1. Controlled Drug Delivery System
Dr. Basavaraj K. Nanjwade
KLE University’s College of Pharmacy
BELGAUM , India
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2. “Ideal” Drug Delivery System
Inert
Biocompatible
Mechanically strong
Comfortable for the patient
Capable of achieving high drug loading
Readily processable
Safe from accidental release
Simple to administer and remove
Easy to fabricate and sterilize
Free of leachable impurities
09/08/2010
KLE COP, NIpani

3. Modified Drug Release Release can be: instantaneous (delayed-release)
zero-order process (sustained release - mostly non-oral)
first-order process (oral extended release)
09/08/2010
KLE COP, NIpani

4. Terminology Sustained release:
any dosage form that provides medication over an extended time
timed release, prolonged release etc
Controlled release:
denotes that the system is able to provide some actual therapeutic control, whether this be of a temporal nature, spatial nature, or both
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KLE COP, NIpani

5. Traditional vs. Controlled Release Drug Dosing
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KLE COP, NIpani

6. Traditional vs. Controlled Release
With traditional administration, the drug active must remain between a maximum blood level value which may represent a toxic level and a minimum value below which the drug is no longer effective
With controlled administration, the blood levels are constant between the desired maximum and minimum for an extended period of time
09/08/2010
KLE COP, NIpani

7. Controlled Drug Delivery
Controlled drug delivery occurs when a polymer is combined with a drug or active agent such that the release from the bulk material is pre-designed.
not all controlled systems are sustaining
targeted drug delivery
prodrugs, others
09/08/2010
KLE COP, NIpani

8. Advantages of Controlled Drug Delivery
Eliminate over or underdosing
Maintain drug levels in desired range
Need for less dosing
Increased patient compliance
Prevention of side effects
09/08/2010
KLE COP, NIpani

9. Design of Controlled Drug Delivery
Biopharmaceutic Characteristics of the Drug
Molecular weight, Aqueous solubility, Partition coefficient, Drug Pka and Ionization, Route of administration, Drug stability etc
Pharmacokinetic Characteristics of the Drug
Absorption rate, Elimination Half-Life, Rate of metabolism etc.
Pharmacodynamic Characteristics of the Drug
Therapeutic Range, Therapeutic index, Plasma concentration response relatioship
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KLE COP, NIpani

10. Controlled Drug Delivery
Depending on the formulation and the application, the time of release can be quite varied
Procardia XL - 24 hours
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KLE COP, NIpani

11. Controlled Drug Delivery
Lupron Depot - 1 month
Norplant - 5 years
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KLE COP, NIpani

12. Polymers for Controlled Release
These are some of the first materials selected for delivery systems bases on their intended non-biological physical properties:
Polyurethanes for elasticity
Polysiloxanes for insulating ability
Polymethyl methacrylate for physical strength and transparency
Polyvinyl alcohol for hydrophilicity and swelling
Polyvinyl pyrrolidone for suspension capabilities
09/08/2010
KLE COP, NIpani

13. Current Polymers used in Controlled Drug Delivery
These polymers became usable in controlled delivery due to their inert physical characteristics and being free of leachable impurities
Poly 2-hydroxy ethyl methacrylate
Poly N-vinyl pyrrolidone
Polyvinyl alcohol
Polyacrylic acid
Polyethylene glycol
Polymethacrylic acid
09/08/2010
KLE COP, NIpani

14. Oral Dosage Form Biological Factors Half-life Absorption Metabolism
active vs passive
GI transit time
floating systems
bioadhesives
penetration enhancers
Metabolism
09/08/2010
KLE COP, NIpani

15. Oral Dosage Form Physicochemical Factors Dose Size (0.5-1.0 g)
Ionization, pKa and aqueous solubility
solubility less 0.01 mg/ml (digoxin, griseofulvin)
Partition Coefficient
Stability
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KLE COP, NIpani

16. Diffusion-Controlled Systems
Reservoir Devices
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KLE COP, NIpani

17. Characteristics of a Reservoir Diffusional Systems
Advantages
zero-order delivery is possible
release rate variable with polymer type
Disadvantages
removal of system from implants
bad for high-molecular weight compounds
cost
potential toxicity if system fails
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KLE COP, NIpani

18. Reservoir Diffusional Products
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KLE COP, NIpani

19. Matrix Devices
consists of drug dispersed homogeneously throughout a polymer matrix.
Drug in the outside layer is exposed to the bathing solution is dissolved and diffuses out of the matrix.
This process continues with the interface between bathing solution and the solid drug moving toward the interior.
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KLE COP, NIpani

20. Matrix Diffusional System
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KLE COP, NIpani

21. Characteristics of Matrix Diffusion Systems
Advantages
easier to produce than reservoir devices
can deliver high molecular-weight compounds
Disadvantages
cannot obtain zero-order release
removal of remaining matrix is necessary for implanted systems
09/08/2010
KLE COP, NIpani

22. Matrix Diffusional Products
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KLE COP, NIpani

23. Dissolution-Controlled Systems
alternating layers of rate-controlling coats
group of beads with different coatings
(Spansule, SmithKline Beecham)
dC/dt = kd*A(Cs-C) = D/h*A(Cs-C)
dC/dt=dissolution rate, kd=dissolution rate const
D=diffusion coefficient, Cs=saturation solubility
C=concentration of solute in bulk solution
09/08/2010
KLE COP, NIpani

24. Types of Dissolution Controlled Systems
Two types of dissolution- controlled, pulsed delivery systems
A: Single bead-type device with alternating drug and rate controlling layer
B: Beads containing drug with differing thickness of dissolving coats
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KLE COP, NIpani

25. Encapsulated Dissolution Products
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KLE COP, NIpani

26. Matrix Dissolution Products
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KLE COP, NIpani

27. Bioerodible and Combination Diffusion and Dissolution System
Strictly speaking, therapeutic systems will never be dependent on dissolution only or diffusion only.
Bioerodibile devices, however, constitute a group of systems for which mathematical descriptions of release is complex.
The complexity of the system arises from the fact that, as the polymer dissolves, the diffusion path length for the drug may change. this usually results in a moving-boundary diffusion system.
Zero-order release can occur only if surface erosion occurs and surface area does not change with time.
The inherent advantage of such a system is that the bioerodible property of the matrix does not result in a ghost matrix.
09/08/2010
KLE COP, NIpani

28. Bioerodible Matrix System
Representation of a
Bioerodible Matrix System
Drug is dispersed in the matrix before release at time = 0. At time = t, partial release by drug diffusion or matrix erosion has occurred
09/08/2010
KLE COP, NIpani

29. Characteristics of Bioerodible Matrix Systems
Advantages
all the advantages of matrix dissolution system
removal from implant sites is not necessary
Disadvantages
difficult to control kinetics owing to multiple processes of release
potential toxicity of degraded polymer
09/08/2010
KLE COP, NIpani

30. Bioerodible and Biodegradable Controlled Release Polymers
These polymers are designed to degrade within the body
Polylactides (PLA)
Polyglycolides (PGA)
Polylactide-co-glycolides (PLGA)
Polyanhydrides
Polyorthoesters
09/08/2010
KLE COP, NIpani

31. Degradation of Biodegradable Polymers
These materials degrade within the body as a result of natural biological processes, eliminating the need to remove a drug delivery system after release of the active agent has been completed
Bulk hydrolysis - the polymer degrades in a fairly uniform manner throughout the matrix
Surface Eroding - degradation occurs only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system
09/08/2010
KLE COP, NIpani

32. Biodegradable Polymers
Drug delivery from
(a) bulk-eroding and (b) surface-eroding biodegradable systems.
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KLE COP, NIpani

33. (a) bulk-eroding and (b) surface-eroding biodegradable systems.
Biodegradable (surface eroding) Polyorthoester rods after (left) 9 weeks and (right) 16 weeks of implantation
Drug delivery from
(a) bulk-eroding and (b) surface-eroding biodegradable systems.
09/08/2010
KLE COP, NIpani

34. Major Companies Involved in Polymeric Delivery Technology
Alza - DUROS, OROS
Alkermes Inc - Ring Caps
Nobex Corp. - Drug/Polymer Conjugates
Elan - MODAS, PRODAS
Andrx - SCOT, DPHS
09/08/2010
KLE COP, NIpani

35. Osmotically Controlled Systems
osmotic pressure provides the driving force to generate controlled release of drug.
Consider a semipermeable membrane that is permeable to water, but not to drug. When this device is exposed to water or any body fluid, water will flow into the tablet owing to the osmotic pressure difference.
dV/dt= Ak/h(P)
k=membrane permeability, A=area of the membrane, h=membrane thickness
 = osmotic pressure difference, P =hydrostatic pressure difference
09/08/2010
KLE COP, NIpani

36. Types of Osmotically Controlled Systems
Type A contains a osmotic core with drug
Type B contains the drug solution in a flexible bag, with the osmotic core surrounding
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KLE COP, NIpani

37. Types of Osmotically Controlled Systems
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KLE COP, NIpani

38. Immediate Release Oxybutynin V/s Controlled Release Ditropan XL
09/08/2010
KLE COP, NIpani

39. Characteristics of Osmotically Controlled Devices
Advantages
Zero-order release is obtainable
reformulation is not required for different drugs
release of drug is independent of environment of the system
Disadvantages
systems can be very expensive
quality control is more extensive
09/08/2010
KLE COP, NIpani

40. Examples of Osmotic Pump Systems
Acutrim Appetite suppressant
Concerta ADHD
Procardia Hypertension/angina
Volmax Bronchiodilator
Ditropan Overactive bladder
09/08/2010
KLE COP, NIpani

41. Hydrodynamic Pressure Controlled Systems
Hydrodynamic pressure generated by swelling of a hydrophilic gum
The device comprises of a rigid, shape retaining housing enclosing a collapsible, impermeable containing liquid drug
The gun imbibes water in GIT through an opening at the lower side of external housing and swells creating an hydrodynamic pressure
The pressure thus created squeeze the collapsible drug reservoir to release the medicament through the delivery orifice
09/08/2010
KLE COP, NIpani

42. Delayed Transit Release Systems
Altered Density Systems
High Density Pellets
Low Density Pellets
Mucoadhesive Systems
Cross linked Polyacrylic acid tablet
Intestinal Release Systems
Peyer’s patches – Proteins, Peptides, Antigens
Colonic Release Systems
pH sensitive bioerodiable polymer polymethacrylates
Divinylbenzene cross linked polymers – azoreductase of colonic bacteria
09/08/2010
KLE COP, NIpani

43. Ion-Exchange Systems
Ion-exchange systems generally use resins composed of water soluble cross-linked polymers
These polymers contain salt forming functional groups in repeating position on the polymer chain
The drug is bound to the resin and released by exchanging with appropriately charged ions in contact with the ion exchange groups
Resin+ - drug- + X resin+ - X- + drug-
Where X- are ions in the GI tract
09/08/2010
KLE COP, NIpani

44. Different Novel Drug Delivery Systems
Microspheres, Liposomes, Niosomes
Implants
Pharmacosomes
Nanoparticles
Polymeric Films
Local drug delivery systems, etc
09/08/2010
KLE COP, NIpani

45. Classes of Drugs for Novel Drug Delivery
Anti-cancer agents
Anti-hypertensive agents
Anti-psychotic agents
Non steroidal anti-inflammatory agents
Anti infective agents
Anti-diabetic agents
Protein and peptide drugs
Biotechnological products
09/08/2010
KLE COP, NIpani

46. Routes of Administration
Peroral Route
Parenteral Route
Subdermal implants
Buccal Administration
Occular Delivery
Transdermal delivery
Pulmonary Drug Delivery
Nasal delivery
Colon drug delivery
09/08/2010
KLE COP, NIpani

47. Parenteral Controlled Release Systems
Injectables
Solutions
Dispersions
Microspheres and Microcapsules
Nanoparticles and Niosomes
Liposomes and Pharmacosomes
Resealed erythrocytes
Implants
Infusion Devices
Osmotic Pumps (Alzet)
Vapor Pressure Powered Pumps (Infusaid)
Battery Powered Pumps
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KLE COP, NIpani

48. Infusaid Model 400 Implantable Pump
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KLE COP, NIpani

49. Bone Implants
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50. Administration of Implant to Rabbit Femur
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KLE COP, NIpani

51. Transdermal Drug Delivery Systems
Membrane permeation-controlled system
Transderm – Scop (scopolamine; Ciba-Geigy)
Adhesive dispersion-type system
Deponit (nithroglycerin; Wyeth)
Matrix diffusion-controlled system
Nitrodur (nitroglycerin; Key)
Microresevoir dissolution-controlled system
Nitrodisc (Nitroglycerin; Searle)
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KLE COP, NIpani

52. Transdermal Device
Monolithic
Membrane
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KLE COP, NIpani

53. Transdermal Device Transdermal device for the delivery of scopolamine
09/08/2010
KLE COP, NIpani

54. Nasal and Pulmonary Drug Delivery Systems
Dry Powder Inhalations
Aerosols
Nasal Gels
Nasal Sprays
Insuffulations
09/08/2010
KLE COP, NIpani

55. Buccal Delivery Delivery protein and peptide like drugs
Examples: Insulin, Oxytocin, Vasopressin analogues, Buserelin, Calcitonin, etc which cannot be given orally
09/08/2010
KLE COP, NIpani

56. Occular Drug Delivery Systems
Liposomes and Niosomes as carriers for antibiotics and protein and peptides.
Biodegradable matrix drug delivery to the anterior segment. Polymeric dispersion to prolong the delivery of Pilocarpine.
Microemulsions, Self Emulsifying Drug Delivery Systems
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KLE COP, NIpani

57. Occular Delivery Systems
Ocusert intraocular device for release of pilocarpine
09/08/2010
KLE COP, NIpani

58. Dental Systems
Local administration of drugs to periodontal pocket using biodegradable polymers
We are working on delivery of drugs to periodontal pocket using biodegradable in situ gels and matrix implants
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KLE COP, NIpani

59. Administration of Implant to Periodontal Pocket
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KLE COP, NIpani

60. Administration of In situ gel to Periodontal Pocket
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KLE COP, NIpani

61. Current and Future Trends in Polymer Drug Delivery Systems
Hydrogels
Ringcap Technology
Pulsincap Technology
Novel Drug Delivery for Insulin
Oral Insulin
Molecular Gates
09/08/2010
KLE COP, NIpani

62. Hydrogels
Hydrogels consist of polymers that swell without dissolving in an aqueous environment (water or other biological fluid)
At equilibrium, the gels comprise 60-90% fluid and only 10-30% polymer
Factors that affect release include pH, ionic strength, and temperature
Polymers commonly used in Hydrogels include
Poly-(N-isopropylacrylamide)
Poly(methacrylic acid)
Polyethylene Glycol
09/08/2010
KLE COP, NIpani

63. Ringcap Technology Based on a tablet (usually film coated)
Tablet is partially coated with a series of “rings”
Rings can be made of any insoluble polymer that does not erode or degrade during the dispensing period
The number of rings, the position of the rings, and the thickness of rings control the rate of release of drug in the final dosage form
09/08/2010
KLE COP, NIpani

64. Pulsincap Water insoluble capsule body and a water soluble cap
Capsule body contains drug and hydrogel polymer capable of rapidly expelling the drug at the predetermined time
As the soluble cap erodes, the hydrogel swells and pushes out the drug
The hydration rate depends on the hydrogel plug, the length of the plug and the fit ratio (plug diameter to body diameter)
09/08/2010
KLE COP, NIpani

65. Oral Protein Delivery
Nobex Corp. has designed a polymer that binds to specific sites on drug structure to form drug polymer conjugates and allows for oral delivery.
Benefits include increased stability in the body, ability to retain normal biological actions, improved efficacy and safety, and increased patient compliance
This technology is being used to develop many new products, one of which is oral insulin.
09/08/2010
KLE COP, NIpani

66. Synthesis of the Drug-Polymer Molecule
The polymer blocks enzymes from attacking the protein
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KLE COP, NIpani

67. Molecular Gates
A new gel has been developed that is used to make a “molecular gate”
The gel expands at high pH and shrinks at low pH.
The gel contains two polymers
Polymethacrylic acid
Polyethylene glycol
09/08/2010
KLE COP, NIpani

68. Molecular Gates
Adding the enzyme glucose oxidase causes the gel to respond to changes in glucose levels because the glucose and enzyme chemically react to produce an acid.
The gates would shrink or open at low pH to release insulin
As the glucose levels drop, the pH rises causing the gates to expand and block the release of insulin
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KLE COP, NIpani

69. Questions?
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KLE COP, NIpani

70. E-mail: bknanjwade@yahoo.co.in
Thank You
Cell No:
09/08/2010
KLE COP, NIpani