Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery

Introduction: Oral administration of most therapeutic peptides and proteins is mainly restricted due to the enzymatic and absorption membrane barrier of the GI tract. In order to overcome these barriers, various technologies have been explored. Among them, self-emulsifying drug delivery systems (SEDDS) received considerable attention as potential carriers to facilitate oral peptide and protein delivery in recent years.

Areas covered: This review article intends to summarize physiological barriers which limit the bioavailability of orally administrated peptide and protein drugs. Furthermore, the potential of SEDDS to protect incorporated peptides and proteins towards peptidases and proteases and to penetrate the mucus layer is reviewed. Their permeation-enhancing properties and their ability to release the drug in a controlled way are described. Moreover, this review covers the results of in vivo studies providing evidence for this promising approach.

Expert opinion: As SEDDS can: i) provide a protective effect towards a presystemic metabolism; ii) efficiently permeate the intestinal mucus gel layer in order to reach the absorption membrane; and iii) be produced in a very simple and cost-effective manner, they are a promising tool for oral peptide and protein drug delivery.     

Oral delivery of therapeutic proteins and peptides: a review on recent developments

Abstract

Advent of recombinant technology in protein synthesis has given birth to a new range of biopharmaceuticals. These therapeutic peptides and proteins are now emerging as an imperative part of various treatment protocols especially in the cancer therapeutics. Despite extensive research efforts, oral delivery of therapeutic peptide or protein is still a challenge for pharmaceutical industries and researchers. Number of factors including high proteolytic activity and low pH conditions of gastrointestinal tract act as major barriers in the successful delivery of intact protein/peptide to the targeted site. Low permeability of protein/peptide across the intestinal barrier is also a factor adding to the low bioavailability. Therefore, because of the short circulatory half-life exhibited by peptides in vivo, they need to be administered frequently resulting in increased cost of treatment and low patient compliance. Nano-carrier-based delivery presents an appropriate choice of drug carriers owing to their property to protect proteins from degradation by the low pH conditions in stomach or by the proteolytic enzymes in the gastrointestinal tract. This review focuses on recent aspects and patents on oral delivery of therapeutic proteins and peptides with special emphasis on nano-carrier-based approach.     

Polymeric micelles for oral drug administration enabling locoregional and systemic treatments

Introduction: Amphiphilic block copolymers are recognized components of parenteral drug nanocarriers. However, their performance in oral administration has barely been evaluated to any great extent.

Areas covered: This review provides an overview of the methods used to prepare drug-loaded polymeric micelles and to evaluate their stability in gastrointestinal (GI) fluids, and then analyzes in detail recent in vitro and in vivo results about their performance in oral drug delivery. Oral administration of polymeric micelles has been tested for a variety of therapeutic purposes, namely, to increase apparent drug solubility in the GI fluids and facilitate absorption, to penetrate in pathological regions of the GI tract for locoregional treatment, to carry the drug directly toward the blood stream minimizing presystemic loses, and to target the drug after oral absorption to specific tissue or cells in the body.

Expert opinion: Each therapeutic purpose demands micelles with different performance regarding stability in the GI tract, ability to overcome physiological barriers and drug release patterns. Depending on the block copolymer composition and structure, a wealth of self-assembled micelles with different morphologies and stability can be prepared. Moreover, copolymer unimers can play a role in improving drug absorption through the GI mucosa, either by increasing membrane permeability to the drug and/or the carrier or by inhibiting drug efflux transporters or first-pass metabolism. Therefore, polymeric micelles can be pointed out as versatile vehicles to increase oral bioavailability of drugs that exhibit poor solubility or permeability and may even be an alternative to parenteral carriers when targeting is pursued.     

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

Oral administration is a desirable alternative of parenteral administration due to the convenience and increased compliance to patients, especially for chronic diseases that require frequent administration. The oral drug delivery is a dynamic research field despite the numerous challenges limiting their effective delivery, such as enzyme degradation, hydrolysis and low permeability of intestinal epithelium in the gastrointestinal (GI) tract. pH-Responsive carriers offer excellent potential as oral therapeutic systems due to enhancing the stability of drug delivery in stomach and achieving controlled release in intestines. This review provides a wide perspective on current status of pH-responsive oral drug delivery systems prepared mainly with organic polymers or inorganic materials, including the strategies used to overcome GI barriers, the challenges in their development and future prospects, with focus on technology trends to improve the bioavailability of orally delivered drugs, the mechanisms of drug release from pH-responsive oral formulations, and their application for drug delivery, such as protein and peptide therapeutics, vaccination, inflammatory bowel disease (IBD) and bacterial infections.     

Advances in oral macromolecular drug delivery

Introduction: Various macromolecules including polypeptides, proteins, genes and polysaccharides have been drawing attention for their therapeutic potential. The passage through intestinal epithelium is the major barrier for the oral delivery of macromolecules, by either paracellular or transcellular pathways. However, most macromolecules are poorly absorbed in oral route due to their high molecular weight and low stability in the gastrointestinal (GI) tract. Nonetheless, advancing in oral macromolecular drug delivery will be significant in expanding the clinical use of therapeutic macromolecules.

Areas covered: Technologies using chemical conjugation, absorption enhancers and nano-/micro-particulate systems have been developed to improve oral bioavailability of macromolecules, and some of them are in the process of clinical trials. In this review, they are discussed in the context of their progression states, hurdles and modes of action.

Expert opinion: According to the better understanding of receptor or transporter structure and transport mechanisms in the GI tract, the progress ineffective oral delivery systems for therapeutic macromolecules is anticipated over the next decades. In addition, the advent of numerous particulate systems will also speed up the development of novel drug delivery technologies. This offers an optimistic perspective on the potential clinical usage of oral macromolecular drugs.     

The colon as a possible target for orally administered peptide and protein drugs

Oral administration offers a potential portal to the superficial layers of the gastrointestinal (GI) tract (local delivery) and to the blood and lymphatics (systemic delivery). The harsh hydrolytic environment of the GI tract and the epithelial barriers to absorption, however, pose major challenges to the success of this mode of drug delivery for peptide and protein drugs. One approach to minimizing enzymatic degradation in the GI tract is to target drugs to the apparently less proteolytically active colon. In this review, the evidence supporting the colon as an attractive site for peptide and protein drug delivery will be discussed. The discussion will be confined to specific examples of delivery systems bearing both peptides and proteins that have been tested in the colonic context.     

Intestinal Patches for Oral Drug Delivery

Purpose. Oral route offers an attractive mode of drug administration, although its applications are limited by poor stability of peptides and proteins in the gastrointestinal tract. In this article, we report a novel method based on intestinal patches for oral drug delivery. This method involves the use of millimeter size mucoadhesive patches that adhere to the intestinal wall and direct solute diffusion towards the wall similar to that observed in the case of a transdermal patch. Methods. Intestinal patches were prepared by sandwiching a film of cross-linked bovine serum albumin microspheres between a film of ethyl cellulose and Carbopol/pectin. Delivery of three model drugs, sulforhodamine B, phenol red, and dextran was assessed in vitro using rat intestine. Results. In vitro tests confirmed substantial unidirectional diffusion of model drugs from the patch across the intestinal wall. The presence of ethyl cellulose layer minimized release from the edges as well as from the back side of the patch into the intestinal lumen. In vitro experiments with rat intestine showed that patches were effective in delivering model drugs across the intestine. Trans-lumenal flux of model drugs from intestinal patches was about 100-fold higher compared to that from a solution due to localization of the solute near the intestinal wall and due to minimization of drug loss into the intestinal lumen. Conclusions. Intestinal patches offer a novel approach for oral drug delivery.     

Oral delivery of peptides and proteins using lipid-based drug delivery systems

Introduction: In order to successfully develop lipid-based drug delivery systems (DDS) for oral administration of peptides and proteins, it is important to gain an understanding of the colloid structures formed by these DDS, the mode of peptide and protein incorporation as well as the mechanism by which intestinal absorption of peptides and proteins is promoted.

Areas covered: The present paper reviews the literature on lipid-based DDS, employed for oral delivery of peptides and proteins and highlights the mechanisms by which the different lipid-based carriers are expected to overcome the two most important barriers (extensive enzymatic degradation and poor transmucosal permeability). This paper also gives a clear-cut idea about advantages and drawbacks of using different lipidic colloidal carriers ((micro)emulsions, solid lipid core particles and liposomes) for oral delivery of peptides and proteins.

Expert opinion: Lipid-based DDS are safe and suitable for oral delivery of peptides and proteins. Significant progress has been made in this area with several technologies on clinical trials. However, a better understanding of the mechanism of action in vivo is needed in order to improve the design and development of lipid-based DDS with the desired bioavailability and therapeutic profile.     

Orally active-targeted drug delivery systems for proteins and peptides

Introduction: In the past decade, extensive efforts have been devoted to designing ‘active targeted’ drug delivery systems (ATDDS) to improve oral absorption of proteins and peptides. Such ATDDS enhance cellular internalization and permeability of proteins and peptides via molecular recognition processes such as ligand–receptor or antigen?antibody interaction, and thus enhance drug absorption.

Areas covered: This review focuses on recent advances with orally ATDDS, including ligand–protein conjugates, recombinant ligand–protein fusion proteins and ligand-modified carriers. In addition to traditional intestinal active transport systems of substrates and their corresponding receptors, transporters and carriers, new targets such as intercellular adhesion molecule-1 and β-integrin are also discussed.

Expert opinion: ATDDS can improve oral absorption of proteins and peptides. However, currently, no clinical studies on ATDDS for proteins and peptides are underway, perhaps due to the complexity and limited knowledge of transport mechanisms. Therefore, more research is warranted to optimize ATDDS efficiency.     

Advances in oral delivery of anti-cancer prodrugs

ABSTRACT

Introduction: Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route.

Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed.

Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.     

Oral Delivery of New Heparin Derivatives in Rats

Purpose. In this study, conjugates of heparin and deoxycholic acid were synthesized in order to enhance the heparin absorption in the GI tract. Oral delivery of heparin is a preferred therapy in the treatment of patients who are at high risk of deep vein thrombosis and pulmonary embolism. Methods. Several different kinds of heparin derivatives were synthesized, and their absorption in the GI tract was determined by activated partial thromboplastin time (aPTT) and factor Xa (FXa) assay. Any histological changes caused by heparin derivatives were examined by hematoxylin and eosin (H&E) stain and transmission electron microscopy (TEM). Results. After administering heparin-DOCA orally, the clotting time in aPTT assay was increased with the increase of the coupled DOCA amount. The maximum clotting time of heparin-DOCA was 136±33 sec at 200 mg/kg of oral dose. This value was 7 times higher than the baseline. The absorption of heparin-cholesterol, heparin-palmitic acid, and heparin-lauric acid conjugates in the GI tract was lower than that of heparin-DOCA. Histological examination of the GI tract indicated that heparin derivatives did not cause any damage to the microvilli and the cell layer. Conclusions. DOCA coupled with heparin greatly enhanced absorption of heparin in the GI tract, and this enhancing effect was induced without changing the tissue structure of the GI wall.     

Enhanced oral bioavailability of insulin using PLGA nanoparticles co-modified with cell-penetrating peptides and Engrailed secretion peptide (Sec)

Abstract

Biodegradable polymer nanoparticle drug carriers are an attractive strategy for oral delivery of peptide and protein drugs. However, their ability to cross the intestinal epithelium membrane is largely limited. Therefore, in the present study, cell-penetrating peptides (R8, Tat, penetratin) and a secretion peptide (Sec) with N-terminal stearylation were introduced to modify nanoparticles (NPs) on the surface to improve oral bioavailability of peptide and protein drugs. In vitro studies conducted in Caco-2 cells showed the value of the apparent permeability coefficient (P_app) of the nanoparticles co-modified with Sec and penetratin (Sec-Pen-NPs) was about two-times greater than that of the nanoparticles modified with only penetratin (Pen-NPs), while the increase of transcellular transport of nanoparticles modified together with Sec and R8 (Sec-R8-NPs), or Sec and Tat (Sec-Tat-NPs), was not significant compared with nanoparticles modified with only R8 (R8-NPs) or Tat (Tat-NPs). Using insulin as the model drug, in vivo studies performed on rats indicated that compared to Pen-NPs, the relative bioavailability of insulin for Sec-Pen-NPs was 1.71-times increased after ileal segments administration, and stronger hypoglycemic effects was also observed. Therefore, the nanoparticles co-modified with penetratin and Sec could act as attractive carriers for oral delivery of insulin.     

蛋白质和多肽类药物口服给药研究进展

蛋白质和多肽类药物具有良好的选择性和生物活性,已成为治疗众多疾病的首选药物。由于胃肠道内酶的降解作用以及肠道粘膜的低通透性,蛋白质和多肽类药物口服生物利用度极低,其常规给药一直以注射为主。为了使蛋白质和多肽类药物能够广泛应用于临床,研究人员对蛋白质和多肽类药物口服给药系统做了大量研究。目前用于提高蛋白质和多肽类药物口服生物利用度的方法主要有微粒给药系统、内源性细胞转运系统、应用酶抑制剂和黏附给药系统等。文章就这些方法在蛋白质和多肽类药物口服给药中的应用进行了综述。     

Simultaneous In Vivo Visualization and Localization of Solid Oral Dosage Forms in the Rat Gastrointestinal Tract by Magnetic Resonance Imaging (MRI)

Purpose. Bioavailability of orally administered drugs is much influenced by the behavior, performance and fate of the dosage form within the gastrointestinal (GI) tract. Therefore, MRI in vivo methods that allow for the simultaneous visualization of solid oral dosage forms and anatomical structures of the GI tract have been investigated. Methods. Oral contrast agents containing Gd-DTPA were used to depict the lumen of the digestive organs. Solid oral dosage forms were visualized in a rat model by a ¹H-MRI double contrast technique (magnetite-labelled microtablets) and a combination of ¹H- and ¹⁹F-MRI (fluorine-labelled minicapsules). Results. Simultaneous visualization of solid oral dosage forms and the GI environment in the rat was possible using MRI. Microtablets could reproducibly be monitored in the rat stomach and in the intestines using a ¹H-MRI double contrast technique. Fluorine-labelled minicapsules were detectable in the rat stomach by a combination of ¹H- and ¹⁹F-MRI in vivo. Conclusions. The in vivo ¹H-MRI double contrast technique described allows solid oral dosage forms in the rat GI tract to be depicted. Solid dosage forms can easily be labelled by incorporating trace amounts of non-toxic iron oxide (magnetite) particles. ¹H-MRI is a promising tool for observing such pharmaceutical dosage forms in humans. Combined ¹H- and ¹⁹F-MRI offer a means of unambiguously localizing solid oral dosage forms in more distal parts of the GI tract. Studies correlating MRI examinations with drug plasma levels could provide valuable information for the development of pharmaceutical dosage forms.     

Strategies and industrial perspectives to improve oral absorption of biological macromolecules

Introduction: Therapeutic proteins have become a highly attractive drug of choice due to minimal toxicity, high activity and exquisite specificity. Oral delivery of protein drugs is a very interesting area for research, and, naturally, numerous technologies are required to improve the oral bioavailability of therapeutic proteins.

Areas covered: This review article systemically generalized the major physiological barriers facing oral macromolecule delivery as well as the current approaches and novel developments in the field, including permeation enhancers, enzyme inhibitors, particulate drug delivery system, ligand delivery system, mucoadhesive delivery system, mucus penetration delivery system and other strategies.

Expert opinion: The development of composite formulation methods need to meet regulatory requirements for reproducibility, manufacturing cost, and bioavailability. So far, oral delivery of protein and peptide drugs is still facing immense challenges despite of the fact that some clinical studies are undergoing. The most advanced clinical strategies for therapeutic proteins are co-administration of absorption enhancers or protease inhibitors. Besides, rising new technologies in the field also provides a growing opportunity, such as nanotechnology, mucoadhesive and mucus penetration particulate delivery system.     

Polymeric nanoparticle drug delivery technologies for oral delivery applications

Introduction: Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles (NPs) are one technology being developed to enable clinically feasible oral delivery.

Areas covered: This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal (GI) barriers using polymeric NPs will be considered, including mucoadhesive biomaterials and targeting of NPs to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations.

Expert opinion: There have been many approaches used to overcome the transport barriers presented by the GI tract, but most have been limited by low bioavailability. Recent strategies targeting NPs to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and NPs across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric NP technologies and enable the translation of these technologies to clinical practice.     

The role of chitosan on oral delivery of peptide-loaded nanoparticle formulation

Therapeutic peptides are conventionally administered via subcutaneous injection. Chitosan-based nanoparticles are gaining increased attention for their ability to serve as a carrier for oral delivery of peptides and vaccination. They offered superior biocompatibiltiy, controlled drug release profile and facilitated gastrointestinal (GI) absorption. The encapsulated peptides can withstand enzymatic degradation and various pH. Chitosan-based nanoparticles can also be modified by ligand conjugation to the surface of nanoparticle for transcellular absorption and specific-targeted delivery of macromolecules to the tissue of interest. Current research suggests that chitosan-based nanoparticles can deliver therapeutic peptide for the treatment of several medical conditions such as diabetes, bacterial infection and cancer. This review summarises the role of chitosan in oral nanoparticle delivery and identifies the clinical application of peptide-loaded chitosan-based nanoparticles.     

Therapeutic applications of hydrogels in oral drug delivery

Introduction: Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

Areas covered: This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Expert opinion: Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.     

Dependency of Gastrointestinal Toxicity on Release Rate of Tiaprofenic Acid: A Novel Pharmacokinetic-Pharmacodynamic Model

Purpose. To test the hypothesis that modification of release pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) formulations shifts gastrointestinal (GI) toxicity of the drugs from the upper GI region to the distal intestine. Methods. We assessed tiaprofenic acid (TA)-induced upper and lower increased GI permeability (a surrogate marker of toxicity) after administration of 20 mg and 40 mg/kg regular release (powder) and modified release formulations [sustained release (SR) beads and diethyl--cyclo-dextrin (DCD):TA inclusion complex (INC)]. Urinary excretion of oral doses of GI permeability probes sucrose and ⁵¹Cr-EDTA was determined as measures of gastroduodenal and distal intestine, respectively. Pharmacokinetics of TA enantiomers were also studied following administration of a single 20 mg/kg dose of racemic TA as oral SR beads and iv solution. For powder and INC, previously reported pharmacokinetic data were used. Results. Regular powder significantly increased the permeability at the gastroduodenal level. Modified-release formulations, on the other hand, did not cause damage in the gastroduodenum but produced significant increase in the permeability of the lower intestine. Consequently, to assess the pharmacokinetic-pharmacodynamic relationship, a new model was developed in which contribution of toxicity resulted from direct exposure to the drug was considered. Conclusions. Since the observed site of GI damage corresponds to the site of release and absorption of NSAID from the formulation, the possibility of a shift in the site of damage must be considered for the modified release formulations. A parallel evaluation of upper and lower GI toxicity is essential for a complete assessment of NSAID-induced GI damage.     

Solid lipid nanoparticles: an oral bioavailability enhancer vehicle

Introduction: The therapeutic efficacy of perorally administered drugs is often obscured by their poor oral bioavailability (BA) and low metabolic stability in the gastrointestinal tract (GIT). Solid lipid nanoparticles (SLNs) have emerged as potential BA enhancer vehicles for various Class II, III and IV drug molecules.

Area covered: This review examines the recent advancements in SLN technology, with regards to oral drug delivery. The discussion critically examines the effect of various key constituents on SLN absorption and their applications in oral drug delivery. The relationship between the complexity of absorption (and various factors involved during absorption, including particle size), stability and the self-emulsifying ability of the lipids used has been explored.

Expert opinion: The protective effect of SLNs, coupled with their sustained/controlled release properties, prevents drugs/macromolecules from premature degradation and improves their stability in the GIT. An extensive literature survey reveals that direct peroral administration of SLNs improves the BA of drugs by 2- to 25-fold. Overall, the ease of large-scale production, avoidance of organic solvents and improvement of oral BA make SLNs a potential BA enhancer vehicle for various Class II, III and IV drugs.