Characterization of human insulin microcrystals and their absorption enhancement by protease inhibitors in rat lungs

Park, Sang Ha; Kwon, Jai Hyun; Lim, Sang Yup; Park, Hye Won; Kim, Chan Wha

doi:10.1016/j.ijpharm.2007.03.003

Cited by 22 publications

(9 citation statements)

References 27 publications

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“…The methods used include incubation with tight junction modulators, which lead to an increase in paracellular transport (though this method may perturb lung homeostasis) [82,83], prevention of the degradation by co-administration with a peptidase/ protease inhibitor [84,85], and conjugation of peptide to a ligand of receptor such as transferrin to deliver the conjugate via the receptor-mediated endocytosis pathway [86,87]. However, a peptidase/protease inhibitor and a conjugation technique are not suitable for enhancing the clearance of existing albumin from the alveolar lining fluids.…”

Section: Possible Receptors For Albumin Endocytosis In Alveolar Epithmentioning

confidence: 99%

Receptor-mediated endocytosis of macromolecules and strategy to enhance their transport in alveolar epithelial cells

Takano

Kawami

Aoki

et al. 2014

Expert Opinion on Drug Delivery

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Although the surface area occupied by type II cells in alveoli is much smaller than that covered by type I cells, type II cells may significantly contribute to the endocytosis/transcytosis of macromolecules such as albumin. Identification of the receptors involved in the cellular uptake of each macromolecule is prerequisite for the understanding and regulation of its transport into and across alveolar epithelial cells. Establishment of novel in-vitro culture cell models of type I and type II cells would be a great help for the future advance of this research field.

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Section: Possible Receptors For Albumin Endocytosis In Alveolar Epithmentioning

confidence: 99%

Receptor-mediated endocytosis of macromolecules and strategy to enhance their transport in alveolar epithelial cells

Takano

Kawami

Aoki

et al. 2014

Expert Opinion on Drug Delivery

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“…A microcrystalline form of insulin in a longacting insulin nebulized inhaler formulation has previously been prepared; however, the duration of effect was reported to be less than 10 h, probably due to insulin degradation by proteolytic activities of the lung [8,9]. This degradation effect could be overcome by the use of protease inhibitors; however, application of protease inhibitors is often limited due to their potential toxicities to the lung tissues [10]. Therefore, the protection of protein from degradation or premature clearance should be considered as an alternative.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of controlled release insulin loaded PLGA microcapsules using dry powder inhaler in diabetic rats

Hamishehkar

Emami

Najafabadi

et al. 2010

Biopharm & Drug Disp

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The pulmonary route is an alternative route of administration for the systemic delivery of peptide and proteins with short-half lives. A long-acting formulation of insulin was prepared by encapsulation of protein into respirable, biodegradable microcapsules prepared by an oil in oil emulsification/solvent evaporation method. Insulin-loaded PLGA microcapsules prepared as a dry powder inhaler formulation were administered via the pulmonary route to diabetic rats and serum insulin and glucose concentrations were monitored. Control treatments consisted of respirable spray-dried insulin (RSDI) powder administered by intratracheal insufflation, insulin-loaded PLGA microcapsules and NPH (long-acting) insulin administered by subcutaneous (SC) administration. Pharmacokinetic analysis demonstrated that insulin administered in PLGA microcapsules illustrated a sustained release profile which resulted in a longer mean residence time, 4 and 5 fold longer than those after pulmonary administration of RSDI and SC injection of NPH insulin, respectively. Accordingly, the hypoglycemic profile followed a stable and sustained pattern which remained constant between 10 and 48 h. Results of the in vitro experiments were in good agreement with those of in vivo studies. Bronchoalveolar lavage fluid analysis indicated that microcapsules administration did not increase the activities of lactate dehydrogenase and total protein. However, histological examination of the lung tissue indicated a minor but detectable effect on the normal physiology of the rat lung. These findings suggest that the encapsulation of peptides and proteins into PLGA microcapsules technique could be a promising controlled delivery system for pulmonary administration.

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“…1,2) The lung is naturally permeable to many proteins in the absence of enhancers and has relatively low metabolic enzyme activity. [3][4][5][6][7][8][9] Unlike the nasal cavity, which has approximately 180 cm 2 of surface area, the lung of an adult offers a large surface area, of approximately 100 m 2 , for drug absorption.…”

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confidence: 99%

“…5,6) Crystallization, as a major technological process of drug formulation in the pharmaceutical industry, plays an important role in enhancing the stability and drug release properties of final dosage forms. 1,19) Furthermore, a dry powder aerosol offers the capacity to provide a wide range of single dose per inhalation, low susceptibility to microbial growth, and suitability for both water-soluble and insoluble drugs. [20][21][22] The thin alveolar epithelium of the lung can be an effective target in delivering drugs as aerosols with mass median aerodynamic diameters of less than 5 mm.…”

mentioning

confidence: 99%

“…[20][21][22] The thin alveolar epithelium of the lung can be an effective target in delivering drugs as aerosols with mass median aerodynamic diameters of less than 5 mm. 1,23) Recently, not only was a unique insulin microcrystallization process using a seed zone method developed, but the bioavailability enhancement and long-acting property of the microcrystals with regard to intrapulmonary inhalation were also confirmed. 1,2,5,6) The obtained microcrystals were homogeneous in size (<5 mm almost 90% in volume) with a narrow distribution of sizes, suggesting that preparation of microfine protein crystals suitable for pulmonary application is possible without harsh mechanical processes.…”

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confidence: 99%

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Human Insulin Microcrystals with Lactose Carriers for Pulmonary Delivery

Lim

Park

Shin

et al. 2009

Bioscience, Biotechnology, and Biochemistry

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Dry powder formulations for pulmonary delivery are attractive because many issues of solubility and stability can be minimized. Human insulin microcrystals with lactose carriers were produced for pulmonary delivery. The average particle diameter was 2.3 microm, with a narrow, monodispersed size distribution. The percentages of high molecular weight proteins (%HMWPs), other insulin-related compounds (%OIRCs), and A-21 desamido insulin (%D(es)) were very low throughout the microcrystal preparation process. Administration of the microcrystal powder by intratracheal insufflation significantly reduced the blood glucose levels of Sprague-Dawley rats. The percent minimum reductions of the blood glucose concentration (%MRBG) produced by the insulin microcrystal powder and by an insulin solution reached 40.4% and 33.4% of the initial glucose levels respectively, and their bioavailability relative to subcutaneous injection (F) was 15% and 10% respectively. These results confirm that the insulin microcrystal powder prepared is suitable for pulmonary delivery in an effective dosage form.

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Characterization of human insulin microcrystals and their absorption enhancement by protease inhibitors in rat lungs

Cited by 22 publications

References 27 publications

Receptor-mediated endocytosis of macromolecules and strategy to enhance their transport in alveolar epithelial cells

Receptor-mediated endocytosis of macromolecules and strategy to enhance their transport in alveolar epithelial cells

Pharmacokinetics and pharmacodynamics of controlled release insulin loaded PLGA microcapsules using dry powder inhaler in diabetic rats

Human Insulin Microcrystals with Lactose Carriers for Pulmonary Delivery

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