ReviewKeynoteIs nanotechnology a boon for oral drug delivery?
Graphical abstract
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.
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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).