., insulin-loaded polylactic acid (PLA) microcapsules were synthesized by an emulsification-solvent evaporation process originally reported by Beck et al. Several parameters in the synthesis process were modified with the intention of optimizing the insulin release profile. Such modifications included variations in types, concentrations, and viscosities of protective colloids used in the emulsification process. Polyvinyl alcohol (PVA), when used as the protective colloid in the fabrication process, was found to produce the PLA microparticles in reproducible quality. Further studies revealed that the concentration PVA directly affects the PLA particle size and the surface characteristics of the microcapsules. With higher concentrations of PVA, microparticles tended to be smaller and to have a smoother surface. When the release profiles of the microcapsules were stud-... 

In vivo studies were undertaken to compare insulin release profiles between microparticles prepared from the simple solid-in-oil dispersion and those prepared from the novel multiple emulsion technique. With the former, a significant initial insulin rise was observed. This rise peaked at 6 h and insulin release was essentially exhausted by 24 h. With the latter, the initial burst was strongly suppressed, and glucose control was achieved for 2 weeks. Insulin release continued for as along as 20 d, although the levels of insulin were not adequate to achieve normal glucose levels for this entire study period. ... 

S. Jose, J.F. Fangueiro, J. Smitha, T.A. Cinu, A.J. Chacko, K. Premaletha, and E.B. Souto, Predictive modeling of insulin release profile from cross-linked chitosan microspheres, Eur. J. Med. Chem., 60,249-253,2013. 

Figure 4. Modulating insulin release profile from pH-/temperature-sensitive beads made of terpolymers of constant NIPAAm/BMA/AA composition 85/5/10 and increasing molecular weight.

Many successful protein products, including antibodies, have been marketed over the years for the treatment of a number of diseases. One of the oldest examples of a protein product is insulin, still one of the most successful drugs after 70-80 years of its discovery. Early insulin preparations, derived from natural sources, are being replaced by recombinant human insulin preparations and new formulations are being marketed that provide a more gradual and continuous release profile and maximise glucose control in diabetic patients. " ... 

In an effort to develop an effective bioadhesive system for buccal administration, insulin was encapsulated into polyacrylamide nanoparticles by the emulsion solvent evaporation method [98]. Though nanoparticle formation ensures even distribution of the drug, pelleting of the nanoparticles was performed to obtain three-dimensional structural conformity. In addition, it was hypothetized that the pelletized particles will remain adhered to the mucosa, leading to good absorption. While studying bioadhesion and drug release profiles, it was found that the... 

Recently a CD-insulin complex was encapsulated in polymethacrylic acid-chi-tosan-polyether[polyethylene glycol (PEG)-propylene glycol] copolymer PMCP nanoparticles from the free-radical polymerization of methacrylic acid in the presence of chitosan and polyether in a medium free of solvents or surfactants. Particles had a size distribution of 500-800 nm. The HP-B-CD inclusion complex with insulin was encapsulated into the nanoparticles, resulting in a pH-dependent release profile as seen in Figure 2. The biological activity of insulin was demonstrated with enzyme-... 

FIGURE 2 pH-dependent release profile for insulin complexed to HP-B-CD and encapsulated in nanoparticles. (Reprinted from S. Sajeesh and C. P. Sharma, International Journal of Pharmaceutics, 325,147-154, 2006, Copyright 2006, with permission from Elsevier.)... 

In islets, A-4166 causes a steep rise in insulin release followed by a slow sustained rise to twice the basal level. The insulinotropic effect is not glucose-dependent and takes place in the absence of glucose [191, 192]. The in vivo pharmacodynamic profile (rapid and short-term action) appears to result from a rapid plasma appearance and disappearance of the compound rather than an intrinsic feature of the mechanism [191]. A-4166 may be useful as therapy for NIDDM patients with secondary failure to sulphonylureas [190]. 

MTP-3631 (94) has a similar profile as MTP-3115 however, it can significantly lower plasma glucose levels in normal rats or ob/ob mice after only 1 hour post-administration. The effect is not accompanied by any insulin release, so that this compound probably acts by a different mechanism from the other thiopyranopyrimidines [399]. The rapid action of MTP-3631 is quite unique among compounds improving insulin sensitivity. 

However, one compound which has highlighted the need for extensive profiling across several tissues is SDZ PCO 400 (15) (see Table 9.1). This compound relaxes smooth muscle tone in vascular and airways tissue and appears to be a typical KCA. However, in pancreatic B-cells, unlike cromakalim (1) and other KCAs, compound (15) inhibits K tp [6]. Thus, SDZ PCO 400 (15) might increase insulin release in a similar manner to the sulphonylureas. 

While the PK profile reported for inhaled insulin seems appropriate to meet prandial insulin requirements, it will not address basal insulin needs. In certain treatment regimes, an injection of a long-acting (basal) insulin preparation will be required unless a pulmonary delivery system capable of producing a sustained release profile is developed. Moreover, if the pharmacological characteristics of inhaled insulin prove... 

FIGURE 4.8 (A) Cumulative release of triptorelin and leuprolide from lipospheres. Lipospheres were prepared from L-PLA and HSPC, as described in Figure 4.6. The release experiment was performed in pH 7.4, phosphate buffer, at 37°C, and analyzed by HPLC for both formulations. (Adapted from [35] with permission from Elsevier.). (B) Comparison of release profiles of thymocartin (loading 9.0%), somatostatin (loading 9.3%), and insulin (loading 6.83%) from glyceryl tripalmitate microparticles. (Adapted from [37] with permission from author.)... 

This ABA-type triblock copolymer was used as a drug release depot for continuous release of hiunan insulin and of glucagons-like peptide-1 (GLP-1). The observation of both reduced initial burst and a constant release of hmnan insulin from ReGel in vitro is due to the domain structure of the gel and to the modification of the association states of insulin by zinc. Animal studies using SD rats were performed to verify the release profile of insuhn from this ABA block copolymer hydrogel. ReGel formrdation maintained insulin release for up to 15 days, which could allow diabetic patients to reduce the number of insulin injections to two per month for basal insulin requirements (31). 

Martins, S. Sarmento, B. Souto, E.B. Ferreira, D.C. Insulin-loaded alginate microspheres for oral delivery—Effect of polysachharide reinforcement on physico-chemical properties and release profile. Carbohydr. Polym. 2007, 69 (4), 725-731. 

FIGURE 6.30 Release profile of insulin-loaded microparticles in response to a glucose stimulus. Source Marek and Peppas [118], figure 7. Reproduced with permission of John Wiley Sons. 

The cross-linking of the hydrogel was identified as an effective parameter to optimize the release profile for an insulin delivery device (Fig. 6.30). 

Due to its hydrophilic nature, dextrans have also been used to conjugate bioactive substances (e.g., dmgs, enzymes, hormones, and antibodies) to prolong circulation lifetimes, increase stability in vivo, or depress antigenicity. For example, dextran nanoparticles have been conjugated with insulin for oral delivery. These nanocarriers can protect insulin from degradation in the gut and modulate release profiles. ... 

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