pathway for skin penetration.ppt(1)

What is skin componentsWhat is skin components ??

http://upload.wikimedia.org/wikipedia/commons/3/34/Skin.jpg

The Human Skin Animation Video.flv

What is penetration ?What is penetration ?

Skin penetration is differs from skin Skin penetration is differs from skin permeation.permeation.

skin penetrationskin penetration is the former describes is the former describes the passage of an ingredients into the the passage of an ingredients into the skin ( we hope to the target skin layer).skin ( we hope to the target skin layer).

Skin permeationSkin permeation is the passage of an is the passage of an ingredient through the skin to the ingredient through the skin to the circulatory system.circulatory system.

Interaction between Interaction between a given compound a given compound

and the skin is and the skin is physicochemical in physicochemical in

nature.nature.

what is the penetration pathway?what is the penetration pathway?(Penetration between SC corenocytes is (Penetration between SC corenocytes is

the pathway by witch most compounds the pathway by witch most compounds penetrate the skinpenetrate the skin ) )

1.1. The intercellular pathway The intercellular pathway .*(.*(5%-30%of 5%-30%of total area)total area)

2.2. The intracellular pathway The intracellular pathway

3. The intrafollicular pathway and the3. The intrafollicular pathway and the

sebaceous glands pathway sebaceous glands pathway

4. The polar pathway . 4. The polar pathway .

http://upload.wikimedia.org/wikipedia/commons/3/34/Skin.jpg

The intercellular pathwayThe intercellular pathwayand the intracellular and the intracellular

pathway pathway

* Hydrophilic compounds * Hydrophilic compounds maymay preferably preferably partition into the intracellular domainpartition into the intracellular domain

*lipophilic compound *lipophilic compound maymay cross the SC cross the SC through the intercellular rout.through the intercellular rout.

So the major pathway for a compound is So the major pathway for a compound is highly dependent upon its partition highly dependent upon its partition coefficient.coefficient.

stratum corneum constituentsstratum corneum constituents75%-80% protein , 5%-15% lipids , 5%-10% unidentified element75%-80% protein , 5%-15% lipids , 5%-10% unidentified element

Skin canSkin can

absorb water absorb water and the proof and the proof

is is wrinklewrinkle of this finger of this finger

http://en.wikipedia.org/wiki/Image:Wrinkly_fingers.jpg

The intrafollicular pathway and theThe intrafollicular pathway and thesebaceous glands pathwaysebaceous glands pathway

*(Mainly for lipid and surprisingly it is for *(Mainly for lipid and surprisingly it is for a charge and large polar molecule) .a charge and large polar molecule) .

sebaceous gland on the total skin surface sebaceous gland on the total skin surface represent not more than 0.1% , but some represent not more than 0.1% , but some time it will be the target such as acnetime it will be the target such as acne

*Delivery System Handbook for Personal Care and Cosmetic Products. By Meyer

Follicle distributionFollicle distribution

The polar pathwayThe polar pathway

This route is believed to be This route is believed to be hydrophilic in natural , it is hydrophilic in natural , it is composed of aqueous region composed of aqueous region surrounded by polar lipids surrounded by polar lipids that create the walls of that create the walls of microchannels.microchannels.


The localization of theThe localization of the

hydrophilic pores is unclear,hydrophilic pores is unclear,

but they think that :but they think that :

1- it is intercellular .1- it is intercellular .

2- it is intracellular keratin .2- it is intracellular keratin .


We need 3-10 corneocytes to create a We need 3-10 corneocytes to create a columns that form a cluster.columns that form a cluster.

Corneocytes edges inside each cluster Corneocytes edges inside each cluster were found to intercalate extensively were found to intercalate extensively , but neighboring cluster were , but neighboring cluster were separated by gaps of a few separated by gaps of a few micrometers.micrometers.

The polar pathwayThe polar pathwaySo know we will say that we have So know we will say that we have

2 different hydrophilic pathway : 2 different hydrophilic pathway : 1- inter-cluster rout (within low 1- inter-cluster rout (within low

penetration resistant)penetration resistant)2- inter-coreocyte pathway (higher 2- inter-coreocyte pathway (higher

penetration resistance), it is penetration resistance), it is twisted between coreocyte ,may twisted between coreocyte ,may be act as an actual channel in be act as an actual channel in the skin. the skin.

Factor Affecting Skin PenetrationFactor Affecting Skin Penetration

1- size of the molecule and MW.1- size of the molecule and MW.

2- affinity of the molecule to the surface of the skin.2- affinity of the molecule to the surface of the skin.

3- compatibility with the intercellular lipids.3- compatibility with the intercellular lipids.

4- the skin condition.4- the skin condition.

5- the moisture content.5- the moisture content.

6- tempreture .6- tempreture .

7- thickness of the SC.7- thickness of the SC.

8- physical integrity.8- physical integrity.

size of the molecule.size of the molecule.*smaller size more penetration.*smaller size more penetration.

*molecular weight (MW) of a*molecular weight (MW) of acompound must be under 500compound must be under 500Dalton to allow skin absorption.Dalton to allow skin absorption.

*Bos ,J.D., Meinardi ,M.M..(2000). The 500 Dalton rule for the skin penetration of chemicalcompounds and drugs. experimental terminology. 9(3), 165-9.

the skin conditionthe skin condition

Scarred skin in Comparison to Scarred skin in Comparison to normal skin will be with no hair normal skin will be with no hair follicle and sebaceouse gland and follicle and sebaceouse gland and thinning of the collagenouse thinning of the collagenouse fibers , penetration rate throw fibers , penetration rate throw Scarred skin will be so less than Scarred skin will be so less than normal skin .normal skin .

compatibility with the intercellular compatibility with the intercellular lipidslipids

To do that we use To do that we use Penetration Penetration enhancersenhancers witch is a substances that witch is a substances that can partition into, and interact with, can partition into, and interact with, skin constituents . skin constituents .

thickness of the SCthickness of the SC

By increasing the thickness of By increasing the thickness of the SC amount of water and the SC amount of water and lipid will increase and lipid will increase and penetration of the skin penetration of the skin increase. (sink condition)increase. (sink condition)

My opinion

The moisture contentThe moisture contentAs the amount of free moisture in the As the amount of free moisture in the

intercellular spaces increases the intercellular spaces increases the intercellular become larger and the intercellular become larger and the amount of a substances penetrating amount of a substances penetrating the skin increase . the skin increase .

(the mechanism by witch hydration (the mechanism by witch hydration increase skin penetration is not will increase skin penetration is not will understood)understood)

Harry s cosmeticology (eighth edition ) page 352

tempreturetempretureAs the tempreture increases the As the tempreture increases the

penetration increase , because of :penetration increase , because of :

1- lowering of the activity coefficient of 1- lowering of the activity coefficient of pharmaceutical substances in the skin.pharmaceutical substances in the skin.

2- increases in drug solubility.2- increases in drug solubility.

3- increase in diffusion and blood flow .3- increase in diffusion and blood flow .

4- transition from gel to liquid crystal of 4- transition from gel to liquid crystal of layer lipid hydrocarbon chain will layer lipid hydrocarbon chain will reduce the viscosity so increase the reduce the viscosity so increase the duffusion.duffusion.

Penetration EnhancerPenetration Enhancer

There are more than one way to There are more than one way to differentiate and classify skin differentiate and classify skin penetration enhancer : penetration enhancer :

11- classifying them according to the - classifying them according to the preferred rout of penetration.preferred rout of penetration.

2- according to carry different molecule .2- according to carry different molecule .

33- according to their mechanism of - according to their mechanism of enhancement.enhancement.

Penetration Enhancer according to Penetration Enhancer according to the the preferred routpreferred rout of penetration of penetration

1- solvent that enhance penetration 1- solvent that enhance penetration through both polar and non-polar through both polar and non-polar pathway.pathway.

2- enhancers that preferentially affect 2- enhancers that preferentially affect the polar route .the polar route .

3- enhancer that mainly modify the 3- enhancer that mainly modify the non-polar route.non-polar route.

Penetration Enhancer according to Penetration Enhancer according to the preferred rout of penetrationthe preferred rout of penetration

1- solvent that enhance penetration 1- solvent that enhance penetration through both polar and non-polar through both polar and non-polar pathway such as:pathway such as:

a.a. 2-pyrrolidone 2-pyrrolidone

b. N-methyl pyrrolidone b. N-methyl pyrrolidone

c.c. N-methyl-formaide N-methyl-formaide

d. propylene glycol in combination d. propylene glycol in combination with azon.with azon.


2- enhancer that mainly 2- enhancer that mainly modify the non-polar route, modify the non-polar route, such as :such as :

a.a. propylene glycol and oleic propylene glycol and oleic acid. acid.

b.b. propylene glycol alone. propylene glycol alone.


3- enhancers that preferentially 3- enhancers that preferentially affect the polar route , such as:affect the polar route , such as:

a. Propylene glycol in combination a. Propylene glycol in combination with decylmethylsulfoxide.with decylmethylsulfoxide.


The 3 major mechanisms (polar) :The 3 major mechanisms (polar) :

1.1. Extraction the SC lipids: (The Extraction the SC lipids: (The permeability coefficient of polar permeability coefficient of polar molecule increased with increasing molecule increased with increasing lipid extraction).lipid extraction).

2. Inducing a relaxation of the polymeric 2. Inducing a relaxation of the polymeric structure of the cytoplasmic matrix in structure of the cytoplasmic matrix in keratinocytes cell.keratinocytes cell.

3. Changing the solvent properties of the 3. Changing the solvent properties of the SC. (surfactant)SC. (surfactant)


*Surfactant:*Surfactant:enhance transport of polar molecule by enhance transport of polar molecule by

solubilization and removal of solubilization and removal of intercellular lipid and binding to keratin intercellular lipid and binding to keratin filament of the intracellular matrix , this filament of the intracellular matrix , this resulted in cell order disruption .resulted in cell order disruption .

non-ionic surfactant were shown to shows non-ionic surfactant were shown to shows fluidizing effect on the SC.fluidizing effect on the SC.

Penetration Enhancer according to Penetration Enhancer according to their their mechanismmechanism of enhancement. of enhancement.

1- Enzyme .1- Enzyme .

2- Chemical enhancers .2- Chemical enhancers .

3- Vesicular system .3- Vesicular system .

4- Ceramides (one of the lipid classes 4- Ceramides (one of the lipid classes in the SC).in the SC).

(1) Enzyme(1) Enzyme

Using an enzyme to affect the Using an enzyme to affect the barrier properties of the SC barrier properties of the SC refer to either affecting activity refer to either affecting activity of :of :

1- enzyme present in the skin.1- enzyme present in the skin.2- Or to enzyme applied to it from 2- Or to enzyme applied to it from

outside.outside.

How dose the enzyme work ?How dose the enzyme work ?

1- by affecting the synthesis of lipid class 1- by affecting the synthesis of lipid class in SC (fatty acid, cholesterol and in SC (fatty acid, cholesterol and ceramides), such as:ceramides), such as:

* 5-(tetradecyloxy)-2-furancarboxylic * 5-(tetradecyloxy)-2-furancarboxylic acid. this will prevent fatty acid acid. this will prevent fatty acid synthesis.synthesis.

* Fluvastatin .* Fluvastatin .

this will prevent cholesterol synthesis .this will prevent cholesterol synthesis .


2-by affecting metabolism and 2-by affecting metabolism and biochemical cascade in the skin , such biochemical cascade in the skin , such as:as:

* papian ; is a proteolytic enzyme , that * papian ; is a proteolytic enzyme , that increase the SC thickness , and the increase the SC thickness , and the living epiderm. living epiderm.


3- subtissues phase separation , 3- subtissues phase separation , lamellar bodies formation and lamellar bodies formation and created disorder in lamellar created disorder in lamellar structures in the SC . structures in the SC .

(2) Chemical enhancers(2) Chemical enhancers

Most chemical enhancers affect the Most chemical enhancers affect the intercellular lipid bilayers in the intercellular lipid bilayers in the SC , it allows the creation of various SC , it allows the creation of various types of (openings) in the bilayers.types of (openings) in the bilayers.

Example:Example:

* isopropyl myristate.* isopropyl myristate.

* isopropyl alcohol.* isopropyl alcohol.

* oleic acid.* oleic acid.

Chemical enhancersChemical enhancers

**oleic acid :oleic acid :

It was observed that oleic acid It was observed that oleic acid make alteration in the SC make alteration in the SC specifically in the intercellular specifically in the intercellular spaces.spaces.

Another Chemical Another Chemical enhancersenhancers

Penetration enhancers (Penetration enhancers (DMSO)DMSO)**Dimethyl sulfoxide (DMSO):Dimethyl sulfoxide (DMSO):By changing in the conformation of the skinBy changing in the conformation of the skinKeratins from an α-helical to a β-sheetKeratins from an α-helical to a β-sheetConformation ,that happen because of (DMSOConformation ,that happen because of (DMSOtended to bind to free water before thetended to bind to free water before theprotein-bound water was replaced and theprotein-bound water was replaced and theprotein conformational changes wereprotein conformational changes wereinduced. induced.

Penetration enhancers (azon)Penetration enhancers (azon)Azone may act on the lipid-rich route Azone may act on the lipid-rich route

because it fluidizes the stratum corneum because it fluidizes the stratum corneum lipids .lipids .

on the water-rich route because it on the water-rich route because it enriches the water content .enriches the water content .

The reason why Azone affects the skin The reason why Azone affects the skin permeation of a relatively broad permeation of a relatively broad spectrum of drugs may be that it affects spectrum of drugs may be that it affects at least two permeation routes in the at least two permeation routes in the skin barrier skin barrier

(3) Vesicular system(3) Vesicular system

What is Vesicular system ?What is Vesicular system ?

It is an Encapsulation of the It is an Encapsulation of the drug in vesicular structures drug in vesicular structures such as liposomessuch as liposomes .

(3) Vesicular system(3) Vesicular system

A major force driving vesicle A major force driving vesicle penetration through the skin penetration through the skin may be the water gradient across may be the water gradient across the epidermis.the epidermis.

(3) Vesicular system(3) Vesicular systemWe have We have

* * classic multi-layered phosphoplipid classic multi-layered phosphoplipid liposomesliposomes : :

Act as a reservoir and would not be the Act as a reservoir and would not be the carrier of choice.carrier of choice.

**SC lipid-based liposomesSC lipid-based liposomes::

were found to deliver a greater amount of were found to deliver a greater amount of the drug to the deep layer of the skin the drug to the deep layer of the skin (epidermis and dermis) , the larger the (epidermis and dermis) , the larger the mean size the poorer the penetration to mean size the poorer the penetration to SC layer.SC layer.

(3) Vesicular system(3) Vesicular systemOn the another hand the scientist found On the another hand the scientist found

that :that :

*phospholipids liposomes increase SC *phospholipids liposomes increase SC lipid bilayer disorder and increase lipid bilayer disorder and increase permeation permeation ..

*SC lipid-based liposomes have a high *SC lipid-based liposomes have a high affinity to the SC and generate a affinity to the SC and generate a reservoir because it increase the order reservoir because it increase the order of the lipid in the intercellular of the lipid in the intercellular lamellaelamellae.

(4) ceramides(4) ceramides

(4) ceramides(4) ceramides

Ceramides in certain concentration were Ceramides in certain concentration were shown to create an imbalance in the shown to create an imbalance in the intercellular lamellar organization and intercellular lamellar organization and to enhance skin penetration .to enhance skin penetration .

In the study *they found that polar head In the study *they found that polar head of an enhancer is responsible for the of an enhancer is responsible for the penetration , and they found *that penetration , and they found *that branched-chain alcohol have lower branched-chain alcohol have lower enhancement capability than the enhancement capability than the primary alcohol. primary alcohol.

It is recommended to choose It is recommended to choose enhancers with different enhancers with different mechanisms of action , mechanisms of action ,

this will prevent this will prevent competition at the site of competition at the site of action and has a better action and has a better

probability of not probability of not provoking irritation provoking irritation

Summary Summary We talk a bout four of the skin penetration We talk a bout four of the skin penetration

pathways (pathways (the intercellular the intercellular pathway ,the intracellular pathway, the pathway ,the intracellular pathway, the

intrafollicular pathway and theintrafollicular pathway and the

sebaceous glands pathway, and the polar sebaceous glands pathway, and the polar pathwaypathway) and four types of penetration ) and four types of penetration

enhancer (enhancer (enzymes, chemical enzymes, chemical enhancer , and the vesicular system , enhancer , and the vesicular system ,

ceramidesceramides) )

ReferencesReferences Cosmetic & toiletries magazine.(vol.120,No. 6/2005)Cosmetic & toiletries magazine.(vol.120,No. 6/2005)

Delivery System Handbook for Personal Care and Cosmetic Delivery System Handbook for Personal Care and Cosmetic Products. By MeyerProducts. By Meyer

Bos ,J.D., Meinardi ,M.M..(2000). The 500 Dalton rule for Bos ,J.D., Meinardi ,M.M..(2000). The 500 Dalton rule for the skin penetration of chemical compounds and drugs. the skin penetration of chemical compounds and drugs. experimental terminology. 9(3), 165-9. experimental terminology. 9(3), 165-9.

Harry s cosmeticology (eighth edition ) page 352 Harry s cosmeticology (eighth edition ) page 352

Tanja ,M.Greve .Kristine ,B.Andersen ,Ole ,F.Nielsen2..Tanja ,M.Greve .Kristine ,B.Andersen ,Ole ,F.Nielsen2..(2008). Penetration mechanism of dimethyl sulfoxide in (2008). Penetration mechanism of dimethyl sulfoxide in human and pig ear skin: An ATR–FTIR and near-FT human and pig ear skin: An ATR–FTIR and near-FT Raman spectroscopic in vivo and in vitro study. 22(9). 405-Raman spectroscopic in vivo and in vitro study. 22(9). 405-417.417.

Mechanism of skin penetration-enhancing effect by Mechanism of skin penetration-enhancing effect by laurocapram (the name of article)laurocapram (the name of article)

pathway for skin penetration.ppt(1)

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