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Clay-Based Pharmaceutical Formulations and Drug Delivery Systems

Authors:
Fátima García Villén at University of Granada
Fátima García Villén
Cesar Viseras at University of Granada
Cesar Viseras
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Abstract

The use of minerals as ingredients in health care products is a classical and active pharmaceutical subject [...]
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pharmaceutics
Editorial
Clay-Based Pharmaceutical Formulations and Drug
Delivery Systems
Fátima García-Villén1and César Viseras 1, 2, *
1Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada,
Campus of Cartuja, 18071 Granada, Spain; fgarvillen@ugr.es
2
Andalusian Institute of Earth Sciences, CSIC-UGR, Avenida de las Palmeras 4, 18100 Armilla, Granada, Spain
*Correspondence: cviseras@ugr.es
Received: 19 November 2020; Accepted: 24 November 2020; Published: 25 November 2020


The use of minerals as ingredients in health care products is a classical and active pharmaceutical
subject. Clays and also zeolites and other silica-based mesoporous inorganic ingredients have been
traditionally used as pharmaceutical and cosmetic ingredients. These inorganic ingredients should
meet the quality and safety standards to be used as ingredients in health care products. Recently,
new and advanced applications of these materials have been proposed, including the design of
modified drug delivery systems and other advanced applications (such as wound healing formulations
and tissue engineering scaffolds).
This Special Issue highlights the most relevant and recent advances in clay-based formulations
and clay-based drug delivery systems. Natural, modified, and synthetic clays with prospects in
nanomedicine and pharmaceutics were considered.
The publication of Maestrelli et al. [
1
] used a combination of cyclodextrins and nanoclays to improve
the biopharmaceutical profile of hydrochlorothiazide, characterized by low solubility and permeability.
Once the best cyclodextrin (RAMEB) and clay (sepiolite) were selected, the co-evaporation technique
was used to prepare a ternary system with an optimal drug:carrier ratio. The combined presence
of RAMEB and sepiolite gave rise to a synergistic improvement in the drug dissolution properties,
resulting in an approximately 12-fold increase in the hydrochlorothiazide solubility compared with
the drug alone. Subsequently, the ternary system was formulated as tablets and a full technological
characterization was performed. The results clearly revealed a better drug dissolution performance
than the commercial hydrochlorothiazide reference tablet (Esidrex®).
The publication by Borrego-S
á
nchez et al. [
2
] studied the interaction between praziquantel, the drug
indicated for schistosomiasis disease, and two clays (sepiolite and montmorillonite). Praziquantel has
a very low aqueous solubility, requiring high oral doses, which usually lead to side effects, therapeutic
noncompliance, and the appearance of resistant forms of the parasite. The drug was dissolved in
organic solvents (ethanol, acetonitrile, and dichloromethane) and encapsulated in nanometric channels
of sepiolite or between the layers of montmorillonite. The results showed that the interaction of
the drug with both clay minerals produced a loss of praziquantel crystallinity, as demonstrated
by different techniques. This led to a significant increase in the dissolution rate of praziquantel in
simulated gastrointestinal tract media, except for the praziquantel–montmorillonite product prepared
in dichloromethane, which presented a controlled release in acid medium. Moreover, the drug–clay
interaction products prepared in ethanol were subjected to in vitro cytotoxicity and cell cycle studies.
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 altered the cell cycle at the highest concentration tested (20–100
µ
M).
In conclusion, drug–clay interaction products, specifically with sepiolite, showed very promising
results, since they accelerated praziquantel oral release.
Pharmaceutics 2020,12, 1142; doi:10.3390/pharmaceutics12121142 www.mdpi.com/journal/pharmaceutics
Pharmaceutics 2020,12, 1142 2 of 4
Inorganic hydrogels formulated with spring waters and clay minerals are topically applied
to treat musculoskeletal disorders and skin affections. From a pharmaceutical quality perspective,
the safety limits of elemental impurities in clay-based hydrogels were studied by Garc
í
a-Vill
é
n et al. [
3
].
Their results showed that the release of a particular element not only depends on its concentration,
but also on its position in the hydrogel network, concluding that hydrogels prepared with sepiolite,
palygorskite, and local spring water could be topically applied without major intoxication risks.
The wound healing properties of these clay-based hydrogels were addressed using Confocal Laser
Scanning Microscopy to study the morphology of fibroblasts during the wound healing process.
The studied clay-based hydrogels promoted
in vitro
fibroblast motility and, therefore, accelerated
wound healing (Garc
í
a-Vill
é
n et al. [
4
]). The underlying mechanism of action for skin disorders of these
formulations is usually ascribed to the chemical composition of the formulation. Garc
í
a-Vill
é
n et al. [
5
]
assessed 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 the Inductively Coupled Plasma technique.
Biocompatibility studies were used to evaluate the potential toxicity of the formulation against
fibroblasts. The studied hydrogels released elements with known therapeutic potential 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.
Pagano et al. [
6
] intercalated ketoprofen into a lamellar anionic clay ZnAl-hydrotalcite (ZnAl-HTlc),
improving the stability to UV rays and the water solubility of the drug. The hybrid was then formulated
in auto-adhesive patches for local pain treatment. The patches were prepared by a casting method,
starting from a hydrogel based on the biocompatible and bioadhesive polymer NaCMC (Sodium
carboxymethycellulose) and glycerol as a plasticizing agent. The addition of ZnAl-KET in the patch
composition caused an improvement in the mechanical properties of the formulation. Moreover,
a sustained and complete drug release was obtained within 8 h. This allowed reducing the frequency
of anti-inflammatory posology compared to the conventional formulations.
Cirri et al. [
7
] designed fast-dissolving glyburide tablets based on a liquisolid approach using
mesoporous clay (Neusilin
®
US2) or silica (Aeroperl
®
300) and dimethylacetamide or 2-pyrrolidone
as drug solvents, without using the coating materials that are necessary in conventional systems.
The resultant liquisolid tablets provided a marked drug dissolution increase, reaching 98% of dissolved
drug after 60 min, compared to the 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 the use of coating materials while considerably
improving the liquid-loading capacity, reducing the amount of carrier necessary to obtain freely flowing
powders. Neusilin
®
US2 showed a superior performance with respect to Aeroperl
®
300 regarding the
tablet’s technological properties.
Sandri et al. [
8
] designed and developed electrospun scaffolds, entirely based on biopolymers,
loaded with montmorillonite or halloysite and intended for skin reparation and regeneration.
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 attachment and proliferation with negligible proinflammatory activity. The capability
to facilitate the cell adhesion is probably due to their unique 3D structure, which assists
in cell homing and would facilitate wound healing
in vivo
. Faccendini et al. [
9
] developed
chitosan/glycosaminoglycan-based scaffolds loaded with norfloxacin (free or in montmorillonite
hybrids). 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 clay-based nanocomposite.
Pharmaceutics 2020,12, 1142 3 of 4
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 synergistic performance, enhancing the
fibroblast proliferation without impairing norfloxacin’s antimicrobial properties. The scaffold based
on chondroitin sulfate, containing 1% norfloxacin in the nanocomposite, demonstrated an adequate
stiffness to sustain fibroblast proliferation and the capability to sustain antimicrobial properties to
prevent/treat non-healing wound infections during the healing process.
The publication by Luo et al. [
10
] focused on halloysite nanotubes (HNTs) functionalized with folic
acid to selectively target cancer cells and a fluorochrome to visualize the nanoparticle. The functionalized
HNTs were loaded with methotrexate. and the cell viability, proliferation, and uptake efficiency in colon
cancer, osteosarcoma, and a pre-osteoblast cell line (MC3T3-E1) were evaluated. The functionalized
HNTs showed a high methotrexate loading efficiency and a prolonged release. Moreover, non-cancerous
cells were unaffected after exposure to the formulation. Consequently, the nanoparticle designed
was demonstrated to exclusively target cancer cells, which consequently reduces the methotrexate
side-effects caused by the off-targeting of anti-cancer drugs.
This Special Issue evidences the high potential and versatility of clay minerals in pharmaceutics.
Despite being ingredients whose use dates back to ancient times, they continue to play a crucial role in
the present, both as excipients and actives in a wide variety of dosage forms and novel technological
strategies, such as tissue engineering and targeted cancer treatments.
Conflicts of Interest: The authors declare no conflict of interest.
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Full-text available
  • Sep 2020
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.
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Safety of Nanoclay/Spring Water Hydrogels: Assessment and Mobility of Hazardous Elements
Article
Full-text available
  • Aug 2020
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/100g 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.
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Polymeric Bioadhesive Patch Based on Ketoprofen-Hydrotalcite Hybrid for Local Treatments
Article
Full-text available
  • Aug 2020
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.
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Development and Characterization of Liquisolid Tablets Based on Mesoporous Clays or Silicas for Improving Glyburide Dissolution
Article
Full-text available
  • Jun 2020
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.
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Wound Healing Activity of Nanoclay/Spring Water Hydrogels
Article
Full-text available
  • May 2020
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.
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Norfloxacin-Loaded Electrospun Scaffolds: Montmorillonite Nanocomposite vs. Free Drug
Article
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  • Apr 2020
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.
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Halloysite- and Montmorillonite-Loaded Scaffolds as Enhancers of Chronic Wound Healing
Article
Full-text available
  • Feb 2020
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.
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Tablets of “Hydrochlorothiazide in Cyclodextrin in Nanoclay”: A New Nanohybrid System with Enhanced Dissolution Properties
Article
Full-text available
  • Jan 2020
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).
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