Controlled Release. Reservoir-Membrane Systems

Transcription

1 Controlled Release Reservoir-Membrane Systems

2 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

3 Components of membrane systems Mechanism: diffusion-controlled Driving force:?c 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

4 History of Membrane Systems Folkman and Long (966 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

5 History (continued) Folkman and Long tested diffusion of dyes and drugs across Si tube walls. Observed that oil-soluble, low MW (<000) dyes permeated membrane Observed that water-soluble, high MW dyes did not. This was the beginning of a research EXPLOSION! First CR device (late 960s) was use of hormones for contraception, which has now been widely studied. 5

6 Theory Fick s First Law J = D dcm dx C = D C h m m Relate C m and C m to surrounding concentrations C membrane C m C m h C <C m the drug prefers the polymer C K Rewrite Flux J = m C C m == DK m C C h Body acts as a sink (C 0) J DK m C h K = m C C m Constant rate can be achieved if C is kept constant. 6

7 What if C is not constant? n Common situation in diffusion cell q q Drug is depleted from reservoir () Drug accumulates in receiver () membrane C Cm Cm h C 7

8 Diffusion cell: Derivation of M (t) Fick s Law J = D dcm dx = DK C USS Mass Balance J d V = A ( C C ) dt dc dt V = A dc dt m = AJ + V V C h Combine USSMB with Fick s Law d ( C C ) Rearrange ( C C ) + ADK = dt l V ( C C ) ( C C ) d ADK = l V V + V dt 8

9 Diffusion cell Integrate with IC: C -C = C 0 -C 0 ln ( C C ) 0 0 ( C C ) Apply mass balance Substitute ADK = l V + V M = M M 0 + M M = C V = C V t 9

10 Diffusion cell Rearrange (see details) ( V V ) 0 M ADK + t M + + V exp V V V lvv = Differentiate to find release rate ( V V ) 0 dm M ADK ADK + = exp dt lv lvv t First Order Release Rate 0

11 Release profile for diffusion cell Drug Release in Diffusion Cell mass of drug in reservoir (mg) time (min)

12 Data Analysis Diffusion Cell Experiment provides data for C vs t Rearrange equation for M Taking natural log of both sides results in linearized eqn ( ) ( ) + = + 0 exp lv V t V ADK V V V M V V M ( ) ( ) mx b y lvv t V ADK V V V M V V M + = + + = + 0 ) ln( ln

13 Graphing diffusion cell data Caffeine Release through Microporous Membrane Experiment: L=.5x0-3 cm V =V =3 cm 3 A = cm K = (water-filled pores) Analysis m = s - m = ( V ) ADK V + lvv Solve for D D=.0 x 0-6 cm /s mass of drug in reservoir (mg) log((m*(v+v)/m0-v) time (min) Aqueous Diffusion Coefficient of Drugs time (s) y = x

14 Burst and Lag Effects Previous analysis was based on steady-state flux in membrane J = D dcm dx C = D membrane C h m m C C m C m h C 4

15 Burst and Lag Lag membrane Burst membrane C C C m C m h C m C Membrane exposed to reservoir at t=0 Initially no drug in membrane Takes time to build up SS concentration gradient C m h Device stored before use C Initial concentration of drug in membrane = C Takes time for drug to desorb and achieve SS concentration gradient 5

16 Lag Time & Burst Effect Equations for the amount of drug released after SS is attained in the membrane: Lag M ADKC l SS = t l 6 D Burst ADKC l M SS = t + l 3D Equations result from solving transport eqns. (Fick s nd Law) for USS diffusion with relevant ICs; then taking limit as t? 8 These equations are for C=const; C=0 6

17 Burst and Lag Effects Lag ADKC l M = t l 6D ADKC slope of M vs t = l x - intercept = l / 6D = - t lag 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 Burst M = slope of ADKC l M t + vs t = l 3D ADKC l 7

18 Effect of lag and burst Membrane thickness 00 microns D = x 0-7 cm /s Calculate Lag time and Burst time Repeat for D = x 0-9 cm /s D = x 0-7 cm /s D = x 0-9 cm /s t lag =.7 min t lag = 77 min t burst = 5.5 min t burst = 555 min 8

19 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: 0-6 cm /s<d<0-4 cm /s Weak dependence on MW In rubbery polymer: 0 - cm /s<d<0-4 cm /s MW is somewhat important In glassy polymer: 0-4 cm /s<d<0-5 cm /s Polymer is very stiff and rigid. Strong dependence on MW 9

20 Diffusion through microporous membranes Molecules move through liquid-filled pores Small molecules do not experience hindered diffusion D eff = Dε τ Porosity 0 < e < Tortuosity typically < t <5 pathlength is longer than membrane thickness 0

21 Membrane materials Silicone (Silastic Dow Corning) EVA Ethylene Vinyl Acetate EVAc- Ethylene Vinyl Acetate copolymer Entrapped fluids Hydrogels and microporous membranes

22 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 0-6 High compared to many polymers

23 Applications of Silicone membranes 5 year contraceptive Transderm Nitro patch: mg/cm /day 3

24 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 4

25 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 5

26 Examples of EVA Systems n Ocusert q q q q q q Pilocarpine glaucoma treatment system by ALZA Thin, flexible contacts behind eyelid Use once a week; replaces drops 4 times per day Releases 0 or 40 mcg per hour Contains 5- mg pilocarpine Sterilized by irradiation Clear EVA membrane Opaque white sealing ring Pilocarpine reservoir Clear EVA membrane q q Oval shape, 6 mm x 3 mm x 0.5 mm Thin EVA membranes 00 microns thick 6

27 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 7

28 Applications of hydrogels membrane systems Fluoride salts in the mough 0..0 mg/day for 6 months Narcotic agonist cyclazocine Prevents opiate effect and is used in rehabilitation Anticancer pouches for direct placement on tumors 8

29 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 98 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 99 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 994 and 998, respectively, for hormone replacement therapy in men with a deficiency or absence of testosterone. Microporous EVAc membrane. (Alza-Lederle) 9

30 ALZA s Transderm Scop Removable strip Adhesive gel layer with priming dose Reservoir with solid drug in highly permeable matrix Rate controlling microporous membrane with highly permeable liquid in pores Foil backing, protective and impermeable Controlled release form maintains low conc of drug, reduces side effects.5 cm area 00 mcg priming dose 0 mcg/h for 7 h steady state delivery 30

31 Diffusion Cell Equations Derivation of M (t) 3

32 Burst and Lag effects Ref. Kydonieus, A. Treatise on Controlled Drug Delivery 3