University:
Massachusetts Institute of Technology
Course:
3.051J | Materials for Biomedical Applications
Academic year:

2023
Views:

402

Pages:

20
Author:

Mara Mathis

1 3.051J/20.340J Lecture 19 Drug Delivery: Controlled Release What do we mean by “controlled” release? Control of: 1. delivery rate 2. site of release/activity Need for Control Traditional drug delivery drug concen. toxic level Therapeutic range t1 time from administration t2 longer period of dose efficacy = toxicity risk 2 3.051J/20.340J drug concen. Controlled drug delivery toxic level Therapeutic range time from administration Types of Devices 1. Diffusion Controlled Delivery Devices • • • • Monolithic Devices Membrane Controlled Devices Osmotic Pressure Devices Swelling-Controlled Devices 2. Chemically Controlled Approaches • • • • Matrix Erosion Combined Erosion/Diffusion Drug Covalently Attached to Polymer Desorption of Adsorbed Drug 3. Electronic/Externally Controlled Devices 3 3.051J/20.340J 1. Diffusion Controlled Devices a) Monolithic Devices Drug is released by diffusion out of a polymer matrix Release rate depends on initial drug concentration i) Case of C0 < Cs (drug concentration C0 is below solubility limit in matrix Cs) ⇒ Diffusion through matrix limits the release rate t0 t1 How can we control release rate? Rate control by choice of matrix: glassy matrix: D~10-10-10-12 cm2/s rubbery matrix: D ~ 10-6-10-7 cm2/s t2 4 3.051J/20.340J Quantifying drug release Governed by Fick’s Laws. For 1D: The drug flux J is: J = −D dC dx ∂C ∂ 2C =D 2 The change in drug concentration with time is: ∂t ∂x We want to calculate: • dMt/dt = release rate • Mt = amount released after time t ⇒ Solve Fick’s 2nd law with initial & boundary conditions. Example: For a 1D slab loaded at an initial concentration of C0, with drug concentration in solution resulting in constant surface concentration of Ci. δ I.C.: C(x,0) = C0 ∂C B.C. 1: ∂x =0 C0 x=0,t B.C. 2: C(δ/2,t) = Ci Solve for C(x,t) dM t dC ( x, t ) = −D Adt dx x=δ / 2 Mt A = cross-sectional area Ci 0 5 3.051J/20.340J The amount of drug released is given by the series solution: ∞ ⎡ − D ( 2n + 1)2 π 2 ⎤ Mt 8 = 1− ∑ exp ⎢ t⎥ 2 2 2 M∞ δ n= 0 ( 2n + 1) π ⎢⎣ ⎦⎥ where: M∞ = amount of drug released at long times (e.g., total amt of drug: M∞ = C0Aδ) δ = slab thickness Mt/M∞ 1 0.5 0 time Release rate (from derivative): dM t ⎡ D ⎤ = 2M ∞ ⎢ 2 ⎥ dt ⎣ πδ t ⎦ 1/ 2 ⎡ −π 2 Dt ⎤ dM t 8DM ∞ = exp ⎢ ⎥ 2 dt δ2 ⎣ δ ⎦ short times: ~ t-1/2 long times: exponential decay 6 3.051J/20.340J NOTE: dMt/dt and Mt depend on geometry. See handout from Encyclopedia of Controlled Drug Delivery dMt/dt release rate ~ t-1/2 ~ exp(-t) 0 time ii) Case of C0 > Cs (drug concentration above solubility limit in matrix) ⇒ Drug dissolution in polymer matrix limits release rate drug conc.= Cs in matrix Higuchi model: assumes Ci = 0 M t = A ⎡⎣ DCs ( 2C0 − Cs ) t ⎤⎦ 1/ 2 1/ 2 −1/ 2 dM t A = ⎡DC 2C − t C ⎤ ( ) s s ⎦ 0 ⎣ 2 dt where A = surface area of the slab drug-rich 2nd phase 7 3.051J/20.340J For Cs << C0: dM t A ⎡ 2DCs C0 ⎤ = ⎢ dt 2⎣ t ⎦⎥ 1/ 2 How can we control release rate? b) Membrane Controlled Devices Drug release is controlled by a semi-permeable membrane ⇒ Diffusion through membrane limits the release rate Advantage: A constant flux device! Semi-permeable membrane Neat or concentrated therapeutic agent Release rate thru membrane described by Fick’s 1st law. For 1D: J= dM t dC = −D Adt dx Typical flux units: g/cm2s 8 3.051J/20.340J i) Nonporous semi-permeable membranes ⇒ Drug diffusion through swollen polymer membrane Conc. inside membrane = C2 dM t DKA = ( C2 − C1 ) δ dt Mt = DKA δ ( C2 − C1 ) t K = membrane “partition” coefficient (unitless metric of drug solubility in membrane) Conc. outside membrane = C1 Which D is referred to? δ dMt/dt Early release rate independent of time 0 time Is this release profile advantageous? 9 3.051J/20.340J ii) Porous semi-permeable membranes ⇒ Drug diffusion through membrane pores Requires replacing D by Deff: Deff = D poreε τ ε = porosity 0 < ε < 1 τ = tortuosity τ ≥ 1 Cross-section of porous semi-permeable membrane c) Osmotic Pressure Devices Osmotic pressure build-up from water in-flux across semi-permeable membrane forces drug release through orifice piston δ delivery orifice semi-permeable membrane osmotic “engine” (NaCl) http://www.alza.com/alza/duros drug reservoir Ex: DUROS Implant (ALZA) • Ti housing, 4mm × 45 mm • ~ 1 year duration • in use for prostate cancer therapy 10 3.051J/20.340J Release rate proportional to change in volume of drug reservoir: dM t dV Ak∆π C = C= δ dt dt A= membrane area ∆π = osmotic pressure differential C = drug concentration in reservoir k= membrane permeability coefficient (~10-6-10-7g/cm/s) dMt/dt zero-order release kinetics 0 time Controlled Release via Solute Choice for Osmotic Engine (∆π) Solute body tissue NaCl KCl sucrose dextrose potassium sulfate Osmotic Pressure (atm) 7 356 245 150 82 39 11 3.051J/20.340J d) Swelling Controlled Devices ¾ Drug dispersed in a glassy, hydrophilic matrix ¾ Swelling in aqueous medium allows drug release glassy polymer matrix with dispersed drug H2O swelling provides mobility for drug release Complex release kinetics: modeled by fitting experimental data to power law expression. Mt = k 't n M∞ ln(Mt/M∞) n=1 ln(k’) ln(t) 12 3.051J/20.340J 2. Chemically Controlled Approaches a) Eroding Monolithic Device Drug is incorporated into a bioerodible or dissolvable polymer matrix t1 t0 t2 i) Surface Erosion Devices dM t = ke Ae dt Ae = instant surface area ke = rxn or dissolution rate const. release rate = strong function of device geometry For a slab: 2M ∞ ≈ const Ae ≈ C0δ dM t 2ke M ∞ = dt C0δ ⇒ zero-order release kinetics δ 13 3.051J/20.340J dMt/dt 0 time For other geometries, Ae is a function of time: dM t = ke Ae (t ) dt For various geometries, the solution to this expression is: ⎡ ⎤ ⎢ kt ⎥ Mt = 1 − ⎢1 − e ⎥ δ M∞ ⎢ C0 ⎥ 2⎦ ⎣ n Geometry δ n slab thickness 1 cylinder diameter 2 sphere diameter 3 14 3.051J/20.340J Matrix Examples: • polyanhydrides O poly(sebacic acid anyhydride) • poly ortho esters O (-(CH2)8- C -O-C -)N DETOSU ii) Bulk Erosion Devices ¾ uniform hydrolysis of bulk matrix polymer ¾ hydrolysis rate vs. drug diffusion controls release rate dM t ~ tn dt ⇒ n = -1/2 drug diffusion limited Matrix Example: poly(lactide-co-glycolide) O O (-O-CH(CH3)-C -)x-r-(-O-CH2-C -)y lactic acid glycolic acid 15 3.051J/20.340J iii) Pulsed release systems Mixture of eroding particles with different degradation rates Degradation Profile for Single Eroding Component (schematic) % degrad. 100 50 0 time in vivo drug concen. in vivo time from administration 16 3.051J/20.340J Degradation Profile for Mixture of Components (ex., microspheres) % degrad. 100 50 0 drug concen. in vivo time in vivo time from administration Applications Example: “one shot” vaccines with multiple antigens TT tetanus toxoid DT diptheria toxoid HBSA hepatitis B surface antigen SEB staphylococcal enterotoxoid B Vaccines stimulate Ab production ⇒ How can we achieve different degradation rates? 17 3.051J/20.340J Factors influencing degradation: • Composition (e.g., PLGA copolymer LA:GA ratio) • Geometry iv) Regulated systems Incorporate a component that responds to the in vivo environment • Enzyme that catalyzes degradation in presence of a substrate Example: GOD-regulated insulin release Glucose + O2 + H2O → Gluconic acid + H2O2 GOD pH drop promotes acid hydrolysis or swelling of matrix 18 3.051J/20.340J b) Polymer-Drug Conjugates Therapeutic agent is covalently or ionically bound to a polymer through a cleavable bond Purposes: ¾ ¾ ¾ ¾ ¾ increase resistance to proteolysis (protein drugs) reduce antigenicity/immunogenicity prolong plasma circulation lifetime enhance water solubility of hydrophobic agents reduce toxicity Example 1: Therapeutic proteins tethered to polyethylene glycol (PEG) protein ⇒ Increases intravascular lifetime—why? PEG Some clinical systems: • PEG-adenosine deaminase (FDA appr. immunodeficiency therapy) • PEG-asparaginase (FDA appr. for lymphoblastic leukemia) • PEG-hemoglobin • PEG-interluekin 2 • PEG-alpha interferon • PEG-colony stimulating factor 19 3.051J/20.340J Example 2: Chemotherapeutic agent attached to water-soluble or hydrolysable backbone maleic anhydride vinyl benzyl fluorouracil (CH CH2-)n (CH CH-)m O=C O C=O N C=O O hydrolysis N F H O (CH CH2-)n (CH O=C C=O OH OH H N CH-)m C=O OH + O N F H O 5-fluorouracil 20 3.051J/20.340J Example 3: Dendrimer Drug Conjugates (early development) Dendrimers – sequentially synthesized, hyperbranched macromolecules 1st generation 2nd generation 3rd generation Two strategies for controlled drug delivery drug-conjugated chain ends Drug-filled core (diffusion-controlled) References Encyclopedia of controlled drug delivery vol. 1, E. Mathiowitz, ed., John Wiley & Sons, NY, 1999. Encyclopedia of controlled drug delivery vol. 2, E. Mathiowitz, ed., John Wiley & Sons, NY, 1999. Biomaterials Science: An introduction to materials in medicine, B.D. Ratner et al., eds., Academic Press, NY 1996.

Lecture 19: Drug Delivery: Controlled Release

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