particle design for stabilization

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  • . . . .sulationconditi. . . .lution ingeted si. . . .l particl

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    Journal of Controlled Release 186 (2014) 1121

    Contents lists available at ScienceDirect

    Journal of Controlled Release

    j ourna l homepage: www.e lsev ie r .com/ locate / jconre l5.8. Polymer-insulin complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185.9. Effect of particle size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195.4. Coated beads with emulsied insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.5. Colloidosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.6. Hydrogel-coated particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.7. Polyelectrolyte complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.3. Comparison between dispersion methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.4. Insulin loading method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

    5. Existing particle designs and their performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145.1. Beads with a single polymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165.2. Beads with blended polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175.3. Coated beads . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Corresponding author at: Chemical Engineering Di5514 5821; fax: +60 3 5514 6207.

    E-mail addresses: lim.hui.peng@monash.edu (H.-P.

    http://dx.doi.org/10.1016/j.jconrel.2014.04.0420168-3659/ 2014 Elsevier B.V. All rights reserved.es and loading of insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.1. Liquidair methods . . . . . . .4.2. Liquidliquid methods . . . . . .Contents

    1. Introduction . . . . . . . . . .2. Design criteria for polymeric encap

    2.1. Formulation and processing2.2. Particle size . . . . . . .2.3. Protection against gastric so2.4. Controlled-release at the tar

    3. Natural biopolymers . . . . . .4. Basic principle for forming hydroge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12of oral insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13the stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13te . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13BiopolymerOral delivery

    design and material formulaReview

    Particle designs for the stabilization and controlled-delivery of proteindrugs by biopolymers: A case study on insulin

    Hui-Peng Lim a, Beng-Ti Tey a,b, Eng-Seng Chan a,b,a Chemical Engineering Discipline, School of Engineering, Monash University, Jalan Lagoon Selatan, Bandar Sunway 46150, Selangor, Malaysiab Multidisciplinary Platform of Advanced Engineering, Monash University, Jalan Lagoon Selatan, Bandar Sunway 46150, Selangor, Malaysia

    a b s t r a c ta r t i c l e i n f o

    Article history:Received 16 January 2014Accepted 23 April 2014Available online 6 May 2014

    Keywords:Protein drugInsulinEncapsulation

    Natural biopolymers have attracted considerable interest for the development of delivery systems for proteindrugs owing to their biocompatibility, non-toxicity, renewability and mild processing conditions. This paperoffers an overview of the current status and future perspectives of particle designs using biopolymers for thestabilization and controlled-delivery of a model protein drug insulin. We rst describe the design criteria forpolymeric encapsulation and subsequently classify the basic principles of particle fabrication as well as theexisting particle designs for oral insulin encapsulation. The performances of these existing particle designs interms of insulin stability and in vitro release behavior in acidic and alkalinemedia, as well as their in vivo perfor-mance are compared and reviewed. This review forms the basis for future works on the optimization of particle

    tion for the development of an improved oral delivery system for protein drugs. 2014 Elsevier B.V. All rights reserved.scipline, School of Engineering, Monash University, Jalan Lagoon Selatan, Bandar Sunway 46150, Selangor, Malaysia. Tel.: +60 3

    Lim), tey.beng.ti@monash.edu (B.-T. Tey), chan.eng.seng@monash.edu (E.-S. Chan).

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    [2023], and lipid-based carriers such as liposomes [2427] and solidlipid nanoparticles (SLN) [28], have been proposed. Insulin-loaded

    A good delivery system should contain biologically active insulinupon the encapsulation process. The native structure of insulin is easily

    12 H.-P. Lim et al. / Journal of Controlled Release 186 (2014) 1121liposomes and SLN were reported to exhibit a hypoglycemic effectwhen orally administered to diabetic rats [24,25]. Nonetheless, theefcacy of the liposomes and SLN was often reduced due to thedegradation of the lipid-based carriers in the GIT [24,25].

    Polymeric encapsulation usinghydrophobic or hydrophilic polymers

    disrupted upon exposure to extreme acidic pH (i.e., pH b 3) [4547],high temperature (i.e., 50 to 80 C) [48], and organic solvents (i.e.,methylene chloride) [49]. The disruption of either level of the hierar-chical structure of insulin can result in insulin degradation, ultimatelyleading to the loss of its blood glucose lowering ability [4,29,50]. There-6. Concluding remarks and future perspectives . . . . . . . . . . . .Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    1. Introduction

    Intensive research investigating the therapeutic potential of proteinsand peptides has introduced a substantial number of protein drugs tothe pharmaceutical industry. For instance, various health-jeopardizingdiseases, such as cancer, infectious diseases, and autoimmune diseases,can now be treated using protein drugs, including aldesleukin, humangrowth hormone, bone morphogenic protein, and others [1]. One ofthe most prominent diseases treated with protein drugs is diabetesmellitus. Diabetes is a hyperglycemia-causing disease that currentlyaffects approximately 382 million people worldwide [2]. Patientsoften have to rely on exogenous insulin to regulate their bloodglucose levels for a healthier life.

    Insulin was rst discovered in the canine pancreas by Banting andBest in 1921 [3]. Throughout the years, insulin has been successfullyisolated from other sources, such as porcine and bovine pancreases.Nevertheless, insulin from animal sources often caused allergic reac-tions in humans. Owing to the advancement of biotechnology, humaninsulin can now be produced in mass quantities through recombinantDNA technology [4]. Today, a variety of insulin formulations [5] withdifferent onsets and durations of action are available on the market tomeet the different needs of diabetes patients.

    Regardless of the formulation type, exogenous insulin is commonlyadministered via subcutaneous injection into the fatty areas of thelower abdomen, thigh, buttocks, and upper arm [6]. A typical diabeticpatient requires more than 60,000 injections throughout his or her life[7]. This route of administration, however, has several drawbacks,such as the inconvenience of multiple injections, occasional hypoglyce-mia due to insulin overdose, a risk of infection at the injection sites, andmost importantly, poor patient compliance with injections [4,8,9].

    Other non-invasive means of insulin delivery, including ocular,vaginal, rectal, buccal or sublingual, oral, and nasal are currently beinginvestigated. Most of the proposed means, however, involve the use ofabsorption enhancers, such as bile salts and surfactants, to overcomethe thick mucosal layers present in the tissues, which may causecomplications if an overdose is administered [1012]. For this reason,oral administration, which has a high level of patient acceptance andprovides a larger area for absorption is a highly desirable alternative.Upon oral administration, a high level of insulin is directly channeledfrom the intestine to the liver and then to the portal blood, mimickingthe endogenous insulin secretion pattern of the -cells of the pancreas[13].

    Nevertheless, the oral delivery of insulin involves uptake of the drugin the gastro-intestinal tract (GIT), which has abundant proteolyticenzymes and varying pH conditions. For instance, the pH in the stomachcan vary from 1 to 5, whereas the pH in the intestine or colon can varyfrom 6.4 to 7.5 [14]. Alternative approaches to deliver insulin effectivelyin the GIT are being investigated. For example, chemical modication ofinsulin molecules [15], co-administration of insulin with absorptionenhancers [16,17] or protease in

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