Editorial

3 pages, 179 KiB

Open AccessEditorial

Topical Drug Delivery: Innovative Controlled Release Systems

by Daniele Ribeiro de Araujo and Cristina Padula

Pharmaceutics 2023, 15(6), 1716; https://doi.org/10.3390/pharmaceutics15061716 - 13 Jun 2023

Cited by 1 | Viewed by 925

One of the most innovative strategies for administrating bioactive molecules is the design of adequate drug delivery systems [...] Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

Research

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14 pages, 6323 KiB

Open AccessArticle

Buccal Permeation of Polysaccharide High Molecular Weight Compounds: Effect of Chemical Permeation Enhancers

by Adriana Fantini, Luca Giulio, Andrea Delledonne, Silvia Pescina, Cristina Sissa, Sara Nicoli, Patrizia Santi and Cristina Padula

Pharmaceutics 2023, 15(1), 129; https://doi.org/10.3390/pharmaceutics15010129 - 30 Dec 2022

Cited by 2 | Viewed by 1682

Abstract

The greatest achievement in the advanced drug delivery field should be the optimization of non-invasive formulations for the delivery of high molecular weight compounds. Peptides, proteins, and other macromolecules can have poor membrane permeation, principally due to their large molecular weight. The aim [...] Read more.

The greatest achievement in the advanced drug delivery field should be the optimization of non-invasive formulations for the delivery of high molecular weight compounds. Peptides, proteins, and other macromolecules can have poor membrane permeation, principally due to their large molecular weight. The aim of this work was to explore the possibility of administering fluorescently labeled dextrans (molecular weight 4–150 kDa) across the buccal mucosa. Permeation experiments across pig esophageal mucosa were carried out using fatty acids and bile salts as penetration enhancers. The data obtained show that it is possible to increase or promote the mucosa permeation of high molecular weight dextrans by using caprylic acid or sodium taurocholate as the chemical enhancers. With these enhancers, dextrans with molecular weight of 70 and 150 kDa, that in passive conditions did not permeate, could cross the mucosa in detectable amounts. FD-70 and FD-150 showed comparable permeability values, despite the molecular weight difference. The results obtained in the present work suggest that the buccal administration of high molecular weight compounds is feasible. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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20 pages, 6492 KiB

Open AccessArticle

Monoketonic Curcuminoid-Lidocaine Co-Deliver Using Thermosensitive Organogels: From Drug Synthesis to Epidermis Structural Studies

by Aryane A. Vigato, Ian P. Machado, Matheus del Valle, Patricia A. da Ana, Anderson F. Sepulveda, Fabiano Yokaichiya, Margareth K. K. D. Franco, Messias C. Loiola, Giovana R. Tófoli, Cintia Maria S. Cereda, Mirela I. de Sairre and Daniele R. de Araujo

Pharmaceutics 2022, 14(2), 293; https://doi.org/10.3390/pharmaceutics14020293 - 27 Jan 2022

Cited by 10 | Viewed by 2949

Abstract

Organogels (ORGs) are remarkable matrices due to their versatile chemical composition and straightforward preparation. This study proposes the development of ORGs as dual drug-carrier systems, considering the application of synthetic monoketonic curcuminoid (m-CUR) and lidocaine (LDC) to treat topical inflammatory lesions. The monoketone [...] Read more.

Organogels (ORGs) are remarkable matrices due to their versatile chemical composition and straightforward preparation. This study proposes the development of ORGs as dual drug-carrier systems, considering the application of synthetic monoketonic curcuminoid (m-CUR) and lidocaine (LDC) to treat topical inflammatory lesions. The monoketone curcuminoid (m-CUR) was synthesized by using an innovative method via a NbCl₅–acid catalysis. ORGs were prepared by associating an aqueous phase composed of Pluronic F127 and LDC hydrochloride with an organic phase comprising isopropyl myristate (IPM), soy lecithin (LEC), and the synthesized m-CUR. Physicochemical characterization was performed to evaluate the influence of the organic phase on the ORGs supramolecular organization, permeation profiles, cytotoxicity, and epidermis structural characteristics. The physico-chemical properties of the ORGs were shown to be strongly dependent on the oil phase constitution. Results revealed that the incorporation of LEC and m-CUR shifted the sol-gel transition temperature, and that the addition of LDC enhanced the rheological G′/G″ ratio to higher values compared to original ORGs. Consequently, highly structured gels lead to gradual and controlled LDC permeation profiles from the ORG formulations. Porcine ear skin epidermis was treated with ORGs and evaluated by infrared spectroscopy (FTIR), where the stratum corneum lipids were shown to transition from a hexagonal to a liquid crystal phase. Quantitative optical coherence tomography (OCT) analysis revealed that LEC and m-CUR additives modify skin structuring. Data from this study pointed ORGs as promising formulations for skin-delivery. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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12 pages, 1741 KiB

Open AccessArticle

New Strategies for Improving Budesonide Skin Retention

by Cristina Padula, Ian Pompermayer Machado, Aryane Alves Vigato and Daniele Ribeiro de Araujo

Pharmaceutics 2022, 14(1), 30; https://doi.org/10.3390/pharmaceutics14010030 - 24 Dec 2021

Cited by 5 | Viewed by 2488

Abstract

The aim of this work was to evaluate the ex vivo effect of the combination of two strategies, complexation with cyclodextrin, and poloxamer hydrogels, for improving water solubility in the dermal absorption of budesonide. Two hydrogels containing 20% poloxamer 407, alone or in [...] Read more.

The aim of this work was to evaluate the ex vivo effect of the combination of two strategies, complexation with cyclodextrin, and poloxamer hydrogels, for improving water solubility in the dermal absorption of budesonide. Two hydrogels containing 20% poloxamer 407, alone or in combination with poloxamer 403, were prepared. Each formulation was loaded with 0.05% budesonide, using either pure budesonide or its inclusion complex with hydroxypropyl-β-cyclodextrin, and applied in finite dose conditions on porcine skin. The obtained results showed that for all formulations, budesonide accumulated preferentially in the epidermis compared to the dermis. The quantity of budesonide recovered in the receptor compartment was, in all cases, lower than the LOQ of the analytical method, suggesting the absence of possible systemic absorption. The use of a binary poloxamer mixture reduced skin retention, in line with the lower release from the vehicle. When the hydrogels were formulated with the inclusion complex, an increase in budesonide skin retention was observed with both hydrogels. Poloxamer hydrogel proved to be a suitable vehicle for cutaneous administration of budesonide. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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23 pages, 6485 KiB

Open AccessArticle

Improvement of Imiquimod Solubilization and Skin Retention via TPGS Micelles: Exploiting the Co-Solubilizing Effect of Oleic Acid

by Martina Ghezzi, Silvia Pescina, Andrea Delledonne, Ilaria Ferraboschi, Cristina Sissa, Francesca Terenziani, Paula De Freitas Rosa Remiro, Patrizia Santi and Sara Nicoli

Pharmaceutics 2021, 13(9), 1476; https://doi.org/10.3390/pharmaceutics13091476 - 15 Sep 2021

Cited by 16 | Viewed by 3662

Abstract

Imiquimod (IMQ) is an immunostimulant drug approved for the topical treatment of actinic keratosis, external genital-perianal warts as well as superficial basal cell carcinoma that is used off-label for the treatment of different forms of skin cancers, including some malignant melanocytic proliferations such [...] Read more.

Imiquimod (IMQ) is an immunostimulant drug approved for the topical treatment of actinic keratosis, external genital-perianal warts as well as superficial basal cell carcinoma that is used off-label for the treatment of different forms of skin cancers, including some malignant melanocytic proliferations such as lentigo maligna, atypical nevi and other in situ melanoma-related diseases. Imiquimod skin delivery has proven to be a real challenge due to its very low water-solubility and reduced skin penetration capacity. The aim of the work was to improve the drug solubility and skin retention using micelles of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of vitamin E, co-encapsulating various lipophilic compounds with the potential ability to improve imiquimod affinity for the micellar core, and thus its loading into the nanocarrier. The formulations were characterized in terms of particle size, zeta potential and stability over time and micelles performance on the skin was evaluated through the quantification of imiquimod retention in the skin layers and the visualization of a micelle-loaded fluorescent dye by two-photon microscopy. The results showed that imiquimod solubility strictly depends on the nature and concentration of the co-encapsulated compounds. The micellar formulation based on TPGS and oleic acid was identified as the most interesting in terms of both drug solubility (which was increased from few µg/mL to 1154.01 ± 112.78 µg/mL) and micellar stability (which was evaluated up to 6 months from micelles preparation). The delivery efficiency after the application of this formulation alone or incorporated in hydrogels showed to be 42- and 25-folds higher than the one of the commercial creams. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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17 pages, 1765 KiB

Open AccessArticle

Improvement of Biophysical Skin Parameters of Topically Applied Fermented Soybean Extract-Loaded Niosomes with No Systemic Toxicity in Ovariectomized Rats

by Wandee Rungseevijitprapa, Bancha Yingngam and Chaiyavat Chaiyasut

Pharmaceutics 2021, 13(7), 1068; https://doi.org/10.3390/pharmaceutics13071068 - 12 Jul 2021

Cited by 8 | Viewed by 2200

Abstract

Despite the known beneficial impacts of estrogen used as hormone replacement therapy to ameliorate signs of skin aging in postmenopausal women, its compliance rates are low. A significant amount of estrogen may be absorbed into the blood circulation and can lead to systemic [...] Read more.

Despite the known beneficial impacts of estrogen used as hormone replacement therapy to ameliorate signs of skin aging in postmenopausal women, its compliance rates are low. A significant amount of estrogen may be absorbed into the blood circulation and can lead to systemic actions. Soy isoflavone exhibits biological activities similar to synthetic estrogen because it is a heterocyclic phenolic compound. The disadvantage of most topical ingredients based on isoflavone is that they contain biologically inactive glycoside forms, which must be converted to a readily absorbed aglycone for the topical application. The purposes of this study were to develop niosomes-loaded Aspergillus oryzae-fermented soybean extract (FSE) to enhance skin absorption with proven systemic side effect compared to estrogen application. Skin hydration and viscoelasticity of 75 days post-ovariectomized (OVX) Wistar rats following 84-day topical treatment with various tested gel formulations containing fermented soybean extract (FSE) were evaluated. The tested formulations were gel + FSE nanoniosomes, gel + FSE microniosomes, gel + FSE (200 µg FSE/9 cm²/rat), gel + blank nanoniosomes (a negative control), and gel + 17β-estradiol (E2) nanoniosomes (a positive control, 20 µg E2/9 cm²/rat). Changes in vaginal cornifications and weights of uteri, livers, and kidneys in the OVX rats and signs of primary skin irritation in the rabbits were evaluated for their toxicities. Results showed that FSE-loaded nanoniosomes improved the skin hydration and viscoelasticity better than gel + FSE microniosomes and gel + FSE, respectively, but lower than those of gel + E2 nanoniosomes (p < 0.05). Unlike all gel + E2 nanoniosomes, the FSE formulations showed no changes in vaginal cells and weights of uteri, livers, and kidneys and no signs of skin irritation. In conclusion, The FSE niosome-based gels should be promising candidates for delivering phytoestrogens against signs of skin aging with no systemic toxicities. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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15 pages, 2667 KiB

Open AccessArticle

Topical Nanoemulgel for the Treatment of Skin Cancer: Proof-of-Technology

by Sreeharsha Nagaraja, Girish Meravanige Basavarajappa, Mahesh Attimarad and Swati Pund

Pharmaceutics 2021, 13(6), 902; https://doi.org/10.3390/pharmaceutics13060902 - 18 Jun 2021

Cited by 27 | Viewed by 4195

Abstract

The present study is a mechanistic validation of ‘proof-of-technology’ for the effective topical delivery of chrysin nanoemulgel for localized, efficient treatment of melanoma-affected skin. Background: Currently available treatments for skin cancer are inefficient due to systemic side effects and poor transcutaneous permeation, thereby [...] Read more.

The present study is a mechanistic validation of ‘proof-of-technology’ for the effective topical delivery of chrysin nanoemulgel for localized, efficient treatment of melanoma-affected skin. Background: Currently available treatments for skin cancer are inefficient due to systemic side effects and poor transcutaneous permeation, thereby presenting a formidable challenge for the development of novel nanocarriers. Methods: We opted for a novel approach and formulated a nanocomplex system composed of hydrophobic chrysin dissolved in a lipid mix, which was further nanoemulsified in Pluronic^® F-127 gel to enhance physicochemical and biopharmaceutic characteristics. Chrysin, a flavone extracted from passion flowers, exhibits potential anti-cancer activities; however, it has limited applicability due to its poor solubility. Pseudo-ternary phase diagrams were constructed to identify the best self-nanoemulsifying region by varying the compositions of oil, Caproyl^® 90 surfactant, Tween^® 80, and co-solvent Transcutol^® HP. Chrysin-loaded nanoemulsifying compositions were characterized for various physicochemical properties. Results: This thermodynamically stable, self-emulsifying drug delivery system showed a mean droplet size of 156.9 nm, polydispersity index of 0.26, and viscosity of 9100 cps after dispersion in gel. Mechanical characterization using Texture Analyzer exhibited that the gel had a hardness of 487 g and adhesiveness of 500 g. Ex vivo permeation through rat abdominal skin revealed significant improvement in percutaneous absorption measured as flux, the apparent permeability coefficient, the steady-state diffusion coefficient, and drug deposition. In vitro cytotoxicity on A375 and SK-MEL-2 cell lines showed a significantly improved therapeutic effect, thus ensuring reduction in dose. The safety of the product was established through biocompatibility testing on the L929 cell line. Conclusion: Aqueous, gel-based, topical, nanoemulsified chrysin is a promising technology approach for effective localized transcutaneous delivery that will help reduce the frequency and overall dose usage and ultimately improve the therapeutic index. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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15 pages, 7533 KiB

Open AccessArticle

Formulations Based on Drug Loaded Aptamer-Conjugated Liposomes as a Viable Strategy for the Topical Treatment of Basal Cell Carcinoma—In Vitro Tests

by Anca N. Cadinoiu, Delia M. Rata, Leonard I. Atanase, Cosmin T. Mihai, Simona E. Bacaita and Marcel Popa

Pharmaceutics 2021, 13(6), 866; https://doi.org/10.3390/pharmaceutics13060866 - 11 Jun 2021

Cited by 31 | Viewed by 2851

Abstract

Topical liposomal drug formulations containing AS1411-aptamer conjugated liposomes were designed to deliver in a sustained way the 5-fluorouracil to the tumor site but also to increase the compliance of patients with basal cell carcinoma. The 5-fluorouracil penetrability efficiency through the Strat-M membrane and [...] Read more.

Topical liposomal drug formulations containing AS1411-aptamer conjugated liposomes were designed to deliver in a sustained way the 5-fluorouracil to the tumor site but also to increase the compliance of patients with basal cell carcinoma. The 5-fluorouracil penetrability efficiency through the Strat-M membrane and the skin irritation potential of the obtained topical liposomal formulations were evaluated in vitro and the Korsmeyer Peppas equation was considered as the most appropriate to model the drug release. Additionally, the efficiency of cytostatic activity for targeted antitumor therapy and the hemolytic capacity were performed in vitro. The obtained results showed that the optimal liposomal formulation is a crosslinked gel based on sodium alginate and hyaluronic acid containing AS1411-aptamer conjugated liposomes loaded with 5-fluorouracil, which appeared to have favorable biosafety effects and may be used as a new therapeutic approach for the topical treatment of basal cell carcinoma. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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16 pages, 4035 KiB

Open AccessArticle

In Vitro–In Vivo Correlation in Dermal Delivery: The Role of Excipients

by Avnish Patel, Fotis Iliopoulos, Peter J. Caspers, Gerwin J. Puppels and Majella E. Lane

Pharmaceutics 2021, 13(4), 542; https://doi.org/10.3390/pharmaceutics13040542 - 13 Apr 2021

Cited by 22 | Viewed by 3653

Abstract

The composition of topical and transdermal formulations is known to determine the rate and the extent of drug delivery to and through the skin. However, to date, the role of excipients in these formulations on skin delivery of actives has received little attention [...] Read more.

The composition of topical and transdermal formulations is known to determine the rate and the extent of drug delivery to and through the skin. However, to date, the role of excipients in these formulations on skin delivery of actives has received little attention from scientists in the field. Monitoring skin absorption of both drug and vehicle may provide insights into the mechanism by which excipients promote permeation and may facilitate the design of effective and safer products. Previously, we have investigated the use of quantitative Confocal Raman Spectroscopy (CRS) to investigate the delivery of an active to the skin, and we also reported the first fully quantitative study that compared this method with the well-established in vitro permeation test (IVPT) model. To further explore the potential of quantitative CRS in assessing topical delivery, the present work investigated the effects of commonly used excipients on the percutaneous absorption of a model drug, ibuprofen (IBU). Permeation of IBU and selected solvents following finite dose applications to human skin was determined in vitro and in vivo by Franz diffusion studies and quantitative CRS, respectively. The solvents used were propylene glycol (PG), dipropylene glycol (DPG), tripropylene glycol (TPG), and polyethylene glycol 300 (PEG 300). Overall, the cumulative amounts of IBU that permeated at 24 h in vitro were similar for PG, DPG, and TPG (p > 0.05). These three vehicles outperformed PEG 300 (p < 0.05) in terms of drug delivery. Concerning the vehicles, the rank order for in vitro skin permeation was DPG ≥ PG > TPG, while PEG 300 did not permeate the skin. A linear relationship between maximum vehicle and IBU flux in vitro was found, with a correlation coefficient (R²) of 0.95. When comparing in vitro with in vivo data, a positive in vitro–in vivo (IVIV) correlation between the cumulative permeation of IBU in vitro and the total amount of IBU that penetrated the stratum corneum (SC) in vivo was observed, with a Pearson correlation coefficient (R²) of 0.90. A strong IVIV correlation, R² = 0.82, was found following the linear regression of the cumulative number of solvents permeated in vitro and the corresponding skin uptake in vivo measured with CRS. This is the first study to correlate in vivo permeation of solvents measured by CRS with data obtained by in vitro diffusion studies. The IVIV correlations suggest that CRS is a powerful tool for profiling drug and vehicle delivery from dermal formulations. Future studies will examine additional excipients with varying physicochemical properties. Ultimately, these findings are expected to lead to new approaches for the design, evaluation, and optimization of formulations that target actives to and through the skin. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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Review

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31 pages, 3437 KiB

Open AccessReview

Improved Topical Drug Delivery: Role of Permeation Enhancers and Advanced Approaches

by Victor Hmingthansanga, Nidhi Singh, Superna Banerjee, Sivakumar Manickam, Ravichandiran Velayutham and Subramanian Natesan

Pharmaceutics 2022, 14(12), 2818; https://doi.org/10.3390/pharmaceutics14122818 - 15 Dec 2022

Cited by 22 | Viewed by 4898

Abstract

The delivery of drugs via transdermal routes is an attractive approach due to ease of administration, bypassing of the first-pass metabolism, and the large skin surface area. However, a major drawback is an inability to surmount the skin’s stratum corneum (SC) layer. Therefore, [...] Read more.

The delivery of drugs via transdermal routes is an attractive approach due to ease of administration, bypassing of the first-pass metabolism, and the large skin surface area. However, a major drawback is an inability to surmount the skin’s stratum corneum (SC) layer. Therefore, techniques reversibly modifying the stratum corneum have been a classical approach. Surmounting the significant barrier properties of the skin in a well-organised, momentary, and harmless approach is still challenging. Chemical permeation enhancers (CPEs) with higher activity are associated with certain side effects restricting their advancement in transdermal drug delivery. Furthermore, complexity in the interaction of CPEs with the skin has led to difficulty in elucidating the mechanism of action. Nevertheless, CPEs-aided transdermal drug delivery will accomplish its full potential due to advancements in analytical techniques, synthetic chemistry, and combinatorial studies. This review focused on techniques such as drug–vehicle interaction, vesicles and their analogues, and novel CPEs such as lipid synthesis inhibitors (LSIs), cell-penetrating peptides (CPPs), and ionic liquids (ILs). In addition, different types of microneedles, including 3D-printed microneedles, have been focused on in this review. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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Other

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11 pages, 4073 KiB

Open AccessPerspective

A Perspective on Imiquimod Microneedles for Treating Warts

by Tsu-Man Chiu, Ping-Chun Hsu, Mohd Yaqub Khan, Cheng-An J. Lin, Chun-Hung Lee, Tsai-Ching Hsu, Min-Hua Chen and Nobutaka Hanagata

Pharmaceutics 2021, 13(5), 607; https://doi.org/10.3390/pharmaceutics13050607 - 22 Apr 2021

Cited by 8 | Viewed by 2744

Abstract

Warts are a common skin problem and are caused by infection with a virus. Warts are currently mainly treated by therapies involving ablating tissue or interrupting cellular division. However, all these existing treatments are either invasive or cause skin pain and tissue destruction. [...] Read more.

Warts are a common skin problem and are caused by infection with a virus. Warts are currently mainly treated by therapies involving ablating tissue or interrupting cellular division. However, all these existing treatments are either invasive or cause skin pain and tissue destruction. Imiquimod is a synthetic compound that belongs to the imidazoquinolinone family. It has been successfully used as a topical drug to treat external anogenital warts. However, topical imiquimod cream for warts is restricted by low skin permeability, and several side effects such as itching, pain, and erosions occur most frequently following topical treatment. Microneedle technology, a minimally invasive drug delivery system, has the potential to overcome the barrier of the stratum corneum. This technique would also offer a painless treatment choice and provide personalized therapies. In the study, we loaded imiquimod within dissolving microneedles using the molding method. Gelatin was used as a structural material for microneedle formation without adding a crosslinker. To our knowledge, this is the first study of using dissolving microneedles and exploring their utilization with imiquimod for the treatment of warts. First, we added fluorescent dye and trypan blue into the microneedles to evaluate the status of drugs in the microneedles and the degradation property of microneedles made of gelatin, respectively. Here we also prove the strength of the imiquimod microneedles and study their capability to penetrate the skin. The results show no apparent differences in mechanical failure after an additional imiquimod-loaded. Besides, we provide evidence that imiquimod microneedles induce secreted embryonic alkaline phosphatase (SEAP) in the RAW 264.7 macrophages. Gelatin does not affect the imiquimod in microneedles; a similar immune response was affected by the imiquimod alone or imiquimod complexed with gelatin. Our research demonstrates a proof of concept of using imiquimod microneedles for future warts treatment. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Innovative Controlled Release Systems)

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