Challenges In Oral Delivery Research Articles

Polymeric nanoparticles for oral delivery of biopharmaceuticals: an overview

Biopharmaceuticals, cutting-edge medications sourced from living organisms, embody the zenith of therapeutic progress driven by biotechnological breakthroughs. While oral drug delivery is convenient, it proves challenging for biopharmaceuticals due to the complex barriers in the gastrointestinal tract. Their delicate structure and susceptibility to degradation in the gut pose formidable obstacles. This scientific conundrum necessitates innovative solutions to ensure their effectiveness. Pseudomonas aeruginosa's Exotoxin A demonstrates the difficulty in traversing the intestinal epithelium, necessitating innovative strategies. Researchers utilize mucoadhesive, biodegradable polymers like alginate and chitosan to create nanoparticles. These nanoparticles form a protective gel in the stomach's acidic environment, enhancing drug stability and absorption. Chitosan and alginate collaborate in nanoparticle formulations, improving mucosal adhesion and prolonging drug retention. Introducing non-toxic Exotoxin A enhances trans-epithelial transport, validated by in vitro studies on Caco-2 cell monolayers and accumulation in the rat small intestine's lamina propria. Utilizing green fluorescent protein as a model within alginate-chitosan nanoparticles showcases their potential for oral drug delivery. Bacterial toxins play a crucial role in enhancing trans-epithelial transport, endorsing these nanoparticles. This fusion of biotechnology and polymer science offers a promising solution for biopharmaceutical oral delivery challenges, highlighting alginate-chitosan nanoparticles as versatile carriers for transformative drug delivery advancements.

Preparation and evaluation of Oral Thin Film of Eugenol for tooth decay

Preparation and evaluation of Oral Thin Film of Eugenol for tooth decay

Self-Nano Emulsifying Drug Delivery System: A Potential Solution to the Challenges of Oral Delivery of Poorly Water-Soluble Drugs

Lipid-based drug delivery systems (LBDDS) are the most promising technique to formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic performance of hydrophobic drugs and has become an essential approach in drug delivery research. Self-Nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the formulation of drugs with poor aqueous solubility. SNEDDS are isotropic mixtures composed of oils, surfactants, and occasionally cosolvents. The ability of these formulations and methods to produce nanoemulsions or fine oil-in-water (o/w) emulsions after moderate stirring and dilution by water phase along the GI tract. SNEDDS has garnered attention during recent years as it improves oral bioavailability, reduces drug dose, and increases drug protection from unsuitable environment in the gastrointestinal tract. It can solve the problems related to the dissolution and bioavailability of the Biopharmaceutics Classifcation System Class II and IV drugs. This review shortly describes the ambiguity between nanoemulsions and microemulsions, mechanism of self-emulsifications, composition and function of various excipients of SNEDDS. This review discusses characterization of SNEDDS, advantage of SNEEDS over other emulsion, biopharmaceutical aspects, and limitation as well as future views. The SNEDDS is a potential formulation for drug delivery. Owing to its small particle size, large surface area, high encapsulation efficiency, and high drug loading, the SNEDDS can improve the rate and extent of oral absorption by maximizing drug solubility in the intestinal absorption site. Moreover, because of the lipid-based formulation of SNEDDS, it can stimulate and enhance lymphatic transport of drugs to avoid hepatic first-pass metabolism, and thus improve their bioavailability.

Biomimetic and temporal-controlled nanocarriers with ileum transporter targeting for achieving oral administration of chemotherapeutic drugs

BackgroundOral chemotherapy is preferred for patients with cancer owing to its multiple advantages, including convenience, better patient compliance, and improved safety. Nevertheless, various physical barriers exist in this route that hamper the development of oral chemotherapeutic formulations, including destruction of drugs in the gastrointestinal tract (GIT), low permeability in enterocytes, and short residence time in the intestine. To overcome these limitations, it is necessary to design an efficient oral drug delivery system with high efficacy and improved safety.ResultsHerein, we designed novel glycocholic acid (GCA)-functionalized double layer nanoparticles (GCA-NPs), which can act via an endogenous pathway and in a temporally controlled manner in the intestine, to enhance the oral bioavailability of hydrophobic chemotherapeutic drugs such as paclitaxel (PTX). GCA-NPs were composed of quercetin (Qu)-modified liposomes (QL) coated with GCA-chitosan oligosaccharide conjugate (GCOS). The GCA-NPs thus prepared showed prolonged intestinal retention time and good GIT stability due to the presence of chitosan oligosaccharide (COS) and enhanced active transportation via intestinal apical sodium-dependent bile acid transporter (ASBT) due to the presence of GCA. GCA-NPs also efficiently inhibited intestinal P-gp induced by Qu. PTX-loaded GCA-NPs (PTX@GCA-NPs) had a particle size of 84 nm and an entrapment efficiency of 98% with good stability. As a result, the oral bioavailability of PTX was increased 19-fold compared to that of oral Taxol® at the same dose. Oral PTX@GCA-NPs displayed superior antitumor efficacy and better safety than Taxol® when administered intravenously.ConclusionsOur novel drug delivery system showed remarkable efficacy in overcoming multiple limitations and is a promising carrier for oral delivery of multiple drugs, which addresses several challenges in oral delivery in the clinical context.Graphical

Microparticles based on alginate/chitosan/casein three‐dimensional system for oral insulin delivery

In the past, oral insulin has been developed to reduce the suffering of diabetic patients. However, the physiological barriers in gastrointestinal (GI) tract are the major challenges in oral delivery of insulin. In this study, a novel oral delivery system of insulin called NiM (NPs in MPs) has been developed to overcome the GI barriers, which based on a three‐dimensional system of biocompatible chitosan/alginate/casein. Alginate/chitosan nanoparticles (AC‐NPs) were firstly prepared by ionic pre‐gel method and complexation with polyelectrolytes. Then, they were subsequently coated with casein as a protective agent to form NiM, which could keep stability and physiological activity of insulin in gastric tract. The characterization of NiM showed stable hydrodynamic parameters, and the entrapment efficiency of insulin reached 51.1%. In vitro, only 13.5% of insulin was released in the simulated gastric fluid for the first 2 h. But about 57.4% of insulin was slowly released in the simulated intestinal fluid for 10 h. These results indicated that the coating of casein could increase stability of insulin in gastric tract and control release of insulin in intestinal tract. Furthermore, NiM provided a sustained and significant reduction of the blood glucose levels of diabetic mice. Overall, the results demonstrated that our formed NiM may be a promising oral delivery system of insulin for diabetic patients.

Polymer-Lipid Hybrid Systems: Scope of Intravenous-To-Oral Switch in Cancer Chemotherapy

Cancer chemotherapeutic administration by oral route has the potential to create “hospitalization free chemotherapy”. Such a therapeutic approach will improve patient compliance and significantly reduce the cost of treatment. In current clinical practice, chemotherapy is primarily carried out by intravenous injection or infusion and leads to various unwanted effects. Despite the presence of oral delivery challenges like poor aqueous solubility, low permeability, drug stability and substrate for multidrug efflux transporter, cancer chemotherapy delivery through oral administration has gained much attention recently due to having more patient compliance compared to the intravenous mode of administration. In order to address the multifaceted oral drug delivery challenges, a hybrid delivery system is conceptualized to merge the benefits of both polymeric and lipid-based drug carriers. Polymer-lipid hybrid systems have presented various significant benefits as an efficient carrier to facilitate oral drug delivery by surmounting the different associated obstacles. This carrier system has been found suitable to overcome the numerous oral absorption hindrances and facilitate the intravenous-to-oral switch in cancer chemotherapy. In this review, we aimed to discuss the different biopharmaceutic challenges in oral delivery of cancer chemotherapy and how this hybrid system may provide solutions to such challenges.

Gastro-protective protein-silica nanoparticles formulation for oral drug delivery: In vitro release, cytotoxicity and mitochondrial activity

Our contribution aims to provide an efficient solution to one of the major challenges of oral delivery of gastro-sensitive drugs, namely preventing their premature release and degradation in the gastric fluid in order to maximize the absorption in the small intestine. Our results show that a pH-responsive protein, i.e., succinylated β-lactoglobulin (BL), together with the key attributes of mesoporous silica nanoparticles (MSNs), can synergetically reduce the release of the gastro-sensitive drug, omeprazole (OMP), in acidic pH and enhance the dissolution in intestinal pH conditions. Two families of MSNs were synthesized, MCM-48-based and dendritic-type MSNs, and both materials were additionally functionalized with trimethylsilyl groups to produce a hydrophobic surface that can further modulate the interaction of the MSNs with the succinylated protein in the nanoformulation. The methyl-functionalization of the MSNs also impacted on the physical state of the confined OMP and consequently on its release in near neutral pH. Our cytotoxicity screening revealed no particular mitochondrial dysfunction originating from the MSNs. Moreover, upon progressive release of the drug confined into dendritic-type MSNs, the cytotoxicity against tumorigenic and non-tumorigenic cells (Caco-2 and HCEC) was significantly lower in comparison to the drug pre-dissolved in DMSO.

Oral formulation strategies to improve the bioavailability and mitigate the food effect of abiraterone acetate

Abiraterone acetate, marketed as Zytiga®, is an antiandrogen medication used in the treatment of prostate cancer. Abiraterone acetate is a BCS Class IV compound associated with several oral delivery challenges. Its low solubility and high lipophilicity lead to poor oral bioavailability (<10%) and a dramatic positive food effect (5-10-fold). Hence, a large dose of abiraterone acetate (1000mg per day) is prescribed to patients who must fast for at least 1h before and 2h after administration. The recent expiry of Zytiga®s' patent has led to the emergence of publications describing improved oral formulation strategies for abiraterone acetate. This review aims to discuss the characteristics of abiraterone acetate that lead to its unfavorable oral delivery, examine the oral formulation strategies that have been applied, and to describe potential alternative oral formulation strategies that have been used for other BCS Class IV drugs, to determine the most valuable strategies to develop novel and improved alternatives to the current commercial product. Specific emphasis of this review is placed on enabling oral formulation strategies that can improve solubilization and bioavailability, reduce the clinical dose and remove the pharmaceutical food effect to ultimately provide prostate cancer patients with a more efficient formulation with greater patient compliance.

Materials for oral delivery of proteins and peptides

Throughout history, oral administration has been regarded as the most convenient mode of drug delivery, as it requires minimal expertise and invasiveness. Although oral delivery works well for small-molecule drugs, oral delivery of macromolecules (particularly proteins and peptides) has been limited by acidic conditions in the stomach and low permeability across the intestinal epithelium. Accordingly, the large numbers of biologic drugs that have become available in the past 10 years typically require administration by injection or infusion. As such, a renewed emphasis has been placed on the development of novel materials that overcome the physiological challenges of oral delivery for macromolecular agents. This Review provides an overview of physiological barriers to the oral delivery of biologics and highlights the advances made in materials across various length scales, from small molecules to macroscopic devices. This Review also describes the current status of materials for oral delivery of protein and peptide drugs. New materials, beyond those that have already obtained regulatory approval, are needed to improve the bioavailability of orally administered proteins. In this Review, barriers to the oral delivery of protein-based therapies are discussed, along with the current translational landscape and state of the art of materials for oral protein delivery.

Solid lipid matrix mediated nanoarchitectonics for improved oral bioavailability of drugs

ABSTRACTIntroduction: Solid matrix mediated lipid nanoparticle formulations (LNFs) retain some of the best features of ideal drug carriers necessary for improving the oral absorption and bioavailability (BA) of both hydrophilic and hydrophobic drugs. LNFs with solid matrices may be typically categorized into three major types of formulations, viz., solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) and lipid–drug conjugate nanoparticles (LDC-NPs). Solid matrix based LNFs are, potentially, the most appropriate delivery systems for poorly water soluble drugs in need of improved drug solubility, permeability, absorption, or increased oral BA. In addition, LNFs as matrices are able to encapsulate both hydrophobic and hydrophilic drugs in a single matrix based on their excellent ability to form cores and shells. Interestingly, LNFs also act as delivery devices to impart chemical stability to various orally administered drugs.Areas covered: Aim of the review is to forecast the presentation of pharmacokinetic characteristics of solid lipid matrix based nanocarriers which are typically biocompatible, biodegradable and non-toxic carrier systems for efficient oral delivery of various drugs. Efficient delivery is broadly mediated by the fact that lipophilic drugs are readily soluble in lipidic substrates that are capable of permeating across the gut epithelium following oral administration, subsequently delivering the moiety of interest more efficiently across the gut mucosal membrane. This enhances the overall BA of many drugs facing oral delivery challenges by improving their pharmacokinetic profile. This article specifically focuses on the biopharmaceutical and pharmacokinetic aspects of such solid lipid matrix based nanoformulations and possible mechanisms for better drug absorption and improved BA following oral administration. It also briefly reviews methods to access the efficacy of LNFs for improving oral BA of drugs, regulatory aspects and some interesting lipid-derived commercial formulations, with a concluding remark.Expert opinion: LNFs enhance the overall BA of many drugs facing oral delivery challenges by improving their pharmacokinetic profile.

SEDDS for intestinal absorption of insulin: Application of Caco-2 and Caco-2/HT29 co-culture monolayers and intra-jejunal instillation in rats

To face the challenges of oral delivery of peptide and protein (P/P) drugs, self-emulsifying drug delivery systems (SEDDSs) containing monoacyl phosphatidylcholine (MAPC), Labrasol (LAB) and medium-chain (MC) monoglycerides as permeation enhancers (PEs) were evaluated for their effect on intestinal absorption of insulin.In this study, insulin was complexed with phosphatidylcholine (SPC) to form an insulin-SPC complex (ins-SPC) with increased lipophilicity. The following three SEDDSs: MCT(MAPC) (MC triglycerides and MAPC included), MCT(RH40) (MC triglycerides and Kolliphor® RH40 included) and LCT(MAPC) (long-chain triglycerides and MAPC included) were loading with ins-SPC (4% or 8% w/w of SPC). Three SEDDSs generated emulsions with droplet sizes between 50 and 470 nm and with zeta potentials between −5 to −25 mV in a simulated intestinal medium. Mucus-secreting Caco-2/HT29-MTX-E12 co-culture and Caco-2 monolayers were used as in vitro cell transport models to investigate insulin permeability. In comparison to insulin HBSS solution, MCT(MAPC) significantly increased the insulin permeability across co-culture and Caco-2 monolayers (2.0–2.5 × 10–7 cm/s). In an intra-jejunal (i.j.) instillation model in rats, MCT(RH40) significantly decreased the rat blood glucose after 0.5 h by 17.0 ± 2.5% and for MCT(MAPC), it was 23.6 ± 10.6%. Furthermore, a lipase inhibitor orlistat was incorporated into MCT(MAPC) to evaluate the effect of lipid digestion on insulin absorption. Results indicated that the incorporation of orlistat did not significantly alter the in vivo insulin absorption. Overall, the SEDDS MCT(MAPC) composed of natural PEs (MAPC and MC glycerides) and synthetic PE (LAB) significantly increased the intestinal absorption of insulin upon i.j. instillation. Although it is not possible to conclude if a single PE is dominating the intestinal absorption of insulin, MCT(MAPC) seems to have the potential for oral insulin delivery.

Porous Silica-Supported Solid Lipid Particles for Enhanced Solubilization of Poorly Soluble Drugs.

Low dissolution of drugs in the intestinal fluid can limit their effectiveness in oral therapies. Here, a novel porous silica-supported solid lipid system was developed to optimize the oral delivery of drugs with limited aqueous solubility. Using lovastatin (LOV) as the model poorly water-soluble drug, two porous silica-supported solid lipid systems (SSL-A and SSL-S) were fabricated from solid lipid (glyceryl monostearate, GMS) and nanoporous silica particles Aerosil 380 (silica-A) and Syloid 244FP (silica-S) via immersion/solvent evaporation. SSL particles demonstrated significantly higher rate and extent of lipolysis in comparison with the pure solid lipid, depending on the lipid loading levels and the morphology. The highest lipid digestion was observed when silica-S was loaded with 34% (w/w) solid lipid, and differential scanning calorimeter (DSC) analysis confirmed the encapsulation of up to 2% (w/w) non-crystalline LOV in this optimal SSL-S formulation. Drug dissolution under non-digesting intestinal conditions revealed a three- to sixfold increase in dissolution efficiencies when compared to the unformulated drug and a LOV-lipid suspension. Furthermore, the SSL-S provided superior drug solubilization under simulated intestinal digesting condition in comparison with the drug-lipid suspension and drug-loaded silica. Therefore, solid lipid and nanoporous silica provides a synergistic effect on optimizing the solubilization of poorly water-soluble compound and the solid lipid-based porous carrier system provides a promising delivery approach to overcome the oral delivery challenges of poorly water-soluble drugs.

Oral Delivery Challenges and Solutions through the Novel Research

Oral Delivery Challenges and Solutions through the Novel Research

Characterization of particulate drug delivery systems for oral delivery of Peptide and protein drugs.

Oral drug delivery is a preferred route because of good patient compliance. However, most peptide/ protein drugs are delivered via parenteral routes because of the absorption barriers in the gastrointestinal (GI) tract such as enzymatic degradation by proteases and low permeability acrossthe biological membranes. To overcome these barriers, different formulation strategies for oral delivery of biomacromolecules have been proposed, including lipid based formulations and polymer-based particulate drug delivery systems (DDS). The aim of this review is to summarize the existing knowledge about oral delivery of peptide/protein drugs and to provide an overview of formulationand characterization strategies. For a better understanding of the challenges in oral delivery of peptide/protein drugs, the composition of GI fluids and the digestion processes of different kinds of excipients in the GI tract are summarized. Additionally, the paper provides an overview of recent studies on characterization of solid drug carriers for peptide/protein drugs, drug distribution in particles, drug release and stability in simulated GI fluids, as well as the absorption of peptide/protein drugs in cell-based models. The use of biorelevant media when applicable can increase the knowledge about the quality of DDS for oral protein delivery. Hopefully, the knowledge provided in this review will aid the establishment of improved biorelevant models capable of forecasting the performance of particulate DDS for oral peptide/protein delivery.

Challenges in Oral Delivery: Role of P-gp Efflux Pump

Drug molecule has to overcome numerous encounters after oral administration and before it reaches to the site of action. The topmost hindrances to drug after oral administration comprise of degradation by enzymes, corporal fence of the intestinal epithelial membrane, biliary excretion and active efflux back into the lumen of the gastrointestinal tract. Nowadays with hurried advances in drug design technologies, druggable compounds have dramatically been introduced. However, several of these molecules have suffered from low bioavailability upon oral administration due to poor permeation across the gastrointestinal epithelia although they exhibit potential therapeutic effects. This issue of poor membrane permeability is mainly due to the transporter proteins present in the membrane. ATP binding cassette [ABC] super family acts as a carrier mediated active efflux transporter. In this family P-glycoprotein [P- gp], MRP1 and ABCG2 are most known multidrug efflux pumps. Amongst all the three efflux transporters, P-gp is extensively distributed in the human body and has enormous variety of substrates specificity for many drugs. Many therapeutically potential drugs have low bioavailability due to P-gp efflux. Therefore, to overcome multidrug resistance and deprived bioavailability of P-gp substrates, P-gp inhibitors have been discovered. The main aim of this review is to underline challenges in oral drug delivery, specifically focusing on P-gp efflux and contemporary strategies used for P-gp inhibition in drug discovery and formulation development. Keywords: ATP-Binding cassette family, bioavailability, cytochromep450, oral drug delivery, P-gp efflux pump, P-gp inhibitors, transporters.

Opportunities and Challenges for Oral Delivery of Hydrophobic Versus Hydrophilic Peptide and protein-like Drugs Using lipid-based Technologies

Peptide and protein-like drugs are macromolecules currently produced in increasing numbers by the pharmaceutical biotechnology industry. The physicochemical properties of these molecules posebarriers to oral administration. Lipid-based drug-delivery systems have the potential to overcome these barriers and may be utilized to formulate safe, stable and efficacious oral medicines. This review outlines the design of such lipid-based technologies. The mechanisms whereby these formulations enhance the absorption of lipophilic versus hydrophilic peptide and protein-like drugs are discussed. In the case of lipophilic compounds, the advantages of lipid-based drug-delivery systems including increased solubilization, decreased intestinal efflux, decreased intracellular metabolism and possible lymphatic transport are well established as is evident from the success of Neoral and other drug products on the market. In contrast, with respect to hydrophilic compounds, the situation is more complex and, while promising formulation approaches have been studied, issues including reproducibility of response, intersubject variability and duration of response require further optimization before commercially viable products are possible.

Controlled Release Biopolymers for Enhancing the Immune Response

Controlled release of biologically active compounds in the context of drug and vaccine delivery is an important area of research with broad implications in many areas of medicine. In particular, the challenges of oral delivery are of specific interest to reduce the cost and potential health risks related to parenteral administration of pharmaceuticals and vaccine formulations. We discuss the biological activities of two biopolymers, beta-glucans and emulsans, both of which offer significant potential for individual formulations related to drug impact, while in combination offer synergistic opportunities in terms of formulation and delivery. beta-Glucans have been established as potent immunomodulatory and biologically active compounds with application in a wide range of disease systems. The emulsan family of biopolymers also has significant potential in vaccine and drug delivery based on recent studies. Each of these biopolymers offers exciting opportunities to modulate biological responses via control of chemistry and physical properties achieved during biosynthesis or postsynthesis modifications. When combined into a delivery system for controlled release, synergistic outcomes may be achieved that offer new and exciting opportunities as described in the present paper. These outcomes represent the combined improvements of solubility in physiological environments and immunomodulation due to the specific chemistry and structures involved. Overall, this approach provides a new direction in controlled release wherein the biomaterial carrier, in this case emulsan, and the drug, in this case beta-glucan, play an active role both in biological activation as well as in delivery profiles.

Novel pH-Sensitive Hydrogels with Peg-Tethered Chains for Oral Delivery of Calcitonin

AbstractMajor challenges in oral delivery of peptides include the need to overcome gastric and intestinal degradation. pH -Sensitive hydrogels are suitable candidates for oral drug delivery of peptides due to their ability to respond to their environment. We have developed a new type of hydrogel composed of poly(methacrylic acid) grafted with poly(ethylene glycol) which can be used as drug delivery carriers for salmon calcitonin. These hydrogels were prepared by free radical solution polymerization and were molecularly designed to contain poly(ethylene glycol) tethered chains promoting mucosal adhesion and providing calcitonin protection, as well as methacrylic acid moieties, which act as calcium binders leading to epithelial cell junction opening. Solutions of approximately 0.1 mg/ml of salmon calcitonin were used to load the protein into the gels at pH = 7 and constant ionic strength of 0.1 M.In vitrorelease studies were performed at pH=7 and 37 °C, while keeping an ionic strength of 0.1 M. Calcitonin release was achieved. The release behavior was explained in terms of diffusional theories.