Controlled Drug Delivery. Martin s Ch 23; - pages Saltzman Ch 9;

Transcription

1 Controlled Drug Delivery Martin s Ch 23; - pages Saltzman Ch 9;

2 Controlled-delivery systems Are used for: - Alternative approach to regulate both the duration and spatial localization of therapeutic agents Are constructed by: - The active agent is combined with other (usually synthetic) components Involve: - Combinations of active agents with inert polymers

3 Controlled-delivery systems 1. Include a component that can be engineered to regulate an essential characteristic (e.g. duration of release, rate of release or targeting) 2. Have a duration of action longer than a day

4 Controlled drug delivery Issues to consider: 1. Nature of disease and theraphy (acute/chorinic) 2. Drug property 3. Route of drug administration 4. Nature of delivery vehicle 5. Mechanism of drug release 6. Targeting ability 7. biocompability

5 Controlled Drug delivery systems Should be: 1. Inert 2. Biocombatible 3. Mechanically strong 4. Convenient for patient 5. Capable of achieving high drug loading 6. Safe from accidental drug release 7. Simple to administer and remove 8. Easy to fabricate 9. Easy to sterilize

6 Drug release from a CR systems 1. Zero-order release: - Drug release does not vary with time - Relatively constant drug level is maintained in plasma over an extended period of time 2. Variable release: - Drug is released at variable rates to match with circadian rhythms or mimic natural biorythms - Drug concentration is increased episodic, followed by a rest period, when drug level falls below the therapeutic level 3. Bioresponsive release: - Drug release is triggered by biological stimulus (ph, T, etc.)

7 Drug release from a CR systems 1. Zero-order release 2. Variable release 3. Bioresponsive release

8 Mechanisms of controlled drug delivery 1. Diffusion controlled release mechanisms 2. Dissolution controlled release mechanisms 3. Osmosis controlled release mechanisms 4. Mechanical controlled release mechanisms

9 1. Diffusion controlled release mechanisms Diffusion through polymeric membrane or polymeric/lipid matrix: a) Rate follows Fick s law b) Rate depends on: - Partition and diffusion coefficients of the drug in the membrane - The available surface area - The membrane thickness - The drug concentration gradient c) The release kinetics depends on the shape of the device: - Monolith, rate decreases with square root of time - Micropsheres act as matrix controlled release

10 1. Diffusion controlled release mechanisms: DEVICES a) Reservoir b) Matrix c) Drug diffusion from a homogeneous controlled drug delivery system

11 2. Dissolution controlled release mechanisms Drug release is controlled by dissolution rate of employed polymer Devices are either reservoir type or matrix type Polymer must be either water soluble and/or degrarable Release is controlled by: - Tickness and/or - Dissolution rate of polymer membrane surrounding the drug core

12 3. Osmosis controlled release mechanisms Osmosis controlled or active efflux controlled drug release -Osmotic p is used to delivery drug with constant rate Diffusion of water through a semipermeable membrane from a solution of low low concerntration (hypotonic) to a solution of high concentration (hypertonic) => incerease in the pressure (p) of solution D p = osmotic p = p required for maintaining equilibrium with no net movement of water

13 4. Mechanical controlled release mechanisms Mechanically driven pumps Bioresponsive controlled release mechanisms: - Drug is released in response to changes in the external environment

14 O the joy of my soul leaning pois d on itself receiving identity through materials, and loving them

15 i) Diffusion through membranes ii) Diffusion through matrix iii) Hydrogel systems iv) Degradable systems v) Particulate systems

16 i) Diffusion through membranes

17 i) Diffusion through membranes Non-degradable, hydrophobic membranes Reservoir devices, in which a liquid reservoir of drug is enclosed in a silicone elastomer tube e.g. Norplant, release of levonorgestrel for 5 years (subcutaneous implantation) Polymers like EVAc (poly[ethylene(-co-(vinyl acetate)] has been used to control the delivery of contraceptive hormones e.g. Progestrasert and lipophilic drugs to eye or skin e.g. Ocusert and Transderm Nitro Advantages : long service life nearly constant release rates

18 i) Diffusion through polymeric membrane 1. Diffusion through Planar Membranes 2. Diffusion through Cylindar Membranes

19 1. Planar membranes For a differential control volume in the membrane, Dx, a mass balance diffusing drug molecule A yields: dc p /dt = Di:p(d2c p /dx 2 ) Where D i:p = diffusion coefficient for the drug within the polymer material C p = concentration of the drug (mg/ml) within the polymer

20 1. Planar membranes At steady state, the drug release from membrane is: dm t /dt = -AD i:p [(c p,1 -c p,s )/L] And taking into account the partition co-efficients: K p:r = [c p /c reservoir fluid ] equilibrium K p:w =[c p /c water ] equilibrium dm t /dt = -AD i:p [(K p:r c r K p:w c w )/L]

21 1. Planar membranes Schematic diagram (Ocusert) Rate-controlled membranes of poly[ethylene-co-(vinyl acetate)] enclose a drug reservoir

22 1. Planar membranes Rate limiting polymer membranes a) Transdermal delivery system b) Planar controlledrelease system c) Cylindar controlledrelease system

23 1. Planar membranes Drug release as a function of L of membrane L= 20 mm L= 40 mm L= 60 mm The cumulative mass released at y-axis is scaled by M 0 = Ac p,1 L L= 120 mm Each of separate curves represents normalized mass released at particular value of D i:p /L 2 (min-1); D i:p = 1x10-8 cm 2 /s

24 Diffusion coefficients and partition coefficients for some typical polymer/drug combinations

25 Diffusion coefficients and partition coefficients for some typical polymer/drug combinations

26 2. Cylinder membranes Rate of drug release can be modified by: a) Changing geometry of the device (b, b/a,or L) b) Changing drug/polymer combination (=> chages in K and D i:p ) L = cylinder length b = cross-sectional radius b-a = wall thickness For a differential control volume in the membrane, Dx, a mass balance diffusing drug molecule A yields:

27 2. Cylinder membranes a) Schematic diagram of transdermal testoterone-releasing system b) A transdermal patch (Androderm) releasing testoterone

28 2. Cylinder membranes For a differential control volume in the membrane, Dx, a mass balance diffusing drug molecule A yields: dc/dt = D i:p r -1 [d/dr r dc/dr) IF the inside of the cylinder is maintained at a constant concentration of drug => c = c 1 at r = a, and outside the cylinder is free of drug => c = 0 at r = b, and the cylinder wall is initially saturated with drug, c = c 1 at a<r<b then the above eq. can be solved to obtain c as a function of position in the cylinder wall

29 2. Cylinder membranes The total mass of drug released at time t, M t, is obtained by: 1)Calculating the flux from the surface of the ring via Fick s law, J r (b) = -D i:p (dc/dr) r=b 2)Multiplying the flux by the total surface area available for release, 2pbL 3)Integrating with respect to time, t To give: M t /2pc 1 L as a function of time, diffusion coefficient D i:p, flux J and a and b. And immersion of the cylinder in water gives the steady state: M t = (2pc 1 LD i:p t)/ln(b/a)

30 2. Cylinder membranes Drug release from a cylinder-reservoir delivery system The cumulative mass of drug released as a function of time for cylindar-reservoir devices with a range of physical characteristics. Overall length of the device, L=2.7 cm, and cross-sectional radius, b=0.5 cm. a) b/a = 0.5-4, with D i:p = 1x10-8 cm 2 /s and c 1 = 20 mg/ml and b) b) D i:p [cm 2 /s] is varied (A, B, C, D, E) with b/a = 0.5 and c1 = 20 mg/ml. A = 5x10-7 ; B = 1x10-7 ; C = 5x10-8 ; D = 1x10-8 and E = 1x10-9

31 ii) Diffusion through matrix

32 ii) Diffusion through matrix In matrix systems the drug molecules are dissolved or dispersed throughout a solid polymer phase Polymer materials are alike in membrane reservoir devices, - silicone elastomers, EVAc New slowly dissolving biodegradable polymers By carefully designing of the material and device, it is possible to desing delivery systems in which the rate of polymer degradation and dissolution controls the rate of drug delivery => new element for controlling the rate of release of dispersed or dissolved drugs

33 ii) Diffusion through matrix 1. Matrix delivery systems with Dissolved Drugs 2. Matrix delivery systems for water-soluble Drugs and Proteins

34 1. Matrix delivery systems with Dissolved Drugs Drug molecules are dissolved homogeneously in biocompatible polymer Drug molecules are released by diffusing through polymer to the surface of the device and further released into the external environment dc/dt = D i:p (d 2 c/dx 2 )

35 1. Matrix delivery systems with Dissolved Drugs Total amount of drug released from matrix can be determined by: M t = c 0 AL - c(x,t)adx Where the total amount of drug initially within matrix is M = c 0 AL Integration results: M t /M = 1- (8/p 2 ) 1/(2n+1) 2 exp[-(d i:p (2n+1) 2 tp 2 )/L 2 ] For the early stages (Mt<0.6 M, the eq. is closely approximated: M t /M 4(D i:p t/pl 2 ) 0.5

36 1. Matrix delivery systems with Dissolved Drugs Drug release from a planar matrix drug delivery systems as a function of the rate of diffusion of the dissolved drug in the matrix D i:p

37 1. Matrix delivery systems with Dissolved Drugs Release of dissolved dexamethasone from an EVAc matrix. a) As a function of time b) b) as a function of the square root of time

38 2. Matrix delivery systems for Watersoluble Drugs and Proteins Small particles of the drug are dispersed througout a polymer matrix Exampleas of release of water-soluble molecules from polymer films are paint and polyolefins, and Variations of these are release of small water-soluble molecules like dopamine, large molecules like proteins and DNA Drug release mechanism appear to be independent of the size of the dispersed molecule

39 2. Matrix delivery systems for watersoluble Drugs and Proteins Matrix systems for proteins Materials used with proteins are: - non-degradable a) hydrophobic polymers; -EVAc, silicone elastomers, polyuretanes b) Hydrophilic polymers; -poly(2-hydroxyethyl metacrylate) Solid particles of proteins are dispersed throughout the polymer Matrices are immersed in water, and proteins are slowly released Particle size and molecular controls the release

40 2. Matrix delivery systems for Watersoluble Drugs and Proteins Particle size Release of BSA from EVAc matrices

41 2. Matrix delivery systems for Watersoluble Drugs and Proteins Tortuosity of protein release from EVAc matrices

42 2. Matrix delivery systems for Watersoluble Drugs and Proteins Molecular weight Tortuosity measured in EVAc matrices with different M w fractions

43 2. Matrix delivery systems for Watersoluble Drugs and Proteins Diffusion coefficient Effective diffusion coefficients for protein release from EVAc matrices

44 iii) Hydrogel systems

45 iii) Hydrogel systems Water-soluble polymers are cross-linked to materials called hyrdogels Hydrogels swell, but do not dissolve in water The rate of drug diffusion in hydrogels depends on the extent of cross linking and size the drug The swelling of these hydrogels is limited osmotic forces and physical integrity of the polymer network. Polymer network can be controlled by the porosity of the hydrogel

46 iii) Hydrogel systems Role of porosity

47 iii) Hydrogel systems Role of cross-linking density of the PVA hydrogel

48 iii) Hydrogel systems Role of ph in to the release of oxprenololhcl from poly[(methyl metacrylate)-co-(methacrylic acid)] beads

49 iv) Degradable systems

50 iv) Degradable systems Degradiation and disappearance of a biodegradable polymer matrix occurs in a sequence of steps Most of the degradation occurs via hydrolysis Therefore water must enter before degradation The rate of water penetration depends on the degree of hydrophobicity and morphology of the polymer matrix Water penetration occurs via diffusion Diffusion of the solute into the hydrated phase increases as predicted by: Free volume theory The hydrolysis of polyester materials such as plga occurs by following the first order rate kinetics

51 iv) Degradable systems Changes in a plga system during degradation and drug release: a) The uptake of water (filled squares) and the decrease in molecular weight (open squares) b) The loss of polymer mass (filled circles) and the release of drugs (open circles) for a weight-avarage molecular plga 50:50 co-polymer

52 Idealized patterns of erosion for matrices of biodegradable polymers In the bulk erosion: a) The degradation or erosion events occur more uniformly throughout the matrix b) The polymer matrix degrades heterogeneously c) Model of erosion in a semicrystalline polymer

53 iv) Degradable systems In most cases the release of drug from matrices of biodegradable polymers has diffusion kinetics similar to that of non-degrable matrices The degradation/erosion of the biodegradable polymers controls the rate of drug release from the matrix Often the property of biodegradability is based on watersoluble polymers combining the advantages of hydrogels Degradability is obtained by e.g. ester or biodegradable hydrogel linkages.

54 v) Particulate systems

55 v) Particulate systems Implantable drug delivery systems Injectable drug delivery systems - Injected to desired tissue site or blood stream - Could be microcapsules, microspheres, nanospheres Ingest able delivery systems

56 v) Particulate systems a) Microcapsules b) Microparticles a) Surface-modified nanoparticles, in which the drug is entrapped in the solid polymer core

57 v) Particulate systems Responsive delivery systems Matching the administration of the drug with biological process that is under treatment => Search for smart methods Figure: CR activated by cellular infiltration and enzyme activity. Release is initiated by cellular invasion of the gel and local secretion of an enzyme that cleaves the peptide.

58 Summary Polymeric membranes can be used to control the rate of release Reservoir and transdermal devices are conceptually simple; => Rate of drug can be predicted by simple mathematical eq. Matrix-type delivery systems are simple to make; => release is controlled by diffusion of drug through polymer matrix Mathematical descriptions are complicated it is difficult to produce a device with constant rate of release Materials are versatile Any compound can be formulated into CR matrix Degradable polymers (hydrolysis) are appealing for clinical medicines Degradiation is difficult to control