Novel drug delivery system: an immense hope for diabetics

Figures & data

Figure 1. Schematic representation of types of DM and their complications.

Table 1. Some antidiabetic drugs in conventional formulations.

S. No.	Drug/formulation	Indication	Trade name	Manufacturer
1	Insulin injections	T1DM and T2DM	Lantus	Sanofi Aventis
			Humulin&Huminsulin	Eli Lilly
			Insugen (Biocon)
			Wosulin (Wockhardt)	Biocon
			Insuman (Sanofi Aventis)	Wockhardt
				Sanofi Aventis
2	Metformin tablets	Gestational& T2DM, Polycystic syndrome	Glucophage	Bristol Myers Squibb
			Riomet	Ranbaxy
			Obimet	Abbott
			Gluformin	AHPL
3	Glimepiride tablets	T2DM	Amaryl	Sanofi Aventis
			Glimy	Shrrishti HC
			Orinase	CCL
			Glimpid	Ranbaxy Lab.
4	Glibenclamide tablets	T2DM	Daonil&Semi-Daonil	Sanofi Aventis
			Euglucon	AHPL
5	Glipizide tablets	T2DM	Glynase	USV
			Glucotrol	Jenburkt
6	Gliclazide tablets	T2DM	Glizid	Panacea
			Glyloc	Cadila
			Reclide	Dr. Reddy’s
7	Rosiglitazone tablets	T2DM	Avandia	Glaxo Smith Kline
8	Miglitol tablets	T2DM	Glyset	Pharmacia and Upjohn Company
9	Repaglinide tablets	T2DM	Prandin	Novo Nordisk INC
10	Acarbose tablets	T2DM	Glucobay	Bayer
			Precose	Genovate
11	Glibenclamide + Metformin tablets	Gestational & T2DM, Polycystic syndrome	Aviglen Forte &Aviglen-MF	Avinash
			BEN-Q-MET	Q Check
			Benclamet	RPG LS
12	Rosiglitazone + Metformin tablets	T2& Gestational DM	Avandamet	Glaxo Smith Kline
13	Rosiglitazone + Glimepiride tablets	T2DM	Avandaryl	Glaxo Smith Kline
14	Liraglutide injection	T2DM	Victoza	Novo Nordisk
15	Exenatide injection	T2DM	Exapride	Sun pharma

Table 2. Novel drug delivery systems for antidiabetics – advantages and limitations.

NDDSs	Antidiabetics	Advantages	Limitations
Microparticles	Insulin	Preserved bioactivity (Silva et al., 2006), Improved proteolytic stability (Bowey et al., 2012), Oral/nasal delivery (Wang et al., 2006; Zhang et al., 2011), Protection from acidic pH of stomach (Leong et al., 2011), Improved bio distribution	• Single method can’t be adapted to core materials all the time • Surface modification may not be uniform • Possibility of termination in therapy is very less if once the particles are administered • Process conditions like change in temperature, pH, solvent addition, and evaporation/agitation may influence the stability of core particles • Clear rapidly when taken by reticuloendothelial cells • Sometime premature drug release may be observed • Release characteristic of surface modified carriers are not always reproducible (Executive Summary; Das et al., 2014)
	Glipizide	Reduced dosing frequency and dose-related side effects and obtained sustain release (Madhusudhan et al., 2010; Maiti et al., 2011)
	Glimepiride	Improved dissolution rate (Ilić et al., 2009)
	Exenatide	Preserved the bio-stability during the preparation process, reduced injection site reactions and transient nausea (Ryan et al., 2013).
Nanoparticles	Insulin	Offered non-invasive way for delivery, encourage self-administration in to the patient (Battaglia et al., 2007, Improved effectiveness even for 22 days (Finotelli et al., 2010), Up to 350% enhancement in bioavailability as compared to insulin solution (Peng et al., 2012), Improved systemic absorption by nasal administration (Zhang et al., 2008), Improved hypoglycaemic effect and permeability (Rekha & Sharma, 2009; Damge et al., 2007), Retained bioactivity (Reis et al., 2007), Targeted to the colon for better absorption (Bayat et al., 2008)	• Particles generally seems as “nuisance dusts” and may exhibit toxic biological effects after an unintended administration through inhalation (Gwinn & Vallyathan, 2006) • Proved to be cost ineffective (Coelho et al., 2010) • Production yield is very less, lesser degree of success • Untoward immunogenic reactions may arise • Inadequate availability of toxicity data • Polyelectrolyte modified particle may disturb the ionic strength of the GI fluid (Executive Summary; Das et al., 2014; Jose et al., 2014; Guo et al., 2014).
	Metformin	Reduced dosing frequency (Cetin et al., 2013)
	Glibenclamide	Improved dissolution rate (Yu et al., 2011)
	Repaglinide	Offered prolonged release and avoided associated side effect (Lekshmi et al., 2010)
Liposomes	Insulin and peptide surrogate	Increased retention-time in lungs and hence reduced extra pulmonary side-effects (Huang & Wang, 2006), Improved proteolytic stability in oral administration (Agrawal et al., 2014), Chemical responsive release (Karathanasis et al., 2006), Sustained release and transmucosal delivery (Jain et al., 2007a)	• Coating may often be non-uniform • Entrapment efficiency is less compared to polymeric carrier systems • Leakage is major cause of instability • Sometime cholesterol which is used for bilayer arrangement, autoxidized and results in to leakage (Agrawal et al., 2014) • Possible allergic reaction due to the presence of lipid (Agrawal et al., 2014; Zhang et al., 2014).
Niosomes	Insulin and peptide drugs	Stabilized against enzymatic degradation in oral (Pardakhty et al., 2007) and vaginal delivery (Ning et al., 2005), Prolonged bioactivity for 6 h (Ning et al., 2005)	• Low entrapment efficiency (Pardakhty et al., 2007) • Instability due to alteration in molecular arrangement of surfactants.
	Metformin	Enhanced bioavailability by oral route and avoidance of associated Lactic acidosis (Hasan et al., 2013)
Gastro retentive granules	Repaglinide	Improved bioavailability (Jain et al., 2007b)	These hydrodynamically balanced systems (HBS) are unreliable in prolonging the gastric retention time (GRT) due to their ‘all-or none’ gastric emptying process and may cause variable bioavailability and local irritation due to the local availability of drug in small area of GIT (Jain et al., 2007b).
Transdermal systems	Glipizide	Avoid the side effects like fatal hypoglycemia and gastric disturbances like nausea, vomiting, heartburn, anorexia i.e. associated with the oral delivery (Mutalik et al., 2006)	• Permeation of the drug may vary in different skin type (Cevc, 2003) • Loss of the drug may be more as compare to oral delivery carriers • Electroporation or iontophoresis may change the skin integrity and cause cell damage (Rastogi et al., 2010b) • Use of penetration enhancers may lead to hypersensitivity over the skin (Rastogi et al., 2010a).
	Insulin	Proved as an ideal alternative to the injectables (Rastogi et al., 2010b), Controlled release for at least 8 h (Rastogi et al., 2010a)
	Glimiperide	Enhanced in vivo hypoglycemic efficacy (Ahmed et al., 2014)
Implant	Insulin	Sustained effect for at least 15 days (Kofuji et al., 2005; Chen et al., 2011)	• Individuals may face discomfort and sometime rejection by body defence mechanism (Coelho et al., 2010) • Requires specific medical expertise for implantation • Usually preferred where long term therapy is required
Nanodiamond	Insulin	Improved systemic availability (Shimkunas et al., 2009)	Chemical mediated desorption is required to bring the drug in active form (Shimkunas et al., 2009).
Microgel beads	Insulin	Sustained release (Nishimura et al., 2012)	–

Figure 2. Pictorial representation of NDDSs used for the delivery of antidiabetics.

Figure 3. A diagrammatical representation of transport mechanism of drugs encapsulated in different NDDSs.

Figure 4. Current trend of antidiabetic drug delivery via NDDSs. A graphical representation of number of published articles on anti-diabetic drugs between January 2005–December 2013.

Table 3. Recent reports on various microparticulate systems for the treatment of diabetes (Year 2005 onward).

Objective	Materials used	Method used	Hypoglycemia	Further remarks	References
1. Insulin
Oral delivery	Poly(fumaric-co-sebacic) anhydride	Phase inversion nanoencapsulation	>14 h	Altered onset, peak and duration of insulin action	Furtado et al. (2008)
Preservation of protein stability	Alginate	Emulsification and internal gelation	2 h	Decreased hyperglycemia, retained bioactivity of insulin	Silva et al. (2006)
Oral delivery	Alginate & chitosan	Membrane emulsification	60 h	Sustained release of bioactive insulin for 60 h	Zhang et al. (2011)
Oral delivery	Chitosan	SPG membrane emulsification	>14 days	Oral delivery of bioactive insulin provided improved bioadhesion, loading and sustained release (>14 days)	Wei et al. (2010)
Improved Stability	Alginate	Spray drying	88% ± 15% bioactivity retained	Spray drying produced bioactive, spherical particles with average diameter 2.1 ± 0.3 μm and EE 38.2% ± 9.5%	Bowey et al. (2012)
Nasal delivery	Aminatedgelatin microspheres (AG)	Emulsion polymerization	>300 min	Insulin release from AGMS was significantly slower than GMS, but there was no difference in the release of model drugs from two microspheres	Wang et al. (2006)
Oral delivery	Chitosan	Emulsion cross-linking	25% for 3–12 h	Efficient oral delivery was done by particles of 29.5μm particles and 71.6 ± 1.3% encapsulation efficiency	Jose et al. (2012)
Protection from GIT environment	Carboxymethylated kappa-carrageenan	Ionic gelation	12–24 h	Insulin release in SGF was found to be 4.2 ± 0.4% during the first 2 h and complete release in SIF in the next 10 h	Leong et al. (2011)
In vivo multi-day release	PLGA	Single o/w emulsion	>9 days	Formulations with drug content of 14% show very low (<1%) initial release of insulin for one day and near zero order drug release after a lag of 3–4 days	Hinds et al. (2005)
Controlled release	Tristearin/phosphatidylcholine/PEG	Supercritical CO2 gas microatomisation	>5 h	Slow release for about 70–80 h was observed according to a diffusive mechanism	Salmaso et al. (2009)
Controlled release	Fe3+ and dextran sulfate	Layer-by-layer deposition	6 h	Improved glucose tolerance i.e. 2 h from free insulin to 12 h from insulin-loaded MPs with 10 bilayers	Zheng et al. (2009)
2. Glibenclamide
Oral delivery	Phospholipon 90G & Softisan 142	Fusion method	>24 h	Higher glucose–lowering effect than that of market formulations	Nnamani et al. (2010)
3. Glimepiride
Oral delivery	Gelucire 50/13, poloxamer 188 and PEG 6000	Spray congealing	Not yet done	Higher dissolution rate was found using Gelucire 50/13 i.e. about 35.6% in 120 min, followed by poloxamer 188 and PEG 6000 with 29.0% and 28.6%, respectively	Ilić et al. (2009)
4. Glipizide
Prolonged Release	Gellan gum	Ionotropic gelation	Not done	Oral delivery, minimizes dosing frequency and dose-related side effects	Maiti et al. (2011)
Oral sustained release	Eudragit (RS 100 & RL 100)	Emulsion solvent evaporation	Up to 12 h	Prolonged hypoglycemic effect i.e. up to 12 h hence better suited for oral sustained delivery	Madhusudhan et al. (2010)
5. Gliclazide
Controlling systemic absorption	Alginate	Ionotropic gelation	>24 h	Maintained optimum blood glucose level and improved patient compliance by enhancing the systemic absorption of gliclazide	Al-Kassas et al. (2007)
Oral sustained drug delivery	Chitosan	Ionic cross-linking	Up to18 h	Antidiabetic effect was seen after 8 h and lasts up to 18 h compared to gliclazide powder (after 4 h) suggesting sustained release	Barakat & Almurshedi (2011)
Oral sustained drug delivery	Poly-E-capro-lactone, Eudragit RS and ethyl cellulose	Solvent evaporation	MRT of drug for up to 12 h	Plasma concentration of gliclazide in PCL-Eudragit RS or ethyl cellulose microparticles was found to be higher than that observed for its solution after oral administration for extended period of time	Barakat et al. (2013)
Oral delivery	Tamarind seed polysaccharide and alginate	Ionotropic gelation	>12 h	Microspheres were found much useful for prolonged action with maintained blood glucose level and enhance patient compliance	Pal & Nayak (2012)
6. Repaglinide
Controlled Release	Eudragit S and Calcium silicate	Emulsion solvent diffusion	Not done	Easily prepared with good buoyancy, high encapsulation efficiency, and sustained drug release over several hours	Jain et al. (2005)
7. Exenatide
Long-effective, sustained delivery, improved glycemic control	PLGA	Premix membrane emulsification technique, emulsion solvent extraction double-emulsion solvent evaporation	Up to 7–30 days	The bio-stability of exenatide in microspheres was preserved during the preparation process and release, hence reduced side effects Exenatide loaded microspheres were proved to have great potential for clinical use. Exenatide microspheres have also shown significant hypoglycemic activity atleast for one month by controlling plasma glucose similar to that of exenatide solution injected twice daily.	(Liu et al., 2010; Ryan et al., 2013; Qi et al., 2013; Xuan et al., 2013)

Figure 5. Reported hypoglycemic effect of insulin fabricated in various NDDSs.

Table 4. Recent reports on different nanoparticulate approaches used for antidiabetics (Year 2005 onward).

Objective	Materials used	Method used	Hypoglycemia	Further remarks	Year Refs.
1. Insulin
Oral peptide delivery	Succinyl and lauryl derivative of chitosan (LSC)	Sodium tripolyphosphate (TPP) cross linking	6 h	Improved release, mucoadhesiveness and permeability	Rekhaand Sharma (2009)
Colon targeting	Chitosan and its quaternized derivatives	Polyelectrolyte complexation	5 h	Better insulin transportation across colon membrane	Bayat et al. (2008)
Sustained release	Poly(alkylcyanoacrylate)	Interfacial polymerization of microemulsion	36 h	Oral delivery by NPs have been achieved along with optimum absorption enhancement	Graf et al. (2009)
Transdermal delivery	DMSO solution	Supercritical antisolvent	–	Release mechanism of insulin was found in accordance with the Fick’s first diffusion law with high permeation rate. Results suggested great potential of TDD system encompassing nanoparticles for the treatment of DM	Zhao et al. (2010)
Improved SC absorption	Poly(isobutylcyanoacrylate)	Anionic in situ polymerization	6 to 72 h	Subcutaneous absorption of entrapped insulin was found significantly better to non-encapsulated insulin	Mesiha et al. (2005)
Permeation enhancement	Trimethyl chitosan (TMC) & its cysteine conjugate	Polyelectrolyte complexation	>8 h	Self-assembled NPs of TMC-Cys and peptides could be an effective and safe carrier for oral delivery as suggested by this study	Yin et al. (2009)
Control insulin release	Poly(lactic-co-glycolic acid) PLGA, PVA	Reverse micelle–solvent evaporation	8 h to 12 h up to 57.4%	NPs are found able to improve the intestinal absorption of insulin	Cui et al. (2006)
Oral delivery	PLGA	Hydrophobic ion pairing	Glycemia reduced to 23.85% for 12 h	Insulin sodium oleate complex loaded PLGA nanoparticles are found to be an effective method for reducing glucose levels as in oral delivery system	Sun et al. (2010)
Sustained delivery	Poly (hydroxyl butyrate-ohydroxy hexanoate)	Solvent evaporation	3 days	5.42% release was found in 8 h and 20% in 31 days, Bioavailability enhanced up to 350% compared to insulin solution	Peng et al. (2012)
Nasal absorption enhancement	PEG-g-chitosan & tripolyphosphate ions	Ionotropic gelation	>5 h	PEG-g-chitosan has improved the systemic absorption of insulin through the nasal mucosa	Zhang et al. (2008)
Pulmonary delivery	Sodium cholate and soya phosphatidyl choline	Reverse micelle-double emulsion	24 h in fasting animals	Improved in vitro and in vivo stability, a pharmacological bioavailability of 24.33% and a relative bioavailability of 22.33% was also observed	Liu et al. (2008a)
Stable peptide delivery	Isovaleric acid, GMS, soy lecithin	Solvent-in-water emulsion–diffusion	Same as insulin alone	Insulin extracted from SLN decreases blood glucose levels quite similar to a conventional insulin suspension and seem to have possibilities as novel system for oral delivery of insulin	Battaglia et al. (2007)
Controlled release	Low-molecular-weight chitosan	Solvent evaporation	>24 h	Burst release for 2 h followed by zero order release along with 95.54% entrapment efficiency was seen	Huang et al. (2009)
Improved oral bioavailability	Alginate, dextran sulfate, oloxamer 188 and chitosan	Ionotropic gelation and polyelectrolyte complexation	40% of glucose level for >24 h	13% oral bioavailability showed a threefold increase in comparison to free insulin	Woitiski et al. (2010)
Sustained action	Chitosan	Ionotropic gelation	>11 h at dose of 100 IU/kg	Pharmacological activity was not observed because of increase in the serum insulin concentration but because of local action of insulin in the intestinal epithelium	Ma et al. (2005)
Oral administration	Poly (-ɛ-caprolactone) & Eudragit RS	Multiple emulsion	>12 h	Hypoglycemia of non-encapsulated insulin was disappeared after 10 h but of encapsulated insulin was seen for >12 h	Damge et al. (2007)
pH sensitive oral delivery	Poly-g-glutamic acid, chitosan	Ionic-gelation	>10 h	Relative bioavailability of insulin was found to be 15.1 ± 0.9%	Sonaje et al. (2009)
Preoral delivery	Dextrans and epichlorohydrin	Emulsion polymerization	>54 h	Burst release was shown initially followed by diffusion controlled first order kinetics with 75–95% release within 48 h	Chalasani et al. (2007)
Trans-nasal delivery	Starch	Cross linking	>6 h	The release rate and higher associated surface could be more amplified when combined with permeation enhancers for making these NPs as an efficient carrier	Jain et al. (2008)
Improved oral bioavailability	Alginate–dextran	Nanoemulsion dispersion followed by triggered in situ gelation	>8 h	Insulin in NPs was found bioactive as demonstrated by in vivo and in vitro bio-assays	Reis et al. (2007)
Magnetic delivery	Fe2O3, sodium alginate, chitosan	Cross linking polymerization	>22 days	50% of the insulin release was found in to water after 800 h of the in-vitro release study	Finotelli et al. (2010)
2. Metformin
Oral sustained release	Eudragit RSPO, Eudragit RSPO and PLGA	Nanoprecipitation	Not done	Sustained release nanoparticles of metformin HCl prepared with reduced dosing frequency and maintained effective plasma concentration which improved patient compliance by reducing the incidence of side-effects	Cetin et al. (2013)
3. Glibenclamide
Stabilization of structure	Polyvinylpyrrolidone and HPMC	Anti-solvent precipitation in high gravity	Not done	Dissolution rate of NPs was found 85% in 5 min as compared to tablets (55% in 5 min) whereas it was found physically stable for >70 days at room temperature	Yu et al. (2011)
4. Glipizide
Sustained release	Poly(D,L-lactic-co-glycolic acid)	Modified emulsification solvent evaporation	In-vivo not done	40% release in 24 h followed by slow release up to 90% within next 48 h, NPs were found stable for 6 months.	Jain & Saraf (2009)
5. Repaglinide
Prolonged drug release	Poly(methylmethacrylate) and PVA	Solvent evaporation	In vivo study is to be done	NPs illustrated prolong drug release and the toxicological studies revealed NPs formulations safe to administer	Lekshmi et al. (2010)
6. Exenatide
Sustained delivery	La-phosphatidylch oline and Pluronic F-68	Layer by layer freeze and drying	24 h	The results demonstrated that the multilayer NPs can be utilized as a delivery vehicle for sustained release of protein-based drugs.	Kim et al. (2013)

Table 5. Vesicular systems developed for antidiabetic drugs.

Objective	Materials used	Method used	Hypoglycemia	Further remarks	Year Refs.
1. Insulin
Liposomes
Pulmonary delivery	Hydrogenated egg phosphatidylcholine (PC) and egg PC	Film shaking & membrane dialyzing	Up to 6 h	Liposome-mediated pulmonary delivery of insulin promoted increase in the drug retention-time of the lungs, reduction in extra pulmonary side-effects which leads to enhanced therapeutic efficacies.	Huang & Wang (2006)
Triggered Release	Phosphatidyletha nolamine & PC	chemical bridges cleavable	20 h	Euglycemic clamp studies verified triggered insulin release from agglomerated vesicles upon application of cysteine	Karathanasis et al. (2006)
Transmucosal delivery	Phosphotidylcholine, cholesterol, bicinchonic acid	Two-step double emulsification	72 h	These mucoadhesive carriers are best alternative for sustained release of insulin by eliminating invasive medication systems.	Jain et al. (2007a)
Enhanced pulmonary delivery	Soya lecithin, cholesterol	Modified reverse phase evaporation	12 h	Intratracheal instillation of insulin-loaded liposomes showed better hypoglycemic effect with blood glucose at its lower level for a longer period of time and showed bioavailability as high as 38.38%.	Bi et al. (2008)
Niosomes
Sustained oral delivery	Polyoxyethylene alkyl ethers	Film hydration	Not done	Niosomes are found able to stabilize insulin against enzymatic degradation and can be a promising candidates for its oral delivery	Pardakhty et al. (2007)
Vaginal delivery	Span 40 and Span 60	Lipid phase evaporation with sonication.	>350 min	This study revealed niosomal delivery of insulin as an active and effective way for vaginal route	Ning et al. (2005)

Table 6. Miscellaneous noteworthy novel carriers for antidiabetics.

Objective	Materials used	Method used	Hypoglycemia	Further remarks	References
1. Insulin
Implantable Systems
Controlled release	Chitosan and sodium hyaluronate	UV-initiated free radical polymerization	-	Subconjunctivally implantable hydrogels have potential for long-term periocular delivery of insulin or other drugs to treat diabetic retinopathy and other retinal diseases.	Misra et al. (2009)
Sustained release gel beads	Chitosan	Chelation with copper ions	15 days	This formulation strategy resulted biocompatible and biodegradable system from which peptide and protein drugs can be encapsulated and targeted.	Kofuji et al. (2005)
Controlled Release	Poly[2-(dimethylamino) ethyl methacrylate	Layer-by-layer	2 weeks	Multilayer film was found to be release enough insulin in vivo in streptocozotin-induced diabetic rats and also found reducing the blood glucose level for a period of 2 weeks.	Chen et al. (2011)
Microgel beads
Sustained Release	Pluronic-LA2-DA macromer	Suspension inverse polymerization	–	Protein stability during encapsulation and after release was confirmed by FTIR, Raman and circular dichroism measurements that revealed the utility of post-fabrication encapsulation technique which is found much unique.	Nishimura et al. (2012)
Nanodiamonds
Improved systemic availability	Nanodiamonds insulin complex	Physical adsorption	–	MTT viability assays and quantitative RT-PCR revealed that bound insulin remains inactive until alkaline-mediated desorption followed by its sorption (insulin in active form).	Shimkunas et al. (2009)
Mesoporous materials
Controlled Release	Folded sheet mesoporous (FSM) silica	Freezing and thawing	–	The smallest pore size of FSM was found suitable for a fast release of insulin while medium-pore FSM with slow release. This shows that the desired release of insulin could be achieved by choosing suitable pore size.	Tozuka et al. (2010)
Transdermal delivery
Transdermal Sustained delivery	PVA, glutaraldehyde	Modulated iontophoresis	8 h	This study revealed the applicability of this system using penetration enhancers in combination for enhancing the flux of molecules such as protein, i.e. insulin to its desired therapeutic levels.	Rastogi et al. (2010a)
Controlled Release	CS and PVA	Cross linking polymerizations	–	In vitro drug release of this system was found in accordance of Fick’s first law of diffusion with high permeation rate (4.421 μg/(cm^2 h)) which suggested it as a promising TDD system for diabetes treatment	Zu et al. (2012)
Transdermal delivery of macromolecules	PEG, e-caprolactone	Electroporation	36 h	Electroporation of polymeric nanoparticles results as an ideal alternative system for injectable administration.	Rastogi et al. (2010b)
2. Glipizide
Transdermal systems
Matrix transdermal systems	PVP/EC and Eudragit RL-100	–	Up to 13% of initial value for 6 weeks	In vivo study revealed its severe hypoglycemic effect in the initial hours and found effective also for long time application. Negligible skin irritation along with better improvement in diabetes is measured compared to oral administration.	Mutalik et al. (2006)
3. Repaglinide
Porous floating granular delivery system
Controlled gastro retentive delivery	HPMC K4M, EC, carbopol 940	Cross-linking polymerizations	–	After formulating relative bioavailability of repaglinide increased 3.8-fold in comparison to that of its marketed capsule with excellent buoyant ability and suitable drug release pattern.	Jain et al. (2007b)

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