Pharmaceutics 2: Drug Delivery for Analgesia: Opioid Focused PDF

Pharmaceutics 2 Drug delivery for analgesia: Opioid focused Dr Maria Marlow  Outline ▪ Routes of delivery/dosage forms for analgesia ▪ Oral controlled release 2  Aim of this lecture ▪ To understand why different routes of administra...

Pharmaceutics 2 Drug delivery for analgesia: Opioid focused Dr Maria Marlow  Outline ▪ Routes of delivery/dosage forms for analgesia ▪ Oral controlled release 2  Aim of this lecture ▪ To understand why different routes of administration and formulations are used in analgesia particularly with opioids ▪ Oral controlled release To understand the definitions of modified release and extended release To be able to describe the advantages and limitations of extended release To understand the drug release mechanisms from hydrophilic matrix, insoluble polymer/ lipid matrix, membrane controlled, and osmotic pumps 3  Routes of Administration ▪ Oral, intravenous, transdermal, epidural, intrathecal, sublingual/buccal, nasal, rectal ▪ Intravenous ▪ Rapid action from drug being presented directly to the circulation ▪ No lag time between administration and action ▪ Physician being able to titrate the dose ▪ More predictable response compared to routes ▪ Incomplete absorption and variability in absorption is eliminated ▪ Sublingual/buccal ▪ Absorption through the oral mucosa (oral cavity); sublingual beneath the tongue ▪ Oral cavity rich in blood vessels -> rapid onset of action and high blood levels ▪ Absorbed directly into the systemic circulation via the jugular vein- no first pass metabolism 4  Buccal delivery Structure of the oral mucosa: shows considerable epithelial tissue Different regions of the mouth: Shaded regions have some keratinisation of the epithelium Some epithelium is keratinised, but thickness and degree of keratinisation (less permeable) varies with the site in the mouth Relative permeability to drugs is: sublingual > buccal 5 Both diagrams from Encyclopaedia of Controlled drug delivery: Ed E Mathiowitz Vol 2, J Wiley&Sons, vol2, p555 (1999)  Sublingual tablets ▪ Used as dosage form for transmucosal delivery ▪ Small/porous fast disintegrating tablet placed under the tongue (BNF example) ▪ Buprenorphine Routes of Administration- break through pain 7  Routes of Administration:Transdermal Transdermal ▪ Drug diffusion from the delivery system (containing a drug reservoir) through the epidermis (main barrier is the stratum corneum) and dermis (rich blood supply) ▪ Two routes through stratum corneum ▪ Hydrophilic keratinised cells and lipid channels ▪ Main route of absorption is lipid channels ▪ Used mainly for small molecular weight lipophilic drugs 8  Routes of administration: Ideal properties for transdermal drug delivery Transdermal Ideal properties for transdermal drug Physicochemical A B C properties/ Drug Log P – partition coefficient between 1 and 4 Log P 5 0.46 4 Molecular weight releases whole dose later e.g enteric coated aspirin (avoids release in stomach & gastric irritation) –DIG in year 1 ▪ Extended release (modified release-BNF) -> releases drug slowly over an extended time -> plasma concentrations maintained at a therapeutic level for a 12 prolonged period of time (12 to 24 hours) Oral extended release: what this means for the patient(1) 13  Oral extended release:what it means for the patient (2) ▪ Extended release: drug plasma concentrations maintained in therapeutic range for extended period of time ▪ Maintain therapy overnight no-dose periods e.g useful in pain control ▪ For example overnight management of pain in terminally ill patients permits improved sleep ▪ Avoids breakthrough of symptoms if plasma levels decrease below the minimum effective concentration e.g morning mobility for OA patients ▪ Avoids side effects if plasma levels increase ▪ Reduction in the total amt of drug admin over treatment period ▪ Reduction in the incidence of local and systemic side effects 14  Oral extended release: what it means for the patient (3) ▪ Reduced dosing frequency (drugs with short half-lifes) ▪ Convenience ▪ Increased compliance? ▪ Health services ▪ Sleep through night, fewer side effects symptoms, doses-> reduction in doctor/nursing time 15  Oral extended release: Limitations ▪ Physiological factors such as gastrointestinal pH, enzyme activity, gastric and intestinal transit rates , food and severity of disease can interfere with the control of release and drug absorption ▪ Rate of transit of ER product along GI tract limits max. period to 24 hours ▪ Stomach 30 mins to 4 hours ▪ Small intestine – 3 to 5 hours ▪ Large intestine - 12- 72 hours ▪ Overdose-slow clearance of drug from the body ▪ Risk of prolonged toxicity if therapeutic index of the drug is too narrow 16  Oral extended release: Limitations continued ▪ Accidental poisoning e.g by chewing; could be fatal!! ▪ Size of tablet/capsule maybe large (3 -4 times drugs) ▪ Difficult to swallow if ~1g e.g Ibuprofen 800mg ▪ Maybe also difficult to formulate with lower levels of excipients if high drug load ▪ Non –bioequivalence ▪ Many MR products may differ even if intent is to have same effect ▪ Different technologies (release mechanism and time release profile ) 17  Oral extended release Factors influencing the design of extended release oral formulations ▪ Physiology of the GIT and absorption ▪ Particulates/pellets leave the stomach rapidly ▪ Single dose units > 7mm can stay in the stomach for upto 10 hours ▪ Aqueous solubility and permeability ▪ Absorbed by passive diffusion (non- site specific absorption) ▪ Ideal: high solubility no issues of dissolution cf low solubility retards dissolutions ▪ Drugs with low permeability maybe not suitable for MR 18  Oral extended release:Different types of commercially available dosage forms Hydrophilic matrix Insoluble polymer/ Membrane Osmotic pumps lipid matrix controlled Type of Tablet (monolithic) Tablet (monolithic) Coated Single Unit dosage tablet/coated form pellet Key Sustained release is Sustained release is Diffusion through Water diffusion features maintained by diffusion maintained by diffusion a polymer coat through a semi- through a swollen through a non-dissolving permeable polymer gel & gel sponge-like polymer membrane erosion scaffold or lipid matrix & lipid digestion Key Hydroxypropylmeythyl Insoluble polymers Water insoluble Osmotically active ingredients cellulose (HPMC), e.g ethylcellulose polymers (e.g filler e.g lactose, PEG ethylcellulose semi permeable lipid matrices (e.g and acrylic membrane e.g glycerol palmitostearate) polymers) cellulose acetate19  Buzz quiz ▪ Why should patients not chew extended release formulations? 20  Insoluble polymer matrix ▪ Insoluble polymer matrices (e.g ethylcellulose, polymethacrylate) ▪ Drug embedded in an insert polymer ▪ Diffusion through insoluble polymeric matrix; drug molecules diffuse through a network of capillaries of polymer compacted particles ▪ Release rate modified by changes in pore structure and tortuosity ▪ Matrices remain intact during GI transit ▪ Less commonly used 21  Hydrophilic matrix Tablet produced from water swelling polymer (eg HPMC) Polymers nots affected by pH changes through the GI tract Can be used in combination with insoluble polymers e.g carbopol matrix swelling matrix/gel erosion surface hydrates => viscous gel structure matrix erodes in GI tract gel is a barrier to liquid ingress into tablet stage important for release of and drug diffusion out water insoluble drugs (stage important for water soluble drugs) 22 Reference: http://link.springer.com/content/pdf/10.1007%2F978-1-59745-210-6.pdf  BNF examples ▪ Hydroxyethylcellulose, hypromellose (=hydroxypropyl methylcellulose) 23  Membrane controlled ▪ Tablet ▪ Conventional tablet coated with an insoluble polymer ▪ Choice of excipients to prevent any osmotic effects e.g lactose, microcrystalline cellulose, dextrose, sucrose ▪ Multi-particulate systems Example = Zomorph Polymer coated ▪ Drug coated sugar spheres ▪ Pellets/spheroids manufactured by an wet extrusion/spheronisation process (lactose, microcrystalline cellulose, binder) Filled into hard gelatin capsules or compressed into a tablet Membrane controlled system: Release mechanism Multi-particulate Single tablet Water enters interior of particle/tablet by Insoluble polymer coating diffusion Drug particle dissolves→ Dissolution of the drug Diffusion of the drug through the polymer coating membrane Normally rate controlling Drug particles step Erosion of the polymer coating Diagrams not to scale  Osmotic pumps ▪ Drug included in water soluble core ▪ Suspend or solubilise drug ▪ Tablet coated with semi-permeable membrane → water passes into the core ▪ Core dissolves and hydrostatic pressure builds up → forces drug solution or suspension through a drilled hole in semi- permeable membrane ▪ Drug release governed by ▪ Membrane ▪ Viscosity of the solution/suspension ▪ Size of the drilled hole Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697821/  Lecture summary ▪ Routes of administration offer rapid onset in pain management ▪ i.v, transmucosal ▪ Extended release has place in pain management ▪ Ability to keep the plasma concentration within therapeutic window ▪ Oral modified release and transdermal ▪ The technologies to achieve oral extended release include Hydrophilic matrix ▪ Hydrophilic matrix, insoluble polymer/ lipid matrix, membrane controlled, osmotic pumps 27