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Nanocrystals of medium soluble actives-Novel concept for improved dermal delivery and production strategy
Abstract
After use in oral pharmaceutical products, nanocrystals are meanwhile applied to improve the dermal penetration of cosmetic actives (e.g., rutin, hesperidin) and of drugs. By now, nanocrystals are only dermally applied made from poorly soluble actives. The novel concept is to formulate nanocrystals also from medium soluble actives, and to apply a dermal formulation containing additionally nanocrystals. The nanocrystals should act as fast dissolving depot, increase saturation solubility and especially accumulate in the hair follicles, to further increase skin penetration. Caffeine was used as model compound with relevance to market products, and a particular process was developed for the production of caffeine nanocrystals to overcome the supersaturation related effect of crystal growth and fiber formation - typical with medium soluble compounds. It is based on low energy milling (pearl milling) in combination with low dielectric constant dispersion media (water-ethanol or ethanol-propylene glycol mixtures) and optimal stabilizers. Most successful was Carbopol(®) 981 (e.g., 20% caffeine in ethanol-propylene glycol 3:7 with 2% Carbopol, w/w). Nanocrystals with varied sizes can now be produced in a controlled process, e.g., 660nm (optimal for hair follicle accumulation) to 250nm (optimal for fast dissolution). The short term test proved stability over 2 months of the present formulation being sufficient to perform in vivo testing of the novel concept.
... The caffeine nanocrystals were slightly negatively charged. The small-sized nanocrystals possessed a zeta potential of about − 15 mV and the larger-sized nanocrystals possessed a zeta potential of about − 18 mV [37,43]. From each of these formulations, a total amount of 10 mg of caffeine was applied to the skin of each volunteer. ...
... Hence, in contrast to the caffeine solution used in the Otberg et al. study [9], the nanocrystal formulations exhibited a higher viscosity and The addition of the gel forming polyacrylate reduced the apparent solubility of caffeine in the ethanol/propylene glycol mixture to < 14 mg/ ml [43]. The formulation of caffeine as nanocrystals in this dispersion medium increased the solubility of caffeine to 20.2 mg/ml (larger nanocrystals) and to 24.2 mg/ml (smaller nanocrystals), which corresponds to an increase in the apparent solubility of caffeine by about 35 % and 70%, respectively [43]. ...
... Hence, in contrast to the caffeine solution used in the Otberg et al. study [9], the nanocrystal formulations exhibited a higher viscosity and The addition of the gel forming polyacrylate reduced the apparent solubility of caffeine in the ethanol/propylene glycol mixture to < 14 mg/ ml [43]. The formulation of caffeine as nanocrystals in this dispersion medium increased the solubility of caffeine to 20.2 mg/ml (larger nanocrystals) and to 24.2 mg/ml (smaller nanocrystals), which corresponds to an increase in the apparent solubility of caffeine by about 35 % and 70%, respectively [43]. Thus, the influence of the nanocrystal size on the apparent solubility of poorly water-soluble substances is nicely demonstrated. ...
The absorption of topically applied substances is challenging due to the effective skin barrier. Encapsulation of substances into nanoparticles was expected to be promising to increase the bioavailability of topically applied products. Since nanoparticles cannot traverse the intact skin barrier, but penetrate into the hair follicles, they could be used to deliver substances via hair follicles, where the active is released and can translocate independently transfollicularly into the viable epidermis.
In the present in vivo study, this effect was investigated for caffeine. Caffeine nanocrystals of two sizes, 206 nm and 694 nm, with equal amounts of caffeine were used to study caffeine serum concentration kinetics after topical application on 5 human volunteers.
The study demonstrated that at early time points, the smaller nanocrystals were more effective in increasing the bioavailability of caffeine, whereas after 20 min, the serum concentration of caffeine was higher when caffeine was applied by larger nanocrystals. Caffeine was still detectable after 5 days. The area under the curve could be increased by 82% when the 694 nm nanocrystals were applied.
Especially larger sized nanocrystals seem to be a promising type of nanoparticulate preparation to increase the bioavailability of topically applied drugs via the transfollicular penetration pathway.
... Nanocrystals can be fabricated by top-down method, bottom up methods or by combining both methods. Due to reduction in particles sizes, nanocrystals enhance the saturation solubility and due to large surface area, they exhibit higher dissolution velocity [6]. These features create a concentration gradient between the topically applied formulations and the membranes of skin that results in improved passive diffusion [6,7]. ...
... Due to reduction in particles sizes, nanocrystals enhance the saturation solubility and due to large surface area, they exhibit higher dissolution velocity [6]. These features create a concentration gradient between the topically applied formulations and the membranes of skin that results in improved passive diffusion [6,7]. Drug particles having sizes in nanometer range provide much deeper penetration into the skin as well as enhanced retention in hair follicles [7]. ...
... Numerous researchers and scientists have worked on dermal delivery of several drugs and observed its potential in topical or transdermal penetration [6][7][8][9][10][11][12][13][14][15]. However, to the best of our knowledge, in vivo studies and the topical delivery of drug nanocrystals of capsaicin have not been explored yet. ...
Nano-crystallization is a new emerging strategy to promote the saturation solubility, dissolution rate and subsequent bioavailability of Biopharmaceutical Class II drugs. Capsaicin belongs to BCS class-II drugs having low water solubility and dissolution rate. Nano-crystals (NC) of pure Capsaicin was developed and optimized in order to increase its water solubility, dissolution and further to promote its adhesiveness to skin epidermis layer. NC formulations were subjected to stability studies, droplet size, surface charge, poly-dispensability index, drug content, entrapment efficiency, thermal analysis, surface morphology, crystalline studies, solubility profile, in vitro release and ex vivo permeation studies. In vivo anti-inflammatory assay (Carrageenan-induced paw edema) was performed in Sprague Dawley rats. Nanocrystals loaded with capsaicin showed particle size 120 ± 3.0 nm with surface charge of −20.7 ± 3.5 and PDI was 0.48 ± 1.5. Drug content and entrapment efficiency of T3 was 85% and 90 ± 1.9% respectively. Thermal studies predicted that melting peak of capsaicin was present in the formulation suggested that there was no interaction between active moieties and excipients in NC formulation. Surface morphology confirmed the presence of Nano-size crystals having rough crystalline surface. XRD proved that the capsaicin NC are successfully developed by using high speed homogenization. The solubility of capsaicin was found to be 12.0 ± 0.013 μg/mL in water. In vitro study revealed that 89.94 ± 1.9% of drug was released within 24 h. Similarly, drug permeation was 68.32 ± 1.83%, drug retained in skin was 16.13 ± 1.11% while drug retained on skin was 9.12 ± 0.14% after 12 h. The nanocrystals showed higher anti-inflammatory activity as compared to marketed product (Dicloran®). The study concluded that improvement in dissolution rate of capsaicin may potentially provide the opportunities in the development of a much cost-effective dosage forms that will produce improved pharmacological effects, but at low dose as compared to the already available products.
... The homogenization pressure and homogenization cycles are the critical process parameters (CPPs) (Kobierski et al., 2009;Zhai et al., 2014) while the percentage of drug, type of stabilizer, and drug to stabilizer ratio are the critical formulation attributes (CFAs) (Bose et al., 2012;Hong et al., 2014) for the microfluidization method. 2 k statistical designs provide advantages to understand the influence of CFAs and CPPs on the critical quality attributes (CQA) of nanosuspensions (Pandya et al., 2011). For that purpose, a 2 3 full factorial design was performed with 2 levels each for 3 factors. ...
... Especially, homogenization pressure effects the PS and PDI significantly. On the basis of univariate ANOVA results, it was found that high homogenization pressure led to a decrease in PS and PDI and these results were supported by other previous studies (Mishra et al., 2009;Zhai et al., 2014). Therefore, in this study, at the constant high homogenization pressure (30,000 psi), 3 3 factorial design was applied to enlarge the scope of the statistical analyses and to optimize the FB nanosuspensions using Design Expert® Version 9. ...
... The hair follicles are important pathways in the percutaneous penetration of topically applied substances (Lademann et al., 2001). Literature revealed that the effect of particle size on follicular penetration regarding to the penetration depth and nanoparticles with sizes ranging from 650 to 750 nm penetrated deeper than smaller or larger ones (Patzelt et al., 2011;Toll et al., 2004;Zhai et al., 2014). The particle size of our FB nanosuspension was found to be in this range. ...
Flurbiprofen (FB) is the one of the non-steroidal anti-inflammatory drugs (NSAIDs) which has low water solubility and dissolution. Nanosuspensions are promising drug delivery systems consisting pure drug particles to overcome poor water solubility issues. Recently, design of experiment (DoE) approaches have often been used to develop new formulations include nanosuspensions. The main objective of this study was to prepare FB nanosuspensions in existence of Plantacare 2000 (PL) as stabilizer using DoE approach to evaluate the critical formulation attributes (CFAs) and critical process parameters (CPPs). Particle size, particle size distribution and zeta potential values were selected as dependent variables and FB%, FB: PL and homogenization cycles were independent variables. Both 23 and 33 factorial designs were used to achieve optimum nanosuspension formulation. The final nanosuspension was freeze-dried and then crystalline state, morphological and thermal properties were investigated using X-ray diffraction, scanning electron microscopy and differential scanning calorimetry, respectively. The saturation solubility studies of nanosuspensions were conducted in comparison with the coarse powder and the physical mixture. The in vitro permeation of nanosuspension and FB solution were determined through dialysis membrane and rat skin. The particle size, polydispersity index and zeta potential values were found to range 665 nm-700 nm, 0.200-0.300 and approximately -30 mV, respectively. Nanosuspensions were obtained with spherical shape and no polymorphic or crystalline state change were observed. The saturation solubility of FB was 5.3 fold increased in nanosuspension formulation. Permeability of FB nanosuspension was higher than FB solution in rat skin. It was concluded that the DoE approach is a useful tool to prepare FB nanosuspensions and nanosuspensions benefit to improve water solubility and dermal permeation of Biopharmaceutical Classification System (BCS) Class II drugs.
... Out of these major advantages, the use of nanocrystals is associated with the solubility-enhancing property of various drugs [167]. Even though there are various available methods like the use of cosolvents, and complexation with cyclodextrins, by which enhancement in the solubility can be obtained, out of these methods currently, the use of nanocrystals (nano crystallization) is increasing day by day due to its higher drug loading capacity as well as the use of completely biodegradable property containing compounds like stabilizers ultimately gives completely safe products containing absolute pure drug materials in the final product/formulations [96,168,169]. There are three well-known methods for the preparation of nanocrystals. ...
... As a result, the use of nanocrystals in the aqueous and nonaqueous phases in the formulations increased. It crosses or penetrates the layers of the skin more efficiently, ultimately enhancing the concentration gradient in the skin due to enhancement in the surface area as well as dissolution [168]. ...
... The nanocrystals for topical delivery were first investigated for cosmetic and subsequently for pharmaceuticals. Cosmetic products like Juvedical age-decoder cream of rutin by Juneva and Cellular serum platinum rare of hesperidin by La Prairie appeared in the market in 2007 [121]. ...
... Apart from nanocrystals of poorly soluble drugs for dermal application, nanocrystals of a sparingly soluble drug such as caffeine resulted in improved topical delivery. The nanocrystals were generated using low energy process (pearl milling) with low dielectric constant dispersion medium (ethanol-PG mixture) and Carbopol 981 as a stabilizer to avoid Ostwald ripening [121]. ...
Poorly water-soluble drugs pose challenge of slow dissolution rate that can translate into low bioavailability. Nanocrystals have been widely used for increasing apparent solubility, dissolution rate, and prolonged stay in gastrointestinal tract due to mucoadhesion. In the current book chapter, fundamentals of nanocrystals, relation of crystal structure with nanonization, phase transformation during nanonization, and optimization of critical process parameters have been discussed. The strategies, interplay of formulation and process parameters in downstream processing of nanocrystals into solid products, are also discussed. Novel concepts in the field of nanocrystals such as miniaturization, IVIVC, functionalization, and applications in non-oral routes have also been captured.
... On the other hand, drug molecules having solubility of 1-10 mg/ml (slightly soluble) and 10-33 mg/ml (sparingly soluble) can be considered as "medium soluble" according to the US pharmacopeia [9][10][11]. The challenge in making nanocrystals of medium soluble drug is supersaturation effect causing recrystallization and crystal growth [12]. Recently, Zhai et al. generated nanocrystals of medium soluble drug, e.g. ...
... Recently, Zhai et al. generated nanocrystals of medium soluble drug, e.g. caffeine for topical delivery [12]. In the present study, we have investigated the ability of nanocrystal technology to improve the topical delivery of the medium soluble drug acyclovir. ...
Acyclovir is “difficult-to-deliver” topically owing to low lipophilicity and high melting point. The aim of the present study was to develop nanocrystal-based formulations of acyclovir for improved topical delivery. Nanosuspension was optimized with sodium lauryl sulphate and hydroxypropyl cellulose-LF as stabilizers using high speed homogenizer followed by wet media milling. Nanosuspension was characterized by optical microscopy, differential scanning calorimetry, powder-X ray diffraction, dynamic light scattering. Acyclovir nanocrystals were crystalline in nature and exhibited mean particle size of 400–500 nm. Saturation solubility of nanocrystals was improved 1.6-fold over micronized acyclovir. Skin permeation and ex-vivo dermatokinetic studies of cream formulations were performed on pig ear skin at dose of 5% w/w using Franz diffusion cells. Skin permeation studies revealed non-detectable amount of acyclovir in the receptor compartment of Franz diffusion cell. Nanosuspension showed 2- and 2.3-folds drug penetration into the stratum corneum (SC) and viable layers (viable epidermis, dermis), respectively over microsuspension. Nanocream showed 1.6-fold drug penetration into the SC and viable layers over microcream. Further, nanosuspension and nanocream showed statistically significant improvement of 6.3-fold and 2.4-fold in penetration into the viable layers than Zovirax® cold sore cream. Thus, these nano-formulations are useful to improve topical delivery of acyclovir and can help in the treatment of herpes simplex virus infections.
... A study with hesperetin nanocrystals, for instance, has shown the decrease in particle size enhances the drug dermal penetration (126). In the same way, the need of optimal intermediate particle sizes to improve hair follicle accumulation and subsequent skin penetration has been identified in a study with caffeine nanocrystals (127). ...
... As illustrated above, most of the reports show that nanocrystals, as opposed to microcrystals, can target the follicle (127)(128)(129)(130). The advantage of using nanocrystals to topical delivery is currently explained by the increase of skin/crystal contact area, the local enhancement of supersaturation and the constant concentration gradient generated in the follicle (128,131). ...
Dapsone (DAP) is a long-established molecule that remains a promising therapeutic agent for various diseases mainly because it combines antimicrobial and anti-inflammatory activities. Its oral application, however, is limited by the dose-dependent hematological side effects that may rise from systemic exposure. As an alternative to overcome this limitation, the administration of DAP to the skin has witnessed prominent interest in the past 20 years, particularly when applied to the treatment of dermatological disorders. In this review, all technological strategies proposed to the topical delivery of DAP are presented. Most of the reported studies have been devoted to the clinical use and safety of a gel formulation containing both solubilized and microcrystalline drug, however, the technological characteristics of such preparation are still missing. In parallel, the incorporation of DAP into vesicular and particulate carriers (e.g. nano- and microemulsions, niosomes, invasomes, bilosomes, cubosomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanocapsules and polymer-lipid-polymer hybrid nanoparticles) appears to be an alternative to provide greater drug release control, enhanced drug solubilization and follicular targeting. Indeed, the main application of DAP topical formulations reported in the literature was the treatment of acne vulgaris, a disease located in the hair follicle. Other diseases affecting different regions of the skin (e.g. cutaneous lupus erythematosus and cutaneous leishmaniasis), however, may also benefit from a topical therapeutic regimen containing DAP. Therefore, the investigation of appendageal route in comparison to passive transmembrane diffusion as a function of targeted disease, as well as pharmacokinetic studies, are perspectives highlighted herein. Such studies may drive future efforts towards the rational development of safe and effective technologies to deliver DAP to the skin.
Graphical abstract
... The first anti-ageing and skin protective cosmetic products based on nanosuspensions of poorly soluble antioxidants were Juvedical® age-decoder cream of rutin by Juneva and Cellular Serum Platinum Rare of hesperidin by La Prairie introduced on the market in the year 2007 [6]. Several researchers have worked on dermal delivery of nanocrystals and observed its potential in topical penetration of drug [6][7][8][9][10][11][12][13][14][15]. ...
... The first anti-ageing and skin protective cosmetic products based on nanosuspensions of poorly soluble antioxidants were Juvedical® age-decoder cream of rutin by Juneva and Cellular Serum Platinum Rare of hesperidin by La Prairie introduced on the market in the year 2007 [6]. Several researchers have worked on dermal delivery of nanocrystals and observed its potential in topical penetration of drug [6][7][8][9][10][11][12][13][14][15]. However, to the best of our knowledge, ex vivo studies on the topical delivery of drug nanocrystals have been less explored for the treatment of psoriasis. ...
Nanocrystals can enhance skin penetration of drug by increased saturation solubility, dissolution rate and adhesion on the skin. Apremilast is ‘difficult-to-deliver’ in viable layers (epidermis, dermis) and stratum corneum (SC) owing to its poor aqueous solubility and modest lipophilicity, respectively. Apremilast is currently available as oral tablet formulation for the indication of psoriasis but its effectiveness is limited by systemic side effects. Therefore, the present study aimed to develop novel nanocrystal-based formulations of apremilast for improved topical delivery. Nanosuspension was prepared using wet media milling and exhibited a mean particle size of 200 nm. The saturation solubility of nanocrystals was improved by 2-fold than micronized apremilast and showed significant advantage during dissolution study. Nanosuspension and micronized apremilast was incorporated into gel and cream and characterized for rheological properties. Skin permeation and ex vivo dermatokinetic study of topical formulations were performed on pig ear skin at a dose of 1% w/w using Franz diffusion cells. Skin permeation studies indicated that non-detectable amount of apremilast permeated through pig ear skin during exposure of formulations. Nanosuspension showed 2.6- and 3.2-fold drug penetration in SC and viable layers, respectively, over microsuspension. Nanogel showed 2.7- and 2.4-fold drug penetration in SC and viable layers, respectively, over microgel. Nanocream showed 1.2- and 2.8-fold drug penetration in SC and viable layers, respectively, over microcream. Thus, nanocrystal-based formulations of apremilast aid in selective delivery into viable layers by crossing the SC barrier. This is of paramount importance in enhancing therapeutic effectiveness utilizing localized delivery and provides an alternative delivery approach for the treatment of psoriasis.
Graphical abstract
... The advent of nanotechnology has created a new boom in all fields, including chemical, physical and life sciences, which has given a new path for drug delivery in pharmaceuticals 13,14 . Various routes for administration of nanocrystals 7 are proposed as well, including oral 15 , parenteral 16 , dermal 17,18 , systemic 19 , pulmonary 20 and ocular [21][22][23] . ...
... Soluplus s is an effective excipient and has been used in formulation development of poorly water-soluble drugs utilizing spray drying, hot melt extrusion, electrospinning, solvent casting, high shear dispersions, solvent evaporation, thermal heating, co-milling and ball milling. Soluplus s was developed by BASF industries to be used in the preparation of the solid solution, but it is used for various other applications including, as a binder in wet granulation 17 85 have reported fenofibrate nanocrystals stabilized with the combination of hydroxypropylmethylcellulose (HPMC) and Soluplus s prepared with media milling technique. Authors have reported better physical stability of prepared nanocrystals due to weaker Ostwald's ripening effect of Soluplus s . ...
Advancements in in silico techniques of lead molecule selection have resulted in the failure of around 70% of new chemical entities (NCEs). Some of these molecules are getting rejected at final developmental stage resulting in wastage of money and resources. Unfavourable physicochemical properties affect ADME profile of any efficacious and potent molecule, which may ultimately lead to killing of NCE at final stage. Numerous techniques are being explored including nanocrystals for solubility enhancement purposes. Nanocrystals are the most successful and the ones which had a shorter gap between invention and subsequent commercialization of the first marketed product. Several nanocrystal-based products are commercially available and there is a paradigm shift in using approach from simply being solubility enhancement technique to more novel and specific applications. Some other aspects in relation to parenteral nanosuspensions are concentrations of surfactant to be used, scalability and in vivo fate. At present, there exists a wide gap due to poor understanding of these critical factors, which we have tried to address in this review. This review will focus on parenteral nanosuspensions, covering varied aspects especially stabilizers used, GRAS (Generally Recognized as Safe) status of stabilizers, scalability challenges, issues of physical and chemical stability, solidification techniques to combat stability problems and in vivo fate. © 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
... The problem of poor drug solubility is becoming a main challenge due to their low dissolution velocity in vivo [1]. Poorly water-soluble drugs have low active concentration and bioavailability in the body [2]. Those reasons limited the drug absorption during clinical therapy. ...
... Preparation of rutin nanocrystals is a suitable solution to overcome low solubility. Rutin nanocrystals are found to occupy 1/500 th the concentration of rutin derivatives, and rutin nanocrystals provide double sun protection than untreated rutin [2,45]. In other words, the antioxidant capacity of rutin nanocrystals is about 1000 times higher than that of water-soluble rutin derivatives and rutin glucoside. ...
The poor penetration and low bioavailability are main challenges for transdermal drug delivery. Nanocrystals technology is an attractive method for water insoluble drug transdermal delivery, as the literature demonstrated that the penetration and bioavailability of the transdermal delivered water insoluble drugs was significantly enhanced and improved by the nanocrystals technology. Currently, the nanocrystals technology has been applied in transdermal delivery of cosmeceutical and for therapy skin diseases, such as diclofenac acid, tretinoin and rutin. This review focused on the advantages of the nanocrystals technology for transdermal delivery. The special features of nanocrystals for the transdermal delivery of poorly soluble drugs are reviewed (skin disease treatment, safety and compliance, applying to cosmeceutical). Furthermore, the factors of influencing the nanocrystals penetration and the approaches of improving nanocrystals transdermal delivery are also discussed in detail.
... Research indicates that the absorption and bioavailability of a drug are influenced not only by the properties of the drug itself but also by factors such as dissolution rate, pH value, route of administration, and first-pass effect. 13 Particularly, poorly soluble drugs with significant pharmacological activities often fail to achieve their full therapeutic potential due to their slow dissolution rates and low solubility, 14,15 leading to issues such as the need for increased drug dosages in clinical settings. 5 It is estimated that about 40% of the compounds on the market and the majority of candidate drugs are poorly soluble, 3,16 mainly categorized under Class II and IV of the Biopharmaceutical Classification System (BCS). ...
This manuscript offers a comprehensive overview of nanotechnology’s impact on the solubility and bioavailability of poorly soluble drugs, with a focus on BCS Class II and IV drugs. We explore various nanoscale drug delivery systems (NDDSs), including lipid-based, polymer-based, nanoemulsions, nanogels, and inorganic carriers. These systems offer improved drug efficacy, targeting, and reduced side effects. Emphasizing the crucial role of nanoparticle size and surface modifications, the review discusses the advancements in NDDSs for enhanced therapeutic outcomes. Challenges such as production cost and safety are acknowledged, yet the potential of NDDSs in transforming drug delivery methods is highlighted. This contribution underscores the importance of nanotechnology in pharmaceutical engineering, suggesting it as a significant advancement for medical applications and patient care.
... Due to this the formulation principle is already often exploited to improve the oral bioavailability of poorly soluble APIs [9][10][11][12][13][14]. However, also the dermal drug delivery of poorly soluble APIs can be fostered with drug nanocrystals [15][16][17][18][19][20][21][22][23][24][25][26]. Thereby, the improved kinetic solubility (cs) of the nanocrystals is considered to be the major parameter that promotes increased dermal Disclaimer/Publisher's Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). ...
Dermal penetration is considered to mainly occur via passive diffusion. Therefore, a high concentration gradient of dissolved active ingredient between formulation and skin is needed to achieve an effective dermal penetration. The concentration gradient between formulation and skin can be changed by changing the amount of dissolved active ingredient in the formulation. In case of poorly soluble active ingredients this can be achieved by using nanosized drug material instead of larger sized material. The smaller size and the resulting larger surface increase the kinetic solubility and thus increase the concentration gradient of dissolved active ingredient between formulation and skin, which then results in an increased dermal penetration. In this study we demonstrated that the concentration gradient between formulation and skin can also be influenced by the number of particles being present in the formulation and by the dose (volume of formulation) applied to the skin. Particles of undissolved active ingredient are known to act as a reservoir by releasing dissolved molecules in the liquid phase of the formulation. It could now be demonstrated that the particles - once the liquid in which they are dispersed evaporates - can connect to the skin via an aqueous meniscus. The aqueous meniscus contains dissolved active ingredient and therefore creates a small local spot with a locally high concentration gradient and improved dermal penetration. Therefore, the dermal penetration can be increased with formulations that contain high amounts of particles. This can be achieved by applying formulations with high numbers of particles and/or by applying larger volumes of particle containing formulations to the skin.
... When NSs are applied dermally, they can have a local effect by penetrating the skin surface, or they can have a systemic effect by passing under the skin through intercellular hydrophilic routes, depending on the increase in saturation solubility. However, it is thought that the depot effect formed by the accumulation of particles in the hair follicles is more effective in the passage of NSs through the skin [145]. Carrier systems such as creams, anhydrous ointments, or gels are used to facilitate the dermal application of NSs and to increase their effectiveness. ...
Nanosuspensions (NSs), which are nanosized colloidal particle systems, have recently become one of the most interesting substances in nanopharmaceuticals. NSs have high commercial potential because they provide the enhanced solubility and dissolution of low-water-soluble drugs by means of their small particle sizes and large surface areas. In addition, they can alter the pharmacokinetics of the drug and, thus, improve its efficacy and safety. These advantages can be used to enhance the bioavailability of poorly soluble drugs in oral, dermal, parenteral, pulmonary, ocular, or nasal routes for systemic or local effects. Although NSs often consist mainly of pure drugs in aqueous media, they can also contain stabilizers, organic solvents, surfactants, co-surfactants, cryoprotectants, osmogents, and other components. The selection of stabilizer types, such as surfactants or/and polymers, and their ratio are the most critical factors in NS formulations. NSs can be prepared both with top-down methods (wet milling, dry milling, high-pressure homogenization, and co-grinding) and with bottom-up methods (anti-solvent precipitation, liquid emulsion, and sono-precipitation) by research laboratories and pharmaceutical professionals. Nowadays, techniques combining these two technologies are also frequently encountered. NSs can be presented to patients in liquid dosage forms, or post-production processes (freeze drying, spray drying, or spray freezing) can also be applied to transform the liquid state into the solid state for the preparation of different dosage forms such as powders, pellets, tablets, capsules, films, or gels. Thus, in the development of NS formulations, the components/amounts, preparation methods, process parameters/levels, administration routes, and dosage forms must be defined. Moreover, those factors that are the most effective for the intended use should be determined and optimized. This review discusses the effect of the formulation and process parameters on the properties of NSs and highlights the recent advances, novel strategies, and practical considerations relevant to the application of NSs to various administration routes.
... 85,86 Nanocrystal-based formulations Nanoscopic crystals facilitate and improve drug permeation for poorly soluble hydrophobic drugs, such as acyclovir, [87][88][89] and range in size between 100 nm and 1000 nm. 90 The reduced particle size in nanocrystals increases their saturation solubility, [91][92][93] which creates a high concentration gradient that increases passive diffusion. 87,94 Based on thermodynamic principles, increased saturation solubility is associated with an increase in thermodynamic activity and, thus, an increase in drug permeation across the skin. ...
Studies have demonstrated the significant role of the thermodynamic activity of drugs in skin drug delivery. This thermodynamic activity works as a driving force for increasing/improving the absorption of drugs by the skin. It can be changed according to the physicochemical parameters (e.g., solubility, partition coefficient, and water activity) of the drug in the vehicle. Thermodynamic principles have been used for the development of novel topical and transdermal delivery systems, demonstrating the importance of thermodynamic activity in enhancing drug
permeation through the skin. In this review, we provide insights into thermodynamic principles and their roles in optimizing topical and transdermal drug delivery systems.
... They are aggregated of hundreds to thousands of atoms combined into a group and are in a size range of 10-400 nm. Generally, they are applied to improve the dermal penetration of poorly soluble cosmetic substances [204][205][206] and creams or lotions [207]. ...
Today, the growth of the cosmetic industry and dramatic technological advances have led to the creation of functional cosmetical products that enhance beauty and health. Such products can be defined as topical cosmetic drugs to improve health and beauty functions or benefits. Implementing nanotechnology and advanced engineering in these products has enabled innovative product formulations and solutions. The search included organic molecules used as cosmeceuticals and nanoparticles (NPs) used in that field. As a result, this document analyses the use of organic and inorganic particles, metals, metal-oxides, and carbon-based particles. Additionally, this document includes lipid and nanoparticles solid lipid systems. In conclusion, using NPs as vehicles of active substances is a potential tool for transporting active ingredients. Finally, this review includes the nanoparticles used in cosmeceuticals while presenting the progress made and highlighting the hidden challenges associated with nanocosmeceuticals.
... The nanocrystal gel achieved 3-fold higher drug permeability through mice skin compared with the coarse drug gel and prevented UV irradiation-induced photoaging and tissue damage. For cosmetic applications, rutin nanocrystal formulation is commercially available under the tradename Juvedical ® (Juvena) [27]. ...
Rutin is a polyphenolic flavonoid with an interestingly wide therapeutic spectrum. However, its clinical benefits are limited by its poor aqueous solubility and low bioavailability. In an attempt to overcome these limitations, rutin nanocrystals were prepared using various stabilizers including nonionic surfactants and nonionic polymers. The nanocrystals were evaluated for particle size, zeta potential, drug entrapment efficiency, morphology, colloidal stability, rutin photostability, dissolution rate, and saturation solubility. The selected nanocrystal formulation was dispersed in a hydrogel base and the drug release kinetics and permeability through mouse skin were characterized. Rutin’s anti-inflammatory efficacy was studied in a carrageenan-induced rat paw edema model. The nanocrystals had a size in the range of around 270–500 nm and a polydispersity index of around 0.3–0.5. Nanocrystals stabilized by hydroxypropyl beta-cyclodextrin (HP-β-CD) had the smallest particle size, highest drug entrapment efficiency, best colloidal stability, and highest drug photostability. Nanocrystals had around a 102- to 202-fold and 2.3- to 6.7-fold increase in the drug aqueous solubility and dissolution rate, respectively, depending on the type of stabilizer. HP-β-CD nanocrystals hydrogel had a significantly higher percent of drug released and permeated through the mouse skin compared with the free drug hydrogel. The cumulative drug amount permeated through the skin was 2.5-fold higher than that of the free drug hydrogel. In vivo studies showed that HP-β-CD-stabilized rutin nanocrystals hydrogel had significantly higher edema inhibition compared with the free drug hydrogel and commercial diclofenac sodium gel. These results highlight the potential of HP-β-CD-stabilized nanocrystals as a promising approach to enhance drug solubility, dissolution rate, and anti-inflammatory properties.
... The samples for SEM were prepared by lightly sprinkling the curcumin nanocrystal powder on a double side adhesive tape, which was stuck on an aluminum stub. The photomicrographs were then captured [23]. ...
Topical curcumin shows poor local availability because of its low aqueous solubility and inadequate tissue absorption. Curcumin nanocrystals were prepared by sonoprecipitation followed by lyophilization to improve surface area and solubility. The formulation was optimized by the Design of Experiment (DoE) approach. The nanocrystals were characterized for particle size, zeta potential, polydispersity index, scanning electron microscopy (SEM), powder x-ray diffraction (PXRD), practical yield and in vitro drug release studies. The nanocrystal-incorporated gel was evaluated for drug content, ex vivo permeation, in vivo skin irritation, and in vivo wound healing activity. Time of sonication and amplitude influenced the optimization of curcumin nanocrystals, but the effect of stabilizer concentrations was not significant beyond 0.5% w/w. SEM images of curcumin nanocrystals revealed irregular and plate-shaped particles with rough surfaces. PXRD patterns of curcumin nanocrystals showed low crystallinity compared to unprocessed curcumin powder. An in vitro drug release study demonstrated significant improvement in the percentage cumulative drug release in the form of nanocrystals compared to the unprocessed curcumin, and the release profile exhibited first-order kinetics. Curcumin nanocrystal gel showed 93.86% drug content and was free of skin irritation potential. Excision wound healing activity in albino rats showed that the curcumin nanocrystal gel exhibited significantly faster wound contraction than curcumin powder-incorporated gel.
... These nanocrystals exhibits enhanced physiochemical properties than their macroscopic molecule. These can be administrated orally and at the same time can penetrate skin easily and therefore they are used in anti-ageing and skin protective products [22,23]. ...
... The production method of smartCrystals was patented in 2006 [114] after industries realized that the characteristics of nanocrystals could be advantageous in cosmetic formulations, overcoming, for example, problems in conventional solubilization techniques, and started introducing active ingredient nanocrystals [110,115] into the aqueous phase of O/W creams and lotions, resulting in nanosuspensions [110,113]. Nanocrystals may also be dispersed in non-aqueous media, such as paraffins, oils, and liquid polyethylene glycols [109]. ...
The daily use of sun protection is essential to prevent the damaging effect of incident
solar UV radiation. Sunscreens are cosmetic products containing UV filters as active
compounds, which are responsible for the absorption and/or reflection of UV radiation
that might otherwise reach the skin surface. Sunscreen formulation has undergone a
major technological transformation over the recent past resulting in improved
sunscreen efficiency and safety. In this context, nanosystems have emerged as
suitable carriers of UV filters, originating the so-called nanosunscreens. The aim of the
present review is to provide a conceptual framework based on several nanosystems at
the forefront of these advances including nanoemulsions, liposomes and
ultradeformable vesicles (transfersomes, ethosomes and transethosomes), solid lipid
nanoparticles, nanostructured lipid carriers, polymeric nanoparticles, mesoporous silica
nanoparticles, nanocrystals and Sunspheres®. Moreover, the beneficial effects these
nanosystems impart to typical formulations are described. Finally, the potential impacts
of these nanosystems on human health is discussed and regulatory approaches by
administrations around the globe are reviewed.
... Furthermore, they can simply penetrate through the stratum corneum and permeate through the sweat glands and hair follicles to the dermal lower layers. The storage effect, which takes place with accumulation in the hair follicles, is supposed to be efficient in the penetration of nanosuspensions through the skin [52]. Although it was reported that a negative zeta potential promotes permeation into the receptor compartment, owing to skin lipid system repulsion [16], skin penetrating efficiency was more pronounced in the NS2 gel compared to the NS12 gel. ...
Luteolin is a natural drug used as an antioxidant and anti-inflammatory, but unfortunately, it possesses low water solubility, which hinders its delivery via the skin. The main objective of this study was to prepare a luteolin-loaded nanosuspension by the antisolvent precipitation/sonication technique and study the effects of four stabilizers (two nonionic stabilizers, Pluronic F127 and Tween 80, and two polymeric stabilizers, HPMC and alginate) on the physicochemical properties of the prepared formulations. The selected formulations were incorporated into a gel base to evaluate their skin permeability and anti-inflammatory efficacy. The particle size was in the nanosize range (in the range from 468.1 ± 18.6 nm to 1024.8 ± 15.9 nm), while the zeta potential was negative and in the range from −41.7 ± 6.3 mV to −15.3 ± 1.9 mV. In particular, alginate-stabilized nanosuspensions showed the smallest particle size, the highest zeta potential value, and excellent stability due to the dual stabilizing effects (electrostatic and steric effects). The DSC results revealed a less crystalline structure of luteolin in lyophilized NS2 and NS12. Formulations stabilized by 1% Pluronic (NS2) and 2% alginate (NS12) were incorporated into a carbopol 940 gel base and showed good organoleptic character (homogenous with no evidenced phase separation or grittiness). In vitro dissolution studies showed that NS12 enhanced luteolin release rates, indicating the effect of particle size on the drug release pattern. On the other hand, NS2 showed enhanced skin permeability and anti-inflammatory effect in a carrageenan-induced paw edema model, revealing the surface activity role of the stabilizers. In conclusion, while alginate increased the nanosuspension stability by means of dual stabilizing effects, Pluronic F127 improved the skin delivery and pharmacodynamic efficacy of luteolin.
... It was investigated to what extent an ex vivo microdialysis setup is able to mimic the in vivo situation. A large difference between the formulations in setup A was expected, while a comparably small difference was expected in setup B. The different caffeine formulations (caffeine gel, caffeine nanocrystals of small and medium particle size) were produced according to previously developed protocols [27]. The gel contained 2.5% (w/w) caffeine (Merck KGaA, Darmstadt, Germany) dissolved in a mixture of 30% ethanol (Fisher Scientific, Loughborough, UK) and 70% propylene glycol (Caesar & Lorentz GmbH, Hilden, Germany) to which 2% Carbopol ® 981 (Lubrizol Advanced Materials Europe BVBA, Brussels, Belgium) was added while mixing with mortar and pestle to obtain a highly viscous gel [13]. ...
Common ex vivo methods for penetration investigations often fail to monitor transfollicular penetration appropriately. In the present investigation, the validity of dermal microdialysis on the ex vivo porcine ear skin to investigate penetration kinetics, including transfollicular penetration, was studied. In setup A, a caffeine nanocrystal formulation was compared to a non-particular caffeine gel formulation. In setup B, two caffeine nanocrystal formulations of different sizes (200 nm, 700 nm) were compared to each other. Microdialysis samples were collected for 46 h. After sampling, the skin layers were separated, homogenized, and caffeine was quantified in all samples. In setup A the area under the curve (AUC) after crystal gel formulation application was 12 times higher than after non-particular formulation application. Setup B showed an increased AUC of 42% in the microdialysis data when the 700 nm caffeine crystals were applied compared to the 200 nm crystals. The microdialysis data was supported by the separation, homogenization and extraction data. Microdialysis performed on ex vivo porcine ear skin is a novel experimental setup. It is of high interest for further investigations since it is able to also capture the impact of follicular and transfollicular penetration kinetics as no other ex vivo setup can.
... Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs [2]. As the particle size of crystals decreases to around 100 nm, the properties of the material, such as solubility are drastically changed [3]. ...
Background: Natamycin belongs to a large group of naturally occurring polyene antifungal antibiotics derived from Streptomyces natalensis. Natamycin has a restrictive pharmaceutical role because of its extremely low aqueous solubility, which severely reduces the bioavailability of the drug. To improve the absorption of the drug, nanocrystals of natamycin were prepared and incorporated into in situ gel. Aim: To improve the solubility and absorption of natamycin nanocrystals by preparing nanocrystal in situ gel of natamycin for ophthalmic delivery Methodology: Natamycin nanocrystal was prepared using Sono-Precipitation method. Box-Behnken approach was employed to assess the influence of independent variables, namely concentration of stabilizer, sonication time and amplitude on particle size and zeta potential of the prepared nanocrystal. Optimized natamycin nanocrystal in situ gel formulations was characterized for various parameters like pH, viscosity, drug content, in vitro drug release and ex vivo permeation studies. Results: The optimized formulation of natamycin nanocrystal with a particle size of 293.9nm and zeta potential -14.6mV was incorporated into in situ gels. The pH triggered in situ gel was prepared using Carbopol and Hydroxypropyl methylcellulose (HPMC)., which showed clear preparation, pH of the formulation was closed to the pH of tear fluid, i.e., 7.4, viscosity showed pseudoplastic behaviour with immediate gelation remained for an extended period, and the drug content was around 99.70%. From the characterizations given above, PF-4 was optimized and evaluated for In vitro drug release showing slow and sustained release when compared to the marketed formulation and followed first-order kinetics with the diffusion-controlled mechanism. Ex vivo permeation through goat's cornea of PF-4 showed better permeation than marketed formulation. The stability studies of PF-4 showed that formulation was stable at the appropriate condition. Conclusion: Nanocrystals formulations of natamycin was successfully formulated and incorporated into in situ gels. Further in vivo studies need to be carried out for confirmation of pharmacological activity
... Nanocrystals can significantly improve the solubility and dissolution rate of water-insoluble and fat-insoluble drugs, and is suitable for transdermal administration of insoluble drugs at high dose. 46 Nanocrystals can form a higher concentration gradient on the skin surface, which facilitates the diffusion of drug molecules into the skin. In addition, nanocrystals have good biological adhesion, which can prolong their retention time on the skin surface, help to maintain a high concentration gradient for a long time, and promote the diffusion of drug molecules into the skin. ...
Nanocarrier technology has been effectively applied to the development of drug delivery systems to overcome the limitations of traditional preparation. Its application has been extended to various pharmaceutical fields from injection preparation to oral preparation and external preparation, and now it has appeared in the field of cosmetics for beauty applications. The widespread influence of nanocarrier in the cosmetics industry is due to the fact that nanocarrier can effectively promote the percutaneous penetration and significantly increase skin retention of active components in functional cosmetics. Meanwhile, nanocarrier can effectively improve the water dispersion of insoluble active cosmetic ingredients, enhance the stability of efficacy components and achieve the codelivery of diverse cosmetics active ingredients. In this review, we summarized the current progress of nanocarrier technology in the functional cosmetics, including the types and the routes of dermal/transdermal drug delivery nanocarriers used in the functional cosmetics, the mechanism of nanocarriers promoting the percutaneous penetration of active cosmetic ingredients, the application and efficacy evaluation of different active cosmetic ingredients in nanocarriers and discussing the potential risks to human. This will provide a useful reference for the further development of nanocarriers in the field of functional cosmetics.
... Nanosuspensions can be prepared with bottom up (precipitation) and top down approaches (wet milling, homogenization) or a combination of them (11). In recent years, the wet milling method has become especially popular in the pharmaceutical industry because of its applicability to various low soluble active ingredients, benefits as an organic solventfree technique, ease of scale-up for manufacturing, and its relatively low cost of preparation. ...
Purpose
The objective of this study was to optimize the Flurbiprofen (FB) nanosuspension (NS) based gel and to investigate the in vitro release, ex vivo permeation, the plasma concentration-time profile and pharmacokinetic parameters.
Methods
FB-NSs were developed using the wet milling process with the Design of Experiment (DoE) approach. The optimum FB-NS was characterized on the basis of SEM, DSC, XRPD, solubility and permeation studies. The dermal gel was prepared by incorporating FB-NS into HPMC gel. Then the in-vitro release, ex vivo permeation studies were performed, and pharmacokinetic studies were evaluated on rats.
Results
The particle size, polydispersity index and zeta potential values of optimum NS were determined as 237.7 ± 6.8 nm, 0.133 ± 0.030 and − 30.4 ± 0.7 mV, respectively. By means of the surfactant content and nanosized particles of the nanosuspension, the solubility of FB was increased about 7-fold. The percentage permeated amount of FB from FB-NS gel (8.40%) was also found to be higher than the physical mixture (5.25%) and coarse suspension (reference) (2.08%) gels. The pharmacokinetic studies showed that the Cmax of FB-NS gel was 2.5 times higher than the reference gel, while AUC0–24 was 2.96 times higher.
Conclusion
FB-NSs were successfully prepared with a wet milling method and optimized with the DoE approach. The optimized FB nanosuspension gel provided better permeation and pharmacokinetic performance compared to FB coarse suspension gel.
... With increasing the water solubility of particles converted to NS form and using surfactants, the permeation is also increased in the hydrophilic intercellular pathway of skin. Moreover, NSs enhance the skin permeation of drugs by improving the particles' penetration into hair follicles (Zhai et al. 2014). Thus, different results of in vitro and ex vivo permeation studies were attributed to the absence of hair follicles on dialysis membrane. ...
Aim
The objective of this study was to develop dermal nanosuspension (NS) based gel formulation of etodolac (ETD).
Methods
Etodolac nanosuspension (ETD-NS) was prepared by wet milling method and dispersed in hydroxypropyl methylcellulose (NS-HPMC) or hydroxyethyl cellulose (NS-HEC) gels. Rheologic and mechanical properties were investigated. In vitro and ex vivo permeability studies were performed. Topical anti-inflammatory and analgesic activity were evaluated in regard to carrageenan-induced inflammatory paw oedema and radiant heat tail-flick method, respectively.
Results
The ETD-NS with approximately 190 nm particle size (PS), 0.16 polydispersity index (PDI), and −15 mV zeta potential (ZP) values were obtained. The work of bioadhesion values of NS-HEC and NS-HPMC gels were 0.229 mJ/cm² for both gels. Dermal permeation of ETD from NS-HEC gel (7.18%) was found significantly higher than the NS-HPMC gel (4.56%). Enhanced anti-inflammatory and analgesic activity of NS-HEC gels were observed in comparison with micronised ETD.
Conclusions
ETD-NS based gel formulation is promising for topical delivery of ETD.
... Importantly, upon intradermal delivery by the MN, the NC acted as a depot, sustaining drug release for days and even weeks in vivo [45][46][47]. Additionally, since NC formulation requires only small amounts of stabiliser, they yield high drug loadings in the MN arrays [49]. This study investigated, for the first time, the combination of NC and dissolving MN technologies as an alternative approach for localised and sustained intradermal delivery of MTX, with a view to enhanced treatment for psoriasis and minimise/avoid the side effects associated with its systemic administration. ...
Methotrexate (MTX), typically used as its sodium salt (MTX Na), is a first-line treatments for moderate to severe psoriasis, showing good efficacy. However, its systemic administration is associated with many side effects. Intradermal delivery into psoriatic tissue could offer an alternative approach. However, successful intradermal administration of MTX Na is currently precluded by its physicochemical properties. Moreover, due to its hydrophilic nature, MTX Na is swiftly cleared from the target tissue, necessitating frequent dosing which may affect patient compliance. To address these limitations, we investigated the combination of nanocrystal (NC) and dissolving microneedle (MN) technologies as an alternative approach for localised and sustained intradermal delivery of MTX Na. Poorly water-soluble MTX nanocrystals (MTX NC) were produced by a bottom-up technique with a mean particle size of 678 ± 15 nm. Sustained in vitro drug release was observed over 72 h. The MTX NC were then incorporated into the shafts of dissolving MN arrays with a drug loading of 2.48 mg/array. The MTX NC-loaded MN arrays exhibited satisfactory mechanical strength and insertion capabilities in the skin-simulant Parafilm M® and their shafts dissolved entirely in less than 20 min after insertion into excised neonatal porcine skin. Importantly, in vivo studies in Sprague Dawley rats revealed that the MN arrays were able to deposit approximately 25.1% of the loaded MTX NC in the skin, which acted, in turn, as a drug depot and released the MTX in a sustained manner over 72 h, while minimising MTX systemic exposure. Indeed, 24 h from MN application, 312.70 ± 161.95 µg/g of MTX was retained in the skin at the application site. This was approximately 322-fold higher than the amount of MTX (0.942 ± 0.59 µg/g) retained in the skin after oral administration of MTX Na. Interestingly, even after 72 h after MN application, around 12.5% of the MTX NC deposited in the skin by the MN was retained. In contrast, the maximal blood concentration of MTX achieved following MN application, was only 40% of that measured after oral administration of MTX Na. Accordingly, MTX NC-loaded dissolving MN arrays could be a promising approach for effective localised and sustained intradermal delivery of MTX as a potential enhanced treatment for psoriasis.
... Reducing particle size to nanometer range can increase the surface area which leads to an increase in kinetic saturation solubility and dissolution velocity according to Kelvin and Noyes-Whitney equations. Membrane penetration and finally enhanced bioavailability can be achieved by particle size reduction Zhai et al., 2014). Nanocrystals are 100% drug molecules with <1000 nm particle size (typically 200-600 nm) (Keck and Müller, 2006). ...
Objectives:
The current study focused on the evaluation of the cytotoxic effect and permeability of ziprasidone hydrochloride monohydrate (ZHM) nanocrystals on Caco-2 cells.
Materials and methods:
ZHM nanocrystals were prepared by the microfluidization method in the presence of polyvinylpyrrolidone as a stabilizer. Particle size (PS), particle size distribution (PDI), and zeta potential (ZP) values were measured in characterization studies. In vitro cytotoxic effects of ZHM nanocrystals were investigated using the 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Caco-2 transport studies were conducted with formulations of ZHM coarse powder and nanocrystals.
Results:
Nanocrystals were obtained with 400-600 nm PS, 0.1-0.4 PDI, and >20 mV ZP values. The cell viability remained 100% for all sample groups. The permeability value of ZHM nanocrystals through Caco-2 cells increased 2.3-fold in comparison with ZHM coarse powder. Cumulative drug transport also increased at the end of the sampling period.
Conclusion:
Nanocrystal technology helps to increase the permeability of drug particles by increasing the saturation solubility.
... This latter is responsible for a more profit diffusion of the active ingredients through the tissues. The greater surface promotes a bigger adhesiveness with consequently superior retention time at the site of action [79,80]. ...
Introduction: Nanotechnology is an increasingly widespread area of research for its various applications and advantages. Accordingly, nanotechnology has been the focus of investment in different areas of science, namely as a technological strategy for the development of cosmetics formulations. Nanosystems allow for a profit skin penetration and an effective release profile of ingredients, which contributes for superior technological and cosmetic effects. The applications of nanocosmetics are numerous, from anti-aging care, make-up, nails, deodorants, oral care, sunscreens and hair care. However, as an area of emerging knowledge, it has now begun to encourage investigations into its toxicology profile, particularly regarding to health damage and environmental pollution. Also, the regulatory area saw its adaptation concerning the use of formulations containing nanotechnology.
Areas covered: A description of the nanosystems so far applied in the development of cosmetics is presented. Moreover, an outline concerning lipid-based-nanosystems, polymeric-based nanoparticles, metal-based nanoparticles, silica nanoparticles and additional nanosystems (dendrimers, nanocrystals, fullerenes, nanodiamonds and cyclodextrins) towards the obtainment of effective cosmetic outcomes is addressed. The concerning toxicological as well as the regulatory aspects are also discussed.
Expert opinion: This innovative and timely review emphasizes that nanosystems constitute a highly promising technology strategy towards the obtainment of superior and ground-breaking cosmetic formulations.
... Yet in parenteral route, particle size may influence pharmacokinetics and the in vivo distribution of crystalline nanoparticles [157,158]. The smaller crystalline ric- cardin D and oridonin nanoparticles (<200 nm) exhibited similar pharmacoki- netics and biodistribution to solutions, while the larger ones (800-900 nm) led to the increase in area under curve, extended clearance and greater accumula- tions to liver, spleen, and lung [153,154]. Furthermore, the particle size distri- bution correlates with the stability of crystalline nanoparticles due to the effects of Ostwald ripening. Particle size and size distribution are usually measured by dynamic light scat- tering (DLS), also known as photon correlation spectroscopy (PCS) (Figure 11.11). ...
Crystalline nanoparticles are drug crystals with particle size ranging from dozens to a few hundreds of nanometers. Crystalline nanoparticles show increased dissolution rate compared to the coarse drug powders. Crystalline nanoparticles can be injected intravenously as aqueous isotonic nanosuspensions. Crystalline nanoparticles can be prepared by either top‐down or bottom‐up techniques. Top‐down techniques comminute coarse drug powders by mechanical attrition through media milling (MM) or high‐pressure homogenization (HPH), while bottom‐up techniques grow crystals from solution. Top‐down process is a universal technique to prepare crystalline nanoparticles and flexible in production scale. This chapter introduces the preparation methods of crystalline nanoparticles. It explores the stabilization, application, and characterization of crystalline nanoparticles. Precipitation by solvent‐antisolvent mixing is the most commonly used bottom‐up technology, because it is the simplest and the most cost effective one among the various precipitation techniques. Crystalline nanoparticles are thermodynamically unstable colloid dispersion systems due to the large specific surface area and surface energy.
... Nanocrystals also facilitate the accumulation of the drug in hair follicles. Nanocrystals promote the depot and stabilization of the concentration gradient and consequently the constant dermal penetration [19,29]. ...
Nanotechnology has provided nanostructure-based delivery of drugs, among which nanocrystals have been investigated and explored for feasible topical drug delivery. Nanocrystals are nano-sized colloidal carriers, considered pure solid particles with a maximum drug load and a very small amount of stabilizer. The size or mean diameter of the nanocrystals is less than 1 μm and has a crystalline character. Prominent synthesis methods include the utilization of microfluidic- driven platforms as well as the milling approach, which is both adaptable and adjustable. Nanocrystals have shown a high capacity for loading drugs, utilization of negligible amounts of excipients, greater chemical stability, lower toxic effects, and ease of scale-up, as well as manufacturing. They have gained interest as drug delivery platforms, and the significantly large surface area of the skin makes it a potential approach for topical therapeutic formulations for different skin disorders including fungal and bacterial infections, psoriasis, wound healing, and skin cancers, etc. This article explores the preparation techniques, applications, and recent patents of nanocrystals for treating various skin conditions.
The main issues with local delivery of cosmetics are their high sensitivity and limited drug loading of active pharmaceutical ingredient. Nanocrystal technology offers consumers cutting-edge and effective products and exhibits enormous development potential in the beauty business as a new delivery method to address the issue of low solubility and low permeability of sensitive chemicals. In this review, we described the processes for making NCs, along with the impacts of loading and the uses of different carriers. Among them, nanocrystalline loaded gel and emulsion are widely used and may further improve the stability of the system. Then, we introduced the beauty efficacy of drug NCs from five aspects: anti-inflammation and acne, anti-bacterial, lightening and freckle removal, anti-aging as well as UV protection. Following that, we presented the current scenario about stability and safety. Finally, the challenges and vacancy were discussed along with the potential uses of NCs in the cosmetics industry. This review serves as a resource for the advancement of nanocrystal technology in the cosmetics sector.
Background:
A drug with poor water-solubility, like Dexamethasone acetate, can present lower bioavailability conventional for pharmaceutical formulations, and the presence of polymorphs in the raw material can lead to drug quality problems.
Objective:
In this study, nanocrystals of dexamethasone acetate were synthesized by high pressure homogenizer (HPH) method in surfactant poloxamer 188 (P188) solid dispersion and the bioavailable in raw material with polymorphism presence was evaluated.
Methods:
The powder pre-suspension was prepared by the HPH process, and the nanoparticles formed were incorporated in P188 solutions. The nanocrystals formed were characterized by techniques of XRD, SEM, FTIR, thermal analysis by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), dynamic light scattering (DLS) to analyze the particle size and zeta potential, and in vitro evaluation by dissolution studies.
Results:
The characterization techniques were adequate to show the presence of raw material with physical moisture between two dexamethasone acetate polymorphs. The nanocrystals formed in the presence of the P188 in the formulation showed a considerable increase in the rate of dissolution of the drug in the medium and in the size of the stable nanocrystals, even in the presence of dexamethasone acetate polymorphs.
Conclusion:
The results showed that it was possible to produce dexamethasone nanocrystals by HPH process with regular size by the presence of the small amount of P188 surfactant. This article presents a novelty in the development of dexamethasone nanoparticles that have different polymorphic forms in their physical composition.
Skin conditions are amongst the most prevalent health issues in the world and come with a heavy economic, social, and psychological burden. Incurable and chronic skin conditions like eczema, psoriasis, fungal infections are linked to major morbidity in the manner of physical pain and a reduction in quality life of patients. Several drugs have difficulties for penetrating the skin due to the barrier mechanism of the skin layers and the incompatible physicochemical characteristics of the drugs. This has led to the introduction of innovative drug delivery methods. Currently, formulations depend on nanocrystals have indeed been researched for topical administration of drugs and have resulted in enhanced skin penetration. This review focuses on skin penetration barriers, modern methods to enhance topical distribution, and the use of nanocrystals to overcome these barriers. By means of mechanisms such as adherence to skin, creation of diffusional corona, targeting of hair follicles, and the generation of a greater concentration gradient throughout the skin, nanocrystals could enhance transport across the skin. Scientists working on product formulations incorporating chemicals that are "challenging-to-deliver" topically may find the most current findings to be of relevance.
Rosacea is a chronic, inflammatory skin disease that affects about 10% of the population. Metronidazole-containing ointments are typically recommended for the daily treatment of symptoms. For increasing bioavailability and effectiveness, it is needed to reduce the particle size. Therefore, micronized metronidazole was prepared by spray freeze-drying (SFD) method, then its most important features were examined such as morphology, crystallinity and particle size. The anti-inflammatory effect of the as-prepared agent was tested on a mouse model of rosacea for effectiveness against oedema and redness of the ears, and it was compared to a reference cream.
Metronidazole size was reduced successfully by SFD to 2.7 μm from 162.6 μm. The material was non-porous and preserved its crystalline state. The spray freeze-dried metronidazole mixed into ointment was effective against oedema and ear-redness. The ointment reduced oedema in five times lower doses (2 × 0.04 mg metronidazole) and the ear-redness in half dose (2 × 0.2 mg metronidazole) than the cream containing reference metronidazole (2 × 0.2 mg and 2 × 0.4 mg metronidazole, respectively). In conclusion, the SFD technique is an adequate and gentle procedure for reducing the size of metronidazole, which is highly effective in rosacea.
Cancer accounts for the high mortality rate and limits the life expectancy of an individual. As per the WHO report of 2020, Cancer accounts for >10 million deaths globally. Scientists are continuously pitching toward the development of novel techniques to combat this menace and enhance the efficacy of prevailing molecules. In the early phases of the drug development process, >40% of promising new therapeutic molecules are hydrophobic. Low aqueous solubility results in compromised bioavailability on administration. This limitation is a major drawback for the therapeutic use of the anticancer drug. Drug nanocrystals (NCs) have sparked a lot of interest in drug delivery. This might be due to their excellent physicochemical characteristics like tailored dissolution, high drug loading efficiency, extended circulation period, and high structural stability. These are ‘n’ number of the characteristics that make drug nanocrystals a promising formulation for the treatment of cancer. In the last few years, many hydrophobic or lipophilic drugs like camptothecin, paclitaxel, cyclosporin, busulfan, and thymectacin had been formulated as drug nanocrystals against anticancer therapeutics. Various formulation technologies have been developed in conjunction with nanocrystal development. This includes top-down approaches, bottom-up approaches, as well as combination technology. In this article, we will focus on the various manufacturing processes, biological fate and therapeutic applications of NCs, and future perspectives in the management of cancer.
Topical drug delivery methods are important in the treatment of skin diseases. Drug nanocrystals, which are nanometersized particles of active pharmaceutical ingredients, offer efficient topical delivery with high stability, high drug loading capacity, steady dissolution, and sustained drug release profiles. The use of nanocrystals for the topical delivery of skin disease therapies is currently being evaluated; this review focuses on how nanocrystals facilitate active pharmaceutical ingredient transport across skin barriers, exploring the underlying transportation mechanisms of the nanocrystals and active pharmaceutical ingredient molecules to the dermal and epidermal skin cells. In topical delivery, previous skin treatments, choice of excipients and vehicles, and penetration enhancement strategies critically influence the topical delivery of drug nanocrystals. Various research and applications of drug nanocrystals in skin disease therapy are highlighted in this review, and intellectual property protection for drug nanocrystal formulations, clinical trial data, and products with commercial potential are also discussed.
The barrier function of skin and the non-optimal physicochemical properties of drugs present challenges to the skin penetration of many drugs, motivating the development of novel drug-delivery systems. Recently, nanocrystal-based formulations have been investigated for topical drug delivery and have demonstrated improved skin penetration. This review highlights barriers in skin penetration, current techniques to improve topical delivery and the application of nanocrystals to conquer obstacles for topical delivery. Nanocrystals can improve delivery through the skin by mechanisms including the creation of a higher concentration gradient across skin resulting in increased passive diffusion, hair follicle targeting, formation of diffusional corona, and adhesion to skin. These mechanisms are of interest for formulation scientists seeking to develop products involving molecules that are ‘difficult-to-deliver’ topically.
Flurbiprofen (FB) is an analgesic and anti-inflammatory drug, but its low water solubility (BCS Class II) limits its dermal bioavailability. The aim of this study is to develop a FB nanosuspension (NS) based gel and to evaluate its analgesic and anti-inflammatory activities in rats. FB-NS was produced by the wet milling method with Plantacare 2000 Ⓡ, as stabilizer. The FB-NS was then incorporated in different carrier gels such as hydroxypropyl methyl cellulose (HPMC), polycarbophil, oleogel, and chitosan. To select the optimum gel type, visual examinations, pH and rheological property measurements, texture profile analysis, in vitro release and ex vivo permeation studies were performed. Following these tests, the analgesic and anti-inflammatory activities of the optimum NS based gel were evaluated using the tail flick and carrageenan-induced paw edema methods consecutively. The NS was successfully prepared with the wet milling method, and the PS, PDI and ZP values were found to be 237.7±6.8 nm, 0.133±0.030, and -30.4±0.7 mV; respectively. Among the NS-based gels, HPMC gel showed more suitable rheological and mechanical properties, also the percentage of permeated FB and the flux value observed for HPMC gel were higher for HPMC than for the other gels. Thus, HPMC gel was selected as a carrier gel for in vivo pharmacodynamics studies. The anti-inflammatory activity of FB-NS HPMC gel was higher than that of the physical mixture gel and that of the coarse suspension gel. Results of our analgesic activity studies showed that, in the 180th min of FB nanosuspension treatment, the latency time was significantly prolonged compared to that of the control group (p<0.05). As a conclusion, while nanosuspensions increased the in vivo pharmacodynamics effect of FB by means of nanosized particles and a large surface area, the HPMC gel as a carrier prolonged the contact time of NSs with skin and eased the dermal application.
Although flurbiprofen (FB), as one of non-steroidal anti-inflammatory drugs, has various pharmacological applications, it shows low dermal bioavailability due to its low water solubility. To overcome this solubility problem, FB nanosuspensions were developed and the effects of stabilizers were investigated with regard to critical quality attributes. While PVP K30 and HPMC 3 cps were used as non-ionic polymeric stabilizer, Tween 80 and Plantacare 2000 (PL) were used as non-ionic surfactants. The influence of these types of stabilizers and their different ratios were tested. The selected formulations according to results of experimental design were also characterized by SEM, FTIR, XRPD, DSC, and the stability studies were performed. According to results of characterization studies, PL was selected as the appropriate stabilizer. The determined nanosuspension stabilized with PL had the nanosized, spherical, and homogenous dispersed particles. There is no polymorphic change on the crystalline state of FB while producing nanosuspension stabilized with PL. It also retained its stability compared with PVP stabilized nanosuspensions for one month. It was concluded that the design of experimental approach is a useful tool to determine the effect of stabilizer on quality attributes of nanosuspensions and to select the optimum type and ratio of stabilizer for obtaining more stable nanosuspensions.
Introduction: The improvement of percutaneous absorption represents a clear dermatopharmaceutical aim. Recently, the hair follicle was recognized to be an important penetration pathway. Especially nanoparticles show an enhanced intrafollicular penetration and can be utilized to target specific cell populations within the hair follicle.
Areas covered: The present review briefly summarizes the recent advances in follicular drug delivery of nanoparticles. Moreover, the particularities of the hair follicle as a penetration pathway are summarized which include its structure and specific barrier properties. Recently, the mechanism of the follicular penetration process has been clarified.
In the meantime, different strategies have been developed to successfully improve follicular drug delivery of nanoparticles. One approach is to equip the nanocarriers with a triggered release system enabling them to release their drug load at the right time and place.
Expert opinion: Follicular drug delivery with smart nanocarrier-based drug delivery systems represents a promising approach to increase the percutaneous absorption of topically applied substances. Although technical achievements and efficacy proofs concerning an increased penetration of substances are already available, the practical implementation into clinical application still represents an additional challenge and should be in the focus of interest in future research.
Flurbiprofen (FB) is an effective nonsteroidal anti-inflammatory and BCS class II drug and its poor solubility plays a critical role in limiting its bioavailability. Nanosuspensions can be defined as nanosized colloidal dispersions of drug particles stabilized with stabilizers. The solubility of poor soluble drugs can be increased thanks to their small size and large surface area. The aim of this study is to optimize FB nanosuspensions. The formulations were stabilized with Plantacare 2000® as a surfactant using a combination of High Speed Homogenization (HSH) and High Pressure Homogenization techniques (HPH). We also investigated the effects of the critical process parameters (CPPs) of these techniques (homogenization speed & time for HSH and homogenization pressure & cycle for HPH) on three critical quality attributes of nanosuspensions, being the particle size (PS), polydispersity index (PDI) and zeta potential (ZP). After the optimization of HSH, the macrosuspension was transferred to a high pressure homogenizer. After producing FB nanosuspensions by the HPH technique, seven processes which comprise different homogenization pressures, or combinations and different cycles, were applied. Due to the combination of HSH and HPH techniques and the optimization of CPPs, an optimum formulation for a dermal application was found using a 3³ full factorial design with these process parameters, and characterization studies were also performed.
Nanoparticles are tiny and cannot be seen by the naked eye. They possess different properties than macro-sized material and most of the well-established characterization methods for larger sized materials cannot be applied for nanomaterials. Hence, different techniques need to be used for a meaningful characterization of the nanosized material. This chapter will focus on the most important characterization methods that need to be applied to characterize and develop nanocarrier for cosmetic applications.
Dermal application of actives aims at delivering the active to the desired place of action, typically to the deeper layers of the skin. Passive diffusion is the main driving force of absorption into the skin, and a main prerequisite for effective passive diffusion is a sufficient amount of dissolved active within the formulation, because only dissolved molecules can be taken up. Many cosmetic and cosmeceutical actives possess poor solubility and can therefore not be delivered to the skin by classical formulation approaches. One of the modern and most powerful strategies to overcome poor solubility is the use of nanocrystals, which are addressed in this chapter.
Background: Hair loss encompasses a group of scarring and nonscarring diseases with limited treatment options. Understanding the pathogenesis of alopecias has led to the experimental use of phosphodiesterase inhibitors (PDEi).
Objective: To perform a systematic review of literature surrounding the use of PDEi for alopecia.
Materials and methods: A search was conducted using PubMed in February 2019 on PDEi and alopecia. Inclusion criteria were clinical trials, prospective or retrospective studies, case series and case reports written in English, using PDEi in human subjects for the treatment of alopecia.
Results: Fifteen articles were included for review – eight discussing the use of topical caffeine 0.2%–2.5% for the treatment of androgenetic alopecia (AGA) and telogen effluvium (TE), one using injectable caffeine for AGA, one using topical sildenafil for pediatric alopecia areata (AA), and five using oral apremilast for adult AA.
Conclusions: Preliminary results using topical caffeine for AGA or TE are promising with minimal adverse events. However, these studies are primarily single-center trials with few patients. Studies using topical or systemic PDEi for AA demonstrate limited success. Current research using PDEi for alopecia is limited, however new clinical trials are being conducted.
Puerarin (PU) has emerged as a promising herb-derived anti-Parkinsonism compound. However, the undesirable water solubility as well as unwanted bioavailability of PU limit its application. Therefore, this study aimed to develop and characterize PU nanocrystals (PU-NCs) with enhanced oral bioavailability and improved brain accumulation for the treatment of Parkinson’s disease (PD). The fabricated PU-NCs were approximately spherical, with a mean size of 83.05 ± 1.96 nm, a PDI of 0.047 ± 0.009, a drug loading of 72.7%, and a rapid dissolution rate in vitro. Molecular dynamics simulation of PU and Pluronic F68 demonstrated the interaction energy and binding energy of -88.1kJ/mol and -40.201 ± 0.685 kJ/mol, respectively, indicating a spontaneous binding with van der Waals interactions. In addition, the cellular uptake and permeability of PU-NCs were significantly enhanced as compared to PU alone (p<0.01). Moreover, PU-NCs exerted a significant neuroprotective effect against the cellular damage induced by 1-methyl-4-phenylpyridinium ion (MPP+). Besides, PU-NCs demonstrated no obvious toxic effects on zebrafish, as evidenced by the unaltered morphology, hatching, survival rate, body length, and heart rate. Fluorescence resonance energy transfer (FRET) imaging revealed that intact nanocrystals were found in the intestine and brain of adult zebrafish gavaged with DiO/DiI/PU-NCs. Increased values of Cmax and AUC0-t were observed in the plasma of rats following oral administration of PU-NCs compared to PU suspension. Likewise, brain accumulation of PU-NCs was higher than that of PU suspension. Furthermore, PU-NCs attenuated dopamine depletion, ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits and enhanced the levels of dopamine and its metabolites. Taken altogether, this study provides evidence that PU-NCs could be exploited as a potential oral delivery system to treat PD, by improving the poor bioavailability of PU and enhancing their delivery into the brain. Keywords: Nanocrystals; Puerarin; Oral delivery; Brain accumulation; Parkinson’s disease
Nanotechnology will affect our lives tremendously over the next decade in very different fields, including medicine and pharmacy. Transfer of materials into the nanodimension changes their physical properties which were used in pharmaceutics to develop a new innovative formulation principle for poorly soluble drugs: the drug nanocrystals. The drug nanocrystals do not belong to the future; the first products are already on the market. The industrially relevant production technologies, pearl milling and high pressure homogenization, are reviewed. The physics behind the drug nanocrystals and changes of their physical properties are discussed. The marketed products are presented and the special physical effects of nanocrystals explained which are utilized in each market product. Examples of products in the development pipelines (clinical phases) are presented and the benefits for in vivo administration of drug nanocrystals are summarized in an overview.
Surface-active agents (surfactants) are characterized by the possession of 2 different moieties, both polar and non-polar regions on the same molecule. Surfactants are broadly classified as anionic, cationic, amphoteric, or non-ionic, according to the nature of the hydrophile yielded in aqueous solution. In currently marketed household, personal, and industrial cleaners, anionic surfactants are the most common class because of their relative ability to solubilize fats and oils, lower the surface tension of aqueous solutions, or form microemulsions. Many surfactants elicit irritant reactions when applied to the skin, partially due to their relative ability to solubilize lipid membranes. Hence, surfactants have become important implements in skin irritation investigations. In general, the physicochemical properties of surfactants are a crucial factor in eliciting skin irritation. Anionic surfactants are broadly accepted as potent irritants to human and animal skin. Cationic surfactants are reputedly at least equally irritating, but more cytotoxic than anionic, while the irritation potential of non-ionic surfactants is considered the lowest. Such classification of innumerable surfactants is convenient and held in high practical esteem. however, the categorization does not permit the exact determination of irritation and cytotoxicity potential of each surfactant. Ranking of surfactant skin irritancy and cytotoxicity obtained by both in vitro and in vivo assays provides a helpful orientation for future work.
The solubility of caffeine in water, ethyl acetate, ethanol, carbon tetrachloride, methanol, chloroform, dichloromethane and acetone were measured by a gravimetrical method from (298 to 323) K and the solubility data was correlated against temperature. The solubility of caffeine in chloroform and dichloromethane was high compared with other solvents.
Nanoparticle engineering of drug crystals is an important basic tool for efficient and intelligent drug delivery. Recently, the wet comminution process of drug nanocrystals in the presence of polymeric stabilizers has been successfully developed, but it has not been well understood yet how to select a proper stabilizer for a drug. In this study, the nature of interactions between polymeric stabilizers and drugs was investigated by analyzing the steady state particle sizes of 7 drugs obtained by wet comminution. The surface energy of drugs and polymers measured by contact angle measurement was found to be an important factor, although it could not solely determine the steady state values of particle size. In addition to surface energy, specific interactions between functional groups appeared to play a certain role. The stabilization ability of polymers and the subsequent steady state particle size of drug nanocrystals depend on various parameters including surface energy and specific interactions.
Introduction:
The optimization of drug delivery to and via the hair follicles is gaining more and more importance as it has been recognized that the hair follicles are an interesting target site for topical applications. They are closely surrounded by capillaries and antigen-presenting cells, are associated with the sebaceous glands and are the host of stem cells in the bulge region of the hair follicle.
Areas covered:
The present review shortly summarizes the complexity of the structure, biology and functions of the hair follicle and presents the models and methods suitable to investigate follicular penetration. Drug delivery to hair follicles was clearly shown to be dependent on the physicochemical properties of the applied substances and vehicles as well as on the activity status, size and density of the hair follicles. Especially particulate substances were demonstrated to be proficient drug carriers into the hair follicles, whereas dependent data for transfollicular penetration into the deeper viable skin layers could only be found for non-particulate substances which then, however, received rapid access to the circulation when the follicular pathway was accessible.
Expert opinion:
Promising concepts to optimize hair follicle delivery and to beneficially utilize particulate substances for efficient follicular drug delivery are the application of external or internal stimuli for controlled drug release from the particles such as the combined application with protease or the usage of gold nanoparticles in combination with near-infrared irradiation.
Propylene glycol is an aliphatic alcohol that functions as a skin conditioning agent, viscosity decreasing agent, solvent, and fragrance ingredient in cosmetics. Tripropylene glycol functions as a humectant, antioxidant, and emulsion stabilizer. Polypropylene glycols (PPGs), including PPG-3, PPG-7, PPG-9, PPG-12, PPG-13, PPG-15, PPG-16, PPG-17, PPG-20, PPG-26, PPG-30, PPG-33, PPG-34, PPG-51, PPG-52, and PPG-69, function primarily as skin conditioning agents, with some solvent use. The majority of the safety and toxicity information presented is for propylene glycol (PG). Propylene glycol is generally nontoxic and is noncarcinogenic. Clinical studies demonstrated an absence of dermal sensitization at use concentrations, although concerns about irritation remained. The CIR Expert Panel determined that the available information support the safety of tripropylene glycol as well as all the PPGs. The Expert Panel concluded that PG, tripropylene glycol, and PPGs ≥3 are safe as used in cosmetic formulations when formulated to be nonirritating.
Curcumin, a naturally occuring polyphenolic phytoconstituent, is isolated from the rhizomes of Curcuma longa Linn. (Zingiberaceae). It is water insoluble under acidic or neutral conditions but dissolves in alkaline environment. In neutral or alkaline conditions, curcumin is highly unstable undergoing rapid hydrolytic degradation to feruloyl methane and ferulic acid. Thus, the use of curcumin is limited by its poor aqueous solubility in acidic or neutral conditions and instability in alkaline pH. In the present study, curcumin nanocrystals were prepared using high-pressure homogenization, to improve its solubility. Five different stabilizers [polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), sodium dodecyl sulfate (SDS), carboxymethylcellulose sodium salt] possessing different stabilization mechanism were investigated. The nanoparticles were characterized with regard to size, surface charge, shape and morphology, thermal property, and crystallinity. A short-term stability study was performed storing the differently stabilized nanoparticles at 4°C and room temperature. PVA, PVP, TPGS, and SDS successfully produced curcumin nanoparticle with the particle size in the range of 500-700 nm. PVA, PVP, and TPGS showed similar performance in preserving the curcumin nanosuspension stability. However, PVP is the most efficient polymer to stabilize curcumin nanoparticle. This study illustrates that the developed curcumin nanoparticle held great potential as a possible approach to improve the curcumin solubility then enhancing bioavailability. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
This study aimed to examine the long-term physical stability of quercetin nanocrystals produced by three methods.
Quercetin nanocrystals were prepared by high pressure homogenization, bead milling and cavi-precipitation. The nanocrystals produced by these methods were compared for particle size, saturation solubility and dissolution of the drug particles, and were subjected to stability testing.
The X-ray diffraction study and microscopic pictures taken under polarized light indicated the crystalline nature of the nanocrystals produced by the three methods. As the crystalline state is relatively more stable than the amorphous state, a good physical stability was expected from the quercetin nanocrystals prepared. The high-pressure homogenized and bead-milled quercetin nanocrystals showed excellent physical stability when stored under refrigeration (4±2°C) and at room temperature (25±2°C) for 180 days. The dissolution properties were not significantly affected on storage at room temperature. However, increase in the storage temperature to 40±2°C led to physical instability. On the other hand, the cavi-precipitated quercetin nanocrystals exhibited a lower stability than the bead-milled and homogenized formulations and did not show the optimum zeta potential values as well. In the case of cavi-precipitated nanocrystals, recrystallization and agglomeration were responsible for the increasing particle size besides the Ostwald ripening phenomenon. The solvents used during cavi-precipitation might have competed with the surfactant for hydration leading to a partial dehydration of the surfactant, which subsequently affected the stability of the quercetin nanocrystals.
High-pressure homogenized and bead-milled quercetin nanocrystals showed better physical stability than the cavi-precipitated ones. Freeze drying immediately after nanocrystal production can help to prevent their agglomeration and thus improve physical stability.
The aim of this study was to assess the usefulness of kinetic and thermodynamic solubility data in guiding medicinal chemistry during lead optimization. The solubility of 465 research compounds was measured using a kinetic and a thermodynamic solubility assay. In the thermodynamic assay, polarized-light microscopy was used to investigate whether the result referred to the crystalline or to the amorphous compound. From the comparison of kinetic and thermodynamic solubility data it was noted that kinetic solubility measurements frequently yielded results which show considerably higher solubility compared to thermodynamic solubility. This observation is ascribed to the fact that a kinetic solubility assay typically delivers results which refer to the amorphous compound. In contrast, results from thermodynamic solubility determinations more frequently refer to a crystalline phase. Accordingly, thermodynamic solubility data - especially when used together with an assessment of the solid state form - are deemed to be more useful in guiding solubility optimization for research compounds.
Surface-active agents (surfactants) are characterized by the possession of 2 different moieties, both polar and non-polar regions on the same molecule. Surfactants are broadly classified as anionic, cationic, amphoteric, or non-ionic, according to the nature of the hydrophile yielded in aqueous solution. In currently marketed household, personal, and industrial cleaners, anionic surfactants are the most common class because of their relative ability to solubilize fats is and oils, lower the surface tension of aqueous solutions, or form microemulsions. Many surfactants elicit irritant reactions when applied to the skin, partially due to their relative ability to solubilize lipid membranes. Hence, surfactants have become important implements in skin irritation investigations. In general, the physicochemical properties of surfactants are a crucial factor in eliciting skin irritation. Anionic surfactants are broadly accepted as potent irritants to human and animal skin. Cationic surfactants are reputedly at least equally irritating, but more cytotoxic than anionic, while the irritation potential of non-ionic surfactants is considered the lowest. Such classification of innumerable surfactants is convenient and held in high practical esteem. However, the categorization does not permit the exact determination of irritation and cytotoxicity potential of each surfactant. Ranking of surfactant skin irritancy and cytotoxicity obtained by both in vitro and in vivo assays provides a helpful orientation for future Work.
Bacteria and fungi are located in the stratum corneum and the hair follicles. Therefore, the development and assessment of efficient drugs requires standard in vivo investigation methods permitting a differentiation between intercellular and follicular penetration and storage of topically applied anti-microbial substances. In the present study, the penetration and storage of Isoconazole nitrate in the stratum corneum and hair follicles was investigated by differential stripping after a 14-day topical application period and during a follow-up period of a further 21 days. One week after the application had terminated, Isoconazole nitrate could still be detected in concentrations above the minimal inhibition concentration in the stratum corneum and the hair follicles. In some subjects, Isoconazole nitrate could even be detected 14 days after the last application. No relevant changes in TEWL values were measured, indicating that the investigated compound did not induce an impairment of the barrier function. The study showed that differential stripping is suited to investigate the penetration and storage of topically applied substances into the stratum corneum and the hair follicles. Also, the hair follicles are a long-term reservoir for topically applied substances. This is of clinical importance, where a long-lasting therapeutic effect beyond the application time is required.
The main aim of this study was to prepare quercetin nanocrystals using three fabrication methods, viz. high-pressure homogenization, bead milling, and cavi-precipitation. The three fabrication methods were compared in terms of particle size, saturation solubility, and dissolution of the products obtained. The average particle size of the coarse quercetin was 50.1 μm. The three methods produced quercetin particles in the nanometre range (276-787 nm) and the smallest nanocrystals of around 276.7 nm were fabricated by bead milling. The particle size, polydispersity index, zeta potential, and saturation solubility values for the products fabricated by both high-pressure homogenization and bead mill were similar and thus both represented an efficient means to fabricate quercetin nanosuspensions. According to X-ray diffraction analysis, all nanocrystals were still in the crystalline state after being fabricated by the three methods. The cavi-precipitated product exhibited larger particle size and did not show an optimum stability as suggested by the zeta potential values. However, cavi-precipitated quercetin nanosuspension showed the higher saturation solubility due to the presence of ethanol. The bead milled products with the lowest particle size exhibited a saturation solubility of 25.59 ± 1.11 μg/ml, approximately nine times higher than coarse quercetin. Overall, the dissolution rates of the quercetin nanosuspensions fabricated by these three methods enhanced compared to the coarse quercetin.
Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards. The special features of nanocrystals for the delivery of poorly soluble drugs are briefly reviewed (saturation solubility, dissolution velocity, adhesiveness). The industrially relevant bottom up (precipitation) and top down production technologies (pearl milling, high pressure homogenization, combination technologies) are presented. As nanotoxicological aspects, the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocrystals in the low/non-risk group. Intracellular uptake plays a minor or no role for dermal and oral nanocrystals, but it plays a key role for intravenously injected nanocrystals (e.g. nevirapine, paclitaxel, itraconazole). Uptake by the macrophages of the mononuclear phagocytic system (MPS, liver spleen) can modify/optimize blood profiles via prolonged release from the MPS (itraconazole), but also target toxicity by too high organ concentrations and thus cause nanotoxicity. The balance in the competitive intracellular uptake by MPS and the target cells (e.g. blood-brain barrier) decides about therapeutic efficiency. The concept of "differential protein adsorption" to modulate this balance is shown for its applicability to nanocrystals for intracellular delivery to the cells of the blood-brain barrier (atovaquone).
Hair follicles represent interesting target sites for topically applied substances such as topical vaccinations or agents used in the field of regenerative medicine. In recent years, it could be shown that particles penetrate very effectively into the hair follicles. In the present study, the influence of particle size on the follicular penetration depths was examined. The penetration depths of two different types of particles sized 122 to 1000 nm were determined in vitro on porcine skin. The results revealed that the particles of medium size (643 and 646 nm, respectively) penetrated deeper into the porcine hair follicles than smaller or larger particles. It was concluded that by varying the particle size, different sites within the porcine hair follicle can be targeted selectively. For the human terminal hair follicle, the situation can be expected to be similar due to a similar size ratio of the hair follicles.
Wet milling is a common technique to produce drug nanocrystals. Stability of the nanocrystals is a critical question, and different kinds of stabilizers, e.g. polymers, celluloses, surfactants and lipids, have been tested for various drugs. Still, the question about how to select the best stabilizer to a certain drug material and also to a selected process is open.
Many different factors, such as surface energy, hydrophobicity, solubility, viscosity and functional groups, affect the stability of the formed nanosuspensions. Affinity of the stabilizer to the particle surfaces seems to be the most important parameter. This affinity is partly related to the surface energy and hydrophobicity of the surfaces and stabilizers.
In this review the most important factors affecting nanocrystal formulation and efficacy of stabilizers are presented. In order to widen understanding of the milling process, the most important variables related to milling techniques and particle fracturing processes during the milling are briefly presented.
Poor solubility of new drugs and their related low oral bioavailability and general delivery problems are becoming a major challenge. Nanocrystals being a kind of "universal" formulation approach for these molecules are reviewed in this paper regarding the industrial feasibility, i.e. industrially available production processes (bottom-up and top-down technologies), regulatory aspects and nanotoxicology. This article also includes second generation nanocrystals (<100 nm) as smartCrystals. The status of products on the market and in clinical phases is presented. The different special features of nanocrystals, which are exploited in different products, are described (tablets, capsule, aqueous nanosuspension). The main focus is given for oral and intravenous products. However, the potential and delivery strategies for other administration routes are discussed, i.e. dermal and mucosal, ocular, pulmonary and targeted delivery (e.g. via differential protein adsorption to the brain). In addition, the potential of the nanocrystal technology for delivery of poorly soluble, non-pharmaceutical actives is highlighted, i.e. in cosmetics or nutraceuticals.
The crystal growth mechanism, kinetics, and microstructure development play a fundamental role in tailoring the materials with controllable sizes and morphologies. The classical crystal growth kinetics-Ostwald ripening (OR) theory is usually used to explain the diffusion-controlled crystal growth process, in which larger particles grow at the expense of smaller particles. In nanoscale systems, another significant mechanism named "oriented attachment (OA)" was found, where nanoparticles with common crystallographic orientations directly combine together to form larger ones. Comparing with the classical atom/molecular-mediated crystallization pathway, the OA mechanism shows its specific characteristics and roles in the process of nanocrystal growth. In recent years, the OA mechanism has been widely reported in preparing low-dimension nanostructural materials and reveals remarkable effects on directing and mediating the self-assembly of nanocrystals. Currently, the interests are more focused on the investigation of its role rather than the comprehensive insight of the mechanism and kinetics. The inner complicacy of crystal growth and the occurrence of coexisting mechanisms lead to the difficulty and lack of understanding this growth process by the OA mechanism.In this context, we review the progress of the OA mechanism and its impact on materials science, and especially highlight the OA-based growth kinetics aiming to achieve a further understanding of this crystal growth route. To explore the OA-limited growth, the influence of the OR mechanism needs to be eliminated. The introduction of strong surface adsorption was reported as the effective solution to hinder OR from occurring and facilitate the exclusive OA growth stage. A detailed survey of the nanocrystal growth kinetics under the effect of surface adsorption was presented and summarized. Moreover, the development of OA kinetic models was systematically generalized, in which the "molecular-like" kinetic models were built to take the OA nanocrystal growth behavior as the collision and reaction between molecules. The development of OA growth kinetics can provide a sufficient understanding of crystal growth, and the awareness of underlying factors in the growth will offer promising guidance on how to control the size distribution and shape development of nanostructural materials.
Due to ethical reasons, in vivo penetration studies are not applicable at all stages of development of new substances. Therefore, the development of appropriate in vitro methods is essential, as well as the comparison of the obtained in vivo and in vitro data, in order to identify their transferability. The aim of the present study was to investigate the follicular penetration of caffeine in vitro and to compare the data with the in vivo results determined previously under similar conditions.
The Follicular Closing Technique (FCT) represents a method to investigate the follicular penetration selectively. In the present study, FCT was combined with the Franz diffusion cell in order to differentiate between follicular and intercellular penetration of caffeine into the receptor medium in vitro. Subsequently, the results were compared with the data obtained in an earlier study investigating follicular and intercellular penetration of caffeine in vivo.
The comparison of the data revealed that the in vitro experiments were valuable for the investigation of the follicular penetration pathway, which contributed in vivo as well as in vitro to approximately 50% of the total penetration, whereas the kinetics of caffeine penetration were shown to be significantly different.
The combination of FCT with the Franz diffusion cell represents a valuable method to investigate follicular penetration in vitro. Nevertheless, in vivo experiments should not be abandoned as in vitro, structural changes of skin occur and blood flow and metabolism are absent, probably accounting for reduced penetration rates in vitro.
The important role of hair follicles as penetration pathways and reservoir structures for topically applied compounds has been validated in numerous animal models as well as in humans. Follicular penetration rates are modulated by regional variations in size and proportions and the functional status. Advances have especially been made in the targeting of hair follicle-associated cell populations including antigen-presenting cells and stem cells. Improved investigative methods based on differential stripping, spectrophotometry and confocal laser scanning microscopy have led to the determination of the penetration profiles and kinetics for a multiplicity of drugs and drug delivery systems. The observation that particulate delivery systems aggregate and remain in hair follicle openings and their penetration along the follicular duct occurs in a size-dependent manner, which has led to advanced concepts of targeted drug delivery of bioactive compounds in the field of solid particles, as well as semi-solid particles, such as liposomes. This review summarizes the recent progress in this field, and underlines the necessity for pilot studies in human volunteers to further the development of clinical applications for follicular targeting.
During the last 10-15 years, the formulation of drugs as nanocrystals has rapidly evolved into a mature drug delivery strategy, with currently five products on the market. The major characteristic of these systems is the rapid dissolution velocity, enabling bioavailability enhancement after oral administration. This mini-review focuses on recent advances with respect to three topics considering drug nanocrystals. The first topic is nanosuspension stabilization. A current literature status is provided and special attention is given to studies attempting to extend our physicochemical understanding of the underlying principles. The second part describes recent advances on miniaturization of nanosuspension production, to enable formulation screening during preclinical development. Finally, literature available on further nanosuspensions solidification is discussed, focussing on the maintenance of the preservation of the rapid dissolution properties of the nanocrystals after further downstream processing.
Tensile functions of the skin and subcutaneous tissues contribute to the appearance of the aged and photodamaged skin and to the effects of various other pathophysiological processes. The assessment of tensile functions of skin can be performed by distinct approaches mainly characterized by the orientation and magnitude of the imposed stress and strain over time. Testing methods are basically grouped into five major classes which include tensile, torsional, indentation, impact and elevation modes. Computed tensile variables are reproducible when the experimental procedure occurs under fully controlled conditions. Consistent and relevant information is yielded when the limitations and pitfalls typical for each test method are taken into consideration.
Transport of xenobiotics across the stratum corneum, the rate-controlling membrane of skin, is slow and the mechanism appears complex. However, the basic transfer is controlled by fundamental physicochemical concepts, the predominant of which are partition (K), diffusion (D) and solubility (C(s)). In order to change the rate of penetration it is therefore clear that it is these parameters that should be targeted. In most instances enhancement strategies are adopted to improve D, K or C(s), however there are instances in which permeation reduction may be beneficial. Examples include the topical application of sunscreens or insect repellents. This publication demonstrates the way in which modulation effects can be assessed and the difficulties involved in determining which of the physicochemical parameter(s) are being affected. If the formulation influences more than one, synergism can often be seen. Advances in computer modelling have provided an insight into the mechanisms of action of some of the chemical enhancers at a molecular level. Enhanced skin absorption has been reported for the delivery of macromolecules such as insulin (associated with transfersomes) or DNA (as a DOTAP complex). The barrier property of the skin must be modulated for this to be achieved. However the precise mechanisms of action have not been elucidated.
In the superficial layer of the skin, the stratum corneum (SC), the lipids form two crystalline lamellar phases with periodicities of 6.4 and 13.4 nm (long-periodicity phase). The main lipid classes in SC are ceramides, free fatty acids and cholesterol. Studies with mixtures prepared with isolated ceramides revealed that cholesterol and ceramides are very important for the formation of the lamellar phases, and the presence of ceramide 1 is crucial for the formation of the long-periodicity phase. This observation and the broad-narrow-broad sequence of lipid layers in the 13.4-nm phase led us to propose a molecular model for this phase. This consists of one narrow central lipid layer with fluid domains on both sides of a broad layer with a crystalline structure. This model is referred to as 'the sandwich model'. While the presence of free fatty acids does not substantially affect the lipid lamellar organization, it is crucial for the formation of the orthorhombic sublattice, since the addition of free fatty acids to cholesterol/ceramide mixtures results in transition from a hexagonal to a crystalline lipid phase. Studies examining lipid organization in SC derived from dry or lamellar X-linked ichthyosis skin revealed that in native tissue the role of ceramide 1 and free fatty acids is similar to that observed with mixtures prepared with isolated SC lipids. From this we conclude that the results obtained with lipid mixtures can be used to predict the SC lipid organization in native tissue.
The influence of specific follicle properties, sebum production and hair growth on the follicular penetration of topically applied substances was investigated. The behavior of follicles identified in selected skin areas of volunteers was analyzed by various tape stripping and staining methods in combination with laser scanning microscopy. Furthermore hair growth in the selected skin areas was determined. A correlation between sebum production, hair growth activity and follicular penetration was observed.
Dielectric constants of water-ethanol-glycerin and water-ethanol-propylene glycol systems have been experimentally determined. The measured values were found to differ from values calculated according to simplification of the Onsager-Kirkwood equation, regardless of whether composition of the various solutions was expressed on the basis of weight percentage or volume percentage. Dielectric constant values presented in this paper are recommended for precise adjustment of solvent polarity in formulation work and data are presented to be of maximum use in this respect.
The transfollicular administration of pharmacologically active molecules is of current therapeutic interest, mainly with regard to delivery to specific sites of the hair follicle (HF) and the reduction of hepatic metabolism and systemic toxicity. HF are privileged pathways for specific molecules depending on formulations, which enter faster into these shunts than through the stratum corneum. The aim was to optimize the delivery of fluorescent microspheres into the HF, thereby, developing a standardized protocol for follicular targeting with microspheres. The number of HF showing penetration, as well as the depth of penetration, was determined. Freshly excised skin samples with terminal HF were divided into groups, with or without prior treatment with cyanoacrylate skin surface stripping-technique (CSSS). Thereafter microspheres at a size of 0.75-6.0 microm were applied according to the developed standardized protocol. Skin biopsies were obtained, shock-frozen, and sectioned in 5 microm slices. We demonstrated a selective penetration route of the microspheres into the HF. Optimal microsphere size proved to be approximately 1.5 microm, with a 55% rate of all HF, and with a maximum penetration depth of >2300 microm. Without previous CSSS treatment of the skin, the transfollicular microsphere penetration was below 27% with a maximum penetration depth of 1000 microm. Thus, the basis for follicular targeting of essential structures containing stem cells for keratinocytes, melanocytes, and mast cells has been laid.
For many new chemical entities (NCE) of very low solubility oral bioavailability enhancement by micronisation is not sufficient, the next step taken was nanonisation. The production of drug nanocrystals by bottom up techniques (precipitation) is briefly described, main focus is given on particle diminution by high pressure homogenisation. Homogenisation can be performed in water (DissoCubes) or alternatively in non-aqueous media or water-reduced media (Nanopure). There is also a combination process of precipitation followed by a second high energy step, e.g. homogenisation (NANOEDGE). The result is a suspension of drug nanocrystals in a liquid, the so-called nanosuspension. Presented are the physical background of the diminution process, effects of production parameters (power density, number of homogenisation cycles) on crystal size, clinical batch production and scaling up of the production. As an important point the transfer of the liquid nanosuspensions to patient convenient oral dosage forms such as tablets and capsules is described.
We formulated a solid-in-oil nanosuspension (SONS) as a novel transdermal delivery carrier for diclofenac sodium (DFNa). The basic transdermal characteristics of the SONS were evaluated using a Yucatan micropig (YMP) skin model.
DFNa-sucrose erucate (i.e. surfactant) complexes were prepared via the formation of a water-in-oil emulsion. The complexes were suspended in isopropyl myristate (IPM) to form a SONS. The basic transdermal characteristics of the SONS were examined using full-thickness YMP dorsal skin in a Franz-type diffusion cell. DFNa powder suspended in IPM without complex formation was used as a control. The effect of the weight ratio of surfactant to DFNa on DFNa penetration of the skin was evaluated.
DFNa was successfully dispersed into IPM as a nanosized suspension via complex formation with sucrose erucate. The resultant SONS increased the permeability flux of DFNa across the YMP skin by up to 3.8-fold compared with the control. The size of the SONS depended on the weight ratio of the surfactant to DFNa. The optimal weight ratio for the highest DFNa permeation was 8.8, at which point the mean diameter of the SONS was 14.4 nm.
The SONS formulation can enhance the percutaneous absorption of DFNa.
Investigations concerning the penetration of topically applied drugs are the subject of a multiplicity of research, as the exact knowledge of these mechanisms is the prerequisite for the optimization of such substances. As the hair follicles represent a good long-term reservoir for topically applied substances, it can be assumed that they also represent a reservoir for microorganisms residing on and in the skin. Therefore, the hair follicles must be seen as one main site of action for antimicrobial substances and a simple non-invasive in vivo method for the determination of penetration of antimicrobial substances into the hair follicles. The aim of the present study was to show that differential stripping, by removing the hair follicle content selectively, represents a suitable method to demonstrate the penetration of antifungal substances into the hair follicles. The follicular casts, removed from skin areas of human volunteers, which were partially pre-treated with brilliant green (well-known antifungal properties), were applied on agar plates inoculated with Candida albicans. The results showed inhibited growth of C. albicans, if the follicular casts were removed from skin areas pre-treated with brilliant green. This indicates clear evidence that brilliant green had penetrated into the hair follicles. Therefore, differential stripping represents a suitable method to determine the penetration of antifungal substances into the hair follicles, which is of clinical importance for the optimization of topical antifungal therapeutics.
What is already known about this subject:
* In recent years, it has been suggested that hair follicles represent important shunt routes into the skin for drugs and chemicals [1-3]. * In vitro studies have shown the importance of skin appendages for skin penetration by hydrophilic compounds [4]. Investigation of follicular penetration in vivo has been difficult due to the absence of appropriate analytical methods or suitable animal model systems. * Recently, a new method was described that quantifies follicular penetration in vivo by using selective closure of hair follicles [5]. * Caffeine is frequently used in skin penetration experiments as a model for highly water-soluble compounds. Occlusion [6] and skin thickness [7] seem to have little influence on the penetration of caffeine. However, percutaneous absorption rates for caffeine exhibit regional skin differences in humans in vivo[1].
What this study adds:
* The results of the present study demonstrate that a fast drug delivery of caffeine occurs through shunt routes. Therefore, hair follicles are considerable weak spots in our protective sheath against penetration into the body by hydrophilic substances. * We showed that there is a quantitative distinction between follicular penetration and interfollicular diffusion of caffeine in vivo. * These findings are of importance for the development and optimization of topically applied drugs and cosmetics. In addition, such properties must be considered in the development of skin protection measures.
Aims:
The skin and its appendages are our protective shield against the environment and are necessary for the maintenance of homeostasis. Hypotheses concerning the penetration of substances into the skin have assumed diffusion through the lipid domains of the stratum corneum. It is believed that while hair follicles represent a weakness in the shield, they play a subordinate role in the percutaneous penetration processes. Previous investigation of follicular penetration has mostly addressed methodical and technical problems. Our study utilized a selective closure technique of hair follicle orifices in vivo, for the comparison of interfollicular and follicular absorption rates of caffeine in humans.
Methods:
Every single hair follicle within a delimited area of skin was blocked with a microdrop of a special varnish-wax-mixture in vivo. Caffeine in solution was topically applied and transcutaneous absorption into the blood was measured by a new surface ionization mass spectrometry (SI/MS) technique, which enabled a clear distinction to be made between interfollicular and follicular penetration of a topically applied substance.
Results:
Caffeine (3.75 ng ml(-1)) was detected in blood samples, 5 min after topical application, when the follicles remained open. When the follicles were blocked, caffeine was detectable after 20 min (2.45 ng ml(-1)). Highest values (11.75 ng caffeine ml(-1)) were found 1 h after application when the follicles were open.
Conclusions:
Our findings demonstrate that hair follicles are considerable weak spots in our protective sheath against certain hydrophilic drugs and may allow a fast delivery of topically applied substances.
Development and characterization of caffeine nanocrystals for dermal delivery. Diploma Dissertation Modulation of the barrier function of the skin
- M Fratus
Fratus, M., 2011. Development and characterization of caffeine nanocrystals for dermal delivery. Diploma Dissertation. Freie Universität, Berlin. Hadgraft, J., 2001. Modulation of the barrier function of the skin. Skin Pharmacol. Appl. Skin Physiol. 14, 72–81.
Physicochemical characteristics of lyophilised coenzyme Q 10 nanocrystals
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- R H Müller
Mauludin, R., Hommoss, A., Knauer, J., Müller, R.H., 2008. Physicochemical characteristics of lyophilised coenzyme Q 10 nanocrystals. Int. Symp. Control Rel. Bioact. Mater. New York City.
Nanocrystals for use in topical cosmetic formulations and method of production thereof. US patent
- R Petersen
Petersen, R., 2006. Nanocrystals for use in topical cosmetic formulations and method of production thereof. US patent, 60/8866233.