Editorial

4 pages, 185 KiB

Open AccessEditorial

Clay-Based Pharmaceutical Formulations and Drug Delivery Systems

by Fátima García-Villén and César Viseras

Pharmaceutics 2020, 12(12), 1142; https://doi.org/10.3390/pharmaceutics12121142 - 25 Nov 2020

Cited by 5 | Viewed by 1853

The use of minerals as ingredients in health care products is a classical and active pharmaceutical subject [...] Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

Research

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15 pages, 5804 KiB

Open AccessArticle

Cellular Analysis and Chemotherapeutic Potential of a Bi-Functionalized Halloysite Nanotube

by Yangyang Luo, Ahmed Humayun, Teresa A. Murray, Benjamin S. Kemp, Antwine McFarland, Xuan Liu and David K. Mills

Pharmaceutics 2020, 12(10), 962; https://doi.org/10.3390/pharmaceutics12100962 - 13 Oct 2020

Cited by 21 | Viewed by 2407

Abstract

The surface of halloysite nanotubes (HNTs) was bifunctionalized with two ligands—folic acid and a fluorochrome. In tandem, this combination should selectively target cancer cells and provide a means for imaging the nanoparticle. Modified bi-functionalized HNTs (bi-HNTs) were then doped with the anti-cancer drug [...] Read more.

The surface of halloysite nanotubes (HNTs) was bifunctionalized with two ligands—folic acid and a fluorochrome. In tandem, this combination should selectively target cancer cells and provide a means for imaging the nanoparticle. Modified bi-functionalized HNTs (bi-HNTs) were then doped with the anti-cancer drug methotrexate. bi-HNTs were characterized and subjected to in vitro tests to assess cellular growth and changes in cellular behavior in three cell lines—colon cancer, osteosarcoma, and a pre-osteoblast cell line (MC3T3-E1). Cell viability, proliferation, and cell uptake efficiency were assessed. The bi-HNTs showed cytocompatibility at a wide range of concentrations. Compared with regular-sized HNTs, reduced HNTs (~6 microns) were taken up by cells in more significant amounts, but increased cytotoxicity lead to apoptosis. Multi-photon images confirmed the intracellular location of bi-HNTs, and the method of cell entry was mainly through caveolae-mediated endocytosis. The bi-HNTs showed a high drug loading efficiency with methotrexate and a prolonged period of release. Most importantly, bi-HNTs were designed as a drug carrier to target cancer cells specifically, and imaging data shows that non-cancerous cells were unaffected after exposure to MTX-doped bi-HNTs. All data provide support for our nanoparticle design as a mechanism to selectively target cancer cells and significantly reduce the side-effects caused by off-targeting of anti-cancer drugs. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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16 pages, 3224 KiB

Open AccessArticle

Praziquantel–Clays as Accelerated Release Systems to Enhance the Low Solubility of the Drug

by Ana Borrego-Sánchez, Rita Sánchez-Espejo, Fátima García-Villén, César Viseras and C. Ignacio Sainz-Díaz

Pharmaceutics 2020, 12(10), 914; https://doi.org/10.3390/pharmaceutics12100914 - 24 Sep 2020

Cited by 18 | Viewed by 2744

Abstract

Praziquantel is an antiparasitic drug indicated for the treatment of the schistosomiasis disease. This drug has very low aqueous solubility, requiring high oral doses for its administration which gives rise to side effects, therapeutic noncompliance and the appearance of resistant forms of the [...] Read more.

Praziquantel is an antiparasitic drug indicated for the treatment of the schistosomiasis disease. This drug has very low aqueous solubility, requiring high oral doses for its administration which gives rise to side effects, therapeutic noncompliance and the appearance of resistant forms of the parasite. Clay minerals, like sepiolite and montmorillonite, are innocuous, non-toxic, biocompatible and low-cost excipients. Additionally, clays have high adsorbent properties that allow them to encapsulate drugs in nanometric spaces present in the channels in the case of the sepiolite or between the layers in the case of the montmorillonite. The interactions between the drug and clay minerals are studied experimentally with the strategy for preparing interactions products in organic solvents (ethanol, acetonitrile and dichloromethane) so that the interaction will be more effective and will be enhanced the aqueous solubility of praziquantel. The results showed that in the interaction products, the drug interacted with both clay minerals, which produced the loss of the crystallinity of the drug demonstrated by different techniques. This led to a significant increase in the dissolution rate of the praziquantel in all the interaction products in the simulated gastrointestinal tract media, except for the praziquantel–montmorillonite product prepared in dichloromethane that presented a controlled release in acid medium. Moreover, in vitro cytotoxicity and cell cycle studies were performed in the interaction products prepared with ethanol. The interaction product with sepiolite was biocompatible with the HTC116 line cells, and it did not produce alterations in the cell cycle. However, interaction products with montmorillonite did not produce cell death, but they showed affectation and damage of cells in the cell cycle study at the highest concentration tested (20–100 µM). Therefore, the different organic solvents used are adequate for the improvement of the biopharmaceutical profile of praziquantel. Drug–clay interaction products, specifically with sepiolite, showed very promising results in which new accelerated oral release systems of the praziquantel were obtained. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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20 pages, 2414 KiB

Open AccessArticle

Correlation between Elemental Composition/Mobility and Skin Cell Proliferation of Fibrous Nanoclay/Spring Water Hydrogels

by Fátima García-Villén, Rita Sánchez-Espejo, Ana Borrego-Sánchez, Pilar Cerezo, Lucia Cucca, Giuseppina Sandri and César Viseras

Pharmaceutics 2020, 12(9), 891; https://doi.org/10.3390/pharmaceutics12090891 - 18 Sep 2020

Cited by 5 | Viewed by 2481

Abstract

Inorganic hydrogels formulated with spring waters and clay minerals are used to treat musculoskeletal disorders and skin affections. Their underlying mechanism of action for skin disorders is not clear, although it is usually ascribed to the chemical composition of the formulation. The aim [...] Read more.

Inorganic hydrogels formulated with spring waters and clay minerals are used to treat musculoskeletal disorders and skin affections. Their underlying mechanism of action for skin disorders is not clear, although it is usually ascribed to the chemical composition of the formulation. The aim of this study was to assess the composition and in vitro release of elements with potential wound healing effects from hydrogels prepared with two nanoclays and natural spring water. In vitro Franz cell studies were used and the element concentration was measured by inductively coupled plasma techniques. Biocompatibility studies were used to evaluate the potential toxicity of the formulation against fibroblasts. The studied hydrogels released elements with known therapeutic interest in wound healing. The released ratios of some elements, such as Mg:Ca or Zn:Ca, played a significant role in the final therapeutic activity of the formulation. In particular, the proliferative activity of fibroblasts was ascribed to the release of Mn and the Zn:Ca ratio. Moreover, the importance of formulative studies is highlighted, since it is the optimal combination of the correct ingredients that makes a formulation effective. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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17 pages, 1522 KiB

Open AccessFeature PaperArticle

Safety of Nanoclay/Spring Water Hydrogels: Assessment and Mobility of Hazardous Elements

by Fátima García-Villén, Rita Sánchez-Espejo, Ana Borrego-Sánchez, Pilar Cerezo, Luana Perioli and César Viseras

Pharmaceutics 2020, 12(8), 764; https://doi.org/10.3390/pharmaceutics12080764 - 12 Aug 2020

Cited by 9 | Viewed by 2831

Abstract

The presence of impurities in medicinal products have to be controlled within safety limits from a pharmaceutical quality perspective. This matter is of special significance for those countries and regions where the directives, guidelines, or legislations, which prescribe the rules for the application [...] Read more.

The presence of impurities in medicinal products have to be controlled within safety limits from a pharmaceutical quality perspective. This matter is of special significance for those countries and regions where the directives, guidelines, or legislations, which prescribe the rules for the application of some products is quite selective or incomplete. Clay-based hydrogels are quite an example of this matter since they are topically administered, but, in some regions, they are not subjected to well-defined legal regulations. Since hydrogels establish an intimate contact with the skin, hazardous elements present in the ingredients could potentially be bioavailable and compromise their safety. The elemental composition and mobility of elements present in two hydrogels have been assessed. Sepiolite, palygorskite, and natural spring water were used as ingredients. The release of a particular element mainly depends on its position in the structure of the hydrogels, not only on its concentration in each ingredient. As a general trend, elements’ mobility reduced with time. Among the most dangerous elements, whose presence in cosmetics is strictly forbidden by European legal regulations, As and Cd were mobile, although in very low amounts (0.1 and 0.2 μg/100 g of hydrogel, respectively). That is, assuming 100% bioavailability, the studied hydrogels would be completely safe at normal doses. Although there is no sufficient evidence to confirm that their presence is detrimental to hydrogels safety, legally speaking, their mobility could hinder the authorization of these hydrogels as medicines or cosmetics. In conclusion, the present study demonstrates that hydrogels prepared with sepiolite, palygorskite, and Alicún spring water could be topically applied without major intoxication risks. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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15 pages, 3900 KiB

Open AccessArticle

Polymeric Bioadhesive Patch Based on Ketoprofen-Hydrotalcite Hybrid for Local Treatments

by Cinzia Pagano, Loredana Latterini, Alessandro Di Michele, Francesca Luzi, Debora Puglia, Maurizio Ricci, César Antonio Viseras Iborra and Luana Perioli

Pharmaceutics 2020, 12(8), 733; https://doi.org/10.3390/pharmaceutics12080733 - 04 Aug 2020

Cited by 10 | Viewed by 2972

Abstract

Ketoprofen (KET) represents one of the most common drugs used in the topical treatment of pain and inflammations. However, its potential is rather limited due to the very low solubility and photochemical instability. The local administration of KET by conventional products, such as [...] Read more.

Ketoprofen (KET) represents one of the most common drugs used in the topical treatment of pain and inflammations. However, its potential is rather limited due to the very low solubility and photochemical instability. The local administration of KET by conventional products, such as gels, emulgels, creams, and foams, does not guarantee an efficacious and safe treatment because of its low absorption (due to low solubility) and its sensitivity to UV rays. The photodegradation of KET makes many photoproducts responsible for different adverse effects. In the present work, KET was intercalated into the lamellar anionic clay ZnAl-hydrotalcite (ZnAl-HTlc), obtaining the hybrid ZnAl-KET with improved stability to UV rays and water solubility in comparison to the crystalline form (not intercalated KET). The hybrid was then formulated in autoadhesive patches for local pain treatment. The patches were prepared by casting method starting from a hydrogel based on the biocompatible and bioadhesive polymer NaCMC (Sodium carboxymethycellulose) and glycerol as a plasticizing agent. The introduction of ZnAl-KET in the patch composition demonstrated the improvement in the mechanical properties of the formulation. Moreover, a sustained and complete KET release was obtained within 8 h. This allowed reducing the frequency of anti-inflammatory administration, compared to the conventional formulations. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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18 pages, 5290 KiB

Open AccessArticle

Development and Characterization of Liquisolid Tablets Based on Mesoporous Clays or Silicas for Improving Glyburide Dissolution

by Marzia Cirri, Paola Mura, Maurizio Valleri and Letizia Brunetti

Pharmaceutics 2020, 12(6), 503; https://doi.org/10.3390/pharmaceutics12060503 - 01 Jun 2020

Cited by 10 | Viewed by 3345

Abstract

The aim of this work was to evaluate the effectiveness of mesoporous clays or silicas to develop fast-dissolving glyburide tablets based on a liquisolid approach. Selected clay (Neusilin^®US2) and silica (Aeroperl^®300) allowed preparation of innovative drug liquisolid systems containing [...] Read more.

The aim of this work was to evaluate the effectiveness of mesoporous clays or silicas to develop fast-dissolving glyburide tablets based on a liquisolid approach. Selected clay (Neusilin^®US2) and silica (Aeroperl^®300) allowed preparation of innovative drug liquisolid systems containing dimethylacetamide or 2-pyrrolidone as drug solvents, without using coating materials which are necessary in conventional systems. The obtained liquisolid powders were characterized for solid-state properties, flowability, compressibility, morphology, granulometry, and then used for directly compressed tablet preparation. The developed liquisolid tablets provided a marked drug dissolution increase, reaching 98% dissolved drug after 60 min, compared to 40% and 50% obtained from a reference tablet containing the plain drug, and a commercial tablet. The improved glyburide dissolution was attributed to its increased wetting properties and surface area, due to its amorphization/solubilization within the liquisolid matrix, as confirmed by DSC and PXRD studies. Mesoporous clay and silica, owing to their excellent adsorbent, flow, and compressibility properties, avoided use of coating materials and considerably improved liquid-loading capacity, reducing the carrier amount necessary to obtain freely flowing powders. Neusilin^®US2 showed a superior performance than Aeroperl^®300 in terms of the tablet’s technological properties. Finally, simplicity and cost-effectiveness of the proposed approach make it particularly advantageous for industrial scale-up. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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24 pages, 5376 KiB

Open AccessArticle

Wound Healing Activity of Nanoclay/Spring Water Hydrogels

by Fátima García-Villén, Angela Faccendini, Dalila Miele, Marco Ruggeri, Rita Sánchez-Espejo, Ana Borrego-Sánchez, Pilar Cerezo, Silvia Rossi, César Viseras and Giuseppina Sandri

Pharmaceutics 2020, 12(5), 467; https://doi.org/10.3390/pharmaceutics12050467 - 21 May 2020

Cited by 24 | Viewed by 4370

Abstract

Background: hydrogels prepared with natural inorganic excipients and spring waters are commonly used in medical hydrology. Design of these clay-based formulations continues to be a field scarcely addressed. Safety and wound healing properties of different fibrous nanoclay/spring water hydrogels were addressed. Methods: in [...] Read more.

Background: hydrogels prepared with natural inorganic excipients and spring waters are commonly used in medical hydrology. Design of these clay-based formulations continues to be a field scarcely addressed. Safety and wound healing properties of different fibrous nanoclay/spring water hydrogels were addressed. Methods: in vitro biocompatibility, by means of MTT assay, and wound healing properties were studied. Confocal Laser Scanning Microscopy was used to study the morphology of fibroblasts during the wound healing process. Results: all the ingredients demonstrated to be biocompatible towards fibroblasts. Particularly, the formulation of nanoclays as hydrogels improved biocompatibility with respect to powder samples at the same concentration. Spring waters and hydrogels were even able to promote in vitro fibroblasts motility and, therefore, accelerate wound healing with respect to the control. Conclusion: fibrous nanoclay/spring water hydrogels proved to be skin-biocompatible and to possess a high potential as wound healing formulations. Moreover, these results open new prospects for these ingredients to be used in new therapeutic or cosmetic formulations. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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24 pages, 12726 KiB

Open AccessArticle

Norfloxacin-Loaded Electrospun Scaffolds: Montmorillonite Nanocomposite vs. Free Drug

by Angela Faccendini, Marco Ruggeri, Dalila Miele, Silvia Rossi, Maria Cristina Bonferoni, Carola Aguzzi, Pietro Grisoli, Cesar Viseras, Barbara Vigani, Giuseppina Sandri and Franca Ferrari

Pharmaceutics 2020, 12(4), 325; https://doi.org/10.3390/pharmaceutics12040325 - 04 Apr 2020

Cited by 30 | Viewed by 2984

Abstract

Infections in nonhealing wounds remain one of the major challenges. Recently, nanomedicine approach seems a valid option to overcome the antibiotic resistance mechanisms. The aim of this study was the development of three types of polysaccharide-based scaffolds (chitosan-based (CH), chitosan/chondroitin sulfate-based (CH/CS), chitosan/hyaluronic [...] Read more.

Infections in nonhealing wounds remain one of the major challenges. Recently, nanomedicine approach seems a valid option to overcome the antibiotic resistance mechanisms. The aim of this study was the development of three types of polysaccharide-based scaffolds (chitosan-based (CH), chitosan/chondroitin sulfate-based (CH/CS), chitosan/hyaluronic acid-based (CH/HA)), as dermal substitutes, to be loaded with norfloxacin, intended for the treatment of infected wounds. The scaffolds have been loaded with norfloxacin as a free drug (N scaffolds) or in montmorillonite nanocomposite (H—hybrid-scaffolds). Chitosan/glycosaminoglycan (chondroitin sulfate or hyaluronic acid) scaffolds were prepared by means of electrospinning with a simple, one-step process. The scaffolds were characterized by 500 nm diameter fibers with homogeneous structures when norfloxacin was loaded as a free drug. On the contrary, the presence of nanocomposite caused a certain degree of surface roughness, with fibers having 1000 nm diameters. The presence of norfloxacin–montmorillonite nanocomposite (1%) caused higher deformability (90–120%) and lower elasticity (5–10 mN/cm²), decreasing the mechanical resistance of the systems. All the scaffolds were proven to be degraded via lysozyme (this should ensure scaffold resorption) and this sustained the drug release (from 50% to 100% in 3 days, depending on system composition), especially when the drug was loaded in the scaffolds as a nanocomposite. Moreover, the scaffolds were able to decrease the bioburden at least 100-fold, proving that drug loading in the scaffolds did not impair the antimicrobial activity of norfloxacin. Chondroitin sulfate and montmorillonite in the scaffolds are proven to possess a synergic performance, enhancing the fibroblast proliferation without impairing norfloxacin’s antimicrobial properties. The scaffold based on chondroitin sulfate, containing 1% norfloxacin in the nanocomposite, demonstrated adequate stiffness to sustain fibroblast proliferation and the capability to sustain antimicrobial properties to prevent/treat nonhealing wound infection during the healing process. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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19 pages, 9790 KiB

Open AccessArticle

Halloysite- and Montmorillonite-Loaded Scaffolds as Enhancers of Chronic Wound Healing

by Giuseppina Sandri, Angela Faccendini, Marysol Longo, Marco Ruggeri, Silvia Rossi, Maria Cristina Bonferoni, Dalila Miele, Adriele Prina-Mello, Carola Aguzzi, Cesar Viseras and Franca Ferrari

Pharmaceutics 2020, 12(2), 179; https://doi.org/10.3390/pharmaceutics12020179 - 20 Feb 2020

Cited by 31 | Viewed by 3265

Abstract

The increase in life expectancy and the increasing prevalence of diabetic disease and venous insufficiency lead to the increase of chronic wounds. The prevalence of ulcers ranges from 1% in the adult population to 3–5% in the over 65 years population, with 3–5.5% [...] Read more.

The increase in life expectancy and the increasing prevalence of diabetic disease and venous insufficiency lead to the increase of chronic wounds. The prevalence of ulcers ranges from 1% in the adult population to 3–5% in the over 65 years population, with 3–5.5% of the total healthcare expenditure, as recently estimated. The aim of this work was the design and the development of electrospun scaffolds, entirely based on biopolymers, loaded with montmorillonite (MMT) or halloysite (HNT) and intended for skin reparation and regeneration, as a 3D substrate mimicking the dermal ECM. The scaffolds were manufactured by means of electrospinning and were characterized for their chemico-physical and preclinical properties. The scaffolds proved to possess the capability to enhance fibroblast cells attachment and proliferation with negligible proinflammatory activity. The capability to facilitate the cell adhesion is probably due to their unique 3D structure which are assisting cell homing and would facilitate wound healing in vivo. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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16 pages, 3031 KiB

Open AccessArticle

Tablets of “Hydrochlorothiazide in Cyclodextrin in Nanoclay”: A New Nanohybrid System with Enhanced Dissolution Properties

by Francesca Maestrelli, Marzia Cirri, Fátima García-Villén, Ana Borrego-Sánchez, César Viseras Iborra and Paola Mura

Pharmaceutics 2020, 12(2), 104; https://doi.org/10.3390/pharmaceutics12020104 - 28 Jan 2020

Cited by 10 | Viewed by 2904

Abstract

Hydrochlorothiazide (HCT), a Biopharmaceutical Classification System (BCS) class IV drug, is characterized by low solubility and permeability, that negatively affect its oral bioavailability, reducing its therapeutic efficacy. The combined use of cyclodextrins (CDs) and nanoclays (NCs) recently proved to be a successful strategy [...] Read more.

Hydrochlorothiazide (HCT), a Biopharmaceutical Classification System (BCS) class IV drug, is characterized by low solubility and permeability, that negatively affect its oral bioavailability, reducing its therapeutic efficacy. The combined use of cyclodextrins (CDs) and nanoclays (NCs) recently proved to be a successful strategy in developing delivery systems able to merge the potential benefits of both carriers. In this work, several binary systems of CDs or NCs with the drug were obtained, using different drug:carrier ratios and preparation techniques, and characterized in solution and in solid state, to properly select the most effective system and preparation method. Then, the best CD (RAMEB) and NC (sepiolite), at the best drug:carrier ratio, was selected for preparation of the ternary system by co-evaporation and emerged as the most effective preparation method. The combined presence of RAMEB and sepiolite gave rise to a synergistic improvement of drug dissolution properties, with a two-fold increase in the amount of drug dissolved as compared with the corresponding HCT-RAMEB system, resulting in an approximately 12-fold increase in drug solubility as compared with the drug alone. The ternary system that was co-evaporated was then selected for a tablet formulation. The obtained tablets were fully characterized for technological properties and clearly revealed a better drug dissolution performance than the commercial reference tablet (Esidrex^®). Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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