PR5304+09sep24+Transdermal+LESSON.pdf

Skin and transdermal delivery 9 September 2024 1 ## NUS Restricted ##  Learning Objectives Describe the anatomy and physiology of skin...

Skin and transdermal delivery 9 September 2024 1 ## NUS Restricted ##  Learning Objectives Describe the anatomy and physiology of skin Describe the role and composition of the stratum corneum Understand skin barrier and skin permeability Describe the main approaches for permeation through the skin, with special focus on active technologies 2 ## NUS Restricted ##  Human skin Hair follicoles The matrix contains rapidly dividing keratinocytes, which give rise to the keratinized hair shaft Melanocytes transfer packets of melanin to the hair follicle matrix keratinocytes, which confers color to the hair shaft Hair loss is usually reversible (except with hormonal drop) and it is observed after trauma, such as childbirth, surgery, weight loss, and severe stress, and also is associated with drugs and malnutrition 3 ## NUS Restricted ##  Epidermis Stratum corneum Brick and mortar system” 1. The corneocytes: stacked up to 18–20 layers; these provide the physical barrier 2. It functions as a dynamic feature rather than a fixed, inflexible barrier layer 3. The mortar lipids: about 13 species lipids, which provide the permeability barrier 4 ## NUS Restricted ##  5 ## NUS Restricted ##  Stratum corneum The epidermal permeability barrier prevents both loss and ingress of substances This is important to: avoid dehydration, maintain body temperature Substances of larger than 500 Da are unable to penetrate into the Stratum Corneum (but it also depends on other parameters) The stratum corneum is acidified: acidification of the stratum corneum increases antimicrobial defense (e.g. with pH below 5.5, the growth of Pseudomonas acne, Staphyrococcus epidermidis and Staphylococcus aureus, are suppressed) α- and γ-tocopherol (vit. E), ascorbic acid (vit. C) and glutathione are present in the stratum corneum and maintain normal conditions of the skin (homeostasis) Moreover, an innate immune component, antimicrobial peptides (AMPs), is present especially in the stratum corneum to combat broad ranges of microbes 6 ## NUS Restricted ##  The skin is a complex organ, in which the stratum corneum is the main mechanical and physical barrier, also against UV radiation The knowledge of skin physiology enables the design of products that are either applied on the skin surface (i.e. topical applications) or to migrate through the skin into the underneath blood-stream for a systemic effect (transdermal applications) Transdermal delivery requires the passage through the stratum corneum, hence substances with good aqueous and lipid solubility characteristics are good candidates for diffusion through the stratum corneum, the epidermis and dermis 7 ## NUS Restricted ##  What is transdermal delivery? Transdermal delivery: medications are absorbed through the skin or mucosal membranes instead of by oral or injectable routes, and are intended to have an effect in areas of the body away from the site of application Transdermal administration is an excellent option when a patient is unable to swallow or for medications that are significantly metabolized by the liver It is utilized for several purposes, such as anti-nausea drugs, hormone replacement therapy and generalized pain Flux which is expressed as the cumulative amount of drug permeated through a specified area of skin over a time interval is expressed as follows: J = K*Dm*Co / h where J = steady state flux, V = receptor fluid/blood volume, dc/dt = change of drug concentration c, with time, t, A = effective diffusional skin area, Co = drug concentration in donor compartment/dosage form, P = permeability coefficient of drug; K = partition coefficient of drug, Dm = diffusion coefficient of drug and h = skin thickness 8 ## NUS Restricted ##  In order to deliver beneficial ingredients inside the skin, the barrier function of the skin must be overcome selectively; however, it must not be so altered as to fail in protecting the inner organism nor functioning as a barrier There are three main entry sites into the skin: Cells in the skin, Hair follicles & glands, Pores & spaces between cells 9 ## NUS Restricted ##  Transcellular route Skin cells have an external membrane composed of lipid soluble (fat dissolvable) membranes The interior of these skin cells is mostly water and to remain there, a substance must be dissolvable in water (water soluble) This makes delivery of cosmetic ingredients quite complex because water soluble substances will not pass through the border of the cell to the inside Transappendageal route Minimal contribution, as represents only 0.1% of the whole skin (steroids) The highest hair follicle density is in the forehead and calf regions The plantar and palmar regions are the only sites completely devoid of hair and sebaceous glands An example for this route is Minoxidil for hair growth 10 ## NUS Restricted ##  Stratum Corneum Intercellular Lipid Lamella Intercellular vs transcellular route Extract/fluidize stratum corneum lipid bilayers Denature keratin of corneocytes Emulsify sebum 11 ## NUS Restricted ##  Transdermal delivery technology 12 ## NUS Restricted ##  Passive technology Nanocarriers Pharmaceutical applications: between 50-500 nm Increased specific surface area Enhanced penetration and permeation, which lead to increased drug bioavailability Reduced required drug dose and therefore educed drug toxicity Vesicular carriers Liposomes Ethosomes Transfersomes Niosomes Magnetosomes 13 ## NUS Restricted ##  Liposomes/ Magnetosomes Size as low as 30 nm to several micrometers Lipid bilayers (phospholipids) surrounded an aqueous core Lipophilic drug in lipid bilayer / Hydrophilic drug in aqueous core Surface or deep skin drug release via hair follicles and skin appendages Merge with cellular membrane and have drug release into target cells Ethosomes Modified liposomes – 50 to 200 nm Typically, they are made of 2 % to 5 % of phosphotidylcholine, 20 % to 45 % of ethanol and water Enhanced delivery of hydrophilic and hydrophobic drugs to the deeper strata of skin or enhanced systemic absorption when compared to conventional liposomes or hydroethanolic Increases vesicle deformability solutions Fluidises or extract lipid bilayer of stratum corneum 14 ## NUS Restricted ##  Beclomethasone loaded liposomes enriched with mucin Beclomethasone was loaded into liposome formulations specifically tailored for skin delivery These formulations were enhanced with mucin (0.1 and 0.5 % w/v) to further ensure prolonged formulation permanence at the site of application The addition of 0.5 % w/v mucin resulted in the formation of small unilamellar vesicles and multicompartment vesicles Effectiveness on animal model, Polydispersity as indicator for particle size, Toxicity Ines Castangia, Matteo Aroffu, Mohamad Allaw, Matteo Perra, Biancamaria Baroli, Iris Usach, José Esteban Peris, Donatella Valenti, Octavio Diez-Sales, Amparo Ruiz Sauri, Amparo Nacher, Xavier Fernàndez-Busquets, Maria Manconi, Maria Letizia Manca, Beclomethasone loaded liposomes enriched with mucin: A suitable approach for the control of skin disorders, Biomedicine & Pharmacotherapy, Volume 177, 2024, 116998, ISSN 0753-3322, https://doi.org/10.1016/j.biopha.2024.116998 15 ## NUS Restricted ##  Transfersomes Modified liposomes - 70 to 250 nm with the inclusion of edge activator e.g. surfactant or amphiphile drug. Promote vesicular deformability and elasticity Hydrotaxis: transfersomes are attracted to moisture in the deeper skin layers: they tend to migrate in the direction of dermis as the outer surroundings of vesicles are susceptible to drying due to the evaporation of moisture from transfersomes that are applied onto the surfaces of the skin The hydration gradient is considered to be the main driving force for skin penetration of transfersomes 16 ## NUS Restricted ##  Niosomes Modified liposomes – as small as 50 nm to as large as 2 µm Inclusion of non-ionic surfactants to fluidize/extract lipid bilayer of skin Surfactants (HLB 14-17) – freely hydrated surfactants fail to aggregate and coalesce into lipid lamellar structure Surfactants (HLB 8.6) – provide good drug entrapment efficiency 17 ## NUS Restricted ##  Permeation Enhancers They should be non-toxic, non-irritating and non-allergenic They would ideally work rapidly with no pharmacological activity within the body The penetration enhancers should be unidirectional When removed from the skin, barrier properties should return to normal rapidly and completely They should be cosmetically acceptable with an appropriate skin feel 18 ## NUS Restricted ##  Comparison of technologies for delivery Patches Matrix/monolithic – matrix polymer controls drug release Reservoir/membrane – rate limiting membrane between polymer matrix and adhesive controls drug release 19 ## NUS Restricted ##  Polymer Membrane Partition-Controlled System Solid drug dispersed in solid polymer matrix, suspended in unleachable viscous liquid or dissolved in releasable solvent Microporous or nonporous membrane (ethylene-vinyl acetate membrane) Drug-compatible, hypoallergenic, pressure sensitive, adhesive polymer eg. silicone adhesive TransdermScop (scopolamine patch for 3 days ) and TransdermNitr (nitroglycerine for 1 day treatment of angina pectoris) 20 ## NUS Restricted ##  Polymer Matrix Diffusion-Controlled System Solid drug in hydrophilic or hydrophobic polymer matrix The drug reservoir is mounted in occlusive base plate in a compartment fabricated from a drug impermeable plastic backing Adhesive is applied along patch circumference 21 ## NUS Restricted ##  Development, optimization and ex-vivo evaluation of a transdermal formulation containing trazodone Trazadone HCL in transdermal patch for controlled release delivery Effect of pH, drug concentration and fatty acid as permeation enhancers The effect of pH of the vehicle on the permeation of trazodone across the skin is quite complex, because it influences both solubility and partitioning and that the presence of fatty acids in the vehicle has a notable effect on permeation Anna Demurtas, Sara Nicoli, Silvia Pescina, Leonardo Marchitto, Lorella Ragni, Vincenzo Russo, Giampaolo Tommasi, Patrizia Santi, Cristina Padula, Development, optimization and ex-vivo evaluation of a transdermal formulation containing trazodone, European Journal of Pharmaceutical Sciences, Volume 201, 2024, 106874, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2024.106874 22 ## NUS Restricted ##  Film forming agents Non-solid dosage form that produces a film in situ Drug and film forming excipients in a vehicle, upon contact with skin, form film upon solvent evaporation The formed film can be a solid polymeric material or a residual liquid film Octylcyanoacrylate Glycols: propylene glycol, polyethylene glycol Ethylcyanoacrylate Alcohol: ethanol, butanol, isopropanol, Poly(methylmethacrylate) benzyl alcohol, lanolin alcohol, fatty alcohol Poly(butylmethacrylate) Others: ethyl acetate, oleic acid, isopropyl Polyvinylpyrrolidone myristate Hydroxypropylmethylcellulose Polyethylene glycol Silicone, polydimethylsiloxane Polyvinyl alcohol Chitosan Liquid or semisolid 23 ## NUS Restricted ##  Spray/solution Drug Polymer – anti-nucleating agent and crystallization inhibitor Permeation enhancer Volatile vehicle Non-volatile vehicle: prevents drug precipitation when volatile solvent evaporates off; rapid partitioning into stratum corneum, disturbs lipid bilayer, promotes drug diffusion Gel Gelling agent: Gellan gum, carbomer, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, poloxamer, acrylamide/sodium acryldimethyltaurate copolymer Emulsion Oil phase Aqueous phase – volatile component Film forming polymers 24 ## NUS Restricted ##  25 ## NUS Restricted ##  Iontophoresis It acts by applying a small electric current to the skin (< 500 µA/cm2), mainly through the skin appendages) for charged particles to diffuse across Not suitable for molecules >7,000 Da Initially used for bleaching skin and local anesthesia 26 ## NUS Restricted ##  Electrophoresis Electrophoresis utilizes high voltage (>100V) for short duration, creating transient pores across the skin Although the electric field is located at the SC, it may also affect the deeper tissues to cause pain and muscle contractions are usually induced Combining ultrasound and surfactant, the transport of rigid nanoparticles across the skin is promoted Mechanism of sonophoresis with reference to inertial cavitation: a) shock wave on skin surface, b) microjet on skin surface, c) microjet into stratum corneum 27 ## NUS Restricted ##  Termal ablation or laser Micropores formation in SC or membrane disruption coupled with water evaporation Short time Suitable for big molecule, like DNA plasmid and insulin Magnetophoresis Magnetic field (5 to 300 mT) to enhance transdermal drug delivery where diamagnetic drugs such as lidocaine can be repelled away from the magnetic field and migrated into the skin Magnetorepulsion takes place when diamagnetic drug molecules are driven away from the external magnetic field Magnetohydrokinesis mediates drug transport through moving water/solvent across the skin barrier by an external magnetic field, similar to electroosmosis in iontophoresis Microwaves One mW microwave at 2450 MHz for up to 5 min or 5 + 5 min Fluidize lipid bilayer of stratum corneum and/or condense keratin of corneocytes, thereby enlarging aqueous pore for drug/nanoparticles diffusion 28 ## NUS Restricted ##  Microneedles Microneedles, an array of micron scale needles, are thought to be the hybrid between convenient and safe transdermal patches and efficient hypodermic injections Some are permanent, some are dissolvable Solid – create pores in skin with patch applied thereafter Coated – focus on relatively potent molecules and peptides that are amenable to be deposited (up to 300 µg) and dried on tips of a microneedle array Polymer – dissolving, non- dissolving, hydrogel forming in conjunction with drug release Hollow – delivery of drug solution into the highly vascularized dermis (12 microneedles, 1500 µm height or slightly less, 10 µm diameter, 2 ml drug solution) 29 ## NUS Restricted ##  A= solid Poly-L-lactic acid B= dissolvable Poly-glycolic acid C/D= hollow Poly-lactic-co-glycolic acid Carboxymethylcellulose Amylopectin Bovine serum albumin + carboxymethylcellulose Polyvinylpyrrolidone Chitosan Hyaluronic acid 30 ## NUS Restricted ##  Hollow microneedles as a tool for transdermal delivery of teriflunomide loaded solid lipid nanoparticles Teriflunomide has poor solubility and severe side effects upon oral administration Release in vitro to assess the effect of the formulation followed by in- vivo testing for the final dosage forms with the selected formulation 1. Targeted delivery to reduce the side effects 2. Nanoparticles to improve drug characteristics 3. Patch as a delivery method Heba Abd-El-Azim, Haidy Abbas, Nesrine S. El Sayed, Ahmed M. Fayez, Mariam Zewail, Non-invasive management of rheumatoid arthritis using hollow microneedles as a tool for transdermal delivery of teriflunomide loaded solid lipid nanoparticles, International Journal of Pharmaceutics, Volume 644, 2023, 123334, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2023.123334 31 ## NUS Restricted ##  How to approach with Oral Dosage Forms? Characteristics of the drug Type of release Materials Additional control method 32 ## NUS Restricted ##  Transdermal gel of berberine Berberine is a low solubility and low permeability drug that can promote cartilage regeneration Why transdermal delivery and why proniosomes? Transdermal instead of injection for patience’s compliance Proniosomes for enhance permeation, contact time and stability (shelf-life) Altay Benetti A, Thwin MT, Suhaimi A, Liang RST, Ng LF, Lum FM, Benetti C. Development of Proniosome Gel Formulation for CHIKV Infection. Pharmaceutics. 2024 Jul 26;16(8):994. doi:10.3390/pharmaceutics16080994 33 ## NUS Restricted ##  Can patches be an alternative? Yes, contact time can be even higher: controlled release coupled with high drug loading can lower the number of administrations Why non-ionic surfactants? They can form proniosomes but they also are permeation enhancers Can I use anything else? Like liposomes for example The difference is the charge of the lipids that may affect permeation and stability (via complexation or chemical interaction) 34 ## NUS Restricted ##  Additional control methods? Proniosomes and patches can be combined in the same dosage form to increase the half-life The decision depends on the PK parameters and on how long the effect of the drug last after the administration 35 ## NUS Restricted ##