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Controlled-Release Drug Delivery Systems for Anti-Inflammatory and Wound Healing Action

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

Deadline for manuscript submissions: 31 July 2025 | Viewed by 2092

Special Issue Editors


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Guest Editor
Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
Interests: chronic diseases; metabolic disorders; oxidative stress; inflammation; wound healing pathophysiology; natural products for biomedical application

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Guest Editor
Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
Interests: natural products; oxidative stress; development of dermocosmetic products; skin emulsions; plant extracts with anti-inflammatory and wound healing potential

E-Mail Website
Guest Editor
Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, Serbia
Interests: plant-based products; skin semi-solid formulations; natural antioxidants; wound repair and regeneration; plant extracts and secondary metabolites as anti-inflammatory agents

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this new Special Issue, entitled “Controlled-Release Drug Delivery Systems for Anti-inflammatory and Wound Healing Action”.

Wound healing represents a natural bodily reaction that is formed as a tissue response to injury. The restoration of the structural and functional integrity of injured tissues is a highly coordinated process involving various overlapping phases such as hemostasis, inflammation, proliferation, and maturation. In recent years, drug delivery systems (DDSs) with controlled release have attracted considerable attention in wound healing and inflammation management due to their significant benefits compared to conventional drugs. The advantages of controlled DDSs for oral administration include enhanced bioavailability, the protection of the drug from metabolic deactivation and the maintenance of the drug concentration over a prolonged period. On the other hand, DDSs with controlled release intended for cutaneous application have led to improvements in drug permeation and modified release at a physiologically relevant rate.

The scope of this Special Issue includes the design and assessment of DDSs for the delivery of active compounds in pharmaceutical formulations with the potential to accelerate wound repair and reduce inflammation in various acute and chronic conditions.

This Special Issue welcomes the submission of articles that address the following topics: the development of DDSs; physicochemical characterization; the evaluation of rheological properties; stability tests; and in silico, in vitro and in vivo assessments of their anti-inflammatory and wound-healing effects. Moreover, formulations based on medicinal plants and natural products that act as major sources of wound healing and anti-inflammatory compounds are of particular interest.

Dr. Vladimir Zivkovic
Dr. Jovana Bradic
Dr. Anica M. Petrović
Guest Editors

Manuscript Submission Information

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Keywords

  • controlled drug delivery systems
  • systems for topical delivery
  • physicochemical characterization
  • stability studies
  • rheological properties
  • release and permeation testing
  • anti-inflammatory properties
  • wound-healing properties
  • natural products

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Published Papers (2 papers)

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Research

17 pages, 7070 KiB  
Article
Colon-Targeted Poly(ADP-ribose) Polymerase Inhibitors Synergize Therapeutic Effects of Mesalazine Against Rat Colitis Induced by 2,4-Dinitrobenzenesulfonic Acid
by Changyu Kang, Jaejeong Kim, Yeonhee Jeong, Jin-Wook Yoo and Yunjin Jung
Pharmaceutics 2024, 16(12), 1546; https://doi.org/10.3390/pharmaceutics16121546 - 2 Dec 2024
Viewed by 524
Abstract
Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) [...] Read more.
Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA. Full article
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Figure 1

Figure 1
<p><b>Synthetic scheme and colonic activation of derivatives of PARP inhibitors.</b> (<b>A</b>) Synthetic scheme of derivatives of PARP inhibitors. 3-AB: 3-aminobenzamide, 5-AIQ: 5-aminoisoquinoline, ABSA: 3-AB azo-linked with SA, AQSA: 5-AIQ azo-linked with SA, ACN: acetonitrile, CDI: 1,1′-carbonydiimidazole, AQSA-Asp: <span class="html-italic">L</span>-aspartic acid-conjugated AQSA, AQSA-Glu: <span class="html-italic">L</span>-glutamic acid-conjugated AQSA. (<b>B</b>) Colonic activation of derivatives of PARP inhibitors. 5-ASA: 5-aminosalicylic acid.</p>
Full article ">Figure 2
<p><b>Derivatives of PARP inhibitors are colon-specific.</b> (<b>A</b>) AQSA, AQSA-Glu, and AQSA-Asp (1 mM) were incubated with 10% cecal contents suspended in PBS (pH 6.8) under nitrogen. The concentrations of 5-AIQ were analyzed using HPLC at appropriate time intervals. (<b>B</b>) The same experiment was conducted using ABSA (1 mM). (<b>C</b>) 5-AIQ, AQSA, AQSA-Glu, and AQSA-Asp (500 µM, 2 mL) dissolved in DMEM medium without phenol red were added to the apical compartment of the Caco-2 cell monolayer. At appropriate time intervals, the concentrations of each drug were determined in the basolateral compartment filled with the medium (3 mL) using HPLC. (<b>D</b>) The same experiment was conducted using 3-AB and ABSA (500 µM, 2 mL). (<b>E</b>,<b>F</b>) 5-AIQ (10.0 mg/kg) or AQSA-Glu (29.3 mg/kg, equivalent to 10 mg/kg of 5-AIQ) suspended in PBS (1 mL) was administered orally to rats. The rats were killed 2, 4, and 8 h after oral administration (<b>E</b>). The same experiment was conducted using 3-AB (17 mg/kg) and ABSA (36 mg/kg, equivalent to 17 mg/kg of 3-AB) (<b>F</b>). The concentrations of 5-AIQ and 3-AB in the cecum were analyzed using HPLC. The data in (<b>A</b>–<b>F</b>) are presented as mean ± SD (n = 3).</p>
Full article ">Figure 3
<p><b>AQSA-Glu potentiates the anticolitic activity of 5-AIQ.</b> Three days after colitis induction by DNBS, 5-AIQ (5 mg/kg) and AQSA-Glu [7.5 mg/kg, equivalent to 2.5 mg/kg of 5-AIQ (L) and 15 mg/kg, equivalent to 5 mg/kg of 5-AIQ (H)] were administered orally to rats once per day, and the rats were euthanized 24 h after the sixth treatment. (<b>A</b>) Left panel: photos of the distal colons of rats in which serosal and luminal sides are shown separately. Right panel: overall colonic damage was scored for each group and presented as colonic damage score (CDS). * α &lt; 0.05 vs. DNBS control. (<b>B</b>) H &amp; E staining was performed with the colonic tissue sections of rats subjected to various treatments. Upper panel: representative images of 100× magnification. Lower panel: representative images of 200× magnification for the dotted boxes in the upper panel. In the inflamed distal colons (4.0 cm), (<b>C</b>) myeloperoxidase (MPO) activity was measured in addition to determining the levels of (<b>D</b>) CINC-3 and (<b>E</b>) iNOS and COX-2 using an Elisa kit and Western blotting. A loading control (α-Tubulin) was used for Western blot analysis of COX-2 and iNOS. NM: not measurable. The data are represented as mean ± SD (n = 5). * <span class="html-italic">p</span> &lt; 0.05 vs. DNBS control <sup>#</sup> <span class="html-italic">p</span> &lt; 0.05.</p>
Full article ">Figure 4
<p><b>Colon-targeted PARP inhibitors synergize the anticolitic effects of mesalazine.</b> (<b>A</b>) RAW264.7 cells pretreated with 5-ASA (20 mM), 3-AB (1 mM), and 5-AIQ (10 μM) for 1 h were challenged with LPS for 24 h. The levels of iNOS and COX-2 proteins were analyzed using Western blotting. (<b>B</b>) SSZ (50 mg/kg) and ABSA (36 mg/kg, equimolar to 50 mg/kg of SSZ) suspended in PBS (1 mL) were administered orally to rats. The rats were killed 2, 4, and 8 h after oral administration. The concentrations of 5-ASA in the cecum were analyzed using HPLC. (<b>C</b>) Three days after colitis induction by DNBS, SSZ (50 mg/kg), AQSA-Glu (15 mg/kg), a mixture of AQSA-Glu (15 mg/kg) + olsalazine (OSZ, 19 mg/kg, half-equimolar to 50 mg/kg of SSZ), and ABSA (36 mg/kg, equimolar to 50 mg/kg of SSZ) were administered orally to rats once per day, and the rats were euthanized 24 h after the sixth treatment. (<b>C</b>) Left panel: photos of the distal colons of rats where serosal and luminal sides are shown separately. Right panel: overall colonic damage was scored for each group and presented as colonic damage score (CDS). * α &lt; 0.05 vs. DNBS control. (<b>D</b>) H &amp; E staining was performed with the colonic tissue sections of rats subjected to various treatments. Upper panel: representative images of 100× magnification. Lower panel: representative images of 200× magnification for the dotted boxes in the upper panel. In the inflamed distal colons (4.0 cm), (<b>E</b>) myeloperoxidase (MPO) activity was measured in addition to determining the levels of (<b>F</b>) CINC-3 and (<b>G</b>) iNOS and COX-2 using an Elisa kit and Western blotting. A loading control (α-Tubulin) was used for Western blot analysis of COX-2 and iNOS. NM: not measurable. The data are represented as mean ± SD (n = 5). * <span class="html-italic">p</span> &lt; 0.05 vs. DNBS control <sup>#</sup> <span class="html-italic">p</span> &lt; 0.05.</p>
Full article ">Figure 4 Cont.
<p><b>Colon-targeted PARP inhibitors synergize the anticolitic effects of mesalazine.</b> (<b>A</b>) RAW264.7 cells pretreated with 5-ASA (20 mM), 3-AB (1 mM), and 5-AIQ (10 μM) for 1 h were challenged with LPS for 24 h. The levels of iNOS and COX-2 proteins were analyzed using Western blotting. (<b>B</b>) SSZ (50 mg/kg) and ABSA (36 mg/kg, equimolar to 50 mg/kg of SSZ) suspended in PBS (1 mL) were administered orally to rats. The rats were killed 2, 4, and 8 h after oral administration. The concentrations of 5-ASA in the cecum were analyzed using HPLC. (<b>C</b>) Three days after colitis induction by DNBS, SSZ (50 mg/kg), AQSA-Glu (15 mg/kg), a mixture of AQSA-Glu (15 mg/kg) + olsalazine (OSZ, 19 mg/kg, half-equimolar to 50 mg/kg of SSZ), and ABSA (36 mg/kg, equimolar to 50 mg/kg of SSZ) were administered orally to rats once per day, and the rats were euthanized 24 h after the sixth treatment. (<b>C</b>) Left panel: photos of the distal colons of rats where serosal and luminal sides are shown separately. Right panel: overall colonic damage was scored for each group and presented as colonic damage score (CDS). * α &lt; 0.05 vs. DNBS control. (<b>D</b>) H &amp; E staining was performed with the colonic tissue sections of rats subjected to various treatments. Upper panel: representative images of 100× magnification. Lower panel: representative images of 200× magnification for the dotted boxes in the upper panel. In the inflamed distal colons (4.0 cm), (<b>E</b>) myeloperoxidase (MPO) activity was measured in addition to determining the levels of (<b>F</b>) CINC-3 and (<b>G</b>) iNOS and COX-2 using an Elisa kit and Western blotting. A loading control (α-Tubulin) was used for Western blot analysis of COX-2 and iNOS. NM: not measurable. The data are represented as mean ± SD (n = 5). * <span class="html-italic">p</span> &lt; 0.05 vs. DNBS control <sup>#</sup> <span class="html-italic">p</span> &lt; 0.05.</p>
Full article ">Figure 5
<p><b>Colon-targeted PARP inhibitors reduce the risk of systemic side effects of PARP inhibitors.</b> (<b>A</b>) ABSA (36 mg/kg, equivalent to 17 mg/kg of 3-AB) and 3-AB (17 mg/kg) suspended in PBS (1 mL) were administered orally to rats. The rats were killed 2, 4, and 8 h after oral administration. The concentrations of 3-AB in the blood were analyzed using HPLC. (<b>B</b>) The same experiment was conducted with 5-AIQ (10 mg/kg) and AQSA-Glu (30 mg/kg, equivalent to 10 mg/kg of 5-AIQ). The data in A and B are presented as mean ± SD (n = 3).</p>
Full article ">
23 pages, 8929 KiB  
Article
Development of a Multilayer Film Including the Soluble Eggshell Membrane Fraction for the Treatment of Oral Mucosa Lesions
by Karthik Neduri, Giorgia Ailuno, Guendalina Zuccari, Anna Maria Bassi, Stefania Vernazza, Anna Maria Schito, Gabriele Caviglioli and Sara Baldassari
Pharmaceutics 2024, 16(10), 1342; https://doi.org/10.3390/pharmaceutics16101342 - 19 Oct 2024
Viewed by 1077
Abstract
Background/Objectives: Oral diseases causing mucosal lesions are normally treated with local or systemic anti-inflammatory, analgesic and antimicrobial agents. The development of topical formulations, including wound-healing promoters, might speed up the recovery process, improving patients’ quality of life, and reduce the risk of deterioration [...] Read more.
Background/Objectives: Oral diseases causing mucosal lesions are normally treated with local or systemic anti-inflammatory, analgesic and antimicrobial agents. The development of topical formulations, including wound-healing promoters, might speed up the recovery process, improving patients’ quality of life, and reduce the risk of deterioration in health conditions. In this study, a mucoadhesive multilayer film, including a novel biocompatible substance (solubilized eggshell membrane, SESM), was rationally designed. Methods: The SESM preparation procedure was optimized and its biological effects on cell proliferation and inflammation marker gene expression were evaluated in vitro; preformulation studies were conducted to identify the most promising polymers with film-forming properties; then, trilayer films, consisting of an outer layer including chlorhexidine digluconate as a model drug, a supporting layer and a mucoadhesive layer, incorporating SESM, were prepared using the casting method and their mechanical, adhesion and drug release control properties were evaluated. Results: SESM proved to possess a notable wound-healing capacity, inducing a wound closure of 84% in 24 h without inhibiting blood clotting. The films revealed a maximum detachment force from porcine mucosa of approx. 1.7 kPa and maximum in vivo residence time of approx. 200–240 min; finally, they released up to 98% of the loaded drug within 4 h. Conclusions: The formulated trilayer films were found to possess adequate properties, making them potentially suitable for protecting oral lesions and favoring their rapid healing, while releasing antimicrobial substances that might be beneficial in reducing the risk of bacterial infections. Full article
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Figure 1

Figure 1
<p>(<b>a</b>) Viability index extrapolated from MTS assay at 48 and 72 h; (<b>b</b>) IL-8 gene expression at 6 and 24 h (values represented as mean ± SD, <span class="html-italic">n</span> = 3; the symbol (*) denotes statistical significance from the corresponding control (CTR); the symbol (#) denotes statistical significance from the corresponding treatment with LPS (<span class="html-italic">p</span> &lt; 0.05)).</p>
Full article ">Figure 2
<p>(<b>a</b>) Effect of SESM on HaCaT keratinocyte migration at 0, 24 and 48 h; (<b>b</b>) quantitative analysis of wound-healing effect in cell cultures incubated with FBS (positive control), without FBS (negative control) and SESM (values represented as mean ± SD, <span class="html-italic">n</span> = 4; the symbol (*) denotes statistical significance from the negative control; the symbol (#) denotes statistical significance from the positive control (<span class="html-italic">p</span> &lt; 0.05); scale bar = 200 µm).</p>
Full article ">Figure 3
<p>Surface morphology of films with different HPC GF/SESM ratios (scale bar 100 µm).</p>
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<p>Maximum detachment force (<b>a</b>) and work of adhesion (<b>b</b>) of films made of HPC G with/without biopolymers tested on mucin tablet (values represented as mean ± SD, <span class="html-italic">n</span> = 3).</p>
Full article ">Figure 5
<p>YS (<b>a</b>), YM (<b>b</b>), EB (<b>c</b>) and an exemplificative elongation/stress curve (<b>d</b>) of monolayer films (values represented as mean ± SD, <span class="html-italic">n</span> = 3; the symbol (*) denotes statistical significance from the other compositions (<span class="html-italic">p</span> &lt; 0.05)).</p>
Full article ">Figure 6
<p>Blood clotting index. PTFE/SESM denotes SESM deposited on PTFE (values represented as mean ± SD, <span class="html-italic">n</span> = 3; the symbol (*) denotes statistical significance from the other compositions (<span class="html-italic">p</span> &lt; 0.05)).</p>
Full article ">Figure 7
<p>YS (<b>a</b>), YM (<b>b</b>), EB (<b>c</b>) and puncture strength (<b>d</b>) of bilayer films (values represented as mean ± SD, <span class="html-italic">n</span> = 3; the symbol (*) denotes statistical significance from the other compositions (<span class="html-italic">p</span> &lt; 0.05)).</p>
Full article ">Figure 8
<p>Image (<b>a</b>) and scheme (<b>b</b>) of a trilayer film obtained by casting.</p>
Full article ">Figure 9
<p>Maximum detachment force (<b>a</b>) and work of adhesion (<b>b</b>) of trilayer films (only the composition of the backing layer is indicated) tested on mucin tablet (values represented as mean ± SD, <span class="html-italic">n</span> = 3).</p>
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<p>Maximum detachment force (<b>a</b>) and work of adhesion (<b>b</b>) of trilayer films (only the composition of the backing layer is indicated) tested on porcine mucosa (values represented as mean ± SD, <span class="html-italic">n</span> = 3).</p>
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<p>YM (<b>a</b>), EB (<b>b</b>) and puncture strength (<b>c</b>) of trilayer films (only the composition of the backing layer is indicated in the legend; values represented as mean ± SD, <span class="html-italic">n</span> = 3; the symbol (*) denotes statistical significance from the other compositions (<span class="html-italic">p</span> &lt; 0.05)).</p>
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<p>Swelling (<b>a</b>) and erosion (<b>b</b>) indexes of the prepared trilayer films tested in pH 6.8 PBS (only the composition of the backing layer is indicated in the legend; values represented as mean ± SD, <span class="html-italic">n</span> = 3).</p>
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<p>In vitro drug release profiles of the prepared trilayer films tested in simulated saliva (only the composition of the backing layer is indicated in the legend; values represented as mean ± SD, <span class="html-italic">n</span> = 3).</p>
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