Elsevier

Drug Discovery Today

Volume 19, Issue 10, October 2014, Pages 1530-1546
Drug Discovery Today

Review
Keynote
Is nanotechnology a boon for oral drug delivery?

https://doi.org/10.1016/j.drudis.2014.04.011Get rights and content

Highlights

  • Oral route is the most convenient and extensively used route of drug administration.

  • Nanotechnology presents promotional benefits in oral drug delivery.

  • Polymers used for oral drug delivery show robust structural characteristics.

  • Polymeric nanocarriers impart stability and controlled release of drugs.

  • Oral drug-delivery-based regulatory aspects and toxicity issues are discussed.

The oral route for drug delivery is regarded as the optimal route for achieving therapeutic benefits owing to increased patient compliance. Despite phenomenal advances in injectable, transdermal, nasal and other routes of administration, the reality is that oral drug delivery remains well ahead of the pack as the preferred delivery route. Nanocarriers can overcome the major challenges associated with this route of administration: mainly poor solubility, stability and biocompatibility of drugs. This review focuses on the potential of various polymeric drug delivery systems in oral administration, their pharmacokinetics, in vitro and in vivo models, toxicity and regulatory aspects.

Introduction

Oral delivery is the most convenient and extensively used route of drug administration. Because oral dosage provides the benefit of effortless administration, most drugs are designed for oral ingestion [1]. The choice of route is driven by patient acceptability, properties of the drug, access to a disease location and effectiveness in dealing with the specific disease. It is by far the most dominant and convenient administration route with good patient compliance, especially in the opinions of patients themselves. Despite these benefits, there are also disadvantages associated with oral administration usually related to immediate release of the drug causing toxicity in practice, low aqueous solubility and low penetration across intestinal membranes [2]. Nevertheless, current knowledge on mechanism of drug absorption, gastrointestinal (GI) transit, microenvironment of GI tract and stability within the GI tract is still incomplete and challengeable [3]. Oral administration is also beset by constraints such as chemical degradation, gastric emptying and intestinal motility. Although convenient from a patient perspective, there has been demand for more-patient-compliant dosage forms.

The GI tract forms barriers to severe physiological factors (e.g. varied enzymatic activities, difference in pH, and specific transport mechanisms), which restrict intestinal drug absorption. Moreover, oral bioavailability of drugs is strongly influenced by solubility and permeability. Drugs are divided into four categories based on their solubility and permeability according to the Biopharmaceutic Classification System [4]. A drug that is administered orally must survive in the harsh environment of the GI tract and should be absorbed. The bioavailability of drugs where dissolution is rate limiting becomes a challenge for effective delivery via the oral route. Hence, protective measures are required to avoid drug destruction on one hand and potentiation of absorption on the other hand in the GI tract. This objective can be accomplished by incorporating the drug into various novel drug delivery systems. A significant number of polymeric nanocarrier systems have emerged, encompassing diverse routes of drug administration, to achieve controlled and targeted drug delivery [5].

Section snippets

Challenges to oral delivery

More than 60% of conventional small molecule drug products available on the market are administered via the oral route. The physiological and anatomical barriers to bioactive absorption via the GI tract are primarily chemical, enzymatic and permeability related (e.g. mucus layer, intestinal epithelium). Poor hydrophilicity and intrinsic dissolution rate are the major factors that affect oral delivery of many existing drugs. Figure 1 compiles all the essential challenging parameters for oral

Polymer-based drug delivery systems addressing the challenges of oral drug delivery

A large number of polymers are available to form various nanocarrier systems and can be categorized into either natural or synthetic polymers. Natural materials used for the nanoparticle formulation include chitosan, dextran, gelatin, alginate and agar (Fig. 3). Poly(lactide) (PLA), poly(glycolide) (PGA), poly(lactide-co-glycolide) (PLGA), poly(cyanoacrylate) (PCA), polyethylenimine (PEI) and polycaprolactone (PCL) are the synthetic polymers that are used in the design of nanocarriers [8].

Polymeric nanoparticles

Nanoparticles are novel carriers that are collectively known as the colloidal drug delivery system. In vitro cytotoxicity of the docetaxel-loaded nanoparticle was evaluated by the cell counting kit (CCK)-8 assay for cancer cells. In vivo pharmacokinetic parameters were measured in male Sprague–Dawley rats, and compared with the current clinical product of docetaxel (i.e. Taxotere®). There was an increase in the Caco-2 cellular uptake with increased nanoparticle concentration. It has been

Micelles

Micelles are molecular aggregates of approximately 20–100 nm formed from surfactants or amphiphilic polymers above their critical micellar concentration (CMC) in colloidal dispersions. The systems contain hydrophobic cores that act as a reservoir for lipophilic drug molecules surrounded by the hydrophilic corona (usually PEG) that provides steric stabilization assuring the integrity of the system in an aqueous environment holding the adequate amount of guest drug molecules [32]. Oral

Microspheres

Polymeric microspheres present a flexible platform for applications in drug delivery, diagnostics and bioseparations and can be administered via different routes. They can be coated with peptides, antigens, antibodies and nucleic acid probes, and can be loaded with hydrophobic bioactives. Microsphere drug delivery systems can be fabricated by techniques including combinations of phase separation or precipitation, spraying methods and emulsion or solvent evaporation. Microspheres of

Dendrimers

Dendritic architecture holds unique physical and chemical properties that make it a potential carrier particularly in the field of drug delivery. Oral delivery of many drugs via plain as well as surface-modified dendrimers has been widely investigated. Poly (amido amine) (PAMAM) dendrimers have shown promise as transepithelial permeability enhancers, intestinal-penetration enhancers, drug solubilizers and drug carriers for oral delivery. It was found that generation size, concentration of

Solid lipid nanoparticles

Lipid nanocarriers have been widely employed for improving the oral bioavailability of various drugs. Solid lipid nanoparticles (SLNs) and self emulsifying drug delivery systems have been extensively beneficial in enhancing oral drug delivery. SLNs are devices made from lipids that are solid at room temperature. Because they are derived from physiologically compatible lipids such as fatty acids (e.g. stearic acid), fatty acid esters (e.g. glyceryl monostearate, glyceryl behenate), triglycerides

Self-emulsifying drug delivery systems

Self-emulsifying drug delivery systems (SEDDS) enhance the oral bioavailability of poorly soluble drugs by maintaining the drug in a dissolved state and enhancing the rate and the extent of drug absorption. They consist of a mixture of oil and surfactant that is capable of forming emulsion (oil-in-water) upon gentle agitation provided by the GI motion. Abdul et al. concluded a glimepiride-containing solid self-nanoemulsifying drug delivery system increases in vitro drug release and therapeutic

Polymeric nanocarriers in oral gene delivery

Currently, numerous biotechnological efforts are being made to attain goals toward oral and/or mucosal gene delivery. The principal benefits offered by oral gene delivery are the ease of target approachability, patient compliance owing to noninvasive delivery and the feasibility of local and systemic gene therapy [67]. In the cases of short hairpin RNA (shRNA) or small interfering RNA (siRNA), denoted RNA interference (RNAi) and DNA vaccine, oral delivery might attract extensive attention owing

Importance of micro- versus nano-particles in oral delivery

Particle size for oral drug delivery is an important factor because it is concerned with their adhesion and interaction with the cell and drug release dynamics. The mechanism enabling the particles to pass through GI barriers includes paracellular passage of the particles (<50 nm), particles endocytosed by intestinal enterocytes (<500 nm) and uptake by M cells of the Peyer's patches (<5 μm) [73]. Studies have shown higher uptake of particles with mean diameters of 50–100 nm in the rat intestine as

Biofate of nanocarriers and release of drug in the GI tract

Nanoparticles can pass through the GI tract by passive and active transport and are rapidly eliminated through feces and urine indicating their absorption across the GI tract barrier and entry into the systemic circulation [75]. Oral delivery leads to exposure to the bacterial population present in the GI tract. Polymeric drug delivery materials are capable of converting into less-complex products via chemical degradation. Alterations in the polymer side groups and destruction of macromolecular

Pharmacokinetics of orally administered nanocarriers

Nanocarrier stability and uptake by enterocytes or M cells depends upon size, composition, surface characteristics and architecture. Nanocarriers made up of water-soluble polymers that form stable carriers are absorbed as particles, whereas polymers forming less-stable particles like polyelectrolyte complexes (e.g. chitosan) or polymeric micelles partly dissociate and are not completely absorbed as a particle. Absorption of the polymer depends upon its physicochemical characteristics (e.g. its

In vitro, in vivo and ex vivo techniques or models for the study of oral delivery of polymeric nanocarriers

In vitro techniques are useful in interpretation of the ability of the nanocarrier system to overcome the barriers in the GI tract in the in vivo environment. Models such as simulated gastric fluids and membrane analysis can be used to correlate the in vivo environment without the use of human cell lines. Because the GI tract presents a unique microenvironment of enzymes and ionic strength it affects the chemical and colloidal stability of the nanocarrier. Simulated gastric (pH 1.2) and

Toxicity issues

Local toxicity associated with oral delivery of chemotherapeutics is a matter of concern so that potent compounds can be delivered orally without causing damage to the gut epithelium. Toxicity studies are vital to establish the potential of nanocarriers [91]. Further studies are needed to determine the physicochemical and molecular properties as well as biodistribution of nanoparticles. Despite the research in recent years in nanotoxicology, precise information about the behavior and

Regulatory aspects

The main governmental body that is entitled to regulate nanocarriers through the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH) is the FDA [95]. In 1996, the National Nanotechnology Initiative (NNI), a federal research and development program, was established to coordinate governmental multiagency efforts in nanoscale science, engineering and technology [75]. There are

Concluding remarks and future prospects

The increasing relevance of the potential of various nanocarriers in drug delivery emphasizes the need to explore the routes by which they can be administered. Theoretically, nanocarriers should be able to overcome several of the possible problems relating to the solubilization and bioavailability of drugs. From the vast amount of knowledge about developments and advancements on the GI barriers for therapeutic macromolecules and nanotechnology over the past few decades, it is now essential to

Conflicts of interest

The authors have no conflicts of interest to declare.

Acknowledgements

Udita Agrawal and Rajeev Sharma are grateful to the Council of Scientific and Industrial Research (CSIR) New Delhi grant no. 09/150/(0109)/2012/EMR-I dated 17/02/2012 and Indian Council of Medical Research (ICMR) India grant no. 45/11/2012/-Nan/BMS, respectively, for financial support in the form of Senior Research Fellowship.

Glossary

Controlled release
Includes any drug delivery system from which the drug is delivered at a predetermined rate over a prolonged period of time.
Dendrimer
Dendrimers are highly branched symmetrical macromolecules of nanosized dimensions, have well-defined molecular mass and geometry consisting of a central core, repeating units and terminal functional groups.
Micelles
Micelles are nanoscopic aggregates of colloidal dimensions (i.e. association of colloids) formed reversibly from amphiphile molecules.

Udita Agrawal is pursuing her PhD as senior research fellow under the supervision of Prof. S.P. Vyas at Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr H.S. Gour University, Sagar (MP) India. She has received various awards in the field of drug delivery for her outstanding innovative research work. She is currently working on targeted drug delivery and nanobiotechnology.

References (114)

  • S. Feng

    Poly(lactide)–vitamins E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel

    Biomaterials

    (2009)
  • Y.V.R. Prasad

    Enhanced intestinal absorption of vancomycin with labrasol and d-alphatocopheryl PEG 1000 succinate in rats

    Int. J. Pharm.

    (2003)
  • N.K. Swarnakar

    Oral bioavailability, therapeutic efficacy and reactive oxygen species scavenging properties of coenzyme Q10-loaded polymeric nanoparticles

    Biomaterials

    (2011)
  • Z.M. Wu

    HP55-coated capsule containing PLGA/RS nanoparticles for oral delivery of insulin

    Int. J. Pharm.

    (2012)
  • S. Hao

    Rapid preparation of pH-sensitive polymeric nanoparticle with high loading capacity using electrospray for oral drug delivery

    Mat. Sci. Eng. C: Mater. Biol. Appl.

    (2013)
  • H. Yu

    Supersaturated polymeric micelles for oral cyclosporine A delivery

    Eur. J. Pharm. Biopharm.

    (2013)
  • W. Du

    Transferrin receptor specific nanocarriers conjugated with functional 7 peptide for oral drug delivery

    Biomaterials

    (2013)
  • G. Gaucher

    Polymeric micelles for oral drug delivery

    Eur. J. Pharm. Biopharm.

    (2010)
  • F. Mathot

    Intestinal uptake and biodistribution of novel polymeric micelles after oral administration

    J. Control. Release

    (2006)
  • M. Sadoqi

    Investigation of the micellar properties of the tocopheryl polyethylene glycol succinate surfactants TPGS 400 and TPGS 1000 by steady state fluorometry

    J. Colloid. Interface Sci.

    (2009)
  • H.J. Yao

    The antitumor efficacy of functional paclitaxel nanomicelles in treating resistant breast cancers by oral delivery

    Biomaterials

    (2011)
  • N. Li

    The use of polyion complex micelles to enhance the oral delivery of salmon calcitonin and transport mechanism across the intestinal epithelial barrier

    Biomaterials

    (2012)
  • X. Huang

    Micelles/sodium-alginate composite gel beads: a new matrix for oral drug delivery of indomethacin

    Carbohyd. Polym.

    (2012)
  • S. Furtado

    Oral delivery of insulin loaded poly(fumaric-co-sebacic) anhydride microspheres

    Int. J. Pharm. Sci.

    (2008)
  • P. He

    Polyester amide: blend microspheres for oral insulin delivery

    Int. J. Pharm.

    (2013)
  • W. Ke

    Enhanced oral bioavailability of doxorubicin in a dendrimer drug delivery system

    J. Pharm. Sci.

    (2008)
  • M. Najlah

    In vitro evaluation of dendrimer prodrugs for oral drug delivery

    Int. J. Pharm. Sci.

    (2007)
  • M. Najlah

    Synthesis, characterization and stability of dendrimer prodrugs

    Int. J. Pharm. Sci.

    (2006)
  • Y. Lin

    Polyamidoamine dendrimers as novel potential absorption enhancers for improving the small intestinal absorption of poorly absorbable drugs in rats

    J. Control. Release

    (2011)
  • S.K. Yandrapu

    Development and optimization of thiolated dendrimer as a viable mucoadhesive excipient for the controlled drug delivery: an acyclovir model formulation

    Nanomed. Nanotechnol. Biol. Med.

    (2013)
  • S. Cohen

    Bioreducible poly(amidoamine)s as carriers for intracellular protein delivery to intestinal cells

    Biomaterials

    (2012)
  • H.M. Teow

    Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier

    Int. J. Pharm.

    (2013)
  • S. Sadekar

    Poly(amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin

    Int. J. Pharm.

    (2013)
  • G. Thiagarajan

    Charge affects the oral toxicity of poly(amidoamine) dendrimers

    Eur. J. Pharm. Biopharm.

    (2013)
  • E. Roger

    Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis

    J. Control. Release

    (2009)
  • A.C. Silva

    Long-term stability, biocompatibility and oral delivery potential of risperidone-loaded solid lipid nanoparticles

    Int. J. Pharm.

    (2012)
  • Z. Zhang

    A self-assembled nanocarrier loading teniposide improves the oral delivery and drug concentration in tumor

    J. Control. Release

    (2013)
  • R.H. Müller

    Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN®) versus drug nanocrystals

    Int. J. Pharm.

    (2006)
  • N. Sermkaew

    Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from crude extract of Andrographis paniculata

    Eur. J. Pharm. Sci.

    (2013)
  • L. Han

    Oral delivery of shRNA and siRNA via multifunctional polymeric nanoparticles for synergistic cancer therapy

    Biomaterials

    (2014)
  • C. He

    Multifunctional polymeric nanoparticles for oral delivery of TNF-α siRNA to macrophages

    Biomaterials

    (2013)
  • K. Bowman

    Gene transfer to hemophilia A mice via oral delivery of FVIII–chitosan nanoparticles

    J. Control. Release

    (2008)
  • H.Y. Nam

    Cellular uptake mechanism and intracellular fate of hydrophobically modified glycol chitosan nanoparticles

    J. Control. Release

    (2009)
  • G. Mittal

    Development and evaluation of polymer nanoparticles for oral delivery of estradiol to rat brain in a model of Alzheimer's pathology

    J. Control. Release

    (2011)
  • Y.H. Lin

    Multi-ion-crosslinked nanoparticles with pH-responsive characteristics for oral delivery of protein drugs

    J. Control. Release

    (2008)
  • D.K. Sahana

    PLGA nanoparticles for oral delivery of hydrophobic drugs: influence of organic solvent on nanoparticle formation and release behavior in vitro and in vivo using estradiol as a model drug

    J. Pharm. Sci.

    (2008)
  • J.L. Italia

    PLGA nanoparticles for oral delivery of cyclosporine: nephrotoxicity and pharmacokinetic studies in comparison to Sandimmune Neoral®

    J. Control. Release

    (2007)
  • S. McClean

    Binding and uptake of biodegradable poly-dl-lactide micro- and nanoparticles in intestinal epithelia

    Eur. J. Pharm. Sci.

    (1998)
  • G.J. Mahler

    Characterization of Caco-2 and HT29-MTX cocultures in an in vitro digestion/cell culture model used to predict iron bioavailability

    J. Nutr. Biochem.

    (2009)
  • E. Gullberg

    Expression of specific markers and particle transport in a new human intestinal M-cell model

    Biochem. Biophys. Res. Commun.

    (2000)
  • Cited by (0)

    Udita Agrawal is pursuing her PhD as senior research fellow under the supervision of Prof. S.P. Vyas at Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr H.S. Gour University, Sagar (MP) India. She has received various awards in the field of drug delivery for her outstanding innovative research work. She is currently working on targeted drug delivery and nanobiotechnology.

    Rajeev Sharma is a senior research fellow in the Department of Pharmaceutical Sciences, Dr Hari Singh Gour Vishwavidyalaya, Sagar, India. He is currently working on targeted drug delivery and immunology.

    Madhu Gupta is working as an assistant professor in the Shri Rawatpura Sarkar Institute of Pharmacy, Datia, India. She is associated with the field of nanotechnology and drug delivery. Her research interests include exploiting bioligands for targeting of bioactives and drug moiety and biopolymers.

    Suresh P. Vyas is a professor in the Department of Pharmaceutical Sciences, Dr Hari Singh Gour Vishwavidyalaya, Sagar, India. He has ∼32 years of teaching and research experience. He is a pioneer scientist in the field of nanobiotechnology and immunology. He has exploited bioligands for targeting bioactives and antigens. He has authored over 310 research publications and 14 reference books. He is a commonwealth postdoctoral fellowship recipient and has worked under fellowship at the School of Pharmacy University of London (UK).

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