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“DESIGN, FORMULATION AND EVALUATION OF TRANSDERMAL PATCHES FOR ANTI HYPERTENSIVE DRUG”

A dissertation submitted to Andhra University,

In partial fulfillment for the award of the degree of MASTER OF PHARMACY

In

PHARMACEUTICAL TECHNOLOGY

(2011-2013)

Submitted by

KORUKONDA SRIKANTH KUMAR , B.Pharm(Reg.No: 611289801014)

Under the Joint Guidance of

ACKNOWLEDGEMENTS

Industrial Guide Mr. Santosh Kumar. Tata M.Pharm

Manager Director carpouscles research solutions, Visakhapatnam

Institutional Guide Dr.k.e.v Nagoji M.Pharm PhD.

Principal Sri Venkkateswara college of Pharmacy

SRI VENKATESWARA COLLEGE OF PHARMACY, ETCHERLA

Affiliated to ANDHRA UNIVERSITY VISAKHAPATNAM

I am thankful to Almighty God, whose blessings made it possible to

complete the dissertation work successfully.

I have received great help from many of my teachers and friends in a

number of ways in preparing this dissertation work, I want to thank all of them.

It is my proud privilege to express my heartfelt gratitude to my beloved

institutional guides Dr. K.E.V.NAGOJI M.Pharm., Ph.D, Principal, Sri

Venkateswara College Of Pharmacy, Etcherla for his encouraging words that

enabled me to act with quality and precision. I am highly indebted to him for the

encouragement, patience and help rendered to me at all stages of my work

I take this opportunity to express my greatfulness and gratitude to Ms.

Padmasri , Ms. Lakshmi Deepthi and the entire staff of Sri Venkateswara

College of Pharmacy for their support and encouragement during the course of

my study.

I express my deep sense of gratitude to my industrial guide Mr. Santosh.

Tata Manager and Head and also research guide from, CORPUSCLE

RESEARCH SOLUTIONS, Visakhapatnam

I thank Loving thanks to my dearest friends

swetha ,somesh ,ramareddy ,suresh ,indu ,swamy, padmavathi, chandrashekar,

for their support and encouragement.

I thank specially to Mr. Lokesh, Mr. Lakshmana murthy, Srinivas,

Ramana and all other non-teaching staff for their timely help

Finally, with deep sense of veneration and gratitude, I recall the

affectionate help, endless encouragement and constant support of my parents

shri Satyanarayana and ramadevi .

As a final word, I would like to thank each and every person who have

been a source of support and encouragement and helped me to achieve my goals

and complete my dissertation work successfully

K.SRIKANTH KUMAR

SRI VENKATESWARA COLLEGE OF PHARMACY

NH-5; ETCHERLA, SRIKAKULAM-532410.

(Affiliated to ANDHRA UNIVERSITY), Vishakapatnam

Approved by AICTE & PCI, NEW DELHI.

CERTIFICATEThis is to certify that the project work entitled “ DESIGN,

FORMULATION AND EVALUTION OF TRANSDERMALL

PATCHES FOR ANTI HYPERTENSIVE DRUG ” submitted to Andhra

University,Visakhapatnam for the partial fulfillment of the award of degree of

Master of pharmacy in Pharmaceutical Technology was carried out by

K.Srikanth Kumar (Regd. No.611289801014) in the department of

Pharmaceutics, Sri Venkateswara College of Pharmacy, Etcherla under

my guidance and supervision.

This work is original and has not been submitted in part or full to any other

degree of Andhra University or any other university

Place: Etcherla Dr. K.E.V.NAGOJI, M.PHARM, PhD

Date: Principal

Sri Venkateswara College of Pharmacy

Etcherla.

DECLARATION

I do here by declare that the work presented in this thesis entitled “DESIGN,

FORMULATION AND EVALUTION OF TRANSDERMALL

PATCHES FOR ANTI HYPERTENSIVE DRUG” was out by me at

corpuscle research solutions, Vishakapatnam and in the department of

Pharmaceutics, Sri Venkateswara College of Pharmacy under the supervision

of Sri. Dr. K.E.V.Nagoji, M. PHARM, PhD, Principal of Sri Venkateswara College

of Pharmacy, Etcherla and co-guidance of TATA. SANTOSH, Deputy

manager, Corpuscles Research Solutions, Visakhapatnam.

This work is original & has not been submitted in part or full for the award of

other degree or diploma of any other university.

Place: Etcherla K.Srikanth kumar

Date: Regd. No. 611289801014

LIST OF ABBREVIATIONS

Abs Absorbance

AUC Area under curve

°C Degree Celsius

Cm Centimeter

Cmax Peak plasma concentration

Conc. Concentration

CDR Cumulative Drug Release

CR Controlled release

DMSO Di Methyl sulphoxide

DSC Differential Scanning Calorimetry

e.g., For Example

FTIRFourier transform Infra-red

Spectrophotometer

GIT Gastro intestinal tract

Hrs Hour

HPLC High performance liquid chromatography

ICHInternational Conference on

Harmonization

IP Indian Pharmacopoeia

K-C cell Keshary-Chien diffusion cell

Mg Milligram

min. Minutes

ml Milliliter

Mm Mile meter

NMRNuclear magnetic resonance

spectroscopy

nm Nanometer

PEG-400 Polyethylene glycol

Rpm Revolution per minute

RH Relative humidity

SD Standard deviation

TDDS Transdermal Drug Delivery System

t1/2 Half life

USP United States Pharmacopeia

UV Ultraviolet

Vd Volume distribution

v/v Volume by volume

w/w Weight by weight

g/ml Microgram per milliliter

% Percentage

max Absorption maxima

CONTENTS

CHAPTER

NO.

CHAPTERS PAGE NO.

1. INTRODUCTION 1

2. AIM AND OBJECTIVE 18

3. LITERATURE REVIEW 19

4. DRUG AND EXCIPIENT PROFILE 25

5. METHODOLOGY 32

6. RESULTS & DISCUSSION 42

7. CONCLUSION 81

8. SUMMARY 83

9. BIBLIOGRAPHY 84

LIST OF TABLES

SRN

O

Contents Page

no

1 Ideal properties of drug 3

2 Examples of FDA Approved Transdermal Patches 17

3 Materials Used 32

4 Equipments used 33

5 Spectrophotometric data for construction of standard graph

Labetalol

35

6 Formulation chart of Labetalol transdermal films 38

7 Preformulation studies of Labetalol 42

8 Data of IR spectral peaks of Labetalol and polymers 44

9 Physicochemical parameters of prepared formulation F1-F9 46

10 Comparative data of percentage drug release from the

formulations F1-F9

48

11 Comparison of zero order of in vitro drug release F1-F9 50

12 Comparison of first order of in vitro drug release F1-F9 52

13 Comparison of higuchi model of in vitro drug release F1-F9 54

14 Comparison of Korsmeyer equation of in vitro drug release F1-

F9

56

15 Comparison of orders of in vitro release of Labetalol from the

formulation F1-F9

58

16 Anova for repose surface linear model-Response1 59

17 Estimated regression coefficient-Response1 59







24 Composition of optimized formula- 71

25 Response variable of optimized formula1 71

26 Data of various parameters of model fitting of labetalol of

optimized formulation

71

27 Drug release studies of optimized formula 72

28 Comparison between the Experimental and Predicted value for

the optimized formula

75

29 Physicochemical properties of most satisfactory formulations

F5(after stability)

75

30 In vitro drug diffusion studies of most satisfactory formulations

F5(after stability)

76

LIST OF FIGURES

SRN

OContents

Page

no

1 Cross Section of the Skin 4

2Transepidermal (A) and transappendageal route of transport into

the skin.

8

3 Pentration enhancer activity 11

4 Penetration pathway of drug molecules through the skin 11

5 Types of Transdermal Drug Delivery Systems 16

6 standard graph of Labetalol in phosphate buffer pH7.4 35

7 In-vitro studies by using Franz diffusion cell 40

8 Ex-vivo studies on the rat skin 40

9 FTIR Spectrum of Labetalol 43

10 FTIR Spectrum of physical mixture of drug with Eudragit RSPO 44

11 FTIR Spectrum of physical mixture of drug with Eudragit RLPO 45

12 Drug content of all formulation 47

13 Comparative In-vitro diffusion study of all formulationsF1-F9 49

14 Comparison of zero order of in vitro drug release F1-F9 51

15 Comparison of first order of in vitro drug release F1-F9 53

16 Comparison of higuchi model of in vitro drug release F1-F9 55

17Comparison of Korsmeyer equation of in vitro drug release F1-

F9

57

18Correlation between actual and predicted valu for folding

endurance-Response1

60

19 3D-Graph showing the effect of EUDRAGIT-RSPO,RLPO and 60-61

DMSO ,PEG on folding endurance-Response1

20Correlation between actual and predicted valu for 4th hr drug

release-Response2

63

213D-Graph showing the effect of EUDRAGIT-RSPO,RLPO and

DMSO ,PEG on 4th hr drug release-Response2

63-64

22Correlation between actual and predicted valu for 12th hr drug

release-Response3

66



66-67

24Correlation between actual and predicted valu for 24thdrug

release-Response4

68



68-70

26 Zero order kinetics of optimized formula 73

27 First order plot of optimized formula 73

28 Higuhi plot for optimized formula 74

29 Korsmyer-peppas polot for optimized formula 74

30 In vitro drug diffusion studies of most satisfactory formulations

F5(after stability)

77

INTRODUCTION

1. INTRODUCTION

1.1TRANSDERMAL DRUG DELIVERY SYSTEM:

Transdermal drug delivery systems are defined as self-contained discrete dosage

forms which, when applied to the intact skin, deliver the drug(s), through the

skin, at controlled rate to the systemic circulation.1

These techniques are capable of controlling rate of drug delivery, sustaining the

duration of therapeutic activity, and/or targeting the delivery of drug to a tissue.

In responses to these advances, several transdermal drug delivery systems have

recently been developed aiming to achieve the objective of systemic medication

through topical application on the intact skin surface. The principle of

transdermal drug delivery systems is that they could provide sustained drug

delivery over a prolonged period of time. Thus, it is anticipated that transdermal

drug delivery systems can be designed to input drugs at appropriate rates to

maintain suitable plasma-drug levels for therapeutic efficacy, without the periodic

sojourns into plasma concentrations that would accompany toxicity or lack of

efficacy. Ultimately, the success of all transdermal system depends on the ability

of the drug to permeate skin in sufficient quantities to achieve its desired

therapeutic effect.2

1.2 MECHANISM OF DRUG PERMEATION THROUGH THE SKIN:

When drugs are applied on the skin surface, penetration into and through the skin

can occur via various routes.

Drugs penetrate either via the stratum corneum (transepidermal) or via

the appendages (transappendageal) (Figure 3). During penetration through the

stratum corneum, two possible routes can be distinguished.20

i) Penetration alternating through the corneocytes and the lipid lamellae

(transcellular route) and

ii) Penetration along the tortuous pathway along the lipid lamellae (intercellular

route).

Dept of pharmaceutical Technology Page 1

INTRODUCTION

Generally it is accepted that the predominant route of penetration through

the stratum corneum is the intercellular route. This is mainly caused by the

densely cross-linked cornified envelope coating the keratinocytes. However

transcellular transport for small hydrophilic molecules such as water cannot

completely be excluded The appendage route or shunt route includes either the

duct of the eccrine sweat glands or the follicular duct. The content of the eccrine

sweat glands is mainly hydrophilic, while the content of the follicular duct is

lipophilic.

1.3 ADVANTAGES OF TRANSDERMAL DRUG DELIVERY:

1. Prevents the variation in the absorption and metabolism associated with oral drug

administration.

2. Prevents the risk and inconvenience of intravenous therapy.

3. Permits continuous zero-order drug administration and the use of drugs with short

biological half-lives.

4. Increases the bioavailability and efficacy of drugs, since it bypasses hepatic first-

pass elimination.

5. Provide a simple therapeutic regimen, leading to good patient compliance that can

be easily terminated by simple removal of the patch.

6. Transdermal medication delivers a steady infusion of a drug over an extended

period of time. Adverse effects or therapeutic failures frequently associated with

intermittent dosing can also be avoided.

7. Self-medication is possible.

8. Allows continued drug administration permitting the use of a drug with short

biological half-life.1,2,6,7

1.4 DISADVANTAGES:

1. One of the greatest disadvantages of transdermal drug delivery is the possibility

that a local irritation may develop at the site of application.

2. The drug, the adhesive or other excipients in the patch formulation can cause

erythema, itching, and local edema.

3. Another significant disadvantage of transdermal drug delivery is that the skin’s

low permeability which limit the number of drugs that can be delivered in this

manner.


INTRODUCTION

4. Many drugs especially drugs with hydrophilic structures permeate the skin too

slowly to be of therapeutic benefit.

5. The barrier function of the skin changes from one site to another on the same

person, from person to person and also with age.1,2,6,7

1.5 IDEAL PROPERTIES OF DRUG CANDIDATE FOR

TRANSDERMAL DRUG DELIVERY:

Table1. Ideal properties of the drug

Parameter Properties

Half-life in h 10 or less

Molecular weight <400

Partition coefficientLog P (octanol-water)

between-1.0 and 4

Skin permeability

coefficient>0.5 × 10−3 cm/h

Skin reactionNon irritating and non-

sensitizing

Oral bioavailability Low

Therapeutic index Low

1.6 PHYSIOLOGY AND ANATOMY OF THE SKIN:

1.6.1PHYSIOLOGY OF THE SKIN:

The skin of an average adult body covers a surface area of approximately

2m2 and receives about one-third of the blood circulation through the body. The

permeability barrier in the skin consists of three distinct layers in series.2,3

1) The Stratum corneum (10/μm thick)

2) The Viable epidermis (100/μm thick)

3) The Papillary layer of the dermis (100-200/μm thick)


INTRODUCTION

This composite structure is pierced at various places by two types of

potential diffusion shunts: hair follicles and sweat glands. These skin appendages

actually occupy only 0.1% of the total human skin surface. This trans-appendage

route of percutaneous absorption, however, provides a very limited contribution

to the overall kinetic profile of transdermal permeation. Therefore, the

transdermal permeation of most neutral molecules at a steady state can, thus be

considered as a process of passive diffusion through the intact stratum corneum in

the inter follicular region.

The skin serves as the port of administration for systemically active drugs, the

drug applied topically is distributed following absorption first into the systemic

circulation and then transported to target tissues. An average adult skin has a

surface area of approximately 2 square meters and receives about one third of the

blood circulating through the body. It is one of the most readily accessible organs

of the human body with a thickness of only a few millimeters (2.97+/-0.28 mm).

Its major roles are to regulate body temperature, protect tissues from infection,

prevent fluid loss, and cushion internal structures. 18,19 The skin is a multilayered

organ composed of many histological layers. It is generally described in terms of

three major tissue layers.2,4

The epidermis – thin protective outer layer.

The dermis – the tough elastic second layer.

The hypodermis – layer of fatty and connective tissue.

1.6.2 ANATOMY OF THE SKIN:


INTRODUCTION

a. The Epidermis:

The outer (epidermal) layer of the skin is composed of stratified squamus

epithelial cells. The multilayered envelope of the epidermis varies in thickness,

depending on cell size and then number of cells and then number of cell layers,

ranging from about 0.8mm on the palms and the soles down to 0.66mm on the

eyelids. Cells which provide epithelial tissue differ from those of all other organs

provide epithelial tissue differ from those of all other organs in that as they

change in an ordered fashion from metabolically active and dividing cells to

dense, dead, keratinized protein.

b. Stratum germinativum (basal layer):

The basal cells are nucleated, columnar, and about 6 microns wide, with their

long axis at right angles to the dermoepidermal junction; they connect by

cytoplasmic intercellular bridges. Mitosis of the basal cells constantly renews the

epidermis and this proliferation in healthy skin balances the loss of dead horny

cells from the skin surface. The epidermis thus remains constant in thickness.

Below the basal cell layer lies the complex dermoepidermal junction, which

constitutes an anatomic functional unit. The junction serves three functions of

dermal-epidermal adherence, mechanical support for the epidermis, and control

of the passage of cells and some large molecules across the junction.

c. Stratum spinosum (prickle cell layer):

As the cells produced by the basal layer move outward, they alter

morphologically and histochemically. The cells flatten and their nuclei shrink.

These polygonal cells are called as prickle cells because they interconnect by fine

prickles.

d. Stratum granulosum (granular layer):

As the Keratinocytes approach the surface, they manufacture basic staining

particles, the keratohyalin granules. It was suggested that these granules represent

an early form of keratin 3, 4. The term transitional zone is convenient region

between living cells and dead keratin.


INTRODUCTION

e. Stratum lucidum:

In the palms and the soles an anatomically distinct, poorly staining hyaline zone

forms a thin, translucent layer immediately above layer immediately above the

granular layer. This region is the stratum lucidum.

f. Stratum corneum (horny layer):

The stratum corneum is also normally devoid of nuclei and consist of eosinophilic

layers of keratin. Intraepidermal nerve endings are present in the fromofMerckel

cells which are touch receptors.

g. The Dermis:

The dermis (corium) consists essentially of a matrix of connective tissue woven

from fibrous proteins which embed in an amorphous ground substance on

mucopolysaccharides providing about 20% of the mass. Blood vessels, nerves,

and lymphatics cross this matrix and skin appendages (eccrine sweat glands,

apocrine glands and pilosebaceous units) penetrate it. In man, the dermis divides

into a superficial, thin papillary layer which forms a negative image of the rigid

lower surface of the epidermis, and a thick underlying reticular layer which

merges with the fat-containing subcutaneous tissue.

The dermis needs a rich blood supply which regulates temperature and

pressure, delivers nutrients to the skin and removes waste products, mobilizes

defense forces, and contributes to skin color. The blood supply reaches to within

0.2mm of the skin surface, So that it readily absorbs and systemically dilutes

most chemicals which penetrate past the stratum corneum and the viable

epidermis. The vascular surface available for the viableepidermis. The vascular

surface available for the exchange of materials between local tissues and the

blood is enormous. Of particular relevance to biopharmaceutical studies is the

fact that this generous blood volume usually functions as a “sink” with respect to

the diffusing molecules which reach it during the process of percutaneous

absorption. This sink condition ensures that the penetrant concentration in the

dermis remains near and therefore the concentration gradient across the epidermis

is maximal.

h. The Hypodermis: This is a sheet of fat-containing areolar tissue known as

superficial fascia, attaching the dermis to the underlying structure.


INTRODUCTION

i. Skin Appendages:

The epidermis and dermis support several appendages: The eccrine,

apocrine and sebaceous glands, the hair follicles and the nails. Of these, hair

follicles and sweat ducts can act as diffusion shunts, i.e. relatively easy pathways

for diffusion through the rate-limiting stratum corneum.

Figure 2.Transepidermal (A) and transappendageal route of transport into the

skin. The transappendageal route (B) includes diffusion via the hair follicle and

the sweat gland.

j. Eccrine Sweat glands: Eccrine sweat glands develop over the skin surface but

not over mucous membranes. The gland density varies greatly with skin site; for

example, the thighs possess about 120 glands per square centimeter and the soles

of the feet have about 620per square centimeter. The composition and the

quantity of the sweat varies greatly with subject, time, environmental conditions,

exertion and skin site.

k. Apocrine Sweat Glands: Apocrine sweat glands are epidermal appendages

which develop throughout the skin of the embryo as part of the pilosebaceous

follicle. Most of the glands subsequently disappear so that the characteristic adult

distribution is in the axilla, the perianal region and the areola of the breasts.

l. Hair follicles: Hair follicles developed over the entire skin surface except the

palms the soles, the red portion of the lips and the parts of the sex organs. The

average fractional surface area of the openings is about 0.1%. Hair contains


INTRODUCTION

“hard” keratin, which differs from the “soft” keratin of desquamating tissues in its

high sulfur content.

m. Sebaceous Glands: Sebaceous glands are largest and most numerous on the

back. The palms and soles are usually free of them. The flask like sebaceous

glands from ducts which usually open into the neck of the hair follicle. Sebum is

complex mixture of lipids i.e. glycerides, free fatty acids, wax esters, squalene,

cholesterol, esters. Several functions have been attributed to sebum, such as

controlling water loss, and protecting the skin from fungal and bacterial infection.

Figure 3. Penetration pathway of drug molecules through the skin30

1.7 BASIC COMPONENTS OF TRANSDERMAL DRUG DELIVERY

SYSTEMS:

The components of transdermal devices include:2

a) Polymer matrix or matrices

b) The drug

c) Permeation enhancers

d) Other excipients

a) Polymer matrix:

The Polymer controls the release of the dug from the device. The following

criteria should be satisfied for a polymer to be used in a transdermal system.


INTRODUCTION

M.Wt, glass transition temperature and chemical functionality of the polymer

should be such that the specific drug diffuses properly and released through it.

The polymer should be stable, non-reactive with the drug, easily manufactured

and fabricated into the desired product and inexpensive.

The polymer and its degradation products must be non-toxic or non-antagonistic

to the host.

The mechanical properties of the polymer should not deteriorate excessively

when large amount of active agent is incorporated into it.

Possible useful polymers for transdermal devices are:

Natural Polymers: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins,

Gums and their derivatives, Natural rubber, starch etc.

Synthetic elastomers:Polybutadiene, Hydrin rubber, Polysiloxane, Silicone

rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadiene rubber, Neoprene

etc.

Synthetic Polymers: Polyvinyl alcohol, Polyvinyl chloride, Polyethylene,

Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone,

Polymethyl methacrylate, Epoxy etc.

b) The Drug:

For successful development of transdermal drug delivery system, the drug should

be chosen with great care.

i. The drug must not induce a cutaneous irritant or allergic response.

ii. Drugs, which degrade in the GI tract or are inactivated by hepatic firstpass effect,

are suitable candidates for transdermal delivery.

iii. Tolerance to the drug must not develop under the near zero-order release profile

of transdermal delivery.


INTRODUCTION

iv. Drugs, which have to be administered for a long period of time or which cause

adverse effects to non-target tissues can also be formulated for transdermal

delivery.

c) Permeation Enhancers:

These are the compounds, which promote skin permeability by altering the

behaviour of skin as barrier to the flux of a desired penetrant. The flux, J, of

drugs across the skin can be written as21

J=D dc/dx ------- (1)

Where,

D is the diffusion coefficient and is a function of the size, shape and

flexibility of the diffusing molecule as well as the membrane resistance;

C is the concentration of the diffusing species;

x is the spatial coordinate.

Thus enhancement of flux across membranes depends on the considerations of:

Thermodynamics (lattice energies, distribution coefficients)

Molecular size and shape

Reducing the energy required to make a molecular hole in the membrane

Mechanism:

The enhancement in absorption of oil soluble drugs is apparently due to the

partial leaching of the epidermal lipids by the chemical enhancers, resulting in the

improvement of the skin conditions for wetting and for transepidermal and

transfollicular penetration. The miscibility and solution properties of the

enhancers used could be responsible for the enhanced transdermal permeation of

water-soluble drugs.


INTRODUCTION

Figure 5: Penetration enhancer activity. (a) Action at intercellular lipids. Some

of the ways bywhich penetration enhancers attack and modify the well-organized

intercellular lipid domain of the stratum corneum.

Some of them alter the composition of the cell content while others affect the

cohesiveness between cells and composition of intercellular material or have a

direct effect on cell membrane. The composition of intercellular lipids undergoes

a solid-lipid phase transition at 40oC. It is possible that some penetration

enhancers act to disrupt the structure of intercellular lipids and lower the phase

transition temperature, thereby increasing the permeability of skin to more polar

compounds. To increase the rate of transfer of lipophilic compounds, it is

necessary to modify the partitioning characteristics at the stratum corneum viable

tissue interface. This may be possible by combining a penetration enhancer with a

co-solvent. Some agents can establish a reservoir in stratum corneum, which may

facilitate diffusion of drug, when penetrating the epidermis, may carry drug

through, by acting as a solvent Many of these agents may act by a combination of

various effects on the skin while others may be involved in a direct chemical

insult on the skin, When the specified lipid film, made up of sebaceous secretion,

desquamated cells, sweats and other components, the percutaneous absorption is

enhanced slightly. When lipids are removed from the skin as by means of

prolonged exposure to polar solvents, however, considerably enhanced absorption


INTRODUCTION

of applied materials. it is quite likely that lipid solvents must damage the lipid

portion of the membrane before much change in passage through the skin can

take place.

Classification of penetration enhancers:

i. Terpenes(essential oils): E.g. Nerodilol, menthol, 1 8 cineol,limonene, carvone

etc.

ii. Pyrrolidones: E.g. N-methyl-2-pyrrolidone(NMP), azone etc.

iii. Fatty acids and esters: E.g. Oleic acid, linoleic acid, lauric acid, capric acid etc.

iv. Sulphoxides and similar compounds: E.g. Dimethyl Sulphoxide(DMSO),

N,Ndimethylformamide.

v. Alcohols, Glycols, and Glycerides: E.g. Ethanol, Propylene glycol, Octyl alcohol.

vi. Micellaneous enhancers: E.g. Phospholipids, Cyclodextrins, Amino acid

derivatives, Enzymes etc.

Desirable characteristics of penetration enhancers:

These are the some of the desirable characteristics of penetration enhancers:

It should be pharmacologically inert within the body, either locally or

systemically.

It should not irritate or induce allergic responses.

The operation of enhancement (both in terms of activity and duration of effect)

should be predictable and reproducible.

The penetration enhancer should work unidirectionally, i.e., should allow

medicaments to enter the body while preventing the release of endogenous

materials.

It should be cosmetically acceptable, being odorless, colorless, and with

appropriate skin feel.

Sulfoxides and other similar compounds:


INTRODUCTION

Dimethylsulfoxide (DMSO), the archetypal penetration enhancer, is a powerful

aprotic solvent that is colorless, odorless, and hygroscopic; its value as an

enhancer may be predicted from its use chemically as a universal solvent.

Extensive investigations on the accelerant activities of DMSO show it to be

effective in promoting the flux of both lipophilic and hydrophilic permeants, e.g.,

antiviral agents, steroids, and antibiotics. DMSO works rapidly but its effects are

markedly concentration dependent and generally cosolvents containing more than

60% DMSO are needed for acceptable enhancement. The mechanisms of action

of the sulfoxide enhancers are complex. DMSO denatures proteins and on

application to human skin alters the intercellular keratin confirmation, changing it

from an α-helical to a β-sheet. DMSO also interacts with the intercellular lipid

domains of human stratum corneum. Considering its small highly polar nature it

is feasible that DMSO interacts with the head groups of some bilayer lipids to

distort their packing geometry, as well as dissolving in, and extracting, lipids.

Further, DMSO dissolved within skin membranes may alter the polarity and

facilitate drug partitioning from a formulation

into this universal solvent within the tissue.

OTHER EXCIPIENTS:

Adhesives:

The fastening of all Transdermal devices to the skin has so far been done by using

a pressure sensitive adhesive. The pressure sensitive adhesive can be positioned

on the face of the device or in the back of the device and extending peripherally.

Both adhesive systems should fulfill the following criteria.

Should not irritate or sensitize the skin or cause an imbalance in the normal skin

flora during its contact time with the skin.

Should adhere to the skin aggressively during the dosing interval without its

position being disturbed by activities such as bathing, exercise etc.

Should be easily removed.

Should not leave an unwashable residue on the skin.


INTRODUCTION

Should have excellent (intimate) contact with the skin at macroscopic and

microscopic level.

Backing membrane:

Backing membranes are flexible and they provide a good bond to the drug

reservoir, prevent drug from leaving the dosage form through the top, and accept

printing. It is impermeable and protects the product during use on the skin e.g.

metallic plastic laminate, plastic backing with absorbent pad and occlusive base

plate a (aluminum foil), adhesive foam pad (flexible polyurethane) with occlusive

base plate (aluminum foil disc) etc.

1.8 TECHNOLOGIES FOR DEVELOPING TRANSDERMAL DRUG

DELIVERY SYSTEMS:

Several technologies have been successfully developed to provide rate control

over the release and skin permeation of drugs. These technologies can be

classified into four basic approaches.14,17

a) Polymer membrane permeation-controlled TDD Systems

b) Polymer matrix Diffusion-Controlled TDD Systems

c) Drug Reservoir Gradient-Controlled TDD Systems

d) Micro-reservoir Dissolution-Controlled TDD Systems

a) Reservoir System: In this system, the drug reservoir is embedded between an

impervious backing layer and a rate controlling membrane (Fig. 6a) The drug

releases only through the rate-controlling membrane, which can be microporous

or nonporous. In the drug reservoir compartment, the drug can be in the form of a

solution, suspension, or gel or dispersed in a solid polymer matrix. On the outer

surface of the polymeric membrane a thin layer of drug-compatible,

hypoallergenic adhesive polymer can be applied.

Eg.Transderm-Nitro system, Transderm-Scop system, the Catapres TTS system,

the Estraderm system, and the Duragesic system.


INTRODUCTION

b) Matrix systems: Drug-in-adhesive system: The drug reservoir is formed by

dissolving or dispersing the drug in an adhesive polymer and then spreading the

medicated polymer adhesive by solvent casting or by melting the adhesive (in the

case of hot-melt adhesives) onto an impervious backing layer (Fig. 6b). On top of

the reservoir, layers of unmedicated adhesive polymer are applied.

Eg.Isosorbidedinitrate transdermal therapeutic system (Frandol tape).

c) Matrix-dispersion system: The drug is dispersed homogeneously in a

hydrophilic or lipophilic polymer matrix. This drug containing polymer disk is

then fixed onto an occlusive base plate in a compartment fabricated from a drug-

impermeable backing layer (Fig. 6c). Instead of applying the adhesive on the

face of the drug reservoir, it is spread along the circumference to form a strip of

adhesive rim.

Eg.Nitro-Dur system and the NTS system.

d) Micro-reservoir system: This drug delivery system is a combination of

reservoir and matrix-dispersion systems. The drug reservoir is formed by first

suspending the drug in an aqueous solution of water-soluble polymer and then

dispersing the solution homogeneously in a lipophillic polymer to form thousands

of unleachable, microscopic spheres of drug reservoirs (Fig. 6d).

Eg.Nitrodisc system.


INTRODUCTION

(a) Reservoir System

(b) Matrix Dispersion System

(c)Peripheral adhesive Design

(d) Microreservoir system

Figure 5. Types of Transdermal Drug Delivery Systems


INTRODUCTION

Table No. 2: Examples of FDA Approved Transdermal Patches

Product

nameDrug Manufacturer Indication

TransdermSc

op

Scopolamn

eAlza/Norvatis Motion sickness

Transderm

Nitro

Nitroglycei

nAlza/Norvatis Angina pectoris

Vivelle Estradiol

Noven

Pharmaceuticals/No

rvatis

Postmenstrual

syndrome

Catapres-

TTSClonidine

Alza/

BoehingerIngelheimHypertension

Duragesic Fentanyl

Alza/

JanssenPharmaceuti

cl

Moderate/severe

pain

Habitraol Nicotine Novartis Smoking cessation

Androderm TestosteroeTheraTech/

GlaxoSmithKlie

Hypogonadism in

males.

Nuvelle TS

Estrogen/

Progestero

ne

Ethical

Holdings/Schering

Hormone

replacement


INTRODUCTION


AIM AND OBJECTIVES

2. AIM

Labetalol is an α and β receptor antagonist. It has a biological

half-life of only 6 to 8 hr and its oral bioavailability is around 25%.

Main reason for selecting the Labetalol is it goes through the

first pass metabolism.To avoid this present work is to formulate a

transdermal film for an anti-hypertensive to improve bioavailability drug

using these polymers like Eudragit-RSPO, RLPO and DMSO

2.1 OBJECTIVE Treatment of chronic diseases like hypertensive disorders by

transdermal route of drug absorption proved and it has several advantages

over other routes. Labetalol is an α and β receptor antagonist. It has a

biological half-life of only 6 to 8hr and its oral bioavailability is around

25%. Therefore, the objective of the present work is to formulate a

transdermal film for an anti-hypertensive drug.

Following are the main objectives of the present study.

1. Optimising and design of matrix type transdermal film of anti-

hypertensive drug by using polymers such as EUDRAGIT RSPO and

RLPO.

2. Studied the effect of polymer concentration on drug release.

3. Preparation of transdermal films of Labetalol by solvent casting method.

4. Characterized the films for various physicochemical parameters and to

investigate In vitro release patterns and In vitro diffusion of the drug.

5. Skin irritation test studies using the rat skin.

6. Short term stability studies on the most satisfactory formulation as per

ICH guidelines.

Dept Of Pharmaceutical Technology Page 18

LITERATURE REVIEW

LITERATURE REVIEW

AgarwalSS et al.,2007,22 Transdermal patch of atenolol and metoprolol

tartrate was prepared by solvent evoparation method by using different

polymers in combination with plasticizer and penetration enhancer. They

used polymers like PVP, CAP, HPMC phthalate and EC, propylene glycol

as plasticizer and 1,8-cineole as penetration enhancer. In-vitro permeation

studies were performed using rat abdominal skin, the results found that at

48h 85% and 44% of atenolol and metoprolol tartrate, respectively.

Anil J et al.,2008,23 Developed transdermal matrix patches of tramadol

hydrochloride using HPMC, ERL-100 and ERS-100 in different ratios

with tri ethyl citrate as plasticizer and di-methyl Sulphoxide as

penetration enhancer. The batch containing ERL-100:HPMC(8:2) showed

79.65% release within 12hrs and batch containing ERS-100:HPMC(2:8)

showed only 58.30% release in 12hrs. This is because that the eudragit

produce crystallization free patch.

Gupta JRD et al.,2009,24 Matrix type of transdermal patches of

glibenclamide were prepared by using HPMC, PVP K-30 and Eudragit

RS-100 as polymers, PEG-400 as plasticizer and Dimethyl Sulphoxide

(DMSO) as penetration enhancer using solvet evaporation technique. On

the basis of in-vitro drug release and skin permeation performance

HPMC:PVP-30K (9:1) is the better than other formulations and it was

selected as the optimized formulation.

Mi-Kyeong kim et al.,2001,25 Reservoir type transdermal delivery system

of testosterone was developed using ethanol/water. Using cosolvent

system as a vehical a new transdermal system for testosterone was

formulated using ethyl vinyl acetate membrane coated with pressure

sensitive adhesive and HPMC as a gelling agent. By conducting the

comparable plasma concentration in-vitro study by comparing with

commercial product


LITERATURE REVIEW

JamakandiG et al.,2009,26 Designed matrix type transdermal patch of

nicardil using different polymeric grades of HPMC (6cps, 15cps, and

K4M). They used porcine ear skin for exvivo study. Among 6 different

HPMC formulations, transdermal patch with 6cps & 6% w/v DMSO as

parmeation enhancer showed maximum release of the drug.

Prasanna Kumari J et al.,2010,27 Transdermal drug delivery of

metoprolol tartarate were prepared using polymers EC, PVA, eudragit

RL-100, eudragit L-100 and Di-n-butylphthalate as plasticizer. Films were

prepared using solvent casting method. They studied in-vitro diffusion

using rat skin and they conclude the combination of EC, PVA, E L100

and Di-n-butylphthalate can potentially be optimized to develop an

effective transderma drug delivery system for metoprolol tartarate.

Iman IS et al.,2010,28 Prepared transdermal patches of chlorpheniramine

maleate (CPM). They used rabbit ear skin membrane for ex-vitro

diffusion studies and they used polymers like ethyl cellulose, cellulose

acetate, and poly vinyl pyrrolidone with different plasticizers such as

propylene glycol and polyethylene glycol 400. They compare the CPM

transdermal patch with CPM oral tablets and they found the results

showed that CPM transdermal patch has higher bioavailability than oral

tablet of same dose, with lower plasma fluctuation and less administration

frequency.

Samip.S et al.,2010,29 Formulation & evaluation of transdermal patches of

papaverine hydrochloride prepared by the solvent casting method using

EC:PVP, PVA:PVP & ERL-100:ERS-100 using different ratios. The

formulation containing PVA:PVP shows faster release rate (hydrophilic

polymers) compared to ERL-100:ERS-100 (hydrophobic polymers) or

combination of hydrophilic & hydrophobic polymers (EC & PVP).

Sivakumar et al.,2010,30 Designed and evaluated transdermal drug

delivery of ketotifen fumarate with different different ratios of HPMC-E5

(hydrophilic) and EC (hydrophobic) as polymers, 5 % v/w of DMSO as

penetration enhancer, and 10 % v/w of dibutyl phthalate as plasticizer in


LITERATURE REVIEW

Chloroform and methanol (1:1) as solvent system by solvent evaporation

technique. The diffusion studies shows maximum release is observed with

HPMC-E5 alone.

Ramesh G et al.,2007,31 The matrix type TDDS of NTDP were prepared

by solvent evaporation technique.All formulations carried 6% v/w of

carvone as penetration enhancer and 15% v/w of propylene glycol used as

plasticizer in dichloromethane

&methanol solvent system. The prepared TDDS were evaluated for in vi

tro release,

ex vivo permeation, moisture absorption, and moisture content and mec

hanical properties. The physic chemical interactions between

nitrendipine and polymers were investigated by Fourier Transform

Infrared (FTIR) spectroscopy.

Sadhana PG et al.,2005,32 Metaprolol Tartarate in transdermal drug

delivery system was investigated for controlled release of drug for

extended period of time. Eudragit RL and hydroxy propyl methyl

cellulose were used for fabrication of the formulation. These systems were

characterized for their thickness, tensile strength and drug content. Then it

was evaluated in vitro release kinetics and skin permeation studies and

compared its drug plasma profile with Metaprolol tartarate.

Agrawal SS et al.,1996,33 Rapid permeation of Verapamil hydrochloride

(VHC1) across the skin using finite dose loading was documented.

Transdermal drug delivery systems (TDDS) of VHCI using hydrophilic

polymers like polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP)

and different Concentrations of an enhancer, d-limonene were developed.

In-vitro permeation profiles across the guinea-pig dorsal and human

cadaver skins using a Keshary-Chien diffusion cell are reported. The

permeation rate was enhanced and followed approximately zero order

kinetics.

Manvi FV et al.,2003,34 Formulated transdermal films of ketotifen

fumarate using combination of Eudragit L-100, hydroxypropyl methyl

cellulose and ethyl cellulose HPMC polymeric combinations plasticized


LITERATURE REVIEW

with polyethylene glycol 400. Effects of permeation enhancers like diethyl

sulphoxide and propylene glycol at different concentrations were studies

on skin permeation kinetics. It was concluded that above polymeric

combinations might be feasible for formulation rate controlled

Transdermal therapeutic system of Ketotifen Fumarate for effective

control and prophylaxis of allergic asthma.

Aqil M et al.,2002,35 The monolithic matrix type transdermal drug

delivery systems of pinacidil monohydrate (PM) were prepared by film

casting technique on mercury substrate and characterised in vitro by drug

release studies using paddle over disc assembly, skin permeation studies

using Keshary Chein diffusion cell on albino rat skin and drug-excipients

interaction analysis. Four formulations were developed which differed in

the ratio of matrix forming polymers, Eudragit RL-100 and PVP K-30, i.e.

8:2, 4:6, 2:8 and 6:4 and were coded as B-1, B-2, B-3 and B-4,

respectively. All the four formulations carried 20% w/w of PM, 5% w/w

of plasticizer, PEG-400 and 5% w/w of DMSO in isopropyl alcohol:

dichloromethane (40:60) solvent system. On the basis of in vitro drug

release and skin permeation performance, formulation B-4 was found to

be better than the other three formulations and it was selected as the

optimized formulation.

Changshun Ren et al.,2009,36 Develop and evaluated novel drug in

adhesive transdermal system for indapamide. The in-vivo study was

conducted by comparing the pka parameters like Tmax, Cmax, Mean

residual time, AUC (0-t) and T1/2 with oral administration of indapamide.

Kulkarni RV et al.,2002,37 Monolithic matrix type transdermal drug

delivery systems of atomoxetine hydrochloride (A-HCl) were prepared

by the film casting on a mercury substrate and characterized by

physicochemical characteristics like thickness, weight variation, drug

content, flatness, folding endurance and in vitro drug release studies, ex-

vivo skin permeation studies.

Amit Misra et al.,1996,38 Which is the method of choice in the adhesive

tape industry.Three series of formulation of adhesive dispersion variety


LITERATURE REVIEW

were prepared and coated on to fabric.Uniformity of the thickness, weight

and content was estimated with in batches and between the batches.

Jain S et al.,2007,39 Matrix type transdermal drug delivery system of

haloperidol lactate was prepared using different ratios of ethyl cellulose:

polyvinyl pyrrolidone by solvent-evaporation technique. Physicochemical

parameters were characterized, and dissolution studies of the formulated

films were performed. In vitro permeation studies were done using

modified Franz diffusion cell through human cadaver skin utilizing 20%

PEG 400 in normal saline. Higuchi and Peppas models were used for

optimizing the formulation.

Wahid A et al.,2008,40 Ethosomal formulations were prepared using

lamivudine as model drug and characterized in vitro, ex vivo and in vivo.

Transmission electron microscopy, scanning electron microscopy, and

fluorescence microscopy were employed to determine the effect of

ethosome on ultra structure of skin. The optimized ethosomal formulation

showed 25 times higher transdermal flux (68.4 ± 3.5 μg/cm2/h) across the

rat skin as compared with that of lamivudine solution (2.8 ± 0.2

μg/cm2/h). The results of the characterization studies indicate that lipid

perturbation along with elasticity of ethosomes vesicles seems to be the

main contributor for improved skin permeation.

Nirvaseth et al.,2011,41 Designed and formulated transdermal drug

delivery of eugenol using HPMC, PVC, EC and glycerol is plasticizer.

Then it was evaluated in vitro release kinetics, drug release, skin

permeation studies.

Kelvin et al.,2009,42 Transdermal films of Diclofenac Sodium were

formulated by using natural polymer gelatin and plasticizer glycerin in

different proportion. The placebo and medicated films were evaluated for

physical and mechanical properties and also medicated films were

evaluated for area variation, drug content and percent cumulative drug

release. Optimized gelatin to glycerin ratio containing transdermal films

shown effective physical and mechanical property along with in vitro drug

release profile. The release rate was found to follow first order rate and


LITERATURE REVIEW

Higuchi model. Primary irritation study shows that the transdermal films

are non-irritant.

Manvi FV et al.,2003,43 Monolithic matrix transdermal system containing

tramadol HCl were prepared using various ratios of polymer blends of

HPMC and Eudragit S100 with triethyl citrate as a plasticizers. The

concentration of HPMC and Eudragit S100 were used as independent

variables, while drug was selected as dependent variables. In Vitro

diffusion studies were performed using cellulose acetate membrane (pore

size 0.45) in Franz diffusion cell. The concentration of diffused drug was

measured using UV-visible spectrophotometer at 272 nm. The

experimental result shows that the transdermal drug delivery system

containing Eudragit in higher proportion gives sustained release of drug.

Sanap GS et al.,2008,44 Formulated transdermal films of ketotifen

fumarate using combination of Eudragit L-100, hydroxypropyl methyl

cellulose and ethyl cellulose HPMC polymeric combinations plasticized

with polyethylene glycol 400. Effects of permeation enhancers like diethyl

sulphoxide and propylene glycol at different concentrations were studies

on skin permeation kinetics. It was concluded that above polymeric

combinations might be feasible for formulation rate controlled

Transdermal therapeutic system of Ketotifen Fumarate for effective

control and prophylaxis of allergic asthma.

Agrawal SS et al.,2008,45 Transdermal drug delivery systems of

indapamide have been formulated by using solvent casting method.

Monolithic systems were prepared by using hydroxy propyl methyl

cellulose (HPMC) and ethyl cellulose (EC) polymers by incorporating

glycerine and dibutyl phthalate as plasticizers, respectively. A total of

eight monolithic systems were prepared by using a drug polymer ratio of

1:4 and incorporated different vegetable oils as permeation enhancers in

different concentrations. The in vitro release studies revealed that the

release was sustained up to 24 h and it follows zero-order kinetics. All the

films were found to be stable at 37°C and 45°C with respect to their

physical parameters and drug content.


DRUG & EXCIPIENT PROFILE

DRUG PROFILE

LABETALOL 9

Synonyms : Labetalol Hcl, labetalol hydrochloride,

labetalolum Labrocol, trandate, presdate

Chemical Structure :

IUPAC name : (RS)-2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-

phenyl

propyl) amino] ethyl}benzamide

Chemical Formula : C19H24N2O3

Molecular weight : 328.406

Melting point (°C) : 1880C

Category : anti-hypertensive

Description : white powder.

Solubility : Freely soluble in Water & methanol, very slightly

soluble in Acetone

Storage : Store in tightly closed container

Pharmacokinetic and metabolism

Bioavailability (%) : 25%

Bound in plasma (%) :50%

Half life : 6-8hours

Vd (L/kg) :3-16L/kg

Cmax (ng/ml) : 300 mg/ml

Tmax(hrs) : 1.2

Log P : 3.09



Mechanism of action: Labetalol combines both selective, competitive,

alpha-1-adrenergic blocking and nonselective, competitive, beta-

adrenergic blocking activity in a single substance. In man, the ratios of

alpha- to beta- blockade have been estimated to be approximately 1:3 and

1:7 following oral and intravenous (IV) administration, respectively. The

principal physiologic action of labetalol is to competitively block

adrenergic stimulation of β-receptors within the myocardium (β1-

receptors) and within bronchial and vascular smooth muscle (β2-

receptors), and α1-receptors within vascular smooth muscle. This causes a

decrease in systemic arterial blood pressure and systemic vascular

resistance without a substantial reduction in resting heart rate, cardiac

output, or stroke volume, apparently because of its combined α- and β-

adrenergic blocking activity.

Pharmacokinetics: Labetalol is well absorbed from gastrointestinal tract

but it subjected to extensive first pass metabolism in liver; the absolute

bioavailability is about 25%. Peak plasma concentration occurs in 2 hrs

after drug administration. Volume of distribution of approximately 3-16

L/Kg& only50% bound to plasma proteins. It is extensively metabolized

in liver, the metabolites excreted mainly in urine. The elimination half-life

is about 5.5 h.

Metabolism: The metabolism of labetalol is mainly through conjugation

to glucuronide metabolites. These metabolites are present in plasma and

are excreted in the urine and, via the bile, into the feces. Approximately

55% to 60% of a dose appears in the urine as conjugates or unchanged

labetalol HCl within the first 24 hours of dosing.

Elimination: Total body Cl is 430 to 610 mL/min. Creatinine Cl is 5

mL/min.



DRUGINTERACTIONS

TOLAZAMIDE The beta-blocker, labetalol, may decrease symptoms of

Hyperglycemia.

TOBUTAMIDE The beta-blocker, Labetalol, may decrease symptoms of

Hyperglycemia

SALBUTAMOL Antagonism.

Food Interactions: Always take at the same time with respect to meals,

avoid alcohol, take with food.

Contraindications: obstructive air way disease, overt cardiac failure,

cardiogenic shock, severe bradycardia

Storage: Protect from moisture and sun light, stored below 400c.

Dose: 50, 100, 200 and 300.

EXCIPIENTS PROFILE

A. Review of polymers:

1. EUDRAGIT RLPO10

Nonproprietary name : Ammonio Methacrylate Copolymer(BP),

Methacrylic Acid Copolymer(USP-NF),

.

Synonym : Eastacryl; Eudragit,

Kollicoat MAE,

polyacrylatis Dispersio 30 per centum;

polymeric methacrylates.



Structural formula:

Where R1=H,CH3 ;R2=CH3,C2H5; R3=CH3

Chemical Name: Poly(ethyl acrylate, methyl methacrylate,

Trimethylammonioethyl methacrylate chloride) 1 : 2 :0.2.

Functional category: Coating agent, film-former, rate-controlling

polymer for sustained release, tablet binder, tablet diluent.

Molecular Weight : 32,000 g/mol

Description: Eudragit RLPO in form of white powder with a faint amine-

like odour

Density : 0.816-0.836 g/cm3

Solubility: Soluble in acetone, alcohols, dichloromethane and ethyl

acetate.Insoluble in water and petroleum ether

Stability and storage conditions:Eudragit RLPO powder is a stable at

temperature less than 30ºC. above this temperature powders tend to form

clumps. Eudragit RLPO powder should be stored in a well-closed

container, in a cool & dry place.

Applications:

Eudragit RLPO used to form water-insoluble film coats for sustained

release products.

Polymethcrylates are primarily used as oral capsule and tablet

formulations as film-forming agents.

Polymethacrylates are also used as binder in both aqueous & organic wet

granulation process.

Larger quantities (5-20%) of dry polymer are used to control the release of

an active substance from a tablet matrix.



2. EUDRAGIT RSPO11

Synonyms : Eudragit, poly methacrylates.

Structure:

R1 = H, CH3, R2 = CH3, C2H5, R3 = CH3

Molecular formula : (C5H8O2)n

Chemical name : Poly (ethyl acrylate, methyl methacrylate,

Trimethylammonio ethyl methacrylate chloride)

Fuctional category : 1. Film forming agent

2. In the preparation of sustained release dosag forms.

Molecular weight : 32,000 g/mol

Grades : Eudragit RSPO, Eudragit RS 12.5, E RS 100, EudragitRS 30D

Description : EUDRAGIT® RS PO is a copolymer of ethyl acrylate,

methyl methacrylate and a low content of methacrylic acid ester with

quaternary ammonium groups.The ammonium groups are present as salts

and make the polymers permeable. It is a solid substance in the form of

white powder with a faint amine – like odour.

Density : 0.816 to 0.836 G/cm3

Solubility: Soluble in methanol, ethanol, and isopropyl alcohol as well

as in acetone, ethyl acetate and ethylene chloride to give clear to

cloudysolutions.



Storage: Protect from warm temperature and moisture. Dry powders are

stable for atleast 3 years in tightly closed container at less than 30°C.

Safety : A daily intake of 2 mg/kg body weight of Eudragit may be

regarded as essentially safe in humans. It generally regarded as nontoxic

and nonirritant materials.

Incompatibilities: Incompatibilities occur with certain polymethacrylate

dispersion depending upon the ionic and physical properties of the

polymer & Solvent

Application : It is used to form water-insoluble films. Primarily used in

capsule and tablet formulations and transdermal delivery. It is also used as

binders in both aq. and organic wet granulation. Larger quantities (5-20%)

of dry polymer are used to control the release of active substance from a

tablet matrix. Solid polymers may be used in direct compression process

in quantities of 10-50%

B. Review of plasticizers:

POLY ETHYLENE GLYCOL-40010

Synonym : Carbowax,PEG,polyoxyethylene glycol.

Structural Formula:

Chemical Name: α-Hydro-ω-hydroxypoly (oxy-1,2-ethanediyl)

Molecular Formula: C16H22O4

Molecular Weight: 380-420

Category : Plasticizer, solvent, ointment base.

Description : It is a clear, colourless or slightly yellow-coloured,

viscous liquid.



Density : 1.120 g/cm3

Boiling Point : 330oC

Refractive Index : 1.465

Solubility : soluble in water, acetone, alcohols, benzene, glycerine

and insoluble in mineral oils.

Storage : It should be stored in a tightly-closed container.

C. Review of permeation enhancers

DIMETHYL SULFOXIDE10

It increases in drug penetration have been reported with dimethyl

sulfoxide concentrations as low as 15%, but significant increases in

permeability generally require concentrations higher than 60–

80%.Dimethyl sulfoxide is now incorporated into a number of regulated

products for healthcare and drug delivery applications,including

stabilizing product formulations, sustained-release applications,and for the

delivery of medical polymers.

Structural formula :

Chemical name : Sulfinylbismethane

Molecular formula : C2H6OS

Molecular weight : 78.13g/mol

Category : It is used as a penetration agent, solvent.

Description : It is colorless, viscous fluid.

Boiling point : 1890C



Solubility : It is miscible with water, alcohol, and ether.

Storage : It should be stored in air tight, light resistant container.


METHODOLOGY

4. MATERIALS AND EQUIPMENTS

Table No. 3: Materials Used:

Materials Source

LABETALOL

Yarochem pvt ltd,

MUMBAI.

EUDRAGIT RSPO Evonik Degussa (P)

Ltd.

EUDRAGIT RLPO Evonik Degussa (P)

Ltd.

PEG-400 Karnataka fine chem.

DMSOYarochem pvt ltd,

MUMBAI.


METHODOLOGY

Table No. 4: Equipments used:

Equipments Model/ Company

UV-Visible

Spectrophotometer

Shimadzu UV-VIS

Spectrophotometer.

UV – 1700, Japan.

Electronic Analytical

balanceShimadzu AUX-224

FTIRPerkin Elmer Spectrum

Gx

Melting point apparatus

DBK programmable Melting Point apparatus

pH meter 7007EUTECH Instruments,

pH tutor.

Humidity chamber Thermo lab.

Hot air ovenServe well instruments

Pvt LTD.

Franz diffusion cell Scientific works.

Screw gauge Bioaids Instruments.


METHODOLOGY

METHODOLOGY

Methods:

Analytical methods:

a) Determination of λmax:

100 mg of Labetalol was dissolved in 100ml 0.2Hydrochloric acid;

suitable dilutions were made and finally scanned for maximum

absorbance using U.V spectrophotometer (double beam) in the U.V.

rangefrom 200 to 400 nm. Averages of triplicate readings were taken.

b) Estimation of Labetalol:

In present study, the spectrophotometric method was adopted for the

estimation of Labetalol using double beam U.V. spectrophotometer.

c) Preparation of pH 7.4 phosphate buffer: Fifty ml of 0.2M potassium

dihydrogen phosphate was taken in 200 ml volumetric flask, to which

39.1 ml of 0.2 M sodium hydroxide solution was added and the volume

was made up to the mark with distilled water.

d) Preparation of Standard Stock Solution:

100 mg Labetalol drug was accurately weighed and transferred to 100 ml

of volumetric flask and the volume was made with 0.2 hydrochloric acid

to get stock solution of concentration 1000 µg/ml. 1 ml of this solution

was diluted to 100 ml which gives a stock solution of 10µg/ml. From the

resulting 10 µg/ml solution 10, 15, 20, 25, 30 ml diluted to 10ml, the

resulting solution gives the concentration 10-30 µg/ml. The absorbance of

the resulting solution was measured spectrophotometrically at 240 nm.


METHODOLOGY

Table.No.5. Spectrophotometric data for construction of standard

graph Labetalol

Concentration(µg/

ml) Absorbance

0 0

10 0.080±0.07

15 0.126±0.13

20 0.168±0.17

25 0.219±0.19

30 0.261±0.25

*n=3

Fig. No.6. standard graph of Labetalol HCL in 0.2M

Hydrochloric acid

5 10 15 20 25 30 350

0.05

0.1

0.15

0.2

0.25

0.3

f(x) = 0.00893999999999999 x − 0.0093999999999998R² = 0.999684798270893

Chart Title

Series2Linear (Series2)

Axis Title

Axis

Title


METHODOLOGY

Preformulation studies of the selected drug:

a) Solubility determination: The solubility of the selected drug was

determined in distilled water andphosphate buffer of pH 7.4 using

standard method.

Procedure

Excess amount of the selected drug was taken and dissolved in a

measuredamount of above solvents separately in a glass beaker to get a

saturated solution. Thesolution was shaken intermittently to assist the

attainment of equilibrium with theundissolved drug particles. Then

measured quantity of the filtered drug solution waswithdrawn after 24hrs

and successively diluted with respective solvents and theconcentration

was measured Spectrophotometrically. Averages of triplicate readings

weretaken.

b) Melting point determination: Melting point of the drug was

determined by taking a small amount of the drug inacapillary tube closed

at one end and was placed in Thiel’s melting point apparatus andthe

temperature at which the drug melts was noted. Averages of triplicate

readings were taken.

c) Partition coefficient:

A drug solution of 1mg/ml was prepared in n-octanol. 25ml of this

solution wastaken in a separating funnel and shaken with an equal volume

of phosphate buffer of pH7.4 (aqueous phase) for 10 minutes and allowed

to stand for two hrs. Then aqueous phase50 and organic phase were

collected separately and centrifuged at 2000 rpm. Both the phases were

analyzed for the drug concentration using U.V. spectrophotometer.

Partitioncoefficient was calculated by taking the ratio of the drug

concentration in n-octanol to drug concentration in aqueous phase.

Triplicate readings were taken.


METHODOLOGY

d) Permeability coefficient: The permeability coefficient of drug was

calculated by “Potts and Guy equation”,

Log Kp = -2.7 + 0.71 x log Ko/w – 0.0061 x Molecular weight

. Where,

Log Kp = Permeability coefficient

Ko/w = Partition coefficient

e) Infrared (IR) absorption spectroscopy:

To investigate any possible interaction between the drug and the utilized

polymers ( EudragitRLPO, RSPO), IR spectrum of pure drug (Labetalol)

and its physical mixture was carried by using FTIR the range selected was

from 400cm-1 to4000 cm-1

Preparation of transdermal films:

The matrix-type transdermal films containing Labetalol were

prepared by solvent casting method. Eudragit RSPO and RLPO were used

as polymers in the preparation of transdermal films. PEG-400 was used as

a plasticizer, DMSO was used as a penetration enhancer and aluminum

foil was used as backing membrane.24,26,39

Weighed required quantity of polymers and dissolved in 4 ml of solvent

mixture consisting of 1:1 ratio of Dichloromethane and Ethanol. The

polymeric solutions were kept a side for swelling. Then required quantity

of plasticizer and drug solution are added and vertexed for 10 minutes.

Further, it is set-a side for some time to exclude any entrapped air and is

then poured on to the mercury surface in a petriplate and this was kept a

side for solvent evaporation. The rate of solvent evaporation was

controlled by inverting a glass funnel over the petriplate. After overnight,

the dried films were cut into a 2 cm2 piece and stored in desiccators until

further use.


METHODOLOGY

Table No. 6: Formulation chart of Labetalol transdermal films

Formulatio

n Code

Amoun

t of

Drug

(mg)

% of Eudrag

it RSPO(mg)

% of Eudra

git RSPO

(mg)

PEG-

400(m

)

DMSO(l)

Amount

of

Solvent

(ml)

F1 168.8 160 120 0.75 1 4

F2 168.8 200 120 1 0.75 4

F3 168.8 160 160 1 0.5 4

F4 168.8 200 160 0.5 1 4

F5 168.8 200 200 0.75 0.5 4

F6 168.8 120 120 0.5 0.5 4

F7 168.8 120 160 0.75 0.75 4

F8 168.8 160 200 0.5 0.75 4

F9 168.8 120 200 1 1 4

Evaluation:

The prepared transdermal patches were evaluated for the following;

1. Physical appearance

2. Weight variation

3. Film Thickness

4. Folding endurance

5. Drug content uniformity

6. Percentage of moisture content

7. Percentage of moisture uptake


METHODOLOGY

8. In vitro drug diffusion studies

9. In vivo study includes:

a. Skin irritation test

10. Stability studies at different temperature (37˚C and 45˚C)

1. Physical appearance:

All the transdermal patches were visually inspected for color, clarity,

flexibilityand smoothness.

2. Weight Variation:

Weight variation was studied by individually weighing 3 randomly

selected films. Such determination was performed for each formulation.37,

38

3. Film Thickness:

The thickness of films was measured at three different places using a

Screw gauge and mean values were calculated.37, 38

4. Folding Endurance:

Folding endurance was determined by repeatedly folding the film at the

same place until it broke. The number of times the film could be folded at

the same place without breaking was the folding endurance value.37

5. Determination of Drug Content in the Film:

The uniformity of drug distribution was evaluated by determining drug

content of the film by a spectrophotometric method. A known weight of

film was dissolved and diluted subsequently with ethyl alcohol and the

concentration of Labetalol was spectrophotometrically measured at 302

nm against the blank ethyl alcohol solution containing the same amount of

polymer and plasticizer without drug.37

6. Percentage of Moisture Content:

The films were weighed individually and kept in desiccator

containing activated silica at room temperature for 24 h. Individual films

were weighed repeatedly until they showed a constant weight. The


METHODOLOGY

percentage of moisture content was calculated as the difference between

initial and final weight with respect to final weight.31

% Moisture content = Initial weight – Final weight X 100

Final weight

7. Percentage of Moisture Uptake:

A weighed film kept in a desiccator at room temperature for 24 h was

taken out and exposed to 84% relative humidity (a saturated solution of

aluminum chloride) in a desiccator until a constant weight for the film was

obtained. The percentage of moisture uptake was calculated as the

difference between final and initial weight with respect to initial weight.31

% moisture uptake = Final weight – Initial weight X 100

Initial weight

8. In Vitro Drug Diffusion Studies:

In vitro diffusion studies were performed by using a Franz diffusion cell

with a receptor compartment capacity of 140 ml. The dialysis membrane

was mounted between the donor and receptor compartment of the

diffusion cell. The film was placed on cellulose acetate membrane and

covered with aluminum foil. The receptor compartment of the diffusion

cell was filled with phosphate buffer pH 7.4. The whole assembly was

fixed on a hot plate magnetic stirrer, and solution in the receptor

compartment was constantly and continuously stirred using magnetic

beads and the temperature was mentioned at 37 ± 0.5°C. The samples

were withdrawn at different time intervals and analyzed for drug content

spectrophotometrically. The receptor phase was replenished with an equal

volume of phosphate buffer at each sample withdrawal. 25, 30, 31


METHODOLOGY

Fig.No.7: Invitro studies by using Franz diffusion cell

9. In-vivo studies:

a. skin irritation test: A primary skin irritation test was performed

since skin is vital organ through which drug is transported. Test was

carried out on healthy rabbits weighing 1.3 to 1.5 k.g. Drug free polymeric

film of diameter 4.1 cm were used as control. The dorsal surface of rabbit

was cleared well and the skin was cleared with rectified spirit. The

patches were applied to the shaved skin of rabbits and secured using

adhesive tape USP. On one side the back control patche (with out

drug,group1) and other side an experimental patch( group II) were

secured. A 0.8%v/v aqeous solution of formaldehyde was applied as a

standard irritant(group III) and its effect was compared with test.The

animal were observed for any size of erythema or odema for a period of 7

days.

10. Stability Studies:

The purpose of stability testing is to provide evidence on how the quality

of a drug substance or drug product varies with time under the influence

of a variety of environmental factors such as temperature, humidity and

light and to establish a re-test period for the drug substance or a shelf life

for the drug product and recommended storage conditions. To assess the

drug and formulation stability, stability studies were done according to

ICH guidelines Q1C.

Stability studies were carried out on the films of most satisfactory as per

ICH Guidelines Q1C. The most satisfactory formulation stored in sealed


METHODOLOGY

in aluminum foil. These were stored at room temperature for 2 months.

Films were evaluated for In vitro drug release, In vivo diffusion study and

various physical characteristics.52


RESULTS AND DISCUSSION

5. RESULTS

Table No. 7: Preformulation studies of Labetalol

s.no Drug

name

Melting

point(0C)

Solubility

(mg/ml)

Partitioncoefficient (P) Log P

Water Buffer

pH 7.4

Amount in

aqueous

phase

(mg/ml)

Amount in

octonolol

(mg/ml)

1 Labetalol 201.5 0.588 0.125 61.42 39.88 3.09



Labetalol pure

Fig.No.8: FTIR Spectrum of Labetalol



RSPO+drug

Fig.No.9: FTIR Spectrum of physical mixture of drug with Eudragit-RSPO



RLPO+drug

Fig.No.10: FTIR Spectrum of physical mixture of drug with Eudragit-RLPO



Table No. 9: Physicochemical parameters of prepared formulations F1-F9

Formulation

code

Weight

variation

(mg)

Film

thickness

(mm)

Folding

endurance

% Conten

t

uniformity

% Moisture

content

% Moisture

uptake

F1 267±0.0430.27 ±

0.01103± 0.9 95.6± 2.5 2.13 ± 1.42 1.21 ± 1.58

F2308±

0.026

0.21 ± 0.0

3116 ± 2.1 96.5± 7.6 1.98 ± 2.42 1.59 ± 1.01

F3301±

0.068

0.24 ± 0.0

6107 ± 10 97.6± 2.9 1.99 ± 0.53 1.67 ± 0.44

F4 344±0.0050.21 ± 0.0

1114± 4 95.7± 5.6 1.84 ± 0.31 1.25 ± 2.07

F5 384 ±0.010.29 ± 0.0

4123 ± 2 97.0± 0.9 1.15 ± 1.25 3.66 ± 0.96

F6232±

0.047

0.20 ± 0.0

497 ± 7 99.1 ± 6.8 1.67± 0.37 1.65 ± 1.29

F7 273±0.015 0.17 ± 0.0 114 ± 1.5 96.8± 4.6 1.59 ±1.27 1.25 ± 2.42



1

F8 340±0.0300.21 ± 0.0

1108 ± 3 98.3± 5.8 1.54± 0.61 1.34 ± 0.91

F9 312±0.020.23 ± 0.0

2105 ± 1.6 97.5± 6.5 1.64± 0.24

1.94 ±

0.71

n=3

Fig .No.11: Drug content

f1 f2 f3 f4 f5 f6 f7 f8 f993

94

95

96

97

98

99

100

Series1

IN VTRO DIFFUSION STUDY:



In vitro diffusion studies of Labetalol transdermal films were carried

out by using dialysis membrane and diffusion cell in PBS pH 7.4

solution. The release data were given in the Tables 9 to 17 respectively for

formulation F1 to F9.

Table No.10:Comparative data of percentage drug release from the formulations F1 to F9



Fig. No. 12: Comparative In-vitro diffusion study of formulation F1-F5


Time(hr) f1 f2 f3 f4 f5 f6 f7 f8 f9

0 0 0 0 0 0 0 0 0 0

1 4.193 6.896 3.261 6.057 2.236 3.261 3.448 8.014 9.132

2 8.137 8.995 8.689 8.616 5.420 5.428 5.70910.21

410.03

6

311.92

2 9.71110.98

810.82

1 7.043 6.771 6.58812.71

013.36

9

416.38

713.97

3 12.9312.94

7 9.143 8.683 9.15118.29

818.30

9

518.18

018.17

218.23

917.69

811.81

713.96

313.96

820.75

721.88

6

623.06

121.18

922.74

820.24

612.92

617.78

917.60

828.07

828.00

4

727.60

225.15

828.31

225.79

218.42

118.47

318.57

033.30

734.07

1

828.91

328.12

931.12

028.86

220.69

322.51

622.24

137.82

739.34

2

933.77

430.93

437.20

832.88

322.70

225.65

525.28

541.25

944.79

2

1037.17

737.11

343.15

136.65

326.68

027.79

127.88

447.78

946.82

3

1141.72

038.86

147.27

239.88

830.59

332.27

032.08

454.73

655.34

7

1245.54

945.74

554.68

146.96

635.83

750.01

250.75

763.31

563.55

7

2485.65

489.85

992.14

887.17

580.25

690.05

993.04

695.62

297.26

4


0 5 10 15 20 25 300

102030405060708090

100

f1f2f3f4f5

Time(hr)

%DR

Fig. No. 13: Comparative In-vitro diffusion study of formulation F6-

F9

0 5 10 15 20 25 300

20

40

60

80

100

120

f6F7F8F9

time

%cd

r

Kinetics of drug release:

Table No. 11: comparison of zero order of in vitro drug release F1-F9



Time(hr) f1 f2 f3 f4 f5 f6 f7 f8 f9

1 4.193 6.896 3.261 6.057 2.236 3.261 3.448 8.014 9.132

2 8.137 8.995 8.689 8.616 5.420 5.428 5.709 10.214 10.036

3 11.922 9.711 10.988 10.821 7.043 6.771 6.588 12.710 13.369

4 16.387 13.973 12.93 12.947 9.143 8.683 9.151 18.298 18.309

5 18.180 18.172 18.239 17.698 11.817 13.963 13.968 20.757 21.886

6 23.061 21.189 22.748 20.246 12.926 17.789 17.608 28.078 28.004

7 27.602 25.158 28.312 25.792 18.421 18.473 18.570 33.307 34.071

8 28.913 28.129 31.120 28.862 20.693 22.516 22.241 37.827 39.342

9 33.774 30.934 37.208 32.883 22.702 25.655 25.285 41.259 44.792

10 37.177 37.113 43.151 36.653 26.680 27.791 27.884 47.789 46.823

11 41.720 38.861 47.272 39.888 30.593 32.270 32.084 54.736 55.347

12 45.549 45.745 54.681 46.966 35.837 50.012 50.75763.315

4 63.557

24 85.654 89.859 92.148 87.175 80.256 90.059 93.04695.622

7 97.264

Fig. No. 14:comparison of zero order of in vitro drug release F1-F5



0 5 10 15 20 25 300

102030405060708090

100

zero order

f1f2f3f4f5

Time(hr)

%cd

r

Fig. No. 15:comparison of zero order of in vitro drug release F5-F8

0 5 10 15 20 25 300

20

40

60

80

100

120

zero order

f6F7F8F9

time

%cd

r



Table No. 12: comparison of Firstorder of in vitro drug release F1-F9

Time(hr)

F1 F2 F4 F5 F6 F7 F8 F9

1 1.973 1.961 1.965 1.984 1.979 1.979 1.952 1.948

2 1.955 1.952 1.953 1.969 1.969 1.968 1.943 1.944

3 1.937 1.947 1.943 1.962 1.962 1.963 1.929 1.927

4 1.914 1.927 1.931 1.952 1.954 1.952 1.903 1.903

5 1.904 1.904 1.909 1.939 1.928 1.928 1.888 1.883

6 1.878 1.890 1.893 1.934 1.909 1.909 1.847 1.847

7 1.851 1.866 1.864 1.906 1.905 1.905 1.812 1.810

8 1.845 1.851 1.846 1.894 1.883 1.886 1.783 1.773

9 1.817 1.833 1.821 1.885 1.866 1.869 1.761 1.736

10 1.794 1.795 1.796 1.861 1.855 1.855 1.716 1.719

11 1.762 1.783 1.775 1.837 1.825 1.830 1.645 1.646

12 1.735 1.734 1.724 1.805 1.698 1.692 1.564 1.570

24 1.159 1.010 1.108 1.295 0.997 0.838 0.661 0.438s



Fig. No.16: comparison of Firstorder of in vitro drug release F1-F5

0 5 10 15 20 25 300

0.5

1

1.5

2

2.5

f(x) = − 0.0284763996138422 x + 2.08718366466246R² = 0.899227687008401f(x) = − 0.0359784016400436 x + 2.09259985579111R² = 0.918201860280524f(x) = − 0.0455148375726418 x + 2.13227571410842R² = 0.923194672530634f(x) = − 0.0394038289873515 x + 2.11367182659306R² = 0.889587596879513f(x) = − 0.0338353537414168 x + 2.07551385450958R² = 0.932230901925438

first order

f1Linear (f1)f2Linear (f2)f3Linear (f3)f4Linear (f4)f5Linear (f5)

Time(hr)

log

of re

mai

ng

Fig. No.17: comparison of First order of in vitro drug release F6-F9

0 5 10 15 20 25 300

0.5

1

1.5

2

2.5

f(x) = − 0.0631581470083122 x + 2.19934090029599R² = 0.894076399748058f(x) = − 0.0548347662809895 x + 2.15415480789699R² = 0.920493332602919f(x) = − 0.0468098498122515 x + 2.18114829898843R² = 0.847497953032005f(x) = − 0.0407736577911099 x + 2.14563658482255R² = 0.871741137972752

first order

f6Linear (f6)f7Linear (f7)f8Linear (f8)f9Linear (f9)

time

log

of re

mai

ng



Table No. 13: comparison of Higuchi model of in vitro drug release F1-F9

SQRT of time F1 F2 F3 F4 F5 F6 F7 F8 F9

1 4.193 6.896 3.261 6.057 2.236 3.261 3.448 8.014 9.132

1.414 8.137 8.995 8.689 8.616 5.420 5.428 5.709 10.214 10.036

1.732 11.922 9.711 10.988 10.821 7.043 6.771 6.588 12.710 13.369

2 16.387 13.973 12.93 12.947 9.143 8.683 9.151 18.298 18.309

2.236 18.180 18.172 18.239 17.698 11.817 13.963 13.968 20.757 21.886

2.449 23.061 21.189 22.748 20.246 12.926 17.789 17.608 28.078 28.004

2.645 27.602 25.158 28.312 25.792 18.421 18.473 18.570 33.307 34.071

2.828 28.913 28.129 31.120 28.862 20.693 22.516 22.241 37.827 39.342

3 33.774 30.934 37.208 32.883 22.702 25.655 25.285 41.259 44.792

3.162 37.177 37.113 43.151 36.653 26.680 27.791 27.884 47.789 46.823

3.316 41.720 38.861 47.272 39.888 30.593 32.270 32.084 54.736 55.347

3.464 45.549 45.745 54.681 46.966 35.837 50.012 50.757 63.315 63.557

4.898 85.654 89.859 92.148 87.175 80.256 90.059 93.046 95.622 97.264



Fig.No.18: comparison of Higuchi model of in vitro drug release F1-F5

0 10 20 30 40 50 60 70 80 900

102030405060708090

100

f(x) = 0.808724887695931 xR² = 0.97716337881528f(x) = 0.808724887695931 xR² = 0.97716337881528

f(x) = 0.993140593634322 xR² = 0.997801297834615

f(x) = 1.09332492112834 xR² = 0.996066053899067f(x) = 0.998222357713358 xR² = 0.996226955402873

higuchif1f2Linear (f2)f3Linear (f3)f4Linear (f4)f5Linear (f5)Linear (f5)

SQRT(Time)

%CD

R

Fig. No. 19: comparison of Higuchi model of in vitro drug release F6-F9

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.50

20

40

60

80

100

120

f(x) = 15.3391360181027 xR² = 0.943831257999233f(x) = 15.0549920246767 xR² = 0.941333868313028f(x) = 11.0759719347602 xR² = 0.82341535362968f(x) = 10.918805333017 xR² = 0.832629225750772

HIGUCHI

f6Linear (f6)f7Linear (f7)f8Linear (f8)f9Linear (f9)

SQRT

%CD

R



Table No. 14: comparison of Korsmeyers-peppasequation of in vitro drug release F1-F9

Log T f1 f2 f3 f4 f5 f6 f7 f8 f9

0 0.769 0.924 0.708 0.882 0.546 0.671 0.669 1.019 1.048

0.301 0.991 1.016 1.027 1.007 0.828 0.836 0.843 1.085 1.079

0.477 1.128 1.052 1.101 1.087 0.915 0.915 0.903 1.174 1.187

0.602 1.253 1.189 1.161 1.161 1.011 0.999 1.013 1.297 1.301

0.698 1.293 1.294 1.297 1.275 1.116 1.181 1.178 1.355 1.373

0.778 1.388 1.347 1.385 1.335 1.148 1.275 1.273 1.470 1.471

0.845 1.461 1.423 1.469 1.428 1.289 1.290 1.290 1.545 1.548

0.903 1.476 1.462 1.504 1.473 1.334 1.370 1.363 1.593 1.608

0.954 1.536 1.502 1.582 1.527 1.366 1.423 1.414 1.625 1.657

1 1.576 1.574 1.642 1.573 1.435 1.453 1.452 1.680 1.677

1.041 1.624 1.594 1.678 1.605 1.494 1.520 1.509 1.746 1.745

1.079 1.658 1.660 1.735 1.672 1.558 1.699 1.705 1.801 1.798

1.380 1.932 1.953 1.964 1.940 1.904 1.954 1.968 1.979 1.987



Fig. No. 20: comparison of Korsmeyers-peppasequation of in vitro drug release F1-F5

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60

0.5

1

1.5

2

2.5

f(x) = 0.963951071972092 x + 0.48086707039718R² = 0.979570710331028f(x) = 0.800910507725789 x + 0.762657279164125R² = 0.964759319647131f(x) = 0.930909370689302 x + 0.684021383514926R² = 0.986865488590058f(x) = 0.777195841176939 x + 0.782968970547218R² = 0.95124255895885f(x) = 0.843350654046961 x + 0.738834617172486R² = 0.996312327445671

peppasf1Linear (f1)f2Linear (f2)f3Linear (f3)f4Linear (f4)f5Linear (f5)

Log T

log

of cd

r

Fig. No. 21: comparison of Korsmeyers-peppasequation of in vitro drug release F6-F9

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60

0.5

1

1.5

2

2.5

f(x) = 0.772333661668658 x + 0.901261654264482R² = 0.951921659685113f(x) = 0.781662934323325 x + 0.885531212475262R² = 0.956518551842836f(x) = 0.964868740645544 x + 0.529226846095218R² = 0.951326310281287f(x) = 0.962043277889753 x + 0.531734506961068R² = 0.953896166084995

peppas

f6Linear (f6)F7Linear (F7)F8Linear (F8)F9Linear (F9)

log t

log

of cd

r



Table No. 15:Comparison of orders of in vitro release of Labetalol from the formulation F1 to F9.

KINETIC VALUES OBTAINED FROM THE FORMULATION F1-F9:Formulation Zero – order First – order Higuchi Peppas

R2 K R2 K R2 R2 N

F1 0.996 3.680 0.932 0.075 0.928 0.996 0.84

F2 0.994 3.68 0.889 0.089 0.989 0.951 0.77

F3 0.986 4.024 0.923 0.103 0.988 0.986 0.93

F4 0.995 3.659 0.918 0.082 0.993 0.964 0.80

F5 0.965 2.99 0.899 0.064 0.948 0.979 0.96

F6 0.947 3.409 0.871 0.092 0.629 0.953 0.96

F7 0.939 3.471 0.847 0.105 0.616 0.951 0.96

F8 0.959 4.448 0.920 0.124 0.800 0.956 0.78

F9 0.959 4.526 0.894 0.145 0.811 0.951 0.77

HALF – LIFE VALUES OBTAINED FOR THE FORMULATIONS F1 TO F9

Formulation Zero – order First – order

K t1/2 (hrs.) K t1/2 (hrs.)

F1 3.680 22.9 0.075 9.24F2 3.68 22.9 0.089 7.786F3 4.024 20.9 0.103 6.72F4 3.659 23.06 0.082 8.45F5 2.99 28.22 0.064 10.82F6 3.409 24.75 0.092 7.53F7 3.471 24.31 0.105 6.6F8 4.448 18.9 0.124 5.58F9 4.526 18.6 0.145 4.7

Response 1: Folding endurance



Table No. 16: ANOVA for Response Surface linear Model :

source

Sum of

squraes Df

Mean

squares F VALUE

P-Value

Prob>F

Model 495.333 6 82.555 6.816 0.133

A-RSPO 321.555 2 160.777 13.275 0.070

B-RLPO 69.555 2 34.777 2.871 0.258

C-DMSO 104.222 2 52.111 4.302 0.188

Residual 24.222 2 12.111 - -

Cor Total 519.555 8 - - -

Table No.17: Estimated Regression Coefficients:

Factor Coefficient estimate Standard DF

A-1 -3.888 1

A-2 -4.555 1

B-1 -3.888 1

B-2 2.444 1

C-1 -4.222 1

C-2 4.111 1

Final Equation in Terms of Coded Factors: Coded factor for folding

endurance=109.22-3.88*A[1]-4.55*A[2]-3.88*B[1]-2.44*B[2]- 4.22*C[1]+4.11C[3]

Fig. No.22. Correlation between actual and predicted values for Folding

endurance (R1)



Design-Expert® Softwarefolding endurance

Color points by value offolding endurance:

123

97

Actual

Pre

dic

ted

Predicted vs. Actual

95.00

100.00

105.00

110.00

115.00

120.00

125.00

95.00 100.00 105.00 110.00 115.00 120.00 125.00

Fig. No.23. 3-D graph showing effect of Eudragit-RSPO,RLPO and

DMSO and Poly Ethylene Glycol Folding endurance (R1)

Design-Expert® SoftwareFactor Coding: Actualfolding endurance

Design points below predicted value

X1 = A: RSPOX2 = B: RLPO

Actual FactorsC: DMSO = 0.5D: PEG-400 = 0.5

120

160

200

120

160

200

80

90

100

110

120

fo

ldin

g e

nd

ura

nc

e

A: RSPO B: RLPO





X1 = C: DMSOX2 = D: PEG-400

Actual FactorsA: RSPO = 120B: RLPO = 120

0.5

0.75

1

0.5

0.75

1

80

90

100

110

120

fo

ldin

g e

nd

ura

nc

e

C: DMSO D: PEG-400



X1 = B: RLPOX2 = C: DMSO

Actual FactorsA: RSPO = 120D: PEG-400 = 0.5

0.5

0.75

1

120

160

200

80

90

100

110

120

fo

ldin

g e

nd

ura

nc

e

B: RLPO C: DMSO



Response 2: Drug Release at 4th hr.

Table No. 18:ANOVA for Response Surface Linear Model:

Source

Sum of

squares Df

Mean

square F-value

P-value

Prob>F

Model 51.074 6 8.512 0.234 0.9294

A-RSPO 30.288 2 15.144 0.417 0.7054

B-RLPO 11.527 2 5.763 0.158 0.8629

C-DMSO 9.258 2 4.629 0.1276 0.8868

Residual 72.529 2 36.264 - -

Cor Total 123.603 8 - - -

Table No. 19: Estimated Regression Coefficients:

FACTOR COEFFICIENT

ESTIMATE

STANDARD DF

A[1] -1.204 1

A[2] 2.592 1

B[1] -0.354 1

B[2] 1.528 1

C[1] -0.041 1

C[2] 1.262 1

Final Equation in Terms of Coded Factors:coded factor for 4th hr release=14.77-

1.204*A[1]+2.59*A[2]-0.35*B[1]+1.52*B[2]-0.04*C[1]+1.26*C[2]



Fig. No.24. Correlation between actual and predicted values for Drug

Release at 4thhr (R2)

Design-Expert® Softwaredrug release 4th hr

Color points by value ofdrug release 4th hr:

20.01

9.9

Actual

Pre

dic

ted


8.00

10.00

12.00

14.00

16.00

18.00

20.00

22.00

8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00


DMSO, Poly Ethylene Glycol Drug Release at 4thhr (R2)

Design-Expert® SoftwareFactor Coding: Actualdrug release 4th hr




120

160

200

120

160

200

-10

0

10

20

30

40

d

rug

re

lea

se

4th

hr

A: RSPO B: RLPO







0.5

0.75

1

120

160

200

-10

0

10

20

30

40

d

rug

re

lea

se

4th

hr

B: RLPO C: DMSO





0.5

0.75

1

0.5

0.75

1

-10

0

10

20

30

40

d

rug

re

lea

se

4th

hr

C: DMSO D: PEG-400




Table No. 20: ANOVA for Response Surface Linear Model:


Final Equation in Terms of Coded Factors: coded factor for12th hr

release=50.51+3.75*A[1]+3.855*A[2]-3.41*B[1]+3.88*B[2]+2.92*C[1]-

2.64*C[2]


SourceSum of squares Df

Mean square F- value

p-valueProb>F

Model 388.486 6 64.747 0.679 0.698A-RSPO 260.695 2 130.347 1.367 0.422B-RLPO 80.962 2 40.481 0.424 0.701C-DMSO 46.828 2 23.414 0.245 0.802Residual 190.602 2 95.301 - -Cor Total 579.088 8 - - -

FACTOR COEFFICIENT

ESTIMATE

STANDARD DF

A[1] 3.755 1

A[2] 3.855 1

B[1] -3.411 1

B[2] 3.888 1

C[1] 2.922 1

C[2] -2.644 1



Release at 12th hr (R3)



63.3

36.1

Actual

Pre

dic

ted


35.00

40.00

45.00

50.00

55.00

60.00

65.00

35.00 40.00 45.00 50.00 55.00 60.00 65.00


DMSO, Poly Ethylene Glycol Drug Release at 12thhr (R3)





120

160

200

120

160

200

0

20

40

60

80

100

d

rug

re

lea

se

12

th h

r

A: RSPO B: RLPO







0.5

0.75

1

120

160

200

0

20

40

60

80

100

d

rug

re

lea

se

12

th h

r

B: RLPO C: DMSO





0.5

0.75

1

0.5

0.75

1

0

20

40

60

80

100

d

rug

re

lea

se

12

th h

r

C: DMSO D: PEG-400




Table No. 22:ANOVA for Response Surface Linear Model:

Source

Sum of

squares Df

Mean

square F value

p-value

prog>f

Model 143.763 6 23.960 0.630 0.720

A-RSPO 95.095 2 47.547 1.250 0.444

B-RLPO 21.691 2 10.845 0.285 0.778

C-DMSO 26.976 2 13.488 0.354 0.738

Residual 76.035 2 38.017 - -

Cor Total 219.799 8 - - -


FACTORS COEFFICIENT

ESTIMATE

STANDARD DF

A[1] 3.413 1

A[2] 0.96 1

B[1] -1.62 1

B[2] 2.093 1

C[1] 0.813 1

C[2] -2.406 1

Final Equation in Terms of Coded Factors:Coded factor for drug

release=90.04+3.14*A[1]+0.96*A[2]-1.62B[1]+2.093*B[2]+0.813*C[1]-

2.40*C[2]S




Release at 24th hr (R4)



97.2

80.2

Actual

Pre

dic

ted


80.00

85.00

90.00

95.00

100.00

80.00 85.00 90.00 95.00 100.00

Fig. No.29.3-D graph showing effect of Eudragit-RSPO, RLPO and

DMSO Poly Ethylene Glycol Drug Release at 24thhr (R4)





120

160

200

120

160

200

60

70

80

90

100

110

d

rug

re

lea

se

24

th h

r

A: RSPO B: RLPO







0.5

0.75

1

120

160

200

60

70

80

90

100

110

120

d

rug

re

lea

se

24

th h

r

B: RLPO C: DMSO





0.5

0.75

1

0.5

0.75

1

60

70

80

90

100

110

120

d

rug

re

lea

se

24

th h

r

C: DMSO D: PEG-400



5.5. Optimized formula:

Table No. 24: Composition of the optimized formula:

Ingredients R

labetalol 0.168

Eudragit-RSPO 0.160

Eudragit-RLPO 0.160

DMSO 1

PEG-400 0.5

All the quantities expressed are in gm but DMSO and PEG in ml

Table No. 25: Response variables of optimized formula:

Formulation Code Folding endurance

Optimized Formula 107 ± 10

Table No. 26: Data of various parameters of model fitting for

Labetalol for optimized formulation:

Zero order First order Higuchi Korsmeyer-

Peppas

0.986 0.923 0.957 0.986



Table No. 27:Drug release studies of optimized formula(F3):

Time (hrs) % CDR

0 0

1 3.261

2 8.689

3 10.988

4 12.34

5 18.239

6 22.748

7 28.312

8 31.120

9 37.208

10 43.151

11 47.272

12 54.370

24 93.231



Fig. No.30.Zero order kinetics of optimized formula:

0 5 10 15 20 25 300

102030405060708090

100f(x) = 4.02040819920243 x + 0.0516716773322372R² = 0.985981890305445

zero order

zero orderLinear (zero order)

Time(hr)

%cd

r

Fig. No.31.First order kinetics of optimized formula:

0 5 10 15 20 25 300

0.5

1

1.5

2

2.5

f(x) = − 0.0455148375699973 x + 2.13227571405835R² = 0.92319467284128

first order

first orderLinear (first order)

Time

log

of re

mai

ng



Fig. No 32.Higuchi plot for optimized formula:

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.50

102030405060708090

100

f(x) = 23.3025938182498 x − 29.614094964659R² = 0.957166993904025

Higuchi

HiguchiLinear (Higuchi)

SQRT(Time)

%cd

r

Fig. No.33.Korsmeyer-Peppas plot for optimized formula

Table No. 28.Comparison between the experimental (E) and predicted (P) values

for the optimal formulation

Optimize

d formula

Drug release

at 4thhr (%)

Drug release

at 12thhr

Drug release

at 24thhr

Folding

endurance



(%) (%)

Pred. 17.674 57.977 94.686 107.22

Exp. 15.314 54.681 92.331 107.122

8)

Stability study:

STABILITY STUDY OF MOST OPTIMIZED FORMULATION

Table No. 29. Physicochemical properties of most satisfactory formulations

(After stability)


0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60

0.5

1

1.5

2

2.5

f(x) = 0.930909370661006 x + 0.684021383517411R² = 0.986865488576466

peppas

peppasLinear (peppas)

LOG T

log

cdr

Formulation code F3

Time (Days) 30 60

Folding

endurance*

A 111.66 ±7.6 112 ± 11.01

% Content

uniformity*

A 96.04 ± 0.15 94.19 ± 2.92

% Moisture

content*

A 1.99 ± 0.53 1.42 ± 0.91

% Moisture

uptake*

A 1.67 ± 0.47 1.47± 0.42


Where A: 40°C±2°C/75%±5% RH.*n = 2

Table No. 28:In vitro drug diffusion studies of most satisfactory

formulations

(After stability)

W he

re A:

40°C±2°C/75%±5% RH.


Formulation codeF3

30Days 60 Days

A A

% C

umul

ativ

e dr

ug d

iffus

ion

± SD

1 5.111 3.261

2 10.643 8.689

3 12.634 10.988

4 14.489 12.34

5 19.516 18.237

6 24.285 22.748

7 29.458 28.312

8 31.968 31.120

9 38.196 37.208

10 43.922 43.151

11 47.699 47.272

12 54.681 54.370

24 92.176 92.176


0 5 10 15 20 25 300

102030405060708090

100

30days60days

time

%cd

r

Fig.No.34: %cumulative drug permeation Vs time profile of most satisfactoryFormulationF3(After stability)

6. DISCUSSION:

The pure drug Labetalol which was obtained as a gift sample from

Yarochem pvt(ltd), Mumbai, was used in the present investigation. In the

first phase of ourstudy the drug was subjected to various Preformulation

parameters namely solubility, melting point, partition coefficient (aqueous

& octonolol), permeability coefficient. The results are shown in table 7.

The solubility of drug in water and buffer of pH 7.4, melting point,

partitioncoefficient and permeability coefficients were found to be 0.588

mg/ml, 0.125 mg/ml, 201.50C, 61.42 mg/ml, 39.88 mg/ml and

3.09respectively. The λmax of the selected drug found to be 232 nm and it

wasused throughout the study for the estimation of drug in the

formulations.

The peaks observed in the Table No.8 can be considered as

characteristic peaks of Labetalol. These peaks were not affected and

prominently observed in IR spectra of Labetalol along with polymers as



shown in Figures 8 to 10. This indicates there is no interaction between

Labetalol and polymers.

Transdermal patches of Labetalol were prepared successfully

by solvent casting method using different polymers ( Eudragit

RSPO,RLPO) in different combinations and proportions. PEG used as a

plasticizer, DMSO used as permeation enhancer.

Physicochemical properties

The films prepared by general procedure were evaluated for the following

properties:

Weight Variation Test:

The results of weight variation test for various transdermal films are

shown in Table No. 9.weight variation of the developed formulation F1 to

F9 varied from 0.232 to 0.340 mg. Results of weight variation test

indicated uniformity in weight of patches, as evidenced by SD values.

Thickness Variation Test:

Thickness of the developed formulations F1 to F9 varied from 0.21 to

0.29 mm andwas found to be uniform. The thickness increased with

increase in RLPOandRSPO concentration. The SD values were less than

11 for all formulations, an indication of more uniform patches (Table No.

9).

Folding endurance:

Folding Endurance of the developed formulations F1 to F9 varied from 95

to 123. Folding Endurance of the film increases with increase in the

Eudragit proportion.



Drug content uniformity:

Good uniformity in drug content was observed in all transdermal

patches as evidenced by Table No.9. The drug content is ranged from 94.6

to 99.03%. From the results obtained (i.e., lowest SD values), it was clear

that there was proper distribution of Labetalolin the film formulations.

Hence it was concluded that drug was uniformly distributed in all the

formulations.

Moisture content test:

Moisture contentof the developed formulations F1 to F9 varied

from 2.13to 1.15%. The formulations F1 which is having high moisture

absorption was found to be 2.13%. The formulations F5 which is having

less moisture absorption was found to be 1.15%.Theresultsrevealed

thatthemoisturecontentwasfoundto increasewithincreasing concentration

o f lipophilic polymer(RLPO,RSPO).The moisture content of the prepared

formulations was low, which could help the formulations remain stable

and reduce brittleness during long term storage.

Moisture uptake test:

Moisture uptakeof the developed formulations F1 to F9varied from

3.36 to 1.25%. The formulations F5 which is having high moisture

content was found to be 3.36%. The formulations F7 which is having less

moisture absorption was found to be 1.25%.so that based on results

increasing the lipophillic polymer concentration(RSPO) moisture uptake

was increases.The moisture uptake of the formulations was also low,



which could protect the formulations from microbial contamination and

reduce bulkiness.

In-vitro Drug Release Studies from Transdermal Patches:

Fig.No.12, 13.Show the release profile of Labetalol from the transdermal

patches. Formulation F8 and F9 exhibits greatest(95%,97%) percentage

of drug release values (Table no.10),when increasing the concentration

of the RSPO releasing property of following formulation are

decreases(F5, and F1,F4).In these present observed that depending on

the concentration RLPO the releasing of the drug is substantially

increased. And based on the kinetics(zero order, first order, higuchi and

Peppas).Higuchi most appropriate model to describe the kinetics from all

patches. The ‘n’ value(0.77,< n> 0.96) it indicates that amount of released

drug was by non-fickian diffusion

Skin irritation test: A primary skin irritation test of patch formulation 3

on rabbit was studied. No signs of erythema, oedema or ulceration were

observed on the skin of albino rabbits after 7 days.

Stability Study:

Stability studies were carried out on most satisfactory formulation

as per ICH Guidelines Q1C. The most satisfactory formulation was sealed

in aluminum foil and stored in stability chamber. These were stored at

room temperature for 2 months, after 2 months drug content of most

satisfactory formulation was determined by method discussed previously

in entrapment efficiency section. Tables 29 showed that there were no



significant changes found in physicochemical parameters and in vitro

diffusion of the most satisfactory formulations (F3) after stability study.


CONCLUSION

7. CONCLUSION:

The present investigation is concern with the development of the

transdermal films and to increase the bioavailability of the drug and its

half life.

The following conclusions were drawn from results obtained;

1) A suitable method of analysis of Labetalol by UV Spectroscopy was

developed. Labetalol showed maximum absorption at wave length 232nm

in 0.2hcl. The value of regression coefficient of standard curve was found

to be 0.997 which showed linear relationship between concentration and

absorbance. Preformulation studies for drug-polymer compatibility by

FTIR gave confirmation about their purity and showed no interaction

between the drug and selected polymers.

2) Various formulations were developed by using release rate controlling

polymers like Eudragit-RSPO RLPO in combination by solvent casting

method to these formulation following evaluation are conducted required

physicochemical properties such as drug content uniformity,folding

endurance, weight uniformity,thickness uniformity, moisture content

&moisture uptake .

3) From the results of the drug content determination, it shows that drug was

proper distribution of drug in films and deviations are within the

level.Optimized Formulation F3(Eudragit RSPO-0.120 RLPO-0.160) was

found to be best among all batches of its consistent release rate for 24 hrs

and the extent of drug release 94.20%.

4) Graphical treatment of F5 according to Higuchi’s equation has shown the

drug release was diffusion mediated.Primary skin irritation studies

revealed that the formulation F3 has shown no erythema and edema.

5) Stability study of the formulations showed no significant changes in the

drug content as well as physical characteristics of the film.


CONCLUSION

It is concluded from the present studies that the transdermal patches of

Labetalol are capable of exhibiting controlled release with thestability and

the formulation F3 EudragitRSPO,RLPO (1:9%) has fulfilled the

objectives of the present study like reduction in the frequency of

administration, improved patient compliance.

Studies have shown promising results, and there is a scope for

furtherpharmacodynamic and pharmacokinetic evaluation. There is a need

to conduct toxicity studies using various experimental animals and

evaluate the safety and efficacy of selected formulations.


SUMMARY

8. SUMMARY

Preformulation studies : A Preformulation study for the estimation

of labetalol was developed and drug-polymer compatibility studies were

carried out. Method was developed for estimation of drugs and

calibration curves in simulated 0.2m hydrochloric acid were obtained for

labetalol(range 10-30μg/ml). FT-IR study was carried out to rule out any

possible interactions between the drug and the polymers, thus confirming

the compatibility between the selected range of drug and the polymers. As

next step, various formulations were developed for the selected drug.

Transdermal films of Labetalol HCL:

The half-life of labetalol HCL is 6 to 8 h. Transdermal films of

labetalol were developed by Eudragit RSPO&RLPO and using solvent

casting method. In present study, PEG-400 was used as plasticizer and

DMSO was used as permeation enhancers in different proportions.

Uniformity in drug content among the batches was observed with all

formulations and ranged from 96.5 to 99.2%. Folding endurance of the

films ranged from 95 ± 2.1 to 123.3 ± 3, which was satisfactory. The

thickness and weight variation of the films ranged from 0.21 ± 0.01 to

0.29±0.01mm and232 ± 0.047 to 340 ±0.30 mg respectively. Percentage

moisture content of the developed formulations F1 to F9was varied from

2.13± 0.31 to 1.15± 2.42%. Moisture uptakeof the developed formulations

F1 to F9was varied from 1.21± 1.58 to 3.36± 0.96%.In vitro diffusion

studieswere conducted using modified Franz diffusion cell with dialysis

membrane as a permeation barrier. The amount of drug permeated at the

end of 24h was found to be higher from formulations F7 to F9 compared

to formulations F1 to F4 which could be due to the presence of RLPO at

higher concentrations. Formulations F5 showed slow release due to

presence of RSPO. Optmized F3was the most satisfactory formulations as

it closely met to expected data and continuously permeated drug for 24 h

that can maintain desired therapeutic concentration in

plasma.Optimized F3 were subjected to short term stability studies which

showed slight change in physicochemical parameters and drug diffusion

profiles.


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