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

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

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

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

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

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.

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)

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

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

Nicoderm transdermal nicotine patches

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

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

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

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

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]

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?

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

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

Common classes of biodegradable polymers

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

Can be combination of different approaches: drug eluting stent

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

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.

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

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.

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

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

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

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)

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

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.