Sonicated transdermal drug transport – paper by Joshi and Raje, 2002

Sonophoresis is defined as the use of ultrasound to increase the movement of drugs across living skin, underlying phenomena:

1. cavitation, the generation, oscillation, and breaking of tiny gas bubbles

2. thermal effects, T goes up, shown though to be negligible3. induces convection transport, but not by much4. mechanical effects due to stresses caused as a result of

P variations, negligible effect

Cavitation plays a key role1. For initial 4 hours there

is a 13 fold increase inthe transport flux

2. After that the flux becomesthe regardless of whethersonication is used

3. Ultrasound degasses thethe skin hence no morecavitation to the facilitatethe drug transport

4. Cavitation proportional to1/f

5. Common conditions usedare f = 1-3 MHz andintensity 0 – 2 W/cm2

Slope is the transport rate

The sonophoretic enhancement of transdermal drug transport canbe qunatitatively predicted based on the knowledge of the drug’spassive skin permeability (PSC) and the octanol-water partition coefficientKo/w, using the following equation

SC

wo

Px

Ke

4

75./

104

If e >1 there is a sonophoretic enhancement to the drug’s transport,and if e <1 then no effect

In general drugs that passively diffuse through the skin at a slow rateare the ones most enhanced by the application of ultrasound

amount of time, effort, and experimental material.

Joshi & Rajepaper discussingoverall PKmethod.

Other methods for enhancing transport of drugs across skin

1. Chemical enhancers, increase transport bya. increasing the drug solubilityb. increasing the partioning into the SCc. fluidization of the lipid bilayersd. disruption of intracellular proteinse. can also use a combination of different chemicals

2. electroporation, creates a transient high permeability state asa result of the application of high voltage for a short period oftime, can also be combined with chemical enhancers andultrasound

More fascinating quotes from Joshiand Raje’s article

Krewson et al. 1995 in Brain Research published an interestingstudy on an implantable device to release NGF for treatment ofneurological disorders like Alzheimer’s, BBB will not allow transportof systemic drugs like NGF

They wanted to quantify the transport of NGF within the brain interstitium

So they implanted CR polymeric disks with NGF into the brains of adult male rats

They measured the spatial distribution of NGF in brain tissue slicessurrounding the implants for up to 1 week, they used NGF, [125I]NGFand used ELISA, radiation counters, and autoradiography

Some definitions if you read the paper:ipsilateral means the same siderostal means a structure located closer to the head or higher

than anothercaudal means closer to the feet or lower

O O 0

Coronal section

OCUSERT PILO 40, a contact lens like material designed tocontinually release pilocarpine following placement in the cul-de-sacof the eye, produces pupillary constriction and increases aqueoushumor outflow decreasing intraocular pressure, wear it for one week,treats glaucoma

5.5 mm diameter

13 mm

.5 mm thick

Basically a thin disk so onecould use model shown inSection 5.6.1

Combining Equations 5.65and 5.69 then provides the solution for the concentration distribution of

the drug or solute within the polymeric material.

L2

x1n2cose

1n2

1C4t,xC

2e

22

L4

tD1n2n0

(5.70)

Of particular interest would be the flux of drug leaving the polymeric disk, ie. Equation 5.57 at x =

L. After finding dC/dx from the above equation we can solve for the elution flux of the drug given

by the equation below

0n

L4

tD1n2

0eLxS

2e

22

eL

CD2j (5.71)

The above equation can also be combined with a pharmacokinetic model for drug distribution in

the body to predict how the drug concentration in the body changes with time. This is discussed

later in Chapter 7.

People have also proposed approximate solutions for the fraction release that makes it somewhat easier to analyze data, so rather than useEquation 5.73

2

22

4

12

022 12

181 L

tDn

nR

e

en

f

So if 0.4 < fR < 1, then

2

4 2

2

81

L

tD

R

e

ef

Which means n = 0 long times

So take your data and define X = 1 - fR

tL

DX e

2

2

2 4

8lnln

Slope provides De

Nonlinear regression needed

If fR < 0.4, then

2/1

2/1

2

2/1

2 44

44 t

L

D

L

tDf eeR

Slope gives De

From the Bawa paper