Novel drug delivery systems, 2nd edition, by Y.W.

Chein page no.: 338 – 380.

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REFERENCES

Transdermal drug delivery systems

Patch

• Definition:

Transdermal drug delivery is defined as a self

contained discrete dosage form, which when applied to

the intact skin, will deliver the drug at a controlled rate to

the systemic circulation.

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Transdermal drug delivery system

POTENTIAL BENEFITS OF

TRANSDERMAL DRUG DELIVERY

(ADVANTAGES)

• Easy to use.

• Avoid GIT absorption problems for drugs.

• Avoids First Pass hepatic metabolism of drugs.

• More improved and convenient patient compliance.

• Rapid termination in case of toxicity is possible.

• Self medication is possible.

• Reduces frequency of dosing.

• Maintains therapeutic level for 1 to 7 days.

• Controlled delivery resulting in more reliable and predictable blood levels.

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DISADVANTAGES

• Daily dose of more than 10mg is not possible.

• Local irritation is a major problem.

• Drug requiring high blood levels are unsuitable.

• Drug with long half life can not be formulated in TDDS.

• Uncomfortable to wear.

• May not be economical.

• Barrier function changes from person to person and within the same person.

• Heat, cold, sweating (perspiring) and showering prevent the patch from sticking to the surface of the skin for more than one day. A new patch has to be applied daily.

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Routes of drug absorption through skin

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Basic components of Transdermal

drug delivery

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BASIC COMPONENTS OF TRANSDERMAL

DRUG DELIVERY SYSTEM

COMPONENT OF TRANSDERMAL DEVICE INCLUDE:

1) POLYMER MATRIX

2) THE DRUG

3) PERMEATION ENHANCER

4) OTHER EXCEPIENTS

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POLYMER MATRIX Following criteria to be considered in selection a polymer:

Molecular weight, physical of polymer must allow

diffusion of drug at desired rate.

Polymer must be non-reactive, inert, non-toxic, easy

to manufacture, inexpensive.

It should not decompose on storage of the device &

not deteriorate when large amount of active ingredient is

in corporated into it.

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LIST OF POLYMERS USED

NATURAL POLYMERS:

Cellulose derivatives, Zein, Gelatin, Shellac, Waxes,

Gums & Natural rubber

SYNTHETIC ELASTOMER POLYBUTADIENE:

Polysiloxane, Silicon rubber, Nitrile, Acrylonitryle,

Butyl rubber, Styrene butadiene rubber.

SYNTHETIC POLYMER

Poly vinyl alcohol, Poly vinyl chloride, Polyethylene,

Poly propylene, Poly urea, PVP, Polymethacrylate

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DRUG

For successful developing transdermal delivery, drug

should be chosen with great care physicochemical

properties

1. Mol. wt. less than 1000 Daltons

2. Affinity for both lipophilic & hydrophilic phase

3. Drug should have low melting point

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Ideal molecular properties for drug penetration

- A low molecular weight (generally less than 500 Daltons) - An adequate solubility in oil and water - A balanced partition coefficient - A low melting point - Potent drug (maximum 10 mg/day) - Half life of drug should be short. - Non irritant to skin. - Drug prone to ‘first pass effect’ and which degrade in GIT are

ideal candidate.

Hormones

• Estradiol and progesterone

• Avoid hepatic metabolism

Cardiovascular drugs

• Hypertension and angina

• Betablockers : timolol, propranolol

• Hepatic metabolism of propranolol

Analgesics

• Control of chronic pain by transdermal therapy

Antihistamines

• Treatment of allergy E.X Chlorpheniramine

• Maintain histamine-receptor antagonism while reducing CNS side

effects such as drowsiness

Central nervous system drugs

• Physostigmine : cholinesterase inhibitors

• To inhibit breakdown of acetylcholine by 30 to 40% over 4days

DRUG

PERMEATION ENHANCERS

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• Vehicle or device to maximize drug partition into the skin

• Incorporate penetration enhancer into formulation\

penetration enhancer are the agents which promote the skin permeability by altering the skin as a barrier to the flux of desired penetrant. Flux J across the skin can be given by J= D. dc/dx D= diffusion coefficient C= concentration x=Spatial coordinate D is function of size, shape, flexibility of diffusing drug molecule

Optimization of Percutaneous Absorption:

IDEAL CHARACTERISTIC OF

PENETRATION ENHANCERS

1) IT SHOULD BE INERT

2) NON-TOXIC, NON- IRRITATING

3) ACTION SHOULD BE IMMEDIATE& PREDICTABLE

4) SHOULD NOT CAUSE REMOVAL OF BODY FLUID

5) SHOLD BE COMPATIBLE WITH DRUG& EXIPIENTS

6) A SUITABLE SOLVENT FOR DRUG

7) SPREAD WELL ON THE SKIN

8) COSMETICALLY ACCEPTABLE

9) ODORLESS, TASTELESS, COLORLESS & CHEAP

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SOLVENTS

The compounds increase penetration possibly by swelling the polar pathway

and fluidizing the lipid

e.g.. Methanol, ethanol, pyrolidiones, propylene glycol, glycerol etc..

SURFACTANTS

They enhance polar pathway transport of hydrophillic drugs

• ANIONIC SURFACTANTS :

Dioctyl sulpho succinate, SLS, decodemethyl sulphoxide

• NON -IONIC SURFACTANTS :

Pluronic F127, pluronic F58

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Backing membrane

They are flexible and provide a good bond to the drug

reservoir, prevent the drug from leaving the dosage form

through top.

It is an impermeable membrane that protects the product

during the use on the skin.

Contains formulation throughout shelf-life and during

wear period

Must be compatible with formulation (non adsorptive)

Printable

E.g.: Metallic plastic laminate , plastic backing with

adsorbent pad adhesive foam pad. 16

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Schematic Skin absorption of drug

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Topical application-absorption & action

of drugs

SYSTEMIC

DRUG IN TARGET TISSUE

DRUG IN BLOOD CIRCULATION

DISTRIBUTION

ELIMINATION

PHARMACOLOGICAL

RESPONSE

TO

PIC

AL

ABSORPTION

DRUG IN DELIVERY

SYSTEM

DRUG IN SKIN SECRETION

FLUIDS, SWEAT, SEBUM,

pH 4.5--5.5

TR

AN

SD

ER

MA

L

LOCALIZED

RELEASE

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FORMULATION APPROACHES

FOR DEVELOPMENT OF

TRANSDERMAL DRUG

DELIVERY SYSTEM

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TYPES OF FORMULATION

PLATFORM FOR THE DRUG:

• Liquids

• Semisolids : ointments and gels

• Non flowing material

That is …

Polymeric film or rubbery gels and

Solid-state platform 20

TYPES OF PLATFORM MONOLITH : slabs, reservoir, vehicle, film, polymer matrix

FILMS :

Natural or synthetic

Porous and non porous

ADHESIVES: viscoelastic materials which remains permanently tacky

E.g. Natural or synthetic rubber, polyacrylates and silicon elastomer

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1. POLYMER MEMBRANE PERMEATION

CONTROLLED SYSTEM

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The drug reservoir is sandwiched between a drug impermeable

backing laminate and a rate controlling polymeric membrane.

The drug molecules are permitted to release only through the

membrane.

The drug reservoir compartment: The drug is:

1. Dispersed in solid polymer matrix (polyisobutylene)

2. Suspended in unleachable viscous liquid (silicone fluid) to

form paste like suspension.

3. Dissolved in a releasable solvent (alkyl alcohol) to form a

clear drug solution

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1. POLYMER MEMBRANE PERMEATION

CONTROLLED SYSTEM

The membrane:

Microporous or non porous ploymeric (ethylene -vinyl acetate copolymer).

A thin layer of drug compatible, hypoallergenic

adhesive polymer e.g. Silicon or polyacrylet adhesive

may be applied to the external surface.

Rate of drug release affect by varying the polymer

composition, permeability coefficient and thickness

of rate limiting membrane and adhesive.

Accidental breakage of the rate controlling membrane

can result in dose dumping or a rapid release of the

entire drug content.

E.g.

Nitroglycerine releasing trans dermal system for once

a day medication for angina

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Scopolamine-releasing transdermal system for 72 hr.

prophylaxis of motion sickness.

Clonidine releasing transdermal system for 7 day

therapy of hypertension.

Estradiol-releasing transdermal system for treatment

of menopausal syndrome for 3-4 days.

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The intrinsic rate of the drug release from this type of drug delivery system is defined by

dq CR

dt 1/pm + 1/pa

=

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Pm and pa respectively defined as….

pm km/r . Dm

hm

ka/m . Da

ha

=

= pa

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Where,

Km/r and ka/m are the partition coefficient for the

interfacial partitioning of the drug from reservoir to

the membrane and from the membrane to adhesive

layer respectively.

Dm and Da are diffusion coefficient and

hm and ha are the thickness

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Substituting the pm and pa equation in equation 1

dq km/r . Ka/m . Dm . Da

dt km/r. Dm. ha + ka/m . Da . hm

Which define the intrinsic rate of drug release from a

membrane moderated drug delivery system.

If the membrane is porous, porosity and tortuosity of

the membrane should be taken inconsideration.

= cr

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2. POLYMER MATRIX DIFFUSION

CONTROLLED TDDS SYSTEM

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The drug reservoir:

Homogeneous dispersion of the drug solids in hydrophilic or lipophilic polymer matrix, and the medicated polymer is then molded into medicated discs with defined surface area and thickness.

Then mounted onto impermeable plastic backing.

The adhesive polymer is applied to the circumference of the patch.

E.g. of this type of system is nitro-dur I and nitro-

dur II. for continuous transdermal fusion of

nitroglycerine at a daily dose of 0.5 mg/cm2 for

therapy of angina pectoris.

Nitro dur II is modified version of I in which the drug

is dispersed in acrylic based polymer adhesive with a

resinous cross linking agent which result in much

thinner and more elegant patch.

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The rate of drug release from this type of system is

defined as:

A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp are

the solubility and diffusivity of the drug polymer respectively.

Since only the drug species dissolved in the polymer can release , Cp is equal to CR.

At steady state, Q versus t1/2 drug release profile is obtained. (non zero order

release).

1/2

= dq ACp Dp

dt 2t

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3. ADHESIVE DISPERSION-TYPE

SYSTEM

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e.g. of adhesive polymer is poly(isobutylene) or

poly(Acrylet) adhesive

E.g. of this type of system is isosorbide dinitrate

releasing transdermal therapeutic system for once a

day medication of angina pectoris.

It is used for the administration of verapamil.

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The rate of drug release in this system is defined by:

dQ ka/r . Da

dt ha

where,

Ka/r is partition coefficient for the interfacial partitioning

of the drug from the reservoir layer to adhesive layer.

= cr

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4. GRADIENT CONTROLLED TDDS

Drug – impermeable metallic plastic laminate

Drug reservoir

gradient layers

R1>R2>R3

R1 R1

R2

R3

} 39

The rate of drug release from this drug reservoir gradient controlled system is given by:

dQ ka/r . Ds dt ha (t)

Thickness of the adhesive layer for drug molecules to diffuse through increases with time h(t)

E.g. Nitroglycerine TDD patch

A (ha) =

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To overcome the non zero order release, the drug loading level in the reservoir is varied incrementally.

The thickness of the diffusional path increases with time, to compensate for this, the drug loading level in the multilaminate adhesive layer is increased

Deponit system: nitroglycerin releasing TDDS.

5. MICRORESERVIOR TYPE OR

MICROSEALED DISSOLUTION CONTROLLED

SYSTEM

rim

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Hybrid of reservoir and matrix dispersion type.

The drug is suspended in aqueous solution of water miscible drug solubilizer, then dispersing the drug suspension in a lipophilic polymer by shear mechanical force to form thousands of microscopic drug reservoirs.

The medicated disc is then mounted at the center of an adhesive pad.

It is successfully utilized in the preparation of nitro-

disc, a nitroglycerine releasing trans dermal

therapeutic system used in angina pectoris.

This system followed zero order release of drug

without the danger of dose dumping.

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Choose a dry, unbroken, non-hairy part of your skin. The buttocks, lower abdomen, lower back, and upper arm (outer part) are good choices. If the area you choose has body hair, clip (do not shave) the hair close to the skin with scissors.

the area is clean. If there is any oil or powder (from bath products, for example), the patch may not stick properly.

Attach the adhesive side of the patch to skin in the chosen area.

Find an appropriate place to put the patch

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Find an appropriate place to put the patch

ADVANCED RESEARCHES

MICROARRAY NEEDLE

Advanced micro-needle Patch transdermal system

allowing continuous delivery through the skin of

proteins and water-soluble drugs.

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• The device create painlessly micropores in the S.C.

known as microstructered arrays or microneedles.

• These devices have about 400 microneedles.

• The solid silicone needles (coated with drug) or

hollow metal needles (filled with drug solution)

penetrate the horny layer without breaking it or

stimulating nerves in deeper tissues.

• Flux increase up to 1,00,000 fold are reported.

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ADVANCED RESEARCHES

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MICRONEEDLE ARRAY

MICRO TRANS

Applications :

Delivery of large proteins, fragile antibodies, and

hormones.

Delivery of small molecules, particularly those

with difficulty diffusing through skin layers.

Delivery of vaccines, both conventional and DNA-

based.

Fluid sensing of glucose, hormones, blood gases,

and therapeutic drug levels.

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Liposomes and vehicles Liposome are colloidal particles formed as concentric

bimolecular layers that are capable of encapsulating

drugs.

There are many examples of cosmetic products in which the active

ingredients are encapsulated in vesicles. These include humectants such as

glycerol and urea, sunscreening and tanning agents, enzymes, etc.

Phosphatidylcholine from soybean or egg yolk is the most common

composition although many other potential ingredients have been evaluated .

Cholesterol added to the composition tends to stabilize the structure thereby

generating more rigid liposomes.

Solid lipid nanoparticles Solid lipid nanoparticles (SLN) have recently been investigated as carriers for

enhanced skin delivery of sunscreens, vitamins A and E, triptolide and

glucocorticoids.

It is thought their enhanced skin penetration is primarily due to an increase in

skin hydration caused by the occlusive film formed on the skin surface