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Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications

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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 (20 December 2022) | Viewed by 27305

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Dr. Marta Gallo

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DISAT Department, Politecnico di Torino, corso Duca degli Abruzzi 29, 10129 Torino, Italy
Interests: silica particles; polymer; oxide-based and hybrid systems
Special Issues, Collections and Topics in MDPI journals

Dr. Marta Miola

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Department of Applied Science and Technology, Politecnico di Torino, Turin, Italy
Interests: bioactive glasses/glass-ceramics; antibacterial materials; composites; magnetic materials; inorganic nanoparticles
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Natural active principles still attract interest regarding their therapeutic purposes thanks to the lack of side effects, which makes them particularly appealing for the treatment of chronic diseases (e.g., hypertension and atherosclerosis).

However, strategies for optimising the delivery of natural compounds and enhancing their efficacy are still needed. Natural compounds, in fact, are often affected by low bioavailability, low stability or fast degradation.

Different strategies can be proposed, encompassing, for example, nano- or micro-carriers, polymer-based, lipid-based or oxide-based particles or hybrid systems, and specific formulations.

The present Special Issue aims to collect original research articles, review papers, or reviews regarding systems and approaches to delivering natural compounds, protecting them or enhancing their properties, with particular attention to oral and topical delivery.

Authors are encouraged to share their research on both the synthesis of new systems and their characterization. Works including in vitro and in vivo tests are welcome.

Potential topics concern, but are not limited to:

Role of organic/inorganic carrier in the natural active principle delivery;
Natural active principles to treat skin diseases (e.g., infection, cancer and psoriasis);
Delivery systems to improve natural active principles’ bioavailability and pharmacokinetics.

Dr. Marta Gallo
Prof. Dr. Marta Miola
Guest Editors

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Keywords

natural compounds
topical drug delivery
oral drug delivery
micro- and nano-particles
polymer-, lipid-, oxide-based and hybrid systems
synthesis and characterization
in vitro, in vivo tests

Related Special Issue

Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications, 2nd Edition in Pharmaceutics (2 articles)

Published Papers (10 papers)

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Research

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22 pages, 6235 KiB

Open AccessArticle

Dual Anticancer and Antibacterial Properties of Silica-Based Theranostic Nanomaterials Functionalized with Coumarin343, Folic Acid and a Cytotoxic Organotin(IV) Metallodrug

by Maider Ugalde-Arbizu, John Jairo Aguilera-Correa, Victoria García-Almodóvar, Karina Ovejero-Paredes, Diana Díaz-García, Jaime Esteban, Paulina L. Páez, Sanjiv Prashar, Eider San Sebastian, Marco Filice and Santiago Gómez-Ruiz

Pharmaceutics 2023, 15(2), 560; https://doi.org/10.3390/pharmaceutics15020560 - 07 Feb 2023

Cited by 3 | Viewed by 2255

Abstract

Five different silica nanoparticles functionalized with vitamin B12, a derivative of coumarin found in green plants and a minimum content of an organotin(IV) fragment (1-MSN-Sn, 2-MSN-Sn, 2-SBA-Sn, 2-FSPm-Sn and 2-FSPs-Sn), were identified as excellent anticancer agents against triple negative breast cancer, one of the most diagnosed and aggressive cancerous tumors, with very poor prognosis. Notably, compound 2-MSN-Sn shows selectivity for cancer cells and excellent luminescent properties detectable by imaging techniques once internalized. The same compound is also able to interact with and nearly eradicate biofilms of Staphylococcus aureus, the most common bacteria isolated from chronic wounds and burns, whose treatment is a clinical challenge. 2-MSN-Sn is efficiently internalized by bacteria in a biofilm state and destroys the latter through reactive oxygen species (ROS) generation. Its internalization by bacteria was also efficiently monitored by fluorescence imaging. Since silica nanoparticles are particularly suitable for oral or topical administration, and considering both its anticancer and antibacterial activity, 2-MSN-Sn represents a new dual-condition theranostic agent, based primarily on natural products or their derivatives and with only a minimum amount of a novel metallodrug. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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13 pages, 1121 KiB

Open AccessArticle

Evaluation of Pharmacokinetic and Toxicological Parameters of Arnica Tincture after Dermal Application In Vivo

by Franziska M. Jürgens, Sara M. Robledo and Thomas J. Schmidt

Pharmaceutics 2022, 14(11), 2379; https://doi.org/10.3390/pharmaceutics14112379 - 04 Nov 2022

Cited by 2 | Viewed by 1187

Abstract

Cutaneous leishmaniasis (CL) is classified as a neglected tropical disease by the World Health Organization. As the standard drugs for the treatment of this disease suffer from severe unwanted effects, new effective and safe therapeutic options are required. In our previous work, Arnica tincture showed promising antileishmanial effects in vitro and in vivo. For the potential treatment of human CL patients with Arnica tincture, data on the pharmacokinetic properties of the bioactive, antileishmanial compounds (the sesquiterpene lactone (STL) helenalin and its derivatives) are needed. Therefore, we studied the in vivo absorption of the bioactive compounds after the dermal application of Arnica tincture in rats. Moreover, we analyzed the blood plasma, urine, and feces of the animals by ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). Although the majority (84%) of the applied STLs (1.0 mg) were absorbed, the concentrations in the plasma, urine, and feces were below the limit of detection (0.3 ng/mL) in the samples for UHPLC-HRMS analysis. This result may be explained by extensive metabolism and slow permeation accompanied by the accumulation of STLs in the skin, as described in our previous work. Accordingly, the plasma concentration of STLs after the topical application of Arnica tincture was very far from a dose where toxicity could be expected. Additionally, tests for corrosive or irritant activity as well as acute and repeated-dose dermal toxicity did not show any positive results after the administration of the amounts of Arnica tincture that would be needed for the treatment of CL. Consequently, in the treatment of CL patients with Arnica tincture, no toxic effects are expected, other than the known sensitization potential of the STLs. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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14 pages, 3621 KiB

Open AccessArticle

Supercritical Antisolvent Technique for the Production of Breathable Naringin Powder

by Renata Adami, Paola Russo, Chiara Amante, Chiara De Soricellis, Giovanna Della Porta, Ernesto Reverchon and Pasquale Del Gaudio

Pharmaceutics 2022, 14(8), 1623; https://doi.org/10.3390/pharmaceutics14081623 - 03 Aug 2022

Cited by 4 | Viewed by 1601

Abstract

Flavonoids are polyphenolic compounds largely present in fruits and vegetables possessing antioxidant properties, anti-inflammatory and antibacterial activities. Their use in clinical practice is very poor due to their low bioavailability, susceptibility to oxidation and degradation. Moreover, their slight solubility in biological fluids and a consequent low dissolution rate leads to an irregular absorption from solid dosage forms, even though, anti-inflammatory formulations could be used as support for several disease treatment, i.e. the COVID-19 syndrome. To improve flavonoid bioavailability particle size of the powder can be reduced to make it breathable and to promote the absorption in the lung tissues. Supercritical fluid based antisolvent technique has been used to produce naringin particles, with size, shape and density as well as free flowing properties able to fit inhalation needs. The dried particles are produced with the removal of the solvent at lower temperatures compared to the most used traditional micronization processes, such as spray drying. The best breathable fraction for naringin particles is obtained for particles with a d₅₀~7 µm manufactured at 35 °C-150 bar and at 60 °C-130 bar, corresponding to 32.6% and 36.7% respectively. The powder is produced using a high CO₂ molar fraction (0.99) that assure a better removal of the solvent. NuLi-1 cell line of immortalised bronchial epithelial cells adopted to evaluate powder cytotoxicity indicated after 24 h absence of toxicity at concentration of 25 µM. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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20 pages, 3712 KiB

Open AccessArticle

Zein-Stabilized Nanospheres as Nanocarriers for Boosting the Aphrodisiac Activity of Icariin: Response Surface Optimization and In Vivo Assessment

by Hani Z. Asfour, Nabil A. Alhakamy, Usama A. Fahmy, Osama A. A. Ahmed, Waleed Y. Rizg, Raed I. Felimban, Ashraf B. Abdel-Naim, Mohammad A. S. Abourehab, Rasha A. Mansouri, Ulfat M. Omar and Shaimaa M. Badr-Eldin

Pharmaceutics 2022, 14(6), 1279; https://doi.org/10.3390/pharmaceutics14061279 - 16 Jun 2022

Cited by 1 | Viewed by 1878

Abstract

Icariin (ICA), a main active compound of the Epimedium genus, is used as an aphrodisiac in traditional Chinese herbal medicine. Despite its therapeutic efficacy, ICA displays reduced oral absorption, and therefore, low bioavailability hindered its clinical application. Implementing nanotechnology in the field of formulation has been a focus to improve the efficacy of ICA. In this regard, polymeric nanoparticles find a potential application as drug delivery systems. A nanosphere formula was designed, aiming to improve the drug’s efficacy. The proposed ICA nanosphere formula (tocozeinolate) was optimized using D-optimal response surface design. The concentrations of ICA (X₁), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS, X₂), zein (X₃), and sodium deoxycholate (SDC, X₄) expressed as percentages were investigated as quantitative independent variables. As per the experimental design, 23 formulations were developed, which were investigated for particle size (PS, nm), zeta potential (ZP, mV), and entrapment efficiency (EE, %) as response parameters. Numerical optimization and desirability approach were employed to predict the optimized variable levels that, upon combination, could result in minimized size and maximized zeta potential and ICA entrapment. The optimized ICA–tocozeinolate nanospheres showed a particle size of 224.45 nm, zeta potential of 0.961 mV, and drug entrapment of 65.29% that coincide well with the predicted values. The optimized ICA–tocozeinolate nanospheres were evaluated for sexual behavior in Wistar male rats compared to raw ICA at equivalent doses (20 mg/kg). In vivo assessment results showed significant sexual behavior enhancement by the optimized formulation, as evidenced by decreased average time of both mount latency (ML) and ejaculation latency (EL) to almost half those of raw ICA. Additionally, intromission latency (IL) time was reduced by 41% compared to the raw ICA. These results highlighted the potential of the proposed ICA–tocozeinolate nanospheres as a promising platform for improving the delivery and efficacy of therapeutic agents. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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17 pages, 2265 KiB

Open AccessArticle

Dermal Absorption of Sesquiterpene Lactones from Arnica Tincture

by Franziska M. Jürgens, Fabian C. Herrmann, Sara M. Robledo and Thomas J. Schmidt

Pharmaceutics 2022, 14(4), 742; https://doi.org/10.3390/pharmaceutics14040742 - 29 Mar 2022

Cited by 3 | Viewed by 1978

Abstract

Arnica tincture is a traditional herbal medicine used to treat blunt injuries, e.g., bruises and squeezes. In addition, a potential new use in the treatment of cutaneous leishmaniasis is currently under investigation. Therefore, detailed information about the dermal absorption of the tincture and especially its bioactive constituents, sesquiterpene lactones (STLs) of the helenalin- and 11α,13-dihydrohelenalin type, is mandatory. Consequently, this article reports on dermal absorption studies of Arnica tincture using diffusion cells and porcine skin as well as two human skin samples with different permeability. The amounts of STLs on the skin surfaces, in skin extracts and in the receptor fluids were quantified by ultra-high-performance liquid chromatography with high-resolution mass spectrometry (UHPLC-HRMS). It was found that Arnica STLs permeated into the receptor fluid already 4 h after the application, but the amount was rather low. Within 48 h, a maximum of 8.4%, 14.6% and 36.4% of STLs permeated through porcine skin, human skin A (trans-epidermal water loss (TEWL) = 11.518 g·m⁻²·h⁻¹) and the more permeable human skin B (TEWL = 17.271 g·m⁻²·h⁻¹), respectively. The majority of STLs was absorbed (penetrated into the skin; 97.6%, 97.8% and 99.3%) after 48 h but a huge portion could not be extracted from skin and is expected to be irreversibly bound to skin proteins. To better visualize the analytes in different skin layers, a fluorescence-labeled STL, helenalin 3,4-dimethoxycinnamate, was synthesized. Fluorescence microscopic images depict an accumulation of the fluorescent derivative in the epidermis. For the treatment of local, cutaneous complaints, an enrichment of the bioactive substances in the skin may be considered beneficial. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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14 pages, 2497 KiB

Open AccessArticle

Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer

by Yanjie Liu, Fan Yang, Xiuhua Zhao, Siying Wang, Qilei Yang and Xiaoxue Zhang

Pharmaceutics 2022, 14(1), 94; https://doi.org/10.3390/pharmaceutics14010094 - 01 Jan 2022

Cited by 24 | Viewed by 2808

Abstract

Hesperetin (HES) is a key biological active ingredient in citrus peels, and is one of the natural flavonoids that attract the attention of researchers due to its numerous therapeutic bioactivities that have been identified in vitro. As a bioenhancer, piperine (PIP) can effectively improve the absorption of insoluble drugs in vivo. In the present study, a cocrystal of HES and PIP was successfully obtained through solution crystallization. The single-crystal structure was illustrated and comprehensive characterization of the cocrystal was conducted. The cocrystal was formed by two drug molecules at a molar ratio of 1:1, which contained O–H–O hydrogen bonds between the carbonyl and ether oxygen of PIP and the phenolic hydroxyl group of HES. In addition, a solubility experiment was performed on powder cocrystal in simulated gastrointestinal fluid, and the result revealed that the cocrystal improves the dissolution behavior of HES compared with that of the pure substance. Furthermore, HES’s bioavailability in the cocrystal was six times higher than that of pristine drugs. These results may provide an efficient oral formulation for HES. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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22 pages, 5114 KiB

Open AccessArticle

Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide

by Mohamed A. Ali, Magdy I. Mohamed, Mohamed A. Megahed, Tamer M. Abdelghany and Khalid M. El-Say

Pharmaceutics 2021, 13(11), 1741; https://doi.org/10.3390/pharmaceutics13111741 - 20 Oct 2021

Cited by 5 | Viewed by 2431

Abstract

Critical adverse effects and frequent administration, three times per day, limit the use of flutamide (FLT) as a chemotherapeutic agent in the treatment of prostate cancer. Therefore, our research aimed to develop new cholesterol-based nanovesicles for delivering FLT to malignant cells in an endeavor to maximize its therapeutic efficacy and minimize undesired adverse effects. Draper–Lin small composite design was used to optimize the critical quality attributes of FLT-loaded niosomes and ensure the desired product quality. The influence of the selected four independent variables on mean particle size (Y₁), zeta potential (Y₂), drug entrapment efficiency (Y₃), and the cumulative drug release after 24 h (Y₄) was examined. The optimized nanovesicles were assessed for their in vitro cytotoxicity, ex-vivo absorption via freshly excised rabbit intestine as well as in vivo pharmacokinetics on male rats. TEM confirmed nanovescicles’ spherical shape with bilayer structure. Values of dependent variables were 748.6 nm, −48.60 mV, 72.8% and 72.2% for Y₁, Y₂, Y₃ and Y₄, respectively. The optimized FLT-loaded niosomes exerted high cytotoxic efficacy against human prostate cancer cell line (PC-3) with an IC₅₀ value of 0.64 ± 0.04 µg/mL whilst, it was 1.88 ± 0.16 µg/mL for free FLT. Moreover, the IC₅₀ values on breast cancer cell line (MCF-7) were 0.27 ± 0.07 µg/mL and 4.07 ± 0.74 µg/mL for FLT-loaded niosomes and free FLT, respectively. The permeation of the optimized FLT-loaded niosomes through the rabbit intestine showed an enhancement ratio of about 1.5 times that of the free FLT suspension. In vivo pharmacokinetic study displayed an improvement in oral bioavailability of the optimized niosomal formulation with AUC and C_max values of 741.583 ± 33.557 μg/mL × min and 6.950 ± 0.45 μg/mL compared to 364.536 ± 45.215 μg/mL × min and 2.650 ± 0.55 μg/mL for the oral FLT suspension. With these promising findings, we conclude that encapsulation of FLT in cholesterol-loaded nanovesicles enhanced its anticancer activity and oral bioavailability which endorse its use in the management of prostate cancer. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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Review

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24 pages, 2329 KiB

Open AccessReview

Cyclodextrin-Based Delivery Systems and Hydroxycinnamic Acids: Interactions and Effects on Crucial Parameters Influencing Oral Bioavailability—A Review

by Kleyton Santos Veras, Flávia Nathiely Silveira Fachel, Valquiria Linck Bassani, Helder Ferreira Teixeira and Letícia Scherer Koester

Pharmaceutics 2022, 14(11), 2530; https://doi.org/10.3390/pharmaceutics14112530 - 20 Nov 2022

Cited by 3 | Viewed by 1335

Abstract

Hydroxycinnamic acids (HCAs) are a subclass of phenolic acids presenting caffeic acid (CA), chlorogenic acid (CGA), coumaric acid (COA) isomers, ferulic acid (FA), and rosmarinic acid (RA) as the major representants, being broadly distributed into vegetal species and showing a range of biological potentials. Due to the low oral bioavailability of the HCAs, the development of delivery systems to promote better administration by the oral route is demanding. Among the systems, cyclodextrin (CD)-based delivery systems emerge as an important technology to solve this issue. Regarding these aspects, in this review, CD-based delivery systems containing HCAs are displayed, described, and discussed concerning the degree of interaction and their effects on crucial parameters that affect the oral bioavailability of HCAs. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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23 pages, 7060 KiB

Open AccessReview

Injectable Hydrogel-Based Combination Cancer Immunotherapy for Overcoming Localized Therapeutic Efficacy

by Jeongrae Kim, Yongwhan Choi, Dong-Hwee Kim, Hong Yeol Yoon and Kwangmeyung Kim

Pharmaceutics 2022, 14(9), 1908; https://doi.org/10.3390/pharmaceutics14091908 - 08 Sep 2022

Cited by 8 | Viewed by 2776

Abstract

Various immunotherapeutic agents that can elicit antitumor immune responses have recently been developed with the potential for improved efficacy in treating cancer. However, insufficient delivery efficiency at the tumor site, along with severe side effects after systemic administration of these anticancer agents, have hindered their therapeutic application in cancer immunotherapy. Hydrogels that can be directly injected into tumor sites have been developed to help modulate or elicit antitumor responses. Based on the biocompatibility, degradability, and controllable mechanochemical properties of these injectable hydrogels, various types of immunotherapeutic agents, such as hydrophobic anticancer drugs, cytokines, antigens, and adjuvants, have been easily and effectively encapsulated, resulting in the successful elicitation of antitumor immune responses and the retention of long-term immunotherapeutic efficacy following administration. This review summarizes recent advances in combination immunotherapy involving injectable hydrogel-based chemoimmunotherapy, photoimmunotherapy, and radioimmunotherapy. Finally, we briefly discuss the current limitations and future perspectives on injectable hydrogels for the effective combination immunotherapy of tumors. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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21 pages, 1498 KiB

Open AccessReview

Phytosomes as an Emerging Nanotechnology Platform for the Topical Delivery of Bioactive Phytochemicals

by Waleed S. Alharbi, Fahad A. Almughem, Alshaimaa M. Almehmady, Somayah J. Jarallah, Wijdan K. Alsharif, Nouf M. Alzahrani and Abdullah A. Alshehri

Pharmaceutics 2021, 13(9), 1475; https://doi.org/10.3390/pharmaceutics13091475 - 15 Sep 2021

Cited by 67 | Viewed by 7487

Abstract

The emergence of phytosome nanotechnology has a potential impact in the field of drug delivery and could revolutionize the current state of topical bioactive phytochemicals delivery. The main challenge facing the translation of the therapeutic activity of phytochemicals to a clinical setting is the extremely low absorption rate and poor penetration across biological barriers (i.e., the skin). Phytosomes as lipid-based nanocarriers play a crucial function in the enhancement of pharmacokinetic and pharmacodynamic properties of herbal-originated polyphenolic compounds, and make this nanotechnology a promising tool for the development of new topical formulations. The implementation of this nanosized delivery system could enhance the penetration of phytochemicals across biological barriers due to their unique physiochemical characteristics, improving their bioavailability. In this review, we provide an outlook on the current knowledge of the biological barriers of phytoconstituents topical applications. The great potential of the emerging nanotechnology in the delivery of bioactive phytochemicals is reviewed, with particular focus on phytosomes as an innovative lipid-based nanocarrier. Additionally, we compared phytosomes with liposomes as the gold standard of lipid-based nanocarriers for the topical delivery of phytochemicals. Finally, the advantages of phytosomes in topical applications are discussed. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications)

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