Microencapsulated insulin

Elvassore et al. (96) successfully microencapsulated insulin in poly(eth-ylene glycol) (PEG) of various molecular weights and PLA. Particles of a mean size between 400 and 700 nm were formed at 16-22°C and 13 MPa. The insulin retained more than 80% of its native activity in vivo. Release studies on particles containing PEG with a molecular weight <1900 were free of a burst effect and showed a slow constant protein release for 1500 h. Although these PCA-based microencapsulations were successful, high bursts have been reported for some systems [e.g., BSA in PLGA (90)]. 

Lin, S. Y., Ho, L. T., Chiou, H. L., Microencapsulation and controlled release of insulin from polylactic acid microcapsules. Biomater. Med. Devices Artif. Organs. 86, 187, 1985. 

A composition based on diketopiperazine derivatives (3,6-bis (N-fumaryl-N-(n-butyl) amino-2, 5-diketopiperazine) has been investigated as a pulmonary drug delivery system, termed Technospheres (Pharmaceutical Discovery Corp., Elmsford, NY) (Pohl et al. 2000 Steiner et al. 2002). The diketopiperazine derivatives self-assemble into microparticles at low pH with a mean diameter of approximately 2 pm. During self-assembly, diketopiperazine derivatives microencapsulate peptides present in the solution. Insulin incorporated in diketopiperazine derivatives (TI) was administered to five healthy humans by the use of a capsule-based inhaler with a passive powder deagglomeration mechanism. Relative and absolute bioavailability of TI in the first 3 hours (0-180 min) were 26 12% and 15 5%, and for 6 hours (0-360 min) 16 8% and 16 6%, respectively (Steiner et al. 2002). The time to peak action for glucose infusion rates was shorter with both IV (14 6 min) injection and inhalation (39 36 min), as compared to SC administration (163 25 min). This rapid absorption of insulin would be beneficial for diabetic patients who need to rapidly affect their glucose levels. 

Varshosaz, J., H. Sasrai, and R. Alinagari. 2004. Nasal delivery of insulin using chitosan microspheres. J Microencapsul 21 761. 

K. Aiedeh, E. Gianas, I. Orienti, V. Zecchi, Chitosan microcapsules as controlled release systems for insulin, J. Microencapsulation 14 567-576 (1997). 

Transplantation of islets of Langerhans as a means of treating insulin-dependent diabetes mellitus has become an important field of interest [217-219]. However, tissue rejection and relapse of the initial autoimmune process have limited the success of this treatment. Immunoisolation of islets in semipermeable microcapsules has been proposed to prevent their immune destruction [220, 221]. Nevertheless, a pericapsular cellular reaction eventually develops around micro-encapsulated islets, inducing graft failure [222]. Since empty microcapsules elicit a similar reaction [223], the reaction is not related to the presence of islets within the capsule but is, at least partially, caused by the capsule itself. Consequently, microcapsule biocompatibility appears to constitute a major impediment to the successful microencapsulated islet transplantation. 

Yeh, M. K. (2000), The stability of insulin in biodegradable microparticles based on blends of lactide polymers and polyethylene glycol,/. Microencapsul., 17, 743-756. 

Following intramuscular (IM) administration, drugs must cross one or more biological membranes in order to enter the systemic circulation. Intramuscular injection is used mainly for drugs and vaccines that are not absorbed orally, for example, aminoglycosides, insulin, and hepatitis vaccine. The IM route is often used for sustained medication and specialized vehicles, such as aqueous suspensions, oily vehicles, complexes and microencapsulation, which has been developed for slow delivery of drugs by this route. ... 

Fig. 5 shows microencapsulated mice islets intended for intraportal (liver) transplantation to achieve clinical normoglycemia. The islet s p-cells produce insulin in response to a blood glucose stimulus providing a therapeutic alternative to daily insulin injections. The capsule size is optimized to permit oxygen diffusion ... 

Aquiar, M. M. G., Rodrigues, J. M., Cunha, A. S. (2004) Encapsulation of insulin-cyclodextrin complex in PLGA microspheres a new approach to prolonged pulmonary insulin delivery. J. Microencapsul. 21, 553-564. 

Qi R, Pingel M. Gastrointestinal absorption enhancement of insulin by administration of enteric microspheres and SNAC to rats. J Microencapsul 2004 21(l) 37-45. 

Fig. 20. Insulin secretion from microencapsulated islets. 24 h incubation in 50 mg/dL glucose in otMEM. Results reported per islet in syringe, not per islet in capsule (see-text). (Reproduced with permission of Technomic Publishing Co.)...

Choudhari KB, Labhasetwar V, Dorle AK. Liposomes as a carrier for oral administration of insulin effect of formulation factors. J Microencapsul 1994 11 319-325. 

Ilic et al. (2009) used a mixture of acetonitrile and water (80 20, v/v) as the solvent for the extraction of the drug from the microparticles. Then, the drug was quantified by high efficiency liquid chromatography—HPLC. In a study of insulin microencapsulation, the authors proposed that microparticles were initially stirred in a vortex with chloroform, and then insulin was extracted with HCl 0.01 M. After that, the solution was centrifuged and, in the end, insulin was quantified by HPLC (Maschke et al., 2007). 

PEGylated chitosan nanoparticles were shown to enhance insulin absorption to a greater extent compared with non-nanoparticulate forms of chitosan and insulin alone. Chitosan nanoparticles were also found to enhance nasal absorption of insulin in rabbit, regardless of chitosan molecular weight. Recently, Al-Qadi and co-workers reported that intratracheal administration of diy insulin powder microencapsulated in chitosan nanoparticles increased its distribution to the deep lungs, and facilitated release of a biologically active form of insulin to rat blood. Moreover, they observed a more pronounced and prolonged effect compared to non-formulated insulin. ... 

Al-Qadi S, Grenha A, Carrion-Recio D, Seijo B, Remunan-Lopez C. Microencapsulated chitosan nanoparticles for pulmonary protein delivery In vivo evaluation of insulin-loaded formulations. J Control Release. 2012 157(3) 383-90. 

Microencapsulation refers to the formation of a spherical gel around each group of islets, cell cluster or tissue fragment. Microcapsules based on natural or synthetic polymers have been used for the encapsulation of both mammalian and microbial cells as well as various bioactive substances such as enzymes, proteins and drugs. A review of alternative semipermeable microcapsules prepared from oppositely charged water soluble polyelectrolyte pairs has been presented in recent papers. The main advantage of this approach is that cells, or bioactive agents, are isolated from the body by a microporous semipermeable membrane and the encapsulated material is thus protected against the attack of the immune system. In the case of microencapsulated pancreas islets, a suspension of microcapsules is typically introduced in the peritoneal cavity to deliver insulin to the portal circulation. 

Alginic acid from seaweed forms a complex with a multivalent metallic ion and gels. Microencapsulation of islets of Langerhans cells, which produce insulin has already been accomplished and aggregated cells were produced [1,2]. If islet cells suspended in an alginic acid solution are added dropwise to a culture solution that contains a metalhc ion, the metallic ion diffuses into the alginic acid droplets. Furthermore, the ion forms a complex of gel beads in which the islet cells are enclosed. 

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