PF4015 Polymer Stimuli-Responsive Drug Delivery PDF

PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Dr. Katie Ryan Stimuli- and Bio- responsive systems in drug delivery Not all stimulus are...

PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Dr. Katie Ryan Stimuli- and Bio- responsive systems in drug delivery Not all stimulus are of biological origin - heat etc 1 Learning objectives Explain what is meant by stimuli-responsive drug delivery Outline the advantages and limitations of stimuli-responsive drug delivery Differentiate between the materials used in stimuli-responsive scenarios Discuss examples of stimuli-responsive materials used in drug delivery Comment on the current state-of-the-art with respect to closed-loop systems Dr. Katie Ryan 1 2 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Chronopharmacology Control over drug release - intermittent Chronopharmacology takes a person’s circadian rhythm into consideration in determining the timing and sometimes the quantity of medication Chronopharmacology does not involve new medicines but uses exisiting ones in a different approach. Objective: to optimize a drug’s desired effects and minimize undesirable side-effects. Take advantage of biological stimuli to control drug release Dr. Katie Ryan 3 Chronotherapeutical approach - aufrig H2 antagonist Constant infusion of ranitidine over a period of 24 h did not lead to a constant effect. Basic The increase in gastric pH caused by ranitidine was lower during the nightly hours of drug infusion than during daytime, indicating that there might be a partial nocturnal resistance to H2-receptor blockade Dr. Katie Ryan 2 4 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Stimulus sensitive drug delivery Tailor-made drug delivery systems to selectively release their cargo at the desired site of action under a specific stimulus or trigger So-called smart drug delivery systems are designed to respond to certain stimuli like pH, temperature, redox potential, enzymes, light, and ultrasound. erdose ↳ ph. Biological - some of these stimuli occur naturally in vivo, Temperature can be biological or not Different pH values in different cellular compartments Unique to disease pathology - differences in pH e.g. tumour tissue Lo bin pur Other External applied stimuli, like light and ultrasound, time + space Allow the temporal and spatial control of the release, since they are not triggered by any biological event. Switch release on/off as a function of intensity and time to use light Provide on-demand regulation of the process nursing heat general a to stimulus Dr. Katie Ryan causes materials act in Response change- Lo Net as controlled. Nob as Responsive 5 Stimuli-responsive systems Stimuli-responsive systems respond to a stimulus resulting in a change in properties e.g. conformation, solubility, HLB-balance. A combination of several responses simultaneously may also occur. Hydrophilic lypophylic balance -oswelling. Dr. Katie Ryan 3 6 ph controlled polymers utrogestan Ultrasonic high frequency turn medicine into mist nebulizers - ultrasonic + vibrating mesh piaso electro to Response. PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Stimuli responsive drug releasing systems Reduction or oxides by accepting or donating electrons maintaenable Dr. Katie Ryan 7 Responsive controlled release systems anti-cancer- Dr. Katie Ryan 4 8 pick & example for each stimeli. PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Responsive controlled release systems – multiple stimuli Materials response to 2 stimuli More flexibility - but complexity Dr. Katie Ryan 9 Gels - virtual cross links - already swollen so further addition of water causes dilution or polymeric network Hydrogels - covalent cross links - absorbs large amount of water and swells but maintains 3D structure - Electrostatic attractions or doesn’t dissolve loosely attract Property vary Gels v Hydrogels Polymer strands forming a gel and a hydrogel, showing different behaviour in an aqueous environment. Solid circles represent covalent cross-links and hollow circles represent virtual cross-links formed by entanglements. Gels are polymeric networks already swollen to equilibrium, further addition of fluids results in dilution of the polymeric network. -. Hydrogels are a cross-linked network of hydrophilic polymers. They possess the ability to absorb large amounts of water and swell, while maintaining their 3D structure, they do not dissolve. Dr. Katie Ryan 5 Hydro - can take more water 10 Can dissolve and weaken Not seen in covalently linked materials PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Stimuli responsive polymers - Factors affecting polymer swelling verfges ↑ Principle: Highly cross-linked polymers hydrate to form hydrogels with tighter structures that swell less than non- or loosely cross-linked polymer systems Hydrophilic polymers swell to a higher degree than hydrophobic polymers in the presence of water Drug loading (i) soak polymer monoliths in drug solution (ii) during polymerisation (iii) during self-assembly· processes e.g., triblock copolymers 8 - Soak preformed gel in drug solution Surfactant Michelle Uneven distribution Drug release from hydrogels by: approach flexibility have Issue with stability of drug and Change of Diffusion (Fickian) high ro low cone-cross , thend drug structure when swollen linking - to Relaxation of polymer chain 0 pushes outward get as contract Hydrostaticofpressure as hydrogel contracts trigger Squeeze water to >. -. Collapse of swollen hydrogel network at specific intervals can result in a squeezing release process Carefully chosen polymer chemistry can be exploited to control the swelling of the gel using external stimuli. ↳ +. drug intractions Drug release controlled by: Changing the drug’s diffusion coefficient in the hydrogel network &Altering the drug’s affinity for the hydrogel Cross linking impacts Dr. Katie Ryan 11 Swollen Gwen contracts causes Release. drug Hydrogels in drug delivery Issue drug loosely encapsulated -H Dry polymer network Swollen hydrogel Cross-link Mesh size The distance between the chains and cross-linking density determines the mesh size of the hydrogel. Hydrogels, Ch. 7 In Drug Delivery: Fundamental and Applications, Siegel and Alvarez-Lorenzo, Edited by Hilery & Park Dr. Katie Ryan 6 12 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Mesh size can change due to water uptake stimulus or erosion process due to hydrolytic or enzymatic degredation Stimulus or water that initiates swelling Release mechanism of drug with hydrodynamic diameter dh from hydrogel with mesh size ξ,that can remain constant or can be modified as a function of (1) water uptake, (2) the action of a stimulus, or (3) an erosion process due to hydrolytic or enzymatic degradation. Drug properties – e.g. size and hydrophilicity/hydrophobicity affect its diffusion 1 Fragmented loss of polymer network Method of polymer degredation 3 2 Dr. Katie Ryan 13 Effect of proportion of cross-linker on hydrogel mesh size, which in turn determines the molecular size of proteins that can enter the hydrogel (Eichenbaum et al. 1999, Macromolecules 32(15), 4867-4878). Controlling cross linking density and mesh size -o RestrictsCargo aan early spreical not > - b inside. 7 5. nm. Brownishmotion diffusi a ↑ feed Ratio I chain capacity to deliver drug d in mesh size. Dr. Katie Ryan 7 14 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Open and closed loop systems Hydrogels that modulate drug release can function in open or closed loop mode most no Open-loop – control drug release due to an external stimulus e.g. ultrasound, light irradiation rather than the biological environment difficult - ~o Closed-loop (or self-regulated) detect changes in the physiological environment and respond by releasing drug to restore balance to a defined point => viewed as artificial approaches to achieve homeostasis insulin delivery in response to blood glucose measurements, acts to restore levels to desired range. implantable pumps Dr. Katie Ryan 15 Stimuli that may affect hydrogel swelling Dr. Katie Ryan 8 16 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Stimuli-responsive polymers Representative chemical structures of stimuli-responsive polymers. acid A A. pH-sensitive polymer blocks: a) poly(acrylic acid), b) poly(methacrylic acid), c) poly(2-ethyl acrylic acid, d) poly(2-propyl acrylic acid.. change SCI. or permeability - B. Temperature-sensitive polymer blocks: a) N-isopropylacrylamide, b) poly(organophosphazenes). triblock peymes Dr. Katie Ryan 17 Stimuli responsive polymers: pH Polymers with ionic pendant groups whose ionisation state is influenced by environment pH and their pKa risation drug to ability Cationic copolymer Eudragit E dimethylaminoethyl methacrylate, butyl Anionic copolymer Eudragit L methacrylate, and methyl methacrylate methacrylic acid and ethyl acrylate Bioresponsive applications pH pH-sensitive hydrogels have been most frequently used for oral administration e.g., Enteric coated tablets Taste masking foul-tasting drugs in the neutral pH of the mouth solution to get state ↑ thicken. pH-dependent sol-to-gel transformation has been used to develop nasal spray dosage forms for treating allergic rhinitis and sinusitis - OcularDr. Katie Ryan 9 ↳ occara Nasal 18 Lo easier administer liquid than gll-but issue Retention. For lig -o thicken-better drug. Retention. Lo Bioadhesive -o hold properties dug at site for longer PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Exploitation of pH effects in drug-delivery lipids instead. - incorporate of similar ph could be e protective - damaging. ↳ poor 02-0dph. Dr. Katie Ryan develops quick-d Blood supply 19 pH-responsive hydrogels - in acidicosie pH-responsive hydrogels are composed of polymeric backbones with ionic pendant groups. In aqueous media of appropriate pH and ionic strength, the pendant groups ionize and develop fixed charges on the polymer network, generating electrostatic repulsive forces responsible for pH- expand to distance dependent swelling or deswelling of the hydrogel -o negative charged charges- - Repel betweenO 3 changes acidic basil Pendant groups of Anionic hydrogels are un-ionized below and ionized above the pKa of the - polymeric network, leading to swelling of the hydrogel at a pH above the polymer pKa because of a large osmotic swelling force by the presence of ions. basic acidic. Cationic hydrogels – unionised above and ionised below the pKa => polymeric network swells at - lower pH. Dr. Katie Ryan 10 20 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Differential swelling of ionic hydrogels in acidic and alkaline buffers standian up gives pretens ↳ in G charge base. Dr. Katie Ryan 21 Structure and pH-dependent swelling of a) poly-acid b) poly-base and c) polyampholyte hydrogels. acrdic - o donates 44 Base-accepts Swelling/shrinking transitions occur acidic near the pKa values for: O a) the acidic (-COOH, pKa1) 60 b) basic (-NH2; pKa2) groups due to Repulsion Loswells changes in fixed charge density. c) Mixed polyacid/polybase hydrogels exhibit increased swelling at extremes of pH but are relatively shrunken at intermediate pH values. Swell above Dr. Katie Ryan 11 base pka and 22 below acid pka contains both but not Ratio between the 2 two pka differences PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Stimuli responsive polymers Applications exploiting pH- sensitivity pH sensitive systems for glucose sensing Glucose oxidase is probably the most widely used enzyme in glucose sensing. It oxidizes glucose to gluconic acid, resulting in a pH change of the environment. acidic by product pH sensitive systems for solid tumours Tumour environment tends to be significantly more acidic ~pH 6.5 Cellular delivery pH of endosomal and lysosomal vesicles inside the cell is significantly lower than the cytosolic pH Dr. Katie Ryan 23 Lower ph of endosome compared to cytosolic ph allows for stimulus and drug release Stimuli responsive controlled release systems control · geesmpment nomaly p change-change in lipid propera d dug release r charge a lo limited size by barries. + solider Fluid. Dr. Katie Ryan 12 24 Interelular targetting PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Stimuli responsive gels and bioadhesion Bioresponsive e.g. hydrogels and bioadhesive approaches Helps enhance adhesion of drug at target Help prevent leakage and loss of the product vaginal Sustained release Sustained release but in presence of seminal pH responsive systems fluid - gel to sol and bolus release Cellulose acetate phthalate (CAP) At lower pH it gels/solid but increased pH leads to polymer solubility trigger Inc pH with seminal fluid results in- so gel => sol transition facilitating drug release Examples include semen triggered release of anti-HIV drugs from CAP polymer meshes or tablets in the vagina Under normal acidic conditions in the vagina these systems remain intact and can be used for sustained release applications (anti-HIV or contraceptive agents), but semen increase the pH and trigger a bolus of drug release. Lo diff un of diff times Dr. Katie Ryan 6 menstrual cycle 25 HIV developing to ↓ countries Retention cost education around. from site-poor access usage loss of get how does it have ethical long - need to plan work, placeto - to be in Topical ophthalmic delivery In situ gelling – Electrolyte stimuli Timoptic XE gel-forming preparation: The gellan gum is an aqueous solution but forms a gel on contact with the positive Ca2+ cations in the tear film. The cations neutralise the polymer causing a reduction in its solubility. They also bridge the polymer chains forming a structured network. ↑ thickening. ↳ fores get Dr. Katie Ryan 13 26 initiation - ichic PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Factors affected polymer swelling – Temperature Activation of temperature sensitive hydrogels close to body temperature to control drug release polyacrylamide nipaan poly Temperature can also be controlled locally by directed delivery of other energy forms e.g., ultrasound, electromagnetic fields genera Externes - to Positive thermosensitive hydrogels contain mainly 6 hydrophilic monomers and experience an increase in swelling with increase in temperature. https://www.youtube.com/watch?v=by53LP0Yu4c Negative thermosensitive hydrogels contain some E hydrophobic monomers, and experience decreases in swelling with an increase in temperature. Dr. Katie Ryan 27 Factors affected polymer swelling – Temperature Mostly commonly investigated material Poly(N-isopropylacrylamide) PNIPAAm Its lower critical solution temperature (LCST) of ~33ºC in an aqueous environment. close to body - temp Below < LCST, polymer chains are well hydrated Swollen and have a random coil configuration Abover > LCST, polymer chains take on a much neverr more compact configuration by sudden somewe a Collapsed dehydration and increased hydrophobic interactions. ↳ apayme watertake chains- Hydrophilic to hydrophobic transition is due to loss of hydrogen-bonded water PNIPAAm benefits Possible to fine-tune by varying alkyl part or upon copolymerization with other more hydrophilic monomer LCST close to body temperature Potential application in tumour drug delivery in conjunction with application of an external heat source 14 Dr. Katie Ryan 28 unmet need PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Temperature affected polymer swelling of PNIPAAm Structure and temperature-dependent swelling of Poly(N-isopropylacrylamide) hydrogels. A sharp transition in swelling occurs at a “critical” temperature, Tc used to control drug release. transitioan Above lcst - dehydration and compaction Dr. Katie Ryan Hydrogels, Ch. 7 In Drug Delivery: Fundamental and Applications, Siegel and Alvarez-Lorenzo, Edited by Hilery & Park 29 Temperature affected polymer swelling of PNIPAAm %. 88 sensitive paryna on + Temp Polymer has both temp and ph sensitivities Q is amount of water is adsorbed swell Low temp hydrogel swells swellinggst High temp it contracts BUT at low temp and higher ph it swells Can have dual stimulus response Dr. Katie Ryan 15 30 & for change temp than ph. Swelling Ratio in Rather not that strong Has larger change for ph change ¿ PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Polymer has antigen and antibody - allows for cross linking formation - free antigen interacts with antibody displacing original antigen and rupturing cross linking - hydrogel swells and drug releases Factors affected polymer swelling – Analyte sensitive Antigen responsive reversible swelling of hydrogels prepared by copolymerisation of complementary antigen and antibody monomers that can act as reversible cross-links. Hydrogel is prepared by grafting an antigen and a corresponding antibody to different polyacrylamide (PAAm) polymer chains. Interaction of the free antigen (biomarker) with the immobilised antibody leads to rupture of the initial cross-links, causing the hydrogel to swell and trigger drug release. - craped statepre Dr. Katie Ryan aveseeing 31 interacts with antibody. ↑ mesh size easier for dug diffesion Responsive controlled release systems – light sensitive Light stimulus has advantages over other stimuli It can be imposed instantly and delivered in specific amounts. Offers precise control over specific-site of drug release Classes of light-sensitive hydrogels 1) UV-sensitive 2) Visible light-sensitive hydrogels and Near- Infrared (NIR) radiation sources Light responsiveness is most provided by photoactive groups, which undergo reversible structural (7) changes under UV-light such as: Azobenzene Cynnamonyl Spirobenzopyran Triphenylmethane Dr. Katie Ryan 16 32 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Responsive controlled release systems – light sensitive Can’t penetrate deep into tissue sites - good for skin (1) Hydrogels swell in response to UV irradiation but shrink when the UV light is removed. ↑ (1) UV triggered release is restricted to hydrogels on certain sites e.g., the skin or against mucosa since radiation of wavelengths < 600 nm has limited (1 cm) penetration capacity into the body below. Ionisation upon uv radiation Structure of leuco derivative molecule bis(4-(dimethylamino)phenyl)(4-vinylphenyl)methylleucocyanide Dr. Katie Ryan 33 Responsive controlled release systems – light sensitive Near-Infrared (NIR) light (650 - 900 nm) Can penetrate deeper Metal (gold nanoparticles) can absorb NIR light & transform the radiant energy into heat. This can be exploited to trigger drug release from temperature-sensitive networks & to apply thermal ablation Visible light-sensitive hydrogels contain a light-sensitive chromophore Light (e.g., 488 nm) is applied to the hydrogel, chromophore absorbs light, which is then dissipated locally as heat, increasing the ‘local’ temperature of the hydrogel. The temperature increase is proportional to the light intensity and the chromophore concentration. to both No dual sensitive light at The temperature increase alters the swelling behavior of hydrogels, which are also thermo- sensitive hydrogels. Dr. Katie Ryan 17 34 -o heat Light Lo Responsible for changing in properties PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Responsive controlled release systems – limitations Their non-biodegradability. Non-biodegradability is not a problem for oral drug delivery, but it becomes a serious limitation for implantable drug delivery agents or implantable biosensors. There is a need to develop biodegradable, stimuli-sensitive linkers and hydrogels based on polypeptides, proteins and polysaccharides Based on these are they are biologically compatible and will be degraded Need SMARTER MATERIALS Dr. Katie Ryan 35 Stimuli-responsive delivery systems for the transport of active compounds Dr. Katie Ryan 18 36 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. in future slides Stimuli responsive drug-carriers Can add a stimuli responsive carrier to these The composition of each class of these molecular assemblies can be manipulated to obtain nanocarriers with desired stimuli-responsive properties tempare Dr. Katie Ryan 37 Bio-responsive controlled release systems The aim of Bioresponsive systems is to respond to a biological signal e.g., caused by disease, judge the magnitude of signal, and then act to release the right amount of drug in response. Modulation of Biological Drug Release stimulus Alters drug release based on biological environment Biological Controlled Drug modulation Release Dr. Katie Ryan 19 38 Type 1 diabetes PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. (Bio) Responsive controlled release systems – potential advantages Drug delivery is related to fluctuating metabolic requirements or the presence of certain biomolecules in the body Drug delivery could precisely match physiological stimulus e.g., right time and right place Physiologically, numerous bioactive peptides are tightly controlled to maintain a normal metabolic balance via a feedback system called ‘homeostasis’. This can be exploited to achieve precise drug delivery Such a system would require coupling of the drug delivery rate with the physiological need by means of some feedback mechanism – closed-loop systems e.g., artificial pancreas Dr. Katie Ryan 39 Bioresponsive - responding to biological stimulus - magnitude of stimulus - drug release closed loop. Bioresponsive: Artificial Pancreas System (Autonomous System for Glycaemic Control) The Artificial Pancreas Device System is a system of devices that closely mimics the glucose regulating function of a healthy pancreas. The system not only monitors glucose levels in the body but also automatically adjusts insulin delivery to reduce hyperglycemia and minimise incidence of hypoglycemia with little or no input from the patient. Sometimes an artificial pancreas device system is referred to as a "closed-loop" system, an "automated insulin delivery" system, or an "autonomous system for glycaemic control." Dr. Katie Ryan 20 40 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Bioresponsive: Artificial Pancreas System (Autonomous System for Glycaemic Control) https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/HomeHealthandConsumer/ConsumerProducts/ArtificialPancr eas/ucm259548.htm Dr. Katie Ryan 41 Most consist of three types of devices: Continuous glucose monitoring system (CGM) Insulin infusion pump Blood glucose device (e.g. glucose meter) to calibrate the CGM. Computer-controlled algorithm connects the CGM and insulin infusion pump to allow continuous communication between the two devices. https://www.google.ie/webhp?sourceid=chrome- instant&ion=1&espv=2&ie=UTF- 8#q=closed+loop+insulin+pump+medtronic&tbm=vid https://www.youtube.com/watch?v=drAenNuBpPk Dr. Katie Ryan 21 42 PF4015 - Dr. Katie Ryan, School of Pharm acy, 20/01/2025 UCC. Towards Bioresponsive systems Minimed 670G Insulin Pump system Hybrid closed loop system Needs patient input at meals Sept 2016 - U.S. FDA approved Medtronic’s MiniMed 670G hybrid closed looped system, the first FDA- approved device that is intended to automatically monitor glucose and provide appropriate basal insulin doses in people 14 years of age and older with type 1 diabetes. In June 2018, the indication was expanded to include people with T1D between the ages of 7 and 13 years In auto mode - Measures glucose levels every five minutes (using CGM) and automatically administers or withholds insulin. Sensor attaches to the body to measure glucose levels under the skin Insulin pump strapped to the body; and an infusion patch connected to the pump with a catheter that delivers insulin. Device automatically adjusts basal insulin levels; users need to manually request insulin doses to counter carbohydrate (meal) consumption. input of meal patient times https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm522974.htm Dr. Katie Ryan https://www.medtronicdiabetes.com/products/minimed-670g-insulin-pump-system 43 References Drug Delivery: Fundamentals & Applications, 2nd Edition, Ed by A. Hilliery & K. Park. Dirk Schmaljohann, Thermo- and pH-responsive polymers in drug delivery, Advanced Drug Delivery Reviews, 58(15), 2006, Pages 1655-1670 Srinivas Ganta et al. A review of stimuli-responsive nanocarriers for drug and gene delivery, Journal of Controlled Release,126 (3),2008, Pg 187-204 Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: Concepts and applications, Advanced Drug Delivery Reviews, 64 (9) 2012, Pages 866-884. Gupta et al, Hydrogels: from controlled release to pH-responsive drug delivery Drug Discovery Today 7(10), 15 May 2002, Pages 569-579 Eichenbaum et al. 1999, Macromolecules 32(15), 4867-4878 Hydrogels, Ch. 7 In Drug Delivery: Fundamental and Applications, Siegel and Alvarez-Lorenzo, Edited by Hilery & Park Medtronic MiniMed 670G Hybrid Closed-Loop System, Knebel and Neumiller, Clinical Diabetes 2019 Jan; 37(1): 94-95. https://doi.org/10.2337/cd18-0067 & a https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm522974.htm https://www.medtronicdiabetes.com/products/minimed-670g-insulin-pump-system > Dr. Katie Ryan 22 44 Morplant withdrawn from Maret to cut pate Reseucir subdivided system can't be b miroportices & Rish failure. of device