pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms

Figures & data

Table 1. Categories of pH-responsive hydrogel with example polymers and applications for oral drug delivery.

	Polymers	Polymer type	Delivery site	Model drug and ref.
Anionic	P(MAA-g-EG)	Synthetic	Small intestine	Insulin (Bell & Peppas, 1996; Lowman et al., 1999; Ichikawa & Peppas, 2003), calcitonin (Torres-Lugo et al., 2002; Kamei et al., 2009), IFN-α (Kamei et al., 2009)
	P(IA-co-NVP)	Synthetic	Small intestine	Salmon calcitonin, urokinase, rituximab (Koetting et al., 2016)
	P(MAA-co-NVP)	Synthetic	Small intestine	siRNA (Knipe et al., 2016)
	Alginate-based	Natural	Small intestine and colon	Heparin (Huang et al., 2000), hemoglobin (George & Abraham, 2006), melatonin (Chen et al., 2004a), vaccines (Chen et al., 2004b; Kulkarni et al., 2001), peptides (Edelman et al., 2000), probiotic yeast (Rasmussen et al., 2003), cedroxil (Peppas & Huang, 2004)
	Hyaluronic acid-based	Natural	Small intestine	Insulin (Hurteaux et al., 2005), thrombin (Kim et al., 2002), α-chymotrypsin (Fiorica et al., 2013)
Cationic	Chitosan-based	Natural	Small intestine	Insulin (Li et al., 2016), BSA (Patel & Amiji, 1996; Kamei et al., 2009)
Amphiphilic	P(MAA-g-EG) with PMMA nanoparticles	Synthetic	Colon	Doxorubicin (Schoener et al., 2013)
Degrading  polymers	Dextran-based	Natural	Colon	Hydrocortisone (Lee et al., 2008b), salmon calcitonin (Zhou et al., 2013)
	Gelatin-based	Natural	Small intestine and colon	5-fluorouracil (Anirudhan & Mohan, 2014)
	Carboxymethyl cellulose/poly(acrylic acid) hybrid hydrogels	Synthetic	Small intestine	Insulin (Gao et al., 2014)
	Maleic acid cross linked poly (vinyl alcohol)	Synthetic	Colon	Vitamin B12, salicylic acid (Basak & Adhikari, 2009)
	Azoaromatic crosslinks	Synthetic	Colon	siRNA, DNA (Chang Kang & Bae, 2011; Thambi et al., 2011) camptothecin
	BC-g-P(AA)	Combination of synthetic and natural	Small intestine	Insulin (Ahmad et al., 2016)
	Guar gum-poly(acrylic acid)-(-cyclodextrin) (GG-PAA-CD)	Combination of synthetic and natural	Small intestine and colon	Dexamethasone (Das & Subuddhi, 2015)

Table 2. Categories of pH responsive nanoparticles with example materials and applications for oral drug delivery.

	Materials	Delivery site	Model drug and ref.
Polyanions	Eudragits-based	Colon	Budesonide (Makhlof et al., 2009), Sulfasalazine (Kankala et al., 2015), curcumin-celecoxib (Gugulothu et al., 2014)
		Small intestine	CGP 57813 (Leroux et al., 1995), CGP 70726 (De Jaeghere et al., 2000), RR01 (De Jaeghere et al., 2001), cyclosporine A (CyA) (Dai et al., 2004)
	HPMCP	Small intestine	Insulin (Cui et al., 2007)
Polycations	Chitosan-based	Small intestine	Insulin (Rekha & Sharma, 2009, 2015; Cui et al., 2009)
The mixture of polyanions  and polycations	Chitosan + Eudragit	Small intestine, colon	Insulin (Li et al., 2006, 2007; Jelvehgari et al., 2010; Chen et al., 2016), DNA (Momenzadeh et al., 2015), Psoralidin (Yin et al., 2016), Fluconazole (Rencber et al., 2016), CyA (Dai et al., 2015)
	Chitosan + poly(g-glutamic acid)	Small intestine	Insulin (Sonaje et al., 2010c), Amoxicillin (Chang et al., 2010)
	Chitosan + alginate	Small intestine	Bovine serum albumin (Chen et al., 2004b), Insulin (Mukhopadhyay et al., 2015)
	Chitosan + polyaspartic acid	Small intestine	5-fluorouracil (Zheng et al., 2007)
	Chitosan + poly (L-glutamic acid)	Small intestine	Doxorubicin (Deng et al., 2015)
	Chitosan + HPMCP	in vitro	Hepatitis B surface antigen(HBsAg) (Farhadian et al., 2015), Low-molecular weight heparin (Fan et al., 2016)
Inorganic materials	Nano-PSi + chitosan	Small intestine	GLP-1 co-loaded DPP4 inhibitor [No1]
	Nano-PSi + Eudragit	Small intestine	Fenofibrate (Jia et al., 2011), sorafenib (Wang et al., 2011), GLP-1 (Qu et al., 2012), Griseofulvin (Roine et al., 2015)
	Mesoporous silica nanoparticles (MSN)-based	Small intestine	Sulfasalazine (Lee et al., 2008a), Insulin (Guha et al., 2016)
	Calcium phosphate + chitosan + sodium alginate	Small intestine	Insulin (Verma et al., 2016)
Others	Polyacrylamide-grafted-xanthan gum (PAAm-g-XG)	Colon	Curcumin (Mutalik et al., 2016)

Figure 1. Drug release mechanisms and absorption process of pH-responsive oral delivery hydrogels/nanoparticles/microspheres (Wang & Zhang, 2012; Fox et al., 2015). Drugs release from pH-responsive hydrogels/nanoparticles/microspheres after the materials swelling and/or dissolution at specific pH. Drug molecules can cross the mucosal layer followed by a submucosal and areolar cell barrier where they interact with a plethora of transport pathways including paracellular or transcellular pathway or transcytosis pathway to enter systemic circulation. The paracellular pathway allows diffusion of molecules in the space between epithelial cells and is regulated by tight junctions formed between the cells. The transcellular pathway passes through the apical and basolateral cell membranes as well as the cytoplasm. It is restricted to hydrophobic molecules or molecules that have membrane pumps on the cell surface. The transcytosis pathway is an active transport pathway via receptor-mediated endocytosis and carrier-mediated transport. Transcytosis pathways are found in both epithelial and M cells. Particles on the scale of 1–1000 μm are not taken up by M cells (Kreuter, 1996), while particles of 50–1000 nm are phagocytized by M cells in Peyer’s patches. Only the size of the particles under 500 nm are used for cellular internalization in intestinal delivery to the systemic circulation (Moghimi et al., 2001; Sharpe et al., 2014), while particles <10 nm are cleared by lymph drainage (Moghimi et al., 2001).

Table 3. Examples of relative bioavailability improvement of insulin and CyA after oral administration of different pH-responsive carrier.

Drugs	pH-responsive carriers	Relative bioavailability of insulin or CyA	Research object	Ref.
Insulin	PLGA-HP55 NPs	6.27% vs. SC injection	Diabetic rats	Cui et al. (2007)
	Chitosan NPs	14.9% vs. SC injection^a	Diabetic rats	Pan et al. (2002)
	Chitosan and poly(g-glutamic acid) NPs	15.1% vs. SC injection	Diabetic rats	Sonaje et al. (2009)
	Chitosan and poly(g-glutamic acid) NPs filled in enteric-coated capsules	20.1% vs. SC injection	Diabetic rats	Sonaje et al. (2010a)
	[poly (methacrylic acid-co-vinyl triethoxylsilane)] coated mesoporous silica NPs	70.3%		Guha et al. (2016)
	Vitamin B12 functionalized layer by layer calcium phosphate NPs	26.9% vs. SC injection	Diabetic rats	Verma et al. (2016)
	Chitosan and poly(γ-glutamic acid) conjugated with ethylene glycol tetraacetic acid (γPGA-EGTA) NPs	17.8% vs. SC injection	Diabetic rats	Chuang et al. (2013)
	Bacterial cellulose-g-poly(acrylic acid) (BC-g-P(AA)) hydrogel microparticles	7.45-times vs. oral administration	Diabetic rats	Ahmad et al. (2016)
	Poly(ester amide) blend microspheres	5.9%	Healthy rats	He et al. (2013)
	Carboxymethyl cellulose/poly(acrylic acid) hydrogels	6.6% vs. SC injection	Healthy rabbits	Gao et al. (2014)
CyA	Nanoporous silica (Sylysia 350) and Eudragit® S100 nanomatrix	90.8% vs. Neoral	Rats	Dai et al. (2015)
	Eudragit S100 NPs	162.1% vs. Neoral	Rats	Yang et al. (2009)
	CyA-Eudragit® E100 NPs	94.8% vs. Neoral	Rats	Dai et al. (2004)
	CyA-Eudragit® L100-55 NPs	115.2% vs. Neoral	Rats	Dai et al. (2004)
	CyA-Eudragit® L100 NPs	113.6% vs. Neoral	Rats	Dai et al. (2004)
	CyA-Eudragit® S100 NPs	132.5% vs. Neoral	Rats	Dai et al. (2004)
	CyA-HP50 NPs	82.3% vs. Neoral	Rats	Wang et al. (2004)
	CyA-HP55 NPs	119.6% vs. Neoral	Rats	Wang et al. (2004)
	CyA-chitosan NPs	173% vs. Neoral	Beagle dogs	El-Shabouri (2002)

^aPharmacological bioavailability.

Bell CL, Peppas NA. (1996). Swelling/syneresis phenomena in gel-forming interpolymer complexes. J Biomater Sci Polym Ed 7:671–83

 PubMed Web of Science ®Google Scholar

Lowman AM, Morishita M, Kajita M, et al. (1999). Oral delivery of insulin using pH-responsive complexation gels. J Pharm Sci 88:933–7

 PubMed Web of Science ®Google Scholar

Ichikawa H, Peppas NA. (2003). Novel complexation hydrogels for oral peptide delivery: in vitro evaluation of their cytocompatibility and insulin-transport enhancing effects using caco-2 cell monolayers. J Biomed Mater Res A 67:609–17

 PubMed Web of Science ®Google Scholar

Torres-Lugo M, Garcia M, Record R, Peppas NA. (2002). Physicochemical behavior and cytotoxic effects of p(methacrylic acid-g-ethylene glycol) nanospheres for oral delivery of proteins. J Control Release 80:197–205

 PubMed Web of Science ®Google Scholar

Kamei N, Morishita M, Chiba H, et al. (2009). Complexation hydrogels for intestinal delivery of interferon beta and calcitonin. J Control Release 134:98–102

 PubMed Web of Science ®Google Scholar

Koetting MC, Guido JF, Gupta M, et al. (2016). pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: effects of protein size, crosslinking density, and hydrogel degradation on protein delivery. J Control Release 221:18–25

 PubMed Web of Science ®Google Scholar

Knipe JM, Strong LE, Peppas NA. (2016). Enzyme- and pH-responsive microencapsulated nanogels for oral delivery of siRNA to induce TNF-alpha knockdown in the intestine. Biomacromolecules 17:788–97

 PubMed Web of Science ®Google Scholar

Huang Y, Leobandung W, Foss A, Peppas NA. (2000). Molecular aspects of muco- and bioadhesion: tethered structures and site-specific surfaces. J Control Release 65:63–71

 PubMed Web of Science ®Google Scholar

George M, Abraham TE. (2006). Polyionic hydrocolloids for the intestinal delivery of protein drugs: alginate and chitosan-a review. J Control Release 114:1–14

 PubMed Web of Science ®Google Scholar

Chen L, Tian Z, Du Y. (2004a). Synthesis and pH sensitivity of carboxymethyl chitosan-based polyampholyte hydrogels for protein carrier matrices. Biomaterials 25:3725–32

 PubMed Web of Science ®Google Scholar

Chen SC, Wu YC, Mi FL, et al. (2004b). A novel pH-sensitive hydrogel composed of N,O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery. J Control Release 96:285–300

 PubMed Web of Science ®Google Scholar

Kulkarni AR, Soppimath KS, Aminabhavi TM, Rudzinski WE. (2001). In-vitro release kinetics of cefadroxil-loaded sodium alginate interpenetrating network beads. Eur J Pharm Biopharm 51:127–33

 PubMed Web of Science ®Google Scholar

Edelman ER, Nathan A, Katada M, et al. (2000). Perivascular graft heparin delivery using biodegradable polymer wraps. Biomaterials 21:2279–86

 PubMed Web of Science ®Google Scholar

Rasmussen MR, Snabe T, Pedersen LH. (2003). Numerical modelling of insulin and amyloglucosidase release from swelling Ca-alginate beads. J Control Release 91:395–405

 PubMed Web of Science ®Google Scholar

Peppas NA, Huang Y. (2004). Nanoscale technology of mucoadhesive interactions. Adv Drug Deliv Rev 56:1675–87

 PubMed Web of Science ®Google Scholar

Hurteaux R, Edwards-Levy F, Laurent-Maquin D, Levy MC. (2005). Coating alginate microspheres with a serum albumin-alginate membrane: application to the encapsulation of a peptide. Eur J Pharm Sci 24:187–97

 PubMed Web of Science ®Google Scholar

Kim B, Bowersock T, Griebel P, et al. (2002). Mucosal immune responses following oral immunization with rotavirus antigens encapsulated in alginate microspheres. J Control Release 85:191–202

 PubMed Web of Science ®Google Scholar

Fiorica C, Pitarresi G, Palumbo FS, et al. (2013). A new hyaluronic acid pH sensitive derivative obtained by ATRP for potential oral administration of proteins. Int J Pharm 457:150–7

 PubMed Web of Science ®Google Scholar

Li Z, Li H, Wang C, et al. (2016). Sodium dodecyl sulfate/β-cyclodextrin vesicles embedded in chitosan gel for insulin delivery with pH-selective release. Acta Pharm Sin B 6:344–51

 PubMed Web of Science ®Google Scholar

Patel VR, Amiji MM. (1996). Preparation and characterization of freeze-dried chitosan-poly(ethylene oxide) hydrogels for site-specific antibiotic delivery in the stomach. Pharm Res 13:588–93

 PubMed Web of Science ®Google Scholar

Schoener CA, Hutson HN, Peppas NA. (2013). pH-responsive hydrogels with dispersed hydrophobic nanoparticles for the oral delivery of chemotherapeutics. J Biomed Mater Res A 101:2229–36

 PubMed Web of Science ®Google Scholar

Lee ES, Kim D, Youn YS, et al. (2008b). A virus-mimetic nanogel vehicle. Angew Chem Int Ed Engl 47:2418–21

 PubMed Web of Science ®Google Scholar

Zhou T, Xiao C, Fan J, et al. (2013). A nanogel of on-site tunable pH-response for efficient anticancer drug delivery. Acta Biomater 9:4546–57

 PubMed Web of Science ®Google Scholar

Anirudhan TS, Mohan AM. (2014). Novel pH switchable gelatin based hydrogel for the controlled delivery of the anti cancer drug 5-fluorouracil. Rsc Advances 4:12109–18

 Web of Science ®Google Scholar

Gao X, Cao Y, Song X, et al. (2014). Biodegradable, pH-responsive carboxymethyl cellulose/poly(acrylic acid) hydrogels for oral insulin delivery. Macromol Biosci 14:565–75

 PubMed Web of Science ®Google Scholar

Basak P, Adhikari B. (2009). Poly (vinyl alcohol) hydrogels for pH dependent colon targeted drug delivery. J Mater Sci Mater Med 20 Suppl 1:S137–46

 PubMed Web of Science ®Google Scholar

Chang Kang H, Bae YH. (2011). Co-delivery of small interfering RNA and plasmid DNA using a polymeric vector incorporating endosomolytic oligomeric sulfonamide. Biomaterials 32:4914–24

 PubMed Web of Science ®Google Scholar

Thambi T, Yoon HY, Kim K, et al. (2011). Bioreducible block copolymers based on poly(ethylene glycol) and poly(gamma-benzyl L-glutamate) for intracellular delivery of camptothecin. Bioconjug Chem 22:1924–31

 PubMed Web of Science ®Google Scholar

Ahmad N, Mohd Amin MC, Ismail I, Buang F. (2016). Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles. Expert Opin Drug Deliv 13:621–32

 PubMed Web of Science ®Google Scholar

Das S, Subuddhi U. (2015). pH-Responsive guar gum hydrogels for controlled delivery of dexamethasone to the intestine. Int J Biol Macromol 79:856–63

 PubMed Web of Science ®Google Scholar

Makhlof A, Tozuka Y, Takeuchi H. (2009). pH-Sensitive nanospheres for colon-specific drug delivery in experimentally induced colitis rat model. Eur J Pharm Biopharm 72:1–8

 PubMed Web of Science ®Google Scholar

Kankala RK, Kuthati Y, Sie HW, et al. (2015). Multi-laminated metal hydroxide nanocontainers for oral-specific delivery for bioavailability improvement and treatment of inflammatory paw edema in mice. J Colloid Interface Sci 458:217–28

 PubMed Web of Science ®Google Scholar

Gugulothu D, Kulkarni A, Patravale V, Dandekar P. (2014). pH-sensitive nanoparticles of curcumin-celecoxib combination: evaluating drug synergy in ulcerative colitis model. J Pharm Sci 103:687–96

 PubMed Web of Science ®Google Scholar

Leroux JC, Cozens R, Roesel JL, et al. (1995). Pharmacokinetics of a novel HIV-1 protease inhibitor incorporated into biodegradable or enteric nanoparticles following intravenous and oral administration to mice. J Pharm Sci 84:1387–91

 PubMed Web of Science ®Google Scholar

De Jaeghere F, Allemann E, Kubel F, et al. (2000). Oral bioavailability of a poorly water soluble HIV-1 protease inhibitor incorporated into pH-sensitive particles: effect of the particle size and nutritional state. J Control Release 68:291–8

 PubMed Web of Science ®Google Scholar

De Jaeghere F, Allemann E, Cerny R, et al. (2001). pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs. AAPS PharmSci 3:E8

 Google Scholar

Dai J, Nagai T, Wang X, et al. (2004). pH-sensitive nanoparticles for improving the oral bioavailability of cyclosporine A. Int J Pharm 280:229–40

 PubMed Web of Science ®Google Scholar

Cui FD, Tao AJ, Cun DM, et al. (2007). Preparation of insulin loaded PLGA-Hp55 nanoparticles for oral delivery. J Pharm Sci 96:421–7

 PubMed Web of Science ®Google Scholar

Rekha MR, Sharma CP. (2009). Synthesis and evaluation of lauryl succinyl chitosan particles towards oral insulin delivery and absorption. J Control Release 135:144–51

 PubMed Web of Science ®Google Scholar

Rekha MR, Sharma CP. (2015). Simultaneous effect of thiolation and carboxylation of chitosan particles towards mucoadhesive oral insulin delivery applications: an in vitro and in vivo evaluation. J Biomed Nanotechnol 11:165–76

 PubMed Web of Science ®Google Scholar

Cui F, Qian F, Zhao Z, et al. (2009). Preparation, characterization, and oral delivery of insulin loaded carboxylated chitosan grafted poly(methyl methacrylate) nanoparticles. Biomacromolecules 10:1253–8

 PubMed Web of Science ®Google Scholar

Li MG, Lu WL, Wang JC, et al. (2006). Preparation and characterization of insulin nanoparticles employing chitosan and poly(methylmethacrylate/methylmethacrylic acid) copolymer. J Nanosci Nanotechnol 6:2874–86

 PubMed Web of Science ®Google Scholar

Li MG, Lu WL, Wang JC, et al. (2007). Distribution, transition, adhesion and release of insulin loaded nanoparticles in the gut of rats. Int J Pharm 329:182–91

 PubMed Web of Science ®Google Scholar

Jelvehgari M, Zakeri-Milani P, Siahi-Shadbad MR, et al. (2010). Development of pH-sensitive insulin nanoparticles using eudragit L100-55 and chitosan with different molecular weights. AAPS PharmSciTech 11:1237–42

 PubMed Web of Science ®Google Scholar

Chen S, Guo F, Deng T, et al. (2016). Eudragit S100-coated chitosan nanoparticles co-loading tat for enhanced oral colon absorption of insulin. AAPS PharmSciTech. [Epub ahead of print]. doi: 10.1208/s12249-016-0594-z

 Web of Science ®Google Scholar

Momenzadeh S, Sadeghi A, Vatandoust N, Salehi R. (2015). Evaluation of in vivo transfection efficiency of eudragit coated nanoparticles of chitosan-DNA: a pH-sensitive system prepared for oral DNA delivery. Iran Red Crescent Med J 17:e16761

 PubMed Web of Science ®Google Scholar

Yin J, Xiang C, Song X. (2016). Nanoencapsulation of psoralidin via chitosan and Eudragit S100 for enhancement of oral bioavailability. Int J Pharm 510:203–9

 PubMed Web of Science ®Google Scholar

Rencber S, Karavana SY, Yilmaz FF, et al. (2016). Development, characterization, and in vivo assessment of mucoadhesive nanoparticles containing fluconazole for the local treatment of oral candidiasis. Int J Nanomedicine 11:2641–53

 PubMed Web of Science ®Google Scholar

Dai WB, Guo YL, Zhang H, et al. (2015). Sylysia 350/Eudragit S100 solid nanomatrix as a promising system for oral delivery of cyclosporine A. Int J Pharm 478:718–25

 PubMed Web of Science ®Google Scholar

Sonaje K, Lin KJ, Wey SP, et al. (2010c). Biodistribution, pharmacodynamics and pharmacokinetics of insulin analogues in a rat model: oral delivery using pH-responsive nanoparticles vs. subcutaneous injection. Biomaterials 31:6849–58

 PubMed Web of Science ®Google Scholar

Chang CH, Lin YH, Yeh CL, et al. (2010). Nanoparticles incorporated in pH-sensitive hydrogels as amoxicillin delivery for eradication of helicobacter pylori. Biomacromolecules 11:133–42

 PubMed Web of Science ®Google Scholar

Mukhopadhyay P, Chakraborty S, Bhattacharya S, et al. (2015). pH-sensitive chitosan/alginate core-shell nanoparticles for efficient and safe oral insulin delivery. Int J Biol Macromol 72:640–8

 PubMed Web of Science ®Google Scholar

Zheng Y, Yang W, Wang C, et al. (2007). Nanoparticles based on the complex of chitosan and polyaspartic acid sodium salt: preparation, characterization and the use for 5-fluorouracil delivery. Eur J Pharm Biopharm 67:621–31

 PubMed Web of Science ®Google Scholar

Deng L, Dong H, Dong A, Zhang J. (2015). A strategy for oral chemotherapy via dual pH-sensitive polyelectrolyte complex nanoparticles to achieve gastric survivability, intestinal permeability, hemodynamic stability and intracellular activity. Eur J Pharm Biopharm 97:107–17

 PubMed Web of Science ®Google Scholar

Farhadian A, Dounighi NM, Avadi M. (2015). Enteric trimethyl chitosan nanoparticles containing hepatitis B surface antigen for oral delivery. Hum Vaccin Immunother 11:2811–8

 PubMed Web of Science ®Google Scholar

Fan B, Xing Y, Zheng Y, et al. (2016). pH-responsive thiolated chitosan nanoparticles for oral low-molecular weight heparin delivery: in vitro and in vivo evaluation. Drug Deliv 23:238–47

 PubMed Web of Science ®Google Scholar

Jia Z, Lin P, Xiang Y, et al. (2011). A novel nanomatrix system consisted of colloidal silica and pH-sensitive polymethylacrylate improves the oral bioavailability of fenofibrate. Eur J Pharm Biopharm 79:126–34

 PubMed Web of Science ®Google Scholar

Wang XQ, Fan JM, Liu YO, et al. (2011). Bioavailability and pharmacokinetics of sorafenib suspension, nanoparticles and nanomatrix for oral administration to rat. Int J Pharm 419:339–46

 PubMed Web of Science ®Google Scholar

Qu W, Li Y, Hovgaard L, et al. (2012). A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1. Int J Nanomedicine 7:4983–94

 PubMed Web of Science ®Google Scholar

Roine J, Kaasalainen M, Peurla M, et al. (2015). Controlled dissolution of griseofulvin solid dispersions from electrosprayed enteric polymer micromatrix particles: physicochemical characterization and in vitro evaluation. Mol Pharm 12:2254–64

 PubMed Web of Science ®Google Scholar

Lee CH, Lo LW, Mou CY, Yang CS. (2008a). Synthesis and characterization of positive-charge functionalized mesoporous silica nanoparticles for oral drug delivery of an anti-inflammatory drug. Adv Funct Mater 18:3283–92

 Web of Science ®Google Scholar

Guha A, Biswas N, Bhattacharjee K, et al. (2016). pH responsive cylindrical MSN for oral delivery of insulin- design, fabrication and evaluation. Drug Deliv 23:3552–61

 PubMed Web of Science ®Google Scholar

Verma A, Sharma S, Gupta PK, et al. (2016). Vitamin B12 functionalized layer by layer calcium phosphate nanoparticles: a mucoadhesive and pH responsive carrier for improved oral delivery of insulin. Acta Biomater 31:288–300

 PubMed Web of Science ®Google Scholar

Mutalik S, Suthar NA, Managuli RS, et al. (2016). Development and performance evaluation of novel nanoparticles of a grafted copolymer loaded with curcumin. Int J Biol Macromol 86:709–20

 PubMed Web of Science ®Google Scholar

Wang XQ, Zhang Q. (2012). pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs. Eur J Pharm Biopharm 82:219–29

 PubMed Web of Science ®Google Scholar

Fox CB, Kim J, Le LV, et al. (2015). Micro/nanofabricated platforms for oral drug delivery. J Control Release 219:431–44

 PubMed Web of Science ®Google Scholar

Kreuter J. (1996). Nanoparticles and microparticles for drug and vaccine delivery. J Anat 189 (Pt 3):503–5

 PubMed Web of Science ®Google Scholar

Moghimi SM, Hunter AC, Murray JC. (2001). Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 53:283–318

 PubMed Web of Science ®Google Scholar

Sharpe LA, Daily AM, Horava SD, Peppas NA. (2014). Therapeutic applications of hydrogels in oral drug delivery. Expert Opin Drug Deliv 11:901–15

 PubMed Web of Science ®Google Scholar

Pan Y, Li YJ, Zhao HY, et al. (2002). Bioadhesive polysaccharide in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo. Int J Pharm 249:139–47

 PubMed Web of Science ®Google Scholar

Sonaje K, Lin YH, Juang JH, et al. (2009). In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery. Biomaterials 30:2329–39

 PubMed Web of Science ®Google Scholar

Sonaje K, Chen YJ, Chen HL, et al. (2010a). Enteric-coated capsules filled with freeze-dried chitosan/poly(gamma-glutamic acid) nanoparticles for oral insulin delivery. Biomaterials 31:3384–94

 PubMed Web of Science ®Google Scholar

Chuang EY, Lin KJ, Su FY, et al. (2013). Noninvasive imaging oral absorption of insulin delivered by nanoparticles and its stimulated glucose utilization in controlling postprandial hyperglycemia during OGTT in diabetic rats. J Control Release 172:513–22

 PubMed Web of Science ®Google Scholar

He P, Liu H, Tang Z, et al. (2013). Poly(ester amide) blend microspheres for oral insulin delivery. Int J Pharm 455:259–66

 PubMed Web of Science ®Google Scholar

Yang ZQ, Xu J, Pan P, Zhang XN. (2009). Preparation of an alternative freeze-dried pH-sensitive cyclosporine A loaded nanoparticles formulation and its pharmacokinetic profile in rats. Pharmazie 64:26–31

 PubMed Web of Science ®Google Scholar

Wang XQ, Dai JD, Chen Z, et al. (2004). Bioavailability and pharmacokinetics of cyclosporine A-loaded pH-sensitive nanoparticles for oral administration. J Control Release 97:421–9

 PubMed Web of Science ®Google Scholar

El-Shabouri MH. (2002). Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Int J Pharm 249:101–8

 PubMed Web of Science ®Google Scholar