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Pharmaceutics
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Advances in Oral Administration
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Advances in Oral Administration

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: 30 September 2024 | Viewed by 6102

Special Issue Editor

Dr. Guanyu Chen

E-Mail Website
Guest Editor
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
Interests: oral drug delivery; oral bioavailability; nanotechnology; protein and peptide drugs

Special Issue Information

Dear Colleagues,

Oral delivery is a convenient, non-invasive and safe drug administration route, with high patient compliance. However, the oral delivery of protein and peptide drugs (PPDs) remains a huge challenge for scientists. Since PPDs need to overcome intestinal physical barriers and biochemical barriers, including poor drug permeation over the intestinal epithelial membrane and the presence of a strong acidic environment and various proteolytic enzymes, PPDs may easily be degraded. In last decade, many attempts have been made to improve the oral bioavailability of PPDs. A typeical example is the oral semaglutide approved by the U.S. Food and Drug Administration. This was a significant breakthrough for oral PPD delivery, but it still has limited oral bioavailability. To promote PPD oral bioavailablity, strategies have been developed for instantaneously disrupting the intestinal epithelium, such as opening the tight junction. However, this may trigger an absorption of pathogens and toxins, and result in adverse effects. Another commonly used strategy is to incorporate PPDs within nanocarriers to enhance their active transportation, but the use of various synthetic materials or the toxic organic solvents during preparation may also lead to side effects. Therefore, it is crucial to seek more advanced strategies for the oral delivery of PPDs. In this Special Issue, there will be focus on advances in the oral adminstration of PPDs through research with novelty and originality, which will lay a great platform for the future of the oral delivery of PPDs.   

Dr. Guanyu Chen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • oral drug delivery
  • protein and peptide drugs
  • oral bioavailability
  • novel delivery systems
  • intestinal drug permeation

Published Papers (6 papers)

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Research

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15 pages, 2928 KiB  
Article
Cryo-Milled β-Glucan Nanoparticles for Oral Drug Delivery
by Guanyu Chen, Yi Liu, Darren Svirskis, Hongyu Li, Man Ying, Weiyue Lu and Jingyuan Wen
Pharmaceutics 2024, 16(4), 546; https://doi.org/10.3390/pharmaceutics16040546 - 16 Apr 2024
Viewed by 390
Abstract
Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a [...] Read more.
Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a novel nanoparticulate drug delivery system for the oral delivery of gemcitabine to improve its oral bioavailability. In this study, gemcitabine-loaded β-glucan NPs were fabricated using a film-casting method followed by a freezer-milling technique. As a result, the NPs showed a small particle size of 447.6 ± 14.2 nm, and a high drug entrapment efficiency of 64.3 ± 2.1%. By encapsulating gemcitabine into β-glucan NPs, a sustained drug release profile was obtained, and the anomalous diffusion release mechanism was analyzed, indicating that the drug release was governed by diffusion through the NP matrix as well as matrix erosion. The drug-loaded NPs had a greater ex vivo drug permeation through the porcine intestinal epithelial membrane compared to the plain drug solution. Cytotoxicity studies showed a safety profile of the β-glucan polymers, and the IC50s of drug solution and drug-loaded β-glucan NPs were calculated as 228.8 ± 31.2 ng·mL−1 and 306.1 ± 46.3 ng·mL−1, respectively. Additionally, the LD50 of BALB/c nude mice was determined as 204.17 mg/kg in the acute toxicity studies. Notably, pharmacokinetic studies showed that drug-loaded β-glucan NPs could achieve a 7.4-fold longer T1/2 and a 5.1-fold increase in oral bioavailability compared with plain drug solution. Finally, in vivo pharmacodynamic studies showed the promising capability of gemcitabine-loaded β-glucan NPs to inhibit the 4T1 breast tumor growth, with a 3.04- and 1.74-fold reduction compared to the untreated control and drug solution groups, respectively. In conclusion, the presented freezer-milled β-glucan NP system is a suitable drug delivery method for the oral delivery of gemcitabine and demonstrates a promising potential platform for oral chemotherapy. Full article
(This article belongs to the Special Issue Advances in Oral Administration)
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23 pages, 8398 KiB  
Article
Cellular Uptake and Transport Mechanism Investigations of PEGylated Niosomes for Improving the Oral Delivery of Thymopentin
by Mengyang Liu, Darren Svirskis, Thomas Proft, Jacelyn Loh, Yuan Huang and Jingyuan Wen
Pharmaceutics 2024, 16(3), 397; https://doi.org/10.3390/pharmaceutics16030397 - 14 Mar 2024
Viewed by 701
Abstract
Background: Although its immunomodulatory properties make thymopentin (TP5) appealing, its rapid metabolism and inactivation in the digestive system pose significant challenges for global scientists. PEGylated niosomal nanocarriers are hypothesized to improve the physicochemical stability of TP5, and to enhance its intestinal permeability for [...] Read more.
Background: Although its immunomodulatory properties make thymopentin (TP5) appealing, its rapid metabolism and inactivation in the digestive system pose significant challenges for global scientists. PEGylated niosomal nanocarriers are hypothesized to improve the physicochemical stability of TP5, and to enhance its intestinal permeability for oral administration. Methods: TP5-loaded PEGylated niosomes were fabricated using the thin film hydration method. Co-cultured Caco-2 and HT29 cells with different ratios were screened as in vitro intestinal models. The cytotoxicity of TP5 and its formulations were evaluated using an MTT assay. The cellular uptake and transport studies were investigated in the absence or presence of variable inhibitors or enhancers, and their mechanisms were explored. Results and Discussion: All TP5 solutions and their niosomal formulations were nontoxic to Caco-2 and HT-29 cells. The uptake of TP5-PEG-niosomes by cells relied on active endocytosis, exhibiting dependence on time, energy, and concentration, which has the potential to significantly enhance its cellular uptake compared to TP5 in solution. Nevertheless, cellular transport rates were similar between TP5 in solution and its niosomal groups. The cellular transport of TP5 in solution was carried out mainly through MRP5 endocytosis and a passive pathway and effluxed by MRP5 transporters, while that of TP5-niosomes and TP5-PEG-niosomes was carried out through adsorptive- and clathrin-mediated endocytosis requiring energy. The permeability and transport rate was further enhanced when EDTA and sodium taurocholate were used as the penetration enhancers. Conclusions: This research has illustrated that PEG-niosomes were able to enhance the cellular uptake and maintain the cellular transport of TP5. This study also shows this formulation’s potential to serve as an effective carrier for improving the oral delivery of peptides. Full article
(This article belongs to the Special Issue Advances in Oral Administration)
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19 pages, 1977 KiB  
Article
Enhancing Oral Delivery of Biologics: A Non-Competitive and Cross-Reactive Anti-Leptin Receptor Nanofitin Demonstrates a Gut-Crossing Capacity in an Ex Vivo Porcine Intestinal Model
by Solene Masloh, Anne Chevrel, Maxime Culot, Anaëlle Perrocheau, Yogeshvar N. Kalia, Samuel Frehel, Rémi Gaussin, Fabien Gosselet, Simon Huet, Magali Zeisser Labouebe and Leonardo Scapozza
Pharmaceutics 2024, 16(1), 116; https://doi.org/10.3390/pharmaceutics16010116 - 16 Jan 2024
Viewed by 972
Abstract
Biotherapeutics exhibit high efficacy in targeted therapy, but their oral delivery is impeded by the harsh conditions of the gastrointestinal (GI) tract and limited intestinal absorption. This article presents a strategy to overcome the challenges of poor intestinal permeability by using a protein [...] Read more.
Biotherapeutics exhibit high efficacy in targeted therapy, but their oral delivery is impeded by the harsh conditions of the gastrointestinal (GI) tract and limited intestinal absorption. This article presents a strategy to overcome the challenges of poor intestinal permeability by using a protein shuttle that specifically binds to an intestinal target, the leptin receptor (LepR), and exploiting its capacity to perform a receptor-mediated transport. Our proof-of-concept study focuses on the characterization and transport of robust affinity proteins, known as Nanofitins, across an ex vivo porcine intestinal model. We describe the potential to deliver biologically active molecules across the mucosa by fusing them with the Nanofitin 1-F08 targeting the LepR. This particular Nanofitin was selected for its absence of competition with leptin, its cross-reactivity with LepR from human, mouse, and pig hosts, and its shuttle capability associated with its ability to induce a receptor-mediated transport. This study paves the way for future in vivo demonstration of a safe and efficient oral-to-systemic delivery of targeted therapies. Full article
(This article belongs to the Special Issue Advances in Oral Administration)
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11 pages, 1309 KiB  
Article
Compaction Properties of Particulate Proteins in Binary Powder Mixtures with Common Excipients
by Else Holmfred, Cosima Hirschberg and Jukka Rantanen
Pharmaceutics 2024, 16(1), 19; https://doi.org/10.3390/pharmaceutics16010019 - 22 Dec 2023
Viewed by 757
Abstract
The increasing interest in protein- and peptide-based oral pharmaceuticals has culminated in the first protein-based products for oral delivery becoming commercially available. This study investigates the compaction properties of proteins in binary mixtures with common excipients up to 30% (w/w [...] Read more.
The increasing interest in protein- and peptide-based oral pharmaceuticals has culminated in the first protein-based products for oral delivery becoming commercially available. This study investigates the compaction properties of proteins in binary mixtures with common excipients up to 30% (w/w) of particulate protein. Two model proteins, lysozyme and bovine serum albumin, were compacted with either microcrystalline cellulose, spray-dried lactose monohydrate, or calcium hydrogen phosphate dihydrate at two different compaction pressures. Compared to the compacted pure materials, a significant increase in the tensile strength of the compacts was observed for the binary blends containing lysozyme together with the brittle excipients. This could be attributed to the increased bonding forces between the particles in the blend compared to the pure materials. The use of bovine serum albumin with a larger particle size resulted in a decrease in tensile strength for all the compacts. The change in the tensile strength with an increasing protein content was non-linear for both proteins. This work highlights the importance of considering the particulate properties of protein powders and that protein-based compacts can be designed with similar principles as small-molecules in terms of their mechanical tablet properties. Full article
(This article belongs to the Special Issue Advances in Oral Administration)
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Review

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13 pages, 1853 KiB  
Review
Oromucosal Administration of Oxytocin: The Development of ‘Oxipops’
by Dan Xu, Chunmei Lan, Juan Kou, Shuxia Yao, Weihua Zhao and Keith M. Kendrick
Pharmaceutics 2024, 16(3), 333; https://doi.org/10.3390/pharmaceutics16030333 - 27 Feb 2024
Viewed by 894
Abstract
The role of the hypothalamic neuropeptide oxytocin in influencing the brain and behavior has been the subject of widespread research over the last few decades due, most notably, to its reported involvement in promoting social cognition and motivation, reducing anxiety, and relieving pain. [...] Read more.
The role of the hypothalamic neuropeptide oxytocin in influencing the brain and behavior has been the subject of widespread research over the last few decades due, most notably, to its reported involvement in promoting social cognition and motivation, reducing anxiety, and relieving pain. It is also increasingly being considered as an important therapeutic intervention in a variety of disorders with social dysfunction as a symptom. While, in recent years, studies in humans have administered oxytocin primarily via an intranasal route, since it may partly enter the brain directly this way via the olfactory and trigeminal nerves, there is increasing evidence that many of its functional effects can be peripherally mediated via increasing its concentration in the blood. This has opened up an oromucosal administration route as an alternative, which is beneficial since the oral consumption of peptides is problematic due to their rapid breakdown in the acidic environment of the gastrointestinal system. In this review we will discuss both the methodologies we have developed for administering oxytocin via lingual application and medicated lollipops, ‘oxipops’, in terms of increasing blood concentrations and the bioavailability of the peptide, and also their validation in terms of functional effects on the brain and behavior. While areas under the curve are significantly greater in terms of plasma oxytocin concentrations following intranasally relative to oromucosally administered oxytocin, with the estimated absolute bioavailability of the latter being around 4.4% compared with 11.1% for intranasal administration, the time to peak concentrations (around 30 min) and functional effects on the brain and behavior are broadly similar. We will also discuss potential therapeutic advantages of the oromucosal administration of oxytocin in different clinical contexts and its wider application for other peptides which are increasingly being developed for therapeutic use. Full article
(This article belongs to the Special Issue Advances in Oral Administration)
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25 pages, 2341 KiB  
Review
Delivery Strategies of Probiotics from Nano- and Microparticles: Trends in the Treatment of Inflammatory Bowel Disease—An Overview
by Sílvio André Lopes, Cesar Augusto Roque-Borda, Jonatas Lobato Duarte, Leonardo Delello Di Filippo, Vinícius Martinho Borges Cardoso, Fernando Rogério Pavan, Marlus Chorilli and Andréia Bagliotti Meneguin
Pharmaceutics 2023, 15(11), 2600; https://doi.org/10.3390/pharmaceutics15112600 - 08 Nov 2023
Cited by 2 | Viewed by 1589
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, most known as ulcerative colitis (UC) and Crohn’s disease (CD), that affects the gastrointestinal tract (GIT), causing considerable symptoms to millions of people around the world. Conventional therapeutic strategies have limitations and side effects, [...] Read more.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, most known as ulcerative colitis (UC) and Crohn’s disease (CD), that affects the gastrointestinal tract (GIT), causing considerable symptoms to millions of people around the world. Conventional therapeutic strategies have limitations and side effects, prompting the exploration of innovative approaches. Probiotics, known for their potential to restore gut homeostasis, have emerged as promising candidates for IBD management. Probiotics have been shown to minimize disease symptoms, particularly in patients affected by UC, opening important opportunities to better treat this disease. However, they exhibit limitations in terms of stability and targeted delivery. As several studies demonstrate, the encapsulation of the probiotics, as well as the synthetic drug, into micro- and nanoparticles of organic materials offers great potential to solve this problem. They resist the harsh conditions of the upper GIT portions and, thus, protect the probiotic and drug inside, allowing for the delivery of adequate amounts directly into the colon. An overview of UC and CD, the benefits of the use of probiotics, and the potential of micro- and nanoencapsulation technologies to improve IBD treatment are presented. This review sheds light on the remarkable potential of nano- and microparticles loaded with probiotics as a novel and efficient strategy for managing IBD. Nonetheless, further investigations and clinical trials are warranted to validate their long-term safety and efficacy, paving the way for a new era in IBD therapeutics. Full article
(This article belongs to the Special Issue Advances in Oral Administration)
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