Elsevier

Journal of Controlled Release

Volume 321, 10 May 2020, Pages 669-709
Journal of Controlled Release

Review article
Nanoformulation strategies for improving intestinal permeability of drugs: A more precise look at permeability assessment methods and pharmacokinetic properties changes

https://doi.org/10.1016/j.jconrel.2020.02.041Get rights and content

Abstract

The therapeutic efficacy of orally administered drugs is often restricted by their inherent limited oral bioavailability. Low water solubility, limited permeability through the intestinal barrier, instability in harsh environment of the gastrointestinal (GI) tract and being substrate of the efflux pumps and the cytochrome P450 (CYP) can impair oral drug bioavailability resulting in erratic and variable plasma drug profile. As more drugs with low membrane permeability are developed, new interest is growing to enhance their intestinal permeability and bioavailability. A wide variety of nanosystems have been developed to improve drug transport and absorption. Sufficient evidence exists to suggest that nanoparticles are able to increase the transepithelial transport of drug molecules. However, key questions remained unanswered. What types of nanoparticles are more efficient? What are preclinical (or clinical) achievements of each type of nanoformulation in terms of pharmacokinetic (PK) parameters? Addressing this issue in this paper, we have reviewed the current literature regarding permeability enhancement, permeability assessment methods and changes in PK parameters following administration of various nanoformulations. Although permeability enhancement by various nanoformulations holds great promise for oral drug delivery, many challenges still need to be addressed before development of more clinically successful nanoproducts.

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]:P=kT6ηπrh

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.

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