Controlled Released Systems Review

What are the two architectures of diffusion devices? Describe how drug release occurs in each

1) Pores: drug diffuses through pores

2) Matrix: drug diffuses through matrix

In a porous membrane device, what determines the rate of drug diffusion through the pores?

1) Length of pores/tortuosity

2) Solubility of Drug (HPL/HPB drug can require different engineering designs)

3) Viscosity of medium (more viscous such as GI tract the slower the drug diffusion)

How does tortuosity influence drug diffusion? Provide an example of straight vs. “bumpy” path.

The less linear or straight the path is the slower the drug diffusion

Why must hydrophobic porous coatings be used, and how does water interact with them?

HPB coating absorbs little water therefore water creates controlled pore-mediated drug release and won’t swell

Write Fick’s First Law and define each variable.

J = -D(dC/dx)

J = flux

D = diffusion coefficient

dC/dx = concentration gradient

Define diffusion coefficient and label each variable (D)

D = kT/6(pi)(r ) (viscosity)

k = boltzman constant

T = temperature

r = molecular radius

v = viscosity

How does molecular radius influence the diffusion coefficient?

Larger radius = smaller D thus slow diffusion

Explain how viscosity affects diffusivity based on the D = kT / (6πrη) relationship.

higher viscosity = lower D thus slower diffusion

Describe the role of drug solubility in controlling diffusion rate.

Higher drug solubility = higher diffusion

How does crystallinity of a polymer matrix influence drug release?

Higher crystallinity = slower drug release

Why are amorphous matrices preferred for certain slow-release applications?

More permeable thus more controlled release

Describe how matrix diffuse drug

Matrix have no pores, are solid, and are amorphous thus have controlled release of drug

What are the factors that can impact rate of diffusion for drugs embedded in matrices?

1) Crystallinity of matrix (higher = slower diffusion)

2) Solubility of Drug in matrix (higher = faster diffusion)

3) Density of matrix (higher = slower diffusion)

4) Molecule size

What is a hydrogel, and how does crosslinking prevent dissolution while still allowing swelling?

A hydrogel is a network of crosslinked polymers

• absorb water and swell, don’t dissolve thus preventing dissolution

How do you engineer hydrogels?

1)Crosslink existing polymers

• Covalent crosslinking:

  • permanent, strong, stable

  • COOH react with OH → form ester

• Ionic crosslinking:

  • reversible

  • more easily degraded

  • Ca2+ example

2) Synthesize polymer network

What are other ways to form crosslinked polymers?

1) Hydrogen Bonding

2) Interpenetrating networks (IPN): enhance mechanical properties

What are the two methods to load drugs into hydrogels?

1) Include the drug during crosslinking

• caution that drug may be affected and degrade sensitive drugs

2) Load drug onto existing hydrogel

• long process

What determines the rate of drug release in a biodegradable device?

How fast it degrades not diffusion

What are the two types of biodegradable systems (BS)?

1) Surface erosion: water reacts at the outer surface and mechanism shrinks smaller and smaller

• polyanhydrides common surface eroding polymers

2) Bulk erosion: water penetrates devices and erosion/diffusion occur inside by hydrolysis → device become goo

Describe the mechanism of surface erosion, and provide a real-world analogy?

Surface reacts with water → device shrinks like bar of soap

• polyanhydrides (HPB but have hydrolysis sensitive bonds)

Describe bulk erosion and explain what happens as water penetrates the polymer.

Water penetrates and erosion occurs internally by hydrolysis and diffuses the drug → device becomes “goo“

• PLGA (water penetrates, hydrolyzes ester bonds)

What determines degradation rate of biodegradable systems?

1) Monomer ratio (more HPL= faster degradation)

2) Molecular Weight (higher MW = slower degradation)

3) End groups (HPL end groups speeds up hydrolysis = faster degradation)

How do monomer ratios (e.g., CPP:SA vs 20:80, 50:50) influence degradation rate?

Monomer ratios create a balance of HPL/HPB ratios thus influencing the rate of degradation (more HPL = faster degradation)

Explain how hydrophilic vs hydrophobic monomers influence water penetration.

HPL attracts water → faster degradation HPB repels water → slower degradation

How does molecular weight influence degradation rate?

Higher MW = slower degradation

What effect do hydrophilic end groups have on hydrolysis?

Speed up hydrolysis b/c they attract more water thus more water enters and faster degradation

Explain why PLGA degrades by hydrolysis even though it is relatively hydrophobic.

Once water diffuses in thats where hydrolysis will occur on the ester bonds thus degrading it internally

• lactide may slow down hydrolysis due to extra methyl group which results in steric hindrance and slows water access to ester bond

What are the two methods to forming microparticles ?

1) Single emulsion (HPB drugs)

2) Double emulsion (HPL drugs)

Describe the single emulsion process for HPB drugs

1) Polymer + DCM (org solvent) + HPB Drug are dissolved together

• Why DCM? volatile (evaporates easily)

2) Emulsified in water

3) Solvent evaporates

4) Microparticle formed ( Drug inside the core) (o/w solution)

How does polymer concentration affect particle size?

Higher polymer [] = more viscous = harder to form small particles = large particles formed

How does stirring speed (rpm) affect particle size?

Higher speed = smaller particles

Why does decreasing surface tension via PVA (surfactant) decrease particle size?

PVA (surfactant) added to stabilize particles and reduce surface tension = smaller particles

What are three ways to manipulate the size of the particle?

1) Changing [polymer] = higher [polymer] the bigger the particle

2) Adding surfactant (PVA) = stabilize and reduce surface tension thus smaller particle

3) RPM = higher RPM thus the smaller the particle

Describe the double emulsion process for HPL drugs

1) HPL drug + water dissolved together

2) Mix into org. polymer solution (w/o)

3) Emulsify again in water (w/o/w)

4) Evaporate solvent → particle formation

5) Freeze dry (lyophilization) to stabilize them and remove remaining moisture

Compare diffusion-controlled vs. bioerodible release systems in terms of release kinetics.

Diffusion controlled are mechanisms engineer to release drugs by design such as pores or matrix while biodegradable systems release drugs by degradation and depend on the rate of degradation to release drug

Explain why hydrophobicity of the polymer is essential for controlled erosion.

Keeps water out

If a drug is very hydrophilic, which delivery system is likely better: diffusion matrix, hydrogel, or microparticle? Why?

Matrix mechanism (diffusion controlled) :

• usually very HPB and don’t load HPL drugs well thus poor loading

Pores mechanism (diffusion controlled):

• diffuse very quickly

Hydrogels: drug dissolved quickly and diffuses rapdily once water comes in

Microparticle: best because they have a double emulsion method that prevents burst release, protects drug degradation)

Provide one advantage and one disadvantage of surface-eroding systems.

Pro: predictable release

Con: limited drug load and erosion only at the surface

What are the major challenges in encapsulating proteins using double emulsion?

1) Denaturation

2) low encapsulation efficiency