Polymeric microspheres redefining the landscape of colon-targeted delivery: A contemporary update

Abstract

During recent times, the delivery of the medications to the colon has seen more interest by the researchers, as it proved to be providing both options for treating local colon-related conditions and a route for systemic delivery of the various other types of medications. For these to happen, the medication has to provide protection from severe conditions in the stomach and small bowel, which either degrade the medication or may cause its premature release and uptake in the upper part of the digestive track. This review describes the various roles of microspheres as a colon-targeted drug delivery device (CTDDD). Through these review, we try to provide thorough information about the effects of the physiology of the colon. Also, we made an effort to highlight different mechanisms of colon targeting. Along with these, we have pointed out some of the important evaluation factors for carrying out a thorough investigation about the physicochemical and pharmaceutical properties of microspheres for targeting the colon. Also, we exchange views about the applications of microspheres as CTDDD in different diseases and disorders of the colon. Plus, we discuss the different challenges that occur during the formulation and targeting of these microspheres. At last, we share our thoughts on the possibilities in the near future in these domains, which will help in changing the scenario of how we can treat colon-related problems.

Introduction

Colonic diseases are seen to be widely spreading, which obviously demands the development of adroit, targeted treatments to improve the safety and effectiveness of medication therapy [1,2]. Colorectal carcinoma (CRC) is reported as one of the three most rampant causes of cancer-related deaths on the planet, which brings about over 850,000 people to lose their lives annually [3]. Additionally, chronic inflammatory bowel diseases (CIBD) are seen to be more frequent in regions like Asia [4]. Therefore, colonic disease prevention is crucial for global public health. Colon-targeted drug delivery devices (CTDDD) are being sought after to address these concerns. These devices aim to inhibit release and uptake from the upper digestive tract while releasing medications in response to the colonic environment [5]. Non-targeted medicines may cause adverse reactions and lower efficacy due to systemic absorption before reaching the colon. Apart from that, colon-targeted drug delivery devices provide a technique to increase the bioavailability of medications, specifically large biomolecules like proteins and peptides, which are susceptible to breakdown in the acidic and enzymatic conditions of the upper gastrointestinal tract (GIT) [6]. Given its lesser variability and frequency of digesting enzymes than the small intestine, it has been presumed that the colonic part of the GIT provides an ideal place to absorb protein or polypeptide medicines. CTDDD prevents peptide medication hydrolysis along with breakdown by enzymes throughout the duodenum as well as the jejunum and allows release when they reach the ileum or colon, which will eventually lead to higher systemic bioavailability. Additionally, the colon can be susceptible to enhancers of absorption due to the extended residency period (a maximum of five days) [7]. Rectal delivery offers a quicker way to deliver medications to the colon than oral administration, yet it might be challenging to make it to the proximal colon and discomforting for those taking medications. Drug preparations for intra-rectal usage are available in a variety of types, including solutions, foam, and suppositories, to treat the large intestine both systemically and topically. Drug concentration is influenced by formulation variables, retrograde spreading, in addition to retention time. Topical application is principally responsible for the effectiveness of medications absorbed into the colon. Notably, enema solutions have a greater spreading capacity than foam and suppositories, which are primarily held in the rectum and sigmoid colon [8].

For the successful creation of CTDDD, both the changed microenvironment close to disease sites and the special physiological properties of the colon must be taken into account. Throughout the stomach and towards the intestine, the GIT undergoes dynamic fluctuations in pH, enzymatic levels, fluid matter, and motility. Additionally, the colon microenvironment near illness sites is very different from that in healthy areas. All individuals with colonic problems have injuries to the mucosa, elevated reactive oxygen species and inflammatory cytokine levels, and an unbalanced level of vital antioxidants in their bodies. Numerous formulation techniques have been investigated to enhance colonic medication delivery in light of these pathophysiological alterations. These consist of systems that are pH-sensitive, enzyme-activated, and magnetically-driven [[9], [10], [11]]. Receptor-mediated systems have also been researched with the aim of interacting selectively with particular receptors highly expressed around the site(s) of the disease. Microspheres can be made into variable sizes (between the scales of micrometers and millimeters). With their minute size, which leads to a greater surface area, microspheres have an upper hand in medication delivery as they bring forth the release of the medication in a controlled release profile by entrapping the medication as a perfect formulation for site-specific targeting in the large intestine [[12], [13], [14], [15], [16]]. Microspheres, designed as CTDDD, are formulated using pH-dependent and/or enzyme-responsive polymers, which prevent the medication from being released inside the stomach or even small intestinal regions and release the medication in colonic conditions by undergoing either pH-succeptible degradation or enzymatic degradation. Along with that, microspheres are coated with various pH-dependent polymeric coatings to retard medication release in the upper part of the GIT [17]. By means of this review, we want to provide an overview of the microsphere formulation considerations and methods, along with the influence of the colon’s physiology over it [18]. These microspheres can be formulated to target the large intestine, utilizing the diverse types of approaches to targeting the large intestine [19,20]. Additionally, we discuss the challenges, recent trends, and possible developments in this domain in the near future [21].

Table 1 Recent advancements in CTDD via microspheres

Fabrication Technique	Polymer	Medication	Size (μm)	Entrapment Efficiency	Mechanism of Medication release	Uses/Treatment	Study type
	Resistant Starch	Aspirin	–	68.96	Enzymatic degradation	CIBD	In vitro
	Eudragit S100	Lactobacillus rhamnosus GG	5.2–7.3	–	pH susceptible degradation	Probiotics therapy	In vitro
	Eudragit S-100	Mesalamine	4.91	7 ± 0.89	pH susceptible degradation	UC	In vitro
	Chitosan	Curcumin overloaded with ascorbic acid	–	91.2 ± 0.88	pH susceptible degradation	CRC	In vivo
	Inulin	Mesalamine	0.8–10	87	Enzymatic degradation	UC	In vitro
	Polyacrylamide-graft-gum karaya	Capecitabine	1.02–8.19	77.30–88.74	pH susceptible degradation	CRC	In vitro
	Chitosan	Meloxicam	–	65.5 ± 1.5–84.1 ± 1.7	pH susceptible degradation	CRC	In vivo
	Eudragit S-100	5-Fluorouracil	–	99	pH susceptible degradation	CRC	In vivo
	Zein (ZN) and Gantrez® AN119 (PVMMA)	Curcumin	10.15–25.64	89	pH susceptible degradation	CIBD	Ex vivo
	PGA-co-PDL	Indomethacin	–	63.16 ± 3.5	pH susceptible degradation	CIBD	In vitro
	Polyacrylamidegrafted-CMCNa copolymer	Capecitabine	1.00–7.34	70.98 ± 1.23–94.41 ± 0.45	pH susceptible degradation	CRC	In vitro
	Eudragit® FS 30D	Glutathione and S-nitrosoglutathione	5 ± 1–7 ± 1	74 ± 3–82 ± 2	pH susceptible degradation	Therapy for Crohns disease	In vitro
Ionic gelation	Inulin/Chitosan/Alginate	Quercetin	25.1 ± 1.8–79.4 ± 4.5	53.2 ± 1.2	Enzymatic degradation	CIBD	In vitro
	Sodium alginate	Gallic Acid	–	11.26–72.64	Enzymatic degradation	CRC	Ex vivo
	Alginate	Astaxanthin	0.5–3.2	–	Enzymatic degradation	UC	In vitro
	Gum odina - Sodium alginate	Capecitabine	568.33 ± 45.76	45.91 ± 2.94	Enzymatic degradation	CRC	Ex vivo
	Pectin/NaCMC	Progesterone	1031 ± 19	80.1–97.8 %	Enzymatic degradation	Hormone therapy	Ex vivo
	Sodium alginate	Meloxicam	109.16 ± 0.96–1025.12 ± 0.29	50.33 ± 0.40 to 74.93 ± 0.69	Enzymatic degradation	Rheumatoid arthritis management	In vivo
	Konjac glucomannan/Sodium alginate/Graphene oxide	Ciprofloxacin	–	19.11 ± 1.39	Enzymatic degradation	CIBD	In vitro
	Arabinoxylan	Insulin	150–300	71.3 ± 2.7	Enzymatic degradation	Management of Diabetes	In vitro
	Locust bean gum	Mesalamine	1450	32.64 ± 0.57–57.42 ± 1.98	pH susceptible degradation	UC	In vitro
	Portulaca oleracea polysaccharide/Alginate/Borax	5-fluorouracil	930–1140	53–88	Enzymatic degradation	CRC	In vitro
	Chitosan	Flurbiprofen	700–1300	20.3 ± 0.007–78.8 ± 0.003	pH susceptible degradation	Non steroidal anti-inflammatory drug (NSAID)	In vitro
	Pectin/NaCMC	Progesterone	1114 ± 36.9–1447 ± 35.7	82–99	Enzymatic degradation	Hormone therapy	Ex vivo
	Gelan gum	Ketoprofen	700.17–938.32	48.76 to 87.52	pH susceptible degradation	NSAID	In vitro
Double emulsion	Methocel E5/Eudragit L100	Captopril	110–128	95	pH susceptible degradation	–	In vitro
	PLGA/PVA	Fucoxanthin	2.01–10.95	33.09–34.87	pH susceptible degradation	CRC	In vitro
	Eudragit® RS100	Fluorescein isothiocyanate-dextran	31.1 ± 0.5	–	pH susceptible degradation	–	Ex vivo
	Gum Katira	5-fluorouracil	–	79.71 ± 6.01	pH susceptible degradation	CRC	In vivo/Ex vivo
	Eudragit® FS 30D/Eudragit® RS-PO	Enoxaparin sodium	80.64–165.00	62.38–94.89	pH susceptible degradation	Anticoagulant	In vitro
	PLGA/PVA	Fucoxanthin	3.93–17.12	–	pH susceptible degradation	CRC	–
	Tulsion® Thermocoat L 30 D55	Clarithromycin	52.0 ± 0.46	61.0 ± 3.1	pH susceptible degradation	–	In vivo
	PLGA	PEGylated apoptotic protein	14.4 ± 1.8	85.7 % ± 4.1	pH susceptible degradation	CRC	In vivo
Emulsion solvent Evaporation	Cellulose/Alginate	Mesalazine	–	–	pH susceptible degradation	CIBD	In vitro
	Halloysite nanotube/Chitosan	Paeoniflorin	26.7 ± 7.5	–	pH susceptible degradation	UC	In vitro
	Eudragit® FS 100	Curcumin		98.26 ± 6.38	pH susceptible degradation	CIBD	In vivo
	Pectin	Lamivudine	–	30.31–66.32	Enzymatic degradation	Chronic Hepatitis B	In vitro
	Resistant Starch	Ciprofloxacin HCl	0.743–4.156	–	pH susceptible degradation	Antimicrobial	In vitro
	Pectin/Chitosan	Acetoaminophen	24.98 ± 13.67 and 0.62 ± 0.24	18.86–64.33	pH susceptible degradation	–	In vitro
	Eudragit L100–55 and S100	Celecoxib	–	72.67 ± 3.93–84.33 ± 2.12	pH susceptible degradation	UC	In vivo
	Chitosan	Curcumin	10.94 ± 0.16–24.13 ± 0.62	73.88 ± 0.54–83.37 ± 0.62	pH susceptible degradation	CIBD	In vivo
	Chitosan	5-fluorouracil/Leucovorin	15 to 35	11.6 ± 0.09–21.8 ± 0.12	pH susceptible degradation	CRC	In vitro
	Pectin	Metronidazole	14.02 ± 1.03	80.61 ± 2.42–94.52 ± 2.25	Enzymatic degradation	Antimicrobial	In vitro
	PEG-cross-linked Chitosan	5-fluorouracil	316 ± 20	–	pH susceptible degradation	CRC	In vivo
Coacervation	NaCMC/Pectin	Potassium diformate	–	–	pH susceptible degradation	Bacteriostatic	In vitro
	Chitosan-Alginate	Quercetin	–	86.91 ± 1.10–93.11 ± 0.72	pH susceptible degradation	Antimicrobial	In vitro
	Chitosan-Alginate	Ruta graveolens L. Phytocomplex	–	31.99 ± 0.12–75.31 ± 0.96	pH susceptible degradation	Antioxidant	In vitro
	Agave Fructans	Ibuprofen	–	0.8–21.5	Enzymatic degradation	NSAID	In vitro

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Raosaheb S. Shendge, Tejas S. Zalte, Shubhangi B. Khade, Polymeric microspheres redefining the landscape of colon-targeted delivery: A contemporary update, European Journal of Medicinal Chemistry Reports, Volume 11, 2024, 100156, ISSN 2772-4174, https://doi.org/10.1016/j.ejmcr.2024.100156.