Sustained release dosage forms sr

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Sustained release dosage forms sr

  1. 1. Sustained release dosage forms October 23, 2013 1
  2. 2. • • • • • • • Introduction-definition Concept Objectives Advantages and disadvantages Dose considerations Formulation Types of SR systems Diffusion systems Dissolution systems Ion exchange sys October 23, 2013 2
  3. 3. • Oral SR delivery systems design and types • Parentral SR dosage forms types and routes • References October 23, 2013 3
  4. 4. IDEAL DRUG DELIVERY SYSTEM • should deliver drug at a rate dictated by the needs of the body over the period of the treatment. • should channel the active entity solely to the site of action. • This is achieved by development of new various modified drug release dosage forms, like-     Control release dosage forms Time release dosage forms Sustained release dosage forms Site specific or targeted drug delivery systems etc. October 23, 2013 4
  5. 5. “Drug Delivery systems that are designed to achieve prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose.” Basic goal of the therapy to achieve steady state blood level that is therapeutically effective & non toxic for an extended period of time. October 23, 2013 5
  6. 6. Sustained release drug profile October 23, 2013 6
  7. 7. Objectives of drug delivery • Temporal drug delivery: controlling the rate or specific time of drug delivery to the target tissue. • Spatial drug delivery: targeting a drug to a specific organ or tissue. October 23, 2013 7
  8. 8. advantages Reduction in fluctuation in steady state levels Increased safety of high potency drugs Total amount of dose is decreased Improved patient compliance disadvantages Poor in vivo-in vitro correlation Possibility of dose dumping Retrieval of drug is difficult October 23, 2013 Dose adjustments is difficult 8
  9. 9. • Biopharmaceutical properties: Molecular size Aqueous solubility Partition coefficient Dissociation constant less than 600 Daltons more than 0.1 mg/ml between 1 to 2 pka acidic drugs pka>2.5 Basic drugs pka<11 Absorption mechanism passive but not through Window Ionisation at physiological pH NMT 95% October 23, 2013 9
  10. 10. Pharmacokinetic properties • Absorption rate constant ka high(btw 0.170.23/hr) • Elimination half life t1/2 2-6 hrs • Metabolism rate not too high • Dosage form index(ratio of cssmax /css min) One October 23, 2013 10
  11. 11. Pharmacodyanamic properties Dose max 1.0g (in a controlled release form) Therapeutic range wide Therapeutic index wide  PK/PD relationship good October 23, 2013 11
  12. 12. • Divided into two considerations 1.Release rate consideration Release rate consideration :- In conventional dosage form Kr>Ka - release of drug from dosage form is not rate limiting step. October 23, 2013 12
  13. 13. (Kr>>Ka) in immediate release non immediate (Kr<<<Ka) i.e. release is rate limiting step. The release should follow zero order kinetics (clinically equivalent to constant release in many cases) Kr = rate in = rate out = Ke.Vd.Cp Ke = Elimination rate constant (first order kinetics). Vd = Total volume of distribution. Cp = Plasma drug concentration. Kr = zero order release rate constant October 23, 2013 13
  14. 14. b)Dose consideration: for zero order release core Maintenance dose Immediate release component a) Initial (primary) dose Di b)Maintenance dose Dm = kr .Td Td=total time required for extended release dosage form therefore, total dose W October 23, 2013 W= Di + Dm W=Di +Kr.Td 14
  15. 15. If maintenance dose begins to release the drug during dosing t=0 then, W = Di + K r. Td – Kr.Tp Tp = time of peak drug level. October 23, 2013 15
  16. 16. First order release rate in=rate out Dm.kr=ke.Cp.Vd Dm=ke.Cp.Vd/kr W=Di+Dm W=Di+(keCp/kr)Vd kr= first order release rate constant ke=elimination rate constant Cp=plasma drug concentration If drug begins to release maintenance dose at T=0 W=Di+(keCp/kr)Vd - DmkeTp Tp= time of peak plasma drug concentration October 23, 2013 16
  17. 17. Diffusion systems • Porous matrix controlled system Rate controlling element-water swellable material e.g. xanthan gums ,guar gum , high viscosity grades of HPMC,HPC, alginates or non- swellable water insoluble polymers such as ethylcellulose October 23, 2013 17
  18. 18. • Porous membrane controlled system rate controlling element – non-swellable water insoluble polymer e.g. ethylcellulose, PMA. Drug release controlled through micropores. October 23, 2013 18
  19. 19. • Can be in following ways:Slow dissolution of drug 1. Drug with inherently slow dissolution rate. 2. Drugs that transforms into a slow dissolving form. Slow dissolution rate of reservoir memb. & matrix 1. Embedment in slowly dissolving, degrading erodible matrix. 2. Encapsulation or coating with slowly dissolving degrading erodible subs. October 23, 2013 19
  20. 20. • slowly soluble and erodible materials:Ethylcellulose, PVP with cellulose PMA(eudragits), Waxes(glyceryl monostearate) October 23, 2013 20
  21. 21. Erosion controlled Polymer or wax degradation brought about by: enzyme, pH change osmotic pressure • Bulk erosion(A) homogeneous erosion • Surface erosion(B) heterogenous erosion when water penetration is restricted to surface October 23, 2013 21
  22. 22. ORAL SUSTAINED RELEASE DESIGN • Continuous release systems-release drug continuosly over extended period of time. • Pulsatile release systems:characterize by a lag time then rapid & complete /extended release. Advantages:1. Drugs with extended first pass e.g. Propranolol 2. Targeting e.g. in intestinal inflammations 3. Protection of gastric or upper intestinal mucosa from irritating drugs. October 23, 2013 22
  23. 23. Following methods can be used to prepare sustained release oral preparation:• Increasing the particle size of the drug • Embedding the drug in a polymeric matrix. • Coating the drug or dosage form containing drug(microencapsulation). • Forming complexes of the drug with material such as ion exchange resins. October 23, 2013 23
  24. 24. 1)Increasing the particle size of the drug • Increasing particle size decreases the surface to volume ratio slow the rate of drug availability. •This method is limited to poorly soluble drug . October 23, 2013 24
  25. 25. 2) Embedding the drug in matrix • Matrix is a uniform dispersion of drug with polymer matrix • Continuous external phase of the dispersion effectively impede the passage of the drug from the matrix. • Drug release through-diffusion • Least complicated approaches to manufacture sustained release dosage form involves the direct compression of drug, materials & additives to form a tablet . October 23, 2013 25
  26. 26. polymers •Insoluble, inert - polyethylene, polyvinyl chloride, methyl acrylate, ethylcellulose. •Insoluble, erodible – carnauba wax, stearyl alcohol, castor wax. •Hydrophilic – methyl cellulose, hydroxyl ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate. October 23, 2013 26
  27. 27. 3) Microencapsulation • method for retarding drug release by coating its surface with a material(polymers) that retards penetration by the dispersion fluid. • it is a means of applying relatively thin coating to small particles of solid or droplets of liquids and dispersion. Can be done byspray congealing spray drying October 23, 2013 27
  28. 28. Polymers: • • • • • • • • • Polyvinyl alcohol Polyacrylic acid Ethyl cellulose(pH sensitive) Polyethylene Polymethacrylate Poly (ethylene-vinyl acetate) Cellulose nitrite Silicones Poly (lactide-co-glycolide) October 23, 2013 28
  29. 29. 3)Ion exchange resins • Sustained delivery of ionizing acidic & basic drug can be obtained by complexing them with insoluble non-toxic anion exchanger & cation exchanger resin respectively. • Release by diffusion . • The complex can be prepared by incubating the drug-resin solution or passing the drug solution through a column containing ion exchange resin. October 23, 2013 29
  30. 30. Advantages • Resinates prevent dose dumping • Uniform release of drug • Flexibity in designing various dosage forms October 23, 2013 30
  31. 31. Types of resinates • Simple resinates • Microencapsulated or coated resinates-rate controlling membrane of polymers(EC,waxes etc) polymer Drug+resin polymer October 23, 2013 31
  32. 32. • Pennkinetic systems drug resinate is pre treated with PEG 400 Coated with water insoluble polymer PEG-controls rate of swelling of resinate mixture in water. EC-modifies diffusion pattern of ions in & out. • Hollow fibre systems-resinates filled into hollow fibres of suitable polymeric materials October 23, 2013 32
  33. 33. ADVANTAGES • Convenience and ease of administration • Flexibility in DFD • Ease of production. October 23, 2013 33
  34. 34. October 23, 2013 34
  35. 35. INJECTABLES SOLUTIONS Both aqueous & oily aqueous solution • • • • High viscosity solutions For cmpds more than ml wt 750 For water soluble drugs Gelling agents & viscosity enhancers are used October 23, 2013 35
  36. 36. drug release is controlled by:• By increasing viscosity of vehicle by mc,cmc pvp • Forming a complex with macromolecules • Forming complex & decreasing solubility of drug October 23, 2013 36
  37. 37. Oil solutions • Release drug by partioning the drug between oil &aqueous body fluid. • Vegetable oils like-arachis oil,cottonseed oil October 23, 2013 37
  38. 38. • Emulsions- o/w, adm of liquid oily drugs (i.v, s.c,i.m) • Suspensions-solid particles in aqueous vehicle solid content 0.5%-5.0%, size <10μ (s.c,i.m) for drugs insoluble in water • Microspheres-polymeric particles, site specific delivery October 23, 2013 38
  39. 39. • Liposomes- liquid based vesicles diameter range 25nm-10000nm phospholipids i.v,s.c,i.m,intra-CSF • Nanoparticles-polymeric liquid particles biodegradable polymers i.v,s.c, i.m • Niosomes- surfactant vesicles non-ionic surfactant i.v,i.m,s.c October 23, 2013 39
  40. 40. Drug loading-immersing in buffered hypotonic solution Resealing-restoring isotonicity & incubation at 37 Target organs-liver &spleen • Advantages biodegradable & non-immunogenic carry large doses targeted drug delivery October 23, 2013 40
  41. 41. • Leon lachman – The theory and practic of industrial pharmacy • D.M. Brahmankar and Sunil B. Jaiswal, Biopharmaceutics and Pharmacokinetics: A Treatise. 1995, 1st Edn, Published by M. K. Jain for Vallabh Prakashan • .Remington, The science and practice of pharmacy, 21st Edition. October 23, 2013 41
  42. 42. October 23, 2013 42

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