L14 - Drug Delivery

Drug Delivery

1. Drug absorbed in the bloodstream
2. Eliminated from the body
3. Concentration falls out of the therapeutic range
4. Repeat dosages of the drug

Clearance curve: rate of drug removal

History

• Pills and ointments (> 4000 years ago)
• Intravenous (1665)
• Subcutaneous (1853)
• Controlled drug-delivery system (DDS) (1960)
  • Miniaturization of familiar infusion system
  • Deliver insulin, anticoagulants, and cancer chemotherapy

Drug Administration

• Pills
• Injections
• Lotions
• Suppositories

Oral Dosage

Although it is painless, uncomplicated, and self-administered, many drags are degraded within the gastrointestinal tract. So those drugs must be administered by intravenous, intramuscular, or subcutaneous injection.

Bioavailability, safety, patient’s compliance, and cost of administration are factors for choosing certain route for drug administration.

Pharmacokinetic Model

$$\text{In}-\text{Out}+\text{Generation}-\text{Consumption}=\text{Accumulation}$$ $$\begin{array}{rl}& \frac{dM}{dt}=-kM\\ & \\ & M=M_0{e}^{-kt}\\ & c=\frac{M_0}{V_d}{e}^{-kt}\\ & \\ & t_{1/2}=\frac{\ln 2}{k}\end{array}$$

$c$	Concentration
$V_d$	Volume of distribution
$k$	First-order elimination constant

Shorter the half-life, faster the clearance process.

For controlled drug delivery, the release rate is constant.

Controlled Drug Delivery

• Temporal control
  • Maintenance of plasma or tissue drug levels at a constant level
• Spatial control
  • Concentrating drug release to a certain tissue

Mechanisms

• Diffusion through polymer and through medium
  • Controlled by drug diffusion
• Swelling of polymer
  • Controlled by swelling of water
• Degradation of polymer
  • Controlled by rate of polymer erosion
• Digestion of linker between polymer and drug molecule
  • Controlled by kinetics of bond degradation

Drug Reservoir with Polymer Membrane

$$\text{Rate of Drug Release}\approx KS{C}_r$$

$K$	Membrane permeability
$S$	Total surface area of membrane
$C_r$	The drug concentration in the reservoir

Polymers

Large molecules formed by bonding of many smaller chemicals (monomers)

Properties (e.g. charge, hydrophobicity) of polymers are aggregated properties of the monomers, and are also dependent on the nature of bonding (e.g. non-degradable/degradable).

Bio-degradable: will disappear
Bio-compatible: non-harmful

Poly (lactide-co-gycolide) PLGA

A suture material (sewing wounds)

Pros

• Bioerodible sutures
• Safety profile established
• Biodegradable, biocompatible, and non-toxic

Cons

• Bulk erosion $\to$ unstable erosion rate
• Acidic environment within PLGA matrix

Protein Drugs

Problems

• Eliminated very quickly
• Toxic when delivered systemically

Solutions

• Releasing into blood over a long period
• Releasing into a local tissue site

Future

• Biological components $\to$ self-regulation of drug release
  • Enzymes
  • Antibodies
  • Genetically modified cells from patient
• Cell transplantation (bone marrow)
• Islet cell transplants

Systemic Drug Delivery

Pros

• Used with unknown location of delivery
• Used when local delivery cannot access

Cons

• Severe toxicity
• Fast clearance
• Low solubility

Drug Delivery Carriers

• Liposome (hydrophilic head inside and outside) $\to$ hydrophilic drugs
• Micelle (hydrophilic head outside, hydrophobic tail inside) $\to$ hydrophobic drugs

Hydrophobic: reject water
Hydrophilic: likes water