File Name: topical and transdermal drug delivery principles and practice .zip
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Metrics details. Transdermal delivery systems have been intensively studied over the past 2 decades, with the focus on overcoming the skin barrier for more effective application of pharmaceutical and cosmetic products. Although the cosmeceutical industry has made a substantial progress in the development and incorporation of new and effective actives in their products, the barrier function of the skin remains a limiting factor in the penetration and absorption of these actives. Enhancement via modification of the stratum corneum by hydration, acting of chemical enhancers on the structure of stratum corneum lipids, and partitioning and solubility effects are described. This review summarizes the advances in the development and mechanisms of action of chemical components that act as permeation enhancers, as well as the advances in appropriate vehicles, such as gels, emulsions, and vesicular delivery systems, that can be used for effective transdermal delivery.
E-mail: blanzat chimie. At the same time, this has led to the adjustment of a wide diversity of drug carriers. This paper begins with a review of the skin, including its structure and the parameters that influence drug diffusion, followed by strategies to improve dermal drug delivery.
This review will present the state of the art as well as the new trends in this domain. Through the description of these systems, we will try to obtain information on the ideal properties that the carrier must have in order to improve the cutaneous and transcutaneous penetration of the drug.
Many novel techniques to overcome this limitation have thus been developed to improve and control the transport of drugs through the skin. For the past twenty years, most chemical methods developed have focused on the use of skin penetration enhancers to temporarily modify the integrity of the skin barrier by increasing its permeability or by fluidizing its lipid phase. Drug delivery systems offer a gentler alternative to facilitate passive dermal passage.
The stratum corneum SC is the superficial portion of the epidermis. It is a unique biomembrane that serves a barrier function for the skin. It is therefore absolutely essential to understand the SC's structure in order to be able to cross it.
The corneocytes are organized in clusters, separated by channels of a few microns. The cells are held together by a protein structure, called corneodesmosome, which give the corneocytes a high structural stability.
It is the cleavage of these proteins, under the action of proteases, which is at the origin of the phenomenon of desquamation of the first layers, by separating the cells of the network. This lipidic matrix is mainly composed of ceramides, free fatty acids, and cholesterol. These multilayers play a critical role in the barrier function that makes the SC waterproof.
However, the elucidation of their complex structure, facilitated in recent years by analytical techniques, remains a challenge for the scientific world. Variability of the composition and behavior phase within the thickness of the SC makes the task all the more arduous. It is noteworthy that penetration of external molecules into the skin takes place simultaneously by these three parallel penetration pathways. However, their relative contribution can be largely dependent on the physicochemical characteristics of the drug.
Knowing that it is generally impossible to select its characteristics according to the intended application, it is necessary to develop strategies that will promote skin transport. Thus, each stage of penetration has its own kinetics and depends on many factors Fig. The absorption of external molecules is mainly controlled by passive diffusion.
The driving force is therefore linked to the concentration gradient, which depends mainly on the partition coefficient, theoretically defined as the ratio of chemical activities between the two phases. Therefore, the chemical activity gradient across the skin is a fundamental parameter in its penetration into the skin. Thus, the combinations are infinite. The study of the effects of these different parameters makes it possible to define the ideal physicochemical parameters of a permeant.
If the drug does not meet all of these criteria, which is the most common case, it is necessary to find ways to modify its skin penetration profile.
Three distinct approaches exist for improving dermal penetration. First, some strategies are based on a simple improvement in passive permeation, mostly using permeation enhancers; 31 second, the integrity of the SC can be damaged 32 using physical techniques microneedles, 13 electroporation, 15 iontophoresis 16 or sonophoresis 14 in order to reduce the barrier effect of the SC.
These strategies are well adapted for transdermal administration. In this review, we will focus on dermal delivery systems with nanovectors and especially vesicles. While research was focused a few years ago on oral and parenteral administration, more studies are now widely focused on topical applications.
A number of matrix systems are also developed to enhance dermal penetration, 39 but we will not discuss them here. Generally, matrix systems include those systems made of three-dimensional networks formed by polymers, 12,40 surfactants or dendrimers, and in which active principles are trapped, as for instance emulsions, 41,42 hydrogels, 43 dendrimers, 44 nanospheres, 45,46 and solid lipid particles.
Vesicles are defined as colloidal soft matter vectors containing an aqueous or an oily heart, separated from the external environment by a membrane, made of phospholipids, polymers, or surfactants. In addition, the carrying capacity of vesicles is generally greater than that of matrix systems, making it a vector of choice for limiting the quantity of exogenous molecules in the body. Moreover, by varying the nature of the membrane to obtain the appropriate physicochemical properties, vesicles could in particular succeed in crossing the skin barrier to improve the distribution of the encapsulated drug in the deep layers.
In fact, the drug delivery ability of vesicles is largely influenced by their physicochemical characteristics, particularly those of the membrane. We will therefore describe the different types of vesicles according to the family of molecules that comprise them. Ideally, the polymer used should be biodegradable and non-toxic, whether natural or synthetic. It is also possible to find sorbitan monostearate, or even other additives providing an intrinsic effect turmeric oil for its antibacterial and antioxidant action, for example.
Nanocapsules are most often stabilized by poly ethylene glycol derivatives, such as poloxamers, phospholipids, and possibly poly vinyl alcohol. Their outwardly pointing hydrophilic parts provide the necessary hydrophilicity and hindrance to the surface of the particle.
Two different types of preparation methods can be used. If the polymer is not preformed, the nanocapsules are synthesized by interfacial polymerization. This method requires the prior formation of a nanoemulsion, which serves as a template for the future nanoparticles. If the polymer is preformed, the nanocapsules are obtained by precipitation on the surface of oil droplets.
For this, the polymer must be insoluble both in water and in the oily core. The potential of nanocapsules for dermatological or cosmetic uses was evaluated in the early s. Studies on this subject have multiplied for the last ten years. After topical application, nanocapsules have been shown to form a thin film on the skin due to the evaporation of water. This film ensures prolonged delivery and acts as a reservoir of drug for the skin. A positive surface charge of the particles can promote bioadhesiveness and increase the phenomenon.
These properties are particularly interesting in the field of sun protection. For this application, UV screens should be kept in the first layers of the SC to absorb radiation and prevent skin damage. The nanoencapsulation has shown an improvement in skin retention and an absence of penetration of organic sunscreens such as OMC or benzophenone-3, or even TiO 2.
Being isolated from potential reactive species in their environment, their photostability and their ability to block UV were also optimized. Among the variety of existing phospholipids, phosphatidyl-cholines are most commonly used for the production of liposomes. Most often cholesterol is added to it. It does not intrinsically form a bilayer, but the cholesterol intercalates between the phospholipid molecules.
The defects it causes make the membrane more rigid, which reduces the permeability to water-soluble molecules. It also increases the stability of objects in the presence of biological fluids. There are many methods for preparing liposomes, but they generally follow three main steps:. The size of the liposomes can vary from 25 nm to 2. Depending on the method of preparation, it is possible to obtain multilamellar vesicles MLV , small or large unilamellar vesicles SUV or LUV , and even multivesicular vesicles containing several liposomes within a single bilayer.
Of interest to researchers around the world since the s, these systems have naturally found applications in topical administration. Thus, MLVs are already used to encapsulate heparin, sodium diclofenac, and iodides within their aqueous heart, for dermal delivery applications. Microscopic observation of skins treated with rigid vesicles, whose carbon chains are in the gel state, has shown their presence only on the surface. However, the use of vesicles with fluid and elastic bilayers results in the presence of the encapsulated fluorescent probe in the extracellular matrix and in the deeper layers.
This result confirms that skin penetration is greater with flexible vesicles. Their method of preparation is simpler than for conventional liposomes. No solvent removal step is necessary. Numerous studies have demonstrated ethosomes' capacity to vectorize both hydrophilic and hydrophobic drugs for topical applications.
In addition, they have the advantage of being efficient, regardless of the state of hydration of the skin. Therefore, they can be used in occlusive conditions. This effectiveness can be explained by the synergy existing between ethanol and the phospholipid vesicles.
First, ethanol is intrinsically a penetration enhancer and induces a local alteration of the extracellular matrix of the SC. Second, ethanol has an effect on the physicochemical characteristics of ethosomes. It induces a negative surface charge and a reduction in the size of vesicles, as observed in a study on the encapsulation of trihexyphenidyl HCl. The ethosomes had an average diameter of nm, compared to nm for the corresponding liposomes.
The result is vesicles with very fluid and easily deformable membranes, which slide through the disturbed SC to release their charge in the deep layers of the skin. Studied compounds include oleic acid, limonene, propylene glycol, glycerol, and transcutol.
These molecules have a single fatty chain and form objects with a large radius of curvature. These discontinuities in the order of phospholipids make the bilayer less rigid. Edge activators give transfersomes their ultra-deformable properties. Indeed, during a destabilization event, the edge activators accumulate at the pressure points of the vesicle because of their affinity for curved configurations. Changing the shape of the liposome therefore requires less energy.
Deformability is maximum when the membrane attempts to optimize its local composition in response to an anisotropic external stress. Numerous studies have demonstrated the excellent performance of this type of flexible vesicles in the dermal and transdermal delivery of drugs. However, this requires an osmotic gradient, which are non-occlusive conditions, to serve as a driving force. The hydrophilicity of phospholipids pushes them to avoid dry environments. So in order to remain swollen after skin application and vehicle evaporation, the vesicles must follow the local hydration gradient, navigating towards the deeper layers of the skin.
They have the advantage of being able to encapsulate a wide variety of hydrophilic and lipophilic drugs, while being much cheaper and more stable than liposomes. In fact, surfactants are generally less expensive than pure phospholipids and are more resistant to hydrolytic degradation. Niosomes serve as a reservoir system and the release kinetics can be modified by changing their composition.
For pharmaceutical applications, the surfactants chosen should be biocompatible, biodegradable, non-immunogenic, and non-carcinogenic. Stabilization can be further increased by adding charged molecules of the niosome composition.
These additives may provide electrostatic repulsion between objects.
Pay-load deliveries across the skin barrier to the systemic circulation have been one of the most challenging delivery options. Necessitated requirements of the skin and facilitated skin layer cross-over delivery attempts have resulted in development of different non-invasive, non-oral methods, devices and systems which have been standardized, concurrently used and are in continuous upgrade and improvements. Iontophoresis, electroporation, sonophoresis, magnetophoresis, dermal patches, nanocarriers, needled and needle-less shots, and injectors are among some of the methods of transdermal delivery. The transdermal drug delivery system TDDS is a painless, non-invasive method of drug delivery and takes precedence over other conventional delivery routes in this matter. The technique has proven to be a successful substitute for various routes of administration, e. Nonetheless, the dose levels are still not competitive in comparison to the traditional delivery options.
Transdermal drug delivery systems have become an intriguing research topic in pharmaceutical technology area and one of the most frequently developed pharmaceutical products in global market. The use of these systems can overcome associated drawbacks of other delivery routes, such as oral and parenteral. The authors will review current trends, and future applications of transdermal technologies, with specific focus on providing a comprehensive understanding of transdermal drug delivery systems and enhancement strategies. This article will initially discuss each transdermal enhancement method used in the development of first-generation transdermal products. Through suitable design and implementation of active stratum corneum bypassing methods, notably microneedle technology, transdermal delivery systems have been shown to deliver both low and high molecular weight drugs. These have shown that microneedles have been a prospective strategy for improving transdermal delivery systems.
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Topical drug delivery is an interesting approach to treat skin diseases and to avoid pain and low patient compliance in cases where a systemic delivery is required. However, the stratum corneum, which is the outermost skin layer, strongly protects the body from the entrance of substances, especially those hydrophilic. In this context, different physical methods have been studied to overcome the stratum corneum barrier and facilitate penetration of drugs into or through the skin. Among them, iontophoresis, low-frequency ultrasound and microneedles have been widely employed for transdermal drug delivery.
Designed to support the development of new, effective therapeutics, Topical and Transdermal Drug Delivery: Principles and Practice explains the principles underlying the field and then demonstrates how these principles are put into practice in the design and development of new drug products. Drawing together and reviewing the latest research findings, the book focuses on practical, tested, and proven approaches that are backed by industry case studies and the authors' firsthand experience. Moreover, the book emphasizes the mechanistic information that is essential for successful drug product development.
The application of medications to the skin to ease ailments is a practice that has been utilized by humankind over the millennia and has included the application of poultices, gels, ointments, creams, and pastes. These applications were primarily intended for a local topical effect. The use of adhesive skin patches to deliver drugs systemically is a relatively new phenomenon. The first adhesive transdermal delivery system TDDS patch was approved by the Food and Drug Administration in scopolamine patch for motion sickness.
Application of Nanotechnology in Drug Delivery.
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Topical and Transdermal Drug Delivery: Principles and Practice. Editor(s). Heather A. E. Benson; Adam C. Watkinson. First publishedFantvoskschedar 26.03.2021 at 12:52
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