Advanced Oral Dosage Formulation Approaches PDF

Advanced Oral Dosage Formulation Approaches: Solid oral dosage form design: An ideal drug delivery system delivers the correct amount of drug to the site of action a the correct rate to maximise the therapeutic response and minimise side effects Modified release design: Objective = modulate the rate...

Advanced Oral Dosage Formulation Approaches: Solid oral dosage form design: An ideal drug delivery system delivers the correct amount of drug to the site of action a the correct rate to maximise the therapeutic response and minimise side effects Modified release design: Objective = modulate the rate of drug input in the intestinal tract to achieve a predefined plasma profile Includes - Delayed release - Sustained release - Programmed release - Site specific/timed release Modified Release Drug Delivery: The manipulation/modification of drug release from a dosage form with the aim of delivering the API at desired rates, predefined time points or at specific sites in the GIT Advantages: - Can control the rate and site of drug release to reach clinical objectives that otherwise cannot be achieved - Offers sustained blood levels, improved efficacy and optimised performance - Can help to reduce side effects - Allows local treatment of GIT disorders - More convenient, better patient compliance (Chronotherapy) - Protects acid sensitive drugs from the harsh stomach environment - Can design bimodal release drugs – part released immediately and part delayed or extended Drug properties that influence MR dosage forms: Solubility - Good solubility allows for many formulation options - Very low solubility drugs are inherently sustained release due to their slow dissolution Permeability - Drug must be sufficiently permeable (lipophilic – logP 1-5) to provide absorption rate faster than release from dosage form Transport mechanism - Drugs absorbed via carrier mediated transport have too narrow an absorption window to allow delivery of 12-24hrs worth of medication in one administration - Most carriers only act in one specific portion of the gut – the drug won’t be there for long enough Dose - Daily dose must not be too large to swallow (usually 500mg-1g) Enzymatic inactivation - If drugs are inactivated by enzymes faster than they are released then the presystemic drug loss will be mch higher - If absorbed from the colon, extended release formulations can increase bioavailability – some enzymes (e.g. CYP3A4) are missing from the colon, so the drug is not degraded as much Types of Modified Release: 1. Delayed Release: - Drug is released at a time later than immediately after administration - Lag time between taking the medicine and the drug being detectable in the blood - The dosage from dissolves somewhere after the stomach – disintegrate rapidly once the desired area of the GIT has been reached - A membrane is designed to disintegrate or dissolve at a predetermined point o Most common trigger is pH - Most commonly release drugs in the small intestine but can also be used for colonic drug delivery Problems: - Gastrointestinal pH is not always predictable and reproducible in vivo - Some patients have higher than normal stomach pH – risk of early release - IBD patients have delayed gastric transit time – enteric release drug not released quickly enough – use IR Polymers: - Number of polymers used that dissolve at different pH ranges – polymer characteristics and mechanism of drug release control rate of release - Anionic polymethacrylates, methacrylic acid copolymers are widely used - Cellulose based polymers of PVAP are also used - Polymer’s release profile is controlled by the pH-dependent solubility of the polymeric acid functional groups Enteric Coating: - Gastro-resistant acidic polymer coatings which are insoluble at low pH but soluble at higher pH (5-7) - pH sensitive solubility enteric coating are the most common delayed release design - Protect acid labile drugs from harsh stomach environment - Protect the stomach from drugs that can irritate the stomach lining Example: Aspirin 75mg enteric coated tablets: - Aspirin harms GI mucosa by its local and systemic effects, can lead to erosion, ulceration and bleeding - Causes direct topical injury to the epithelium and systemic effects due to prostaglandin depletion - To overcome this – aspirin is formulated with an enteric coating - Methyacrylic acid-ethyl acrylate copolymer (1:1) – soluble above pH 5.5 Patient advice for taking enteric coated drugs: - Do not crush or chew the tablet - Swallow the tablet whole - Do not take any antacids or other drugs that may alter the pH of the stomach with the drug 2. Extended Release: - Formulated to make the drug available over an extended period - Reduced dosing frequency by at least two-fold compared to IR dosage form - More convenient - More consistent plasma concentrations - Fewer adverse reactions - Can control release rate by controlling diffusion, dissolution or osmosis Diffusion Controlled Release: Reservoir Systems: - Drug molecules are present in a drug reservoir that is surrounded by a polymeric membrane that the drugs must diffuse through - Diffusion through this membrane controls the rate of release - The dissolution medium must penetrate the membrane into the reservoir to dissolve the drug - The dissolved drug can then diffuse out of the dosage form and is released - The rate of diffusion depends on the molecular size of the drug and the porosity of the polymer membrane - Non-porous systems: o Release follows Fick’s Law o Factors that influence the diffusion coefficient include: viscosity, density, drug solubility (particle size, crystal form), diffusion medium (wetting agents, fasted/fed state) o For fast diffusion the membrane should be a thin stagnant layer with low viscosity o Using polymeric and lipid based excipients can increase polymer viscosity - Porous Systems: o The size and dimension of the pores is related to the size of the pore-forming agent o Release of frug involves transport of drug through porous pathways o Must consider porosity and tortuosity of path - Insoluble polymers (e.g. ethylcellulose) are semi-permeable and allow drug release independent of pH Matrix Systems – hydrophobic: - Drug substance is homogeneously dispersed with rate controlling material in a matrix system - Drug release occurs either by diffusion or by erosion of the polymer - Hydrophobic systems: o Rate control by water-insoluble inert matrix – drug is embedded in an inert polymer o Generally, water enters matrix, dissolves drug and dissolved drug diffuses out of matrix  o Minimal swelling – stay intact throughout GIT , little change in dimension o Travel through GIT undigested and are excreted in faeces o Rate of release controlled by pore size, number of pores and tortuosity of the matrix o Can add pore-forming agents to facilitate drug release o More limited material options – materials should be biocompatible ▪ Fatty acids and their glycerol esters ▪ Wax-like materials ▪ Silicon ribber ▪ Insoluble polymers such as ethyl cellulose, Eudragit and cellulose esters o Fast release: ▪ Low mw and low viscosity polymers ▪ Formulations with low % polymer o Slow release: ▪ Viscous polymers ▪ High mw polymers, high degree of cross-linking ▪ Formulations with high % polymer ▪ Incorporation of release modifiers o Release of drug decreases with time due to depletion of drug closest to surface of matrix – difficult to achieve zero order release from matrix - Example: o Adizem-SR prolonged release capsules o BD dosing ethylcellulose non-erodible polymer Dissolution Controlled Release: Hydrophobic reservoir systems also dissolution-controlled release – release is controlled by the erosion of the polymer not by the permeation of the drug Matrix Systems – Hydrophilic: - Dissolution = dissolution of the polymer in the matrix, release of drug from degradable device - Degradation either by o Bioerosion: gradual dissolution of polymer by physiological fluids o Biodegradation: breakdown of polymer by chemical or enzymatic processes o Surface erosion: surface exposed to degradation medium is eroded, erosion works in layer-by-layer o Bul erosion: entire polymer undergoes chemical/enzymatic erosion - Hydrophilic systems: o Rate controlling excipients are water-soluble, swellable polymers o Polymer usually powder/granules and is manufactured by direct/roller compression into tablets o Polymers available: ▪ Cellulose derivatives such as HPMC ▪ Synthetic polymers of varying degrees of cross-linking e.g. polyethylene oxide ▪ Natural polymers such as xanthan gum and alginate o Viscosity and solubility of polymers relates to degree and type of substitution and molecular weight of the polymer o On exposure to fluid the polymer starts to swell producing a gel matrix which allows the drug to be released through erosion or dissolution of the gel - Widely used for extended delivery o Can accommodate low and high drug concentrations o Can accommodate drugs with wide range of physicochemical properties o Cost-effective and generally easier to scale up o Manufactured using conventional processes and equipment - Mechanisms controlling release: 1. Hydration of polymer 2. Swelling behaviour of polymer influences 3. Diffusion as gel layer hydrates and forms  4. Bioerosion of gel as dissolution proceeds - Controlling release (Bioerosion) o Must consider dissolution rate of polymer o Degree of swelling (viscosity) of polymer o Combining different polymers can create different release profiles o Drug physicochemical properties need to be considered e.g. solubility o Release profile can be influenced by processing/manufacturing factors e.g. granulation vs direct compression o Dissolution medium can influence rate of dissolution – pH, electrolytes - Bioerosion polymers: o Cellulose esters, HPMC, - Biodegradation polymers: o Natural polymers: chitosan, hyaluronic acid ▪ Mostly undergo enzymatic degradation, can cause immunogenic response, batch to batch variability o Synthetic polymers ▪ Mostly undergo chemical degradation, biologically inert, less variation, more predictable kinetics - Example: o MacroBID – nitrofurantoin BD dosing – Carbopol and PVP o Drug released in the intestine Osmosis Controlled Release: Osmosis = movement of water through a semi-permeable membrane from an area of high concentration to low concentration - Release is independent of pH and other physiological parameters - Rate of drug release can be modified by changing viscosity of solution formed inside the system - Osmotic pump system required sufficient exposure to water to build up osmotic pressure – dependent of fluid volume in the gut Osmotic Pump System: - Drug is in water soluble tablet core that is coated with a semi-permeable membrane - Membrane allows water in, water dissolves the components of the core and pressure builds which pumps the drug solution out through a hole present in the coating - The hole must be small enough to prevent diffusion but large enough to minimise hydrostatic pressure – typically 0.6-1mm - The hole/orifice can be made through laser drilling, indentation or use of leachable substances Elementary osmotic pumps - First used: drug core, semi-permeable membrane, laser drilled orifice - If the drug gets stick in one part of GIT the high pressure and high drug concentrations can cause irritation Controlled-porosity osmotic pumps - Drug core surrounded by microporous membrane - When exposed to water, micropores are created in the membrane, the drug is released at many different points throughout the membrane - Minimises side effects Push-Pull osmotic pumps - Same as elementary with an additional push layer - Push layer is osmotically active and also causes a build up of osmotic pressure forcing the dtug out of the orifice - Same high pressure problem as elementary pumps Formulation factors influencing release: - Drug solubility o Release rate is directly proportional to solubility of drug o Highly soluble or poorly soluble drugs are not good candidates  o May be necessary to modify the apparent solubility of the drug - Osmotic pressure: o Dependent on the number of molecules of solute in the solution o Release is controlled by maintaining a constant osmotic pressure which is achieved by maintaining a saturated solution in the core o If there is not sufficient osmotic pressure, an osmagent can be added e.g. water soluble amino acids - Delivery orifice: o Too small – hydrostatic pressure may develop, deforming or bursting the device o Too large – release is diffusion controlled not osmotic pressure controlled - Coating membrane o Release influenced by thickness of membrane o Can influence the water permeability of the membrane to modify release o Most common used polymer is cellulose acetate, other cellulose derivatives also used Safety/Compliance: - Avoid if there is pre-existing GI injury, resulting in GI narrowing - Large dosage forms – may be difficult to swallow - Patients should be warned about excretion of undigested capsule shells - Not suitable for drugs with narrow absorption windows - If the dosage form is too large it may be retained in the stomach Example: - Cardura XL - Push-pull osmotic pump, once daily dosing Sublingual Drug Delivery: - Drug is placed under the tongue where it dissolves and is absorbed into blood stream – not intended to be swallowed or chewed, should not be absorbed from GIT Advantages: - Avoids FPM, destruction by gastric juices or complexation with food - Fast absorption and entry into systemic circulation - Potency is predictable - Administration is convenient, accessible, well accepted and the patient doesn’t need to be able to swallow - Sublingual mucosa is more permeable than buccal mucosa - Acceptable bioavailability of many drugs Disadvantages: - Cannot be used for controlled release – the area is constantly washed by a considerable amount of saliva - Too difficult to get the device to stay in place Requirements: Drug should - Be tasteless - Dissolve rapidly - Produce therapeutic effects with small amounts of drugs Excipients: - Increase rate of disintegration - Enhance solubility (complexing agents) - Enhance epithelium permeation (solvents, triglycerides) - Taste masking agents, flavourings Types of dosage forms: - Tablets - Sprays - Drops - Films Example: - Nitrolingual pump spray- GTN sublingual spray Buccal Drug Delivery: Administration of drug through the buccal mucosal membrane lining of the mouth Advantages: - Can be used for local and systemic delivery - Good patient compliance – avoids discomfort and pain - Better retention than sublingual – less saliva washing and smooth muscle is relatively immobile - High accessibility, low enzymatic activity, rapid onset, low risk of toxicity Disadvantages: - Lack of dosage form retention – can be improved with bio-adhesive polymers - Absorption lower and slower than sublingual Types of dosage form: - Tablets - Patches - Films - Semi-solids - Powders Oro-dispersible Tablets: Tablets that dissolve/disintegrate on contact with saliva but are absorbed later in the GIT - Used mainly in paediatric and geriatric patients - Superdisintegrants added to give burst of disintegration when in contact with saliva – drug is released in mouth e.g. Crospovidone - Disintegrates in just seconds Advantages: - Quicker absorption - Potential increased bioavailability - Easier administration – swallowing Criteria for ODT: - Low dose of API (