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Controlled Release Reservoir-Membrane Systems 1 Overview History Membrane devices with constant release rate Diffusion cell experiments with first order release Burst and lag effects in membrane systems Diffusion coefficients Membrane materials Applications of membrane systems 2 Components of membrane systems Mechanism: diffusion-controlled Driving force: ΔC across membrane Medium: polymer membrane or liquid-filled pores Resistance: function of film thickness, diffusivity of solute in medium Membrane usually interfaces with biological site. Biocompatibility may be important. 3 History of Membrane Systems Folkman and Long (1966 patent) Folkman studied effect of thyroid hormone on heart block Folkman needed non-inflammatory vehicle for extended release of hormone Long performed a photographic study of turbulence induced by artificial Si rubber heart valves Long noticed that certain dyes permeated Si rubber 4 History (continued) Folkman and Long tested diffusion of dyes and drugs across Si tube walls. Observed that oil-soluble, low MW (<1000) dyes permeated membrane Observed that water-soluble, high MW dyes did not. This was the beginning of a research EXPLOSION! First CR device (late 1960s) was use of hormones for contraception, which has now been widely studied. 5 Theory C1 Fick’s First Law J D Cm2 h C2 Relate Cm1 and Cm2 to surrounding concentrations K m1 dCm C Cm1 D m2 dx h membrane C1<Cm1 the drug Cm1 “prefers” the polymer C m1 C1 K m2 Rewrite Flux Cm 2 C2 C C1 J DK m 2 h Body acts as a sink (C2≈0) C J DK m 1 h Constant rate can be achieved if C1 is kept constant. 6 What if C1 is not constant? Common situation in diffusion cell Drug is depleted from reservoir (1) Drug accumulates in receiver (2) membrane C1 Cm1 Cm2 h www.permegear.com C2 7 Diffusion cell: Derivation of M1(t) Fick’s Law dCm C2 C1 J D DK m dx h dt USS Mass Balance V1 dC1 V2 dC2 A dt A dt 1 1 d C1 C2 AJ dt V1 V2 J Combine USSMB with Fick’s Law d C1 C2 ADK C C 1 l 1 2 V1 1 V2 Rearrange d C1 C2 ADK C1 C2 l 1 1 dt V1 V2 8 Diffusion cell Integrate with IC: C1-C2= C10-C20 C1 C2 ADK ln 0 0 C C l 2 1 1 1 t V1 V2 Apply mass balance M1 M 2 M 0 1 Substitute M 1 C1V1 M 2 C2V2 9 Diffusion cell Rearrange (see details) M 10 M1 V1 V2 ADK V1 V2 t V1 V2 exp lV1V2 Differentiate to find release rate dM 1 M 10 ADK dt lV1 ADK V1 V2 t exp lV1V2 First Order Release Rate 10 Release profile for diffusion cell mass of drug in reservoir (mg) Drug Release in Diffusion Cell 12 10 8 6 4 2 0 0 2000 4000 6000 8000 10000 tim e (m in) 11 Data Analysis Diffusion Cell Experiment provides data for C1 vs t Rearrange equation for M1 ADK V1 V2 t M 1 V1 V2 V1 V2 exp 0 M1 lV1V2 Taking natural log of both sides results in linearized eqn M 1 V1 V2 ADK V1 V2 t ln V1 ln( V2 ) 0 M1 lV1V2 1 y b mx 12 Graphing diffusion cell data Experiment: L=2.5x10-3 cm V1=V2=3 cm3 A = 2 cm2 K = 1 (water-filled pores) Analysis m = -0.000533s-1 m = ADKlVVV V Solve for D D=1.0 x 10-6 cm2/s 1 1 2 2 12 10 8 6 4 2 0 0 2000 4000 6000 8000 10000 time (min) Aqueous Diffusion Coefficient of Drugs 2 log((M1*(V1+V2)/M10-V1) mass of drug in reservoir (mg) Caffeine Release through Microporous Membrane 0 -2 0 -4 5000 10000 15000 20000 -6 25000 30000 35000 y = -0.000533x + 1.098612 -8 -10 -12 -14 -16 time (s) 13 Burst and Lag Effects Previous analysis was based on steady-state flux in membrane J D dCm C Cm1 D m2 dx h membrane C1 Cm1 Cm2 h C2 14 Burst and Lag Lag Burst membrane membrane C1 C1 Cm1 Cm2 C2 h Cm2 Cm1 C2 h Membrane exposed to reservoir at t=0 Device stored before use Initially no drug in membrane Initial concentration of drug in membrane = C1 Takes time to build up SS concentration gradient Takes time for drug to desorb and achieve SS concentration gradient 15 Lag Time & Burst Effect Equations for the amount of drug released after SS is attained in the membrane: Lag SS M2 Burst SS M2 ADKC1 l2 t l 6D ADKC1 l2 t l 3D Equations result from solving transport eqns. (Fick’s 2nd Law) for USS diffusion with relevant ICs; then taking limit as t →∞ These equations are for C1=const; C2=0 16 Burst and Lag Effects Lag ADKC1 l2 t M2 l 6D ADKC1 l x - intercept l 2 / 6 D -tlag slope of M vs t Burst ADKC1 l2 t M2 l 3D The lag time is the time required for the solute to appear on the receiver side. It is also the time required to attain a SS concentration profile in the membrane slope of M 2 vs t ADKC1 l 17 Effect of lag and burst Membrane thickness 100 microns D = 1 x 10 -7 cm2/s Calculate Lag time and Burst time Repeat for D = 1 x 10-9 cm2/s D tlag tburst = 1 x 10 -7 cm2/s = 2.7 min = 5.5 min D tlag tburst = 1 x 10-9 cm2/s = 277 min = 555 min 18 Diffusivity values for polymers Function of MW Greater dependence for solute in polymers than for solute in liquids. For drugs with <400 MW In water: 10-6 cm2/s<D<10-4 cm2/s In rubbery polymer: 10-11 cm2/s<D<10-4 cm2/s Weak dependence on MW MW is somewhat important In glassy polymer: 10-14 cm2/s<D<10-5 cm2/s Polymer is very stiff and rigid. Strong dependence on MW 19 Diffusion through microporous membranes Molecules move through liquid-filled pores Small molecules do not experience hindered diffusion Deff D Porosity 0 < ε <1 Tortuosity typically 1 < τ <5 pathlength is longer than membrane thickness 20 Membrane materials Silicone (Silastic – Dow Corning) EVA – Ethylene Vinyl Acetate EVAc- Ethylene Vinyl Acetate copolymer Entrapped fluids Hydrogels and microporous membranes 21 Silicone membranes Biocompatible and sterilizible High permeability to many steroids Low permeability to ionized species Fick’s law is valid for many compounds D is on the order of 10-6 High compared to many polymers 22 Applications of Silicone membranes 5 year contraceptive Transderm Nitro patch: 0.843 mg/cm2/day 23 EVA Membrane Systems Advantages over silicone Lower permeability to non-polar compounds offers better rate control Easier processing and formation of thermoplastic Extrusion, injection molding, film casting Co-polymers can effect big changes in properties Flexibility, permeability, strength 24 Examples of EVA Systems Progestasert Progesterone contraceptive by ALZA Intrauterine device, 65 mcg per day for 400 days Silicone T-shaped tube with 35 mg drug in Si oil 25 Examples of EVA Systems Ocusert Pilocarpine glaucoma treatment system by ALZA Thin, flexible “contacts” behind eyelid Use once a week; replaces drops 4 times per day Releases 20 or 40 mcg per hour Contains 5-11 mg pilocarpine Sterilized by irradiation 1. 2. 3. 4. Clear EVA membrane Opaque white sealing ring Pilocarpine reservoir Clear EVA membrane Oval shape, 6 mm x 13 mm x 0.5 mm Thin EVA membranes 100 microns thick 26 Hydrogel systems Hydrophilic monomers that make cross-linked networks which hold water Great ease of synthesis Wide range of properties D depends on cross-linking agent and water content 27 Applications of hydrogels membrane systems Fluoride salts in the mough Narcotic agonist – cyclazocine 0.2 – 1.0 mg/day for 6 months Prevents opiate effect and is used in rehabilitation Anticancer pouches for direct placement on tumors 28 Applications of microporous membranes Microporous Membranes – used in many biomedical applications Blood oxygenation, dialysis, wound dressings, drug delivery Drug Delivery Applications Transderm Scop® (scopolamine) —Introduced in 1981 for motion-sickness. Microporous polypropylene membrane. (Alza-Ciba Geigy) Transderm-Nitro® (nitroglycerin) — For angina patients. Alternative to the brief effects of sublingual nitroglycerin and the messiness of nitroglycerin ointment. Microporous EVA membrane. (Alza-Ciba Geigy) Catapres-TTS® (clonidine) — Once-a week patch for hypertension replaces up to four daily oral doses. Uses microporous polypropylene membrane. (Alza-Boehringer/Ingelheim) Estraderm® (estradiol) —Twice-weekly, convenient estrogen replacement therapy. Avoids first pass and therefore uses only a fraction of the drug used in the oral therapy. Uses microporous polypropylene membrane. (Alze-Ciba Geigy) Duragesic® (fentanyl) —Introduced in 1991 for management of chronic pain via opioid analgesia. Uses microporous polyethylene membrane. (Alza) NicoDerm® CQ® (nicotine)—smoking-cessation aid in multiple dosage strengths offering maximum control of the drug delivery rate. Uses microporous polypropylene membrane. (Alza-GSK) Testoderm® and Testoderm® —Introduced in 1994 and 1998, respectively, for hormone replacement therapy in men with a deficiency or absence of testosterone. Microporous EVAc membrane. (AlzaLederle) 29 ALZA’s Transderm Scop Removable strip Adhesive gel layer with priming dose Rate controlling microporous membrane with highly permeable liquid in pores Reservoir with solid drug in highly permeable matrix Foil backing, protective and impermeable Controlled release form maintains low conc of drug, reduces side effects 2.5 cm2 area 200 mcg priming dose 10 mcg/h for 72 h steady state delivery 30 Diffusion Cell Equations Derivation of M1(t) 31 Burst and Lag effects Ref. Kydonieus, A. Treatise on Controlled Drug Delivery 32