Article

Encapsulation and controlled release of retinol from silicone particles for topical delivery

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Abstract

Retinol, a derivative of vitamin A, is a ubiquitous compound used to treat acne, reduce wrinkles and protect against conditions like psoriasis and ichthyosis. While retinol is used as the primary active ingredient (AI) in many skin care formulations, its efficacy is often limited by an extreme sensitivity to degrade and toxicity at high concentrations. While microencapsulation is an appealing method to help overcome these issues, few microencapsulation strategies have made a major translational impact due to challenges with complexity, cost, limited protection of the AI and poor control of the release of the AI. We have developed a class of silicone particles that addresses these challenges for the encapsulation, protection and controlled release of retinol and other hydrophobic compounds. The particles are prepared by the sol-gel polymerization of silane monomers, which enables their rapid and facile synthesis at scale while maintaining a narrow size distribution (i.e., CV < 20%). We show that our particles can: (i) encapsulate retinol with high efficiency (>85%), (ii) protect retinol from degradation (yielding a half-life 9× greater than unencapsulated retinol) and (iii) slowly release retinol over several hours (at rates from 0.14 to 0.67 μg cm-2 s-1/2). To demonstrate that the controlled release of retinol from the particles can reduce irritation, we performed a double blind study on human subjects and found that formulations containing our particles were 12-23% less irritating than identical formulations containing Microsponge® particles (an industry standard by Amcol, Inc.). To show that the silicone particles can elicit a favorable biological response, similar to the Microsponge® particles, we applied both formulations to reconstructed human epidermal tissues and found an upregulation of keratin 19 (K19) and a downregulation of K10, indicating that the reduced irritation observed in the human study was not caused by reduced activity. We also found a decrease in the production of interleukin-1α (IL-1α) compared to formulations containing the Microsponge particles, suggesting lower irritation levels and supporting the findings from the human study. Finally, we show that the silicone particles can encapsulate other AIs, including betamethasone, N, N-diethyl-meta-toluamide (DEET), homosalate and ingenol mebutate, establishing these particles as a true platform technology.

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... Resiquimod content in the cured PDMS particles was determined using the previously described solvent release method (Fig. S1) [23] . Briefly, particles were agitated by vortexing in absolute ethanol and centrifuged at 20,0 0 0x g for 2 min. ...
... The low drug loading efficiency was likely due to the relatively large mesh size of the PDMS. Drug loading was measured by a solvent release assay described elsewhere [23] , where particles are flushed multiple times with a favorable solvent (i.e., ethanol) to extract encapsulated drug for measurement using a calibration curve. This method leads to a more conservative estimation of drug loading than measuring the supernatant after particle synthesis because potential sources of drug loss (e.g., drug trapped on the stir bar, adsorbed to the walls of the container) are accounted for (Fig. S1). ...
... We varied the ratio of tetrafunctional monomers (tetramethoxysilane, TMOS) to difunctional monomers (dimethoxydimethylsilane, DMODMS), which can form up to four or two siloxane bonds after polycondensation, respectively, with an alkaline catalyst. A denser mesh (i.e., due to a higher ratio of TMOS to DMODMS) resulted in slower drug release [23] . Therefore, we evaluated particles made with 1:8, 1:12, and 1:16 molar ratios of TMOS to DMODMS to achieve slow release of palbociclib. ...
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... It is highly sensitive to water, heat, oxygen and light [27][28][29][30]. Many authors work on its encapsulation to protect its integrity and increase its penetration into the skin [31][32][33][34]. NCs made of PEG-block-PLA copolymer showed very interesting performances for retinol delivery to the skin [34,35]. ...
... The chosen length of the PLA chains, deliberately short, led to an effective retinol encapsulation. The encapsulation efficiency (EE) of retinol was of 76.9 ± 11.6% w/w, which is satisfactory compared to the literature data on retinol nanocarriers such as (PEG-block-PLA)based NCs (PLA of ≈15 kDa, EE = 100% [34]), chitosan nanocarriers (EE = 76%, [32]), silicone and silica particles (EE = 85% [31] and 31% [33], respectively), and solid lipid nanocarriers (EE = 74% or up to 97% depending on formulation conditions [50,51]). The nanoprecipitation method and experimental conditions described in this study allow a high encapsulation efficiency of retinol into (PEG-block-PLA)-blend-(PLA) nanocarriers, with a final retinol concentration in water of 28% w/v (Table 1). ...
... The chosen length of the PLA chains, deliberately short, led to an effective retinol encapsulation. The encapsulation efficiency (EE) of retinol was of 76.9 ± 11.6% w/w, which is satisfactory compared to the literature data on retinol nanocarriers such as (PEG-block-PLA)-based NCs (PLA of ≈15 kDa, EE = 100% [34]), chitosan nanocarriers (EE = 76%, [32]), silicone and silica particles (EE = 85% [31] and 31% [33], respectively), and solid lipid nanocarriers (EE = 74% or up to 97% depending on formulation conditions [50,51]). The nanoprecipitation method and experimental conditions described in this study allow a high encapsulation efficiency of retinol into (PEG-block-PLA)-blend-(PLA) nanocarriers, with a final retinol concentration in water of 28% w/v ( Table 1). ...
... It is highly sensitive to water, heat, oxygen and light [27][28][29][30]. Many authors work on its encapsulation to protect its integrity and increase its penetration into the skin [31][32][33][34]. NCs made of PEG-block-PLA copolymer showed very interesting performances for retinol delivery to the skin [34,35]. ...
... The chosen length of the PLA chains, deliberately short, led to an effective retinol encapsulation. The encapsulation efficiency (EE) of retinol was of 76.9 ± 11.6% w/w, which is satisfactory compared to the literature data on retinol nanocarriers such as (PEG-block-PLA)based NCs (PLA of ≈15 kDa, EE = 100% [34]), chitosan nanocarriers (EE = 76%, [32]), silicone and silica particles (EE = 85% [31] and 31% [33], respectively), and solid lipid nanocarriers (EE = 74% or up to 97% depending on formulation conditions [50,51]). The nanoprecipitation method and experimental conditions described in this study allow a high encapsulation efficiency of retinol into (PEG-block-PLA)-blend-(PLA) nanocarriers, with a final retinol concentration in water of 28% w/v (Table 1). ...
... The chosen length of the PLA chains, deliberately short, led to an effective retinol encapsulation. The encapsulation efficiency (EE) of retinol was of 76.9 ± 11.6% w/w, which is satisfactory compared to the literature data on retinol nanocarriers such as (PEG-block-PLA)-based NCs (PLA of ≈15 kDa, EE = 100% [34]), chitosan nanocarriers (EE = 76%, [32]), silicone and silica particles (EE = 85% [31] and 31% [33], respectively), and solid lipid nanocarriers (EE = 74% or up to 97% depending on formulation conditions [50,51]). The nanoprecipitation method and experimental conditions described in this study allow a high encapsulation efficiency of retinol into (PEG-block-PLA)-blend-(PLA) nanocarriers, with a final retinol concentration in water of 28% w/v ( Table 1). ...
Article
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Smart polymeric nanocarriers have been developed to deliver therapeutic agents directly to the intended site of action, with superior efficacy. Herein, a mixture of poly(lactide) (PLA) and redox-responsive poly(ethylene glycol)–block–poly(lactide) (PEG–block–PLA) containing a disulfide bond was synthesized in three steps. The nanoprecipitation method was used to prepare an aqueous suspension of polymeric nanocarriers with a hydrodynamic diameter close to 100 nm. Retinol, an anti-aging agent very common in cosmetics, was loaded into these smart nanocarriers as a model to measure their capacity to encapsulate and to protect a lipophilic active molecule. Retinol was encapsulated with a high efficiency with final loading close to 10% w/w. The stimuli-responsive behavior of these nanocarriers was demonstrated in vitro, in the presence of l-Glutathione, susceptible to break of disulfide bond. The toxicity was low on human keratinocytes in vitro and was mainly related to the active molecule. Those results show that it is not necessary to use 100% of smart copolymer in a nanosystem to obtain a triggered release of their content.
... In a similar way, Wyatt et al. [71] prepared silicon particles loaded with retinol, so as to protect it from degradation and to reduce its toxicity at high concentrations. The authors demonstrated that retinol was slowly released for several hours from the particles and that these reduced irritation in a double-blind skin study performed in 20 healthy subjects [71]. ...
... In a similar way, Wyatt et al. [71] prepared silicon particles loaded with retinol, so as to protect it from degradation and to reduce its toxicity at high concentrations. The authors demonstrated that retinol was slowly released for several hours from the particles and that these reduced irritation in a double-blind skin study performed in 20 healthy subjects [71]. Likewise, a nanoemulsion containing the anti-inflammatory and keratolytic agent salicylic acid was successfully prepared to improve its stability and water solubility as well as to produce a topical localized anti-inflammatory effect in a mouse model [72]. ...
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Inherited ichthyoses are a group of etiologically heterogeneous diseases that affect the function of the skin and that are classified as syndromic and non-syndromic entities. Irrespective of the type, all these disorders are generally produced by mutations in genes involved in a variety of cellular functions in the skin. These mutations lead to disruption of the stratum corneum and impairment of the skin barrier, producing clinical features such as hyperkeratosis, skin scaling, erythema, fissures, pruritus, inflammation, and skin pain. Despite advances in the knowledge of the pathogenesis of ichthyoses, there is, to our knowledge, no definitive cure for skin manifestations, and current treatments consist of moisturizers, emollients, and keratolytic agents. In this respect, the development of new formulations based on nanotechnology could be useful to enhance their therapeutic effectiveness. In this article, we provide a comprehensive description of pharmacological treatments for cutaneous manifestations in patients with inherited ichthyosis and discuss novel approaches with therapeutic potential for this purpose. Moreover, we offer an overview of toxicity concerns related to these treatments.
... Silicones have been used for nano-encapsulation and controlled release of various active substances for topical administration. For example, Shields et al. reported in 2018(Shields et al., 2018) the encapsulation of retinol in silicone particles as a proof of the relevance of encapsulation by silicones. Retinol, a derivative of vitamin A, is a compound used to treat acne, reduce wrinkles and protect against conditions such as psoriasis and ichthyosis. ...
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Silicones, more specifically those of the polydimethylsiloxane type, have been widely used in the pharmaceutical industry for decades, particularly in topical applications. In the dermatological field, in addition to provide undeniable textural and sensory benefits, they can play important functions in the physicochemical properties, stability and biopharmaceutical behavior of these formulations. However, despite the notable advances that can be attributed to the family of silicones, the reputation of these compounds is quite bad. Indeed, silicones, even if they derive from sand, are synthetic compounds. Moreover, they are not biodegradable. They flow into our wastewater and oceans, accumulating in the fauna and flora. This obviously raises many concerns in the common imagination. Do silicones represent a danger for our environment? Should the human species worry about long term toxic effects? Are the claimed benefits really that important? After exploring the various applications of silicone excipients in topical dermatological formulations with a special focus on recent advances which open breathtaking prospects for dermatological applications, this paper shed light on the specific challenges involved in preparation of silicone-based drug as well as, the in vivo behavior of these polymers, the toxicological and environmental risks associated with their application.
... The retinoids are encapsulated into caprolactone-based nanocapsules and liposomes to protect the bioactive compounds from photodegradation [125,126]. Retinol is encapsulated into silicon particles to prepare antiaging and antiacne formulations [127]. Nanospheres are optimized for the encapsulation of adapalene (third-generation retinoid) to deliver the bioactive to hair follicles [128]. ...
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... Moreover, silicones having particulate state (silicone particles) are used as additive to cosmetics, ink, and plastic materials to improve light diffusion, surface smoothness, and impact absorption [35,36]. Generally, cross-linked silicone particles are prepared by the sol-gel reactions of alkoxysilane [37][38][39][40] or by a hydrosilylation reactions of hydromethylsiloxane and methyl vinyl silicone [41][42][43]. The preparation of silicone/ polymer composite particles was also reported [44][45][46][47][48][49][50][51]. ...
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Elastic/glassy Janus composite particles having snowman-like shape were successfully prepared by seeded polymerization of benzyl methacrylate (BzMA) in the presence of cross-linked silicone particles. The morphology of the composite particles was strongly affected by the affinity between silicone seed particles and monomer. In the case of the low affinity monomer, such as BzMA, snowman-like composite particles were obtained. The obtained particles were consisting of poly(benzyl methacrylate) (PBzMA) lobe and silicone phase containing PBzMA small domain. The PBzMA weight ratio of single lobe and inside silicone seed particle were determined as 90 and 70 wt%, respectively, based on the silicone seed particle. According to micro-compression test, the composite particle had both of elasticity derived from silicone phase and hard property derived from PBzMA lobe in one particle, indicating that the composite particles had two different stiffness.
... However, it has some disadvantages in its formulations due to its low aqueous solubility and photosensitivity (highly sensitive to light and oxygen). Additionally, retinol has a narrow therapeutic window, leading it to be ineffective at low concentrations and toxic at high concentrations [27]. Its administration as a hybrid halloysite-retinol system could show good results, improving the elaboration of the formulations and their efficacy. ...
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The adsorption of retinol, niacinamide and glycolic acid active ingredients on the internal surface of halloysite in an aqueous environment was explored at the molecular level by means of calculations based on quantum mechanics and force fields from empirical interatomic potentials. These active ingredients are stably adsorbed on the internal surface of halloysite forming hydrogen bonds between the hydrogen, oxygen and nitrogen atoms with the hydroxyl groups of the inner surface of the halloysite. In addition, electrostatic interaction between these active ingredients with the water molecules was observed. Therefore, the theoretical results indicate that the adsorption of these active principles is favourable in the halloysite nanotube, which allows directing future experimental investigations for the development and design of retinol, niacinamide and glycolic acid with halloysite nanotubes systems, which may be topical formulations for skincare.
... This approach was chosen as no suitable solvent was identified to perform the solvent-release approach [48]. Traces of the coatings were still identified on the nanoparticles through TGA, possibly indicating that not all chlorhexidine was extracted. ...
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Peri-prosthetic joint infections (PJI) are a serious adverse event following joint replacement surgeries; antibiotics are usually added to bone cement to prevent infection offset. For uncemented prosthesis, alternative antimicrobial approaches are necessary in order to prevent PJI; however, despite elution of drug from the surface of the device being shown one of the most promising approach, no effective antimicrobial eluting uncemented device is currently available on the market. Consequently, there is a clinical need for non-antibiotic antimicrobial uncemented prosthesis as these devices present numerous benefits, particularly for young patients, over cemented artificial joints. Moreover, non-antibiotic approaches are driven by the need to address the growing threat posed by antibiotic resistance. We developed a multilayers functional coating on titanium surfaces releasing chlorhexidine, a well-known antimicrobial agent used in mouthwash products and antiseptic creams, embedding the drug between alginate and poly-beta-amino-esters. Chlorhexidine release was sustained for almost 2 months and the material efficacy and safety was proven both in vitro and in vivo. The coatings did not negatively impact osteoblast and fibroblast cells growth and were capable of reducing bacterial load and accelerating wound healing in an excisional wound model. As PJI can develop weeks and months after the initial surgery, these materials could provide a viable solution to prevent infections after arthroplasty in uncemented prosthetic devices and, simultaneously, help the fight against antibiotic resistance.
... Thereby, it is difficult to incorporate retinol into stable and effective formulations. It is also important to note that retinol has a narrow therapeutic window, leading it to be ineffective at low concentrations and toxic at high concentrations [5,9]. As a result, retinol is a good candidate for drug targeting using encapsulation processes. ...
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... It is well known that drug or biomolecules release from nanoparticles take place by several mechanisms, including surface erosion, disintegration, diffusion and desorption [16,18]. The in vitro release study of CPs from prepared nanoparticles was subsequently monitored to understand and to recognize the release mechanism and kinetics of CPs, which is decisive for ulterior applications of CPs-loaded nanocarriers [8,57]. ...
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... Bioactive compounds can be supplied in the form of emulsions, colloidal particles, and spray dried particles. Poor water dispersibility, oral bioavailability, and chemical stability restrict the use of bioactive compounds for topical application (Shields et al., 2018). To overcome this problem, colloidal delivery systems are frequently used to encapsulate, protect, and finally release the bioactive compounds at their target sites. ...
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This book presents cutting-edge research and developments in the field of medical and biological engineering. It gathers the proceedings of the International Conference on Medical and Biological Engineering, CMBEBIH 2021, held partly virtually, partly physically, on April 21–24, 2021, from and in Mostar, Bosnia and Herzegovina. Focusing on the goal to ‘Stay Focused’, contributions report on both basic and applied research in a wide range of related fields, such as biomedical signal processing, medical physics and imaging, biosensors and micro/nanotechnologies, biomaterials, biomechanics and robotics, cardiorespiratory, endocrine and neural systems engineering. Novel models, methods and technologies for bio- and health informatics, as well as applications of machine learning and AI in health care, and advances in genetic engineering are also highlighted. All in all, this book provides academics and professionals with novel, practical solutions to solve the current problems in biomedical research and applications, and a source of inspiration for improving medicine and health care in the future.
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Hyperlipidaemia is a condition that refers to an extremely high level of lipids in the blood. Cholesterol and triglyceride levels are highest in people with hereditary hyperlipidaemias, which are divided into five types. In this article we will discuss type IIb hyperlipidaemia. It is an inherited disorder that results in accelerated atherosclerotic early death, most commonly due to myocardial infarction. The aim of this study was to predict on the basis of blood lipid parameters, the risk of occurrence and development of cardiovascular disease, and to assist doctors in the proper diagnosis of this disease. For the purposes of this paper, artificial neural networks were used. Parameters used in the diagnosis of Familial hyperlipidaemia were: cholesterol (mmol/l), triglycerides (mmol/l), LDL (mmol/l), HDL (mmol/l), Apo B100 (mg/dl), systolic blood pressure and smoking status. The artificial neural network has an accuracy of 97.2%, reliably predicts the disease which means it can be used to help diagnose Familial hyperlipidaemia.
Chapter
Scientific progress continues to deliver new treatments that prolong survival and significantly improve the quality of life of patients. Novel treatment options introduce new challenges for healthcare systems, often requiring novel pricing and payments models. It has been common practice that healthcare problems and challenges, both here and in the countries of the region, are addressed mainly by healthcare experts in broad terms, while interaction with experts in other fields has been rare; even when there is interaction, there are problems in achieving a clear common understanding. Indeed, this is not unique for just the health sector. In developed countries, including some countries of this region, important processes in the country and society are considered meticulously from different perspectives, including the economic perspective in particular, since the biggest challenge of the consistent implementation of defined policies is their stable financing. Needless to say, the health policy is among top priorities in every country by reason of its important share in GDP, overall budgets of national governments and the number of beneficiaries and its vital importance for the whole population.
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Topical application involves application to a specific place on the skin where the given preparation manifests its effect. The properties of finished topical preparations and the incorporated active substances can often change due to various environmental and intrinsic factors. In order to prevent these changes and at the same time improve the efficacy and stability of the preparation, a large number of microencapsulation methods have been developed for the production of microparticles (microcapsules and microspheres) as a delivery system. The results of the study showed that microencapsulation achieves control of the permeation of substances in such a way that the substances remain on the surface of the skin or within a certain layer of the skin where they exert their action. Controlled release of the substances has also been achieved, thus ensuring better efficacy and reducing toxicity.
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Last year and part of this year, we have witnessed a large number of people being infected, and subsequently died, as a result of the corona virus COVID-19. The physical environment plays an important role in transmitting the infection. We must urgently find a solution and answer to all situations in society that have a detrimental effect on human health. When it comes to virus transmission, it is necessary to disinfect both the body and the room. The development of new technologies leads to the development of service robots that are implemented for disinfection in the medical institutions. The paper presents a review of the implementation of service robots that use ultraviolet light for disinfection in medical institutions. UV disinfection of surface with service robots is one of the most promising new technologies for several reasons, of which some are: faster treatment in the room, higher productivity, highly effective treatments, whole room treatment, one room treatment, etc. In addition to service robots for indoor disinfection, service robots for disinfection of outdoor surfaces have also been developed. New materials and technologies are now being introduced into medical facilities in an attempt to reduce the ecological pathway of disease transmission.
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In Bosnia and Herzegovina, legal metrology framework has been implemented as a tool for ensuring safety and performance accuracy of medical devices. This paper presents the analysis of results for these periodical inspections of patient monitor. The analysis is based on 2118 patient monitor inspection reports from April 2015–December 2020. Inspections were conducted in clinical centers, hospitals and several primary healthcare institutions using etalon with documented traceability to SI units. The results show that in six-year period of implementation of this metrology-based framework for medical device management and assessment at national level the drop of 5.38% of patient monitor fault rate was achieved. Also, all performance measurements are available through information system which provides comprehensive management of these medical devices at institutional and national level.
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Consequences of cigarette smoking, on human health are significant and, in many cases, fatal. Smoking affects all hematological parameters acutely and chronically. The objective of this study was to determine the magnitude of the adverse effects of smoking cigarettes on the biochemical properties of blood in the male population from age 18 to 55 by using artificial intelligence techniques such as artificial neural network. A total of 300 healthy adult male subjects were enrolled in this study including smokers (n = 200) and non-smokers as control (n = 100) in the age range from 18 to 55 years. Database for artificial neural network was created by using six parameters: age, WBC-White blood cells, RBC-Red blood cells, HB-Hemoglobin, HTC-Hematocrit and MCVMean Corpuscular Volume. The smokers had higher levels of WBC (white blood cells), RBC (red blood cells), HB (hemoglobin), HCT (hematocrit) and MCV (mean corpuscular volume). Our results have shown that continuous cigarette smoking has significant effects on hematological parameters (e.g. hemoglobin, hematocrit, WBC count) and these alterations could be associated with a higher risk for developing atherosclerosis, polycythemia vera, chronic obstructive pulmonary disease and/or cardiovascular diseases.
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The role of cosmetic products is rapidly evolving in our society, with their use increasingly seen as an essential contribution to personal wellness. This suggests the necessity of a detailed elucidation of the use of nanoparticles (NPs) in cosmetics. The aim of the present work is to offer a critical and comprehensive review discussing the impact of exploiting nanomaterials in advanced cosmetic formulations, emphasizing the beneficial effects of their extensive use in next-generation products despite a persisting prejudice around the application of nanotechnology in cosmetics. The discussion here includes an interpretation of the data underlying generic information reported on the product labels of formulations already available in the marketplace, information that often lacks details identifying specific components of the product, especially when nanomaterials are employed. The emphasis of this review is mainly focused on skincare because it is believed to be the cosmetics market sector in which the impact of nanotechnology is being seen most significantly. To date, nanotechnology has been demonstrated to improve the performance of cosmetics in a number of different ways: 1) increasing both the entrapment efficiency and dermal penetration of the active ingredient, 2) controlling drug release, 3) enhancing physical stability, 4) improving moisturizing power, and 5) providing better UV protection. Specific attention is paid to the effect of nanoparticles contained in semisolid formulations on skin penetration issues. In light of the emerging concerns about nanoparticle toxicity, an entire section has been devoted to listing detailed examples of nanocosmetic products for which safety has been investigated.
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Composite particles consisting of elastic silicone and glassy poly(methyl methacrylate) (PMMA) were prepared. Seeded polymerization of methyl methacrylate (MMA) was carried out in the presence of silicone elastic particles, which were prepared via a radical-mediated thiol–ene click reaction between thiol-terminated silicone oil and a trifunctional allyl compound in a suspension system. The obtained particles exhibited a sea-island structure comprising small PMMA domains and a silicone matrix, and the size of the PMMA domains could be controlled via the polymerization temperature. Moreover, core–shell composite particles consisting of a silicone core and PMMA shell were successfully prepared using highly cross-linked silicone seed particles. Interestingly, the morphology of the composite particles could be alternated between sea-island and core–shell structures by controlling the annealing temperature. Microcompression tests indicated that, the hardness of the composite particles also can be changed: the hardness of sea-island composite particles was similar to the silicone particles, that of the core–shell particles was more than seven times greater than that of the silicone particles.
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Vitamin A is a bioactive compound responsible for many biological functions being, for that reason, extremely beneficial for the human organism. However, its sensitivity to certain adverse conditions as well as their insolubility in water, make infeasible their direct application into functional products. In this context, in the current work, vitamin A was encapsulated by spray-drying, using different blends of gum arabic, maltodextrin and starch, and the obtained particles evaluated in terms of controlled release. Particles with a size between 6.94 and 11.61 μm were obtained, presenting a regular shape and a surface structure that depends on the encapsulating agent used. The release times were influenced by the wall material, being the starch samples associated to lower values of this variable and the maltodextrin particles the ones that lead to more sustained releases. The ternary blend presented an intermediate release time, due to the contribution of the three encapsulating agents. Different kinetic equations were adjusted to the release profiles, being the Weibull model the one that, simultaneously, presented good correlation coefficients (0.9009–0.9655) and adjusted to a great number of points. The product yield and encapsulation efficiency were also calculated, presenting values between 7-39% and 88–98%, respectively. In the end, viable particles were produced, regardless of the encapsulating agent used. However, the ternary blend was the wall material combination that led to particles with better encapsulation efficiencies and, at the same time, to particles that ensured a compromise between all the variables tested, presenting moderate values in terms of size, product yield and release times. For that reason, a ternary blend of gum arabic, maltodextrin and starch would be a wise choice for future formulations of functional products.
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Retinyl palmitate is a vitamin A ester belonging to the family of endogenous natural retinoid and used to treat various skin disorders like acne, skin aging, wrinkles, and dark spots, as well as to protect against psoriasis. Despite the known therapeutic benefits of retinyl palmitate, the conventional topical delivery of retinyl palmitate commonly associated with adverse reactions such as skin irritation, redness, excessive peeling, and dryness. Therefore, the current study aims to encapsulate the retinyl palmitate in nanoemulsion then incorporate it into a hydrogel system to improve the topical delivery and stability. Low-energy emulsification method was used for the nano-encapsulation of retinyl palmitate. The phase behavior study was used for the investigation and the optimization of the formulation. The droplet size of the optimized nanoemulsion was in nano dimension (16.71 nm) with low polydispersity index (PdI) (0.015), negative zeta potential (−20.6 mV). It demonstrated the influence of vortexing on droplet size and PdI during nanoemulsion preparation. The retinyl palmitate loaded nanoemulgel delivery system exhibited significant improvement (p < 0.05) in skin permeability after topical application. Employment of the nano-encapsulation approach afterward dispersion into hydrogel system for the development of a topical delivery system of retinyl palmitate resulted in improvement in its UV and storage stability as well.
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Various drug delivery systems (DDSs) are often used in modern medicine to achieve controlled and targeted drug release. Diffusional release of drugs from DDSs is often the main mechanism, especially at early times. Generally, average dimensions of DDS are used to model the drug release, but our recent work on drug release from fibers demonstrated that taking into account diameter distribution is essential. This work systematically investigated the effect of size distribution on diffusional drug release from DDSs of various geometric forms such as membranes, fibers, and spherical particles. The investigation clearly demonstrated that the size distribution has the largest effect on the drug release profiles from spherical particles compared to other geometric forms. Published experimental data for drug release from polymer microparticles and nanoparticles were fitted, and the diffusion coefficients were determined assuming reported radius distributions. Assuming the average radius when fitting the data leads to up to 5 times underestimation of the diffusion coefficient of drug in the polymer.
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The scope of the present work is to apply multivariate chemometrics methods to the explorative and quantitative analysis of loading and release processes in drug delivery systems (DDSs). The monitoring of processes is conducted using spectrophotometric method as a simple, cost-effective and available technique. Then the chemical information is recovered from spectrophotometric data using sophisticated chemometrics methods such as multivariate hard modelling approach and rank annihilation factor analysis method. Attention is drawn to a curcumin delivery system for addressing some challenges in DDSs then presenting the opportunities based on multivariate analysis. Two main challenges are: how to decrease the possibility of drug adsorption in loading step, which could prevent the initial burst release of drug, and how to achieve the accurate kinetic rate constant of drug release in the presence of side reactions such as drug self-degradation. Furthermore, this research paved the way towards the use of multivariate analysis method to investigate and compare three photo-degradation processes: drug, drug-to-carrier complex and physical mixture of drug and carrier.
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Objective: The rationale behind present research vocation was to develop and investigate a novel microsponge based gel as a topical carrier for the prolonged release and cutaneous drug deposition of fluconazole (FLZ); destined for facilitated fungal therapy. Materials and Methods: Microsponges were prepared using quasi‑emulsion solvent diffusion method using Eudragit S‑100. In the direction of optimization, the effect of formulation variables (drug‑polymer ratio and amount of emulsifier) and diverse factors affecting physical characteristics of microsponge were investigated as well. Fabricated microsponges were characterized by differential scanning calorimetry, Fourier transform‑infrared, scanning electron microscopy (SEM), particle size analysis, and also evaluated for drug content, encapsulation efficiency, in vitro drug release and in vitro antifungal activity. Results: Compatibility studies results reflected no sign of any chemical interaction between the drug and polymers used. Whereas, varied drug‑polymer ratios and emulsifier concentration indicated significant effect on production yield, drug content, encapsulation efficiency, particle size and drug release. Spherical microsponges with a porous surface and 29.327 ± 0.31 μm mean particle size were evident from SEM micrographs. In vitro release outcomes, from microsponge loaded gels depicted that F1 formulation was more efficient to give extended drug release of 85.38% at the end of 8 h, while conventional formulation by releasing 83.17% of drug got exhausted incredibly earlier at the end of 4 h merely. Moreover, microsponge gels demonstrated substantial spreadability and extrudability along with promising antifungal activity. Conclusions: Fabricated microsponges would be impending pharmaceutical topical carriers of FLZ and a leading alternative to conventional therapy for efficient, safe and facilitated eradication of fungal infections.
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Stability studies ensuring the maintenance of product quality, safety and efficacy throughout the shelf life are considered as pre-requisite for the acceptance and approval of any pharmaceutical product. These studies are required to be conducted in a planned way following the guidelines issued by ICH, WHO and or other agencies. Importanceof various methods followed for stability testing of pharmaceutical products, guidelines issued for stability testing and other aspects related to stability of pharmaceutical products have been presented in a concise manner in the present review.
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Recent studies suggest that N, N-diethyl-meta-toluamide (DEET) is an acetylcholinesterase inhibitor and that this action may result in neurotoxicity and pose a risk to humans from its use as an insect repellent. We investigated the mode of action of DEET neurotoxicity in order to define the specific neuronal targets related to its acute toxicity in insects and mammals. Although toxic to mosquitoes (LD50 ca. 1.5 µg/mg), DEET was a poor acetylcholinesterase inhibitor (<10% inhibition), even at a concentration of 10 mM. IC50 values for DEET against Drosophila melanogaster, Musca domestica, and human acetylcholinesterases were 6-12 mM. Neurophysiological recordings showed that DEET had excitatory effects on the housefly larval central nervous system (EC50: 120 µM), but was over 300-fold less potent than propoxur, a standard anticholinesterase insecticide. Phentolamine, an octopamine receptor antagonist, completely blocked the central neuroexcitation by DEET and octopamine, but was essentially ineffective against hyperexcitation by propoxur and 4-aminopyridine, a potassium channel blocker. DEET was found to illuminate the firefly light organ, a tissue utilizing octopamine as the principal neurotransmitter. Additionally, DEET was shown to increase internal free calcium via the octopamine receptors of Sf21 cells, an effect blocked by phentolamine. DEET also blocked Na+ and K+ channels in patch clamped rat cortical neurons, with IC50 values in the micromolar range. These findings suggest DEET is likely targeting octopaminergic synapses to induce neuroexcitation and toxicity in insects, while acetylcholinesterase in both insects and mammals has low (mM) sensitivity to DEET. The ion channel blocking action of DEET in neurons may contribute to the numbness experienced after inadvertent application to the lips or mouth of humans.
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The purpose of this study was to examine the effect of stabilization of retinyl palmitate (RP) on its skin permeation and distribution profiles. Skin permeation and distribution study were performed using Franz diffusion cells along with rat dorsal skin, and the effect of drug concentration and the addition of pectin on skin deposition profiles of RP was observed. The skin distribution of RP increased in a concentration dependent manner and the formulations containing 0.5 and 1 mg of pectin demonstrated significantly increased RP distributions in the epidermis. Furthermore, it was found that skin distribution of RP could be further improved by combined use of pectin and ascorbyl palmitate (AP), due largely to their anti-oxidative effect. These results clearly demonstrate that the skin deposition properties of RP can be improved by stabilizing RP with pectin. Therefore, it is strongly suggested that pectin could be used in the pharmaceutical and cosmetic formulations as an efficient stabilizing agent and as skin penetration modulator.
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Acoustophoresis has been utilized successfully in applications including cell trapping, focusing, and purification. One current limitation of acoustophoresis for cell sorting is the reliance on the inherent physical properties of cells (e.g., compressibility, density) instead of selecting cells based upon biologically relevant surface-presenting antigens. Introducing an acoustophoretic cell sorting approach that allows biochemical specificity may overcome this limitation, thus advancing the value of acoustophoresis approaches for both the basic research and clinical fields. The results presented herein demonstrate the ability for negative acoustic contrast particles (NACPs) to specifically capture and transport positive acoustic contrast particles (PACPs) to the antinode of an ultrasound standing wave. Emulsification and post curing of pre-polymers, either polydimethylsiloxane (PDMS) or polyvinylmethylsiloxane (PVMS), within aqueous surfactant solution results in the formation of stable NACPs that focus onto pressure antinodes. We used either photochemical reactions with biotin-tetrafluorophenyl azide (biotin-TFPA) or end-functionalization of Pluronic F108 surfactant to biofunctionalize NACPs. These biotinylated NACPs bind specifically to streptavidin polystyrene microparticles (as cell surrogates) and transport them to the pressure antinode within an acoustofluidic chip. To the best of our knowledge, this is the first demonstration of using NACPs as carriers for transport of PACPs in an ultrasound standing wave. By using different silicones (i.e., PDMS, PVMS) and curing chemistries, we demonstrate versatility of silicone materials for NACPs and advance the understanding of useful approaches for preparing NACPs. This bioseparation scheme holds potential for applications requiring rapid, continuous separations such as sorting and analysis of cells and biomolecules.
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Psoriasis is a lifelong, chronic, and immune-mediated systemic disease, which affects approximately 1-3% of the Caucasian population. The different presentations of psoriasis require different approaches to treatment and appropriate prescriptions according to disease severity. The use of topical therapy remains a key component of the management of almost all psoriasis patients, and while mild disease is commonly treated only with topical agents, the use of topical therapy as adjuvant therapy in moderate-to-severe disease may also be helpful. This paper focuses on the cutaneous mechanisms of action of corticosteroids and on the currently available topical treatments, taking into account adverse effects, bioavailability, new combination treatments, and strategies to improve the safety of corticosteroids. It is established that the treatment choice should be tailored to match the individual patient's needs and his/her expectations, prescribing to each patient the most suitable vehicle.
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Actinic keratosis is a common precursor to sun-related squamous-cell carcinoma. Treating actinic keratoses and the surrounding skin area (i.e., field therapy) can eradicate clinical and subclinical actinic keratoses. Topical field therapy currently requires weeks or months of treatment. We investigated the efficacy and safety of a new topical field therapy for actinic keratosis, ingenol mebutate gel (0.015% for face and scalp and 0.05% for trunk and extremities). In four multicenter, randomized, double-blind studies, we randomly assigned patients with actinic keratoses on the face or scalp or on the trunk or extremities to receive ingenol mebutate or placebo (vehicle), self-applied to a 25-cm(2) contiguous field once daily for 3 consecutive days for lesions on the face or scalp or for 2 consecutive days for the trunk or extremities. Complete clearance (primary outcome) was assessed at 57 days, and local reactions were quantitatively measured. In a pooled analysis of the two trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2% vs. 3.7%, P<0.001). Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for six types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29. In a pooled analysis of the two trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% vs. 4.7%, P<0.001). Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8. Adverse events were generally mild to moderate in intensity and resolved without sequelae. Ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses. (Funded by LEO Pharma; ClinicalTrials.gov numbers, NCT00742391, NCT00916006, NCT00915551, and NCT00942604.).
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Microsponges are polymeric delivery systems composed of porous microspheres. They are tiny sponge-like spherical particles with a large porous surface. Moreover, they may enhance stability, reduce side effects and modify drug release favorably. Microsponge technology has many favorable characteristics, which make it a versatile drug delivery vehicle. Microsponge Systems are based on microscopic, polymer-based microspheres that can suspend or entrap a wide variety of substances, and can then be incorporated into a formulated product such as a gel, cream, liquid or powder. The outer surface is typically porous, allowing a sustained flow of substances out of the sphere. Microsponges are porous, polymeric microspheres that are used mostly for topical use and have recently been used for oral administration. Microsponges are designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose and also to enhance stability, reduce side effects, and modify drug release.
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Vitamin A and its natural and synthetic metabolites (retinoids) affect growth and differentiation of human skin and among the genes affected by retinoids in epidermis are keratin genes. Keratins are intermediate filament proteins that have essential functions in maintaining the structural integrity of epidermis and its appendages. Their expressions are under strict control to produce keratins that are optimally adapted to their environment. In this article, retinoid regulation of keratin expression in cultured human epidermal keratinocytes and in human skin in vivo will be reviewed. The direct and indirect mechanisms involved will be discussed and novel therapeutic strategies will be proposed for utilizing retinoids in skin disorders due to keratin mutations (e.g., epidermolysis bullosa simplex and epidermolytic ichthyosis).
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The acute and chronic effects of vitamin A toxicity are well documented in the literature. Emerging evidence suggests that subtoxicity without clinical signs of toxicity may be a growing concern, because intake from preformed sources of vitamin A often exceeds the recommended dietary allowances (RDA) for adults, especially in developed countries. Osteoporosis and hip fracture are associated with preformed vitamin A intakes that are only twice the current RDA. Assessing vitamin A status in persons with subtoxicity or toxicity is complicated because serum retinol concentrations are nonsensitive indicators in this range of liver vitamin A reserves. The metabolism in well-nourished persons of preformed vitamin A, provided by either liver or supplements, has been studied by several research groups. To control vitamin A deficiency, large therapeutic doses are administered in developing countries to women and children, who often are undernourished. Nevertheless, little attention has been given to the short-term kinetics (ie, after absorption but before storage) of a large dose of vitamin A or to the short- and long-term effects of such a dose given to lactating women on serum and breast-milk concentrations of retinol and its metabolites. Moreover, appropriate dosing regimens have not been systematically evaluated to ascertain the quantitative improvement in vitamin A status of the women and children who receive these supplements. The known acute and chronic effects of vitamin A toxicity have been reported previously. However, further research is needed to ascertain the areas of the world in which subclinical toxicity exists and to evaluate its effects on overall health and well-being.
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MICROPARTICLES OFFER VARIOUS SIGNIFICANT ADVANTAGES AS DRUG DELIVERY SYSTEMS, INCLUDING: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed.
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We report the validation of a reversed-phase gradient HPLC method allowing simultaneous quantification of retinol, retinyl esters, tocopherols and selected carotenoids in lung, liver and plasma of mouse, rat and guinea pig (gp) using a diode array detector. A significant species difference was observed regarding the distribution of retinol and retinyl esters. The levels of total retinol in lung, liver and plasma were in the following order: mouse > rat > gp; rat >mouse > gp; and gp > rat > mouse, respectively. Furthermore, comparison studies revealed similarities between the vitamin A profiles of human and gp lung samples.
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Establishing the bioequivalence of topical drug products is a costly and time-consuming process since, with few exceptions, clinical efficacy trials are required. To develop a surrogate for clinical bioequivalence testing through evaluation of the kinetics of drug absorption in vitro through excised human skin. The percutaneous absorption of seven approved generic topical drug products was compared with their corresponding reference products during preclinical development using the Franz diffusion cell. Thereafter, following the conduct of bioequivalence trials and regulatory approval of these products in the United States, clinical data became available to which the in vitro data were compared. In six of the seven cases the in vitro test:reference ratio for total absorption was close to one and indicated that the products were equivalent, in agreement with the clinical data. Results from the seventh case, in which the test:reference ratio was only 0.63, indicated that the in vitro model actually had greater sensitivity than the clinical method to detect small differences between products. These data demonstrate the relevance and predictive power of the in vitro human skin model and strongly support its use as a surrogate for in vivo bioequivalence studies.
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In vivo effects of retinoids on epidermal differentiation were investigated by analyzing cytoskeletal proteins in rhino mice treated topically with all-trans-retinoic acid (RA) and other retinoids (13-cis-retinoic acid, etretinate, TTNPB). Non-disulfide-linked cytoskeletal proteins, including keratins from the epidermal “living layers,” were first selectively extracted using 9.5 M urea; subsequently, keratins of the stratum corneum were isolated using 9.5 M urea plus a reducing agent. Gel electrophoresis and immunoblot analysis showed that urea extracts of epidermis from vehicle-treated skin were composed predominantly of four major keratins (analogous to human epidermal keratins K1, K5, K10, and K14), and the keratin filament-associated protein filaggrin. In contrast, extracts of epidermis from retinoid-treated skin contained additional keratins (K6, K16, and K17) and almost no detectable filaggrin. Furthermore, similar analysis of stratum corneum keratins demonstrated that extracts from RA-treated skin did not contain the partially proteolyzed keratins typically observed in stratum corneum extracts of control animals. Hyperplasia-inducing agents (salicylic acid, croton oil) caused an increase in keratins K6, K16, and K17, but they did not effect filaggrin or alter proteolysis of stratum corneum keratins. The result that RA induced expression of keratins K6, K16, and K17, as commonly expressed in hyperproliferative epidermis, is consistent with the notion that retinoids increase epidermal cell proliferation in the basal and/or lower spinous layers. The findings that topical RA decreased filaggrin expression and reduced proteolysis of stratum corneum keratins, despite increased size and number of granular cells and the presence of an anucleate stratum corneum, suggest that topical RA may also modulate a later stage of epidermal differentiation involved in stratum corneum formation.
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The percutaneous absorption characteristics of isotretinoin, etretinate, tretinoin, and acitretin were investigated in vitro to assess the feasibility of their topical application for dermatological disorders. The influence of vehicle, photodegradation, and dose was examined. Retinoid absorption through monkey skin was highly vehicle dependent and followed the order: propylene glycol = isopropyl alcohol greater than mineral oil greater than diisopropyl adipate greater than polyethylene glycol 400. Peak flux of etretinate (an ester) was less than 50% that of the acid retinoids in both human and monkey skin. Exposure to light caused a 60% degradation of isotretinoin on the surface of the skin, but did not change the amount of drug which penetrated the epidermis. In accord with this result, the amount of isotretinoin and acitretin which penetrated epidermis did not increase in proportion to dose over a 25-fold range of dose in human skin. Dermal concentration at doses of 10 micrograms/cm2 of isotretinoin and acitretin were greater than that reported for shave biopsies of human skin following treatment for several months with clinically effective doses of isotretinoin and etretinate (the parent ester of the acid acitretin).
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The Microsponge Delivery System (MDS) is a unique technology for the controlled release of topical agents and consists of macroporous beads, typically 10-25 microns in diameter, loaded with active agent. When applied to the skin, the MDS releases its active ingredient on a time mode and also in response to other stimuli (rubbing, temperature, pH, etc). MDS technology is being used currently in cosmetics, over-the-counter (OTC) skin care, sunscreens and prescription products. By delivering the active gradually to the skin, MDS-benzoyl peroxide formulations, for example, have excellent efficacy with minimal irritation. These are typical benefits from the use of the MDS.
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All-trans retinoic acid (ATRA), a derivative of vitamin A, is a common component in cosmetics and commercial acne creams as well as being a first-line chemotherapeutic agent. Today, formulations for the topical application of ATRA rely on creams and emulsions to incorporate the highly hydrophobic ATRA drug. These strategies, when applied to the skin, deliver ATRA as a single bolus, which is immediately taken up into the skin and contributes to many of the known adverse side effects of ATRA treatment, including skin irritation and hair loss. Herein we present a new concept in topical delivery of retinoids by covalently bonding the drug through a hydrolytically degradable ester linkage to a common hydrophilic polymer, polyvinyl alcohol (PVA), creating an amphiphilic nanomaterial that is water-soluble. This PVA bound ATRA can then act as a pro-drug and accumulate within the skin to allow for the sustained controlled delivery of active ATRA. This approach was demonstrated to release active ATRA out to 10 days in vitro while significantly enhancing dermal accumulation of the ATRA in explant pig skin. In vivo we demonstrate that the pro-drug formulation reduces application site inflammation compared to free ATRA and retains the drug at the application site at measurable quantities for up to six days.
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Advances in microfluidic cell sorting have revolutionized the ways in which cell-containing fluids are processed, now providing performances comparable to, or exceeding, traditional systems, but in a vastly miniaturized format. These technologies exploit a wide variety of physical phenomena to manipulate cells and fluid flow, such as magnetic traps, sound waves and flow-altering micropatterns, and they can evaluate single cells by immobilizing them onto surfaces for chemotherapeutic assessment, encapsulate cells into picoliter droplets for toxicity screenings and examine the interactions between pairs of cells in response to new, experimental drugs. However, despite the massive surge of innovation in these high-performance lab-on-a-chip devices, few have undergone successful commercialization, and no device has been translated to a widely distributed clinical commodity to date. Persistent challenges such as an increasingly saturated patent landscape as well as complex user interfaces are among several factors that may contribute to their slowed progress. In this article, we identify several of the leading microfluidic technologies for sorting cells that are poised for clinical translation; we examine the principal barriers preventing their routine clinical use; finally, we provide a prospectus to elucidate the key criteria that must be met to overcome those barriers. Once established, these tools may soon transform how clinical labs study various ailments and diseases by separating cells for downstream sequencing and enabling other forms of advanced cellular or sub-cellular analysis. This article is protected by copyright. All rights reserved.
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Acoustophoresis uses acoustic radiation force to remotely manipulate particles suspended in a host fluid for many scientific, technological, and medical applications, such as acoustic levitation, acoustic coagulation, contrast ultrasound imaging, ultrasound-assisted drug delivery, etc. To estimate the magnitude of acoustic radiation forces, equations derived for an inviscid host fluid are commonly used. However, there are theoretical predictions that, in the case of a traveling wave, viscous effects can dramatically change the magnitude of acoustic radiation forces, which make the equations obtained for an inviscid host fluid invalid for proper estimation of acoustic radiation forces. To date, experimental verification of these predictions has not been published. Experimental measurements of viscous effects on acoustic radiation forces in a traveling wave were conducted using a confocal optical and acoustic system and values were compared with available theories. Our results show that, even in a low-viscosity fluid such as water, the magnitude of acoustic radiation forces is increased manyfold by viscous effects in comparison with what follows from the equations derived for an inviscid fluid.
Article
Retinoids are a group of substances comprising vitamin A and its natural and synthetic derivatives. Retinoids were first used in dermatology in 1943 by Straumfjord for acne vulgaris. Since that time, retinoids have been utilized in the management and treatment of various skin conditions, including photoaging. Photodamage of the skin occurs as a consequence of cumulative exposure to solar ultraviolet radiation (UVR) and is characterized by deep wrinkles, easy bruising, inelasticity, mottled pigmentation, roughness, and telangiectasias. The mechanism of UVR-induced photodamage is multifactorial. Retinoids have demonstrated efficacy in the treatment of photoaged skin. Indeed, understanding the pathophysiology of photoaging and the molecular mechanism of retinoids can not only provide insight into the effects retinoids can exert in treating photoaging but also provide the rationale for their use in the treatment of other dermatologic diseases.
Article
The aim of the present research was to develop Fluconazole loaded microsponge-based topical delivery system for controlled release and enhanced drug deposition in the skin. Microsponges containing fluconazole were prepared by an emulsion solvent diffusion method. The effect of formulation variables (drug: polymer ratio, internal phase volume and amount of emulsifier) and process variables (stirring time and stirring speed) on the physical characteristics of microsponges like Production yield, Mean particle size, Entrapment efficiency were investigated. The effect of internal phase volume and amount of emulsifier on the physical characteristics of microsponges were examined on optimized drug/polymer ratio, stirring speed and stirring time by 32 factorial design. The optimized microsponges were dispersed into a hydrogel and evaluated. In vitro drug release, Ex vivo drug deposition, primary skin irritancy study and In vivo antibacterial activity of fluconazole-loaded formulations were studied. Spherical and porous FLU microsponge particles were obtained. From 32 factorial design, it was concluded that optimized microsponge possess particle size, production yield and entrapment efficiency of 2.45 μm, 77.38 and 92.33 %, respectively. Microsponge-loaded gels demonstrated controlled release, no irritancy to rat skin and antifungal activity. An In vivo skin deposition study demonstrated four fold higher retention in the stratum corneum layer as compared with marketed cream. Microsponges-based gel formulations showed prolonged efficacy in mouse surgical wound model infected with Candida spp. Fluconazole was stable in topical formulations and showed enhanced retention in the skin indicating better potential of the delivery system for treatment of primary and secondary skin infections.
Book
Hansen solubility parameters (HSPs) are used to predict molecular affinities, solubility, and solubility-related phenomena. Revised and updated throughout, Hansen Solubility Parameters: A User's Handbook, Second Edition features the three Hansen solubility parameters for over 1200 chemicals and correlations for over 400 materials including polymers, inorganic salts, and biological materials. To update his groundbreaking handbook with the latest advances and perspectives, Charles M. Hansen has invited five renowned experts to share their work, theories, and practical applications involving HSPs. New discussions include a new statistical thermodynamics approach for confirming existing HSPs and how they fit into other thermodynamic theories for polymer solutions. Entirely new chapters examine the prediction of environmental stress cracking as well as absorption and diffusion in polymers. Highlighting recent findings on interactions with DNA, the treatment of biological materials also includes skin tissue, proteins, natural fibers, and cholesterol. The book also covers the latest applications of HSPs, such as ozone-safe “designer” solvents, protective clothing, drug delivery systems, and petroleum applications. Presenting a comprehensive survey of the theoretical and practical aspects of HSPs, Hansen Solubility Parameters, Second Edition concludes with a detailed discussion on the necessary research, future directions, and potential applications for which HSPs can provide a useful means of prediction in areas such as biological materials, controlled release applications, nanotechnology, and self-assembly.
Article
Tretinoin is used in the management of acne and it is part of a gold standard treatment for photoaging. It has also been reported as an agent for superficial chemical peeling in highly concentrated formulations with few considerations about skin penetration. The aim of this study was to evaluate the influence of drug concentration and vehicles currently used on skin penetration of tretinoin. In vitro permeation tests were carried out using Franz diffusion cells fitted with porcine ear skin and 10% aqueous methanol in the receptor compartment. Formulations studied, cream or hydroalcoholic dispersion, containing 0.25%, 1% and 5% of tretinoin were placed in the donor compartment for six hours. Tretinoin concentration in skin layers was measured by high performance liquid chromatography. The largest amount of tretinoin from both vehicles was detected in stratum corneum with significant differences among the three concentrations. The hydroalcoholic dispersion was the best vehicle. Significant amounts of tretinoin were found even in deep layers of epidermis. The formulation with 0.25% tretinoin showed better results when considered the amount of tretinoin on skin in terms of percentage. Finally, skin penetration of tretinoin was influenced by vehicle and concentration of this drug used in formulation.
Article
Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and materials advances that are enabling the field to overcome these hurdles for clinical impact.
Article
Microencapsulation is the process of surrounding or enveloping one substance within another substance on a very small scale, yielding capsules ranging from less than one micron to several hundred microns in size. The encapsulation efficiency of the microparticles or microsphere or microcapsule depends upon different factors like concentration of the polymer, solubility of polymer in solvent, rate of solvent removal, solubility of organic solvent in water etc. Microencapsulation may be achieved by a myriad of techniques. Substances may be microencapsulated with the intention that the core material be confined within capsule walls for a specific period of time. Alternatively, core materials may be encapsulated so that the core material will be released either gradually through the capsule walls, known as controlled release or diffusion, or when external conditions trigger the capsule walls to rupture, melt, or dissolve. This article is a review of microencapsulation and materials involved in it, morphology of microcapsules, microencapsulation technologies, purposes of microencapsulation, and benefits of microencapsulation, release mechanisms, and application fields, with special emphasis on microencapsulated additives in building construction materials.
Article
We report an efficient and adaptable method for the microencapsulation of active ingredients by a polydimethylsiloxane (PDMS) shell material. The core–shell microcapsules were obtained by phase separation between the core component and the PDMS shell components after repartitioning of the common solvent THF between the PDMS/core material phase and the water phase. For the shell components, two commercially available functional PDMS polymers containing thiol and vinyl side groups were used. Photo-cross-linking in the presence of 2,2-dimethoxy-2-phenylacetophenone (DMPA) by thiol–ene radical addition was used to form a PDMS-thioether cross-linked shell. Variation of the PDMS component thiol to ene ratio resulted in different functionalities on the microcapsules surface and in the bulk, which was analyzed by attenuated total-reflection infrared spectroscopy (ATR-IR) and high-resolution magic-angle NMR-spectroscopy (HR-MAS NMR). Organically modified silica particles were mixed into the PDMS shell, resulting in better mechanical properties of the shell and control over the shell permeability, as measured on the one hand by tensile testing of representative PDMS bulk samples of identical composition as the actual shell material and on the other hand by leaching experiments of the core compounds, such as a tetrathiol and the UV-absorber octocrylene, followed by UV–vis.
Article
The review of Microencapsulation is a well-established dedicated to the preparation, properties and uses of individually encapsulated novel small particles, as well as significant improvements to tried-and-tested techniques relevant to micro and nano particles and their use in a wide variety of industrial, engineering, pharmaceutical, biotechnology and research applications. Its scope extends beyond conventional microcapsules to all other small particulate systems such as self assembling structures that involve preparative manipulation. The review covers encapsulation materials, physics of release through the capsule wall and / or desorption from carrier, techniques of preparation, many uses to which microcapsules are put.
Article
An approach for the preparation of an oxidized porous silicon microparticle drug delivery system that can provide efficient trapping and sustained release of various drugs is reported. The method uses the contraction of porous silicon’s mesopores, which occurs during oxidation of the silicon matrix, to increase the loading and retention of drugs within the particles. First, a porous Si (pSi) film is prepared by electrochemical etching of p-type silicon with a resistivity of >0.65 Ω cm in a 1:1 (v/v) HF/ethanol electrolyte solution. Under these conditions, the pore walls are sufficiently thin to allow for complete oxidation of the silicon skeleton under mild conditions. The pSi film is then soaked in an aqueous solution containing the drug (cobinamide or rhodamine B test molecules were used in this study) and sodium nitrite. Oxidation of the porous host by nitrite results in a shrinking of the pore openings, which physically traps the drug in the porous matrix. The film is subsequently fractured by ultrasonication into microparticles. Upon comparison with commonly used oxidizing agents for pSi such as water, peroxide, and dimethyl sulfoxide, nitrite is kinetically and thermodynamically sufficient to oxidize the pore walls of the pSi matrix, precluding reductive (by Si) or oxidative (by nitrite) degradation of the drug payload. The drug loading efficiency is significantly increased (by up to 10-fold), and the release rate is significantly prolonged (by 20-fold) relative to control samples in which the drug is loaded by infiltration of pSi particles postoxidation. We find that it is important that the silicon skeleton be completely oxidized to ensure the drug is not reduced or degraded by contact with elemental silicon during the particle dissolution–drug release phase.
Article
Nucleation and growth methods offer scalable means of synthesizing colloidal particles with precisely specified size for applications in chemical research, industry, and medicine. These methods have been used to prepare a class of silicone gel particles that display a range of programmable properties and narrow size distributions. The acoustic contrast factor of these particles in water is estimated and can be tuned such that the particles undergo acoustophoresis to either the pressure nodes or antinodes of acoustic standing waves. These particles can be synthesized to display surface functional groups that can be covalently modified for a range of bioanalytical and acoustophoretic sorting applications.
Article
Over the past 2 decades, considerable progress has been made to further elucidate the complex pathogenesis of psoriasis, facilitating the development of a new armamentarium of more effective, targeted therapies. Despite these important advances, substantial deficits remain in our understanding of psoriasis and its treatment, necessitating further research in many areas. In the sixth section of the American Academy of Dermatology Psoriasis Guidelines of Care, gaps in research and care were identified. We discuss the most important gaps in research that currently exist and make suggestions for studies that should be performed to address these deficits. These encompass both basic science and clinical research studies, including large, prospective epidemiologic studies to determine the true prevalence and natural history of psoriasis; further molecular studies in patients with psoriatic and psoriatic arthritis to understand the function of psoriasis susceptibility genes and to identify novel therapeutic targets; studies to examine the role of environmental factors in the development of psoriasis; further investigation of the relationship between psoriasis and cardiometabolic disease; studies that examine the role of adjunctive therapies such as psychological interventions in appropriate patient groups; and finally, studies to identify biomarkers of disease severity and treatment response to optimize patient therapy.
Article
The involvement of retinoids in supporting vision via light-sensitive rod and cone photoreceptor cells in the retina is studied. Retinol travels in the circulation bound to RBP. In turn, RBP complexes with a transthyretin (TTR) tetramer, which prevents filtration of RBP across the glomeruli of the kidney. Holo-RBP can dissociate from the TTR tetramer and bind to the retinol membrane transporter, STRA6. all-trans-Retinol is picked up on the cytoplasmic side of STRA6 by CRBP, which shuttles the retinoid to the ER of the RPE (retinal pigment epithelium). There it is esterified by LRAT (Lecithin/Retinol Acyl Transferase) to form all-transretinyl-esters, which are either used as substrates for visual chromophore production or stored in lipid bodies known as retinosomes, atROL, all-trans-retinol; atRE, all-trans-retinyl ester.
Article
The aim of this study was to stabilize all-trans-retinol (RE) by complexification with chitosan derivatives through H-bonding. Succinated chitosan (CHI-succ) with three different degrees (5, 10, 20 mol%) of succinylation were synthesized to form complexes with RE. Various weight ratios (w/w) of CHI-succ/RE complexes were prepared and characterized to produce stable complexes in nanometer size. The CHI-succ(0.20)/RE complex with approximate 250 nm in diameter was obtained using a CHI-succ(0.20) concentration of 0.005% (w/v) in double deionized water with various contents of RE. From fine-tuning the degree of succinylation and the weight ratio of the CHI-succ and RE, the formation of supramolecular complexes simultaneously improved water solubility and stability of RE. The cell viability of CHI-succ polymers and their RE complexes in 3T3 cells were all > 85% relative to the control. The antioxidant ability of the CHI-succ(0.20)/RE complexes was significantly greater than that of pure RE using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay (p < 0.01).
Article
BACKGROUND: The majority of people with psoriasis have localised disease, where topical therapy forms the cornerstone of treatment. OBJECTIVE: To summarise evidence on relative efficacy, safety and tolerability of different topical treatments used in plaque psoriasis METHODS: Systematic review and meta-analyses of randomised trial data of UK-licensed topical therapies. The primary outcome was clear or nearly clear status stratified for (i) trunk and limbs and (ii) scalp. Network meta-analyses allowed ranking of treatment efficacy. RESULTS: 48 studies were available for trunk and limb psoriasis and 17 for scalp psoriasis (n=22,028); the majority included people with at least moderate psoriasis severity. Strategies containing potent corticosteroids (alone or in combination with a vitamin D analogue) or very potent corticosteroids, dominated the treatment hierarchy at both sites (trunk and limbs, scalp); coal tar and retinoids were no better than placebo. No significant differences in achievement of clear/nearly clear status were observed between twice and once daily application of the same intervention or between any of the following: combined vitamin D analogue and potent corticosteroid (applied separately or in a single product), very potent corticosteroids, or potent corticosteroids (applied twice daily). Investigator and patient assessment of response differed significantly for some interventions (response rate to very potent corticosteroids 78% and 39% respectively). No significant differences were noted for tolerability or steroid atrophy, but data were limited. CONCLUSIONS: Corticosteroids are highly effective and safe in psoriasis when used continuously for up to 8 weeks and intermittently for up to 52 weeks. Coal tar and retinoids are of limited benefit. There is a lack of long-term efficacy and safety data available on topical interventions used for psoriasis.
Article
The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid-containing treatments have been used since ∼1550BC by the early Egyptians. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930s. Early use of high-dose vitamin A demonstrated efficacy, but because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types.
Article
J. Cosmet. Sci., 60, 485–500 (September/October 2009) Retinol and retinyl palmitate are frequently used in cosmetic products. A simple, rapid, and sensitive reversed-phase high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection was developed for the quantitation of retinol, retinyl palmitate, and retinoic acid in cosmetic preparations. The analytes were extracted from a cosmetic/Celite mixture using a solvent system composed of equal amounts of hexane, isopropanol, and ethyl acetate, and the extract was injected directly into an HPLC chromatograph with a C18 column and UV detector set at 330 nm. Chromatographic separation was achieved by gradient elution with a mobile phase, starting with aqueous ammonium acetate buffer/methanol that was gradually changed to methanol/dichloromethane. The average recoveries of retinol, retinyl palmitate, and retinoic acid from spiked cosmetic products were 95% or higher. In a survey of 29 consumer cosmetic skin care products labeled to contain retinoids, most products were found to contain either retinol or retinyl palmitate at concentrations up to 2.2% (w/w), while a few products contained both ingredients. A number of products also contained cis isomers of retinol that could be quantitatively distinguished from the all-trans compound. The method can be used to quantitate several retinoids and their isomers in cosmetic products. The method will be useful for obtaining information needed to estimate levels of exposure to retinoids from cosmetic products.
Article
We describe droplet microfluidic strategies used to fabricate advanced microparticles that are useful structures for the encapsulation and release of actives; these strategies can be further developed to produce microparticles for advanced drug delivery applications. Microfluidics enables exquisite control in the fabrication of polymer vesicles and thermosensitive microgels from single and higher-order multiple emulsion templates. The strategies used to create the diversity of microparticle structures described in this review, coupled with the scalability of microfluidics, will enable fabrication of large quantities of novel microparticle structures that have potential uses in controlled drug release applications.
Article
Current topical agents for field therapy of actinic keratoses have single mechanisms of action and must be applied for weeks. Ingenol mebutate gel, a novel drug for field therapy of actinic keratoses, appears to have a dual mechanism of action: (1) rapid lesion necrosis and (2) specific neutrophil-mediated, antibody-dependent cellular cytotoxicity. Because of the rapid destruction of actinic keratosis lesions after application of ingenol mebutate gel, treatment is necessary for only 2 or 3 days. The subsequent immune-mediated response targets any residual dysplastic epidermal cells. This dual mechanism of action should provide efficacy equivalent to that of current topical agents with a substantially shorter treatment period.
Article
The use of a "size-tunable" polyurethane resistive pulse sensor for quantitative sizing of nano- and microparticles is presented. A linear relationship, as first suggested by Maxwell, between particle volume and change in electric resistance across the pore was observed. Particle sizes were quantified for a given size-tunable membrane, by first creating a linear calibration curve to a series of monodisperse carboxylated polystyrene particles of various diameters and then applying this curve to calculate the size of "unknown" nanoparticles. The diameters of a selection of synthetic and biological particles, being PMMA and nonfunctionalized polystyrene particles, along with biological nanoparticles (adenovirus) were calculated using this methodology. Calculated particle diameters and coefficients of variation were shown to be in good agreement with both transmission electron microscopy and dynamic light scattering results.
Article
This paper reports on the synthesis of uniformly dye-doped organosilica particles with narrow size distribution. The particle size can be controlled from tenths of nanometers up to several micrometers, whilst still maintaining monodispersity. Microparticles were observed to swell in various solvents up to similar to 2.5 times their original volume, suggesting the presence of a gel-like internal structure. As shown by confocal microscopy, this morphological control of particle Swelling has important implications for the encoding of the nano/micro particles with organic dyes, such as rhodamine B isothiocyanate. Swelling allows the dye to penetrate the organosilica matrix and produce uniformly dye-doped nano- and microparticles. Finally, we suggest a coagulation model for the particle formation which significantly differs from conventional Stober synthesis. (c) 2007 Elsevier Inc. All rights reserved.
Article
Exposure to ultraviolet (UV) radiation is associated with a variety of harmful effects ranging from photoaging to skin cancer. UVB (290 to 320 nm) directly damages the cellular DNA leading to the formation of the 6-4 cyclobutane pyrimidine dimmers, and UVA (320 to 400 nm) indirectly damages the DNA via the production of oxygen radical species. In this review, we focused on the technological and scientific aspects of photoprotection using sunglasses and clothing while attempting to dispel some of the misconceptions. In addition to the basic knowledge relating to sunscreens, we reviewed the current guidelines for testing and labeling UVA protection around the world, controversies associated with nanoparticles, and future sunscreens actives waiting for the Food and Drug Administration approval. Lastly, we reviewed alternative agents, such as antioxidants, that can be used to supplement and augment photoprotection provided by sunscreens.
Article
The human repeated insult patch test (HRIPT) is over half a century old, but is still used in several countries as a confirmatory test in the safety evaluation of skin sensitizers. This is despite the criticism it receives from an ethical perspective and regarding the scientific validity of such testing. In this commentary, the HRIPT is reviewed, with emphasis on ethical aspects and where the test can, and cannot, contribute in a scientifically meaningful manner to safety evaluation. It is concluded that where there is a specific rationale for testing, for example, to substantiate a no-effect level for a sensitizing chemical or to ensure that matrix effects are not making an unexpected contribution to sensitizing potency, then rigorous independent review may confirm that an HRIPT is ethical and scientifically justifiable. The possibility that sensitization may be induced in volunteers dictates that HRIPTs should be conducted rarely and in cases where the benefits overwhelmingly outweigh the risk. However, for the very large majority of HRIPTs conducted concerning the risk of skin sensitization, there is neither scientific justification nor any other merit.
Article
The aim of this research is to investigate the dermal delivery of all-trans-retinol from nanoparticle-coated submicron oil-in-water emulsions as a function of the initial emulsifier type, the loading phase of nanoparticles, and the interfacial structure of nanoparticle layers. The interfacial structure of emulsions was characterized using freeze-fracture-SEM. In-vitro release and skin penetration of all-trans-retinol were studied using Franz diffusion cells with cellulose acetate membrane, and excised porcine skin. The distribution profile was obtained by horizontal sectioning of the skin using microtome-cryostat and HPLC assay. The steady-state flux of all-trans-retinol from silica-coated lecithin emulsions was decreased (up to 90%) and was highly dependent on the initial loading phase of nanoparticles; incorporation from the aqueous phase provided more pronounced sustained release. For oleylamine emulsions, sustained release effect was not affected by initial location of nanoparticles. The skin retention significantly (p < or = 0.05) increased and was higher for positive oleylamine-stabilised droplets. All-trans-retinol was mainly localized in the epidermis with deeper distribution to viable skin layers in the presence of nanoparticles, yet negligible permeation (approximately 1% of topically applied dose) through full-thickness skin. Sustained release and targeted dermal delivery of all-trans-retinol from oil-in-water emulsions by inclusion of silica nanoparticles is demonstrated.
Article
An in vivo technique has been developed which simultaneously compares a skin blanching bioassay with drug content in human stratum corneum following topical application of four 0.05% betamethasone dipropionate formulations. Bioavailability of drug from commercial cream and ointment formulations was assessed by quantification of drug content in tape-stripped stratum corneum and skin blanching in the treated skin site under occluded conditions. Tape-stripping removed stratum corneum to a varying degree between individuals but was consistent (35%) within an individual with all formulations, day to day. A correlation (r = 0.9935) between the amount of drug in the treated stratum corneum normalized for surface area and the corresponding skin blanching score was observed with four 0.05% betamethasone dipropionate formulations. Increasing the amount of drug in the tape-stripped stratum corneum correlated with an increased skin blanching score. Ointment formulations delivered more drug to the skin and produced greater blanching scores than the cream formulations. Topical corticosteroid content in the treated skin site can therefore be quantified and correlates well with the resulting pharmacodynamic activity.
Article
Retinoids, synthetic vitamin A analogs, stimulate mucous metaplasia and gap-junction proliferation in embryonic and neoplastic epidermis. Such effects demonstrate that vitamin A has potent effects on epidermal differentiation. Oddly, however, retinoid action in normal postnatal tissues, where these drugs are used clinically, appears to be quite different. In animals and humans, both topical and systemic retinoids produce acanthosis, hypergranulosis, and a relative (but not absolute) decrease in the thickness of the stratum corneum. These changes reflect the distinct boost in cell turnover that results from retinoid treatment. On the ultrastructural level, desmosomes are actively shed by cells of the spinous layer, resulting in many fewer attachment points along the cell membranes of the outer epidermis. Loss of desmosomes, coupled with decreased tonofilaments, enhanced keratinocyte autolysis, and intercellular deposition of glycoconjugates (not mucin), cause loosening and fragility of the stratum corneum (so-called anti-keratinizing effects). The biochemical basis of retinoid activity, in addition to stimulating increased cell turnover, appears to be a global enhancement of glycoconjugate synthesis and the generation of less mature keratins. The epidermal effects of retinoids can be exploited therapeutically: to cause loosening of thickened stratum corneum, for example in psoriasis or ichthyosis; to enhance penetration of pharmacologic agents such as 5-fluorouracil across hypertrophic actinic keratoses; and to normalize differentiation in neoplastic epidermis involving mucous metaplasia and gap-junction proliferation.
Article
Daily topical application of 0.05% tretinoin in a cream base was compared with its vehicle with regard to moderation of photoaging changes of the face and forearms. In comparison with the control tissue, tretinoin-treated tissue examined by light and electron microscopy showed the following effects: replacement of the atrophic epidermis by hyperplasia, elimination of dysplasia and atypia, eradication of microscopic actinic keratoses, uniform dispersion of melanin granules, new collagen formation in the papillary dermis, new vessel formation (angiogenesis), and exfoliation of retained horn in the follicles. Physiologic studies demonstrated: increased blood flow and dermal clearance, increased transepidermal water loss, and greater permeability and reactivity. It was concluded that topical tretinoin is capable of at least partly reversing the structural damages of excessive sunlight exposure and may be useful in decelerating the photoaging process.