Therapeutic systems lecture 5


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Therapeutic systems lecture 5

  1. 1. THERAPEUTIC SYSTEMS AND NOVEL DRUG DELIVERY DEVICES Prepared by: S. Campbell-Elliott B Pharm., M Pharm Sc
  2. 2. What are these systems/devices? <ul><li>Manipulated formulation design to alter release characteristics </li></ul><ul><li>Drug released is : </li></ul><ul><li>- controlled </li></ul><ul><li>- with predetermined rate </li></ul><ul><li>- with predetermined duration </li></ul><ul><li>- predetermined location of release </li></ul>
  3. 3. Rationale <ul><li>Reduced fluctuations between maximum and minimum morphine levels </li></ul><ul><li>two-way crossover study in healthy men (N=24) comparing sustained-release morphine tablets (SR) with immediate-release morphine. Data represent plasma morphine levels from 48-60 hours. Finn JW, et al. Placebo-blinded study of morphine sulfate sustained-release. </li></ul><ul><li>J Clin Oncol . 1993;11:967972. </li></ul><ul><li>Sustained desired therapeutic concentrations (less peaks/troughs) </li></ul><ul><li>Reduce frequency of admin and compliance </li></ul><ul><li>Reduce side effect profile </li></ul><ul><li>Provides controlled drug release ( ≈ zero order) </li></ul><ul><li>Available in various dosage formulations ( focus will be on oral and TTS) </li></ul>
  4. 4. Types of Modified release oral formulations <ul><li>Prolonged Release : absorption occurs over a long time; onset may be delayed due to slower release rate </li></ul><ul><li>Sustained Release : initial release; then gradual over long period </li></ul><ul><li>Extended Release : drug released slowly; used to maintain plasma levels for long periods; reduces frequency of admin </li></ul><ul><li>Note : Modified/Controlled-release refers to any modification i.e. also includes delayed-release </li></ul>
  5. 5. Criteria for selection <ul><li>Biological Half-life : t 1/2 must be >2hrs but less than 8 hrs </li></ul><ul><li>Absorption : not suitable for slow absorption rates or site-specific absorption </li></ul><ul><li>Metabolism : not suited for drugs with high pre-systemic and hepatic metabolism </li></ul><ul><li>Therapeutic range : ideal for drugs with narrow therapeutic range** </li></ul><ul><li>Dose size : Not useful for large doses </li></ul><ul><li>Aqueous solubility : not suited for drugs with very high or low rates of dissolution </li></ul><ul><li>Partition coefficient : ideal for drugs with logP ≈ 2.5-3.3 </li></ul><ul><li>Stability : suited for relatively stable drug throughout the GIT </li></ul><ul><li>Disease state : considered more useful in chronic vs acute states </li></ul>
  6. 6. Advantages/Disadvantages of Extended/Sustained release Oral preps <ul><li>DISADVANTAGES </li></ul><ul><li>↑ cost </li></ul><ul><li>Based on design unpredictable bioavail. </li></ul><ul><li>Possible ‘dose-dumping’ </li></ul><ul><li>risk of ↑ drug conc in plasma and toxicities </li></ul><ul><li>ADVANTAGES </li></ul><ul><li>↓ frequency of admin </li></ul><ul><li>↑ patient compliance </li></ul><ul><li>↓ plasma drug conc. with </li></ul><ul><li>improved therapeutic goals </li></ul><ul><li>↓ side effect profile </li></ul>
  7. 7. Types of Oral Delivery Devices (extended/sustained-release) <ul><li>OROS Push-Pull </li></ul><ul><li>- contains bilayer; core of drug (60-80%)with </li></ul><ul><li>excipients and push layer (20-40%) with </li></ul><ul><li>hydrophilic expanding compartment </li></ul><ul><li>- Both layers absorb water from GIT to </li></ul><ul><li>form drug solution/susp while push </li></ul><ul><li>compartment swells and drug leaves </li></ul><ul><li>via orifice </li></ul><ul><li>- Rate of release is determined by volume of water </li></ul><ul><li>that enters and force from push compartment </li></ul><ul><li>-pH and GI motility has little effect on formulation </li></ul><ul><li>e.g. Cardura XL ® ; Procardia XL ® ; Concerta ® </li></ul><ul><li>The osmotic push–pull tablet: cross-section of bilayer tablet before and after ingestion. Optional drug ‘overcoat’can be </li></ul><ul><li>included if required. Curr Med Res Opin 2006; 22(10) </li></ul>
  8. 8. OROS Push-Pull System cont’d <ul><li>Advantages: </li></ul><ul><li>Disadvantages: </li></ul><ul><li>Care/Advice: </li></ul>
  9. 9. Types of Oral Delivery Devices cont’d <ul><li>Membrane-Controlled (Reservoir) </li></ul><ul><li>Drug is contained in reservoir surrounded by rate controlling polymer (determines drug release; flux across membrane described by Fick’s Law; system contains more drug than needed to provide driving force </li></ul><ul><li>Partition coefficient of drug will affect drug movement from core </li></ul><ul><li>“ Lag time” may result from delay in diffusion of drug from reservoir to membrane surface or a ‘burst effect’ due to saturation of membrane </li></ul><ul><li>Device vacates the GIT intact </li></ul><ul><li>- Damage may result in ‘dose dumping’ </li></ul><ul><li>e.g. Cardizem CR </li></ul>
  10. 10. Membrane-Controlled (Reservoir) <ul><li>Advantages: </li></ul><ul><li>Disadvantages: </li></ul><ul><li>Care/Advice: </li></ul>
  11. 11. Types of Oral Delivery Devices cont’d <ul><li>Matrix-controlled Device </li></ul><ul><li>- Drug combined with soluble or insoluble matrix/carrier; tablet then compressed </li></ul><ul><li>- With soluble polymers, rate of drug release depends on water entry and this is controlled by tablet porosity or addition of hydrophilic additives </li></ul><ul><li>- ‘Insoluble’ matrices consist of a plastic (polyethylene) and a hydrophilic (methylcellulose) material mixed with drug; this swells when in contact with GI fluids and drug slowly diffuses from matrix </li></ul><ul><li>- Drug release explained by Higuchi* (drug release may be altered by drug and matrix parameters e.g. drug conc. in matrix, drug solubility, porosity, tortuosity and nature of polymer) </li></ul><ul><li>* Higuchi T. Rate of release of medicaments….J.Pharm Sci 1961;50:874 </li></ul>
  12. 12. Matrix-controlled Device cont’d <ul><li>- Remains intact throughout the GIT </li></ul><ul><li>- e.g. Ferrogradumet ® , Theo-Dur ® , Naprosyn ® SR </li></ul><ul><li>BIOERODIBLE MATRIX SYSTEM </li></ul><ul><li>- Drug is dispersed in polymer which erodes when in contact with GITreleasing the drug </li></ul><ul><li>- Similar benefits of matrix system but matrix erodes within the GIT </li></ul><ul><li>e.g. Sinemet ®CR </li></ul>
  13. 13. Matrix-controlled Device cont’d <ul><li>Advantages: </li></ul><ul><li>Disadvantages: </li></ul><ul><li>Care/Advice: </li></ul>
  14. 14. Types of Oral Delivery Devices cont’d <ul><li>Ion-exchange System </li></ul><ul><li>- Consists of drug bound (via ionic bonds) to water-insoluble resins which have salt-forming functional groups </li></ul><ul><li>- Upon contact with GI fluids containing ions of ‘like’ charge to the drug, an exchange occurs at the drug-resin binding site. Drug ‘switches’ binding with endogenous ions e.g. H + , K + , Na + , releasing drug to diffuse from water-swollen resin </li></ul><ul><li>e.g. Duromine ® , Biphetamine ® </li></ul>
  15. 15. Ion-exchange System cont’d <ul><li>Advantages: </li></ul><ul><li>Disadvantages: </li></ul><ul><li>Care/Advice: </li></ul>
  16. 16. Types of Oral Delivery Devices cont’d <ul><li>Spansules </li></ul><ul><li>- drug-loaded granules, pellets or beads which are then coated with a slowly dissolving polymer ( may be compressed or placed in a gelatin capsule) </li></ul><ul><li>- Drug release may be controlled by dissolution rate of coat or ** thickness of the coating used </li></ul><ul><li>- Spansules is a capsule consisting of a number of groups of drug-loaded beads having coats of varying thickness; each group of beads within the capsule are then colour-coded </li></ul><ul><li>e.g. Dexedrine ® , Ornade ® </li></ul>