Dr. Basavaraj K. Nanjwade M. Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: [email protected]@gmail.com

Dr. Basavaraj K. Nanjwade M. Pharm., PhD

KLE University College of PharmacyBELGAUM-590010, Karnataka, India.

E-mail: [email protected] No: 00919742431000

14th December 2012 1KLE College of Pharmacy, Nipani.

mailto:[email protected]

CONTENTS Introduction Objectives of TDDSAdvantages & disadvantages Mechanism of percutenious absorptionPermeation through skinKinetics of transdermal drug delivery systemFactors affecting permeation Basic components of TDDSFormulation approaches used in development of TDDS and

their evaluationPermeation enhancer.References14th December 2012 2KLE College of Pharmacy, Nipani.

When one hears the words transdermal drug

delivery, what comes to mind? More than likely

one thinks about a simple patch that one stick onto

skin like an adhesive bandage such as nicotine

patch.

TRANSDERMAL DRUG DELIVERY SYSTEM (TDDS)


• The NDDS may involve a new dosage form e.g., from thrice a day dosage to once a day dosage form or developing a patch form in place of injections.

• Throughout the past 2 decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage forms.

• Because transdermal drug delivery offers controlled release of the drug into the patient, it enables a steady blood-level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms

Brief History of TDDS


• Transdermal drug delivery system was first introduced more than 20 years ago.

• The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s.

• First transdermal patch was approved in 1981 to prevent the nausea and vomiting associated with motion sickness, the FDA has approved, throughout the past 22 years, more than 35 transdermal patch products, spanning 13 molecules.


Brief History of TDDS

http://www.fda.gov/

INTRODUCTION• 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.


POTENTIAL BENEFITS OF TRANSDERMAL DRUG DELIVERY

(ADVANTAGES)• Easy to use.• Avoid GIT absorption problems for drugs.• Avoids FP 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.14th December 2012 7KLE College of Pharmacy, Nipani.

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.


STRUCTURE OF SKIN• Epidermis:

Stratum corneum (Horny cell layer)

Stratum lucidum (Clear layer)

Stratum granulosum ( Granular Layer)

Stratum spinosum (Prickly layer)

Stratum germinativum

• Dermis:

• Hypodermis or Subcutaneous layer:


STRUCTURE OF SKIN

Epidermis: The outer layer of skin is made up of Stratified Squamous epithelial cells. Epidermis is thickest in palms and soles.The stratum corneum forms the outer most layer (10-15µm thick ) which consists of many layers of compacted , flattened, dehydrated keratinized cells. Keratin contains cells called as Corneosites. Stratum corneum layer forms permeability barrier for external environment.


Water content of stratum corneum is around 20%.

The moisture required for stratum corneum is around 10% (w/w) to maintain flexibility and softness.

It consists of Cermides and neutral lipids such as Sterols, free fatty acids and triglycerides.

The stratum corneum is responsible for the barrier function of the skin and behaves as a primary barrier to the percutaneous absorption.


STRUCTURE OF SKIN

It is made up of three layers in thicker parts stratum granulosum, stratum lucidum,stratum spinosum.

Removal of these layers results in increased

permeability and water loss.


STRUCTURE OF SKIN

DERMIS:

The dermis is made up of regular network of robust collagen fibers of fairly uniform thickness with regularly placed cross striations .

This network or the gel structure is responsible for the elastic properties of the skin.

It is supplied by blood to convey nutrients, remove waste & regulate body temp.

Drug is well absorbed by this route.

Upper portion of the dermis is formed into ridges containing lymphatics and nerve endings.


STRUCTURE OF SKIN

SUBCUTANEOUS TISSUE:

This is a sheet of the fat containing areolar tissue

known as the superficial fascia attaching the dermis to the

underlying structures .

SKIN APPENDAGES:

Sweat glands produces sweat of pH 4-6.8 & absorbs drugs, secretes proteins, lipids and antibodies. Its function is to control heat.

HAIR FOLLICLES

They have sebaceous glands which produces sebum and includes glycerides, cholesterol and squalene.


STRUCTURE OF SKIN

Mechanism of absorption through skin

Mechanism involved is passive diffusion

This can be expressed by FICK’s LAW of DIFFUSION

dq = D K A ( c1 – c2 )

dt h

dq /dt = rate of diffusion

D = diffusion co-efficient

K = partition coefficient

A = surface area of membrane

H = thickness of membrane


Routes of drug absorption through skin

Trans follicular route

Trans epidermal route


Trans follicular route:

• Fractional area available through this route is 0.1 %

• Human skin contains 40-70 hair follicles, 200 to 250

sweat glands on every sq.cm. of skin area.

• Mainly water soluble substance are diffused faster

through appendages than that of other layers.

• Sweat glands and hair follicles act as a shunt i.e. easy

pathway for diffusion through rate limiting ST corneum.



Trans Epidermal route

Epidermal barrier function mainly resides in horny layer

The viable layer may metabolize, inactivate or activate a prodrug.

Dermal capillary contains many capillaries so residence time of drug is only one minute.

Within stratum corneum molecule may penetrate either transcellularly or intercellular.

Intracellular region is filled with lipid rich amorphous material.





FACTORS AFFECTING TRANSDERMAL PERMEABILITY

Physico chemical properties of parent molecule

Solubility and partition coefficient

pH condition

Penetrant concentration

Physico chemical properties of drug delivery system

Release characteristic

Composition of drug delivery system

Permeation enhancer used14th December 2012 20KLE College of Pharmacy, Nipani.

Physiological and pathological condition of skin Lipid film Skin hydration Skin temperature Effect of vehicle Pathological injury to skin

Biological factors Skin age Thickness of S. Corneum Skin condition


Solubility and partition coefficient: Solubility of a drug influences its ability to penetrate the skin. pKa is index of solubility of drug in vehicle and ST corneum has influence on transfer of drug from vehicle to skin.Drug solubility determines concentration presented to absorption site which will effect rate and extent of absorption. Skin permeation can be enhanced by increasing lipophilic character of drug, so that drug penetrates through STC but not through epidermis due to decreased water solubility. Drug which is lipid & water soluble is favored.14th December 2012 22KLE College of Pharmacy, Nipani.

pH & penetration concentration:

Moderate pH is favorable because if solutions with

high or low pH will result in destruction to the skin.

Higher the concentration of the drug in vehicle faster

the absorption.

At higher concentrations than solubility the excess

solid drug will function as a reservoir and helps to

maintain a constant drug constitution for prolonged

period of time.14th December 2012 23KLE College of Pharmacy, Nipani.

Physico-chemical properties of drug delivery system Release characteristic Solubility of drug in vehicle determines the release rate.

Composition of drug delivery system It not only effects the rate of drug release but also the permeability of STC by means of hydration mixing with skin lipids. Example methyl salicylate is more lipophilic than its parent acid (Salicylic acid). When applied to skin from fatty vehicle methylsalicylate yielded higher absorption.



Physiological and pathological condition of skin

Lipid film:It acts as protective layer to prevent removal of

moisture from skin. Defeating of this film will decrease TD absorption.

Skin hydration:It can be achieved by covering skin with plastic

sheeting, which leads to accumulation of sweat, condensed water vapors, increase hydration and increase porosity.14th December 2012 25KLE College of Pharmacy, Nipani.


Effect of vehicle:

A vehicle can influence absorption by its effect on

physical state of drug and skin. Example greases, paraffin

bases are more occlusive while water in oil bases are less.

Humectants in bases will dehydrate the skin and decrease

percutaneous absorption.



Biological factors:

Skin age:

Skin of foetus, young ones and elders is more

permeable than adult tissue.

Skin metabolism:

Viable epidermis is metabolically active than

dermis. If topically applied drug is subjected to

biotransformation during permeation local and systemic

bioavailability is affected.14th December 2012 27KLE College of Pharmacy, Nipani.


BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY

SYSTEMCOMPONENT OF TRANSDERMAL DEVICE INCLUDE:

1) POLYMER MATRIX

2) THE DRUG

3) PERMEATION ENHANCER

4) OTHER EXCEPIENTS


29

Basic components of Transdermal drug delivery


POLYMER MATRIXFollowing 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.


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


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


It should be potent with daily dose of few 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.


BIOLOGICAL PROPERTIES

Ideal properties of drug candidate

PARAMETER PROPERTIES

Dose Sh’d be low( < 20mg/day)

Half life 10 or less

Molecular weight < 400

Skin permeability coefficient > 0.5 X 10 -3 cm/ hr

Skin reaction Non irritating & non sensitizing

Oral Bioavailability low

Therapeutic index low


PERMEATION ENHANCERS

These 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 coordinateD is function of size, shape, flexibility of diffusing drug

molecule14th December 2012 35KLE College of Pharmacy, Nipani.

Activity of penetration enhancers Interaction with the polar head groups of lipid via

hydrogen and ionic bonding

Change in hydration sphere of lipids and affect the packing at the head region

Increase volume of the aqueous layer swelling and hydration

Protein modification- open up the dense keratin structure and make it more permeable


37

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.14th December 2012 KLE College of Pharmacy, Nipani. 37

38

Schematic Skin absorption of drug

14th December 2012 KLE College of Pharmacy, Nipani. 38

Topical application-absorption & action Topical application-absorption & action of drugsof 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 SECRETIONFLUIDS, SWEAT, SEBUM,

pH 4.5--5.5

TR

AN

SDE

RM

AL

LOCALIZED

RELEASE


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FORMULATION APPROACHES FOR DEVELOPMENT OF TRANSDERMAL DRUG

DELIVERY SYSTEM

40KLE College of Pharmacy, Nipani.

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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 platform41KLE College of Pharmacy, Nipani.

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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


http://images.google.co.in/imgres?imgurl=http://www.pharmaceutical-technology.com/contractor_images/lts-ohmann/5s-hrt-patch.jpg&imgrefurl=http://www.pharmaceutical-technology.com/contractors/drug_delivery/gallery.html&h=68&w=150&sz=5&hl=en&start=38&usg=__WuTyTf2zt5T_nJHr86XvjDCmwUg=&tbnid=QJCXiPsXueiU5M:&tbnh=44&tbnw=96&prev=/images%3Fq%3DTRANSDERMAL%2BPATCH%2BPLATFORM%2BIMAGE%26start%3D21%26gbv%3D2%26hl%3Den%26sa%3DN

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1. POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM


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RCM made up of EVA 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.



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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 . Da

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.

= cr


1.POLYMER MEMBRANE PERMEATION CONTROLLED SYSTEM

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2. 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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3. GRADIENT CONTROLLED TDDS

Drug – impermeable metallic plastic laminate

Drug reservoir gradient layersR1>R2>R3

R1R1

R2

R3

}54KLE College of Pharmacy, Nipani.

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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)=


3. GRADIENT CONTROLLED TDDS

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4. POLYMER MATRIX DIFFUSION CONTROLLED TDDS SYSTEM


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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 .

1/2

=dq ACp Dp

dt 2t



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5. MICRORESERVIOR TYPE OR MICROSEALED DISSOLUTION CONTROLLED

SYSTEM

rim


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Silicon elastomer the lipophillic polymer is used for dispersion technique to form unleachable microscopic sphere of drug reservoir.

The quick stabilization occur by cross linking of the polymer chain which produced medicated polymer disc with a constant surface area and fixed thickness according to requirement of drug release.



SYSTEM

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Extra coating is available as a biocompatible polymer to modify the mechanism and rate of drug release.

A trans dermal therapeutic system is produced by positioning the medicated disc at the centrally and surrounded bit with an adhesive rim.



SYSTEM

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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.



SYSTEM

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The rate of release of drugs of the micro reservoir system is defined by,

dq Dp .Dd .m .kp

dt Dphd+Ddhpmkp

DISl (1-n)+n.Sp

hI

1 kI

1km

=



SYSTEM

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Where, m=a/b is the ratio of the bulk of the elution medium over drug solubility of the same medium and b is the ratio of drug concentration at the outer edge of the polymer coating for the drug solubility in the same polymer composition.

n is the ratio of the drug concentration at the inner layer of the interfacial barrier over drug solubility in the polymer matrix.



SYSTEM

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Dl, Dp and Dd and hl, hp and hd; are diffusivities and thickness of liquid layer surrounding the drug particle, polymer coating membrane surrounding the polymer matrix and the hydrodynamic diffusion layer surrounding the polymer coating .

Kl, km and kp are the partition coefficient for the interfacial partitioning of the drug from the liquid compartment to the polymer matrix, from the polymer matrix to the polymer coating membrane and from the polymer coating membrane to the elution solution respectively.



SYSTEM

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Sl and SP are the solubility of the drug in the liquid compartment and in the polymer matrix respectively.

The release of drug from this system can follow either a partition control or matrix diffusion control process depending upon the relative magnitudes of Sl and SP



SYSTEM

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6. POROPLASTIC TYPE SYSTEM

Poroplastic film consists of ultra micro porous membranes which are not sensitizing to skin and are fairly stable at higher than normal temperature and at biological pH.

It is made utilizing the concept of water coagulation of cellulose triacetate solution in organic acid at low temperature.

The coagulation is performed under controlled condition.


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7. TRANSDERMAL DELIVERY OF THE MACROMOLECULE

Macromolecules such as Hormones, interferons, bioactive peptides can be delivered by Trans dermal delivery system.

The devices used for this purpose are divided in to two categories….

1. Devices based on ethylene vinyl acetate copolymers (EVAc).

2. Devices based on silicone elastomer.


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This both the system utilize one common concept i.e.

Matrix must have channel to facilitate the release of macro molecule

This device is used as implants


7. TRANSDERMAL DELIVERY OF THE MACROMOLECULE

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8. OTHER TDDS IONTOPHORESIS

Built-in battery layer Comparable in size to a normal transdermal patch The Lectro Patch, General Medical Co. Treatment time : 20 min Recommended maximum current : 4mA Lidocaine (local anesthesia), dexamethasone

(arthritis), hydrocortisone (arthritis), acetic acid (calcified tendinitis) etc.



IONTOPHORESIS

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Sonophoresis:

The application of high frequency ultrasound to enhance drug penetration.

Examples:. Lidocaine, hydrocortisone, salicylic acid.

Electroporation: Transient high-voltage electrical pulses, to cause rapid

permeabilization of the stratum corneum through which large and small peptides, oligonucleotides and other drugs can pass in significant amounts.


8. OTHER TDDS

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Reverse iontophoresis:

Current passage causes ions and other molecules to move in both directions under both electrodes. Hence it is possible to sample an analyte in the body, and to provide a drug in response to the analyte level, e.g., sugar, glucose.


8. OTHER TDDS

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Trandermal Matrix patch designs

Matrix

Reservoir

Drug in adhesiveMultilaminate

Backing Drug Membrane Adhesive Liner / skin74KLE College of Pharmacy, Nipani.

14th December 2012

Transdermal Production Process


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Transdermal Controlled-Release Products and Devices

Drug Trade Name Type of Devices Indication

Scopolamine Transderm-Scop Reservoir Motion sickness

Nitroglycerine Transderm-Nitro Reservoir Angina

Nitro-Dur Monolithic

Nitrodisc Monolithic

Estradiol Estraderm Reservoir and ethanol enhancer

Hormone treatment


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Transdermal Products under Development

Drug Trade name Producer-Marketer

Minocycline Sunstar American Cyanamide, Takeda

Estradiol+Norethisterone

Estracombi TIS

Ciba-Geigy, Alza

DHEA Pharmedic

Fentanyl

Triamcinolone acetonide

Whitby Pharm.


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Recently approved transdermal contraceptive

Recently approved by FDA (Ortho-McNeil) Once a week for three weeks, fourth week patch free 99 percent effective when used as directed Combination estrogen and progestin One-and-three-quarter inch square applied to the

lower abdomen, buttocks or upper body. Skin irritation or detachment reported in 2-5% of

patients


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EVALUATION


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1.EVALUATION OF ADHESIVE

A. Peel adhesion properties

Peel adhesion is the force required to remove an adhesive coating from a test substrate.

This properties are affected by the molecular wt. of the adhesive polymer, the type and amount of additives, and polymer composition.


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It is tested by measuring the force required to pull a single coated tape, applied to a substrate, at a 180o

angle.



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B. Tack properties: Tack is ability of the polymer to adhere to substrate

with little contact pressure.

It is dependent on the molecular weight and composition of polymer as well as the use of tackifying resin in the polymer.

Tests for tack include....



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a. Rolling ball test:

This test involves measurement of the distance that a stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the farther the ball will travel.


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b. Quick-stick (or peel-tack) test:

The peel force require to break the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90o at a speed at 12 inch/min.

The force is recorded as the tack value and is expressed in ounce or grams per inch width with higher values indicating increasing tack.




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c. Probe tack test:

Here, the force required to pull a probe away from an adhesive at a fixed rate is recorded as tack (in grams)

Adhesive film

Annular weight

Dial

Probe


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C. Shear strength properties:

Shear strength is the measurement of the cohesive strength of an adhesive polymer.

It is affected by molecular weight as well as the type and amount of tackifier added.

Shear strength or creep resistance is determined by measuring the time it takes to pull an adhesive coated tape off a stainless steel plate when a specified weight is hung from the tape which pulls the tape in a direction parallel to the plate


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Stainless steel plate

Adhesive coated tape

Weight



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2. IN-VITRO DRUG RELEASE EVALUATION

In these studies, excised skin is mounted on skin permeation cells.

Skin of hairless mouse is used rather than human cadaver skin.

In-vitro system should be designed in such way that the intrinsic rate of release or permeation which is theoretically independent of the in-vitro design can be accurately determined.


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Several designs of the in-vitro membrane permeation cell, the Jhawer-Lord (J-L), Valia-Chien (V-C) Cell, Ghannam-Chein (G-C) membrane permeation enhancer, Franz Diffusion Cell and the Keshry-Chien(K-C) Cell.

K-C Cell has an effective receptor volume 12ml, skin surface area of 3.14cm2. the receptor solution is stirred by star-head magnet rotating at a constant speed of 600rpm driven by 3W synchronous motor.


2. IN-VITRO DRUG RELEASE EVALUATION

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Franz Diffusion Cell


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ADVANTAGES

It can help in investigating the mechanism of skin permeation of the drug before it can be developed in TDDS.

Time needed to attain steady state permeation and the permeation flux at steady state can be obtained.

It is use to optimize the formulation before more expensive in vivo studies are performed.

Studies on skin metabolism can also be performed.


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It includes also ease of methodology, analytical assay since there are no complication arising from the disposition of the drug in the body and better control over experimental condition than is possible in vivo.


ADVANTAGES

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3. EFFECT OF SKIN UPTAKE AND METABOLISM

In this study, a piece (3cm by 3cm) of full thickness skin (human cadaver skin) or stripped skin freshly excised from a hair less mouse, 5-7 week old, was mounted between the two compartments of each V-C permeation cell.

It was mounted in such a way that either the stratum corneum or the dermis faced the drug solution and the other side of the skin was protected with impermeable aluminum foil.


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The compartment with the skin surface uncovered was filled with a saturated solution of drug in normal saline and the compartment with the skin surface covered with aluminum foil remained empty.

Both the compartment were maintained isothermally at 37oC. Samples were withdrawn from solution compartment at predetermined times and assayed for drug and any possible metabolite.


3. EFFECT OF SKIN UPTAKE AND METABOLISM

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4.IN-VIVO EVALUATION

a. Animal models: The rhesus monkey is the most reliable model for in

vivo evaluation of transdermal drug in man.

Standard radiotracer methodology is used.

The application site is generally the forearm or abdomen which are the least hairy sites on the animal’s body.


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Limitation of using this animal include cost and handling capabilities required.

Ethical consideration also limit the use of rhesus monkey.

Other animals are weanling pig and human skin grafted nude mouse.

Difficulties in using these animals are their non availability and the facilities and skill required for their handling.


4. IN-VIVO EVALUATION

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b. Human models:

Procedure for in vivo evaluation in humans were first described by feldmann and maibach in 1974.

They involve the determination of cutaneous absorption by an indirect method of measuring radio activity in excreta following topical application of the labelled drug.

This method is used since plasma level following trans dermal administration of a drug are too low to use chemical assay procedure.



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The % of dose absorbed transdermally is calculated by

Total radioactivity excreted after topical adm. Total radioactivity excreted after i.v. adm.

Various modification have been made for this method, it is given below.

% Drug absorbed =



RESERVOIR TECHNIQUE It is simple technique, short exposure of the skin to the

compound (radio-labelled) under study followed by removal of the stratum corneum.

From this analysis, it is possible to predict the amount of drug that will penetrate over a longer period of time.

LIMITATION:

o Invasive nature of the technique due to the tape stripping required.

o The single measurement obtained which does not allow detailed kinetic analysis & adm. of large dose of radio active material is required.14th December 2012 100KLE College of Pharmacy, Nipani.

14th December 2012

5. CUTANEOUS TOXICOLOGICAL EVALUATION

CONTACT DERMATITIS:

It can be either

I. Contact irritant dermatitis or

II. Contact allergic dermatitis

I. Contact irritant dermatitis: It results from direct toxic injury to cell membrane,

cytoplasm or nuclei.


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Two types of protocols are used o Ten days primary irritation test &o Twenty one days irritation test

II. Contact allergic dermatitis:

It involves a host immunological reaction to an antigen.

It can be screened by the guinea pig maximization test.


5. CUTANEOUS TOXICOLOGICAL EVALUATION

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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.


ADVANCED RESEARCHES


MICRONEEDLE ARRAY

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Multidose Transdermal Drug Delivery System

It is comprises a laminate composite with a plurality of compartments.

Each compartment is a reservoir for a unit dose of a drug active to be transdermally administered.

Individual seals are provided for resealably enclosing the drug active in each of the reservoirs.

The individual enclosing seals are removable to release the unit dose into contact with the skin of the patient and are actuable to control the transdermal absorption of the drug actives.


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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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• This system makes oversaturation of adhesive polymer with drug forcing partial crystallization.

• Presence of both molecular and solid state, allow higher conc. & consistent supply of drug.

• As skin absorbs dissolved drug, crystals re-dissolve to maintain drug at solubility limit (max. thermodynamic activity) at the site of contact.

• This results in smaller thinner patches with better patient acceptability. Clinical trials with this technology with β2 adrenergic agonist

tulobutarol confirmed superiority of TDDS formulation over oral formulation

Crystal reservoir technology


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PERMEATION ENHANCERSThese are the agents which promote the skin

permeability by altering the skin as a barrier to the flux of desired penetrate

Flux J across the skin can be given by J = D dc

dxD = diffusion coefficient

C = concentrationD is function of size, shape, flexibility of diffusing

drug molecule


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Activity of penetration enhancers

Interaction with the polar head groups of lipid via hydrogen and ionic bonding.

Change in hydration sphere of lipids and affect the packing at the head region.

Increase volume of the aqueous layer:swelling and hydration.

Protein modification- open up the dense keratin structure and make it more permeable.


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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) COSMETICALLY ACCEPTABLE

7) 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, DMSO, DMA, DMF,

pyrolidiones, propylene glycol, glycerol etc..

SURFACTANTS

They enhance polar pathway transport of hydrophillic drugs


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ANIONIC SURFACTANTS -

Dioctyl sulpho succinate, SLS, decodemethyl

sulphoxide

CATIONIC SURFACTANTS - Pluronic F127, pluronic F58


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BINARY SYSTEMS

• These systems open up the multilaminate path way as well as the continuous path way

e.g. Propylene glycol-oleic acid.

1,4, butane diol- linoleic acid.

MISCELLANIOUS CHEMICALS e.g. Urea, N,N- dimethyl m- toluamide


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Simple for patient to use, and fully disposable. Unique manufacturing techniques result in very low

cost. Accurate, reliable delivery of drug to epidermis or

dermis, circumventing the stratum corneum. Passive or active drug delivery profiles. Can be used with Valeritas' e-Patch and h-Patch™

device to deliver a wide range of drug volumes under various extended or time-release profiles


Key Features

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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.

Make sure that 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 your skin in the chosen area.

Find an appropriate place to put the patch


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A stiff protective liner covers the sticky side of the patch - the side that will be put on your skin. Hold the liner at the edge and pull the patch from the liner. Try not to touch the adhesive side of the patch. Throw away the liner.

Press the patch firmly on your skin with the palm of your hand for about 30 seconds. Make sure the patch sticks well to your skin, especially around the edges. If the patch does not stick well, or loosens after you put it on, tape the edges down with first aid tape.

Wash your hands after applying the patch.117KLE College of Pharmacy, Nipani.




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Product Development Challenges Flux sufficient but manageable size

Adequate skin adhesion

Adequate shelf life stability

Non-irritating

Aesthetically pleasing

Easy to handle and use

Comfortable

Unobtrusive

Product cost119KLE College of Pharmacy, Nipani.

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REFERENCES

Transdermal controlled systems medication by Y.W. Chein.

Controlled drug delivery – Fundamental and Application, 2nd edition, by Joseph R. Vincent, H.C. Lee page no.: 524 – 589.

Controlled drug delivery – Concepts and Advances, by S.P. Vyas and Roop K. Khar page no.: 411 – 447.


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Novel drug delivery systems, 2nd edition, by Y.W. Chein page no.: 338 – 380.

The Eastern Pharmacist - “Transdermal drug delivery system”, vol.34,1991

http://www.google.com


REFERENCES

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THANKING YOU


E-mail: [email protected] No: 00919742431000

mailto:[email protected]

Documents

Dr. Basavaraj K. Nanjwade M. Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: [email protected]@gmail.com