Supramolecular Pharmacy 6. Gels and metallogels in pharmacy Ondřej Jurček 1 Gels around us 2 Ideally viscous liquids / Newtonian liquids viscous materials with an elastic portion Ideally elastic solids / Hookean solids More elastic materialsRheology viscoelastic Liquids viscous Solids elastic Gels and metallogels 3 • Gel are present in our everyday life, e.g., jelly, tooth-paste, contact lenses, hair gel, etc. • Gels are formed by two or more components forming a fibrous solid-like phase (typically around 1 wt%) immobilizing large volume of liquid, gel preparation – melting point of gel • Hydrogels and organogels • Metallogels • Aerogels, xerogels (supercritical or freeze drying) • Macroscopic proof of gel – vial inversion test • Microscopic are often formed by bundles of fibres • Covalent polymer or supramolecular assembly of small molecules (low molecular weight gelators (LMWG)) sol gel T aerogel • pHEMA hydrogels and their use as contact lenses • Wound dressings: (a) maintain a moist environment, (b) provide a barrier to bacterial contamination while (c) allowing oxygen access to the injured area, (d) can be removed without damage to the healing surface. • Fat substitutes in food chemistry • Drug delivery Polymeric gels Zhi et al. Food Chem. 2023, 424, 136399. Matrix Oil – solvent Preparation Features of emulsion gels pHEMA • pHEMA hydrogels and their use as contact lenses • Wound dressings: (a) maintain a moist environment, (b) provide a barrier to bacterial contamination while (c) allowing oxygen access to the injured area, (d) can be removed without damage to the healing surface. • Fat substitutes in food chemistry • Drug delivery Polymeric gels Zhi et al. Food Chem. 2023, 424, 136399. Matrix Oil – solvent Preparation Features of emulsion gels pHEMA • Interesting properties of LMWG systems is the reversibility of the supramolecular interactions between the gelator molecules, suggesting the possibility of dynamic behaviour such as selfhealing or slow release Applications • Tissue engineering – gels can act as a form of nanoscaffolding encouraging the growth of slow growing tissue such as nerves through peptide-based gels • Drug delivery – many drugs are already formulated as polymer gels for oral delivery. Small molecule based gels offer the possibility of slow release or a sudden burst of drug from a chemically triggered gel-sol transition • Templating or transcribing self-assembled morphology – gels have been used extensively as growth regulators for the preparation of metallic nanoparticles or as templates for the formation of porous polymers • Napalm – an infamous gel originally made up of the aluminium salts of napthenic and palmitic acids mixed with petrol • Molecular electronics – the long, fibrillar nature of gels strongly suggests that they might find applications in the construction of molecular wires Low molecular weight gelators (LMWG) • Sensing – compound 14.17 is a poor gelator in itself but undergoes a reaction with β-lactamase enzyme to produce 14.18 which is a good gelator. Bacteria resistant to penicillin can perform such hydrolysis - way of sensing the presence of penicillin-resistant bacteria Low molecular weight gelators (LMWG) Molecules of gelator 8 E. Sievänen: RSC Adv. 2012, 2, 4985–5007. Steroidal gelators 9 Sol-gel processes 10 • Sol = colloidal suspension of tiny solid particles in liquid medium (e.g., blood, mud, paint…) – stable, Tyndall effect, 1-100 nm Sol-gel processes 11 • Sol = colloidal suspension of tiny solid particles in liquid medium (blood, mud, paint…) – stable, Tyndall effect, 1-100 nm Aerogel https://wiki.aalto.fi/ Sol-gel processes 12 Pharmaceutical gels 13 • Topical gels – topical drug delivery dosage form • Mixture of gelator, solvent, active drug, and other excipients • Organogels less common (lecithin gel) – occlusive layer traps moisture, allowing hydration of the skin and providing an emollient effect • Hydrogels – biocompatible, swell to a greater volume than organogels when in contact with water and other natural liquids (less greasy, easier to remove) • Transdermal application (largest surface area for absorption), ophthalmic, dental, intranasal, vaginal, rectal and others • Cosmetics, which include shampoos, dentifrices, skin and hair care formulations and fragrance products, and can be used to treat scalp inflammation Gel division by their size a) C. S. A. de Lima et al. Pharmaceutics 2020, 12, 970. b) Z. Sun et al. Mol. Pharmaceutics 2020, 17, 373−391. Macrogel – application in situ injection, in situ implantation, transdermal delivery Microgel – oral delivery, pulmonary delivery, transdermal chemoembolization Nanogel – intravenous injection, in situ injection Pharmaceutical gels 15 a) Trideva S. K. et al. Gels 2022, 8, 316. b) Al-Kinani A. A. Adv. Drug Deliv. Rev. 2018, 126, 113–126. c) T. Yu et al. Expert Opin. Drug Deliv. 2011, 8(10). d) das Neves J. Int. J. Pharm. 2006, 318, 1–14. Mode of action of topical gels 16 • Skin penetration – passive diffusion through epidermis or via hair follicles and sweat glands based on concentration gradient (active, endocytosis) • Drug might penetrate deeper and reach capillaries – systemic circulation Controlled by: • Physiological factors such as skin properties, size of application area, frequency and force of application, hydration, temperature, etc. • Physicochemical properties of the drug such as drug solubility, attraction to the skin and metabolism. • Gel characteristics include stability, thermodynamic activity, and occlusive* properties. * forms a protective film and traps moisture against the skin Gel formulation ingredients 17 • Formulation of topical gels is determined by important factors such as appearance, odor, spreadability, extrudability, consistency, viscosity, pH, texture, microbial contamination potential and bioavailability • Consistency and viscosity affect the adhesion and retention property of the gel, and are important in ensuring the gel is retained at the site of application and effective delivery of the drug • Gelator, solvent, drug, and excipients • Gelator – stabilizer and thickener - natural gelators include tragacanth, gelatin, collagen, and guar gum; semi-synthetic gelators include methylcellulose and other cellulose derivatives; while synthetic gelators include carbomers, polyvinyl alcohol, polyethylene and its copolymers • Solvent – based on application – hydrophilic, lipophilic, or organic (e.g., purified water, glycerin, glycols, alcohols, sucrose, toluene, and mineral oils) • Drug – typically used for drugs which are easily degraded in the GI tract or susceptible to hepatic first pass effect - the drug should be smaller than 500 Da, be reasonably lipophilic, have pH 5-9 in saturated aqueous solution, it should not be irritant or allergenic, under constant delivery no tolerance - drug permeability and concentration Gel formulation ingredients 18 • Excipients – components inert to the drug, which are added into dosage forms to improve its overall quality, i.e., antioxidants (sodium metabisulphite and sodium formaldehyde sulfoxylate), sweetening agents (sucrose, glycerol, sorbitol and liquid glucose), stabilizers, dispersing agents, penetration enhancers (glycerin, sulfoxides and related analogues, pyrrolidines, fatty acids, ethanol, or surfactants), buffers (phosphate, citrate) and preservatives (parabens, phenolics) Gel preparation methods • Increasing the concentration of gelator leads to gelation at gelling point, increasing the gelator concentration increases gel viscosity (stiffness) • pH • Drug content • Viscosity • Spreadability • Extrudability study • Skin irritation studies • In vitro release • In vivo study • Stability (time, temperature) Gel evaluation 19 Gel advantages 20 • Gels are used to achieve optimal cutaneous and percutaneous drug delivery. • They can avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH. • Gels are having property to avoid enzymatic activity and drug interaction with food and drinks. • They can substitute for oral administration of medication when the route is unsuitable. • They can avoid the first pass effect, that is, the initial pass of drug substance through the human body. • They avoid systemic and portal circulation following gastrointestinal absorption. • They are non-invasive and have patient compliance. • They are applied over skin for slow and prolonged absorption. • They have localized effect with minimum side effects. • Excellent spreading property and cooling effect due to solvent evaporation. • They can be washed off easily. • Increased bioavailability, faster drug release from gels than from creams and ointments. Gel disadvantages 21 • Additives of gels might cause allergic reactions. • Drugs of larger size do not absorb through the skin. • Poor permeability of some drugs through the skin. • Water content increases chances for microbial or fungal contamination. • Possible flocculation, salting out, syneresis, changes in rheology due to temperature, humidity changes – more strict storing requirements Fenistil gel 22 • 1 gram of gel contains dimetindeni maleate 1 mg, other excipients: benzalkonium chloride (antimicrobial preservative), dihydrate dinatrium-edetate (stabilizing effect on gelator, effects skin penetration), carbomer 974 P (gelator!), solution of sodium hydroxide 300 g/l (keeps gelator in the form of salt), propylenglycol (caution, possible irritant), purified water (hydrogel!). • Key features of carbomer 974 P: suspension and emulsion stabilizer, taste masking agent • Additional features: extended release agent, thickener/rheology modifier, bioadhesion agent, tablet binder • Recommended for use in the following dosage forms: semisolids & gels, solutions & suspensions, extended release oral solid doses • Recommended for use in the following markets / routes of administration: oral drug delivery, topical drug delivery, ophthalmic drug delivery, oral care Polyacrylic acid • Rheology is the science of the flow and deformation of materials • Gels exhibit different rheological properties. Do not flow at low shear stresses but undergo reversible deformation like elastic solids. • When a characteristic shear stress, called the yield value or yield stress, is exceeded, they flow like liquids (plastic behavior rather than elastic). Rheology studies Two plates model Shear forceF 23Budai L. Gels 2023, 9, 469 Rheology studies Oscillatory tests: Covers the entire range of materials from viscous end to the elastic / detects viscoelastic behavior of materials Rotational tests: uses to measure liquids / detects the viscosity function of the liquid Rotation / Oscillation Rheometer Rotational tests Oscillatory tests Controlled and workable flow 24 Energy storage and loss 25 For viscoelastic solid materials: G’ > G” For viscoelastic liquid materials G’ < G” Uses energy to restore form Stores energy Loaded with deformation energy Elastic behavior Viscoelastic solid materials Storage modulus G’ Viscoelastic liquid material Viscous behavior Loaded with deformation energy Loses energy as heat Loss modulus G” In the next class… Nanoparticles Thank you for your attention! With thanks to Jonathan W. Steed, Jerry L. Atwood for Supramolecular Chemistry, ISBN: 978-1-119-58251-9 and Wikipedia for several lovely images.