Review articleNanoformulation strategies for improving intestinal permeability of drugs: A more precise look at permeability assessment methods and pharmacokinetic properties changes
Graphical abstract
Introduction
It is generally assumed that the oral route is the most convenient means of administering medication. It is an easy way for patients to take the drug at home which reduces their medical expenses and improves their quality of life.
The small intestine is the main site of absorption for oral drug delivery due to the high surface area (approximately 400 m2) and numerous transport mechanisms. Prior to reaching the small intestine, drugs must be able to resist the acidic condition in the stomach. As the small intestine is the main organ of digestion, drugs are exposed to numerous enzymes and bile salts in the intestine that can degrade drugs. On the other hand, our body is almost perfectly protected from exogenous compounds by physiological barriers such as the gastrointestinal (GI) barrier. To be accessible to the body, therapeutic agents should diffuse through the mucus layer followed by the submucosal and epithelial cell barriers into the blood or lymphatic circulation [1,2].
It was previously assumed that permeability is an intrinsic property of drug molecules and drug delivery systems had no or little influence on cargo permeability [3]. However, in the past decades, various approaches to improve oral bioavailability of low permeable drugs have been investigated including permeation enhancers, drug conjugation and modification, ion pairing and micro- and nanoparticulate systems [2].
A large number of researches indicated that proper selection of nanosystems and fine tuning of their physicochemical properties allow the enhancement of drug absorption. In addition to protection against enzymatic and acidic degradation in the GI tract and increase intraluminal drug solubility, that are highly desirable, nanovehicles can enhance transport through the GI barrier.
Nanomedicine appears to be an ideal solution to improve intestinal permeability and therefore oral bioavailability of drugs. The most popular nanosystems used for oral drug delivery are including polymeric nanoparticles (PNPs), liposomes, micelles, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions, self-nanoemulsifying drug delivery systems (SNEDDS), nanocrystals, mesoporous silica nanoparticles (MSNs) and dendrimers (Fig. 1). The study of mechanisms involved in permeability and absorption enhancement of compounds by oral nanoparticles has been less explored compared to the considerable attention given to their design.
This paper presents an in-depth review on permeation studies and pharmacokinetics (PK) properties of the recently investigated oral nanomedicine that resulted in intestinal permeability improvement. Most experimental results on changes in rate (reflected by Tmax and Cmax) and extent (reflected by area under plasma concentration-time curve, AUC) of absorption reported in the literature were summarized.
Section snippets
Barriers to oral delivery and transport mechanisms
The mucus layers overlying the epithelium are secreted by goblet cells (Fig. 2). Mucins are the major components of the mucus layers and consist of large glycoproteins with polymeric protein backbone structure assembling into a gel-like layer [4]. It is regarded as a significant barrier for the transport of nanoparticles. The permeability of nanoparticles through the mucosa can be predicted by the Stokes–Einstein equation [5]:
Where P is the permeability, r is the radius of the
In vitro models for estimation of intestinal drug transport and absorption
Ethical and economical considerations have promoted researchers to use in vitro investigations for estimation of intestinal drug transport and absorption. The commonly utilized in vitro models in the early stage of drug discovery as well as novel formulation (nanoformulation) design are parallel artificial membrane permeability assay (PAMPA), phospholipid vesicle-based permeation assay (PVPA), Permeapad®, Caco-2, organ-on-a-chip and tissue-based permeation models (Fig. 3).
Cell-free biomimetic
Polymeric nanoparticles (PNPs)
PNPs have been extensively studied for peroral drug delivery to enhance drug permeability as well as to improve PK parameters. PNPs have several advantages for oral drug delivery including improving storage stability and minimizing drug degradation, greater drug stability in the GI tract, enhancing drug transport across GI epithelium and controlled drug release properties [45].
Synthetic polyesters such as poly (lactic-co-glycolic acid) (PLGA), poly (lactic acid) (PLA) and poly (Ɛ-caprolactone)
Challenges in nanoformulations marketing and commercialization
It seems that pharmaceutical companies are waiting to see the impact of high number of researches and publications in the nanomedicine field in the nanoformulations market share. Up to now, most nanoproducts in the market are designed for parenteral administration followed by nanoproducts intended for oral administration. Table 10 summarizes oral nanoproducts in the market and their PK parameters. Also oral nanoformulations in the clinical trials were summarized in the Supplementary File
Conclusion and future directions
During the past decades, many efforts have been devoted to the design and characterization of versatile nanocarriers to improve drug oral absorption, and significant progress has been achieved reflected by increasing number of publications. Although oral administration of nanoformulations has a promising potential, there are knowledge gaps about the most efficient type of formulations for permeability enhancement, and a review of current literature in this area is absolutely necessary so that
Author contribution
D.B.: literature searches and review, manuscript writing; M.O. and M.S.D.: literature searches and review, figure design and plotting; S.D.: literature searches and review, manuscript revision; A.H.: literature searches and review, figure design, manuscript writing and revisions.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgements
This work was financially supported by Shahid Beheshti Medical University.
References (246)
- et al.
Micro/nanofabricated platforms for oral drug delivery
J. Control. Release
(2015) - et al.
The developability classification system: application of biopharmaceutics concepts to formulation development
J. Pharm. Sci.
(2010) - et al.
Pharmaceutical nanotechnology for oral delivery of anticancer drugs
Adv. Drug Deliv. Rev.
(2013) - et al.
Targeted nanoparticles with novel non-peptidic ligands for oral delivery
Adv. Drug Deliv. Rev.
(2013) - et al.
Recent advances in chitosan-based nanoparticles for oral delivery of macromolecules
Adv. Drug Deliv. Rev.
(2013) - et al.
Endocytosis of nanomedicines
J. Control. Release
(2010) - et al.
Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier
Adv. Drug Deliv. Rev.
(2016) - et al.
Drug permeability profiling using cell-free permeation tools: Overview and applications
Eur. J. Pharm. Sci.
(2018) - et al.
Mucus-PVPA (mucus Phospholipid Vesicle-based Permeation Assay): An artificial permeability tool for drug screening and formulation development
Int. J. Pharm.
(2018) - et al.
New biomimetic barrier Permeapad for efficient investigation of passive permeability of drugs
Eur. J. Pharm. Sci.
(2015)
In vitro models to evaluate the permeability of poorly soluble drug entities: challenges and perspectives
Eur. J. Pharm. Sci.
Intestinal transport of methylmercury and inorganic mercury in various models of Caco-2 and HT29-MTX cells
Toxicology
Development of PLGA nanoparticles loaded with clofazimine for oral delivery: Assessment of formulation variables and intestinal permeability
Eur. J. Pharm. Sci.
Design and evaluation of solid lipid nanoparticles modified with peptide ligand for oral delivery of protein drugs
Eur. J. Pharm. Biopharm.
Intestinal absorption of insulin nanoparticles: contribution of M cells
Nanomedicine
The interaction of protamine nanocapsules with the intestinal epithelium: A mechanistic approach
J. Control. Release
Establishment of a triple co-culture in vitro cell models to study intestinal absorption of peptide drugs
Eur. J. Pharm. Biopharm.
Towards the characterization of an in vitro triple co-culture intestine cell model for permeability studies
Int. J. Pharm.
Dissecting stromal-epithelial interactions in a 3D in vitro cellularized intestinal model for permeability studies
Biomaterials
Organ/body-on-a-chip based on microfluidic technology for drug discovery
Drug Metab. Pharmacokinet.
Prediction of human absorption of natural compounds by the non-everted rat intestinal sac model
Eur. J. Med. Chem.
Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues
Adv. Drug Deliv. Rev.
Prediction of drug intestinal absorption in human using the Ussing chamber system: A comparison of intestinal tissues from animals and humans
Eur. J. Pharm. Sci.
Controlled release, intestinal transport, and oral bioavailablity of paclitaxel can be considerably increased using suitably tailored pegylated poly(anhydride) nanoparticles
J. Pharm. Sci.
Ex vivo permeation of tamoxifen and its 4-OH metabolite through rat intestine from lecithin/chitosan nanoparticles
Int. J. Pharm.
Pharmacokinetics, tissue distribution and metabolism of senkyunolide I, a major bioactive component in Ligusticum chuanxiong Hort. (Umbelliferae)
J. Ethnopharmacol.
Bioavailability enhancement of zaleplon via proliposomes: role of surface charge
Eur. J. Pharm. Biopharm.
Self-assembled micelles based on N-octyl-N'-phthalyl-O-phosphoryl chitosan derivative as an effective oral carrier of paclitaxel
Carbohydr. Polym.
Enhancing the intestinal absorption of low molecular weight chondroitin sulfate by conjugation with alpha-linolenic acid and the transport mechanism of the conjugates
Int. J. Pharm.
Polymeric nanoparticles: Promising platform for drug delivery
Int. J. Pharm.
Biodegradable polymeric nanoparticles for oral delivery of epirubicin: In vitro, ex vivo, and in vivo investigations
Colloids Surf. B: Biointerfaces
Polymeric nanoparticles for oral delivery of 5-fluorouracil: Formulation optimization, cytotoxicity assay and pre-clinical pharmacokinetics study
Eur. J. Pharm. Sci.
Chitosan nanoconstructs for improved oral delivery of low molecular weight heparin: In vitro and in vivo evaluation
Int. J. Pharm.
Chitosan/o-carboxymethyl chitosan nanoparticles for efficient and safe oral anticancer drug delivery: in vitro and in vivo evaluation
Int. J. Pharm.
Alginate coated chitosan core shell nanoparticles for oral delivery of enoxaparin: in vitro and in vivo assessment
Int. J. Pharm.
Role of nanoparticle size, shape and surface chemistry in oral drug delivery
J. Control. Release
Enhanced bioavailability and intestinal uptake of Gemcitabine HCl loaded PLGA nanoparticles after oral delivery
Eur. J. Pharm. Sci.
Oligoarginine-modified biodegradable nanoparticles improve the intestinal absorption of insulin
Int. J. Pharm.
Preparation, characterization and in vivo pharmacokinetic study of PVP-modified oleanolic acid liposomes
Int. J. Pharm.
Comparative evaluation of proliposomes and self micro-emulsifying drug delivery system for improved oral bioavailability of nisoldipine
Int. J. Pharm.
TPGS-chitosome as an effective oral delivery system for improving the bioavailability of Coenzyme Q10
Eur. J. Pharm. Biopharm.
Improved oral bioavailability of alendronate via the mucoadhesive liposomal delivery system
Eur. J. Pharm. Sci.
Biotinylated liposomes as potential carriers for the oral delivery of insulin
Nanomedicine
Hypoglycemic activity and oral bioavailability of insulin-loaded liposomes containing bile salts in rats: the effect of cholate type, particle size and administered dose
Eur. J. Pharm. Biopharm.
Uptake and transport of insulin across intestinal membrane model using trimethyl chitosan coated insulin niosomes
Mater. Sci. Eng. C Mater. Biol. Appl.
Utilization of chitosan-caged liposomes to push the boundaries of therapeutic delivery
Carbohydr. Polym.
Development and in vitro/in vivo evaluation of controlled release provesicles of a nateglinide-maltodextrin complex
Acta Pharm. Sin. B
Progress of drug-loaded polymeric micelles into clinical studies
J. Control. Release
Mixed micelles self-assembled from block copolymers for drug delivery
Curr. Opin. Colloid Interface Sci.
Goblet cell targeting nanoparticle containing drug-loaded micelle cores for oral delivery of insulin
Int. J. Pharm.
Cited by (60)
Early evaluation of opportunities in oral delivery of PROTACs to overcome their molecular challenges
2024, Drug Discovery TodayOral nanomedicine biointeractions in the gastrointestinal tract in health and disease
2023, Advanced Drug Delivery ReviewsEnabling oral delivery of antiviral drugs: Double emulsion carriers to improve the intestinal absorption of zanamivir
2022, International Journal of PharmaceuticsBilosomes: A controlled delivery system for the sustained release of torularhodin during digestion in the small intestine both in vitro and in vivo
2022, Colloids and Surfaces A: Physicochemical and Engineering Aspects