1. Controlled (and sometimes local) drug release
Tissue Engineering & Drug Delivery BBI 4203
LECTURE #14

2. Controlled/Local delivery
Two General Approaches to Drug Delivery
Systemic delivery (everything so far)
Controlled/Local delivery
Tumor
Release device
Drug
Topical application
Interstitial transport is important for both systemic and local delivery of drugs

3. Tissue or plasma concentration
Conventional systemic drug infusion and controlled/local (sustained) drug release profiles
Toxic levels
Tissue or plasma concentration
clearance
Minimum effective level
Controlled profile exhibits “zeroth order” release where rate of release is constant to maintain constant tissue concentration

4. Comparison of local versus systemic delivery
Local delivery can generate systemic effects through activation of immune systems.

5. Examples of local drug delivery
Direct injection into tissues
Controlled release of drugs from polymeric devices
Local treatment of tissues for improving transport of drugs (e.g., using heat, electric field, ultrasound).
Local perfusion into organs (e.g., limb, lung, liver) via blood vessels
Systemic delivery of drug-containing carriers in combination with the local control of drug release from these carriers (e.g., temperature sensitive liposomes, magnetic beads, photodynamic therapy)
Systemic or local transfection of cells in combination with the local control of gene expression in transfected cells

6. II. Controlled release systems
Robert Langer
Judah Folkman
The field is started in 1960s for small molecules and 1970s for large molecules (Folkman, J.)
The major effort is to design or invent novel systems which can deliver drugs in a controlled manner (Langer, R.)
The fields of application range from basic biology and chemistry for testing scientific hypotheses to vaccinations or clinical treatment of infection, diabetes, allergy, and cancer, etc.
Note: Controlled release differ from un-controlled "sustained release" in terms of drug release, concentration, and responses to unwanted environmental influences.

7. Criteria
Release rates are either independent of environment or dependent on environmental factors in a controlled manner
Release rates can be controlled through the design (e.g., composition of polymers) or external trigger (e.g., heat, pH …)
Release devices are biodegradable in most cases, and the rate of degradation can be controlled.
Devices need to be inert and non-inflammatory (biocompatible)
Devices should maintain biochemical activities of drugs over the release period (e.g., minimal denature, aggregation, inactivation for protein drugs)

8. 4 main controlled release approaches
Diffusion controlled
Membrane and monolithic devices
Chemically controlled
Biodegradable reservoirs
Water penetration controlled
Osmotic and swelling controlled
Environmentally responsive
Stimulation induced disruption of drug carriers

9. Membrane diffusion controlled devices
Drug contained in reservoir core encased by inert polymer membrane
Drug release controlled by diffusion across membrane
Polymer membrane

10. Nicoderm transdermal nicotine patches

11. Monolithic diffusion controlled devices: transdermal patches
Drug dispersed in polymer matrix
Drug release controlled by diffusion out of polymer matrix – no membarne

12. Norplant implantable polymer rod that releases progestin
Toothpick sized rod inserted under skin using needle
Prevents ovulation for up to three years
Nongradable silicone polymer must be removed

13. Quantitative analysis of controlled release of drugs from polymeric devices
Release time and kinetics can be controlled by following variables.
Drug powder size
Drug molecular weight
Drug solubility
Drug loading (drug/polymer ratio)
Geometry of devices

14. Lets just look at the simplest case: drug release from a slab

18. M¥=CoAd (assume eventually everything diffuses out)
For short times the release rate depends only on Co, D and t because everything comes from near the surface
J=dMt/dt = 2(CoAd)[D/pd2t]1/2 = 2Co[D/pt]1/2
For long times geometry comes into play because drug has to traverse a longer distance:
J=dMt/dt = (16DCoA/d)exp[-p2Dt/d2]

19. Diffusion is usually too slow and the release rate tapers off with time
How can you game the system so you are not just dependent on the initial drug loading and diffusion out of the matrix?
How can you make the controlled release also local release?

20. Quantitative analysis of controlled release of drugs from polymeric devices
Release time and kinetics can be controlled by following variables.
Drug powder size
Drug molecular weight
Drug solubility
Drug loading (drug/polymer ratio)
Geometry of devices
Surface coating of the polymer matrices
Rate of polymer degradation, if it is degradable
The composition and structure of polymers
Hydrophobicity of polymers
Application of stimulation

21. Chemically controlled drug release
Drug dispersed in degradable polymer matrix and cannot readily diffuse out of polymer
Drug released as matrix degrades

22. Common classes of biodegradable polymers

23. Gliadel – degradable drug releasing wafers for treating malignant brain tumors
Anti-tumor drug BNCU dispersed in degradable PCPP-SA copolymer for treating glioblastomas following surgery

24. Can be combination of different approaches: drug eluting stent

25. Water penetration controlled devices
Rate of drug release controlled by rate of water diffusion into the device
Drug molecules cannot physically diffuse out of the device without water molecules diffusing in.
Two types:
Swelling-controlled devices
Osmotic pumps

26. Swelling controlled devices
Drug embedded in a hydrophilic polymer that is stiff when dry
When wet the polymer swells when placed in an aqueous environment.
Creates pores in polymer matrix that allows drug to escape.
A typical oral pill formulation is usually a swelling-controlled device.

27. Swelling controlled drug release
Crosslinked hydrogels like hydroxypropyl-methylcellulose embedded with drug swells when wetted
Tylanol

28. Osmotic pumps
Rigid tablets with a water-permeable jacket with one or more laser drilled small holes.
The jacket is a semi-permeable membrane that draws in water to create osmotic pressure, but prevents drug from moving out.
Infusing water swells a gel in the tablet that force drugs out through laser drilled holes.

29. Osmotic pumps Two chamber model with push chamber and drug chamber
One chamber model with drug dispersed in expanding gel

30. Environmentally responsive
Respond to the presence of specific stimuli
Drugs released 4 main ways
Thermally collapsing polymers
pH induced swelling
Sol to gel formation
Externally applied oscillations

31. Thermally and pH collapsing polymer poly(N-isopropylacrylamide)
Hydrophilic swollen coil
Hydrophobic collapsed aggregate
Temperature or pH
At high temperatures and/or pH polymer precipitates into aggregates
At low temperatures and/or pH polymer swells in water

32. Thermally and pH induced drug release from PNiPAMM Micelles
Drug entrapped in core of pNiPAAM micelles
Drug released when PNiPAAM micelle collapses
Cell layer
Can entrap hydrophobic drug in micelles at either low temp or/or low pH (left) and release drug by increasing temp and/or pH by polymer collapse (right)

33. Sol-Gel diblock (A-B) and triblock (A-B-A) copolymer systems
Red: hydrophilic B segment
Blue: hydrophobic and degradable A segment

34. Externally applied stimulus
Low Intensity High Frequency Ultrasound Acoustic Targeting- The release of encapsulated drugs can be enhanced by the application of ultrasound. Used to treat brain tumors.
Magnetic beads - The release of drugs based on the application of magnetic force that disrupts drug carriers. The increase in the release rate can be as high as 30 times.