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Pharmaceutics
Special Issues
Colon-Targeted Drug Delivery
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Colon-Targeted Drug Delivery

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

Deadline for manuscript submissions: closed (10 November 2021) | Viewed by 22606

Special Issue Editor

Prof. Dr. Yunjin Jung

E-Mail Website
Guest Editor
Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan 609‐735, Republic of Korea
Interests: colon-targeted drug delivery; prodrug; codrug; pathologically-targeted drug; molecular pharmacology of anti-colitic agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colon-targeted drug delivery (CTDD) is achieved when a drug is prevented from being systemically absorbed and metabolized in the upper intestine, leading to delivery of a much greater amount of the intact drug to the large intestine. Compared with conventional drug delivery, colon-targeted delivery of a drug increases the concentration of the drug in the large intestine while reducing systemic absorption of the drug. Thus, CTDD should confer therapeutic and toxicological advantages for the treatment of colonic diseases such as inflammatory bowel disease. CTDD can also be utilized for chronotherapy and oral peptide therapy owing to the transit time to and low proteolytic activity in the large intestine. In addition, oral drug delivery systems aiming at sustained release of a drug in the GI tract can reach the large intestine, which affects the pharmacokinetics and therapeutic activity of the drug. This Special Issue welcomes any papers dealing with oral drug delivery system reaching the large intestine, including CTDD.

Prof. Dr. Yunjin Jung
Guest Editor

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Keywords

  • colon targeted drug delivery
  • oral drug delivery
  • colitis
  • oral peptide therapy
  • sustained release

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Published Papers (6 papers)

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Research

16 pages, 3280 KiB  
Article
Ileo-Colon Targeting of the Poorly Water-Soluble Drug Celecoxib Using a pH-Dependent Coating in Combination with Self-Emulsifying Drug Delivery or Solid Dispersion Systems
by Annemarie Broesder, Julia M. E. Berends, Sophie M. Scheepers, Duong N. Nguyen, Henderik W. Frijlink and Wouter L. J. Hinrichs
Pharmaceutics 2021, 13(5), 731; https://doi.org/10.3390/pharmaceutics13050731 - 15 May 2021
Cited by 9 | Viewed by 3773
Abstract
Targeting celecoxib to the ileo-colonic region could be beneficial for the treatment and prevention of colon cancer. Ileo-colonic targeting can be achieved by using pH-dependent coating systems such as ColoPulse. Celecoxib has poor aqueous solubility, which may jeopardize optimal treatment. Therefore, we combined [...] Read more.
Targeting celecoxib to the ileo-colonic region could be beneficial for the treatment and prevention of colon cancer. Ileo-colonic targeting can be achieved by using pH-dependent coating systems such as ColoPulse. Celecoxib has poor aqueous solubility, which may jeopardize optimal treatment. Therefore, we combined a pH-dependent coating with self-emulsifying drug delivery systems (SEDDS) or with solid dispersion systems (SD); two approaches that are often used to improve the dissolution behavior of lipophilic drugs. The dissolution behavior of various formulations of both systems was investigated. Optimized formulations with and without precipitation inhibitors were coated with the ColoPulse and the release of celecoxib was tested under non-sink conditions using an in vitro dissolution system, simulating the pH gradient of the gastrointestinal tract. The dissolution behavior of SDs with and without precipitation inhibitor (sodium dodecyl sulfate) and the SEDDS without precipitation inhibitor was negatively impacted by the coating. Control experiments indicated that components of the coating released in the dissolution medium acted as precipitation mediators. However, the SEDDS formulation with HPMC 4000 cps as a precipitation inhibitor showed excellent dissolution behavior. We hypothesize that HPMC accumulates at the oil/water interface of the emulsion thereby stabilizing the emulsion resulting in maintenance of the supersaturated state. Full article
(This article belongs to the Special Issue Colon-Targeted Drug Delivery)
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19 pages, 4682 KiB  
Article
Preparation and Preliminary Evaluation of Neurotensin Radiolabelled with 68Ga and 177Lu as Potential Theranostic Agent for Colon Cancer
by Radu Anton Leonte, Livia Elena Chilug, Radu Șerban, Cosmin Mustăciosu, Alina Raicu, Gina Manda and Dana Niculae
Pharmaceutics 2021, 13(4), 506; https://doi.org/10.3390/pharmaceutics13040506 - 7 Apr 2021
Cited by 7 | Viewed by 2528
Abstract
The neurotensin is a tridecapeptide involved in the proliferation of colon cancer, the overexpression of neurotensin receptors occurring at an early stage development of many tumours. Targeting neurotensin receptors by using the same biological active molecule is an effective approach for both imaging [...] Read more.
The neurotensin is a tridecapeptide involved in the proliferation of colon cancer, the overexpression of neurotensin receptors occurring at an early stage development of many tumours. Targeting neurotensin receptors by using the same biological active molecule is an effective approach for both imaging quantification and treatment. The present work aimed to demonstrate the ability of radiolabelled neurotensin to specifically target colon cancer cells, and substantiate its usefulness in targeted imaging and radiotherapy, depending on the emission of the coupled radioisotope. Syntheses of 68Ga–DOTA–NT and 177Lu–DOTA–NT were developed to obtain a level of quality suitable for preclinical use with consistent high synthesis yields. Radiochemical purity meets the pharmaceutical requirements, and it is maintained 4 h for 68Ga–DOTA–NT and 48 h for 177Lu–DOTA–NT. Extensive in vitro studies were conducted to assess the uptake and retention of 68Ga–DOTA–NT, the amount of non-specific binding of neurotensin and the effect of 177Lu–DOTA–NT on HT–29 cells. In vivo biodistribution of 68Ga–DOTA–NT revealed significant uptake at the tumour site, along with fast clearance evidenced by decreasing activity in kidneys and blood after 60 min p.i. 177Lu–DOTA–NT exhibited similar uptake in the tumour, but also a significant uptake at 14 days p.i. in the bone marrow was reported. These results successfully demonstrated the potential of neurotensin to deliver imaging/therapeutic 68Ga/177Lu radioisotopes pair, but also the need for further evaluation of the possible radiotoxicity effects on the liver, kidneys or bone marrow. Full article
(This article belongs to the Special Issue Colon-Targeted Drug Delivery)
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22 pages, 3701 KiB  
Article
PEGylated Nanographene Oxide in Combination with Near-Infrared Laser Irradiation as a Smart Nanocarrier in Colon Cancer Targeted Therapy
by Milena Georgieva, Zlatina Gospodinova, Milena Keremidarska-Markova, Trayana Kamenska, Galina Gencheva and Natalia Krasteva
Pharmaceutics 2021, 13(3), 424; https://doi.org/10.3390/pharmaceutics13030424 - 22 Mar 2021
Cited by 22 | Viewed by 3302
Abstract
Anti-cancer therapies that integrate smart nanomaterials are the focus of cancer research in recent years. Here, we present our results with PEGylated nanographene oxide particles (nGO-PEG) and have studied their combined effect with near-infrared (NIR) irradiation on low and high invasive colorectal carcinoma [...] Read more.
Anti-cancer therapies that integrate smart nanomaterials are the focus of cancer research in recent years. Here, we present our results with PEGylated nanographene oxide particles (nGO-PEG) and have studied their combined effect with near-infrared (NIR) irradiation on low and high invasive colorectal carcinoma cells. The aim is to develop nGO-PEG as a smart nanocarrier for colon cancer-targeted therapy. For this purpose, nGO-PEG nanoparticles’ size, zeta potential, surface morphology, dispersion stability, aggregation, and sterility were determined and compared with pristine nGO nanoparticles (NPs). Our results show that PEGylation increased the particle sizes from 256.7 nm (pristine nGO) to 324.6 nm (nGO-PEG), the zeta potential from −32.9 to −21.6 mV, and wrinkled the surface of the nanosheets. Furthermore, nGO-PEG exhibited higher absorbance in the NIR region, as compared to unmodified nGO. PEGylated nGO demonstrated enhanced stability in aqueous solution, improved dispensability in the culture medium, containing 10% fetal bovine serum (FBS) and amended biocompatibility. A strong synergic effect of nGO-PEG activated with NIR irradiation for 5 min (1.5 W/cm−2 laser) was observed on cell growth inhibition of low invasive colon cancer cells (HT29) and their wound closure ability while the effect of NIR on cellular morphology was relatively weak. Our results show that PEGylation of nGO combined with NIR irradiation holds the potential for a biocompatible smart nanocarrier in colon cancer cells with enhanced physicochemical properties and higher biological compatibility. For that reason, further optimization of the irradiation process and detailed screening of nGO-PEG in combination with NIR and chemotherapeutics on the fate of the colon cancer cells is a prerequisite for highly efficient combined nanothermal and photothermal therapy for colon cancer. Full article
(This article belongs to the Special Issue Colon-Targeted Drug Delivery)
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16 pages, 4125 KiB  
Article
Design of Catalase Monolithic Tablets for Intestinal Targeted Delivery
by Mirna Alothman, Pompilia Ispas-Szabo and Mircea Alexandru Mateescu
Pharmaceutics 2021, 13(1), 69; https://doi.org/10.3390/pharmaceutics13010069 - 7 Jan 2021
Cited by 6 | Viewed by 4923
Abstract
Several studies confirmed a correlation between elevated hydrogen peroxide (H2O2) levels in patients with intestinal bowel diseases (IBD) and the negative effects caused by its presence. The objective of this study was to explore the potential use of catalase [...] Read more.
Several studies confirmed a correlation between elevated hydrogen peroxide (H2O2) levels in patients with intestinal bowel diseases (IBD) and the negative effects caused by its presence. The objective of this study was to explore the potential use of catalase (CAT) to diminish the level of H2O2 and its deleterious action on intestinal mucosa. Oral dosage forms of a CAT bioactive agent targeted to the intestines were designed and tested in various simulated gastric and intestinal media. Monolithic tablets (30% loading) were prepared using commercial CarboxyMethylCellulose (CMC) or synthesized CarboxyMethylStarch (CMS) and TriMethylAmineCarboxyMethylStarch (TMACMS) as matrix-forming excipients. For starch derivatives, the presence of the ionic groups (carboxymethyl and trimethylamine) was validated by spectral analysis. In vitro studies have shown that tablets formulated with TMACMS and 30% CAT resisted the acidity of the simulated gastric fluid and gradually released the enzyme into the simulated intestinal fluid. The investigation of the CAT release mechanism revealed the role of anionic and cationic groups of polymeric excipients and their involvement in the modulation of the CAT dissolution profile. The proposed drug delivery system can be considered an efficient solution to target CAT release in the intestine and contribute to the reduction of H2O2 associated with intestinal inflammation. Full article
(This article belongs to the Special Issue Colon-Targeted Drug Delivery)
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13 pages, 2378 KiB  
Article
Preparation and Evaluation of Amino Acid Conjugates of Celecoxib as Prodrugs to Improve the Pharmacokinetic and Therapeutic Properties of Celecoxib
by Yonghyun Lee, Jungyun Kim, Wooseong Kim, In-Soo Yoon and Yunjin Jung
Pharmaceutics 2020, 12(11), 1043; https://doi.org/10.3390/pharmaceutics12111043 - 30 Oct 2020
Cited by 1 | Viewed by 2912
Abstract
Although celecoxib is quite effective in the management of inflammation-related diseases, especially arthritis, its use is limited by concerns including low bioavailability (BA), non-linear pharmacokinetic (PK) profile, and peak concentration-related toxicity. To overcome these issues, we designed and prepared hydrophilic celecoxib prodrugs, namely [...] Read more.
Although celecoxib is quite effective in the management of inflammation-related diseases, especially arthritis, its use is limited by concerns including low bioavailability (BA), non-linear pharmacokinetic (PK) profile, and peak concentration-related toxicity. To overcome these issues, we designed and prepared hydrophilic celecoxib prodrugs, namely N-glycyl-aspart-1yl celecoxib (N-GA1C), glutam-1-yl celecoxib (G1C), and aspart-1yl celecoxib (A1C), for the sustained release of celecoxib in the intestine with limited systemic absorption. The celecoxib derivatives were converted to celecoxib in the intestinal contents. The conversion rates were in order of N-GA1C > G1C > A1C. Oral administration of the celecoxib derivatives (oral celecoxib derivatives) sustained the plasma concentration of celecoxib for 24 h, improving the BA and linearity of the PK profile of celecoxib. The peak concentrations (Cmax) of celecoxib after oral celecoxib derivatives were lower than that after oral celecoxib. In a carrageenan-induced rat paw edema model, oral N-GA1C exhibited greater anti-inflammatory activity for a longer duration compared with oral celecoxib. The order of efficacy of the celecoxib derivatives was N-GA1C > G1C > A1C. Taken together, the prodrug approach is a feasible strategy to improve the PK and therapeutic properties of celecoxib, and among the celecoxib derivatives, N-GA1C may be the most promising prodrug of celecoxib. Full article
(This article belongs to the Special Issue Colon-Targeted Drug Delivery)
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16 pages, 967 KiB  
Article
A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats
by Soojin Kim, Seunghyun Lee, Hanju Lee, Sanghyun Ju, Sohee Park, Doyoung Kwon, Jin-Wook Yoo, In-Soo Yoon, Do Sik Min, Young-Suk Jung and Yunjin Jung
Pharmaceutics 2020, 12(9), 843; https://doi.org/10.3390/pharmaceutics12090843 - 3 Sep 2020
Cited by 15 | Viewed by 3624
Abstract
An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for inflammatory bowel disease (IBD). To develop an ER-stress attenuator that is effective against colitis, 4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with acidic amino [...] Read more.
An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for inflammatory bowel disease (IBD). To develop an ER-stress attenuator that is effective against colitis, 4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with acidic amino acids to yield 4-PBA-glutamic acid (PBA-GA) and 4-PBA-aspartic acid (PBA-AA) conjugates. The PBA derivatives were converted to 4-PBA in the cecal contents, and the conversion was greater with PBA-GA than that with PBA-AA. After oral administration of PBA-GA (oral PBA-GA), up to 2.7 mM PBA was detected in the cecum, whereas 4-PBA was not detected in the blood, indicating that PBA-GA predominantly targeted the large intestine. In 2,4-dinitrobenzenesulfonic acid-induced colitis in rats, oral PBA-GA alleviated the damage and inflammation in the colon and substantially reduced the elevated levels of ER stress marker proteins in the inflamed colon. Moreover, PBA-GA was found to be as effective as the currently used anti-IBD drug, sulfasalazine. In conclusion, PBA-GA is a colon-targeted prodrug of 4-PBA and is effective against rat colitis probably via the attenuation of ER stress in the inflamed colon. Full article
(This article belongs to the Special Issue Colon-Targeted Drug Delivery)
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