Percutaneous Absorption in baths Percutaneous Absorption in baths

Effects of bathingEffects of bathing

mechanical factorsthermal factors chemical factors

Chemical Effects in BathsChemical Effects in BathsTarget organs of primary reactionTarget organs of primary reaction

Chemical Effects in BathsChemical Effects in BathsTarget organs of primary reactionTarget organs of primary reaction

direct to the skin Skin diseases

indirect by skin stimulation to the general system Chronically inflammatory diseases

by percutaneous absorption and elimination by the respiratory system Respiratory diseases

by percutaneous absorption and effect in the general system Diseases of circulatory system and central nervous system

Chemical acute effectsChemical acute effectsby substances in bath watersby substances in bath waters

Skin irritation followed by stimulation of the anti-inflammatory endogenous power of the body (Sulphur, Radon)

Skin irritation followed by decrease of pathologic activated pain sensitivity (Sulphur, Radon)

Improvement of reologic blood factors (CO2)

sedative (Oil of Cymbopogon winterianus or Valerianae officinalis radix)

Antiphlogistic in the skin (Camomile, Matricariae flos) Exsiccation of the skin (Tannic acid) Bronchospasmolytic by elimination (Oil of conifers)

Percutaneous absorptionPercutaneous absorption

Penetration into the skin– Substance disappear on the skin surface. One part disappear by

permeation through the skin an other part is absorbed in the skin.

Permeation through the skin– Substance cross the skin. Permeation amount could be measured

below the skin.

Absorption in the tissue– Substance is storage in a part of tissue. Absorbed amount could be

measured in the tissue.

Percutaneous absorptionPercutaneous absorption

Absorption through the skin– Substance is absorbed by permeation into the circularly

system and will be transported in different compartments. Absorption amount is only one part of permeation amount. Absorption amount can be calculated by the blood level and the renal elimination if the kinetic of distribution in the body is known.

Transfer of substances in Transfer of substances in bathingbathing

Output (elution)Output (elution) Input (deposition)Input (deposition) Permeation (transfer)Permeation (transfer) Chemical reactionChemical reaction

Horny layerHorny layer

Solutions in waterSolutions in water

Permeability of skinPermeability of skinAbsorption of gases and liquids through 2 mAbsorption of gases and liquids through 2 m22 skin skin

L/h10

1

0,1

0,01N2

He Ar H2

H2SO2

CO2Rn

mL/h

100

10

1

n-Pentanoln-Butanol

Wateriso-Butanol

Ethanol

DMSO

0,0001

0,001

0,01

0,1

1

10

100

1000µl solution/cm2/h

Cortisone

Corticosteron

Indomethacine

Salicylic acid

Hydrocortisone

Heparin

Acetylsalicylic acidDMSO

Progesterone

Testosterone

Estron

Methylsalicylat

IodideSulphate

Strontium

CobaltSilver

Pertechnetate

ArsenicBromide

Ferrum II

Selenite

Chromium IIIFerrum III

CadmiumCaesiumCalciumChloridePotassium

Sodium

Phenylmercuryborate

MethanolWater

H2S

RadonCO2

Permeability of skin Permeability of skin of solutions in waterof solutions in waterPermeability of skin Permeability of skin of solutions in waterof solutions in water

Water EthanolPropanolCamphor

CamphenHeptanolOctanol

Permeability of SkinPermeability of SkinSkin-Clearance of solutionsSkin-Clearance of solutions

Gases

Volatile substances

Amphophile substances

Lipophile substances

Hydrophile substances (ions)

Water

mg solution/cm2/h 1000

100

10

1

0,1

0,01

0,001

0,0001

Percutaneous absorption of alcohols Percutaneous absorption of alcohols in watery solutionin watery solution

(Scheuplein 1973) (Scheuplein 1973)

(l /cm2h)

Epidermis.5.5.8

1.22.561332526080

Epidermis.5.5.8

1.22.561332526080

Dermis605335313024202526

Dermis605335313024202526

Distribution coefficient horny cells

Water

.6

.91.12.55

103050

Distribution coefficient horny cells

Water

.6

.91.12.55

103050

Water Methanol Ethanol Propanol Butanol Pentanol Hexanol Heptanol Octanol Nonanol Decanol

Water Methanol Ethanol Propanol Butanol Pentanol Hexanol Heptanol Octanol Nonanol Decanol

Permeation of alcohols increase proportional by the distribution coefficient between horny cell matrix and water

Permeation of alcohols increase proportional by the distribution coefficient between horny cell matrix and water

The limitation of percutaneous The limitation of percutaneous absorption is controlled by the absorption is controlled by the

horny layerhorny layer

Skin-Clearance is the measure of Skin-Clearance is the measure of quantitative transfer for soluted quantitative transfer for soluted

substances through the skinsubstances through the skin

Skin-Clearance = Diffusion coefficient x distribution coefficient function(membrane thickness)

Skin-Clearance = Diffusion coefficient x distribution coefficient function(membrane thickness)

How can be calculated dose by How can be calculated dose by skin-clearance?skin-clearance?

Dose =

Skin-Clearance x Skin area x Concentration of soluted substance x bathing time

Dose =

Skin-Clearance x Skin area x Concentration of soluted substance x bathing time

Dose is limited by the substance amount on the skin

(Never a limit is taken into account in bath tubs)

Dose is limited by the substance amount on the skin

(Never a limit is taken into account in bath tubs)

Skin-Clearance be valid by optimal condition of penetration(Bath, moist skin, occlusion)

Skin-Clearance be valid by optimal condition of penetration(Bath, moist skin, occlusion)

Influence of temperature is very low (low variability of skin temperature) (Q10 : 1,1-1,4)

Influence of temperature is very low (low variability of skin temperature) (Q10 : 1,1-1,4)

Low permeation rates could modify Low permeation rates could modify metabolic processesmetabolic processes

Activation Inhibition K, NH4 Li, Na, K, Cs Ca, Mg, Mn Ca, Mg Zn, Cd Zn, Cd Fe, Co, Ni Cu, Ag, Au, Hg, Pb F, Cl, J F, Cl, Br PO4 PO4, P2O7, AsO4, AsO3 H2S, GSH H2S, SH O3 SO4, SO3, BO4, NO2 UV CN, CO, J2

But percutaneous absorption only can be effective if natural depot concentration increase.

But percutaneous absorption only can be effective if natural depot concentration increase.

Regional differences in water permeability of Regional differences in water permeability of the skin** compared by thickness and number the skin** compared by thickness and number

of cells of the horny layerof cells of the horny layer ( (*Holbrook 1974,**Scheuplein 1971)*Holbrook 1974,**Scheuplein 1971)

Skin region Water mg / cm2 / h

Thickness m

Number of cells

Abdomen 0.34 6.9 – 9.8* 15 – 20.9* Arm volar 0.31 8.1 – 16.2* 16.7 – 30* Back 0.29 8.2 – 11.3* 14 – 21.1* Forehead 0.85 13.0 Scrotum 1.70 5.0 Back of the hand 0.56 49.0 Palm 1.14 400 Sole of the foot 3.90 600

Calculation of Skin-Clearance by Calculation of Skin-Clearance by use of blood levels for COuse of blood levels for CO22

Calculation of Skin-Clearance by Calculation of Skin-Clearance by use of renal elimination foruse of renal elimination for COCO22

Blood level kinetic by Blood level kinetic by percutaneous absorptionpercutaneous absorption

Blood level and permanence of bathingBlood level and permanence of bathing

Bath range

In steady state

no steady state

Blood levelBlood level

timetime

Calculation example of Radon kineticCalculation example of Radon kinetic

Skin Clearance = 200 µl/cm2 *hConcentration in water = 3 kBq/lSkin area = 2 m2

Absorption rate = 200 x 3 x 2/100 = 12 kBq/h

Skin Clearance = 200 µl/cm2 *hConcentration in water = 3 kBq/lSkin area = 2 m2

Absorption rate = 200 x 3 x 2/100 = 12 kBq/h

Distribution volume = 20 l of 80 kg BWElimination constant = 20 h-1

Blood level in steady state= 12 kBq/h / (20 l x 20 h-1) = 0,030 kBq/lBlood level by 10 min. bath duration = 0,030 x (1-e-20 h-1 x 10 min) = 0,029 kBq/l

Water concentration : Blood level = 100 : 1

Distribution volume = 20 l of 80 kg BWElimination constant = 20 h-1

Blood level in steady state= 12 kBq/h / (20 l x 20 h-1) = 0,030 kBq/lBlood level by 10 min. bath duration = 0,030 x (1-e-20 h-1 x 10 min) = 0,029 kBq/l

Water concentration : Blood level = 100 : 1

Distribution of percutaneous Distribution of percutaneous absorbed radioactive Sulphurabsorbed radioactive Sulphur (Andrejev)(Andrejev)

Distribution of sulphur in the skinDistribution of sulphur in the skin

Sulphur is oxidized during percutaneous transfer. Reaction products are ineffective.

Sulphur is oxidized during percutaneous transfer. Reaction products are ineffective.

Sulphur distribution in the horny layerSulphur distribution in the horny layer

Distribution of Salicylic acid in Distribution of Salicylic acid in the horny layerthe horny layer

Same distribution can be found for all indifferent substances in the horny layer

Same distribution can be found for all indifferent substances in the horny layer

Concentration gradient inside of the horny Concentration gradient inside of the horny layer follows an exponential functionlayer follows an exponential function

The permeation rate decrease exponential by thickness of horny layer.

The permeation rate decrease exponential by thickness of horny layer.

Distribution model of penetrating Distribution model of penetrating substances in the horny layersubstances in the horny layer

Concentration of external applied Concentration of external applied substances in the horny layersubstances in the horny layer

Concentration in the horny layer decrease by penetration deepness.

Around the lowest or last layer the concentration is about 1/100 of the surface concentration.

The natural The natural endogenous endogenous

substances in substances in the horny the horny

layerlayer

Concentration of Sodium and Potassium in Concentration of Sodium and Potassium in the horny layer of 10 patientsthe horny layer of 10 patients

Concentration range of Concentration range of Na, K, Si, Cl in the skinNa, K, Si, Cl in the skin

Range of trace elements in the skinRange of trace elements in the skin

Differentiation of skin cellsDifferentiation of skin cells

14 days are needed for total regeneration of the horny layer.

28 days are needed for total regeneration of the epidermis.

14 days are needed for total regeneration of the horny layer.

28 days are needed for total regeneration of the epidermis.

Isotonia of horny layer is equivalent to Isotonia of horny layer is equivalent to about 6 % NaCl !about 6 % NaCl !

By differentiation all inorganic substances in cells are transferred into the horny layer.But the amount of water in the horny layer is about 10% and in stratum spinosum about 65%.The concentration of inorganic substances in water increase by factor 6.5. Result in isotonia of the horny layer in comparison to the living tissue of the body is 0,9 x 6,5 = 6 %

By differentiation all inorganic substances in cells are transferred into the horny layer.But the amount of water in the horny layer is about 10% and in stratum spinosum about 65%.The concentration of inorganic substances in water increase by factor 6.5. Result in isotonia of the horny layer in comparison to the living tissue of the body is 0,9 x 6,5 = 6 %

Distribution of endogenous substances in the Distribution of endogenous substances in the horny layer by example of the amino acidshorny layer by example of the amino acids

Concentration in all cell layers is nearly the sameConcentration in all cell layers is nearly the same

Endogenous substances of the Endogenous substances of the horny layerhorny layer

Concentration in all cell layers is nearly the same. Inorganic substances in the horny layer are transferred

by differentiation of epidermal cells. The part of sweat is unimportant low.

Concentration of inorganic substances in the horny layer is about 6.5 times more than in living deeper cells.

External effects (sweating, washing) decrease normally only the concentration of the outer third of the horny layer.

Transfer of water through the skinTransfer of water through the skinPercutaneous absorption and perspiration insensibilis 20 ml/h

Lost of water without of stratum corneum disjunctum 250 ml/hwithout epidermis 800 ml/h

Permeability of the intact horny layer in sito 2,5 ml/h

Percutaneous absorption and perspiration insensibilis 20 ml/h

Lost of water without of stratum corneum disjunctum 250 ml/hwithout epidermis 800 ml/h

Permeability of the intact horny layer in sito 2,5 ml/h

Water uptake into the horny layerWater uptake into the horny layer

During bathing about 1 µl water per cm2 body surface is deposited in horny layer in few minutes.In the horny layer a solution of 24-43% resulted by endogenous water soluble substances with 0,24 – 0,43 mg/cm2.In relation to higher concentration of salt in bath water the uptake of water into the skin decrease.In saturated salt solutions no water uptake can be found.By water uptake and swelling the permeability of horny layer increase.

During bathing about 1 µl water per cm2 body surface is deposited in horny layer in few minutes.In the horny layer a solution of 24-43% resulted by endogenous water soluble substances with 0,24 – 0,43 mg/cm2.In relation to higher concentration of salt in bath water the uptake of water into the skin decrease.In saturated salt solutions no water uptake can be found.By water uptake and swelling the permeability of horny layer increase.

Elimination of water soluble substances Elimination of water soluble substances of horny layer during bathingof horny layer during bathing

Elimination of skin ureaElimination of skin ureaElimination of skin ureaElimination of skin urea

0

0,1

0,2

n = 10

n = 10

Amount inhorny layer

Eliminationduring a bath Elimination by

desquamationIn one day

µmol/cm2

Elimination by one bath is regenerated in one weekElimination by one bath is regenerated in one week

Usage of bath duration and urea Usage of bath duration and urea amount in the horny layeramount in the horny layer

Usage of bath duration and urea Usage of bath duration and urea amount in the horny layeramount in the horny layer

0

5

10

15

20

25

n = 14

n = 161

n = 17

Lower than 10 min

10 - 30 minduration

More than 30 minr

mol%of Amino acids

Persons with long bath durations have lower amount of natural moistening factors in the horny layer

Persons with long bath durations have lower amount of natural moistening factors in the horny layer

Usage of bath additives and urea Usage of bath additives and urea amount in the horny layeramount in the horny layer

Usage of bath additives and urea Usage of bath additives and urea amount in the horny layeramount in the horny layer

0

2

4

6

8

10

12

14

16

18No bath additives

Few Bath additives

Foam bathadditives

n = 93

n = 63

n = 22

mol%of Amino acids

Persons with usage of bath additives have lower amount of natural moistening factors n the horny layerPersons with usage of bath additives have lower amount of natural moistening factors n the horny layer

Amino acid differences in horny Amino acid differences in horny layer by different persistence of bath layer by different persistence of bath

(Unit: mol %)(Unit: mol %)Substanz n = 14

10 minn = 161

10 –30 minn = 17

30 minHarnstoff 21.04 13.40 8.35Asparagin 1.55 0.83 0.48Prolin 1.54 2.69 0.96Citrullin 7.19 9.14 7.78Histidin 6.50 5.03 4.95Arginin 3.80 2.52 2.22

Amino acid-differences of the horny layer by Amino acid-differences of the horny layer by use of foam bath additives (Unit : mol%)use of foam bath additives (Unit : mol%)

n = 22 foam additive high quality

Substanz n = 93 no additives

n = 63 simple foam additives

6.99 Harnstoff 16.59 10.05 3.08 Asparaginsre. 3.98 3.25 33.15 Serin 29.27 30.17 0.50 Asparagin 1.03 0.59 1.80 Glutaminsre. 2.61 2.17 2.55 Prolin 1.78 2.28 8.35 Citrullin 8.28 10.05 1.30 Isoleucin 1.56 1.41 1.09 Leucin 1.30 1.19 1.39 Tyrosin 1.68 1.72 2.71 Ornithin 3.16 2.01 1.27 Lysin 1.79 1.40 4.91 Histidin 5.57 4.48 1.96 Arginin 2.90 2.34

Intensive baths usage and allergic skin Intensive baths usage and allergic skin reactionsreactions

Change in amount of amino acids in horny layerChange in amount of amino acids in horny layer

Intensive baths usage and allergic skin Intensive baths usage and allergic skin reactionsreactions

Change in amount of amino acids in horny layerChange in amount of amino acids in horny layer

SERSER

ORNORN

LYSLYSHISHIS

ARGARG

HARHAR

UCSUCS

ASPASP

THRTHR

VALVAL

ILEILE

LEULEU

TYRTYR

PHEPHE

ASNASN

GLUGLU

PROPRO

GLYGLY

ALAALA

CITCIT

Daily bathingDaily bathing persons persons

Persons withPersons withallergic skinallergic skin

SERSER

ASNASN

GLUGLUPROPRO

GLYGLY

ALAALA

CITCIT

VALVAL

ILEILE

LEULEU

TYRTYR

PHEPHE

ORNORN

LYSLYS

HISHIS

ARGARG

HARHAR

UCSUCS

ASPASP

THRTHR

n=142+41 n=135+57

Inhibition of arginase-activity in horny Inhibition of arginase-activity in horny layer by detergentslayer by detergents

Inhibition of arginase-activity in horny Inhibition of arginase-activity in horny layer by detergentslayer by detergents

0%

50%

100%Naturalinhibition

Inhibitionby use ofsoaps

Inhibition by use ofdodecyl sulphate

Therapeutic range in concentration of Therapeutic range in concentration of mineral watersmineral waters

Therapeutic range in concentration of Therapeutic range in concentration of mineral watersmineral waters

Ineffective range Therapeutic range Toxic range

• Therapeutic range dependence on indication.• Dosis dependence on:

Application mannerbathing (concentration)drinking (amount of drinking)Inhaling (concentration)

Application frequencyApplication temperature

Lower limit value Upper limit value

Brine water saves the skinBrine water saves the skinElution of Urocanic acid. Measurement of the bath water UV absorptionElution of Urocanic acid. Measurement of the bath water UV absorption

Brine water saves the skinBrine water saves the skinElution of Urocanic acid. Measurement of the bath water UV absorptionElution of Urocanic acid. Measurement of the bath water UV absorption

Water

27%NaCl

0,4

0,3

0,2

0,1

5 15 25 35 45 55

Minutes Bath persistence

E1 cm265 nm

0

Concentration of Sodium and Potassium Concentration of Sodium and Potassium in horny layer after brine bathsin horny layer after brine baths

Concentration of Sodium and Potassium Concentration of Sodium and Potassium in horny layer after brine bathsin horny layer after brine baths

beforebefore

after 1st bath in 6% brineafter 1st bath in 6% brine

after 2nd bath in 6% brineafter 2nd bath in 6% brine

Co

nce

ntr

atio

n in

µg

/cm

2

Stripping with glue tapeSkin surface lowest layers

Stratum corneum conjunctum

7

0

1

6

2

3

4

5

after 1st bath in 6% brineafter 1st bath in 6% brine

after 2nd bath in 6% brineafter 2nd bath in 6% brine

con

cen

trat

ion

in µ

g/c

m2

Stripping with glue tapeSkin surface lowest layers

Stratum corneum conjunctum

12

0

10

2

4

6

8

Concentration of Sodium and Potassium Concentration of Sodium and Potassium in horny layer after brine bathsin horny layer after brine baths

beforebefore

Calculation of concentration balance of Calculation of concentration balance of uptake and elimination of sodiumuptake and elimination of sodium

Concentration is balanced by concentration of minerals in Sea waterConcentration is balanced by concentration of minerals in Sea water

Are brine baths effective?Are brine baths effective?

Effects of salt solutions which are components of the skin too can be effective by osmotic irritation of the skin.Higher uptake than elimination of NaCl is possible by concentrations higher than NaCl in sea water. Osmotic irritation is possible in concentrations higher than 6%.In damaged horny layer (dry or fissured skin) osmotic irritation is possible by lower concentration.Inter individual variation is very high in effectiveness.

Effects of salt solutions which are components of the skin too can be effective by osmotic irritation of the skin.Higher uptake than elimination of NaCl is possible by concentrations higher than NaCl in sea water. Osmotic irritation is possible in concentrations higher than 6%.In damaged horny layer (dry or fissured skin) osmotic irritation is possible by lower concentration.Inter individual variation is very high in effectiveness.

End of End of SlidesSlides