Transdermal Drug Delivery Systems (TDDDs) PDF

Pharmaceutical Technology-II Transdermal Drug Delivery Systems (TDDDs) Assoc. Prof. Dr. Muhammad Sohail Transdermal Drug Delivery Systems (TDDDs) Transdermal delivery may be defined as the delivery of a drug through ‘intact’ skin so that it reaches the systemic circulation in suffici...

Pharmaceutical Technology-II Transdermal Drug Delivery Systems (TDDDs) Assoc. Prof. Dr. Muhammad Sohail Transdermal Drug Delivery Systems (TDDDs) Transdermal delivery may be defined as the delivery of a drug through ‘intact’ skin so that it reaches the systemic circulation in sufficient quantity, to be beneficial after administration of a therapeutic dose. Transdermal systems are ideally suited for diseases that demand chronic treatment. Hence, anti-diabetic agents of both therapeutic and prophylactic usage have been subjected to transdermal investigation. Transdermal Drug Delivery Systems (TDDDs)… Drug delivery system (DDS) is a generic term for a series of physicochemical technologies that can control delivery and release of pharmacologically active substances into cells, tissues and organs, such that these active substances could exert optimal effects. Transdermal Drug Delivery Systems (TDDDs)… TDDS has significantly influenced the delivery of various therapeutic agents, especially in pain management, hormonal therapy, and treatment of diseases of the cardiovascular and central nervous systems. TDDS does not involve passage through the gastrointestinal tract; therefore, there is no loss due to first-pass metabolism, and drugs can be delivered without interference from pH, enzymes, and intestinal bacteria. Transdermal Drug Delivery Systems (TDDDs)… In addition, TDDS can be used to control drug release according to usage restrictions, thereby contributing to the high persistence of this method. Most importantly, because TDDS is a noninvasive administration method and involves minimal pain and burden on the patient, drugs can be safely and conveniently administered to children or the elderly Transdermal Drug Delivery Systems (TDDDs)… However, it still does not utilize its full potential due to the innate skin barrier. The skin is the outermost organ with a multi-layered structure, and the role of the skin is to protect our body by blocking environmental hazards such as chemicals, heat, and toxins. Such skin can be divided into the epidermis, which has the protective function, and the dermis, where blood vessels are located, and produces skin cells, and each layer has elements that interfere with transdermal delivery. Transdermal Drug Delivery Systems (TDDDs)… The stratum corneum, the outermost layer, and have a property of blocking external substances. The barrier effect is very significant in the transport of substances having a large molecular weight. In TDDS, it is generally accepted that the delivery of substances with small molecular weights utilizes the intracellular pathway. However, for substances having a large molecular weight, methods and various mechanisms using the intracellular pathway in addition to the intercellular pathway are introduced and used. This is due to the structure of the skin because the part called lipid containing both cells and hydrophilic substances and hydrophobic substances does not have a perfectly regular position but exists with regularity Transdermal Drug Delivery Systems (TDDDs)… Therefore, the biggest issue of TDDS is to resolve the barrier effect of the stratum corneum, deliver the drug to the skin tissue, and pass through the cellular and vascular tissue to reach the target tissue. The problem is that only a small amount of the drug can be delivered through the skin tissue. BCS Classification of Drugs Enhancement of transdermal delivery by equipment (active delivery) External stimuli, such as electrical, mechanical, or physical stimuli, are known to enhance skin permeability of drugs and biomolecules, as compared to the delivery of drugs by topical application on the skin. TDDS supplemented by appropriate equipment is termed as active transdermal delivery, which is known to deliver drugs quickly and reliably into the skin. In addition, this mode of enhanced TDDS can accelerate the therapeutic efficacy of delivered drugs Iontophoresis Iontophoresis is one of the physical methods. In iontophoresis, cationic or neutral therapeutic agents are placed under an anode or anionic therapeutic agents under a cathode. When a low voltage and low current density is applied, according to simple electro-repulsion, ions are repelled into and through the skin. Iontophoresis… Iontophoresis promotes the movement of ions across the membrane under the influence of a small externally applied potential difference (less than 0.5 mA/cm2), which has been proven to enhance skin penetration and increase release rate of several drugs with poor absorption/permeation profiles. This technique has been utilized in the in vivo transport of ionic or nonionic drugs by the application of an electrochemical potential gradient Iontophoresis… The efficacy of iontophoresis depends on the polarity, valency, and mobility of the drug molecule, the nature of the applied electrical cycle, and the formulation containing the drug. In particular, the dependence on current makes drug absorption through iontophoresis less dependent on biological parameters, unlike most other drug delivery systems Sonophoresis The desired range of ultrasound frequencies generated by an ultrasound device can improve transdermal drug delivery. Low-frequency ultrasound is more effective, because it facilitates drug movement by creating an aqueous path in the perturbed bilayer through cavitation. The drug under consideration is mixed with a specific coupler, such as a gel or a cream, which transmits ultrasonic waves to the skin and disturbs the skin layers, thereby creating an aqueous path through which the drug can be injected. Sonophoresis… Drugs typically pass-through passages created by the application of ultrasonic waves with energy values between 20 kHz and 16 MHz. Ultrasound also increases the local temperature of the skin area and creates a thermal effect, which further promotes drug penetration. Several drugs of different classes have been delivered by this method regardless of their solubility, dissociation and ionization constants, and electrical properties (including hydrophilicity), such as mannitol and high molecular weight (MW) drugs such as insulin. Sonophoresis… However, the exact mechanism of drug penetration through this method is not yet completely understood, and problems with device availability, optimization of duration of exposure and treatment cycles for delivery, and undesirable side effects including burns persist. Electroporation This method uses the application of high voltage electric pulses ranging from 5 to 500 V for short exposure times (~ms) to the skin, which leads to the formation of small pores in the SC that improve permeability and aid drug diffusion. For safe and painless drug administration, electric pulses are introduced using closely positioned electrodes. This is a very safe and painless procedure involving permeabilization of the skin and has been used to demonstrate the successful delivery of not only low MW drugs, such as doxorubicin, mannitol, or calcein, but also high MW ones such as antiangiogenic peptides, oligonucleotides, and the negatively charged anticoagulant heparin. Electroporation… However, this method has the disadvantages of small delivery loads, sometimes including cell death, heating-induced drug damage, and denaturation of protein and other bio-macromolecular therapeutics. Microneedles The microneedle drug delivery system is a novel drug delivery system, in which drugs are delivered to the circulatory system through a needle. This represents one of the most popular methods for transdermal drug delivery and is an active area of current research. This involves a system in which micron-sized needles pierce the superficial layer of the skin, resulting in drug diffusion across the epidermal layer. Because these microneedles are short and thin, these deliver drugs directly to the blood capillary area for active absorption, which helps in avoiding pain. Microneedles… The prepared microneedles could be of several types, such as: Solid microneedles that simply make a physical path through which drugs can be absorbed, Drug-coated microneedles which facilitate delivery of drugs coated on the surfaces of the needles as the latter enter the skin, Dissolving microneedles made of drug formulations that dissolve in the body, Microneedle patches combined with diverse patch types Thermal ablation Thermal ablation, also known as thermophoresis, is a promising technique for selectively disrupting the stratum corneum structure by localized heat which provides enhanced drug delivery through microchannels created in the skin. To ablate the stratum corneum by thermal ablation, a high temperature above 100 °C is required and this leads to heating and vaporization of keratin. Thermal ablation… It is an ideal technique for precise control of drug delivery. The thermal exposure should be short within microseconds to create a high enough temperature gradient across the skin for selective ablation of the stratum corneum without damaging the viable epidermis. Micron-scale defects created from thermal ablation are small enough (50– 100 μm in diameter) to avoid the potential to cause pain, bleeding, irritation, and infection. Thermal ablation… Thermal ablation can usually be induced by laser and radiofrequency methods depending on the different sources of thermal energy. Laser thermal ablation methodologies utilize a laser to induce micropore structure of skin as well as the increase of the skin temperature which increases skin diffusivity. Laser light energy is absorbed by water and pigments of the skin and transforms to thermal energy leading to water excitation and explosive evaporation from the epidermis. TDDS using chemical enhancers (passive delivery) To achieve enhanced transdermal delivery and therapeutic efficacy, Drugs should have low MW (less than 1 kDa), An affinity for lipophilic and hydrophilic phases, Short half-life, and a lack of skin irritability Many factors affect drug penetration through the skin, such as species differences, skin age and site, skin temperature, state of the skin, area of application, duration of exposure, moisture content of the skin, pretreatment methods, and physical characteristics of the penetrant TDDS using chemical enhancers (passive delivery)… Recent studies that have focused on aspects of transdermal drug delivery technologies ranging from the development of chemical enhancers that increase the spread of drugs across the skin or increase the solubility of drugs in the skin to novel innovative approaches that extend this concept to the design of super-strong formulations, microemulsions, and vesicles Vesicles Vesicles are colloidal particles filled with water and consist of amphiphilic molecules in a bilayer arrangement. Under conditions of excess water, these amphiphilic molecules form concentric bilayers with one or more shells (multilayer vesicles). Vesicles can carry water-soluble and fat-soluble drugs to achieve transdermal absorption. When utilized for topical applications, vesicles can be used to achieve sustained release of stored drugs. Vesicles… Owing to the presence of different components, vesicle systems can be divided into several types, such as: liposomes, transfersomes, and ethosomes, depending on the properties of the constituent substances Liposomes Liposomes are circular soft vesicles formed by one or more bilayer membranes that separate an aqueous medium from another. Their main components are usually phospholipids, with or without cholesterol. Phospholipid molecules are mainly composed of different polar head groups and two hydrophobic hydrocarbon chains. Polar groups can be either positively or negatively charged. Hydrocarbon chain molecules have different lengths and different degrees of unsaturation. Liposomes… This unique structure allows liposomes to be both hydrophilic and hydrophobic and affords encapsulation of both water-soluble and fat- soluble substances. However, some studies have shown that liposomes can only remain on the surface of the skin and cannot pass through the granular layer of the epidermis, thereby minimizing the amount of drug absorbed into the blood circulation. This property increases the retention of drugs that stay on the skin, prolong their activity at the site of the lesion, and allow long-term sustained release. Transfersomes Transfersomes are also called deformable liposomes, or elastic or highly flexible liposomes. The most important feature of these vesicles is the elasticity that results from the addition of single-chain surfactants. These surfactants make the phospholipid bilayer fluid and vesicles highly deformable. The possibility of deformation has facilitated the design of transfersomes to those capable of penetrating skin pores 5 to 10 times smaller than their size to enable delivery of skin-penetrating drugs with MW up to 1000 kDa Ethosomes Ethosomes are composed of phospholipids, alcohols, and water. Compared with liposomes, ethosomes have higher alcohol concentrations. Ethosomes promote the percutaneous penetration of drugs, with phospholipids also contributing to the process. The flexibility and fluidity of ethosomes increase as water molecules near the lipid headgroup are replaced by alcohol. Ethosomes have the characteristic size of small particles, a stable structure, and a high capture efficiency that can delay drug release; therefore, compared with regular liposomes, ethosomes can transport drugs with deep penetration or directly through the skin. Polymeric nanoparticles Nanoparticles (NPs) are nanocarriers with sizes ranging between 1 and 1000 nm and can be classified into several types according to their composition. Drug administration in the form of NPs leads to targeted and controlled release behavior, changes in in vivo dynamics of the drug, and extends the drug residence time in the blood, which further lead to improved drug bioavailability and reduced toxicity and side effects. Polymeric nanoparticles… In the field of TDDS, polymeric NPs are gaining increased attention because they can overcome the limitations of other lipid-based systems, such as by conferring protection to unstable drugs against degradation and denaturation and achieving continuous drug release to reduce side effects. Increase in the concentration gradient improves transdermal penetration of the drug.  Polymeric nanoparticles… Depending on the manufacturing method and structure, polymeric NPs can be classified as nanospheres, nanocapsules, and polymer micelles. Widely used polymers include polylactic acid, poly(D,L-lactide-co- glycolide) (PLGA), polycaprolactone, polyacrylic acid, and natural poly esters (including chitosan, gelatin, and alginate). Nanoemulsion Nano-emulsions are a class of emulsions with droplet sizes between 20 and 500 nm. Nano-emulsions are employed in a diverse range of biomedical applications due to the small droplet sizes that render exceptional properties such as robust stability and tunable rheology. Nano-emulsions are commonly used in development of pharmaceutical formulations for topical, ocular, intravenous, and other modes of delivery Thank You