evaluation of transdermal drug delivery systems

PRESENTED BY: GUIDED BY:SANI SINGH Prof. VIKAS ANANDM. Pharm (Pharmaceutics)

2nd Semester

EVALUATION OF TRANSDERMAL DRUG DELIVERY SYSTEMS

SARDAR BHAGWAN SINGH P.G. INSTITUTE OF BIO-MEDICAL SCIENCES & RESEARCH,BALAWALA, DEHRADUN, (UTTARAKHAND)

SECOND SEMINAR (MPHR 120)2016-17

ORGANISATION

Introduction

Evaluation Methods

Physicochemical Evaluation

In-vitro Evaluation

In-vivo Evaluation

Marketed Products Available In India

FDA Approved TDDS Products

Recent Research Report From Pubmed

Transdermal drug delivery systems (TDDS, “Patch”) are self-contained, discrete dosage

forms that, when applied to intact skin, are designed to deliver the drug(s) through the skin

to the systemic circulation.

INTRODUCTION

IDEAL SYSTEM

Agent independent

Flexibility

Monitoring & decision-making

Targeting

Vyas SP, Khar RK. Controlled drug delivery: Concepts and advances. 2nd edition. Vallabh Prakashan.

2012, 397-398.

Physicochemical evaluation

Interaction studies

Thickness of the patch

Weight uniformity

Drug content determination

Content uniformity

Folding endurance

Flatness

Moisture content

Moisture uptake

Water vapour permeability (WVP) evaluation

Tensile strength

Evaluation of adhesive

a) Shear adhesion test

b) Peel adhesion test

c) Tack properties

i. Thumb tack test

ii. Rolling ball test

iii. Quick stick (Peel tack test) test

iv. Probe tack test

Physicochemical evaluation

1. Interaction studies: Interaction studies ( drug and excipients ) are commonly carried out in Thermal analysis,

Fourier transform infrared spectroscopy (FTIR), UV and chromatographic techniques by

comparing their physicochemical characters such as assay, melting point, wave numbers,

absorption maxima etc.

2. Thickness of the patch: * The thickness of the drug loaded patch is measured in different points by using a digital

micrometer, dial gauge, screw gauge.

3. Weight uniformity: * The prepared patches are to be dried at 60°c for 4 hrs before testing. Individually

weighing 10 randomly selected patches a specified area of patch is to be cut in different parts

of the patch and weigh in digital balance.

Lembhe Swapnil, Dev Asish. Trasdermal Drug Delivery System: An Overview. World Journal Of

Pharmacy And Pharmaceutical Science. 2016;5(7): 584-610.

* Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy Research.

2012; 5(1):447-456.

4. Drug content determination: *

accurately weighed portion of film (about

100 mg) is dissolved in 100 ml of suitable

solvent & shaken continuously for 24 h,

then sonicated

After sonication and subsequent

filtration, drug in solution is estimated

spectrophotometrically

10 patches are selected, if 9 out of 10

patches have content between 85% to

115% and 1 has content not less than

75% to 125% of the specified value,

patches pass the test

3 patches range of 75% to 125%, then

additional 20 patches are tested . If

these 20 patches have range from 85%

to 115%, then the transdermal patches

pass the test.

5. Content uniformity test: *


2012; 5(1):447-456.

6. Folding endurance: #

7. Flatness test: *

In flatness determination one strip is cut from the centre and two from each side of

patches. The length of each strip is measured and variation in length is measured by

determining percent constriction. 0 % constriction is equivalent to 100 % flatness.

% constriction = I1 – I2 X 100 I1

I1 = Initial length of each strip

I2 = Final length of each strip

Repeatedly folding a small

strip of the patch at the same place

till it broke.

The number of times the patch could be folded

at the same place without breaking

Folding endurance value

# Chauhan et al. Transdermal Patches: A Review On Novel Approach For Drug Delivery. Indo American

Journal Of Pharmaceutical Research.2015; 5(1):531-548.


2012; 5(1):447-456.

8. Percentage Moisture content: The weighed films are to be kept in a desiccator containing fused calcium chloride at

room temperature for 24 hrs. After 24 hrs the films are to be reweighed and determine the

percentage moisture content from the formula –

Percentage moisture content = [Initial weight - Final weight/ Final weight] ×100

9. Percentage Moisture uptake: The weighed films are to be kept in a desiccator containing saturated solution of

potassium chloride at room temperature for 24 hrs (84% RH). After 24 hrs the films are to be

reweighed and determine the percentage moisture uptake from the formula –

Percentage moisture uptake = [Final weight - Initial weight/ initial weight] ×100



10. Water vapour permeability (WVP) evaluation:

WVP=W/A

Where, WVP is expressed in gm/m2 per 24 hrs,

W is the amount of vapour permeated through the patch (gm/24 hrs)

A is the surface area of the exposure samples (m2)

Water vapour

permeability can be

determined by a natural

air circulation oven. The

WVP can be determined

by the following

formula:



weights are added to the pan attached with the hanging end of the thread. A pointer is used to measure the

elongation of the film. The weight sufficient

to break the film is noted.

One end is fixed with the help of an iron screen &

other end is connected to a freely movable thread over a

pulley.

Polymeric films are sandwiched separately by

corked linear iron plates

11. Tensile Strength: *

Tensile strength= F/a.b (1+L/l)

F is the force required to break;

a is width of film;

b is thickness of film;

L is length of film;

l is elongation of film at break

point.

* Shinde et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy

Research. 2012; 5(1):447-456.

12. Evaluation of adhesive:

a) Shear Adhesion test: Shear adhesion strength is determined by measuring (cohesive strength of an adhesive

polymer) the time it takes to pull the tape off the plate.

Shear strength test for adhesive evaluation

Jain NK. Controlled And Novel Drug Delivery. 1st edition. CBS Publishers & Distributors.1997,107-110.

b) Peel Adhesion test: In this test, the force required to remove an adhesive coating form a test substrate is

referred to as peel adhesion.

Peel adhesion test for adhesive evaluation


c) Tack properties: It is ability of a polymer to adhere to a substrate with little contact pressure. Test is includes.

Thumb tack test:

It is a qualitative test and the force required to remove thumb from adhesive is a measure of

tack.

Rolling ball tack test: In this test, stainless steel ball of 7/16 inches in diameter is released on an inclined track so

that it rolls down and comes into contact with horizontal, upward facing adhesive.

Rolling ball tack test for adhesive evaluation

T Himanshi, S Ruchika. Transdermal Drug Delivery System: A Review. International Journal Of

Pharmaceutical Sciences And Research. 2016;7(6): 2274-90.

Quick Stick (peel-tack) test: The peel force required breaking the bond between an adhesive and substrate is measured by

pulling the tape away from the substrate at 90 at the speed of 12 inch/min.

Quick stick test for adhesive evaluation




Probe Tack test: The tip of a clean probe is contact with adhesive and bond is formed between probe and

adhesive.

The force required to pull the probe away from the adhesive at fixed rate is recorded as tack

and it is expressed in grams.

Probe tack test for adhesive evaluation

Probe

Force gauge




In-vitro drug release studies

In-vitro skin permeation studies

In – vitro evaluation

1. In vitro drug release studies: * A number of mathematical model is describe the drug dissolution kinetics from controlled

release drug delivery system e.g., Higuchi model, First order, Zero order and Peppas &

Korsenmeyer model.

The dissolution data is fitted to these models and obtained the release mechanism of the

drug. There are various methods available for determination of drug release rate of TDDS.

In–vitro evaluation


Research. 2012; 5(1):447-456.

Higuchi model

Peppas &

Korsenmeyer model

A=[D (2C-Cs) Cs x t] ½

Where , A – amount of drug released in time

‘t’ per unit area

C – initial drug concentration

Cs – drug solubility in the matrix media

D – diffusivity of drug molecule in the matrix

substance

F = (Mt/M) = Km tn

Where, F – fraction of drug release at time ‘t’

Mt - amount of drug release at time ‘t’

M – total amount of drug in dosage form

Km - kinetic constant

n – diffusion or release exponent

t - time (hrs)

Paddle over disc: * (USP apparatus 5)

This method the transdermal system is attached to a disc or cell resting at the bottom of

the vessel which contains medium at 32 ±5°C.


Research. 2012; 5(1):447-456.

Cylinder modified USP Basket: * (USP apparatus 6)

This method is similar to the USP basket type dissolution apparatus, except that the

system is attached to the surface of a hollow cylinder immersed in medium at 32 ±5°C.


2012; 5(1):447-456.

Reciprocating disc: * (USP apparatus 7)

In this method patches attached to holders are oscillated in small volumes of medium,

allowing the apparatus to be useful for systems delivering low concentration of drug. In

addition paddle over extraction cell method may be used.


2012; 5(1):447-456.

2. In vitro skin permeation studies: *

The transdermal system is applied to the hydrophilic side of the membrane (donor

compartment) and then mounted in the diffusion cell with lipophilic side in contact with

receptor fluid (receptor compartment, usually temprature 32±5°C for membrane ) in vertical

diffusion cell such as Franz diffusion cell or Keshary-chien (K-C) diffusion cell and is

continuously stirred at a constant rate.

The samples are withdrawn at different time intervals and diluted appropriately then

absorbance is determined spectrophotometrically.

Then the amount of drug permeated per cm2 at each time interval is calculated.


2012; 5(1):447-456.

Franz diffusion cell:



In – vivo evaluation

1. Animal models: #

In-vivo animals models are preferred because considerable time and resources are

required to carry out studies in humans. Some of the species are used : mouse, rat, guinea

pig, rabbit, rat, cat, dog, pig, house, monkey small hairy animals (e.g. rat, rabbit) or rhesus

monkey is most reliable or in vivo evaluation of transdermal patches standard radiotracer

methodology used.

The application site is generally the abdomen which are the least hairy site on the

animals body. The compound is applied after light clipper showing of the site.

In –vivo evaluation

# Chauhan et al. Transdermal Patches: A Review On Novel Approach For Drug Delivery. Indo

American Journal Of Pharmaceutical Research.2015; 5(1):531-548.

2. Human models: # It is first described by Fieldman and Maibach. They includes determination of

percutaneous absorption by an indirect method of measuring radioactivity in excreta

following topical application of the labeled drug. 14C is generally used for radio labeling.

Determination of absorption of know amount of radioactivity retained in the body or

excreted by routes. The percentage of dose absorbed transdermally is then calculated as.

% Close absorbed = Total radioactivity exerted after topical Administration x 100

Total radioactivity exerted intervenes was Administration

The procedure takes 5-7 days for completion.

# Chauhan et al. Transdermal Patches: A Review On Novel Approach For Drug Delivery. Indo

American Journal Of Pharmaceutical Research.2015; 5(1):531-548.



(a) Reservoir

technique :

(b) Mass

balance

technique :

It makes use of the relationship between stratum corneum

reservoir function and in vivo percutaneous absorption to

predict in vivo penetration.

This method is involves a simple, short exposure of the skin

to the compound under study followed by removal of the

stratum corneum by tape stripping and analysis of the content

of the compound in the stratum corneum.

The application site is covered with an occlusive chamber, the

chamber being replaced by a new one after a particular time

interval. The site is also subjected to washing at these time.

Radio labeling techniques are used and the chamber, washing

and the faces and urine of the patients are subjected to analysis.

In this technique include achievement of mass balance

between the applied close and exertion level and measurement

for predicting percutaneous.

3. Biophysical Models:

Models based on steady-state mass balance equation, solution of Fick’s second law of

diffusion for the device, stratum corneum and viable epidermis, as well as linear kinetics

have been described in the literature.

It can be concluded that many techniques for in-vivo evaluation of transdermal systems

have been put forward there is scope for further refinement. Some of the unresolved issues

include the barrier function of the skin with age, skin metabolism, in-vivo functioning of

penetration enhancers etc.


Stability studies: Stability studies are to be conducted according to the ICH guidelines by storing the TDDS

samples at 40±0.5°c and 75±5% RH for 6 months. The samples were withdrawn at 0, 30, 60,

90 and 180 days and analyze suitably for the drug content.

Regulatory requirements: * A transdermal patch is classified by U.S. Food and Drug Administration (FDA) as a

combination product, consisting of a medical device combined with drug or biologic product

that the device is designed to deliver. Prior to sale, any transdermal patch product must

receive approval from FDA, demonstrating safety and efficacy for its intended use.



Shinde Utkarsh P et al. Recent Advances In Transdermal Drug Delivery System. Journal Of Pharmacy

Research. 2012;5(1):447-456.*

Marketed Products

Therapeutic

Agent

Brand Name Manufacturer Name Indication

Fentanyl Fendrop Sun Pharmaceutical

Industries Ltd

Moderate/severe pain

Rivastigmine Alzamine Bliss GVS Pharma

Limited

Dementia

Tulobuterol Astherol Bliss GVS Pharma

Limited

Anti-asthmatic

Fentanyl F- TAN Bliss GVS Pharma

Limited

Moderate/severe pain

Ketoprofen Ketopron Bliss GVS Pharma

Limited

Musculoskeleton pain

and Inflammation

Diclofenac

Diethylamine

Lofnac Bliss GVS Pharma

Limited

Musculoskeleton pain

and Inflammation

Therapeutic

Agent

Brand Name Manufacturer

Name

Indication

Fentanyl Fen-Touch Sparsha Pharma Moderate/severe pain

Ketoprofen Artho-Touch Sparsha Pharma Musculoskeleton pain

and Inflammation

Diclofenac Diclo-Touch Sparsha Pharma Musculoskeleton pain

and Inflammation

Rivastigmine Memory-Touch Sparsha Pharma Dementia

Therapeutic

Agent

Brand Name Manufacturer Name Indication

Diclofenac Nupatch Zydus Cadila

Healthcare Ltd.

Musculoskeleton

pain and

Inflammation

Fentanyl Finrid Dr. Reddy’s Moderate/severe pain

Fentanyl Trofentyl Troikaa Moderate/severe pain

Fentanyl Durogesic Johnson & Johnson Moderate/severe pain

http://www.drugsupdate.com/brand/brand_name/FENDROP http://www.blissgvs.com/products/pharma-products/transdermal-patcheshttp://sparsha.com/fen_touch.html http://sparsha.com/diclo_touch.html http://sparsha.com/artho_touch.htmlhttp://sparsha.com/memory-touch.html http://www.drugsupdate.com/brand/brand_name/NUPATCH http://www.drugsupdate.com/brand/brand_name/FINRID http://www.drugsupdate.com/brand/brand_name/TROFENTYL http://www.drugsupdate.com/brand/brand_name/DUROGESIC

http://www.drugsupdate.com/brand/brand_name/FENDROP

http://www.blissgvs.com/products/pharma-products/transdermal-patches

http://sparsha.com/fen_touch.html

http://sparsha.com/diclo_touch.html

http://sparsha.com/artho_touch.html

http://sparsha.com/memory-touch.html

http://www.drugsupdate.com/brand/brand_name/NUPATCH

http://www.drugsupdate.com/brand/brand_name/FINRID

http://www.drugsupdate.com/brand/brand_name/TROFENTYL

http://www.drugsupdate.com/brand/brand_name/DUROGESIC

FDA Approved TDDS Products

Drug Name Generic Name Approval Date

CATAPRES TTS CLONIDINE October 10, 1984

VIVELLE ESTRADIOL October 28, 1994

CLIMARA ESTRADIOL December 22, 1984

ESTRADERM ESTRADIOL September 10, 1986

CLIMARA PRO ESTRADIOL/LEVONOR

GESTREL

November 21, 2003

ORTHO EVRA NORELGESTROMIN/ET

HINYL ESTRADIOL

November 20, 2001

DURAGESIC FENTANYL August 7, 1990


LIDOCAINE LIDOCAINE May 21, 1996

NITRO-DUR NITROGLYCERIN April 4, 1995

MINITRAN NITROGLYCERIN August 30, 1996

OXYTROL OXYBUTYNIN February 26, 2003

EXELON PATCH RIVASTIGMINE July 6, 2007

TRANSDERM-SCOP SCOPOLAMINE Approved prior to January

1, 1982

ANDRODERM TESTOSTERONE September 29, 1995


NICODERM NICOTINE August 2, 1996

HABITROL NICOTINE November 12, 1999

NICOTROL NICOTINE July 3, 1996

TRANSDERM-NITRO NITROGLYCERIN February 27, 1996

TESTODERM-AT TESTOSTERONE December 18, 1997

Sadrieh Nakissa. Challenges in the Development of Transdermal Drug Delivery Systems. Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. 2009. (www.fda.gov)

Drug Polymer or

Major

Excipients

Type of Patch

and

Preparation

Method

Remarks Reference

IQP-0410

(HIV Inhibitor)

EC, HPMC, PG,

DnBP (Di-n-butyl

phthalate)

EC/HPMC-

based

transdermal films

& solvent casting

technique

Successful in vitro

reduction of HIV-1

activity from the

delivered drug over a

3 day application

suggests the potential

of IQP-0410 to be

administered via

transdermal patches.

Ham et al, 2013

Donepezil Sodium alginate

(matrix-forming

agent), Propylene

glycol and dl-

limonene

Matrix type

transdermal films

Alternative Delivery

Approach in

Alzheimer’s Disease

Treatment

Galipoglu et al,

2014

Drug Polymer or

Major

Excipients

Type of Patch

and

Preparation

Method

Remarks Reference

Buprenorphine Lauryl alcohol,

Tween 80,

Levulinic acid

(Chemical

penetration

enhancers)

Drug In Adhesive

Patch & Using

Box-Behnken

Experimental

Design

Chemical

penetration

enhancers could

enhance

permeation flux

of buprenorphine

through the skin

Taghizadeh et al,

2015

Zolmitriptan Oleic acid and

Span 80,

Isopropyl

myristate (IPM) ,

Triethylamine,

Azone

Drug in Adhesive

Patch & Solvent

evaporation

technique

Pharmacokinetic

parameters were

determined via

i.v. and

transdermal

administrations

using animal

model of rabbit.

Chao Liu and

Liang Fang, 2015

Drug Polymer or

Major

Excipients

Type of Patch

and

Preparation

Method

Remarks Reference

Khardal

(Brassica nigra),

Zanjabeel

(Zingiber

officinale),

Podina (Mentha

arvensis)

Chitosan,

PEG-400,

tween 80

Drug in Adhesive

Patch & solvent

evaporation

technique

Design and development

of an antiemetic

transdermal Unani

formulation in a novel

dosage form for a common

clinical condition, namely,

vomiting/emesis. The patch

was found to be stable &

showed no signs of skin

irritation.

Saleem M

N & Idris

M, 2016

Galipoglu et al. Biopolymer-Based Transdermal Films of Donepezil in Alzheimer’s. AAPS Pharm Sci Tech

2014; 16(2): 284-292.

Taghizadeh et al. Influence of skin penetration enhancers on buprenorphine patch release system. Journal of

Advanced Research . 2015; 6: 155–162.

Chao Liu and Liang Fang. Transdermal Patch of Zolmitriptan and Pharmacokinetic Study. AAPS Pharm

SciTech. 2015; 16 (6): 1245-1253.

Ham et al. IQP-0410 HIV Inhibitor Transdermal Film. PLOS ONE. 2013; 8(9): e 75306.

Saleem MN, Idris M. Formulation Design and Development of a Unani Transdermal Patch for Antiemetic

Therapy and Its Pharmaceutical Evaluation. [P.G. Unani Thesis]. Ayurvedic & Unani Tibbia College, Karol

Bagh, New Delhi, India, 2016.

evaluation of transdermal drug delivery systems

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