Penetration enhancers Used in transdermal drug delivry

MALLIKARJUNAYADAV

MPHARM(PHARMACEUTICS)VAGDEVI COLLEGE OF PHARMACY,

NELLORE

04/10/23 1

04/10/23PENETRATION ENHANCERS 2

To understand the skin structure & its barrier function.

To study factor affecting penetration through skin.

To study various approaches to enhance drug

penetration through skin, including

1. Type

2. Need

3. Mode of action.


The aim of drug administration via skin can be

either the local therapy or the transdermal drug

delivery of the systemic circulation.

Transdermal system delivers medications through

the skin direct into the blood stream.

One long standing approach to increase the range

of drugs that can effectively delivered via this route

has been to use penetration enhancers: chemicals

that interact with skin constituents to promote drug

flux.04/10/23PENETRATION ENHANCERS 4


A diagrammatical cross-section through human skin

Weight of skin: 8 pounds Surface Area: 20,000 sq. cm. Three layers: Epidermis (Stratum corneum):dead

keratinized cells, density 1.55, palms& soles : 100 micrometer. Other portions: 10 micrometer in dry state &

40 to 50 micrometer in hydrated state. Dermis: consists of proteins in a matrix of

muco polysaccharide, blood vessels,lymphatics,nerves,hair follicles, sebaceous & sweat glands.

Subcutaneous layer


04/10/23 8

It involves passive diffusion of substance through skin. Transcorneal penetration:

Intra cellular penetration. Inter cellular penetration.

Transappendegeal Penetration.


Solubility in stratum corneum

Diffusion through stratum corneum

Partitioning

Diffusion through viable skin tissue

Condition of skin

Effect of moisture

Effect of vehicles

Effect of concentration of medicament

Effect of surfactant


Skin penetration enhancement technique have been

developed to improve bioavailability & increase the

range of drugs for which topical & transdermal delivery.

Penetration enhancers penetrates through skin to

decrease the barrier resistance.

Alternatively, physical mechanism such as iontophoresis

& phonophoresis can be used for certain cases of drugs.


Chemical enhancers or penetration enhancers or

absorption promoters are the agents that interact with

skin constituents to promote the drug flux.

Many agent have studied & evaluated for

enhancement properties.

Yet their inclusion in skin formulation is limited due to

unknown mechanism & toxicity.


Non toxic, non irritating, non allergic.

Ideally work rapidly.

Pharmacologically inert.

Its duration of action should be predictable &

reproducible.

Should work unidirectionally.

When removed from skin barrier properties should return

both rapidly & fully.

Cosmetically acceptable.

Compatible with both excipients & drug.


Fick’s 2nd Law of diffusion

dC/ dt = D d2C/dx2 ---------- (1) Where, C = Conc. Of drug x = space co-ordinate D = Diffusion coefficient t = Time

Under steady state condition,

dm / dt = D C0 / h ----------------(2) Where, m= cumulative mass of drug that passes per unit area of membrane in time t C0 = Conc. of diffusant in the first layer of membrane at

the skin surface

h = Membrane thickness


C0 = P C’0 ---------- (3)

where, P = Partition coefficientSubstituting eq. (3) in eq. (2) gives

dm / dt = D C’0 P / h ----------- (4)

From equation it can be seen that : 1. Diffusion coefficient of drug in stratum

corneum. 2. Dissolved effective conc. of drug in the vehicle. 3.Partition coefficient of drug between the

formulation & stratum corneum. 4. Membrane thickness.


1. By increasing the diffusion coefficient of the drug.

2. By increasing the effective concentration of the drug in the

vehicle.

3. By improving partitioning between the formulation and the

stratum corneum.

4. By decreasing the skin thickness.


1. Surfactants : a) Ionic: SLS, Na laureate, etc. b) Non ionic : Tween 80,

Polysorbates, etc.

2. Bile Salts & Derivatives : E.g.. Na glyacolate, Na deoxycholate

3. Fatty Acid & Derivatives : E.g.. Oleic acid, Caprylic acid, etc.

4. Chelating Agents : E.g.. EDTA, Citric acid, etc.


5. Sulphoxide : E.g.. DMSO, DMA, DMF, etc.

6. Polyols : E.g. : PG, PEG, Glycerol, etc.

7. Monohydric Alcohols : E.g. : Ethanol, 2- Propanol, etc.

8. Miscellaneous : E.g. : a) Urea & its derivatives b) Terpenes & Terpenoids c) Phospholipids d) Water


The water content of human stratum corneum is

typically around 15-20% of tissue dry weight.

Soaking the skin in water, exposing the

membrane to high humidities or, occluding allow

the stratum corneum to reach water contents in

equilibrium with underlying epidermal skin cells.

Water content increases to 400%

In general, increased tissue hydration appears to

increase transdermal delivery of both hydrophilic

& lipophilic permeants04/10/23PENETRATION ENHANCERS 20

Water present in stratum corneum is in two form,

bound & free,

Free form act as solvent for polar permeants to

diffuse.

MOA:

- free water act as solvent & alter solubility of

permeants & so its partitioning. .

- The corneocytes take up water and swell, such

swelling of cells would impact upon the lipid

structure between the corneocytes causing some

disruption to the bilayer packing.04/10/23PENETRATION ENHANCERS 21

Dimethyl sulphoxide(DMSO), aprotic solvent which

form hydrogen bond with itself rather than with

water. used in many areas of pharmaceutical sciences as a

‘‘universal solvent’’.

Promotes both hydrophilic & hydrophobic permeants.

Effect is concentration dependent(> 60% needed for

optimum action).

At high concentration – erythema & whales, may

denature proteins.

Metabolite dimethyl sulfide produces foul odor on

breath.04/10/23PENETRATION ENHANCERS 22

To avoid above side effects researchers have investigated chemically related materials – DMAC & DMF

MOA: - denature protein, changes the keratin

confirmation from α - helical to β – sheet. - interacts with the head groups of some bilayer

lipids to distort to the packing geometry. - also may facilitate drug partitioning from

formulation to this universal solvent.



First chemically design molecule as penetration enhancer.

Promote flux both hydrophilic & lipophilic permeants.

Highly lipophilic with Log o/w =6.2.

Effective at low concentration(0.1 – 5%).

Soluble in & compatible with most organic solvents.

Enhances permeation of steroids, antiviral & antibiotics. MOA:

- Interact with the lipid domains of the stratum corneum.

- Partition into the lipid bilayer to disrupt their packing

arrangement.

Mostly used member : 2- Pyrrolidone(2P) & N- Methyl -2-

Pyrrolidone(NMP). NMP & 2P are miscible with most organic solvents. Used for numerous molecules including hydrophilic

(e.g. mannitol, & 5-FU) and lipophilic ( hydrocortisone and progesterone) permeants.

Greater effect on hydrophilic drugs. MOA:- may act by altering the solvent nature of the

membrane and pyrrolidones have been used to generate ‘reservoirs’ within skin membranes.

- Such a reservoir effect offers potential for sustained release of a permeant.


Oleic acid & other long chain fatty acid are used. Effective at low concentration(<10%) Used both for hydrophilic & lipophilic drugs. Saturated alkyl chain lengths of around C10–C12

attached to a polar head group yields a potent enhancer.

In unsaturated compounds, the bent cis configuration is expected to disturb intercellular lipid packing more than trans.

Used for estradiol, acyclovir, 5 FU, Salicylic acid. MOA:- Interacts with & modifies the lipid domains of stratum

corneum discrete lipid domains is induced within stratum corneum bilayer lipid on exposure to oleic acid.


Ethanol is used most commonly in patches.

Used for levonorgestrol, estrdiol, 5 FU, etc.

Its effect is concentration dependent, at high

concentration causes dehydration of biological

membrane & decreases the permeation.

Applied in concentration range from 1 – 10%.

Branched alkanols lower activity

1- Butanol most effective.

1-octanol and 1-propranolol to be effective

enhancers for salicylic acid and nicotinamide.04/10/23PENETRATION ENHANCERS 27

MOA:

- Act as solvent.

- alter solubility property of tissue leads to

improvement in drug partitioning.

- volatile nature of ethanol help in modifying

thermodynamic activity of drug.

- due to evaporation of ethanol drug concentration

increases providing supersaturated state with greater

driving force

- Solvent drag may carry permeant into the tissue.

- As volatile solvent may extract lipid fraction from skin.


Are made up of alkyl or aryl side chain with polar head

group.

Have potential to damage human skin.

Both anionic & cationic surfactant can be used, but non

ionic surfactant are safe.

Non ionic – minor effect, anionic – pronounced effect.

MOA:

- Solubalise the lipophilic active ingredient & also have

potential to solubalise lipids within the stratum corneum.


Used as medicines, flavoring and fragrance agents. Hydrocarbon terpenes less potent, alcohol/ ketone

containing terpenes moderate and oxide & terpenoid shows greatest enhancement .

Smaller terpenes are more active than larger. Non polar(limonene) agents active for lipophilic

drugs & polar(menthol) for hydrophilic drugs. MOA:- Modify the solvent nature of the stratum corneum,

improving drug partitioning.- Alters thermodynamic activity of the permeant.- Terpenes may also modify drug diffusivity through

the membrane.


Hydrating agent, have been used in scaling

conditions such as psoriasis & other skin conditions.

It produces significant stratum corneum hydration,

produces hydrophilic diffusion channels.

Has keratolytic properties, usually when used in

combination with salicylic acid for keratolysis.

Urea itself possesses only marginal penetration

enhancing activity.

Cyclic urea analogues and found them to be as

potent as Azone for promoting indomethacin.


Generally employed as vesicles (liposomes) to carry drugs.

In a non-vesicular form as penetration enhancers.

Phosphatidylcholine & hydrogenated soya bean

phospholipids have been reported to enhance penetration of

theophylline & diclofenac respectively. MOA:

- occlude the skin surface & thus increase tissue hydration.

- phospholipids fuse with stratum corneum lipids.

- this collapse of structure liberates permeant into the vehicle

where drug is poorly soluble and hence thermodynamic

activity could be raised so facilitating drug delivery.

04/10/2332

It is difficult to select rationally a penetration

enhancer for a given permeant.

Penetration enhancers tend to work well with co-

solvents such as PG or ethanol.

Most penetration enhancers have a complex

concentration dependent effect.

Permeation through animal skins & rodent skins

are generally considerably greater than those

obtained with human skin.04/10/23PENETRATION ENHANCERS 33

1. Act on the stratum corneum intracellular keratin,

denature it or modify its conformation.

2. Affect the desmosomes that maintain cohesion

between corneocytes.

3. Modify the intercellular lipid domains to reduce

the barrier resistance of the bilayer lipids.

4. Alter the solvent nature of the stratum corneum

to modify partitioning of the drug.


1. Modification of thermodynamic activity of the vehicle.

2. Solvent permeating through the membrane could

‘drag’ the permeant with it.

3. Solubalising the permeant in the donor, especially

where solubility is very low so that can reduce

depletion effects and prolong drug permeation.



NEEDLE-FREE JET INJECTORS


Basic principle of phonophoresis. Ultrasound pulses are passed through the probe into the skin fluidizing the lipid bilayers by the formation of bubbles

caused by cavitation

PHONOPHORESIS


Ultrasound to Enhance Skin Permeability


IONTOPHORESIS

Basic principle of iontophoresis. A current passed between the active electrode and the indifferent electrode repelling drug away from the active electrode and into the skin,


• Skin electroporation (electropermeabilization) creates transient aqueous pores in the lipid by application of high voltage of electrical pulses of approximately 100–1000 V/Cm for short time(milliseconds). These pores provide pathways for drug penetration that travel straight through the horny layer.

• This technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size including biopharmaceuticals with molecular weights

greater that 7kDA..


Basic principle of electroporation. High voltage current is applied to the skin producing hydrophilic pores in the intercellular bilayers via

momentary realignment of lipids

ELECTROPORATION


Basic design of microneedle delivery system devices. Needles with or without hollow

centre channels are placed onto the skin surface so that they penetrate the SC and epidermis without reaching the nerve endings present in the

upper epidermis.


IN VITRO EVALUATION OF IN VITRO EVALUATION OF

PENETRATIONPENETRATION

Skin: Rat abdominal, Rabbit, Porcine,

Human cadaver

Temp.: 32 +/- 1°C. Media: Simulated

Fluid.PH : 6.8

FRANZ DIFFUSION CELLFRANZ DIFFUSION CELL

SR. NO.

NAME OF DRUG

CPE’s USED INVESTIGATORS

JOURNAL

1 5-FUSesquiterpe

ne(40 fold )

P. A. Cornwell J Pharm Pharmacol

2 Naloxone Lauric acid Bruce J. Aungst J Pharm Pharmacol

3 Acyclovir Azone Mohsen I. Afouna

International Journal of Pharmaceutics

4 CaffeineDimethyl

Formamide(12 fold )

Southwell D.Journal of Biomedical

Optics

5 Levonorgestrel Alcohols David Friend

Journal of Controlled Release


Remington: The Science & Practice of Pharmacy, 21st edition, Vol. 2, Lippicott, Williams & Wilkins, 2006,p.n. 959.

Jain N.K; Controlled and Novel Drug delivery, CBS Publishers & Distributors, first edition, page no-100.

Williams A. C. , Barry B. W. ; Penetration enhancers; Advanced Drug Delivery Reviews ,56, 603– 618(2004) .

Heather A.E. Benson; Transdermal Drug Delivery: Penetration Enhancement Techniques; Current Drug Delivery; Bentham Science Publishers Ltd.;, 2, 23-33(2005).

Pathan I. B. , Setty C M. ; Chemical Penetration Enhancers for Transdermal Drug Delivery Systems; Tropical Journal of Pharmaceutical Research, 8 ,173-179(2009) .

Friend D. , Catz P. , Heller J. , Reid J. , Baker R. , Transdermal delivery of levonorgestrel I. Alkanols as permeation enhancers, J. Control. Release 7 (1988) 243– 250.


Sinha V. R. , Kaur M. P. ; Permeation Enhancers for Transdermal Drug Delivery; Drug Development and Industrial Pharmacy, 26(11), 1131–1140 (2000).

Shembale A. I. , Borole D. K. , Lohiya R. T. ; Useful Permeation Enhancers For Transdermal Drug Delivery: A Review; International Journal of Pharmaceutical Research & Development – Online(IJPRD); 5(2), 1-6(2010).

Aungst B.J. , Rogers N.J., Shefter E. , Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides, Int. J. Pharm. 33 225– 234(1986) .

Cornwell P.A. , Barry B.W., Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil, J. Pharm. Pharmacol. , 46, 261– 269(1994).

Southwell D. , Barry B.W. , Penetration enhancers for human skin: mode of action of 2-pyrrolidone and dimethylformamide on partition and diffusion of model compounds water, n-alcohols and caffeine, J. Invest. Dermatol., 80, 507– 515(1983) .


Penetration enhancers Used in transdermal drug delivry

Documents

Transcript of Penetration enhancers Used in transdermal drug delivry