Adhesive functional requirements for common transdermal patch designs.
\r\n\t
\r\n\tThe aim of this book project is to compile the updated research work on medicinal applications of noble metal complexes mainly focusing the structure activity relationship of metal complexes with targeting biological components.
The term “silicone” is not always used consistently, and should only be used to refer to polymeric materials, avoiding the relatively common confusion with the metallic element silicon (Si). Silicones are synthetic polymers containing Si─O─Si bonds and are used in many industries for their water repellency, ability to wet-out surfaces, high permeability to gases, stability in extreme temperatures, and resistance to thermal, radiation and chemical degradation. The variety of physical forms and physiochemical properties that silicones can display has led to their adoption in a diverse array of healthcare applications including medical devices and as active pharmaceutical ingredients (API) and excipients in medicines for over 60 years [1]. One class of silicone materials that has generated continued interest and research is silicone adhesives, specifically those self-adhering materials that do not require any activation immediately prior to use. Silicone adhesives are used as excipients in transdermal patches, and as skin contact adhesives in prosthetic and wound care device attachment. Recent investigations support the use of silicone based pressure sensitive adhesives for their skin-friendliness, but also to enhance the efficacy of the drug in transdermal drug delivery patch products. Recent silicone technologies like silicone based hybrid pressure sensitive adhesives promise potential performance advantages and improved drug delivery efficacy in transdermal drug delivery systems. Other silicone adhesive types are well known for their atraumatic removal from skin - an ability to remove cleanly from compromised skin without negatively impacting the wound healing process.
\nThis chapter will review silicone based adhesive technologies, applications and characterization, emphasizing those self-adhesive materials often used in skin contact applications. One type of silicone adhesive that is well established in the medical device industry but outside the scope of this work are room temperature vulcanizing (RTV) sealants. While these sealants are an interesting and useful class of materials, they will not be a focus of this chapter. Unlike the self-adhering adhesives discussed in this chapter, once fully crosslinked, the RTV sealants are non-tacky and rubbery and designed to form a permanent bond between substrates. These materials have a similar chemistry to silicone caulks commonly in the construction industry, and have found utility adhering materials to silicone elastomers, bonding parts of medical devices together, and acting as encapsulants and sealants in a variety of medical devices, including pacemakers [2].
\nWhile the term “silicone” persists in common vernacular, “polyorganosiloxane” is a more appropriate term, and has found acceptance in most scientific literature. Polyorganosiloxanes are organosilicon polymers, the most common of which are the trimethylsiloxy-terminated polydimethylsiloxanes (Figure 1) [3].
\nChemical structure of typical polydimethylsiloxanes.
The silicon in polyorganosiloxanes can be combined with one, two or three organic groups, commonly ─CH3, ─CH═CH2 or ─H, with the remaining valence(s) satisfied with oxygen [4]. Branched silicone structures are made possible by substitution of dimethyl siloxane units (i.e., (CH3)2SiO2/2) with those that contain additional Si─O connections (e.g., CH3SiO3/2 or SiO4/2) [4]. It is through the fact that different siloxane units can be combined with one another in the same molecule that the great variety of silicone compounds arises [3].
\nSilicones exhibit an inorganic backbone chain (Si─O)n and organic, (typically methyl) side groups [5]. It is this unusual combination and the resulting physiochemical properties that are responsible for many characteristics of the silicone adhesives. The silicon to oxygen bonds of the backbone are longer and more open than carbon to oxygen bonds permitting the characteristic flexibility of the siloxane chain. By way of comparison, the rotational energy around a ─CH2─CH2 bond is over four times greater than that of a typical (CH3)2Si─O bond. This flexibility is responsible for the characteristic low surface tension observed in silicones which allows them to quickly “wet out” onto surfaces including skin [5].
\nIn addition to increased flexibility, the silicon-oxygen bonds are also stronger than carbon-carbon bonds. The bond energy of a Si─O bond along the backbone of a silicone polymer is 452 kJ/mol while the typical C─C bond of the backbone of an organic polymer is only about 348 kJ/mol [5]. The inherently strong backbone of silicone polymers can help explain the acknowledged chemical stability silicone polymers possess toward a variety of degradation routes including moisture, UV, and a wide range of temperatures. This is equally important at very low and very high temperatures, where some types of silicones maintain their characteristic physical properties and utility from −100°C up to 260°C [6].
\nSilicones in general, are hydrophobic, (i.e., having little or no affinity for water), so one may anticipate silicones to be extremely lipophilic, given the common perspective equating hydrophobicity with lipophilicity (i.e., having a strong affinity with lipids). However, in the case of silicones, only relatively small silicone polymers are lipophilic. Polydimethylsiloxane (PDMS) polymers in excess of six to eight (CH3)2SiO units have little affinity with lipids while larger polymers are essentially lipophobic. These hydrophobic and lipophobic properties impact the ability to solubilize drugs, oils, botanicals and other traditional active ingredients into a silicone matrix [4]. The relatively poor miscibility of silicones with many compounds may be a key to the noted release efficiency of those same compounds from silicones.
\nSilicone pressure sensitive adhesives (PSA) are comprised of high molecular weight silanol-functional silicone polymers and silanol functional MQ siloxane resins. While a simple mixture of silicone polymer and resin can yield an adhesive with adequate peel adhesion and tack properties, sufficient cohesive strength is lacking. The silicone pressure sensitive adhesives most often used in medical applications are the product of a silanol condensation reaction between the polymer and resin components yielding a network structure, commonly referred to as standard pressure sensitive adhesives (Figure 2). These materials have suitable cohesive strength for medical device and transdermal drug delivery system applications, and upon removal from the skin the adhesive layer is removed intact. These adhesives are typically supplied in a volatile solvent which is removed during the coating process.
\nSchematic of the standard silicone PSA.
Silicone PSA have a long history of use in transdermal drug delivery systems but may also be used to attach prostheses and wound care devices. One recent innovative example of the utilization of silicone PSA in medical device attachment is the Embrace® MINIMIZE Silicone Scar Aid which consists of a silicone PSA coated onto silicone elastomer (rubber) sheeting. A unique applicator allows the dressing to be applied to relieve tension on healing skin to minimize scar formation [7, 8].
\nAnother application where silicone PSA have found wide acceptance is in the field of transdermal drug delivery. Second to the active pharmaceutical ingredient (API) or drug, the pressure-sensitive adhesive used in a transdermal drug delivery system can be viewed as the most critical component. Without proper and sustained adhesion to the skin, drug delivery from this dosage form does not occur.
\nMultiple transdermal drug delivery system (TDDS) designs are reported in the literature and are commercially available including reservoir, matrix, and drug-in-adhesive (DIA) systems; slight variants and combinations of each of these patch designs are also found. The functional requirements of the pressure sensitive adhesives in each patch design can vary with the design. (Table 1) [9, 10].
\nAdhesive functional requirement | \nPatch construction | \n||
---|---|---|---|
Matrix with rim adhesive | \nReservoir with rate controlling membrane/face adhesive | \nDrug-in-adhesive | \n|
Biocompatibility | \n+ | \n+ | \n+ | \n
Moisture resistance | \n+ | \n+ | \n+ | \n
Acceptable tack | \n+ | \n+ | \n+ | \n
Good adhesion | \n+ | \n+ | \n+ | \n
Good cohesive strength | \n+ | \n+ | \n+ | \n
Adherence to backing layer | \n+ | \n+ | \n+ | \n
Adherence to rate controlling membrane | \n\n | + | \n+ (in some cases) | \n
Compatible with drug and excipients | \n+ (in some cases) | \n+ | \n+ | \n
Permeable to drug and enhancers | \n\n | + | \n+ | \n
Cold flow resistance | \n+ (esthetic only) | \n++ | \n++ | \n
Stabilize drug and excipients | \n\n | \n | + | \n
Adhesive functional requirements for common transdermal patch designs.
Regardless of the patch design, basic requirements for the adhesive that is in direct contact with the skin include sufficient moisture resistance to stay adhered while perspiring and showering and biocompatibility (i.e., the adhesive must be non-irritating and non-sensitizing at a minimum). The adhesive must also have acceptable tack to adhere quickly on contact, good wetting behavior to achieve sufficient adhesion for the duration of wear (typically from 12 h to 7 days) and possess sufficient cohesive strength to enable removal without residual adhesive remaining on the skin. In most transdermal patch designs, the adhesive must also resist cold flow, or creep, the property of an adhesive to deform, especially at ambient temperature prior to use or at skin temperature when in use.
\nThe TDDS design with the most straightforward adhesive requirements is a matrix patch with a rim adhesive layer around the periphery of the patch. In this type of patch design, the adhesive functions are not significantly different from other device attachment applications as the adhesive must simply adhere the patch to the skin for the intended wear period. If the rim adhesive layer comes into contact with the drug loaded matrix layer, the adhesive must also be compatible with the matrix layer components. Resistance to cold flow for a rim adhesive is esthetically pleasing but does not result in unintended drug exposure or impact the drug contact surface area, so is not usually a mandatory function.
\nReservoir patch designs are typically characterized by a liquid reservoir compartment with solubilized API separated from the skin contact PSA by a semipermeable membrane. For a reservoir patch design with an adhesive layer across the face of the entire patch, the adhesive must adhere to the membrane and provide adequate adhesion to skin, as well as be compatible with the drug and allow diffusion of the drug and any penetration enhancers to the skin interface. The adhesive properties must be resilient to the drug and enhancer(s) reaching saturation in the adhesive layer.
\nIn a drug-in-adhesive (DIA) patch design, the adhesive plays an even greater role in the overall function of the patch. While this type of patch construction is clearly the easiest to manufacture, many formulation challenges exist, particularly with a monolithic (i.e., single layer) design. In addition to the requirements stated above, the adhesive matrix must also stabilize the API and excipients in either a dissolved or dispersed state, and allow controlled release of the drug and enhancers. Cold flow reduction is even more challenging in monolithic patch designs too, as they commonly require a greater adhesive coat weight than constructs that use face adhesive layers.
\nIt is unlikely that any single, off the shelf, adhesive system can meet the demands for all patch formulations and patch types. Silicone PSA, along with acrylic and polyisobutylene (PIB) PSA, are commonly used in transdermal patch applications. The end-use properties of silicone PSA (tack, adhesion, cohesive strength) can easily be modified or customized by varying the resin-to-polymer ratio, the degree of cross-linking and the residual silanol functionality during preparation. Silicone PSA are soluble in a variety of volatile polar and non-polar hydrocarbon solvents and additional customization may be achieved
Schematic of amine compatible silicone adhesives.
Silicone PSA is utilized in a variety of marketed TDDS either as the primary adhesive system or in combination with acrylic adhesives. Table 2 provides a list of commercial TDDS that utilize silicone PSA as a component of the patch construction as of the time of this publication, the respective actives, and other relevant information is also included. The table highlights the evolution of TDDS designs from the first silicone-containing reservoir patch in 1981 to recent approvals of more sophisticated microreservoir and multilayer designs that incorporate different adhesive types to achieve demanding dosage requirements.
\nDrug | \nPatch | \nMarketer | \nConstruction | \nSilicone PSA components | \n
---|---|---|---|---|
Nitroglycerin (1981) | \nTransderm-Nitro® | \nNovartis | \nReservoir | \nSilicone face adhesive layer | \n
Fentanyl (1990) | \nDuragesic® | \nJanssen Pharms | \nReservoir | \nSilicone face adhesive layer | \n
Estradiol (1996) | \nVivelle-Dot® | \nNovartis | \nMicroreservoir monolithic matrix | \nSilicone matrix adhesive continuous phase with acrylate polymer microreservoirs | \n
Nicotine (1997) | \nGeneric (OTC) | \nAveva | \nMultilayer matrix | \nSilicone matrix adhesive continuous phase with acrylate face adhesive | \n
Estradiol / Norethindrone Acetate (1998) | \nCombiPatch® | \nNoven | \nMicroreservoir monolithic matrix | \nSilicone matrix adhesive continuous phase with acrylate polymer microreservoirs | \n
Fentanyl (2005) | \nGeneric | \nMylan Technologies | \nDrug-in-adhesive monolitic | \nSilicone matrix adhesive continuous phase | \n
Fentanyl (2006) | \nGeneric | \nLavipharm Labs | \nMultilayer matrix w/ membrane | \nSilicone matrix adhesive, continuous phase and face adhesive layer | \n
Methylphenidate (2006) | \nDaytrana® | \nNoven | \nMicroreservoir monolithic matrix | \nSilicone matrix adhesive continuous phase with acrylate polymer microreservoirs | \n
Fentanyl (2007) | \nGeneric | \nActavis Labs | \nReservoir | \nSilicone face adhesive layer | \n
Fentanyl (2007) | \nGeneric | \nMayne Pharma | \nReservoir | \nSilicone face adhesive layer | \n
Rivastigmine (2007) | \nExcelon® Patch | \nNovartis | \nMultilayer matrix | \nSilicone face adhesive layer | \n
Rotigotine (2007) | \nNeupro® | \nUCB | \nMicroreservoir monolithic matrix | \nSilicone matrix adhesive continuous phase | \n
Capsaicin (2009) | \nQutenza® | \nAcorda | \nDrug-in-adhesive monolitic | \nSilicone matrix adhesive continuous phase | \n
Clonidine (2009) | \nGeneric | \nAveva | \nMultilayer matrix w/ membrane | \nSilicone matrix adhesive continuous phase with acrylate face adhesive | \n
Fentanyl (2011) | \nGeneric | \nMallinckrodt Inc | \nMultilayer matrix w/ membrane | \nSilicone matrix adhesive, continuous phase and face adhesive layer | \n
Estradiol (2012) | \nMinivelle® | \nNoven | \nMicroreservoir monolithic matrix | \nSilicone matrix adhesive continuous phase with acrylate polymer microreservoirs | \n
Estradiol (2014) | \nGeneric | \nMylan Technologies | \nMicroreservoir monolithic matrix | \nSilicone matrix adhesive continuous phase with acrylate polymer microreservoirs | \n
Commercial TDDS patches utilizing silicone PSA.
In recent years, the nomenclature for silicone PSA listed in the FDA Inactive Ingredient Database (IID) has been standardized to allow patch formulators to more easily identify prior use and maximum potency. Previously, reference to the use of silicone PSA in transdermal patches varied from a description of an adhesive laminate to numeric product codes. The preferred substance name for standard silicone adhesives is now dimethiconol/trimethylsiloxysilicate crosspolymer, and the preferred substance name for amine-compatible silicone adhesives is trimethylsilyl-treated dimethiconol/ trimethylsiloxysilicate crosspolymer. Reference is made to various types of adhesive with the addition of a nominal resin/polymer ratio [12].
\nSilicone and acrylic PSA chemistries as well as combinations of the two are commonly utilized in transdermal drug delivery [13]. The selection of the adhesive is typically drug and TDDS design specific and each adhesive type has its own advantages and disadvantages. Silicone adhesives may be more challenging during patch formulation due to the immiscibility with many drugs and common excipients in the silicone matrix; while acrylic adhesives are often easier to formulate due to the increased solubility of drugs and miscibility of excipients. However, higher drug utilization is often observed from TDDS that employ a silicone PSA over comparable patches that use an acrylic PSA [13, 14]. Yeoh [14] has provided a review of marketed fentanyl patches and has shown patches utilizing silicone adhesives have much greater fentanyl depletion during use and lower residual drug content after their intended use than comparable patches that use an acrylic adhesive. Minimizing the amount of residual drug in the patch at the end of the labeled use period, particularly with opiate drugs, is a focus of a recent FDA Guidance [15].
\nCombining silicone and acrylic pressure sensitive adhesives to form an immiscible polymer blend can provide benefits for transdermal drug delivery through selective modification of the solubility and/or diffusivity of the drug in the polymer blend matrix [16]. These micro-reservoir systems allow the drug to be solubilized in high concentrations in the discontinuous polyacrylate phase [17] and have been shown to be beneficial in decreasing patch size and required drug loading [18]. This technique has been successfully implemented in several commercial transdermal patches on the market including CombiPatch®, Daytrana® and Minivelle® (Noven Pharmaceuticals) as well as Vivelle Dot® (Novartis Pharmaceuticals) [16] A review of label claims for two patches that provide a 0.5 mg/day dose of estradiol reveals that a 5 cm2 Vivelle Dot® patch, which employs the Dot Matrix® technology, can deliver 22.4% of the drug, whereas the 12.5 cm2 Climera® with an acrylic PSA construction only delivers 9.0% of the drug [19]. These immiscible blends do have a major limitation in that they will exhibit macro phase separation in the coating mass if mixing is discontinued which may be exacerbated upon addition of other formulation ingredients such as penetration enhancers [20]. One potential means to prevent macro phase separation of the two immiscible adhesives is to covalently link the two polymer chemistries together, creating a silicone-acrylate hybrid material.
\nHybrid adhesives, in which silicone and acrylic chemistries are combined, have been described following different routes [21, 22]. One approach is the reaction product of a (meth)acrylate-functional silicone PSA and ethylenically unsaturated monomers, [21] whereas a second route toward a hybrid adhesive describes an alkoxysilyl-functional acrylic prepolymer that is further condensed or “bodied” with silicone PSA precursors (i.e., OH-functional silicate resin and OH-terminated PDMS) in the presence of a condensation catalyst [22]. These hybrid adhesives, although produced
Optical micrograph (100X magnification) of (A) 50:50 blend of silicone PSA and non-functional acrylic PSA and (B) silicone-acrylate hybrid adhesive (50% acrylate) [
Drug delivery using silicone-acrylate hybrid adhesives (SilAc I and SilAc II) differing in the ratio of high and low Tg acrylic monomers has been reported, and delivery of estradiol (Figure 5A), clonidine (Figure 5B), and ketoprofen was demonstrated across human cadaver epidermis from these matrices. The authors also noted that the use of silicone-acrylate hybrid PSA, singularly or as blends with silicone PSA resulted in a more desirable wet blend compatibility/stability than those obtained with blends [23].
\nDrug flux from silicone-acrylate hybrid PSA based patches; (A) estradiol 1.5 wt%; (B) clonidine at 1, 1.5 and 2.5 wt%; [
Due to the inherent immiscibility of silicone and acrylate polymers, the hybrid adhesives contain micro-domains which can be observed using transmission electron microscopy (TEM) as presented in Figure 6. Further analysis of the phase behavior reveals the ability to selectively control the domain arrangement (i.e., silicone-in-acrylate or acrylate-in-silicone) of these materials by the choice of casting solvent, with the phase having the highest affinity with the casting solvent remaining external, (i.e., heptane casting solvent exhibiting a silicone continuous phase and polyacrylate discontinuous phase (Figure 6A) or
Transmission electron micrograph of silicone-acrylate hybrid adhesive films, silicone phase appears dark due to the electron density (A) cast from heptane and (B) cast from ethyl acetate.
The selective control of the phase arrangement provides potential options for tuning both the adhesive properties as well as tailored drug release profiles as illustrated in Figure 7.
\nIllustration of silicone-acrylate hybrid adhesive microstructure and potential impact on drug solubility and release.
The impact of casting solvent and silicone content on the material properties has been conducted using a dynamic rheometer (Figure 8A). Blends of silicone PSA and silicone-acrylate hybrid PSA (nominally 50% silicone) were prepared in either heptane or ethyl acetate to yield a range of materials. For materials delivered from ethyl acetate, between 76% and 78% silicone, a precipitous change in tan delta is observed followed by incremental decrease as the silicone content rises. Tan delta is a rheological property that approximates the internal friction of a material. When tan delta is greater than one, a material is more viscous than elastic, and when it is less than one it is more elastic than viscous. TEM analysis suggests this is the result of phase inversion when the silicone becomes the external phase. This change is not observed for materials delivered from heptane as the silicone remains the external phase over the entire range. Films containing either 1.0 wt% estradiol (Figure 8B), 2.5 wt% ibuprofen (Figure 8C), or 2.5 wt% lidocaine (Figure 8D) were prepared using blends of hybrid PSA with silicone PSA to investigate the impact of phase arrangement on the release behavior. All three API demonstrate a change in drug release characteristics between 75 and 80% silicone content, which is where rheology suggests the phase inversion occurs [24].
\nRheology and drug release as a function of silicone content and dispersion solvent; (A) tan delta of the adhesive matrix; (B) estradiol (E2) 6 h cumulative release; (C) ibuprofen (IBU) 1 h cumulative release; (D) lidocaine (Lido) 1 h cumulative release [
The characterization of PSA materials is a critical part of innovation development and production quality control. Historically, tape properties such as peel adhesion, shear and tack have been used to characterize the performance of pressure sensitive adhesives targeted for transdermal applications. However, these tests often have high variability resulting in wide specification limits and poor correlation of test data with adhesive performance in real life applications [25]. Furthermore, tape property tests can be substrate dependent. That is to say, they are influenced by the substrate on which the PSA is coated and also by the substrate on which the adhesive performance is measured. Despite the drawbacks of tape property testing, they are still commonplace and so, warrant some discussion.
\nPeel tests are well described in the literature and are common to the majority of adhesives. The peel test typically occurs at 90o or 180° and the force to remove the adhesive from a substrate (e.g., stainless steel in many cases) is measured. In the case of silicone PSA, the typical adhesive thickness tested is relatively thin, commonly between two and five mil (approximately 51–127 micron). A distinction between peel adhesion and tack of an adhesive is often made. From an analytical test perspective, the distinction between peel adhesion and tack measurements is the time allowed for the adhesive to bond with the substrate. When measuring tack, the measurement is taken almost instantaneously after the adhesive comes in contact with the test substrate, whereas peel adhesion is measured after the adhesive is left in contact with the substrate for a longer time period. The time between application and testing allows the adhesive to wet out on the surface and the adhesion to build.
\nShear testing may have greater relevance to skin contact adhesive applications than the aforementioned peel adhesion and tack tests. Since PSA are condensed materials that have the ability to flow, the extent of cold flow must be characterized to fully understand and anticipate the surface area of adhesive in contact with skin, which can impact the amount of drug delivered from a transdermal patch. Shear tests of fully formulated adhesive matrices may be even more relevant to the performance of the final TDDS. If the skin/adhesive interface changes over time, the transdermal drug diffusion will also change. Typically, a shear test is the measurement of the time for the adhesive to detach from a surface (e.g., stainless steel) under a constant weight.
\nThe advantages of tape property test methodology include ease of set up, reproducibility and a straightforward interpretation of data. However, drawbacks including the considerable influence adhesive coating thickness has on the test, the influence of the substrate on which the adhesive is coated, and the surface on which the test is conducted must also be rationalized. To minimize these influences, there must be accurate control of adhesive thickness and standardization of substrates and test surfaces.
\nAlthough tape property testing may qualitatively predict how quickly a system may bond to a substrate, the extent to which the adhesive resists cold flow, and how much force may be needed to remove it, and perhaps most importantly, the wear performance of the system may not be adequately addressed using classical characterization techniques. In order to better understand and predict the wear performance of transdermal systems, rheology is often used to understand the adhesive bulk viscoelastic behavior. [26] Rheological characterization allows the analyst to overcome the inherent uncertainty linked to peel, tack and shear tests by minimizing the influence of sample preparation and substrate variability on adhesive characterization results. Rheology is a technique to characterize viscoelastic properties of polymers and also predict wear performance of pressure sensitive adhesives. As shown below in Figure 9, a typical rheological curve can be correlated to tape properties [27, 28, 29, 30].
\nA schematic representation of the link between the rheological profile and the final pressure sensitive (PSA) wear performance [
Data have shown that for viscoelastic materials, such as silicone pressure sensitive adhesives, frequency sweep curves are sensitive to structural differences (e.g., crosslink density) and formulation changes (e.g., resin-to-polymer ratio). This sensitivity provides a means to identify, characterize and predict adhesive wear performance [26].
\nStorage modulus (G′) is an indicator of how elastic the adhesive is and how much energy is stored during deformation, while the loss modulus (G″) indicates the viscous component of the PSA and how much energy is lost as heat, while complex viscosity (η*) is an indicator of the adhesive bulk viscosity and can be related to the cold flow [25]. Bonding of a transdermal system occurs at a low deformation rate, and is dependent on the wetting behavior of the adhesive when it comes into contact with skin [26]. Rheologically, the storage modulus, G′, values at low frequency may be used for predicting wetting and creep (cold flow) resistance. Optimum wetting occurs when the adhesive modulus is low. Subsequently, debonding of a transdermal system occurs at high deformation rates [26].
\nRheologically, the storage modulus, G′, and loss modulus, G″, at high frequency may be related to the peel adhesion and quick stick (i.e., tack) properties of an adhesive and the subsequent TDDS [31, 32]. For bonding, the viscous contribution should be higher than the elastic contribution to the PSA viscoelastic profile. In rheological terms, this means that at low frequencies, G′ < G″ and the opposite for the debonding step, represented at high frequencies where G′ should be equal to or higher than G″. Based on this interpretation, the rheological traces in Figure 10 suggest that the increase of resin content should lead to reduced cold flow (i.e., an increase of the complex viscosity with resin content) and an increase of the adhesion strength (i.e., increase of both G′ and G″ with resin content). Dynamic frequency sweeps (0.01–100 rad/s) were conducted on dried adhesive solids using a TA ARES-G2 rheometer. The adhesives with high and medium resin content were tested using 8 mm parallel plates, at 0.35% and 0.5% strain respectively. The adhesive with low resin content was tested using 25 mm plates, at 0.5% strain. All samples were tested at 30°C with a 1.5 mm gap.
\nTypical frequency sweeps of silicone PSA at three common resin contents.
In the early 1990s, E.P. Chang developed a theory to interpret rheological data of pressure sensitive adhesives and establish criteria for PSA classification when used in conjunction with the Dahlquist’s criteria [33]. This theory is now well known as “Chang viscoelastic window.” As depicted in Figure 11, a G′ vs. G″ graph, is divided into four quadrants with a central axis. The location of the analyzed PSA within this graph allows a straightforward extrapolation from rheological properties to real-world adhesion performance. For example, the top right hand quadrant corresponds to high modulus and high dissipation. Therefore, materials in this quadrant with characteristically high G′ modulus compensated by the high G″ are anticipated to be adhesive materials with high adhesion but low tack and high shear resistance. Conversely, the bottom left quadrant corresponds to low modulus and low dissipation; these materials, are anticipated to exhibit low peel values because of the comparatively low debonding cohesive strength and low dissipation.
\nChang viscoelastic window concept adapted for low resin content silicone pressure sensitive adhesive (PSA) with differing amounts of isopropyl myristate (IPM) [
Changes in the Chang viscoelastic window, of a typical low resin content silicone PSA can be observed as differing amounts of a commonly used permeation enhancer, isopropyl myristate (IPM), are added (Figure 11) [34]. The Chang viscoelastic window of the neat adhesive moves from the upper right quadrant to the lower left quadrant as more IPM is added. The lowermost edge of the window which is linked to bonding of the adhesive is far below Dahlquist’s criteria, so the adhesive would be expected to have reasonable tack. There is a significant shift in the position of the upper right corner as IPM content increases which is linked to debonding (peel) efficiency suggesting that an increase of IPM content decreases peel efficiency [34]. Finally, the window size increase indicates a decrease of the PSA shear strength likely due to better solvent compatibility in the PSA. These data coincide with observed changes in adhesive properties as plasticizing agents like IPM are added and support the further use of rheological measurements to characterize changes in wear properties.
\nSilicones have more than 30 year history of safety and efficacy in advanced wound care applications. Much of the success of silicones in wound care is due to an adhesive technology referred to in the literature by many names including soft skin adhesives (SSA), tacky gels, silicone gels and silicone tacky gels among others [35]. The technology was introduced to the wound care market by Dow Corning Corporation in the 1990s and similar materials are offered today by many silicone suppliers under a variety of brand names [36, 37, 38]. In a segment that was historically controlled primarily by acrylic adhesives, the tacky gel technology concept was disruptive by securing wound dressings while providing gentle adhesion upon removal. SSAs have become the material of choice in many advanced wound care applications, due to their reliable adhesiveness, while being easier to remove and causing less pain than many other adhesive technologies of the day.
\nSSAs are based on a polydimethylsiloxane network which supports the critical adhesive attributes required for securing the device in place and removing it without leaving residue or damaging the skin. Unlike silicone PSAs that build their adhesiveness on a viscous phase bodied with a silicate resin, SSAs are based on the silicone elastomer technology modified to deliver the relevant visco-elastic profile. They also differ from analogous silicone elastomers (e.g., liquid silicone rubber (LSR) technology) by the absence of reinforcing silica filler. As a result, they have a similar consistency to gels, but SSAs are not a typical polymeric gel because they are not based on an insoluble polymer network swollen with fluids. The visco-elastic behavior of SSA also differs from silicone PSA, despite their low consistency and a high degree of compressibility, SSAs show resilience and quick recovery under cyclic deformation [35].
\nThe pressure sensitive adhesive property of SSAs are based on the capacity of the elastomer surface to quickly wet the skin and conform to skin irregularities without an additional compression step as required for a silicone PSA [35]. Thanks to the low intensity of the viscous component of the SSA rheological profile, the adhesive does not flow significantly, and very little dissipation of the energy occurs when deformation pressure is applied to the SSA. As a result, SSA debonding happens at low peel force, without skin stripping and painful skin pulling when the adhesive device is removed. Being elastomeric by nature, SSAs have a low viscous component that limits their flow and consequently the ability to pick up materials on or from the surface of the skin [35]. Therefore, unlike silicone PSA, the adhesive surface of SSAs remain relatively clean upon removal from the skin, allowing for removal and easy reapplication of the dressing or device to the skin, making wound dressing repositioning possible.
\nThe elastomeric structure of SSAs is obtained by cross-linking a network of polydimethylsiloxane (PDMS). The reaction is based on an addition reaction (hydrosilylation) between vinyl functional PDMS (polymer) and hydrogen functional siloxanes (cross-linker) as shown in Figure 12. The cure reaction is catalyzed by a platinum complex, which can occur at room temperature or be accelerated at elevated temperature (80–145°C), without the formation of reaction by-products [35]. As thermoset materials, SSAs have a low susceptibility to cold flow and plasticizing effects.
\nTypical hydrosilylation reaction schematic.
The SSA technology has been extensively used in scar treatment and advanced wound management, demonstrating safety and efficacy recognized by wound care professionals [35]. The use of SSA may be recommended when designing medical adhesive devices, tapes, bandages, drapes, and wound dressings and have been noted for the many benefits including high tack for quick bonding to skin, reliable adhesiveness and cohesiveness, gentle adhesion to fragile and compromised skin, no skin stripping and pain-free removal of the device, as well as permeability to moisture and gases (e.g., CO2, O2) [35].
\nSSAs are supplied as two-part systems with the catalyst in one part and the cross-linker in the other. The materials are characteristically transparent before and after curing into a solid matrix. They are typically processed by mixing the two parts and coating the mixture directly onto the final substrate (i.e., backing film), understanding that this film must be impermeable enough to prevent the uncured liquid SSA from wicking through. The typical coat weight for SSA can vary widely depending on the desired final properties, but often range between 150 and 250 g/m2. The curing phase is typically completed at elevated temperature adjusted according to the temperature sensitivity of the substrate. After cooling, the adhesive surface is protected by a release liner which is peeled off when the end user applies the adhesive to skin.
\nSubstrate selection is important when designing an adhesive device based on SSA, as the nature of the substrate can significantly impact the coating and cure conditions during the manufacturing phase. The anchorage of the adhesive to the substrate and the cohesion of the adhesive after cure, as well as the ultimate wear behavior of the device when applied to the body can all be impacted by the substrate selection.
\nThe choice of release liner is also a critical factor as it can affect the device stability, making it unusable if this protective film cannot be easily removed from the adhesive prior to use. Traditional silicone release liners that are used ubiquitously with acrylic adhesives cannot be used with SSA as the silicone release liner chemistry is similar enough to SSA that they are highly likely to interact and experience an irreversible lock-up effect upon storage. However, uncoated polyethylene films, especially LDPE (low density polyethylene) grade, can provide an acceptably low and reasonably consistent release force from the SSA [39].
\nNew SSA technology are being developed that can achieve higher adhesion and longer wear times as well as improved drug compatibility to address emerging medical system market trends including wearable devices and topical drug delivery patches [35]. The use of SSA technology to formulate drug delivery matrices enables drug delivery system designs which address the needs for secure and gentle fixation to fragile, sensitive or compromised skin conditions common in dermatology, wound care, pediatrics and gerontology. Several studies were conducted to evaluate the compatibility of various drugs and their release from SSA matrices. A variety of API have been studied including those indicated for pain relief and local anesthesia, antibiotics, and dermatological actives [39]. Wound care products that utilize silicone tacky gels as the skin contact adhesive and are loaded with chlorhexidine gluconate and other antimicrobial agents have also been investigated [40]. This may signal further interest in the utilization of SSA in even more advanced active-loaded therapies in addition to the traditional wound therapies where it has been used historically.
\nMany of the analytical techniques used to characterize silicone PSA have been modified to characterize the SSA materials, although shear tests are less emphasized for SSA due to the characteristically low cohesion of the SSA. In addition to adhesive peel measurements, the measurement of the softness of the SSA by penetration test is often performed. Over a broad range, the penetration measurement shows correlation to adhesion performance values within a formulation type and is linked to the adhesive network chemistry; therefore, it is often used as a quality control measurement.
\nPeel tests are commonly used in the adhesive industry, because for many applications these relatively easy to perform tests fit well with the final application of the adhesive. The substrates upon which most adhesives are tested to evaluate adhesive strength (e.g., stainless steel) often are not predictive of the relative strength SSA will exhibit in practice on skin. Therefore, some users have resorted to using substrates that have a surface energy more similar to that of skin as the test substrate for SSA. The number and diverse composition of substrates including plastic films, paper and even artificial skin materials, make standardization across the industry difficult, and comparison between users problematic. Testing is conducted similarly to that described for PSA, with the SSA typically being cast and cured at a consistent thickness directly onto a film. This substrate may influence the peel adhesion result due to its intrinsic elasticity and also potentially through interactions with the SSA. The gel on the backing substrate is then applied on a test substrate, taking care to apply the adhesive with a constant force. After a designated equilibration time, the adhesive is peeled from the substrate, typically at a 180° angle, and the force required to remove it is measured.
\nWhile this method provides relative adhesion strength, allowing comparison of adhesive values, the results may be significantly influenced by the backing substrate, as well as the test substrate used, so the results do not necessarily simulate the application of the adhesive to skin.
\nRheological measurements have been developed and used for decades to characterize silicone PSA and provide more realistic predictions of real-world adhesive performance than classical peel tests are capable of providing. Recently, similar rheological measurements have been applied to characterize the intrinsic properties of the SSA and offer a characterization method more capable of harmonization across the industry. The SSA rheological characterization is performed on free standing gels and is able to characterize the adhesive properties without the influence of backing or test substrates unlike the aforementioned adhesion tests. SSAs may be characterized in dynamic oscillation modes, using strain and frequency sweeps to measure the viscoelastic characteristics (e.g., storage modulus, G′ and loss modulus, G″). Different SSA, which exhibit significant differences with respect to adhesion can also be discriminated using rheological analysis. Identifying the true viscoelastic properties of the adhesives is critical to understand the adhesion performance of such products. Using the data generated from the rheometer, it is possible to correlate viscoelastic properties to adhesion, and to better understand structure-property relationships.
\nTo understand the rheological characteristics of this material one must identify the linear viscoelastic (LVE) zone by submitting the sample to an oscillatory strain sweep analysis. In the LVE zone, the elastic modulus (G′) and the loss modulus (G″) are independent of the shear strain, indicating that within this strain zone, the response of the material does not depend on the strain applied, and there are no modifications of the material structure. In the LVE zone identification test, the strain is the only parameter which varies, all other parameters, (e.g., temperature and oscillation frequency) are fixed. The LVE graph for the SSA exhibits a large linear viscoelastic zone from 0.5 to 30% logarithmic strain, providing some flexibility to set the strain when performing the frequency sweep at a fixed strain is the next step of the measurement process. Knowing the LVE zone of the material allows one to carry out the second phase of the rheological evaluation, the oscillatory frequency sweep test. Previously unreported data is shown to elucidate this concept in Figure 13. Samples were prepared by weighing equal amounts (±2%) of the two parts of the SSA and mixed to ensure homogeneity and then were degassed in a vacuum chamber. The mixed, uncured SSA was coated onto a polytetrafluoroethylene (PTFE) film at a thickness of 0.9 mm, and placed in a forced air oven at a temperature of 130°C for 4 min to cure the SSA. The cured laminate was removed from the oven and allowed to cool to ambient temperature. A second PTFE film was applied using a 6.8 kg (15 lb.) rubber coated roller to ensure complete and consistent contact between SSA and PTFE. The film was allowed to rest for 24 h after which a disc was cut from the SSA laminate using a 24 mm stainless steel punch. Dynamic frequency sweeps (1–100 rad/s) were conducted on SSA with a TA ARES-G2 rheometer at 32°C using 25 mm stainless steel parallel plates and a gap of 0.5 mm with a 10% strain (in the linear viscoelastic region). Data collection was set for 5 pts./decade.
\nFrequency sweep of three typical SSA.
The frequency sweep test is the most suitable rheological test to assess SSA adhesive properties in the final application. The viscoelastic behavior at low frequencies is related to the bonding step which occurs at low deformation rates and is linked to the SSA ability to wet the surface. Alternatively, the viscoelastic behavior at high frequencies is related to debonding (peel) which occurs at high deformation rates and is linked to the elasticity and energy dissipation during the removal. SSAs with varying adhesive levels can be effectively discriminated based on their rheological profiles. The rheological characterization agrees with the results experienced by skin adhesion, where adhesives with higher G′ and G″ provide higher skin adhesion.
\nThis rheology methodology should be an effective tool and a suitable starting point to understand the structure-property relationships of the SSA technology. It should also provide a means to separate the innate adhesive performance from the influences of substrates. Understanding the relationships between the SSA chemistry, adhesion and rheological profiles will provide key and essential information on structure-property relationships to push the boundaries of SSA even further.
\nSilicone adhesives have been safely and effectively used in a variety of medical applications and are notably present in drug delivery and wound care applications because of the unique benefits and properties provided. Continued investigation has resulted in recent, innovative product developments using established silicone adhesive technologies including innovative TDDS designs, wound care devices that prevent scar formation and those that are loaded with antimicrobial actives. Adhesive chemistry research has resulted in novel chemistries that combine seemingly incompatible acrylate and silicone adhesive technologies, whereas advances in measurement techniques have brought about clearer understanding of adhesive structure property relationships, avoiding many pitfalls experienced by previous researchers. Despite being used for several decades, the number and variety of recent developments suggest that identifying new medical applications of silicone adhesives remains relevant and the extent to which it may be used has not yet been tapped.
\nThe authors wish to acknowledge the following without whom this work would not have been possible; Chana Evans, Dave Gantner, Roger Gibas, Tim Mitchell, and Audrey Wipret. We would also like to acknowledge the work of Dr. Meng Gu and the microscopy team at The Dow Chemical Analytical Department for their assistance and collaboration.
\nThe Edited Volume, also known as the IntechOpen Book, is an IntechOpen pioneered publishing product. Edited Volumes make up the core of our business - and as pioneers and developers of this Open Access book publishing format, we have helped change the way scholars and scientists publish their scientific papers - as scientific chapters.
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\n\nCURRENT PROJECTS
\n\nTo view current Open Access book projects that are Open for Submissions visit us here.
\n\nNot sure if this is the right publishing option for you? Feel free to contact us at book.department@intechopen.com.
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Generally, the phytochemical constituents of plants fall into two categories based on their role in basic metabolic processes, namely primary and secondary metabolites. Primary plant metabolites are involved in basic life functions; therefore, they are more or less similar in all living cells. On the other hand, secondary plant metabolites are products of subsidiary pathways as the shikimic acid pathway. In the course of studying, the medicinal effect of herbals is oriented towards the secondary plant metabolites. Secondary plant metabolites played an important role in alleviating several aliments in the traditional medicine and folk uses. In modern medicine, they provided lead compounds for the production of medications for treating various diseases from migraine up to cancer. Secondary plant metabolites are classified according to their chemical structures into various classes. In this chapter, we will be presenting various classes of secondary plant metabolites, their distribution in different plant families and their important medicinal uses.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]},{id:"64851",doi:"10.5772/intechopen.80348",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:14206,totalCrossrefCites:30,totalDimensionsCites:52,abstract:"African traditional medicine is a form of holistic health care system organized into three levels of specialty, namely divination, spiritualism, and herbalism. The traditional healer provides health care services based on culture, religious background, knowledge, attitudes, and beliefs that are prevalent in his community. Illness is regarded as having both natural and supernatural causes and thus must be treated by both physical and spiritual means, using divination, incantations, animal sacrifice, exorcism, and herbs. Herbal medicine is the cornerstone of traditional medicine but may include minerals and animal parts. The adjustment is ok, but may be replaced with –‘ Herbal medicine was once termed primitive by western medicine but through scientific investigations there is a better understanding of its therapeutic activities such that many pharmaceuticals have been modeled on phytochemicals derived from it. Major obstacles to the use of African medicinal plants are their poor quality control and safety. Traditional medical practices are still shrouded with much secrecy, with few reports or documentations of adverse reactions. However, the future of African traditional medicine is bright if viewed in the context of service provision, increase of health care coverage, economic potential, and poverty reduction. Formal recognition and integration of traditional medicine into conventional medicine will hold much promise for the future.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ezekwesili-Ofili",slug:"josephine-ezekwesili-ofili",fullName:"Josephine Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"54028",doi:"10.5772/67291",title:"Chemical Composition and Biological Activities of Mentha Species",slug:"chemical-composition-and-biological-activities-of-mentha-species",totalDownloads:7474,totalCrossrefCites:13,totalDimensionsCites:46,abstract:"The genus Mentha L. (Lamiaceae) is distributed all over the world and can be found in many environments. Mentha species, one of the world’s oldest and most popular herbs, are widely used in cooking, in cosmetics, and as alternative or complementary therapy, mainly for the treatment of gastrointestinal disorders like flatulence, indigestion, nausea, vomiting, anorexia, and ulcerative colitis. Furthermore, it is well documented that the essential oil and extracts of Mentha species possess antimicrobial, fungicidal, antiviral, insecticidal, and antioxidant properties. The economic importance of mints is also evident; mint oil and its constituents and derivatives are used as flavoring agents throughout the world in food, pharmaceutical, herbal, perfumery, and flavoring industry. To provide a scientific basis for their traditional uses, several studies have been conducted to determine the chemical composition of mints and assess their biological activities. This chapter describes the therapeutic effects and uses of Mentha species and their constituents, particularly essential oils and phenolic compounds; some additional biological activities will also be considered.",book:{id:"5612",slug:"aromatic-and-medicinal-plants-back-to-nature",title:"Aromatic and Medicinal Plants",fullTitle:"Aromatic and Medicinal Plants - Back to Nature"},signatures:"Fatiha Brahmi, Madani Khodir, Chibane Mohamed and Duez Pierre",authors:[{id:"193281",title:"Dr.",name:"Fatiha",middleName:null,surname:"Brahmi",slug:"fatiha-brahmi",fullName:"Fatiha Brahmi"},{id:"199693",title:"Prof.",name:"Khodir",middleName:null,surname:"Madani",slug:"khodir-madani",fullName:"Khodir Madani"},{id:"199694",title:"Prof.",name:"Pierre",middleName:null,surname:"Duez",slug:"pierre-duez",fullName:"Pierre Duez"},{id:"203738",title:"Prof.",name:"Mohamed",middleName:null,surname:"Chibane",slug:"mohamed-chibane",fullName:"Mohamed Chibane"}]},{id:"58270",doi:"10.5772/intechopen.72437",title:"Toxicity and Safety Implications of Herbal Medicines Used in Africa",slug:"toxicity-and-safety-implications-of-herbal-medicines-used-in-africa",totalDownloads:3376,totalCrossrefCites:16,totalDimensionsCites:39,abstract:"The use of herbal medicines has seen a great upsurge globally. In developing countries, many patronize them largely due to cultural acceptability, availability and cost. In developed countries, they are used because they are natural and therefore assumed to be safer than allopathic medicines. In recent times, however, there has been a growing concern about their safety. This has created a situation of ambivalence in discussions regarding their use. Some medicinal plants are intrinsically toxic by virtue of their constituents and can cause adverse reactions if inappropriately used. Other factors such as herb-drug interactions, lack of adherence to good manufacturing practice (GMP), poor regulatory measures and adulteration may also lead to adverse events in their use. Many in vivo tests on aqueous extracts largely support the safety of herbal medicines, whereas most in vitro tests on isolated single cells mostly with extracts other than aqueous ones show contrary results and thus continue the debate on herbal medicine safety. It is expected that toxicity studies concerning herbal medicine should reflect their traditional use to allow for rational discussions regarding their safety for their beneficial use. While various attempts continue to establish the safety of various herbal medicines in man, their cautious and responsible use is required.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Merlin L.K. Mensah, Gustav Komlaga, Arnold D. Forkuo, Caleb\nFirempong, Alexander K. Anning and Rita A. Dickson",authors:[{id:"190435",title:"Dr.",name:"Caleb",middleName:null,surname:"Firempong",slug:"caleb-firempong",fullName:"Caleb Firempong"},{id:"212111",title:"Dr.",name:"Gustav",middleName:null,surname:"Komlaga",slug:"gustav-komlaga",fullName:"Gustav Komlaga"},{id:"217045",title:"Dr.",name:"Arnold Forkuo",middleName:null,surname:"Donkor",slug:"arnold-forkuo-donkor",fullName:"Arnold Forkuo Donkor"},{id:"217049",title:"Prof.",name:"Merlin Lincoln Kwao",middleName:null,surname:"Mensah",slug:"merlin-lincoln-kwao-mensah",fullName:"Merlin Lincoln Kwao Mensah"},{id:"217488",title:"Dr.",name:"Alexander K.",middleName:null,surname:"Anning",slug:"alexander-k.-anning",fullName:"Alexander K. Anning"},{id:"223959",title:"Prof.",name:"Akosua Rita",middleName:null,surname:"Dickson",slug:"akosua-rita-dickson",fullName:"Akosua Rita Dickson"}]},{id:"26489",doi:"10.5772/28224",title:"Alternative and Traditional Medicines Systems in Pakistan: History, Regulation, Trends, Usefulness, Challenges, Prospects and Limitations",slug:"alternative-and-traditional-medicines-systems-in-pakistan-history-regulation-trends-usefulness-chall",totalDownloads:9199,totalCrossrefCites:9,totalDimensionsCites:21,abstract:null,book:{id:"542",slug:"a-compendium-of-essays-on-alternative-therapy",title:"A Compendium of Essays on Alternative Therapy",fullTitle:"A Compendium of Essays on Alternative Therapy"},signatures:"Shahzad Hussain, Farnaz Malik, Nadeem Khalid, Muhammad Abdul Qayyum and Humayun Riaz",authors:[{id:"73162",title:"Dr.",name:"Shahzad",middleName:null,surname:"Hussain",slug:"shahzad-hussain",fullName:"Shahzad Hussain"},{id:"82266",title:"Dr.",name:"Farnaz",middleName:null,surname:"Malik",slug:"farnaz-malik",fullName:"Farnaz Malik"},{id:"124185",title:"Dr.",name:"Humayun",middleName:null,surname:"Riaz",slug:"humayun-riaz",fullName:"Humayun Riaz"},{id:"124186",title:"Mr.",name:"Muhammad Abdul",middleName:null,surname:"Qayyum",slug:"muhammad-abdul-qayyum",fullName:"Muhammad Abdul Qayyum"},{id:"125340",title:"Mr.",name:"Nadeem",middleName:null,surname:"Khalid",slug:"nadeem-khalid",fullName:"Nadeem Khalid"}]}],mostDownloadedChaptersLast30Days:[{id:"64851",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:14207,totalCrossrefCites:30,totalDimensionsCites:52,abstract:"African traditional medicine is a form of holistic health care system organized into three levels of specialty, namely divination, spiritualism, and herbalism. The traditional healer provides health care services based on culture, religious background, knowledge, attitudes, and beliefs that are prevalent in his community. Illness is regarded as having both natural and supernatural causes and thus must be treated by both physical and spiritual means, using divination, incantations, animal sacrifice, exorcism, and herbs. Herbal medicine is the cornerstone of traditional medicine but may include minerals and animal parts. The adjustment is ok, but may be replaced with –‘ Herbal medicine was once termed primitive by western medicine but through scientific investigations there is a better understanding of its therapeutic activities such that many pharmaceuticals have been modeled on phytochemicals derived from it. Major obstacles to the use of African medicinal plants are their poor quality control and safety. Traditional medical practices are still shrouded with much secrecy, with few reports or documentations of adverse reactions. However, the future of African traditional medicine is bright if viewed in the context of service provision, increase of health care coverage, economic potential, and poverty reduction. Formal recognition and integration of traditional medicine into conventional medicine will hold much promise for the future.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ezekwesili-Ofili",slug:"josephine-ezekwesili-ofili",fullName:"Josephine Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"61866",title:"Plants Secondary Metabolites: The Key Drivers of the Pharmacological Actions of Medicinal Plants",slug:"plants-secondary-metabolites-the-key-drivers-of-the-pharmacological-actions-of-medicinal-plants",totalDownloads:8875,totalCrossrefCites:56,totalDimensionsCites:140,abstract:"The vast and versatile pharmacological effects of medicinal plants are basically dependent on their phytochemical constituents. Generally, the phytochemical constituents of plants fall into two categories based on their role in basic metabolic processes, namely primary and secondary metabolites. Primary plant metabolites are involved in basic life functions; therefore, they are more or less similar in all living cells. On the other hand, secondary plant metabolites are products of subsidiary pathways as the shikimic acid pathway. In the course of studying, the medicinal effect of herbals is oriented towards the secondary plant metabolites. Secondary plant metabolites played an important role in alleviating several aliments in the traditional medicine and folk uses. In modern medicine, they provided lead compounds for the production of medications for treating various diseases from migraine up to cancer. Secondary plant metabolites are classified according to their chemical structures into various classes. In this chapter, we will be presenting various classes of secondary plant metabolites, their distribution in different plant families and their important medicinal uses.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]},{id:"77433",title:"Extraction of Bioactive Compounds from Medicinal Plants and Herbs",slug:"extraction-of-bioactive-compounds-from-medicinal-plants-and-herbs",totalDownloads:1266,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Human beings have relied on herbs and medicinal plants as sources of food and remedy from time immemorial. Bioactive compounds from plants are currently the subject of much research interest, but their extraction as part of phytochemical and/or biological investigations present specific challenges. Herbalists or scientists have developed many protocols of extraction of bioactive ingredients to ensure the effectiveness and the efficacy of crude drugs that were used to get relief from sickness. With the advent of new leads from plants such as morphine, quinine, taxol, artemisinin, and alkaloids from Voacanga species, a lot of attention is paid to the mode of extraction of active phytochemicals to limit the cost linked to the synthesis and isolation. Thus, the extraction of active compounds from plants needs appropriate extraction methods and techniques that provide bioactive ingredients-rich extracts and fractions. The extraction procedures, therefore, play a critical role in the yield, the nature of phytochemical content, etc. This chapter aims to present, describe, and compare extraction procedures of bioactive compounds from herbs and medicinal plants.",book:{id:"10356",slug:"natural-medicinal-plants",title:"Natural Medicinal Plants",fullTitle:"Natural Medicinal Plants"},signatures:"Fongang Fotsing Yannick Stéphane, Bankeu Kezetas Jean Jules, Gaber El-Saber Batiha, Iftikhar Ali and Lenta Ndjakou Bruno",authors:[{id:"224515",title:"Dr.",name:"Fongang Fotsing",middleName:null,surname:"Yannick Stéphane",slug:"fongang-fotsing-yannick-stephane",fullName:"Fongang Fotsing Yannick Stéphane"},{id:"227816",title:"Dr.",name:"Bankeu Kezetas",middleName:null,surname:"Jean Jules",slug:"bankeu-kezetas-jean-jules",fullName:"Bankeu Kezetas Jean Jules"},{id:"227817",title:"Prof.",name:"Lenta Ndjakou",middleName:null,surname:"Bruno",slug:"lenta-ndjakou-bruno",fullName:"Lenta Ndjakou Bruno"},{id:"349790",title:"Prof.",name:"Gaber",middleName:null,surname:"El-Saber Batiha",slug:"gaber-el-saber-batiha",fullName:"Gaber El-Saber Batiha"},{id:"357350",title:"Dr.",name:"Iftikhar",middleName:null,surname:"Ali",slug:"iftikhar-ali",fullName:"Iftikhar Ali"}]},{id:"26491",title:"Homeopathy: Treatment of Cancer with the Banerji Protocols",slug:"homeopathy-treatment-of-cancer-with-the-banerji-protocols",totalDownloads:54048,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"542",slug:"a-compendium-of-essays-on-alternative-therapy",title:"A Compendium of Essays on Alternative Therapy",fullTitle:"A Compendium of Essays on Alternative Therapy"},signatures:"Prasanta Banerji and Pratip Banerji",authors:[{id:"79939",title:"Dr",name:"Prasanta",middleName:null,surname:"Banerji",slug:"prasanta-banerji",fullName:"Prasanta Banerji"},{id:"79943",title:"Dr.",name:"Pratip",middleName:null,surname:"Banerji",slug:"pratip-banerji",fullName:"Pratip Banerji"}]},{id:"54028",title:"Chemical Composition and Biological Activities of Mentha Species",slug:"chemical-composition-and-biological-activities-of-mentha-species",totalDownloads:7474,totalCrossrefCites:13,totalDimensionsCites:46,abstract:"The genus Mentha L. (Lamiaceae) is distributed all over the world and can be found in many environments. Mentha species, one of the world’s oldest and most popular herbs, are widely used in cooking, in cosmetics, and as alternative or complementary therapy, mainly for the treatment of gastrointestinal disorders like flatulence, indigestion, nausea, vomiting, anorexia, and ulcerative colitis. Furthermore, it is well documented that the essential oil and extracts of Mentha species possess antimicrobial, fungicidal, antiviral, insecticidal, and antioxidant properties. The economic importance of mints is also evident; mint oil and its constituents and derivatives are used as flavoring agents throughout the world in food, pharmaceutical, herbal, perfumery, and flavoring industry. To provide a scientific basis for their traditional uses, several studies have been conducted to determine the chemical composition of mints and assess their biological activities. This chapter describes the therapeutic effects and uses of Mentha species and their constituents, particularly essential oils and phenolic compounds; some additional biological activities will also be considered.",book:{id:"5612",slug:"aromatic-and-medicinal-plants-back-to-nature",title:"Aromatic and Medicinal Plants",fullTitle:"Aromatic and Medicinal Plants - Back to Nature"},signatures:"Fatiha Brahmi, Madani Khodir, Chibane Mohamed and Duez Pierre",authors:[{id:"193281",title:"Dr.",name:"Fatiha",middleName:null,surname:"Brahmi",slug:"fatiha-brahmi",fullName:"Fatiha Brahmi"},{id:"199693",title:"Prof.",name:"Khodir",middleName:null,surname:"Madani",slug:"khodir-madani",fullName:"Khodir Madani"},{id:"199694",title:"Prof.",name:"Pierre",middleName:null,surname:"Duez",slug:"pierre-duez",fullName:"Pierre Duez"},{id:"203738",title:"Prof.",name:"Mohamed",middleName:null,surname:"Chibane",slug:"mohamed-chibane",fullName:"Mohamed Chibane"}]}],onlineFirstChaptersFilter:{topicId:"991",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"June 20th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",isOpenForSubmission:!0,editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}},editorThree:null},{id:"13",title:"Plant Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",isOpenForSubmission:!0,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/332229/images/system/332229.png",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung, Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture. 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