Transdermal Drug Delivery Technology Revisited: Recent Advances

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Transdermal Drug Delivery Technology Revisited : Recent Advances
By Shreeraj Shah - 10/14/2008

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• Vol. 6 Issue 5
• 2008
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The number of medications and the ways in which they can be administered have expanded dramatically over the years.
One such advance has been the development of transdermal patch delivery systems.
Transdermal drug technology specialists are continuing to search for new methods that can
effectively and painlessly deliver larger molecules in therapeutic quantities to overcome the
difficulties associated with the oral route. Transdermal Drug Delivery System is the system in
which the delivery of the active ingredients of the drug occurs by the means of skin. Skin is an
effective medium from which absorption of the drug takes place and enters the circulatory
system. Various types of transdermal patches are used to incorporate the active ingredients into
the circulatory system via skin. The patches have been proved effective because of its large
advantages over other controlled drug delivery systems. This review article covers a brief
outline of various components of transdermal patch, applications of transdermal patch, their
advantages, disadvantages, when the transdermal patch are used and when their use should
be avoid and some of the recent development in the field along with the latest patents in this
field.
Introduction1,4,5,6
Transdermal drug delivery system has been in existence for a long time. In the past, the most
commonly applied systems were topically applied creams and ointments for dermatological
disorders. The occurrence of systemic side-effects with some of these formulations is indicative
of absorption through the skin. A number of drugs have been applied to the skin for systemic
treatment. In a broad sense, the term transdermal delivery system includes all topically
administered drug formulations intended to deliver the active ingredient into the general
circulation. Transdermal therapeutic systems have been designed to provide controlled
continuous delivery of drugs via the skin to the systemic circulation. Moreover, it over comes
various side effects like painful delivery of the drugs and the first pass metabolism of the drug
occurred by other means of drug delivery systems. So, this Transdermal Drug Delivery System
has been a great field of interest in the recent time. Many drugs which can be injected directly
into the blood stream via skin have been formulated. The main advantages of this system are
that there is controlled release of the drug and the medication is painless. The drug is mainly
delivered to the skin with the help of a transdermal patch which adheres to the skin. A
Transdermal Patch has several components like liners, adherents, drug reservoirs, drug release
membrane etc. which play a vital role in the release of the drug via skin. Various types of
patches along with various methods of applications have been discovered to delivery the drug
from the transdermal patch. Because of its great advantages, it has become one of the highly
research field among the various drug delivery system. Here, a general view over the
transdermal patch has been discussed along with its advantages, disadvantages, methods of
applying, care taken while applying, types and applications of transdermal patch and recent
advances along with recent patents and market products.
Definition
A transdermal patch or skin patch is a medicated adhesive patch that is placed on the skin to
deliver a specific dose of medication through the skin and into the bloodstream.
The first commercially available prescription patch was approved by the U.S. Food and Drug
Administration in December 1979, which administered scopolamine for motion sickness. 2, 3
Components of Transdermal Patch5
(1)Liner - Protects the patch during storage. The liner is removed prior to use. (2) Drug - Drug
solution in direct contact with release liner. (3) Adhesive - Serves to adhere the components of
the patch together along with adhering the patch to the skin. (4) Membrane - Controls the
release of the drug from the reservoir and multi-layer patches. (5) Backing - Protects the patch
from the outer environment.
Conditions in which Transdermal Patches are used 8
Transdermal patch is used when:

(1)When the patient has intolerable side effects (including constipation) and who is unable to
take oral medication (dysphagia) and is requesting an alternative method of drug delivery. (2)
Where the pain control might be improved by reliable administration. This might be useful in
patients with cognitive impairment or those who for other reasons are not able to self-medicate
with their analgesia. (3) It can be used in combination with other enhancement strategies to
produce synergistic effects.
Conditions in which Transdermal Patches are not used 9
The use of transdermal patch is not suitable when:
(1)Cure for acute pain is required. (2) Where rapid dose titration is required. (3) Where
requirement of dose is equal to or less then 30 mg/24 hrs.
Marketed Products of Transdermal Patches:10, 11, 12, 13, 14, 15
Brand Name Drug Manufacturer Indications
NicotinellR Nicotine Novartis Pharmacological

smoking cessation
MatrifenR Fentanyl Nycomed Pain relief patch
Ortho EvraTM Norelgostromin/ ORTHO-McNEIL Postmenstrual

syndrome
Ethinyl Estradiol
NuPatch 100 Diclofenac Zydus Cadila Anti Inflammatory

diethylamine
NeuproR Rigotine UCB and Schwarz Pharma early-stage idiopathic

Parkinson’s disease
Alora Estradiol TheraTech/Proctol and Postmenstrual

Gamble syndrome
NicodermR Nicotine Alza/GlaxoSmithKline Smoking cessation
Estraderm Estradiol Alza/Norvatis Postmenstrual

syndrome
Climara Estradiol 3M Pharmaceuticals/Berlex Postmenstrual

Labs syndrome
Androderm Testosterone TheraTech/GlaxoSmithKline Hypogonadism in

males
Nitrodisc Nitroglycerin Roberts Pharmaceuticals Angina pectoris
Transderm- ScopR Scopolamine Alza/Norvatis Motion sickness
Nuvelle TS Estrogen/Proge Ethical Holdings/Schering Hormone

sterone replacement therapy
Deponit Nitroglycerin Schwarz-Pharma Angina pectoris
Nitro-dur Nitroglycerin Key Pharmaceuticals Angina pectoris
Catapres TTSR Clonidine Alza/Boehinger Ingelheim Hypertension
FemPatch Estradiol Parke-Davis Postmenstrual

syndrome
Minitran Nitroglycerin 3M Pharmaceuticals Angina pectoris
Climaderm Estradiol Ethical Holdings/Wyeth- Postmenstrual

Ayerest syndrome
DuragesicR Fentanyl Alza/Janssen Pharmaceutical Moderate/severe

pain
Estraderm Estradiol Alza/Norvatis Postmenstrual
syndrome
Fematrix Estrogen Ethical Holdings/Solvay Postmenstrual

Healthcare Ltd. syndrome
Transderm- NitroR Nitroglycerin Alza/Norvatis Angina pectoris
Testoderm TTSR Testosterone Alza Hypogonadism in

males
OxytrolR oxybutynin Watson Pharma Overactive bladder
Prostep Nicotine Elan Corp./Lederle Labs Smoking cessation

Factors affecting transdermal bioavaibility4, 16
Two major factors affect the bioavaibility of the drug via transdermal routes:
(1)Physiological factors (2) Formulation factors

Physiological factors include4, 16
(1)Stratum corneum layer of the skin (2) Anatomic site of application on the body (3) Skin
condition and disease (4) Age of the patient (5) Skin metabolism (6) Desquamation (peeling or
flaking of the surface of the skin) (7) Skin irritation and sensitization (7) Race
Formulation factors include4, 16
(1)Physical chemistry of transport (2) Vehicles and membrane used (3) Penetration enhancers
used (4) Method of application (5) Device used
Care taken while applying transdermal patch17
(1)The part of the skin where the patch is to be applied should be properly cleaned. (2) Patch
should not be cut because cutting the patch destroys the drug delivery system. (3) Before
applying a new patch it should me made sure that the old patch is removed from the site. (4)
Care should be taken while applying or removing the patch because anyone handling the patch
can absorb the drug from the patch. (5) The patch should be applied accurately to the site of
administration.
Mechanism of Action of Transdermal Patch
The application of the transdermal patch and the flow of the active drug constituent from the
patch to the circulatory system via skin occur through various methods.
1. Iontophoresis18, 19
Iontophoresis passes a few milliamperes of current to a few square centimeters of skin through
the electrode placed in contact with the formulation, which facilitates drug delivery across the
barrier. Mainly used of pilocarpine delivery to induce sweating as part of cystic fibrosis
diagnostic test. Iontophoretic delivery of lidocaine appears to be a promising approach for rapid
onset of anesthesia.
2.Electroporation18, 20, 21, 22, 23
Electroporation is a method of application of short, high-voltage electrical pulses to the skin.

After electroporation, the permeability of the skin for diffusion of drugs is increased by 4 orders
of magnitude. The electrical pulses are believed to form transient aqueous pores in the stratum
corneum, through which drug transport occurs. It is safe and the electrical pulses can be
administered painlessly using closely spaced electrodes to constrain the electric field within the
nerve-free stratum corneum.
3.Application by ultrasound18, 24
Application of ultrasound, particularly low frequency ultrasound, has been shown to enhance
transdermal transport of various drugs including macromolecules. It is also known as
sonophoresis. Katz et al. reported on the use of low-frequency sonophoresis for topical delivery
of EMLA cream.
4.Use of microscopic projection18
Transdermal patches with microscopic projections called microneedles were used to facilitate
transdermal drug transport. Needles ranging from approximately 10-100 µm in length are
arranged in arrays. When pressed into the skin, the arrays make microscopic punctures that are
large enough to deliver macromolecules, but small enough that the patient does not feel the
penetration or pain. The drug is surface coated on the microneedles to aid in rapid absorption.
They are used in development of cutaneous vaccines for tetanus and influenza.
Various other methods are also used for the application of the transdermal patches like thermal
poration, magnetophoresis, and photomechanical waves. However, these methods are in their
early stage of development and required further detail studying.
Types of Transdermal Patch25
1. Single-layer Drug-in-Adhesive
The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer
not only serves to adhere the various layers together, along with the entire system to the skin,
but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a
temporary liner and a backing.
2. Multi-layer Drug-in-Adhesive
The multi-layer drug-in adhesive patch is similar to the single-layer system in that both adhesive
layers are also responsible for the releasing of the drug. The multi-layer system is different
however that it adds another layer of drug-in-adhesive, usually separated by a membrane (but
not in all cases). This patch also has a temporary liner-layer and a permanent backing.
3. Reservoir
Unlike the Single-layer and Multi-layer Drug-in-adhesive systems the reservoir transdermal
system has a separate drug layer. The drug layer is a liquid compartment containing a drug
solution or suspension separated by the adhesive layer. This patch is also backed by the
backing layer. In this type of system the rate of release is zero order.
4. Matrix
The Matrix system has a drug layer of a semisolid matrix containing a drug solution or
suspension. The adhesive layer in this patch surrounds the drug layer partially overlaying it.
5. Vapour Patch
In this type of patch the adhesive layer not only serves to adhere the various layers together but
also to release vapour. The vapour patches are new on the market and they release essential
oils for up to 6 hours. The vapours patches release essential oils and are used in cases of
decongestion mainly. Other vapour patches on the market are controller vapour patches that
improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one
smokes in a month are also available on the market.
Drugs used in the Transdermal Patch25
(1) Nicotine: to quit tobacco smoking (2) Fentanyl: analgesic for severe pain (3) Estrogen:
menopause and osteoporosis (4) Nitroglycerin: angina (5) Lidocaine: peripheral pain of shingles
(herpes zoster). Recent developments expanded their use to the delivery of hormonal
contraceptives, antidepressants and even pain killers and stimulants for Attention Deficit
HyperactivityDisorder/ADHD.
Recent research done in the field:
Many research works have been and are few are going on in this field. Few of the latest
research done in the field of transdermal patches are stated below:
Pain-free diabetic monitoring using transdermal patches26
The first prototype patch measures about 1cm2 and is made using polymers and thin metallic
films. The 5×5 sampling array can be clearly seen, as well as their metallic interconnections.
When the seal is compromised, the interstitial fluid, and the biomolecules contained therein,
becomes accessible on the skin surface. Utilizing micro-heating elements integrated into the
structural layer of the patch closest to the skin surface, a high-temperature heat pulse can be
applied locally, breaching the stratum corneum. During this ablation process, the skin surface
experiences temperatures of 130°C for 30ms duration. The temperature diminishes rapidly from
the skin surface and neither the living tissue nor the nerve endings are affected. This painless
and bloodless process results in disruption of a 40–50μm diameter region of the dead skin
layer, approximately the size of a hair follicle, allowing the interstitial fluid to interact with the
patch's electrode sites.
Testosterone Transdermal Patch System in Young Women with Spontaneous Premature Ovarian Failure27
In premenopausal women, the daily testosterone production is approximately 300 µg, of which
approximately half is derived from the ovaries and half from the adrenal glands. Young women
with spontaneous premature ovarian failure (sPOF) may have lower androgen levels, compared
with normal ovulatory women. Testosterone transdermal patch (TTP) was designed to deliver
the normal ovarian production rate of testosterone. The addition of TTP to cyclic E2/MPA
therapy in women with sPOF produced mean free testosterone levels that approximate the
upper limit of normal.
Transdermal Patch of Oxybutynin used in overactive Bladder28, 29, 30
The product is a transdermal patch containing Oxybutynin HCl and is approved in US under the
brand name of Oxytrol and in Europe under the brand name of Kentera. OXYTROL is a thin,
flexible and clear patch that is applied to the abdomen, hip or buttock twice weekly and provides
continuous and consistent delivery of oxybutynin over a three to four day interval. OXYTROL
offers OAB patient’s continuous effective bladder control with some of the side effects, such as
dry mouth and constipation encountered with and oral formulation. In most patients these side
effects however are not a troublesome.
Transdermal Patch (Ortho Evra™) 31
The patch is 4.5 square centimeters in size and has three layers: the inner release liner which
should be removed before application, a layer containing hormones, and an outer polyester
protective layer. The patch contains 6 milligram of progestin, Norelgestromin 0.75 milligram of
Ethinyle Estradiol. The patch is applied on the skin through which the hormones are absorbed in
order to provide continuous flow of hormones during menstrual cycle. The patch is marketed by
Ortho McNeil Pharmaceutical with the brand name Ortho Evra.
Rotigotine transdermal patch32
The rotigotine transdermal patch is used for symptom control in Parkinson’s disease. The
patches are effective in reducing the symptoms of early Parkinson’s disease, and in reducing
“off” time in advanced Parkinson’s disease. It is available in market under the brand name of
NeuproR.
Most recent Patents:
Below are listed some of the most recent patents made in the field of transdermal patch.
Patent No. Date Title Information
US741530633 Aug. 19, Transdermal The present invention provides a transdermal

2008 Delivery delivery system for hydrophilic anti-emetic agents
System for and methods of using thereof. The system includes
Anti-Emetic an anti-emetic hydrophilic adhesive composition of
Medication a hydrophilic polymer and hydrophilic anti-emetic
agent, a patch containing at least one hydrophilic
layer of the composition, and an apparatus that
generates hydrophilic micro-channels in skin of a
subject using the patch or composition
US741374834 Aug. 19, Transdermal A specific dosage regimen of buprenorphine

2008 Buprenorphine achieves pain relief from painful episodes due to
to treat Pain in sickle cell disease. The dosage regimen comprises
Sickle Cell administering to a patient in need of pain relief
Crisis from sickle cell disease at least one BTDS
transdermal patch.
US738778935 Jul. 17, Transdermal The present invention provides a transdermal drug
2008 Delivery of delivery system which comprises: a therapeutically
Non-Steroidal effective amount of a non-steroidal anti-
Anti inflammatory drug; at least one dermal penetration
Inflammatory enhancer, which is a safe skin-tolerant ester
Drugs sunscreen ester; and at least one volatile liquid. The
invention also provides a method for administering
at least one systemic or locally acting non-steroidal
anti-inflammatory drug to an animal
US739812136 Jul. 8, Iontophoresis An iontophoresis device useful for administering

2008 Device an ionic drug by iontophoresis has an iontophoresis
electrode section
and a ground electrode section
Both of which are to be connected to a power
source. The iontophoresis device includes elements
(members) of both of the electrode sections are all
formed of membrane bodies, and includes ion
exchange membranes different in ion selectivity,
one being selective to ions of the same species as
charged ions of the ionic drug and the other to ions
different in species from the charged ions of the
ionic drug that are arranged in the iontophoresis
electrode section, and at least an ion exchange
membrane selective to ions opposite to the charged
ions of the ionic drug is arranged in the ground
electrode section. The iontophoresis device can
administer the ionic drug stably over a long period
of time at high transport efficiency.
US739511137 Jul. 1, Transdermal The present invention provides a system for

2008 Delivery transdermal delivery of water insoluble drugs and
System for methods using the same. The system includes a
Water pharmaceutical composition of a water insoluble
Insoluble Drug drug and a carrier molecule that enhances the
solubility of the drug in aqueous solution, a
medical patch containing the same and an
apparatus that generates hydrophilic micro-
channels in an area of skin of a subject using the
composition or patch.
Conclusion7
A lot of progress has been done in the field of Transdermal Patches. Due to large advantages of
the Transdermal Drug Delivery System, this system interests a lot of researchers. Many new
researches are going on in the present day to incorporate newer drugs via this system. Various
devices which help in increasing the rate of absorption and penetration of the drug are also
being studied. However, in the present time due to certain disadvantages like large drug
molecules cannot be delivered, large dose cannot be given, the rate of absorption of the drug is
less, skin irritation, and etc. the use of the Transdermal Drug Delivery System has been limited.
But, with the invention of the new devices and new drugs which can be incorporated via this
system, it used is increasing rapidly in the present time.
References:
1. Ranade, V, V.; Drug delivery systems. 6. Transdermal drug delivery, The Clinical Journal
Of Pharmacology Available http://jcp.sagepub.com/cgi/content/abstract/31/5/401
2. Segal, Marian. "Patches, Pumps and Timed Release: New Ways to Deliver
Drugs". Food and Drug Administration. Retrieved on 2007-02-24.
3. "FDA approves scopolamine patch to prevent peri-operative nausea". Food and Drug
Administration (1997-11-10). Retrieved on 2007-02-12.
4. Jacoby, David B., Youngson, R. M., Marshall Cavendish Corporation; Encyclopedia Of

Family Health, Published by Marshall Cavendish, 2004, Pg: 2259
5. Bayarski, Yury; Transdermal Drug Delivery, Transdermal Patches

Available: http://ezinearticles.com/?Transdermal-Drug-Delivery,-Transdermal-Patches...
6. MANAGED CARE April 2004. ©MediMedia USA ,

Available : http://www.managedcaremag.com/archives/0404/0404.biotech.html
7. Hillery, Anya M, Lloyd, Andrew W., Swarbrick, James; Drug Delivery and Targeting for
Pharmacists and Pharmaceutical Scientists, Published by Taylor & Francis, 2001 Pg 216
8. Guy, Richard H., Hadgraft, Jonathan; Transdermal Drug Delivery Second Edition
Published by Informa Health Care, 2002 Pg 322
9. Arcangelo , Virginia P., Peterson, Andrew M.; Pharmacotherapeutics for Advanced

Practice, Published by Lippincott Williams & Wilkins, 2005 Pg 74
10. http://images.google.co.in/imgres?imgurl=http://www.chimei.org.tw/main/r...
11. http://images.google.co.in/imgres?imgurl=http://www.fda.gov/bbs/topics/n...
12. http://images.google.co.in/imgres?imgurl=http://lh4.ggpht.com/_m8Z9nkvXX...
13. http://images.google.co.in/imgres?imgurl=http://www.prescribingreference...
14. Kumar, Ritesh and Philip, Anil; Modified Transdermal Technologies: Breaking the
Barriers of Drug Permeation via the Skin; Tropical Journal of Pharmaceutical Research,
March 2007; 6 (1): 633-644
15. Jain N, Talegonkar S, Jain N K. New ways to enter the blood stream: Emerging
strategies in transdermal drug delivery. The Pharma Review 2004; Oct.: 41- 59.
16. Williams, Adrian; Transdermal and Topical Drug Delivery Published by Pharmaceutical
Press, 2003; Pg: 14-18
17. Elling, Bob, Elling, Kirsten M. Rothenberg, Mikel A.; Why-Driven EMS Enrichment
Published by Thomson Delmar Learning, 2001 Pg 103
18.Medscape Today journal Available http://www.medscape.com/viewarticle/530060_4

19.The Indian Anaesthetists' Forum - On-Line Journal ( http://www.theiaforum.org/ ) April
2004 available http://www.theiaforum.org/april2004.htm
20.Electroporation From Wikipedia, the free encyclopedia

available http://en.wikipedia.org/wiki/Electroporation
21. Neumann E, Schaefer-Ridder M, Wang Y, Hofschneider PH (1982). "Gene transfer into

mouse lyoma cells by electroporation in high electric fields". EMBO J. 1 (7): 841–5.
PMID 6329708.
22.Sugar IP, Neumann E (1984). "Stochastic model for electric field-induced membrane
pores. Electroporation". Biophys . Chem. 19 (3): 211–25. doi : 10.1016/0301-
4622(84)87003-9. PMID 6722274 .
23.^ Sarah Yang ( 2007 - 02-12 ). " New medical technique punches holes in cells, could
treat tumors". Retrieved on 2007 - 12-13 .
24.Sonophoresis From Wikipedia, the free encyclopedia

available http://en.wikipedia.org/wiki/Sonophoresis
25.Transdermal patch From Wikipedia, the free encyclopedia

available : http://en.wikipedia.org/wiki/Transdermal_patch
26.Paranjape, Makarand; Biomedical Optics & Medical Imaging, Pain-free diabetic

monitoring using transdermal patches Available: http://spie.org/x27077.xml
27.Kalantaridou, Sophia N., Calis, Karim A., Mazer, Norman A., Godoy, Heidy, Nelson,
Lawrence M.; A Pilot Study of an Investigational Testosterone Transdermal Patch
System in Young Women with Spontaneous Premature Ovarian Failure The Journal of
Clinical Endocrinology & Metabolism Vol. 90, No. 12 6549-6552 Copyright © 2005 by
The Endocrine Society
Available http://jcem.endojournals.org/cgi/content/abstract/90/12/6549
28.Anandi Krishnan, Pharmainfo.net

Available http://www.pharmainfo.net/reviews/overactive-bladder-disease-overview-re...
29. http://en.wikipedia.org/wiki/Kidney
30.Watson Pharmaceuticals' OXYTROL(R) Receives Positive Opinion for Approval in the

European Union CORONA, Calif., Nov. 24 /PRNewswire-FirstCall; Web
site:http://www.watsonpharm.com
31.Pill, Yasmin, Ring, Nuva, Ortho Evra Patch, Lunelle Injectable; Contraceptive Advances
Available http://www.reproline.jhu.edu/english/1fp/1advances/1combined/patch.htm
32.Issue in Emerging Health Technology, Issue 112 February 2008
Available http://cadth.ca/media/pdf/E0056_Rotigotine-Patch-Parkinsons-Disease_ceta...
33. http://www.freepatentsonline.com/US7415306.html?query=PN/US7415306%20OR%...
About Authors:
S. H. Shah, D.Shah
S. H. Shah
L.J. Institute of Pharmacy, Gujarat University, Ahmedabad- 382 210, Gujarat, India
D.Shah
L.J. Institute of Pharmacy, Gujarat University, Ahmedabad- 382 210, Gujarat, India
Excellent article. Can you
Submitted by rkeefer on Fri, 07/03/2009 - 15:47.

5
Excellent article. Can you also provide a list of the biocompatible polymers that are used in
transdermal patches...and even implants?
rkeefer09
rkeefer09
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Transdermal patch
From Wikipedia, the free encyclopedia
Not to be confused with dermal patch.
A 21mg dose Nicoderm CQ patch applied to the left arm

Contraceptive patch
Clonidine tablets and transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream.
Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of medication delivery such as oral,
topical, intravenous, intramuscular, etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane
covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal
delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin
can be delivered in this method. A wide variety of pharmaceuticals are now available in transdermal patch form.
The first commercially available prescription patch was approved by the U.S. Food and Drug Administration in December 1979. These patches
administered scopolaminefor motion sickness.[1][2]
Contents
[hide]
• 1 Development
• 2 Popular uses
• 3 Adverse events
• 4 Components
• 5 Types
○ 5.1 Single-layer
Drug-in-Adhesive
○ 5.2 Multi-layer
Drug-in-Adhesive
○ 5.3 Reservoir
○ 5.4 Matrix
○ 5.5 Vapour Patch
• 6 Regulatory aspects
• 7 See also
• 8 References
• 9 Further reading
• 10 External links
[edit]Development
Before these patches go into the market, they have to be carefully studied. One way to study these patches are through the use of Franz Diffusion Cell systems.
This system is used to study the effects of temperature on the permeated amount of a specific drug on a certain type of membrane, which in this case would be
the membrane that is used in the patches. A Franz Diffusion Cell system is composed of a receptor and a donor cell. In many of these research studies the
following procedure is used. The donor cell is set at a specific temperature (the temperature of the body), while the receptor cell is set at different one (temperature
of the environment).
Different runs are performed using different temperatures to study the impact of temperature on the release of a certain medicament through a certain type of
membrane. Although different concentrations of the medicament are used in this study, they do not affect the amount permeated through the membrane (the
process is constant). From Chemical kinetics it’s concluded that these studies are zero order, since the concentration plays no role in the permeated amount
through the membrane.
Some pharmaceuticals must be combined with substances, such as alcohol, within the patch to increase their ability to penetrate the skin in order to be used in a
transdermal patch. Others can overwhelm the body if applied in only one place, and are often cut into sections and applied to different parts of the body to avoid
this, such as nitroglycerin. Many molecules, however, such as insulin, are too large to pass through the skin without it being modified in some way. Several new
technologies are being investigated to allow larger molecules to be delivered transdermally.[3]
[edit]Popular uses
 The highest selling transdermal patch in the United States is the nicotine patch, which releases nicotine in
controlled doses to help with cessation of tobacco smoking. The first commercially available vapour patch to
reduce smoking was approved in Europe in 2007.
 Two opioid medications used to provide round-the-clock relief for severe pain are often prescribed in patch
form: Fentanyl (marketed as Duragesic) and Buprenorphine (marketed as BuTrans).
 Estrogen patches are sometimes prescribed to treat menopausal symptoms as well as post-
menopausal osteoporosis. Other transdermal patches for hormone delivery include the contraceptive
patch (marketed as Ortho Evra or Evra). Testosterone patches are available for both men and women, but mens
patches (such as Androderm) contain a much higher dosage than womens patches such as Intrinsa.
 Nitroglycerin patches are sometimes prescribed for the treatment of angina in lieu of sublingual pills.
 Transdermal scopolamine is commonly used as a treatment for motion sickness.[4]
 The anti-hypertensive drug Clonidine is available in transdermal patch form[5] under the brand name Catapres-
TTS[6].
 Emsam, a transdermal form of the MAOI selegiline, became the first transdermal delivery agent for
an antidepressant approved for use in the U.S. in March 2006[7].
 Daytrana, the first transdermal delivery agent for the Attention Deficit Hyperactivity Disorder (ADHD)
drug methylphenidate (otherwise known as Ritalin or Concerta), was approved by the FDA in April 2006[8].
 Vitamin B12 may also be administered through a transdermal patch. Cyanocobalamin, a highly stable form of
vitamin B12, is compatible with transdermal patching.
[edit]Adverse events
 In 2005, the FDA announced that they were investigating reports of death and other serious adverse events
related to narcotic overdose in patients using Duragesic, the fentanyl transdermal patch for pain control. The
Duragesic product label was subsequently updated to add safety information in June 2005.[9]
 In 2007, Shire and Noven Pharmaceuticals, manufacturers of the Daytrana ADHD patch, announced a voluntary
recall of several lots of the patch due to problems with separating the patch from its protective release liner[10].
Since then, no further problems with either the patch or its protective packaging have been reported.
 In 2008, two manufacturers of the Fentanyl patch, ALZA Pharmaceuticals (a division of major medical
manufacturer Johnson & Johnson) and Sandoz, subsequently issued a recall of their versions of the patch due to
a manufacturing defect that allowed the gel containing the medication to leak out of its pouch too quickly, which
could result in overdose and death[11]. As of March 2009, Sandoz--now manufactured by ALZA--no longer uses gel
in its transdermal fentanyl patch; instead, Sandoz-branded fentanyl patches use a matrix/adhesive suspension
(where the medication is blended with the adhesive instead of held in a separate pouch with a porous membrane),
similar to other fentanyl patch manufacturers such as Mylan and Janssen[12].
 In 2009, the FDA announced a public health advisory warning of the risk of burns during MRI scans from
transdermal drug patches with metallic backings. Patients should be advised to removed any medicated patch
prior to an MRI scan and replace it with a new patch after the scan is complete.[13]
 In 2009, an article in Europace journal detailed stories of skin burns that occurred with transdermal patches that
contain metal (usually as a backing material) caused by shock therapy from external as well as internal
cardioverter defibrillators (ICD)[14].
[edit]Components
The main components to a transdermal patch are:
 Liner - Protects the patch during storage. The liner is removed prior to use.
 Drug - Drug solution in direct contact with release liner
 Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin
 Membrane - Controls the release of the drug from the reservoir and multi-layer patches
 Backing - Protects the patch from the outer environment
[edit]Types
Sample transdermal patches. On left is a 'reservoir' type, on the right a 'Single-layer Drug-in-Adhesive' version. Both contain exactly the same level of the same active ingredient with identical
release rates.
There are five main types of transdermal patches.
[edit]Single-layer Drug-in-Adhesive
The adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with
the entire system to the skin, but is also responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing.
[edit]Multi-layer Drug-in-Adhesive
The multi-layer drug-in adhesive patch is similar to the single-layer system in that both adhesive layers are also responsible for the releasing of the drug.One of the
layers is for immediate release of the drug and other layer is for control release of drug from the reservoir. The multi-layer system is different however that it adds
another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). This patch also has a temporary liner-layer and a permanent backing.
[edit]Reservoir
Unlike the Single-layer and Multi-layer Drug-in-adhesive systems the reservoir transdermal system has a separate drug layer. The drug layer is a liquid
compartment containing a drug solution or suspension separated by the adhesive layer. This patch is also backed by the backing layer. In this type of system the
rate of release is zero order.
[edit]Matrix
The Matrix system has a drug layer of a semisolid matrix containing a drug solution or suspension. The adhesive layer in this patch surrounds the drug layer
partially overlaying it. Also known as a monolithic device.
[edit]Vapour Patch
In this type of patch the adhesive layer not only serves to adhere the various layers together but also to release vapour. The vapour patches are new on the
market and they release essential oils for up to 6 hours. The vapour patches release essential oils and are used in cases of decongestion mainly. Other vapour
patches on the market are controller vapour patches that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a
month are also available on the market.
[edit]Regulatory aspects
A transdermal patch is classified by the U.S. Food and Drug Administration as a combination product, consisting of a medical device combined with a drug or
biological product that the device is designed to deliver. Prior to sale in the United States, any transdermal patch product must apply for and receive approval from
the Food and Drug Administration, demonstrating safety and efficacy for its intended use. (needs citation)
[edit]See also
 Route of administration
 Metered dose transdermal spray
[edit]References
1. ^ Segal, Marian. "Patches, Pumps and Timed Release: New Ways to Deliver Drugs". Food and Drug Administration.
Archived from the original on 2007-02-10. Retrieved 2007-02-24.
2. ^ "FDA approves scopolamine patch to prevent peri-operative nausea". Food and Drug Administration. 1997-11-10.
Archived from the original on 2006-12-19. Retrieved 2007-02-12.
3. ^ Prausnitz M, Langer R. Transdermal drug delivery. Nature Biotechnology. Volume 26, Number 11, Pages 1261-
1268, November 2006

4. ^ Nachum Z, Shupak A, Gordon CR (2006). "Transdermal scopolamine for prevention of motion sickness : clinical
pharmacokinetics and therapeutic applications". Clinical Pharmacokinetics 45 (6): 543–66.PMID 16719539.
5. ^ Berner B, John VA (February 1994). "Pharmacokinetic characterisation of transdermal delivery systems". Clinical
pharmacokinetics 26 (2): 121–34. doi:10.2165/00003088-199426020-00005. PMID 8162656.
6. ^ First Databank Inc.. "Clonidine - Transdermal (Catapres-TTS) side effects, medical uses, and drug interactions".
Retrieved 2010-09-28.
7. ^ Peck, Peggy (2006-03-01). "FDA Approves First Antidepressant Transdermal Patch". Retrieved 2010-09-28.
8. ^ Cabray, Matthew (2006-04-12). "Transdermal Patch Approved For Treatment Of ADHD". Retrieved 2010-09-28.
9. ^ "FDA ALERT (07/2005): Narcotic Overdose and Death". Food and Drug Administration. 2005-07-15. Archived
from the original on 2007-02-20. Retrieved 2007-02-24.
10. ^ Megget, Katrina (2007-09-05). "ADHD Transdermal Patches Withdrawn". Retrieved 2010-09-28.
11. ^ Silverman, Ed (2008-02-12). "J&J and Sandoz Recall Fentanyl Patches". Retrieved 2010-09-28.
12. ^ As stated on the packaging and labels of Sandoz-branded Fentanyl Transdermal System products, revised March
2009.
13. ^ "FDA Public Health Advisory: Risk of Burns during MRI Scans from Transdermal Drug Patches with Metallic
Backings". Retrieved March 9, 2009.[dead link]
14. ^ Brown, MR: "Analgesic patches and defibrillators: a cautionary tale", Europace,2009 Nov;11(11):1552-3
[edit]Further reading
 "Transderm Scōp" (PDF). Food and Drug Administration. 1998. Archived from the original on 2007-08-10.
Retrieved 2007-02-12.
[edit]External links
 PlastoPharma
 The 10th US-Japan Symposium on Drug Delivery Systems
Wikimedia Commons has
media related
to: Transdermal patches
[hide]v · d · eRoutes of administration / Dosage forms
Oral SolidsPill • Tablet • Capsule • Osmotic controlled release capsule (OROS) • Softgel
Digestive tract (enteral)
LiquidsSolution • Suspension • Emulsion • Syrup • Elixir • Tincture • Hydrogel
Buccal / Sublabial / Sublingual SolidsOrally Disintegrating Tablet (ODT) • Film • Lollipop • Lozenges • Chewing gum
LiquidsMouthwash • Toothpaste • Ointment • Oral spray
SolidsSmoking device • Dry Powder Inhaler (DPI)
Respiratory tract Liquidspressurized Metered Dose Inhaler (pMDI) • Nebulizer • Vaporizer
GasOxygen mask • Oxygen concentrator • Anaesthetic machine • Relative analgesia m
Ocular / Otologic / Nas

Nasal spray • Ear drops • Eye drops • Ointment • Hydrogel • Nanosphere suspension • Mucoadhesive microdisc (microsphere tablet)
al
Urogenital Ointment • Pessary (vaginal suppository) • Vaginal ring • Vaginal douche • Intrauterine device (IUD) • Extra-amniotic infusion • Intravesical infusion
Rectal (enteral) Ointment • Suppository • Enema (Solution • Hydrogel) • Murphy drip • Nutrient enema
Dermal Ointment • Liniment • Paste • Film • Hydrogel • Liposomes • Transfersome vesicals • Cream • Lotion • Lip balm • Medicated shampoo • Dermal patch • Transdermal patch • Transdermal spray • Jet injector
SkinIntradermal • Subcutaneous • Transdermal implant
OrgansIntracavernous • Intravitreal • Transscleral

Injection / Infusion
(into tissue/blood)
Central nervous systemIntracerebral • Intrathecal • Epidural
Circulatory / MusculoskeletalIntravenous • Intracardiac • Intramuscular • Intraosseous • Intraperitoneal • Nanocell injection
Mucous membranes are used by the human body to absorb the dosage for all routes of administration, except for "Dermal" and "Injection/Infusion".
Administration routes can also be grouped as Topical (local effect) or Systemic (defined as Enteral = Digestive tract/Rectal, or Parenteral = All other routes).
Additional
explanation:
[show]v · d · eRoutes of administration by organ system
Categories: Pharmacology | Drug delivery devices | Dosage forms | Transdermal patches
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dissertations
DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY ...
DETACH
NO HIGHLIGHTING
DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY
SYSTEM FOR DICLOFENAC SODIUM
By
RUDRESH. S. P
Dissertation submitted to
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore
In partial fulfillment of the requirement

for the Degree of
MASTER OF PHARMACY
In
PHARMACEUTICS
Under the Guidance of
Mr. B. ANROOP
Assistant Professor
Department of Pharmaceutics,
P.E.S. College of Pharmacy,
Bangalore - 560050.
January 2006
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE
DECLARTION BY THE CANDIDATE
I here by declare that this dissertation /thesis

entitled “Development of Transdermal
Drug Delivery System for Diclofenac sodium” is a bonafide and
genuine research
work carried out by me under the guidance of Mr. B. Anroop,
Assistant Professor,
Department of Pharmaceutics, P.E.S. College of Pharmacy,
Bangalore.
Date:
Place: Bangalore Rudresh. S. P
P.E.S. COLLEGE OF PHARMACY

Hanumanth Nagar, Bangalore - 560050
Certificate by the Guide

This is to certify that the dissertation entitled “Development of
Transdermal Drug
Delivery System for Diclofenac sodium” is a bonafide research
work done by Mr.
Rudresh. S. P in partial fulfillment of the requirement for
the Degree of Master of
Pharmacy in Pharmaceutics.
B. Anroop
Assistant Professor
Date:
Dept of Pharmaceutics
P.E.S. College of Pharmacy
Place: Bangalore Bangalore - 560050
P.E.S. COLLEGE OF PHARMACY
Hanumanth Nagar, Bangalore - 560050
ENDORSEMENT BY THE HOD, PRINCIPAL OF THE

INSTITUTION
This is to certify that the dissertation entitled “Development of

Transdermal Drug
Delivery System for Diclofenac sodium” is a bonafide research
work done by Mr.
Rudresh. S. P under the guidance of Mr. B. Anroop, Assistant
Professor,
Bangalore-560050.
Prof. V. S. Datta Murthy Prof. Dr. S. Mohan

HOD, Department of Pharmaceutics Principal
Date:
Place: Bangalore
COPYRIGHT
DECLARATION BY THE CANDIDATE
I hereby declare that the Rajiv Gandhi University of Health Sciences,

Karnataka shall
have the rights to preserve, use and disseminate this dissertation /
thesis in print or
electronic format for academic / research purpose.
Date:
Rudresh. S. P
Place: Bangalore
© Rajiv Gandhi University of Health Sciences, Karnataka
ACKNOWLEDGMENT
The work on this project has been an inspiring, often exciting,

sometimes
challenging, but always interesting and an enjoyable experience.
Thankfully, I’ve had the opportunity to work with a great many
people who are
far more talented, dedicated, and experienced than me at every
step of the way. I know I
can be quite a handful at times, but many of my mentors have been
generous enough with
their time and trust to permit me to pursue my own paths.
First of all, I would like to thank my supervisor Mr. B. Anroop,
Assistant
Professor, Department of Pharmaceutics, P.E.S. College of
Pharmacy, who guided this
project work and helped whenever I was in need. He has always had
time for discussions
and continually shown great interest in my research. Among his
absolutely best sides is
his ability to stimulate one’s imagination and creativity.
I would also like to thank Prof. V. S. Datta Murthy, Professor and
Head,
Department of Pharmaceutics, P.E.S. College of Pharmacy for his
outstanding advice
and valuable contributions throughout my project work.
I owe a huge debt of gratitude to Prof. Dr. S. Mohan, Principal
P.E.S. College of
Pharmacy for providing me all the facilities and encouragement for
the successful
completion of my project work.
I remain thankful to Mrs. S. Vasanti, Assistant Professor, Mr. Suresh
Gupta
Mr.Nagashekar, Department of Pharmaceutics, P.E.S. College of
Pharmacy for their
valuable and timely suggestions.
I am grateful to Prof. Dr. J. Saravanan, HOD, Department of
Pharmaceutical
Chemistry, Prof. Dr. Mahesh Attimarad, HOD, Department of
Pharmaceutical Analysis,
P.E.S. College of Pharmacy for their support.
Dr. Raghu Prasad, Dr. Meera Sumanth, Dr. Laksman, Mr. Venkatesh
Prasad
Mr. Shiva Prasad, Mr. Laksmeesha, Mr. Srinath and other teaching
staff members of
P.E.S. College of pharmacy also acknowledged for creating an
enjoyable and stimulating
atmosphere, which helped me in the successful completion of my
project.
I am grateful to Dr. H.N. Shiva kumar, K.L.E College of Pharmacy,
Bangalore
for his valuable support.
I am thankful to my friends Chandrasekhar Reddy, Basavaraj,

Srinivasa Murthy,
Nagabasayya, Sharan, Shivanand, Manjunath, Santosh, Pran
Kishore, Sajal, Barnali,
Kunthal and Harish for their constant support and encouragement.
I am also grateful to my seniors, juniors and all friends for their
constant support
and encouragement.
I express my immense sense of gratitude to Mr. Hari Prasad, Mr.
Hari
Prakashaiah, and Mr. Basavaraj and other non-teaching staff
members for their
unforgettable help.
I gratefully acknowledge my close friend Dr. Prashanth kumar
Scientist-ADMET,
Synchron research services Pvt. Ltd, Ahmedabad, for his
extraordinary encouragement
and providing useful moral and financial support, without which
M.Pharm would have
been remained as dream for me.
I thank my close friends, Rajagopal who assisted in getting financial
support from
UCO Bank, Kiran kumar and Shantharam Nayak for their constant
encouragement.
My heartfelt acknowledgment must go to my wife Mamatha for her
support,
encouragement, and companionship.
I would like to express my deepest gratitude for the constant
support and
encouragement, which I received from my brothers Dr. Rajanna,
Sriranga and all my
family members.
These acknowledgments would not be complete without thanking
my sister
Smt.Sreerangamma and brother-in-law Sri.Anjanappa for their
continuous support and
encouragement throughout my carrier. They deserve far more credit
than I can ever give
them.
I thank one and all, who helped me directly or indirectly for the
successful
completion of my project work.
Date: January 2006

Place: Bangalore Rudresh. S.P
LIST OF ABBREVIATIONS
0C
Degree
centigrade
CMC Carboxy methyl cellulose
HPMC
Hydroxy
propyl
methyl
cellulose
h Hour
NaCl
Sodium
chloride
MC
Methyl
cellulose
mg
Milligram
ml
Milliliter
µg
Microgram
µmol
Micromole
nm
Nanometer
PG
Propylene
glycol
pH
Hydrogen ion concentration

SE
Standard error
UV
Ultra violet
Wt.
Weight
w/w
Weight/Weight
w/v
Weight/Volume
ABSTRACT
Diclofenac sodium, a NSAID widely used in the treatment of

rheumatic disorders and
other chronic inflammatory diseases. Administration of these agents
via dermal route can
bypass various disadvantages caused when administered orally and
may maintain
relatively consistent plasma levels for long-term therapy. The
present study is an attempt
to develop transdermal drug delivery system for diclofenac sodium.
Alcohol: water
(30:70) cosolvent system is selected for the preparation of
diclofenac sodium gels using
different polymers, as it has better permeability coefficient in
comparison with propylene
glycol: water (30:70) cosolvent. Permeation through the porcine skin
was carried using
0.9% w/v sodium chloride solution as receptor fluid in a Franz
diffusion cell (1.74 cm2).
Gels containing 1% diclofenac sodium with different polymers has
shown better
permeability coefficient in comparison with 1.5% and 2%. Diclofenac
sodium gels
formulated using carbopol with permeation enhancer has shown
better flux enhancement
in comparison with gels formulated using HPMC and methylcellulose.
Carbopol gel with
menthol 5% shown maximum flux enhancement of 1.596 fold in
comparison with oleic
acid 5% (1.418). It can be concluded that diclofenac sodium (1%)
gels prepared using
carbopol as polymer has shown better flux enhancement with
menthol (5%) as
permeation enhancer.
Keywords: Diclofenac sodium; TDDS; porcine skin; alcohol;

propylene glycol; carbopol;
HPMC; methyl cellulose; menthol; oleic acid.
TABLE OF CONTENTS
Sl. No
CONTENTS
Page No.
1
Introduction
01
2
Objectives
11
3
Review of Literature
12
4
Methodology
30
5
Results
38
6
Discussion
61
7
Conclusion
66
8
Summary
67
9
Bibliography
68
10
Annexures
73
Introduction
1. INTRODUCTION
Continuous intravenous infusion at a programmed rate has been
recognized as a superior
mode of drug delivery not only to bypass the hepatic first-pass
elimination but also to
maintain a constant, prolonged, and therapeutically effective drug
level in the body. A
closely monitored intravenous infusion can provide both the
advantages of direct entry of
drug into the systemic circulation and control of circulating drug
levels. However, such a
mode of drug delivery entails certain risks and therefore
necessitates hospitalization of
patients and close medical supervision of the medication. Recently
there has been an
increasing awareness that the benefits of intravenous drug infusion
can be closely
duplicated, without its potential hazards, by continuous transdermal
drug administration
through intact skin.1
1.1. TRANSDERMAL DRUG DELIVERY SYSTEMS
DEFINITION
Transdermal drug delivery systems are defined as self-
contained, discrete dosage forms
which, when applied to the intact skin, deliver the drug,
through the skin, at a
controlled rate to the systemic circulation.2
ADVANTAGES 2
1. Transdermal medication delivers a steady infusion of a drug over
an extended period
of time. Adverse effects or therapeutic failure frequently associated
with intermittent
dosing can also be avoided.
2. Transdermal delivery can increase the therapeutic value of many
drugs by avoiding
specific problems associated with the drug e.g., gastro-intestinal
irritation, low
Bangalore.
1
Introduction
absorption, decomposition due to hepatic "first-pass" effect,
formation of metabolites
that cause side effects, short half-life necessitating frequent dosing
etc.
3. Due to the above advantage, it is possible that an equivalent
therapeutic effect can be
elicited via transdermal drug input with a lower daily dose of the
drug than is
necessary, if, for example, the drug is given orally.
4. The simplified medication regimen leads to improved patient
compliance and reduced
inter and intra-patient variability.
5. At times the maintenance of the constant drug concentration
within the biophase is not
desired. Application and removal of transdermal patch produce the
optimal sequence
of pharmacological effect.
6. Self-administration is possible with these systems.
7. The drug input can be terminated at any point of time by
removing transdermal patch.
DISADVANTAGES 2
1. The drug must have some desirable physicochemical properties
for penetration
through stratum corneum and if the drug dosage required for
therapeutic value is more
then 10 mg/day, the transdermal delivery will be very difficult if not
impossible. Daily
doses of less than 5 mg/day are preferred.
2. Skin irritation or contact dermatitis due to the drug, excipients
and enhancers of the
drug used to increase percutaneous absorption is another
limitation.
3. Clinical need is another area that has to be examined carefully
before a decision is
made to develop a transdermal product.
4. The barrier function of the skin changes from one site to another
on the same person,
form person to person and with age.
Bangalore.
2
Introduction
PRESENT STATUS
A review by Barry 10 in 2001 showed, the transdermal route has
vied with oral treatment
as the most successful innovative research area in drug delivery. In
the USA (the most
important clinical market), out of 129 drug delivery candidate
products under clinical
evaluation, 51 are transdermal or dermal systems; 30 % of 77
candidate products in
preclinical development represent such drug delivery. The
worldwide transdermal patch
market approaches £2 billion, yet is based on only 13 drug
molecules: fentanyl,
nitroglycerin, estradiol, ethinyl estradiol, norethindrone acetate,
testosterone, clonidine,
nicotine, lidocaine, prilocaine, scopolamine, norelgestromin and
oxybutynin 9. Few
molecules that are under clinical development are listed below.
Table No.1: Transdermal products that are in clinical
development
in the United States 9
COMPOUND
TDD TECHNOLOGY DEVELOPMENT
STAGE
Alprostadil
Gel Preclinical
Buprenorphine
Patch Phase
III
Dexamethasone
Iontophoresis Phase
III
Dextroamphetamine
Patch Preclinical
Diclofenac
Patch Preclinical
Dihydrotestosterone
Gel Phase
III
Estradiol
Gel Phase
III
Androgen/Estradiol
Patch Phase
II
Estradiol/Progestin
Patch Submitted
NDA
Testosterone/Estradiol
Patch Phase
III
Fentanyl
Patch, Iontophoresis
Preclinical to Phase III
Flurbiprofen
Patch Preclinical
Lidocaine
Iontophoresis Phase
III
Glucagon-like peptide-1
Microneedle Preclinical
Methylphenidate
Patch Submitted
NDA
Parathyroid hormone
Microneedle Preclinical
Rotigotine
Patch Phase
III
Testosterone
Gel Submitted
NDA
Vaccines
Patch Preclinical
Bangalore.
3
Introduction
1.2. SKIN 2
For Understanding the concept of transdermal drug delivery
systems, it is important to
review the structural and biochemical features of human skin and
those characteristics
which contribute to the barrier function and the rate of drug access
into the body via skin.
1.2.1. Physiology of skin
The skin is one of the most extensive organs of the human body
covering an area of about
2m2 in an average human adult. This multilayered organ receives
approximately one-third
of all blood circulating through the body. It has varied functions and
properties. With a
thickness of only a millimeter, the skin separates the underlying
blood circulation
network from the outside environment, serves as a barrier against
physical, chemical ad
microbial attacks, acts as a thermostat in maintaining body
temperature, protects against
harmful ultraviolet rays of the sun and plays a role in the regulation
of blood pressure.
Anatomically, the skin has many histological layers but in general, it
is described
in terms of three major tissue layers: the epidermis, the dermis and
the hypodermis. The
epidermis results from an active epithelial basal cell population and
is approximately 150
µm thick. It is the outermost layer of the skin and the process of
differentiation results in
migration of cells from the basal layer towards the skin surface. The
end result of this
process is the formation of a thin, stratified and extremely resilient
layer at the skin
surface. Below this layer are the other layers of the epidermis-the
stratum lucidum,
stratum granulosum, stratum spinosum and stratum germinativum.
Together, these other
layers constitute the viable epidermis. The stratum corneum or the
horny layer is the rate-
limiting barrier that restricts the inward and outward movement of
chemical substances.
Over most of the body, the stratum corneum is composed of 15 to
25 layers of acutely
Bangalore.
4
Introduction
Fig. No: 1 Cross section of Skin
flattened, metabolically inactive, somewhat polygonal cells having a

dry weight density
of 1.3-1.4 g/cm3. The thickness of individual cell layers varies from
0.2 µm to 0.5 µm
depending on their location. The interior of these cells is
crisscrossed with densely
packed bundles of keratin fibres. Due to this, the dry composition of
the horny layer is
75-85% protein, most of which is the intracellular keratin and a part
being associated
with a network of cell membranes. The bulk of the remainder of the
substance of the
stratum corneum is a complicated mixture of lipids which lies
between the cells. It
appears to be organised into bilayers. The stratum corneum thus
has two distinct chemical
regions, the mass of intracellular protein and the intercellular
lipoidal medium. The
epidermis rests on the much thicker (2000 µm) dermis.
Bangalore.
5
Introduction
A rich bed of capillaries is encountered 20 µm or so into the dermal
field. Also contained
within the dermis are lymphatics, nerves and the epidermal
appendages such as hair
follicles, sebaceous glands and sweat glands. Excepting the soles of
the feet, the palms of
the hand, the red portion of the lips and select portions of the sex
organs, the entire skin
surface contains hair follicles. Each hair follicle is associated with
one or more sebaceous
glands which are outgrowths of epithelial cells. The duct of
sebaceous gland is filled with
a soft, slowly extruded lipoidal medium-sebum. About 1/1000 of the
total skin surface is
occupied by hair follicles. The sweat glands are divided into the
eccrine and apocrine
types and are widely distributed over the surfaces of the body.
Eccrine glands are
particularly concentrated in palms and soles (400glands/cm2). The
apocrine glands are
found in the axillae (armpits), in anogenital regions and around
nipples. These are coiled
tubular glands, about ten times larger than eccrine glands and
extend entirely through the
dermis and well into the subcutaneous layer. The sweat glands
serve to control body heat
by secretion of a dilute salt solution.
1.2.2. Biochemistry of skin
Like other tissues of body, the skin has two metabolic requirements,
small molecular
weight building blocks and chemical energy. Dissimilarities peculiar
to the skin are
discussed here, as it might affect transdermal drug delivery.
Dermis
Protein synthesis (from amino acid precursors) is key factor in
dermal metabolism.
Fibroblasts produce and deposit extracellularly, huge quantities of
collagen and elastin.
This becomes important in repair/turnover of dermal proteins
altered by environmental
Bangalore.
6
Introduction
sunlight. Extensive protein synthesis also occurs in hair follicles
where hair, consisting of
approximately 95% protein originates.
The sebaceous glands produce large quantities of liquid. The energy
derived from the
intracellular aerobic carbohydrate metabolism is used for cellular
synthetic process.
Epidermis
The surface of energy for the lower portions of the epidermis is also
glucose and the end
product of metabolism, lactic acid accumulates in skin, which results
in a tissue pH from
the usual 7 to less than 6.
The cells rely primarily on fatty acids for cellular functions. These
fatty acids are derived
from the degradation of phospholipids from membranes. The energy
derived is used in
synthesis of the protein and lipids for construction of stratum
corneum.
During differentiation from basal cells to stratum corneum by
degradation of the existing
cellular components, the entire cellular make-up changes.
Specialised cellular organelles
called lysosomes contain a host of lytic enzymes which they release
for intracellular lysis.
The epidermis is reservoir of such lytic enzymes. Many of these
enzymes are inactivated
in upper granular layer; however, many also survive into the
stratum corneum. The
stratum corneum also has proteolytic enzymes involved in this
desquamation.
1.3. VARIOUS APPROACHES TO ENHANCE THE
TRANSDERMAL
PERMEATION OF DRUGS 1
1.3.1. PHYSICAL APPROACHES
a) Iontophoresis:
Iontophoresis is a process that facilitates the transport of ionic
species by the application
of a physiologically acceptable electrical current
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7
Introduction
b) Phonophoresis:
Phonophoresis, also known as sonophoresis, generally utilizes an
ultrasound apparatus
that generates frequencies of 0.7 to 1.1 MHz. The ultrasound
intensities employed usually
range from 0.0 to 3.0 Watts per cm2.
1.3.2. CHEMICAL APPROACH
1.3.2.1 Co administration of skin permeation enhancer:
Permeation Enhancers 33
These are compounds which promote skin permeability by altering

the skin as a barrier to
the flux of a desired penetrant. The flux, J, of drugs across the skin
can be written as:
dc
J=Ddx
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.
Mechanism of action of permeation enhancers
⇒
They act on the stratum corneum intracellular keratin, denature it to
or modify its
conformation causing swelling and increased hydration.
⇒
Effects desmosomes that maintain cohesion between corneocytes.
⇒
Modify the intracellular lipid domains to reduce the barrier
resistance of the
bilayer lipids.
⇒
Alter the solvent nature of the stratum corneum to modify
partitioning of the drug
or of a co-solvent into the tissue.
⇒
Modification of thermodynamic activity of the vehicle.
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Introduction
A large number of compounds have been investigated for their
ability to enhance stratum
corneum permeability. They are classified under following headings:
a) Solvents
These compounds increase penetration possibly by swelling the
polar pathway and/or by
fluidizing lipids. Examples include water alcohols - methanol and
ethanol; alkyl methyl
sulfoxides - dimethyl sulfoxide, alkyl homologs of methyl sulfoxide,
dimethyl acetamide
and dimethyl formamide; pyrrolidones - 2-pyrrolidone, N-methyl, 2-
pyrrolidone;
laurocapram (Azone), miscellaneous solvents - propylene glycol,
glycerol, silicone fluids,
isopropyl palmitate.
b) Surfactants
These compounds are proposed to enhance polar pathway
transport, especially of
hydrophilic drugs. The ability of a surfactant to alter penetration is a
function of the polar
head group and the hydrocarbon chain length. These compounds
are skin irritants;
therefore, a balance between penetration enhancement and
irritation has to be considered.
Anionic surfactants can penetrate and interact strongly with the
skin. Once these
surfactants have penetrated the skin, they can induce large
alterations. Cationic
surfactants are reportedly more irritant than the anionic surfactants
and they have not
been widely studied as skin permeation enhancers. Of the three
major classes of
surfactants, the nonionics have long been recognized as those with
the least potential for
irritation and have been widely studied. Examples of commonly
used surfactants are:
Anionic Surfactants: Dioctyl sulphosuccinate, Sodium lauryl
sulphate, Decodecylmethyl
sulphoxide etc.
Nonionic Surfactants : Pluronic F127, Pluronic F68, etc.
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9
Introduction
Bile Salts: Sodium taurocholate, Sodium deoxycholate, Sodium
tauroglycocholate.
c) Binary systems
These systems apparently open up the heterogeneous
multilaminate pathway as well as
the continuous pathway. Examples include: propylene glycol-oleic
acid and 1, 4-butane
diol-linoleic acid.
d) Miscellaneous chemicals
These include urea, a hydrating and keratolytic agent; N, N-
dimethyl-m-toluamide;
calcium thioglycolate; anticholinergic agents.
1.3.3. BIOCHEMICAL APPROACH
Synthesis of bioconvertible prodrugs
Prodrugs can be viewed as the therapeutically inactive derivatives
of a therapeutically
active drug. In a biological environment they undergo bioconversion,
either by hydrolytic
or enzymatic transformation, to regenerate the therapeutically
active parent drug before
reaching the target tissues to exhibit their pharmacological
activities. The objective of
applying bioconvertible prodrug concept to transdermal controlled
drug delivery is to
modify the skin permeability of a drug by altering its
physicochemical properties such
that its rate of transdermal permeation is greatly enhanced. A drug
with poor skin
permeability may be chemically modified to form a prodrug with
improved skin
permeation characteristics.

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Objectives
2. OBJECTIVES
Objectives of the study
The objective of the study is to optimize the conditions to deliver

Diclofenac sodium by
Transdermal drug delivery system i.e.
1. Effect of various solvents, polymers on the permeation rate.
2. Effect of permeation enhancers on the flux enhancement from the

selected
solvents and polymers.

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3. REVIEW OF LITERATURE
3.1. LITERATURE REVIEW

Sang 13 et al investigated percutaneous absorption of Piroxicam
from poloxamer
gels in rats. They have shown that the percutaneous absorption of
piroxicam from the gel
containing polyoxyethylene-2-oleyl ether as an enhancer was 1.8
fold higher than that
from the gel without enhancer. Percutaneous administration of
piroxicam gel containing
polyoxyethylene-2-oleyl ether to rats showed a relatively constant,
sustained blood
concentration with minimal fluctuation.
Yasuko 14 et al synthesized l-cyclohexanol derivatives for

percutaneous
absorption enhancers selecting l-menthol as lead compound. An in
vivo percutaneous
absorption study was performed using rats with hydrogel containing
ketoprofen and the
plasma concentration was determined after the application of
hydrogel to the abdominal
area of rats. They have suggested that the optimum log P value
reflects the promoting
activity to enhance percutaneous absorption.
Iervolivo 15 et al studied on the membrane penetration

enhancement of Ibuprofen
using super saturation formed using the cosolvent technique across
silicone as model
membrane. The flux of Ibuprofen was increased with the degree of
saturation prepared in
a 40:60 propylene glycol, water cosolvent mixture.
Elvira 16 et al studied on the transdermal permeation of diclofenac

sodium using
different liquid formulations. In-vitro permeation studies were
carried out using human
skin as membrane. They have reported that there is no skin
irritation with the inclusion of
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permeation enhancers like oleic acid. They suggested that the
topical delivery of
diclofenac sodium with an absorption enhancer such as oleic acid
and d-limonene may be
an effective for both dermal and subdermal injuries.
Valenta 17 et al studied the effect of permeation enhancers on the

permeation of
progesterone through porcine skin. In diffusion experiments with
porcine skin, there was
enhanced steady state flux of progesterone, it was increased upto
2.4 fold using 15 mol %
6-ketocholestanol and 1.4 fold using 30 mol % phloretin.
Cordero 18 et al carried out a comprehensive study of transdermal

penetration of
series of Nonsteroidal antiinflammatory drugs (Indomethacin,
Ketoprofen, Diclofenac
sodium, Piroxicam, Tenoxicam, Ketorolac, and Aceclofenac). They
have determined the
permeation parameters (permeability rate constant kp, lag time TL
and flux J) as a
measure of the intrinsic transdermal permeabilities of these drugs to
predict their
potential for formulation in a transdermal therapeutic system.
Diclofenac sodium had
highest value of in-vitro transdermal penetration at ~ 0%
ionization.
Dave 19 et al formulated diclofenac sodium gels containing

permeation enhancers
using carbomer as polymer. Formulation containing l-limonene
showed better flux
through excised rat skin than that of formulation containing same
composition without
limonene from 5% to 10% w/w. It was found that in presence of
higher amount of
ethanol, flux of diclofenac sodium through rat skin decreased.

Bangalore.
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Jonathan 20 et al conducted an analysis to show the penetration for

the selection of
non steroidal antiinflammatory agents (NSAIDs) through the skin.
They suggest that the
bioeffectiveness of the NSAIDs will be a function of both its
penetration through the skin
and its potency. Most NSAIDs are carboxylic acid, therefore the pKa
will be an important
determination in ionization and hence penetration.
Arellano 21 et al investigated the influence of propylene glycol on
the in vitro
penetration of Diclofenac sodium through a synthetic membrane
and abdominal rat skin
from carbopol gel. The gel containing 40 % PG showed the highest
permeation indicating
that a releasing maximum exists for PG content which provides the
fully solubilized drug
in the vehicle. Diclofenac sodium flux decreased with increasing PG
content of the gels
due to increase of the drug affinity to the vehicle. Maximum
enhancing activity was
obtained from gels containing 40 % PG which yielded an
enhancement ratio of about 8.
Increasing IPM content from 3 to 5 % increased the flux and
decreased the lag time taken
to reach a steady-state level.
Loganathan 22 et al studied the effects of polymers and permeation

enhancers of
Flurbiprofen from gel formulation. Flurbiprofen gel formulations were
made with
different polymers like carbopol, HPMC containing various
permeation enhancers at
different proportions having 1% concentration of drug. The
formulated gels were
evaluated for drug content, pH, viscosity and in vitro release
through the sigma
membrane. The physical stability study revealed that the carbopol
940 gels were highly
Bangalore.
14
stable and the gels with HPMC were physically unstable. In vivo
study for the selected
formulations showed significant (P<0.001) antiinflammatory activity
in rat.
Pandey 23 et al prepared different transdermal nimesulide gels

using sodium
alginate, HPMC, sodium CMC and methylcellulose. In-vitro release
studies of the
prepared formulation were performed using dialysis membrane. The
release pattern of
drug from the marketed gel was found to be better than from other
gels, the reason may
be that the 66% alcohol content of the gels that might have
enhanced the solubility of the
drug.
Gohel 24 et al reported on the application of simplex lattice design
for the
development of transdermal gels diclofenac sodium. They have
prepared and evaluated
diclofenac sodium gels using Acrypol 940 as gelling agent. A simplex
lattice design was
employed for preparation of the gel possessing optimized
characteristics. The amount of
ethanol, propylene glycol and polyethylene glycol 400 were chosen
as the independent
variables to study the combined effect of cosolvents.
Patavardhan 25 et al have developed and evaluated the formulation

of diclofenac
sodium hydroxy ethyl pyrrolidine containing penetration enhancers.
They formulated the
DHEP gel using carbopol 940 and 941 grade separately
incorporating different
penetration enhancers, and evaluated for their physicochemical
properties. In-vitro drug
permeation studies were carried out in a keshary-chien glass
diffusion cells using freshly
isolated guinea pig skin for all the formulation in comparison with
gels containing no
penetration enhancers.
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Sang 26 et al have developed tretinoin gels using carbopol. The
release
characteristics of drug from the carbopol gel were compared in
different conditions
(temperature, receptor medium and drug concentration). It is
observed that the
concentration in the donor had influence on the permeation rate.
Jae 27 et al carried out a study to determine the feasibility of using

gel formulation
for the transdermal delivery of triamcinolone acetonide (TA) and to
develop the carbopol
gels of TA.
Babua 28 et al have designed and evaluated different gel reservoir

type
formulation of bupranolol (BPL) with penetration enhancers. They
have excised rat skin
as a barrier for permeation experiments. The release rate of BPL
from nonionic polymer
gel reservoirs (HPMC) was much higher than anionic polymer gel
reservoirs (sodium
CMC, sodium alginate). Permeation rates of the devices containing
(5% w/v) pyrrolidine
or 1-methyl –2-pyrrolidone were about 3 and 1.5 fold higher than
control.
Estelle 29 et al have studied the influence of the physicochemical

and
pharmacokinetic properties of selected NSAIDs on their transdermal
absorption after
topical gel administration. They have concluded that most reliable
parameter for
transdermal absorption was lipophilic character of a drug (log P
value). The molecular
mass, solubility constraint and percentage unionized moiety can
only be used in
combination with other properties in the prediction of possible
Transdermal drug
delivery.
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3.2. DRUG PROFILE 3, 4, 5, 6, 8
DICLOFENAC SODIUM: (Phenyl acetic acid derivative NSAID)
Physicochemical properties
Molecular
weight
: 318.1
Category : Analgesic, anti-inflammatory

Molecular formula
: C H Cl NNaO
14 10
2
2
CH COONa
Structure
2
NH
Cl
Cl
Chemical name
: [2-(2, 6-Di chloro phenyl) amino] benzene
acetic acid mono sodium salt
Description : Odorless, white or off-white crystalline,

slightly hygroscopic powder.
Solubility : Freely soluble in methanol, soluble in

ethanol (95%), sparingly soluble in water
and glacial acetic acid, practically insoluble
in ether, chloroform, toluene.
Melting
point
: 283-286°C
Storage : Store at room temperature and protect from

moisture.

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MECHANISM OF ACTION:
The term NSAID is an abbreviation of a class of drugs known as non-

steroidal anti-
inflammatory drugs. This nomenclature was given to the class as a
differentiation from
steroids, the other major anti-inflammatory class of drugs. In
addition to their
antiinflammatory effects, agents belonging to the NSAID class
possess both analgesic
and antipyretic activities.
Diclofenac sodium belongs to a group of medicines called non-
steroidal anti-
inflammatory drugs (NSAIDs). Prostaglandins are a related family of
chemicals that are
produced by the cells of the body and have several important
functions. They promote
inflammation, pain, and fever, support the function of platelets that
are necessary for the
clotting of blood, and protect the lining of the stomach from the
damaging effects of acid.
Prostaglandins are produced within the body's cells by the enzyme
cyclooxygenase
(Cox). There actually are two Cox enzymes, Cox-1 and Cox-2. Both
enzymes produce
prostaglandins that promote inflammation, pain, and fever.
However, only Cox-1
produces prostaglandins that support platelets and protect the
stomach. Nonsteroidal anti-
inflammatory drugs (NSAIDs) block the Cox enzymes and reduce
prostaglandins
throughout the body. As a consequence, ongoing inflammation,
pain, and fever are
reduced. Since the prostaglandins that protect the stomach and
support the platelets and
blood clotting also are reduced, NSAIDs can cause ulcers in the
stomach and promote
bleeding. NSAIDs differ in how strongly they inhibit Cox-1 and,
therefore, in their
tendency to cause ulcers and promote bleeding.Most NSAIDs act as
non-selective
inhibitors of the enzyme cyclooxygenase, inhibiting both the
cyclooxygenase-1 (COX-1)
and cyclooxygenase-2 (COX-2) isoenzymes.
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Pharmacokinetic data 6
Table No.2
Bioavailability (Oral)
54 ± 2 %
Urinary excretion
<1%
Bound in plasma
> 99.5 %
Clearance (ml min-1 kg-1)
4.2 ± 0.9
Volume of distribution (L kg-1)
0.17 ± 0.11
Half-life (hours)
1.1 ± 0.2
Peak time (hours) for SR*
5.3
Effective concentration (µg/ml)for SR * 0.42 ± 0.17
* SR: Sustained release tablet
THERAPEUTIC INFORMATION:
Indications:
⇒ Inflammatory and degenerative forms of rheumatism: rheumatoid
arthritis,
ankylosing spondylitis, osteoarthritis and rheumatism.
⇒ Post-traumatic and postoperative pain, inflammation, and
swelling, e.g.
following dental or orthopaedic surgery.
⇒ Painful and/or inflammatory conditions in gynaecology, e.g.
primary
dysmenorrhoea or adexitis.
Adverse effects:
Gastro-intestinal tract:
Occasional: epigastric pain, other gastro-intestinal disorders (e.g.
nausea, vomiting,
diarrhoea)
Rare: Gastro-intestinal bleeding, peptic ulcer.
In isolated cases: peptic ulcer with perforation lower gut disorders
(e.g. non-specific
haemorrhagic colitis and exacerbations of ulcerative
colitis),constipation, pancreatitis
Dose: For the symptomatic treatment of acute chronic rheumatoid
arthritis, 150 mg
daily, administered in divided doses of 75 mg (delayed release
tablets only) twice daily or
50 mg 3 times daily.
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3.3. EXCIPIENT PROFILE 7
3.3.1. ALCOHOL
Synonyms: Ethyl alcohol; ethyl hydroxide; grain alcohol; methyl

carbinol.
Chemical Name: Ethanol.
Empirical Formula: C2H6O
Molecular weight: 46.07

Structural Formula: C2H5OH
Functional Category: Antimicrobial preservative; disinfectant; skin
penetrant; solvent.
Applications:
Ethanol is primarily used as a solvent; it is also employed in
solutions as an antimicrobial
preservative. Topical ethanol solutions are also used as penetration
enhancers and as
disinfectants.
Description: Alcohol is clear, colorless, mobile and volatile liquid
with a slight,
characteristic odor and burning taste.
Solubility: miscible with chloroform, ether, glycerin and water (with
rise of temperature
and contraction of temperature and contraction of volume).
Stability and Storage Conditions: Aqueous ethanol solutions
may be sterilized by
autoclaving or by filtration and should be stored in airtight
containers, in a cool place.
Incompatibilities: In acidic conditions, ethanol solutions may react
vigorously with
oxidizing materials. Mixtures with alkali may darken in color due to a
reaction with
residual amounts of aldehyde. Ethanol solutions are also
incompatible with aluminum
containers and may interact with some drugs.

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3.3.2. CARBOMER
Synonyms: Acritamer; acrylic acid polymer; Carbopol; carboxyvinyl
polymer.
Chemical Name: Carboxypolymethylene
Functional Category: Emulsifying agent; suspending agent;
viscosity increasing agent.
Applications: Carbomers are used mainly in liquid or semisolid
pharmaceutical
formulations as suspending or viscosity-increasing agents.
Formulations include creams,
gels, and ointments, and may be used in ophthalmic, rectal and
topical preparations.
Use
Concentration (%)
Emulsifying agent
0.1-0.5
Gelling agent
0.5-2.0
Description: Carbomers are white-colored, ‘fluffy’, acidic,

hygroscopic powders with a
slight characteristic odor.
Solubility: soluble in water, and after neutralization in ethanol
(95%) and glycerin.
Viscosity: Carbomers disperse in water to form acidic colloidal
solutions of low viscosity
which when neutralized produce highly viscous gels. Agents used to
neutralize Carbomer
include sodium hydroxide, polar organic solvents such as
triethanolamine.
Stability and Storage Conditions: Carbomers are stable, though
hygroscopic materials,
and may be heated at temperatures below 104oC for up to two
hours without affecting
their thickening efficiency. However, exposure to excessive
temperatures can result in
discoloration and reduced stability. Complete decomposition occurs
on heating for 30
minutes at 260oC.
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Dry powder forms of Carbomer do not support the growth of molds
and fungi. However,
microorganisms grow well in unpreserved aqueous Carbomer
dispersions and therefore
an antimicrobial preservative such as 0.1% w/v chlorocresol, 0.1%
w/v methyl paraben
should be added.
At room temperature, Carbomer dispersions maintain their viscosity
during storage for
prolonged periods of time. Exposure to light causes oxidation, which
is reflected in a
decrease in dispersion viscosity. The UV stability of Carbomer gels
may also be
improved by using triethanolamine as the neutralizing base.
Carbomer powder should be stored in an airtight, corrosion resistant
container in a cool,
dry, place.
Incompatibilities: Carbomers are discolored by resorcinol and are
incompatible with
phenol, cationic polymers, strong acids and high concentrations of
electrolytes. Intense
heat may be generated if a Carbomer is in contact with a strongly
basic material such s
ammonia, potassium hydroxide, sodium hydroxide, or strongly basic
amines.
3.3.3. HYDROXY PROPYL METHYL CELLULOSE

Synonyms: Cellulose, Hydroxypropyl methyl ether; E464 HPMC;
Methocel;
methylcellulose propylene glycol ether; methyl hydroxylcellulose;
Pharmacoart.
Chemical Name: Cellulose, 2-hydroxuypropyl methyl ether.
Molecular Weight: 10 000-1500 000
Functional Category: Coating agent; film-former; stabilizing
agent; suspending agent;
tablet binder; viscosity-increasing agent.
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Applications: HPMC is widely used in oral and topical
pharmaceutical formulations.
HPMC is used as a suspending and thickening agent in topical
formulations.
Description: HPMC is an odorless and tasteless, white or creamy-
white colored fibrous
or granular powder.
Solubility: soluble in cold water, forming a viscous colloidal
solution; practically
insoluble in chloroform, ethanol (95%) and ether, but soluble in
mixtures of ethanol and
dichloromethane, and mixtures of methanol and dichloromethane.
Stability and Storage Conditions: HPMC powder is a stable
material although it is
hygroscopic after drying. Increasing temperature reduces the
viscosity of solutions.
Hydroxypropyl methylcellulose powder should be stored in a well-
closed container, in a
cool, dry, place.
Incompatibilities: HPMC is incompatible with some oxidizing
agents. Since it is
nonionic, HPMC will not complex with metallic salts and ionic
organics to form
insoluble precipitates.
3.3.4. MENTHOL
Synonyms: Hexahydrothymol; 2-isopropyl-5-methylcyclohexanol;
4-iso-propyl-1-
methylcyclohxan-3-ol; p-menthon-3-ol; peppermint camphor;
racemic menthol.
Chemical Name: (+)-5-Methyl-2-(1-methylethyl) cyclohexanol.
Empirical Formula: C10H20O
Molecular Weight: 156.27
Functional Category: Flavoring agent; therapeutic agent.

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Applications:
Menthol is widely used in pharmaceuticals, confectionery and
toiletry products as a
flavoring agent or odor enhancer. In addition to its characteristic
peppermint flavor, l-
menthol, which occurs naturally, also exerts a cooling or refreshing
sensation which is
exploited in many topical preparations. Unlike mannitol, which
exerts similar effect due
to a negative heat of solution, l-menthol interacts directly with the
body’s coldness
receptors. d-Menthol has no cooling effect, while racemic menthol
imparts an effect
approximately half that of l -menthol.
Description: Racemic menthol is a mixture of equal parts of the
(1R, 2S, 5R) and
(1S,2R,5S)- isomers of menthol. It is a free flowing and
agglomerated crystalline powder
or colorless, prismatic of acicular shiny crystals, with a strong
characteristic odor and
taste. The crystalline form may change with time due to sublimation
within closed vessel.
Solubility: very soluble in ethanol (95%), chloroform and ether;
very slightly soluble in
glycerin; practically insoluble water.
Stability and Storage Conditions: Store in a well-closed
container at a temperature not
exceed 25oC, since methanol sublimes readily.
Incompatibilities: Incompatible with β-naphthol, butylchloral
hydrate, chromium
trioxide, phenol, potassium permanganate, pyrogallol, resorcinol
and thymol

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3.3.5. METHYL CELLULOSE
Synonyms: Benecel; Celacol; Culminal MC; Methocel; Metolose.

Chemical Name: Cellulose methyl ether.
Functional Category: Coating agent; emulsifying agent;
suspending agent; tablet and capsule
disintegrant; tablet binder; viscosity-increasing agent.
Description: Methylcellulose occurs as practically odorless and
tasteless, white to yellowish-
white colored granules or as a powder.
Applications:
Methylcellulose is widely used in oral and topical pharmaceutical
formulations. High viscosity
grades of methylcellulose are used to thicken topically applied
products such as creams and gels.
An antimicrobial preservative such as benzalkonium chloride should
also be included. For gels
1-5% should be used.
Stability and Storage Conditions:
Methylcellulose powder is stable although it is slightly hygroscopic.
Solutions of methylcellulose
are stable to alkalis and dilute acids between pH 3-11 at room
temperature. At less than pH 3, the
viscosity of methylcellulose solutions are reduced.
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3.3.6. OLEIC ACID
Synonyms: Crodolene; elaic acid; Emersol; Glycon; Groco; Hy-Phi;
Industrene;
Metaupon; Neo-Fat; cis-9-octadecenoic acid; 9,10-octadecenoic acid;
oleinic acid.
Chemical Name: (Z)-9-Octadecenoic acid
Empirical Formula: C18H34O2
Molecular Weigh: 282.47

Structural Formula: CH3 (CH2)7CH=CH (CH2)7COOH
Functional Category: Emulsifying agent; skin penetrant.
Applications: Oleic acid is used as an emulsifying agent in foods
and topical
pharmaceutical formulations. It has also been used as penetration
enhancer in transdermal
formulations, to improve the bioavailability of poorly water soluble
drugs in tablet
formulation, and as part of a vehicle in soft gelatin capsules.
Description: A yellowish to pale brown, oily liquid with a
characteristic odor.
Solubility: very soluble in benzene, chloroform, ethanol (95%),
ether, hexane, fixed and
volatile oils; practically insoluble in water.
Stability and Storage Conditions: On exposure to air oleic acid
darkens in color and its
odor becomes more pronounced.
Oleic acid should be stored in a well-filled, well-closed container,
protected from light, in
a cool, dry, place.

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3.3.7. PROPYLENE GLYCOL
Synonyms: 1, 2-Dihydroxypropane; 2-hydroxypropanol; methyl
ethylene glycol; methyl
glycol; propane-1, 2-diol.
Chemical Name: 1, 2-Propanediol Empirical Formula: C3 H8 O2
Structural Formula: CH3CHOHCH2OH
Functional Category: Antimicrobial preservative disinfectant;
humectant; plasticizer;
solvent; stabilizer for vitamins; water-miscible cosolvent.
Applications: Propylene glycol has become widely used as a
solvent, extractant and
preservative in a variety of parenteral and nonparenteral
pharmaceutical formulations. It
is a better general solvent than glycerin and dissolves a wide variety
of materials. Used as
Humectant ∼ 15 (%), Solvent or cosolvent 5-80 (%) in Topicals.
Description
Propylene glycol is a clear, colorless, viscous, practically odorless
liquid with a sweet,
slightly acrid taste resembling glycerin.
Solubility: Miscible with acetone, chloroform, ethanol (95%),
glycerin and water;
soluble 1 in 6 parts of ether; not miscible with light mineral oil or
fixed oils, but will
dissolve some essential oils.
Stability: At cool temperatures, propylene glycol is stable in a well-
closed container, but
at high temperatures, in the open, it tends to oxidize, giving rise to
products such as
propionaldehyde, lactic acid, pyruvic acid and acetic acid. Propylene
glycol is chemically
stable when mixed with ethanol (95%), glycerin, or water; aqueous
solutions may be
sterilized by autoclaving.
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3.3.8. SODIUM CHLORIDE
Synonyms: Common salt; natural halite; rock salt; salt; sea salt;
table salt.
Chemical Name: Sodium Chloride
Structural Formula: NaCl
Functional category: Tablet and capsule diluent; tonicity agent.
Applications: Sodium chloride is widely used in a variety of
parenteral and nonprenteral
pharmaceutical formulations. Its primary use, in parenteral and
ophthalmic preparations,
is to produce isotonic solutions.
Description: Sodium chloride occurs as a white crystalline powder
or colorless crystals;
it has a saline taste. The crystal lattice is a face centered cubic
structure.
Solubility: The solubility of sodium chloride in different solvents is;
slightly soluble in
ethanol, 1 in 250 for ethanol (95%), 1 in 2.8 for water.
Stability and Storage Conditions: Aqueous sodium chloride
solutions are stable but
may cause the separation of glass particles from certain types of
glass containers. The
sodium material is stable and should be stored in a well-closed
container, in a cool, dry,
place.
Incompatibilities: Aqueous sodium chloride solutions are corrosive
to iron, they can
react to form precipitates with silver, lead and mercury salts. Strong
oxidizing agents
liberate chlorine from acidified solutions of sodium chloride.

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3.3.9. TRIETHANOLAMINE
Synonyms: TEA; triethylolamine; trihydroxytriethylamine; tris
(hydroxyethyl) amine.
Chemical Name: 2, 2’, 2”-Nitrilotriethanol
Empirical Formula: C6H15NO3
Structural Formula: N (CH2CH2OH) 3
Functional Category: Alkalizing agent; emulsifying agent.
Applications: Triethanolamine is widely used in topical
pharmaceutical formulations
primarily in the formation of emulsions. When mixed in
equimolecular proportions with
a fatty acid, such as stearic or oleic acid, triethanolamine forms an
anionic soap which
may be used as an emulsifying agent to produce fine grained,
stable, oil-in-water
emulsions with a pH of about 8.
Description: The USPNF XVII describes triethanolamine as a
variable mixture of
alkanolamines consisting largely of triethanolamine with some
diethanolamine and
monoethanolmine.
Triethanolamine is a clear, colorless to pale yellow-colored viscous
liquid having a slight
ammoniacal odor.
Solubility: Triethanolamine is miscible in ethanol (95%) methanol
and water.
Stability and Storage Conditions: Triethanolamine may turn
brown on exposure to air
and light. The 85% grade of triethanolamine tends to stratify below
15oC; homogeneity
can be restored by warming and mixing before use. Triethanolamine
should be stored in
an airtight container, protected from light, in a cool, dry, place.
Incompatibilities: Triethanolamine is a tertiary amine which
contains a hydroxy group.
It is thus capable of undergoing reactions typical of tertiary amines
and alcohols.
Bangalore.
29
Methodology
4. METHODOLOGY
Materials used and their sources

Diclofenac sodium - BPRL, Bangalore
Carbopol 941- Rohm Pharma- Germany
HPMC- Rolex Laboratories- Bangalore
Methyl cellulose- E-Merck- Mumbai
Menthol - S.d. fine chem Limited, Mumbai
Octanol - Ranbaxy Fine Chemicals, New Delhi
Oleic acid - Merck Limited, Mumbai
Propylene glycol - S.d. fine chem Limited, Mumbai
Sodium Chloride - Ranbaxy Fine Chemicals, New Delhi
Triethanolamine- Spectrochem- Bangalore
All the other chemicals used were of analytical grade.
Instruments and Equipments used and their make
Constant temperature water bath - Analytical technologies,
Bangalore
Diffusion cell – Neutron scientific, Kolkata
Digital pH meter - Dig sun Electronics - DI 707, Mumbai
Electronic Balance - Shimadzu AX 200, Japan
Hot Air Oven - Analytical technologies, Bangalore
Micropipette - Tarsons Accupipet - T1000, Mumbai
Magnetic Stirrer with Hot Plate - Remi Equipments, Ambala
Rotary Shaker - Analytical technologies, Bangalore
UV Visible Spectrophotometer - Shimadzu -1601, Japan
Bangalore.
30
Methodology
4.1. Standard curve of Diclofenac sodium in water
Weighed 50 mg of diclofenac sodium, dissolved in 50 ml of water in

a volumetric flask
(stock solution I). From stock solution I, 10 ml solution was taken
and the volume was
made (100ml) with water (stock solution II). From stock solution II,
aliquots of 2, 4, 6, 8,
10, 12 ml solution was drawn and transferred to 50 ml volumetric
flasks and the volume
was made up. UV Absorbance is noted at 276 nm, using water as
blank.
Table No. 3: Spectrophotometric data of standard curve for
diclofenac sodium in water
Sl No
Concentration
Absorbance
µg/ml (x)
at 276 nm
10
0
24
0.153
38
0.306
4 12
0.445
5 16
0.593
6 20
0.760
7 24
0.904
Fig No. 2: Standard curve for Diclofenac sodium in water

λmax: 276 nm
1
y = 0.0376x + 0.0002
R2 = 0.9997
0.8
0.6
b
sorbance
0.4
A
0.2
0
0
5
10
15
20
25
Concentration (µ g/ml)

Bangalore.
31
Methodology
4.2. Physico-chemical parameters of diclofenac sodium

a) Determination of Melting Point
Small quantity of diclofenac sodium was taken in capillary tube

(fused at one end),
placed in melting point apparatus and the temperature at which
drug melts was recorded.
b) Solubility measurements 44
A normal equilibrium solubility determination was carried out by the

method of Okumara
et al. An excess amount of drug was added and dissolved in

measured amount of distilled
water in a glass vial to get a saturated solution. The system was
stirred for 24 hours at
25°C and kept at rest for 1 hour to assist the attainment of
equilibrium. The solution was
then filtered through a membrane filter and diluted. The solubility of
drug was
determined spectrophotometrically at 276 nm.
c) Partition coefficient determination 41
n-Octanol and distilled water were presaturated with each other for
atleast 24 hours
before the experiment. To the pre-equilibrated water (10 ml), known
quantity of drug is
dissolved. Ten ml of octanol was added to equal volume of aqueous
solution of drug in a
separating funnel. The system was kept for 24 hours with
intermittent shaking. Finally,
the aqueous layer was separated, clarified by centrifugation and
assayed
spectrophotometrically.
4.3 Physico-chemical parameters of porcine skin 45
a) Determination of Lipid content
Lipid content in stratum corneum was measured by the method of
Raykar et al with slight
modification. Pre-weighed dry stratum corneum samples were
placed in 10 ml screw cap
glass tubes containing 7 ml of 2:1 chloroform- methanol mixture and
shaken for 20 hours
Bangalore.
32
Methodology
at room temperature. At the end of this period, the de-lipidized
stratum corneum samples
were removed, rinsed with fresh chloroform /methanol mixture, and
dried to constant
weight. The lipid content of the stratum corneum was determined by
its change in weight
of solvent extraction.
b) Water uptake by the skin
Accurately weighed stratum corneum samples were placed in glass
tubes containing 7 ml
of water and equilibrated at 37°C for 72 hours. At the end of this
period the samples were
gently blotted to remove excess water and immediately weighed.
Water uptake was
calculated by weight change in stratum corneum.
4.4. DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY

SYSTEM FOR
DICLOFENAC SODIUM
4.4.1. Preparation of diclofenac Sodium Solutions
Table No.4: Percentage Composition (w/w) of the Diclofenac Sodium

Solutions
Ingredients (w/w)
A1
A2
A3
P1
P2
P3
Diclofenac sodium
50 75 100 50 75 100
Alcohol
333---
Propylene Glycol
---333
Water q.s
10 10 10 10 10 10
a. Alcohol/water co-solvent solution
A solution of diclofenac sodium in alcohol/water cosolvent mixtures

(30% alcohol and
70% water) was prepared by weighing 50, 75,100 mg diclofenac
sodium. It was dissolved
in 3ml of alcohol separately, in 10 ml volumetric flask and volume is
made up to 10ml.
Passive permeation study was carried out using 2ml of the above
solution.
Bangalore.
33
Methodology
b. PG /water co-solvent solution
A solution of diclofenac sodium in alcohol/water cosolvent mixtures

(30% PG and 70%
water) was prepared by weighing 50, 75,100 mg diclofenac sodium.
It was dissolved in
3ml of PG separately, in 10 ml volumetric flask and volume is made
up to 10ml.
Passive permeation study was carried out using 2ml of the above
solution.
4.4.2. PREPARATION OF DICLOFENAC SODIUM GEL
Polymer (table.1) was taken in a beaker and added distilled water.
This was allowed to
soak for 24 hours. Diclofenac sodium was dissolved along with other
excipients in
ethanol (30%w/w) and added to the dispersion of polymer with
stirring to get a
homogeneous dispersion of drug in the gel. (pH of the gel is
adjusted with
Triethanolamine when carbopol gel are prepared).
Determination of viscosity
Viscosity of gels was determined using LV-2 spindle in a Brookefield
Viscometer Model
LVDV-E, USA.
Bangalore.
34
Methodology
Table No.5: Percentage composition (w/w) of the diclofenac sodium

gels
Formulations
COMPONENT
C 1 C 2 C 3 H 1 H 2 H 3 M 1 M 2 M 3 CPE1 CPE2 HPE1 HPE2

MPE1 MPE2
Diclofenac sodium
1 1.5 2 1 1.
5
2
1
1.
5
21
1
1
1
1
1
Carbopol
1 1 1 -- -- -- -- -- -- 1 1 -- -- -- --
HPMC
--
--
--
3
3
3
--
--
--
-- -- 3 3 -- --
Methyl cellulose
-- -- -- -- -- -- 5 5 5 -- -- -- -- 5
5
Triethanolamine
0.7
0.7
0.7 -- -- -- -- -- -- 0.7 0.7 -- -- -- --
Menthol
-- -- -- -- -- -- -- -- -- 5 -- 5 -- 5 --
Oleic acid
-- -- -- -- -- -- -- -- -- -- 5 -- 5 -- 5
Ethanol
30 3
0
3
0
3
0
3
0
3
0
3
0
3
0
3
0
3
0
3
0
3
0
3
0
3
0
3
0
Distilled water (q.s) 100 10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
10
0
Bangalore.
35
Methodology
4.4.3. In vitro permeation studies
a. Preparation of skin membrane
Ear was obtained from a local abattoir of freshly slaughtered pigs.
The skin was removed
carefully from the outer region of the ear and separated from the
underlying cartilage
with a scalpel. After separating the full thickness skin, the fat
adhering to the dermis side
was removed using a scalpel and isopropyl alcohol. Finally, skin was
washed in tap water
and stored at -200 C in aluminum foil packing and was used within a
week.
b. Procedure of drug diffusion through skin membrane
The in vitro permeation studies were performed using a Franz
diffusion cell. The excised
skin was mounted between the half-cells with the dermis in contact
with receptor fluid,
0.9% NaCl and was equilibrated for 1 hr. The receiving chamber had
a volume of 50 ml
and the area available for diffusion was about 1.74 cm2. The donor
cell was covered with
an aluminum foil to prevent the evaporation of vehicle. The fluid in
the receptor
compartment was maintained at 37 ±0.5° C. Under these
conditions, the temperature at
the skin surface was 32 ±0.5° C, the skin sections were initially left
in the Franz cells for
2 hr in order to facilitate the hydration of membranes. After this
period, 2ml of the
appropriate formulation (binary solution of PG and water or binary
solution of ethanol
and water) of diclofenac sodium (1mg, 1.5mg, 2mg) or 1grm of gel
was deposited on to
the surface of each skin sample. For chemical enhancer studies, the
formulation contained
5% v/v concentration of the appropriate enhancer (either menthol or
oleic acid) dissolved
in appropriate drug solution. The receptor fluid 10 ml was with
drawn at regular intervals
and replaced with fresh 37°C normal saline to maintain sink
condition. The samples were
assayed after suitable dilution using UV-visible spectrophotometer
at 276nm.
Bangalore.
36
Methodology
c. Data analysis
Cumulative amount of drugs permeated per unit skin surface area
was plotted against
time and the slope of the linear portion of the plot was estimated as
the steady-state flux
(Jss). Permeability coefficient (kp) was calculated by using the
equation kp = Jss/CV;
where CV is the total donor concentration of the solute or gel.
Enhancement factor (EF) in
fold is calculated by the equation.
s te a d y - s ta te f lu x o f g e ls w ith p e r m e a tio n e n h a n c e r
s
EF=
s te a d y - s ta te f lu x o f p a s s iv e p e r m e a tio n
Both Student’s t-test and one-way analysis of variants (ANOVA) were

utilized as an
appropriate to test the various treatment effects.

Bangalore.
37
Results
5. RESULTS
PHYSICO-CHEMICAL PARAMETERS OF DICLOFENAC SODIUM

Melting Point: Melting Point of diclofenac sodium was found to be
2850 C.
Table No.6: Physicochemical parameters of diclofenac sodium
Parameter
I
II
III
Mean
S.E
Solubility *
1.78
1.83
1.85
1.82
0.0294
(mg/ml)
Solubility **
1.43
1.36
1.40
1.39
0.0287
(mg/ml)
pKa
4.12 4.08 4.15 4.17 0.0252
* Solubility in water at 25°C

** Solubility in 0.9% w/v NaCl
pKa – Dissociation constant
PHYSICO-CHEMICAL PARAMETERS OF PORCINE SKIN
Table 7: Physicochemical parameters of Porcine skin

PARAMETER
I
II
III
Mean
S.E
Lipid
content
(%)
37.20 62.77 60.51 53.49 11.5580
Water Uptake
3.55 3.90 4.75 4.06 0.503
(mg/ml)

Bangalore.
38
Results
Table No.8: Permeation data of diclofenac sodium from alcohol:

water (30:70) (A 1)
Time
Flux through skin (µmol/cm2)
(hours)
Mean
S.E
I II III
1
0.844 0.855 0.838 0.845 0.0072
2
1.035 1.037 1.035 1.035 0.0011
3
1.248 1.264 1.262 1.258 0.0072
4
1.597 1.615 1.591 1.601 0.0103
5
1.881 1.887 1.858 1.872 0.0099
6
2.100 2.126 2.146 2.123 0.0187
7
2.426 2.430 2.489 2.448 0.0287
8
2.690 2.682 2.685 2.685 0.0033
9
2.865 2.888 2.851 2.868 0.0149

water (30:70) (A 2)
Time
(hours)
Mean
S.E
I II III
1
0.952 0.976 0.963 0.963 0.0097
2
1.168 1.179 1.177 1.174 0.0048
3
1.388 1.398 1.394 1.393 0.0040
4
1.757 1.710 1.760 1.742 0.0228
5
2.038 1.960 2.050 2.015 0.0399
6
2.339 2.261 2.376 2.320 0.0477
7
2.713 2.646 2.756 2.704 0.0453
8
2.940 2.867 2.954 2.910 0.0511
9
3.147 3.089 3.131 3.122 0.0242

water (30:70) (A 3)
Time
(hours)
Mean
S.E
I II III
1
1.108 1.122 1.120 1.116 0.0059
2
1.343 1.391 1.400 1.377 0.0250
3
1.633 1.644 1.667 1.648 0.0142
4
2.031 2.070 2.058 2.053 0.0163
5
2.397 2.404 2.398 2.400 0.0028
6
2.631 2.659 2.718 2.668 0.0360
7
2.968 3.017 3.059 3.014 0.0371
8
3.166 3.248 3.315 3.242 0.0606
9
3.418 3.462 3.540 3.473 0.0504
Bangalore.
39
Results
Table No.11: Permeation data of diclofenac sodium from PG: water

(30:70) (P 1)
Time
(hours)
Mean
S.E
I II III
1
0.792 0.801 0.806 0.799 0.0057
2
0.926 0.943 0.936 0.935 0.0069
3
1.030 1.039 1.024 1.031 0.0061
4
1.213 1.230 1.222 1.221 0.0069
5
1.539 1.586 1.558 1.561 0.0193
6
1.831 1.824 1.819 1.824 0.0049
7
2.121 2.134 2.129 2.128 0.0053
8
2.440 2.399 2.436 2.425 0.0184
9
2.636 2.621 2.629 2.628 0.0061

(30:70) (P 2)
Time
(hours)
Mean
S.E
I II III
1
0.814 0.824 0.830 0.822 0.0065
2
0.962 0.960 0.959 0.960 0.0012
3
1.179 1.184 1.190 1.184 0.0044
4
1.384 1.389 1.396 1.389 0.0049
5
1.742 1.731 1.736 1.736 0.0044
6
2.016 2.011 2.010 2.012 0.0026
7
2.321 2.333 2.346 2.333 0.0102
8
2.708 2.714 2.719 2.713 0.0044
9
2.919 2.924 2.930 2.924 0.0044

(30:70) (P 3)
Time
(hours)
Mean
S.E
I II III
1
0.921 0.929 0.931 0.927 0.0043
2
1.106 1.111 1.122 1.113 0.0066
3
1.371 1.392 1.384 1.382 0.0086
4
1.651 1.648 1.639 1.646 0.0050
5
2.050 2.048 2.041 2.046 0.0038
6
2.410 2.415 2.419 2.414 0.0036
7
2.656 2.659 2.648 2.654 0.0046
8
3.010 3.019 3.024 3.017 0.0057
9
3.240 3.231 3.229 3.233 0.0047
Bangalore.
40
Results
Table No.14: Permeation data of diclofenac sodium gel using

carbopol (C 1)
Time
(hours)
Mean
S.E
I II III
1
0.824 0.862 0.871 0.852 0.0203
2
1.008 1.092 1.076 1.059 0.0364
3
1.198 1.319 1.277 1.264 0.0499
4
1.458 1.576 1.567 1.533 0.0538
5
1.753 1.776 1.803 1.777 0.0203
6
1.944 1.950 2.003 1.956 0.0264
7
2.206 2.203 2.276 2.228 0.0336
8
2.433 2.342 2.450 2.408 0.0462
9
2.534 2.546 2.623 2.595 0.0352
carbopol (C 2)
Time
(hours)
Mean
S.E
I II III
1
0.910 0.885 0.902 0.899 0.0105
2
1.135 1.141 1.130 1.135 0.0045
3
1.334 1.347 1.333 1.338 0.0062
4
1.634 1.649 1.644 1.642 0.0060
5
1.861 1.865 1.863 1.863 0.0016
6
2.073 2.093 2.081 2.083 0.0082
7
2.345 2.363 2.340 2.349 0.0096
8
2.493 2.570 2.518 2.527 0.0308
9
2.665 2.697 2.700 2.688 0.0158

carbopol (C 3)
Time
(hours)
Mean
S.E
I II III
1
0.990 0.933 0.963 0.962 0.0234
2
1.174 1.214 1.160 1.182 0.0224
3
1.390 1.436 1.367 1.398 0.0284
4
1.694 1.692 1.665 1.683 0.0129
5
1.938 1.917 1.917 1.923 0.0101
6
2.128 2.139 2.131 2.133 0.0044
7
2.440 2.426 2.405 2.423 0.0142
8
2.668 2.590 2.597 2.618 0.0354
9
2.879 2.823 2.797 2.833 0.0343
Bangalore.
41
Results

HPMC (H 1)
Time
(hours)
Mean
S.E
I II III
1
0.812 0.777 0.712 0.767 0.0415
2
1.087 1.052 0.972 1.037 0.0478
3
1.281 1.253 1.165 1.233 0.0491
4
1.537 1.552 1.444 1.510 0.0477
5
1.671 1.726 1.663 1.663 0.0270
6
1.829 1.884 1.833 1.848 0.0243
7
2.049 2.125 2.045 2.073 0.0234
8
2.185 2.266 2.207 2.219 0.0336
9
2.300 2.450 2.363 2.324 0.0308

HPMC (H 2)
Time
(hours)
Mean
S.E
I II III
1
0.840 0.852 0.857 0.849 0.0068
2
1.090 1.074 1.068 1.076 0.0095
3
1.292 1.315 1.287 1.297 0.0120
4
1.617 1.634 1.610 1.620 0.0101
5
1.873 1.881 1.864 1.872 0.0071
6
2.062 2.072 2.058 2.131 0.0918
7
2.342 2.359 2.346 2.349 0.0070
8
2.549 2.563 2.522 2.545 0.0168
9
2.702 2.692 2.690 2.695 0.0049

HPMC (H 3)
Time
(hours)
Mean
S.E
I II III
1
0.855 0.982 0.953 0.930 0.0533
2
1.164 1.324 1.230 1.239 0.0647
3
1.390 1.570 1.459 1.475 0.0710
4
1.698 1.960 1.809 1.822 0.1066
5
1.864 2.123 2.074 2.020 0.1120
6
2.107 2.313 2.336 2.251 0.1026
7
2.388 2.573 2.620 2.527 0.0994
8
2.578 2.735 2.828 2.902 0.1022
9
2.763 2.920 3.025 2.902 0.1064
Bangalore.
42
Results
Table No.20: Permeation data of diclofenac sodium gel using MC (M

1)
Time
(hours)
Mean
S.E
I II III
1
0.556 0.561 0.574 0.563 0.0073
2
0.708 0.725 0.720 0.717 0.0068
3
0.920 0.933 0.920 0.924 0.0059
4
1.252 1.213 1.231 1.232 0.0159
5
1.507 1.452 1.462 1.474 0.0228
6
1.690 1.678 1.698 1.688 0.0823
7
1.857 1.862 1.904 1.874 0.0207
8
1.944 1.960 2.067 1.990 0.0547
9
2.083 2.097 2.237 2.139 0.0694

2)
Time
(hours)
Mean
S.E
I II III
1
0.589 0.604 0.585 0.593 0.0081
2
0.797 0.810 0.803 0.803 0.0050
3
1.022 1.031 1.000 1.017 0.0127
4
1.372 1.360 1.325 1.352 0.0190
5
1.647 1.655 1.594 1.632 0.0268
6
1.804 1.811 1.752 1.788 0.0264
7
2.004 2.002 1.948 1.985 0.0257
8
2.177 2.179 2.111 2.156 0.0316
9
2.343 2.326 2.262 2.310 0.0348

3)
Time
(hours)
Mean
S.E
I II III
1
0.612 0.632 0.617 0.619 0.0085
2
0.819 0.815 0.817 0.861 0.0015
3
1.040 1.018 1.014 1.023 0.0111
4
1.335 1.329 1.321 1.328 0.0055
5
1.620 1.598 1.564 1.594 0.0834
6
1.864 1.852 1.822 1.845 0.0175
7
2.163 2.116 2.133 2.137 0.0190
8
2.342 2.287 2.326 2.318 0.0229
9
2.490 2.436 2.483 2.469 0.0238
Bangalore.
43
Results
carbopol
with permeation enhancer (menthol) (C-PE 1)
Time
(hours)
Mean
S.E
I II III
1
1.401 1.460 1.432 1.431 0.0240
2
1.764 1.798 1.732 1.764 0.0269
3
2.156 2.109 2.132 2.132 0.0191
4
2.524 3.509 2.536 2.523 0.0110
5
3.067 3.098 3.035 3.063 0.0299
6
3.304 3.317 3.296 3.305 0.0086
7
3.750 3.741 3.734 3.741 0.0065
8
4.014 4.001 3.996 4.003 0.0075
9
4.181 4.170 4.167 4.172 0.0060

carbopol
with permeation enhancer (oleic acid) (C-PE 2)
Time
(hours)
Mean
S.E
I II III
1
1.318 1.296 1.289 1.301 0.0123
2
1.569 1.518 1.521 1.536 0.0233
3
1.989 1.976 2.032 1.999 0.0239
4
2.333 2.301 2.343 2.325 0.0179
5
2.876 2.841 2.865 2.860 0.0146
6
3.051 3.010 3.079 3.046 0.0280
7
3.229 3.234 3.314 3.259 0.0389
8
3.421 3.476 3.404 3.433 0.0307
9
3.751 3.704 3.739 3.731 0.0199
Table No.25: Permeation data of diclofenac sodium gel using HPMC

with permeation enhancer (menthol) (H-PE 1)
Time
(hours)
Mean
S.E
I II III
1
1.369 1.404 1.390 1.387 0.0143
2
1.601 1.594 1.587 1.594 0.0057
3
1.978 1.990 1.981 1.983 0.0050
4
2.239 2.220 2.214 2.224 0.0106
5
2.871 2.863 2.859 2.864 0.0049
6
3.032 3.019 2.996 3.015 0.0148
7
3.218 3.240 3.211 3.223 0.0123
8
3.401 3.464 3.424 3.429 0.0260
9
3.459 3.561 3.536 3.518 0.0434
Bangalore.
44
Results
with permeation enhancer (oleic acid) (H-PE 2)
Time
(hours)
Mean
S.E
I II III
1
1.234 1.301 1.276 1.270 0.0276
2
1.612 1.546 1.514 1.557 0.0408
3
1.814 1.803 1.794 1.803 0.0081
4
2.106 2.089 2.112 2.102 0.0097
5
2.694 2.681 2.679 2.684 0.0066
6
2.916 2.901 2.894 2.903 0.0091
7
3.107 3.094 3.079 3.093 0.0114
8
3.214 3.201 3.156 3.190 0.0248
9
3.319 3.379 3.346 3.348 0.0245

with permeation enhancer (menthol) (M-PE 1)
Time
(hours)
Mean
S.E
I II III
1
0.985 1.044 1.059 1.029 0.0319
2
1.203 1.304 1.244 1.250 0.0414
3
1.592 1.573 1.564 1.576 0.0113
4
1.798 1.774 1.734 1.768 0.0263
5
1.997 2.041 1.986 2.008 0.0237
6
2.364 2.341 2.305 2.336 0.0242
7
2.769 2.801 2.809 2.793 0.0172
8
3.109 3.041 3.021 3.057 0.0376
9
3.332 3.312 3.345 3.329 0.0135
Table No.28: Permeation data of diclofenac sodium gel using MC

with permeation enhancer (oleic acid) (M-PE 2)
Time
(hours)
Mean
S.E
I II III
1
0.970 0.981 0.979 0.976 0.0047
2
1.204 1.198 1.216 1.206 0.0074
3
1.497 1.514 1.542 1.517 0.0185
4
1.792 1.764 1.749 1.768 0.0178
5
1.904 1.932 1.914 1.916 0.0115
6
2.309 2.315 2.329 2.321 0.0129
7
2.713 2.741 2.726 2.726 0.0114
8
3.104 3.010 2.993 3.035 0.0488
9
3.302 3.294 3.289 3.295 0.0053
Bangalore.
45
Results
Table No.29: Steady state flux Jss for every 3 hours of diclofenac
sodium gels
Formulation Steady state flux Jss ( µ mol/cm2/h) for every 3

hours
code
For 0-3 hr
For 3-9 hr
For 6-9 hr
Mean ± SE
Mean ± SE
Mean ± SE
A1
0.419 ± 0.0021 0.288
± 0.0041
0.248 ± 0.0092
A2
0.458 ± 0.0089
0.310 ± 0.0169
0.265 ± 0.0105
A3
0.549 ± 0.0045
0.336 ± 0.0114
0.267 ± 0.0049
P1
0.343 ± 0.0020
0.264 ± 0.0026
0.267 ± 0.0020
P2
0.394 ± 0.0012
0.276 ± 0.0024
0.303 ± 0.0020
P3
0.460 ± 0.0028
0.344 ± 0.0012
0.272 ± 0.0024
C1
0.421 ± 0.0065
0.233 ± 0.0166
0.200 ± 0.0043
C2
0.445 ± 0.0023
0.247 ± 0.0012
0.201 ± 0.0036
C3
0.465 ± 0.0095
0.244 ± 0.0082
0.233 ± 0.0120
H1
0.410 ± 0.0165
0.204 ± 0.0167
0.173 ± 0.0127
H2
0.432 ± 0.0040
0.255 ± 0.0021
0.209 ± 0.0028
H3
0.490 ± 0.0247
0.259 ± 0.0233
0.216 ± 0.0110
M1
0.307 ± 0.0023
0.254 ± 0.0046
0.149 ± 0.0209
M2
0.338 ± 0.0041
0.256 ± 0.0047
0.173 ± 0.0040
M3
0.341 ± 0.0035
0.273 ± 0.0036
0.207 ± 0.0106
C-PE 1
0.710 ± 0.0061
0.390 ± 0.0083
0.288 ± 0.0033
C-PE 2
0.666 ± 0.0080
0.349 ± 0.0040
0.228 ± 0.0057
H-PE 1
0.660 ± 0.0016
0.344 ± 0.0053
0.167 ± 0.0179
H-PE 2
0.601 ± 0.0024
0.366 ± 0.0047
0.147 ± 0.0103
M-PE 1
0.525 ± 0.0037
0.253 ± 0.0044
0.330 ± 0.0110
M-PE 2
0.505 ± 0.0062
0.266 ± 0.0032
0.325 ± 0.0044
Bangalore.
46
Results
Table No.30: Permeation parameters of diclofenac sodium gels
Steady state flux Jss

Permeability coefficient
Enhancement
Formulation µ mol/cm2/h (for 9 hours)
kp x 10-3(cm/h)
Factor (fold)
Code
Mean ± SE
Mean ± SE
Mean ± SE
A1
0.252 ± 0.0012
8.025 ± 0.0392
--
A2
0.269 ± 0.0041
5.725 ± 0.0881
--
A3
0.294 ± 0.0058
4.680 ± 0.0935
--
P1
0.228 ± 0.0014
7.260 ± 0.0445
--
P2
0.262 ± 0.0004
5.569 ± 0.0095
--
P3
0.287 ± 0.0009
4.580 ± 0.0140
--
C1
0.214 ± 0.0037
6.814 ± 0.1190
1
C2
0.223 ± 0.0029
4.734 ± 0.0624
--
C3
0.233 ± 0.0032
3.720 ± 0.0526
--
H1
0.200 ± 0.0102
6.379 ± 0.3259
1
H2
0.230 ± 0.0012
4.889 ± 0.0263
--
H3
0.246 ± 0.0009
3.922 ± 0.1458
--
M1
0.196 ± 0.0070
6.252 ± 0.2415
1
M2
0.214 ± 0.0040
4.520 ± 0.1270
--
M3
0.230 ± 0.0040
3.672 ± 0.0642
--
C-PE 1
0.342 ± 0.0037
10.891 ± 0.1183
1.596 ± 0.0174
C-PE 2
0.303 ± 0.0020
9.670 ± 0.0658
1.418 ± 0.0090
H-PE 1
0.266 ± 0.0035
8.471 ± 0.1132
1.330 ± 0.0177
H-PE 2
0.259 ± 0.0008
8.248 ± 0.0269
1.295 ± 0.0036
M-PE 1
0.287 ± 0.0043
9.139 ± 0.1372
1.463 ± 0.0219
M-PE 2
0.289 ± 0.0012
9.213 ± 0.0396
1.475 ± 0.0060

Bangalore.
47
Results
4
D ic lo fe n a c s o d iu m 1 % (A 1 )
3 .5
D ic lo fe n a c s o d iu m 1 .5 % (A 2 )
)2
D ic lo fe n a c s o d iu m 2 % (A 3 )
3
cm
2 .5
µ
mol/
in (
2
e sk
h th
1 .5
1
x
throug
Flu
0 .5
0
0
2
4
6
8
10
T im e (h )
F i g N o .3 : P e r m e a ti o n pr o fi l e s o f d i c l o fe n a c s
o d i u m s o l u ti o n s w i th
d i ffe r e n t c o n c e n tr a ti o n s u s i n g a l c o h o l :w a
te r (3 0 :7 0 )
4
D ic lo fe n a c s o d iu m 1 % (P 1 )
3 .5
D ic lo fe n a c s o d iu m 1 .5 % (P 2 )
)2
D ic lo fe n a c s o d iu m 2 % (P 3 )
3
cm
2 .5
µ
mol/
in (
2
e sk
h th
1 .5
1
x
throug
Flu
0 .5
0
0
2
4
6
8
10
T im e (h )
F i g N o .4 : P e r m e a ti o n p r o fi l e s o f di c l o fe n a c s
o di u m s o l u ti o n s w i th
d i ffe r e n t c o n c e n tr a ti o n s u s i n g P G :w a te r (3 0
:7 0 )

Bangalore.
48
Results
3.5
D ic lo fe n a c s o d iu m 1 % (C 1 )
3
D ic lo fe n a c s o d iu m 1 .5 % (C 2 )
)2
cm 2 .5
µ
mol/
2
in (
e sk 1 .5
h th
1
x
throug
0.5
Flu
0
0
2
4
6
8
T im e ( h )
10
F i g N o . 5 : P e r m e a ti o n p r o fi l e s o f d i c l o fe n a c
s o d i u m g e l s w i th d i ffe r e n t
c o n c e n tr a ti o n s u s i n g c a r b o p o l
3.5
D ic lo fe n a c s o d iu m 1 % (H 1 )
3
D ic lo fe n a c s o d iu m 1 .5 % (H 2 )
)2
cm 2 .5
µ
mol/
2
in (
e sk 1.5
h th
1
x
throug
Flu 0 .5
0
0
2
4
T im e ( h )
6
8
10
F i g N o . 6 :P e r m e a ti o n pr o fi l e s o f d i c l o fe n a c s
o d i u m g e l s a t d i ffe r e n t
c o n c e n tr a ti o n s u s i n g H P M C

Bangalore.
49
Results
3
D ic lo fe n a c s o d iu m 1 % (M 1 )
2.5
D ic lo fe n a c s o d iu m 1 .5 % (M 2 )
)2
cm
2
µ
mol/
in ( 1 .5
e sk
h th
1
x
throug 0 .5
Flu
0
0
2
4
6
8
10
T im e ( h )
F i g N o .7 : P e r m e a ti o n p r o fi l e s o f d i c l o fe n a c
s o d i u m g e l s a t d i ffe r e n t
c o n c e n tr a ti o n s u s i n g m e th y l c e l l u l o s e
D ic lo fe n a c
D ic lo fe n a c
0.25
D ic lo fe n a c
s o d iu m 2 %
s o d iu m 1 .5 %
s o d iu m 1 %
r)
0.2
/h2
l/cm
mo 0 .1 5
µ
J
ss (
ux
0.1
0.05
Steady state fl
0
C1
C2
C3
F o rm u la t io n
F i g N o .8 : C o m p a r i s o n o f s te a dy s ta te fl u x e s o
f d i c l o fe n a c s o d i u m g e l s a t
d i ffe r e n t c o n c e n tr a ti o n s u s i n g c a r b o p o l

Bangalore.
50
Results
0.4
Menthol5%
0.35
r)
O le ic a c id 5 %
/h2
0.3
l/cm
w it h o u t
0.25
mo
enhancer
µ
0.2
J
ss (
ux
0.15
0.1
0.05
Steady state fl
0
C1
C-PE1
C-PE2
F o m u la t io n
F i g N o .9 : C o m p a r i s o n o f s te a d y s ta te fl u x e s o
f d i c l o fe n a c s o d i u m g e l s
u s i n g c a r b o p o l w i th a n d w i th o u t d i ffe r e n t p
e r m e a ti o n e n h a n c e r s
0.3
D ic lo fe n a c
D ic lo fe n a c
s o d iu m 2 %
0.25
r)
D ic lo fe n a c
s o d iu m 1 .5 %
/h2
s o d iu m 1 %
l/cm
0.2
mo
µ
0.15
J
ss (
ux
0.1
0.05
Steady state fl
0
H1
H2
H3
F o rm u la t io n
F i g N o .1 0 : C o m p a r i s o n o f s te a d y s ta te fl u x e s
o f d i c l o fe n a c s o d i u m g e l s a t
d i ffe r e n t c o n c e n tr a ti o n s u s i n g H P M C

Bangalore.
51
Results
0.3
Menthol5%
O le ic a c id 5 %
0.25
r)
w it h o u t
/h2
enhancer
l/cm
0.2
mo
µ
0.15
J
ss (
ux
0.1
0.05
Steady state fl
0
H1
H-PE1
H-PE2
F o rm u la t io n
o f d i c l o fe n a c s o d i u m g e l s
u s i n g H P M C w i th a n d w i th o u t d i ffe r e n t p e r m
e a ti o n e n h a n c e r s
D ic lo fe n a c
0 .2 5
D ic lo fe n a c
s o d iu m 2 %
D ic lo fe n a c
s o d iu m 1 .5 %
s o d iu m 1 %
r)
/h
0 .2
2
l/cm
mo
0 .1 5
µ
J
ss (
0 .1
ux
0 .0 5
Steady state fl
0
M1
M2
M3
F o rm u la t io n
d i ffe r e n t c o n c e n tr a ti o n s u s i n g m e th y l c e l l u
lose

Bangalore.
52
Results
0.35
Menthol5%
O le ic a c id 5 %
0.3
r)
/h2
0.25
l/cm
w it h o u t
mo
e n h a n c e rs
µ
0.2
J
ss (
ux
0.15
0.1
0.05
Steady state fl
0
M1
M-PE1
M-PE2
F o rm u la t io n
u s i n g m e th y l c e l l u l o s e w i th a n d w i th o u t d i
ffe r e n t p e r m e a ti o n e n h a n c e r s
8
D ic lo fe n a c
)
/h
s o d iu m 1 %
2
7
(cm
–3
6
D ic lo fe n a c
x 10
s o d iu m 1 .5 %
5
D ic lo fe n a c
t
kp
4
s o d iu m 2 %
efficien
3
co
ility
2
1
Permeab
0
C1
C2
C3
F o rm u la t io n
F i g N o .1 4 : C o m p a r i s o n o f p e r m e a b i l i ty c o e
ffi c i e n t o f d i c l o fe n a c s o d i u m
g e l s a t d i ffe r e n t c o n c e n tr a ti o n s u s i n g c a r b
opol

Bangalore.
53
Results
12
Menthol5%
)
/h2
O le ic a c id 5 %
10
(cm
–3
w it h o u t
8
x 10
enhancer
t
kp
6
efficien
4
co
ility
2
0
C1
CPE1
CPE2
F o rm u la t io n
g e l s u s i n g c a r b o p o l w i th a n d w i th o u t d i ffe r e
n t p e r m e a ti o n e n h a n c e r s
8
D ic lo fe n a c
) Permeab
/h2
7
s o d iu m 1 %
(cm
–3
6
D ic lo fe n a c
10
s o d iu m 1 .5 %
x
5
D ic lo fe n a c
t
kp
s o d iu m 2 %
4
efficien
3
co
ility
2
1
Permeab
0
H1
H2
H3
F o rm u la t io n
g e l s a t d i ffe r e n t c o n c e n tr a ti o n s u s i n g H P M
C

Bangalore.
54
Results
10
)
9
Menthol5%
/h
O le ic a c id 5 %
2
8
w it h o u t
(cm
–3
enhancer
7
10
x
6
t
kp
5
efficien
4
co
3
ility
2
1
0
H1
H -P E 1
H -P E 2
F o rm u la t io n
g e l s u s i n g H P M C w i th a n d w i th o u t d i ffe r e n t p
D ic lo fe n a c
7
) Permeab
s o d iu m 1 %
/h2
6
(cm
–3
D ic lo fe n a c
10
5
s o d iu m 1 .5 %
x
D ic lo fe n a c
t
kp
4
s o d iu m 2 %
efficien
3
co
ility
2
1
Permeab
0
M1
M2
M3
F o rm u la t io n
g e l s a t d i ffe r e n t c o n c e n tr a ti o n s u s i n g m e th
ylcellulose

Bangalore.
55
Results
10
Menthol5%
O le ic a c id 5 %
)
/h2
9
(cm
8
w it h o u t
–3 10
7
enhancer
x
6
t
kp
5
efficien
4
co
3
ility
2
1
Permeab
0
M1
M -P E 1
M -P E 2
F o rm u la t io n
g e l s u s i n g m e th y l c e l l u l o s e w i th a n d w i th o u
t d i ffe r e n t p e r m e a ti o n
enhancers
0 .5
C3
C2
C1
D ic lo fe n a c s o d iu m 1 .5 % (C 2 )
r)
0 .4
/h2
l/cm
0 .3
mo
µ
C1
C2
C3
C3
J
ss (
C1
C2
0 .2
ux
0 .1
Steady state fl
0
0 -3
3 -6
6 -9
T im e In t e rv a l
a t d i ffe r e n t c o n c e n tr a ti o n s u s i n g c a r b o p o l
(E ve r y 3 h r s )

Bangalore.
56
Results
0 .8
C-PE1
D ic lo fe n a c s o d iu m 1 % (w ith o u t e n h a n c e r)
C-PE2
0 .7
r)
/h
D ic lo fe n a c s o d iu m 1 % (w ith m e n th o l 5 % )
2
0 .6
D ic lo fe n a c s o d iu m 1 % (w ith o le ic a c id 5 % )
l/cm
mo 0 .5
µ
C1
C-PE1
J
ss ( 0.4
C-PE2
ux
C-PE1
0 .3
C1
C-PE2
C1
0 .2
Steady state fl 0 .1
0
0 -3
3 -6
6 -9
u s i n g c a r b o p o l w i th a n d w i th o u t d i ffe r e n t p
e r m e a to n e n h a n c e r s
(E ve r y 3 h r s )
0 .6
H3
D ic lo fe n a c s o d iu m 1 .5 % (H 2 )
0 .5
H2
r)
H1
/h2 0.4
l/cm
mo
H3
µ
0 .3
H2
J
ss (
H1
H2
H3
ux
0 .2
H1
0 .1
Steady state fl
0
0 -3
3 -6
6 -9
a t d i ffe r e n t c o n c e n tr a ti o n s u s i n g H P M C (E ve
ry3hrs)

Bangalore.
57
Results
0.8
H-PE1
0.7
r)
H-PE2
/h2 0 .6
l/cm 0 .5
mo
H1
µ
H-PE2
0.4
H-PE1
J
ss (
ux 0 .3
H1
H1
0.2
H - P E 1 H -P E 2
0.1
Steady state fl
0
0-3
3-6
6-9
T im e In t e rv e l
u s i n g H P M C w i th a n d w i th o u t d i ffe r e n t pe r m e
a ti o n e n h a n c e r s
(E ve r y 3 h r s )
0 .4
M2M3
D ic lo fe n a c s o d iu m 1 .5 % (M 2 )
r)
M1
/h2 0.3
M3
l/cm
M1
M2
mo
µ
M3
J
ss ( 0 .2
M2
ux
M1
0 .1
Steady state fl
0
0-3
3-6
6-9
T im e I n t e r v e l
d i ffe r e n t c o n c e n tr a ti o n s u s i n g m e th y l ve l l u
l o s e (E ve r y 3 h r s )

Bangalore.
58
Results
0.6
M-PE1
M-PE2
r)
0.5
/h2
l/cm
0.4
mo
M-PE1M-P E2
µ
M1
J
ss (
0.3
M1M-PE1M-PE2
ux
M1
0.2
0.1
Steady state fl
0
0-3
3-6
6-9
T im e In t e rv e l
u s i n g m e th y l c e l l u l o s e w i th a n d w i th o u t d i
ffe r e n t p e r m e a ti o n e n h a n c e r s
(E ve r y 3 h r s )
1.8
Menthol5%
1.6
O le ic a c id 5 %
1.4
1.2
1
t
i
n
f
o
l
d
en
0.8
h
a
n
cem
0.6
0.4
F
l
u
x
en
0.2
0
CPE1
CPE2
F o rm u la t io n
F i g N o .2 6 : C o m p a r i s o n o f fl u x e n h a n c e m e n t
(fo l d ) o f d i c l o fe n a c s o d i u m
g e l s u s i n g c a r b o p o l w i th d i ffe r e n t p e r m e a ti
onenhancers

Bangalore.
59
Results
1 .6
Menthol5%
O le ic a c id 5 %
1 .4
1 .2
1
e
n
t
i
n
0 .8
l
d
fo
n
c
e
m
0 .6
nha
0 .4
F
l
ux e
0 .2
0
HPE1
HPE2
F o rm u la t io n
g e l s u s i n g H P M C w i th d i ffe r e n t p e r m e a ti o n e
nhancers
1 .6
Menthol5%
O le ic a c id 5 %
1 .4
1 .2
1
t
i
n
f
o
l
d
en 0 .8
0 .6
h
a
n
cem
0 .4
F
l
u
x
en
0 .2
0
MPE1
MPE2
F o rm u la t io n
g e l s u s i n g m e th y l c e l l u l o s e w i th d i ffe r e n t p

Bangalore.
60
Discussion
6. DISCUSSION
Recently, there has been resurgence in development of transdermal
system for therapeutic
use because of its better safety profile, better bioavailability, and
better patient
compliance. Numerous products are available in market as
transdermal patches.
However, these constitute only ten molecules of different categories
including Non-
steroidal anti-inflammatory drugs (NSAIDs) 9.
NSAIDs are the drugs most commonly used to reduce inflammation
and pain. Oral
therapy is very effective, but the clinical use is often limited because
of their potential to
cause adverse effects such as irritation and ulceration of the
gastrointestinal (GI) mucosa.
Administration of these agents via the dermal route can by pass
these disadvantages of
the oral route and may maintain relatively consistent plasma levels
for long-term therapy
from a single dose. The adverse effects associated with oral
diclofenac sodium include
gastric and duodenal irritation. Furthermore diclofenac is subjected
to fast first-pass
metabolism with only 50% of the absorbed dose available
systemically11. An improved
diclofenac formula with a high degree of skin permeation could be
useful in the treatment
of not only locally inflamed skin tissues, but also inflammatory and
painful states of
supporting structures of the body – bones, ligaments, joints, tendons
and muscles 16.
Drug delivery through the transdermal route is limited due to the
low permeability of the
skin. The stratum corneum, the outermost layer of the skin acts as a
major barrier and is
often rate limiting. There is continuous search for novel methods to
enhance skin
permeation 15. Out of several techniques, the use of permeation
enhancers is being widely
investigated 22, 31, 37. Permeation enhancers can enter the
hydrophobic tails of the stratum
corneum lipid layer disrupting their packing, increasing their fluidity
and decreasing
Bangalore.
61
Discussion
diffusion resistance to permeation. The permeation of the drugs
through the skin is highly
dependent on the physicochemical properties of the drug such as
solubility, partition
coefficient and pKa.
Initially, the saturated solubility of the drug in water was determined
at 250 C. Since the
receptor fluid was 0.9% w/v NaCl, the saturated solubility was also
determined in this
medium. The values were depicted in the Table No.6. The drug has a
relatively high
solubility in water (1.83 mg/ml) than in 0.9% w/v NaCl (1.39 mg/ml)
indicating an
overall low solubility in the later.
The partition coefficient (p) was determined in the n-octanol and
water systems at 250 C.
The n-octanol-water partition coefficient serves as a parameter of
lipophilicity. The
values are depicted in the Table No.6, and the mean was found to
be 4.17.
Physicochemical parameters of porcine skin like lipid content
(53.49%), water uptake
(4.06 mg/ml) was also determined to identify the variation in the
skin used. However,
there was not much difference in the lipid content and water uptake
values are shown in
Table No.7.
Permeation studies were carried out using a Franz diffusion cell with
diffusion area of
1.74 cm2. The drug was delivered from the donor as solution form
or as gel. However in
both the cases it was occluded using aluminum foil to prevent the
evaporation of solvent.
Attempts were not made to remove the hairs of porcine skin, to
avoid the accidental
damage to epidermis.
In the first attempt, the permeation studies were carried out using
diclofenac sodium
solutions at different concentrations 1%, 1.5% and 2% in alcohol:
water (30: 70) co
solvent mixture (A 1, A 2, and A 3) and PG: water co solvent
mixtures (P 1, P 2, & P 3).
Bangalore.
62
Discussion
The permeation rates are depicted in Table No. 8, 9, 10 for alcohol:
water cosolvent
mixtures and in table no 11, 12, and 13 for PG: water cosolvent
mixtures. As the
concentration of drug increased, as expected, the cumulative
amount of drug permeated
also increased, in both the cases. The permeation profile was similar
in all the cases.
However the initial hour permeation was slightly higher when
compared to later hours.
No significance difference (p> 0.001) was observed between the
two mixtures. When the
permeability coefficients were compared, the solvent system with
alcohol has showed a
slightly higher value than its counterpart. However, the permeability
coefficients
decreased with increase in concentration. As alcohol containing
system showed greater
permeability coefficient, further studies were carried using this
system.
Secondly, gels were prepared at different concentrations (1%, 1.5%
and 2%) using
carbopol 1% (C 1, C 2 and C 3), HPMC 3% (H 1, H 2 and H 3), methyl
cellulose 5% (M
1, M 2 and M 3) using formula as shown in Table No.5. To maintain
uniform viscosity of
the gel, carbopol 1%, HPMC 3%, methyl cellulose 5% were used in
the preparation of
gels. The cumulative amount of drug permeated from diclofenac
sodium with1%, 1.5%,
and 2% gels using carbopol, HPMC, methyl cellulose are show in
Table No.14 to 22.
Comparison of permeation profiles of diclofenac sodium gels at
different concentration
using carbopol are shown in Fig No.5, HPMC in Fig No.6 and
methylcellulose in Fig
No.7. The permeation profile was more or less similar in all the
cases. Comparison of
steady state fluxes of diclofenac sodium gels are shown in Fig No.8,
10, and 12. The
permeation increased with increase in concentration here too.
Among the polymers,
HPMC has shown the highest permeation while methyl cellulose
showed the least.
However, there was no significant difference in the permeation rate.
When compared to
Bangalore.
63
Discussion
the permeation of diclofenac sodium from gel with solution, no
significant difference was
recorded in any cases. (p>0.001)
The steady state fluxes of the drug were when compared, it
increases with increase in
concentration in all the cases (Figure No. 8, 10, 12). Similarly when
permeability
coefficients were compared, the highest value was recorded at 1%
level. Among the
polymers, carbopol have shown the maximum value (6.814 cm/h).
Comparing the permeability coefficients, it can be concluded that
diclofenac sodium 1%
gels prepared using different polymers showed better permeability
coefficients as shown
in Fig No.14, 16, and 18. Hence diclofenac sodium 1% gels were
optimized for the
further studies.
In an attempt to enhance the permeation of diclofenac sodium,
menthol (5%) and oleic
acid (5%) were used as permeation enhancers. Both permeation
enhancers used in the
study showed improved flux through the skin (p< 0.05). The
cumulative amount of drug
permeated from diclofenac sodium gels using different polymers
with permeation
enhancers, menthol 5% and oleic acid 5% were depicted in Table
No.23 to 28. Addition
of permeation enhancers increased the steady state flux (Fig No. 9,
11, 13), and
permeability coefficient (Fig No 15, 17, 19). To determine the effect
of permeation
enhancers, data were represented in folds. In another attempt to
assess the permeation
rate, steady state fluxes were calculated for every 3 hours.
Flux enhancement (in fold) with menthol 5% and oleic acid for
different polymers was
depicted in Fig No. 26, 27 and 28. Diclofenac sodium gels prepared
using carbopol with
menthol 5% has shown highest flux enhancement of 1.596 fold and
1.418 fold with oleic
acid at 5%.Oleic acid 5% addition has increased the flux of
diclofenac sodium gels using
Bangalore.
64
Discussion
methylcellulose upto 1.475 fold. Formulations with addition of
enhancers in order of
increase in flux enhancement decreased as follows,
C-PE 1 >M-PE 2 >M-PE 1 >C-PE 2 >H-PE 1 >H-PE 2: 1.596 >1.475
>1.463 >1.418
>1.330 >1.295
The enhancement by the permeation enhancers may be attributed
by its known
mechanisms given below.
Menthol preferentially distributes into the intercellular spaces of
stratum corneum and
possibly causes the reversible disruption of lipid domains, thus
enhancing the permeation
of drugs 31. Oleic acid has cis double bond at C9, which causes a
kink in the alkyl chain
and disrupts the skin lipids more effectively 16.

Bangalore.
65
Conclusion
7. CONCLUSION
The present study was an attempt to develop transdermal drug
delivery for diclofenac
sodium. In order to select suitable solvent system for the
formulation of diclofenac gels,
alcohol: water, PG: water co solvent mixtures were selected for the
preparation of
solutions; effect of these solvents on the permeation of diclofenac
sodium was studied.
Diclofenac sodium gels at different concentrations were prepared
using different
polymers like carbopol, HPMC, methyl cellulose. To maintain uniform
viscosity of the
gel, carbopol (1%), HPMC (3%), methyl cellulose (5%) were used in
the preparation of
gels. Permeation enhancers like menthol 5% and oleic acid 5% were
used to study their
effect on the permeation rate. It was found that addition of menthol
5% in diclofenac gel
prepared using carbopol showed maximum flux enhancement of
1.596 fold.
Bangalore.
66
Summary
8. SUMMARY
Diclofenac sodium, a NSAID widely used in the treatment of
rheumatic disorders and
other chronic inflammatory diseases. Administration of these agents
via dermal route can
bypass various disadvantages caused when administered orally and
may maintain
relatively consistent plasma levels for long-term therapy.
The present study is an attempt to develop transdermal drug
delivery system for
diclofenac sodium. Alcohol: water (30:70) cosolvent system was
selected for the
preparation of diclofenac sodium gels using different polymers
(carbopol, HPMC, methyl
cellulose), as it has better permeability coefficient in comparison
with propylene glycol:
Water (30:70) cosolvent. Permeation through the porcine skin was
carried using 0.9%
w/v sodium chloride solution as receptor fluid in a Franz diffusion
cell (1.74 cm2). Gels
containing 1% diclofenac sodium with different polymers has shown
better permeability
coefficient in comparison with 1.5% and 2%. Hence 1% diclofenac
sodium gel was
selected & used for further studies containing menthol (5%) and
oleic acid (5%) as
permeation enhancers. Diclofenac sodium gels formulated using
carbopol with
permeation enhancer as showed better flux enhancement in
comparison with gels
formulated using HPMC and methylcellulose. Carbopol gel with
menthol 5% shown
maximum flux enhancement of 1.596 fold in comparison with oleic
acid 5% (1.418). It
can be concluded that diclofenac sodium (1%) gels prepared using
carbopol as polymer
have shown better flux enhancement with menthol (5%) as
permeation enhancer.

Bangalore.
67
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Bangalore.
72
Annexures
LIST OF TABLES
Table
Page
No
Title of Table
No.
1
Transdermal products that are in clinical development
03
2
Pharmacokinetic data of diclofenac sodium
19
3
Spectrophotometric data of standard curve for diclofenac sodium
31
4
Percentage composition of the diclofenac sodium solutions
33
5
Percentage composition of the diclofenac sodium gels
35
6 Physicochemical
parameters of diclofenac sodium
38
7
Physicochemical parameters of Porcine skin
38
8
Permeation data of diclofenac sodium from alcohol: water (A 1)
39
9
39
10
39
11
Permeation data of diclofenac sodium from PG: water (P 1)
40
12
40
13
40
14
Permeation data of diclofenac sodium gel using carbopol (C 1)
41
15
41
16
41
17
Permeation data of diclofenac sodium gel using HPMC (H 1)
42
18
42
19
42
20
Permeation data of diclofenac sodium gel using MC (M 1)
43
21
43
22
43
23
Permeation data of diclofenac sodium gel using carbopol
44
with permeation enhancer (menthol) (C-PE 1)
24
Permeation data of diclofenac sodium gels using carbopol
44
with permeation enhancer (oleic acid) (C-PE 2)
25
44
with permeation enhancer (menthol) (H-PE 1)
26
45
with permeation enhancer (oleic acid ) (H-PE 2)
27
45
with permeation enhancer (menthol) (M-PE 1)
28
45
with permeation enhancer (oleic acid ) (M-PE 2)
29
Steady state flux Jss for every 3 hours of diclofenac sodium gels
46
30
Permeation parameters of diclofenac sodium gels
47

Bangalore.
73
Annexures
LIST OF FIGURES
Fig.
Page
No
Title of Figures
No.
1
Cross section of skin
05
2
Standard curve for diclofenac sodium in water
31
3
Permeation profiles of diclofenac sodium solutions with different
48
concentrations using alcohol: water(30:70)
4
Permeation profiles of diclofenac sodium solutions with different
48
concentrations using PG: water(30:70)
5
Permeation profiles of diclofenac sodium gels with different
49
concentrations using carbopol
6
49
concentrations using HPMC
7
50
concentrations using methyl cellulose
8
Comparison of steady state fluxes of diclofenac sodium gels at
50
different concentrations using carbopol
9
Comparison of steady state fluxes of diclofenac sodium gels using
51
carbopol with and without different permeation enhancers
10
51
different concentrations using HPMC
11
52
HPMC with and without different permeation enhancers
12
52
different concentrations using methyl cellulose
13
53
methyl cellulose with and without different permeation enhancers
14
Comparison of permeability coefficient of diclofenac sodium gels
53
at different concentrations using carbopol
15
54
using carbopol with and without different permeation enhancers
16
54
at different concentrations using HPMC
17
55
using HPMC with and without different permeation enhancers
18
55
at different concentrations using methyl cellulose
19
56
using methyl cellulose with and without different permeation
enhancers
20
Comparison of fluxes of diclofenac sodium gels at different
56
concentrations using carbopol (every 3hrs)
21
Comparison of fluxes of diclofenac sodium gels using carbopol
57
with and without different permeation enhancers (every 3hrs)
Bangalore.
74
Annexures
22
Comparison of fluxes of diclofenac sodium gels at different
57
concentrations using HPMC (every 3hrs)
23
Comparison of fluxes of diclofenac sodium gels using HPMC with
58
and without different permeation enhancers (every 3hrs)
24
Comparison of permeation fluxes of diclofenac sodium gels at
58
different concentrations using methyl cellulose (every 3hrs)
25
Comparison of permeation fluxes of diclofenac sodium gels using
59
methyl cellulose with and without different permeation enhancers
(every 3hrs)
26
Comparison of flux enhancement (fold) of diclofenac sodium gels
59
using carbopol with different permeation enhancers
27
60
using HPMC with different permeation enhancers
28
60
using methyl cellulose with different permeation enhancers

Bangalore.
75
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U-Strip Insulin Patch, the next generation of transdermal drug delivery for the treatment of diabetics, at Chicago's American
Diabetic Association this week. (Bruce Redding)
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SOURCE: Encapsulation Systems Inc.
Jun 22, 2007 07:00 ET
Encapsulation Systems Previews the U-Strip Insulin Patch, the Next Generation of Transdermal Drug Delivery for the
TM
Treatment of Diabetes
Step Aside Needles and Inhalants, the U-Strip Will Empower Millions of Diabetics With the First Wearable,
Programmable and Non-Invasive Drug Delivery System
CHICAGO, IL--(Marketwire - June 22, 2007) - ADA's 67th Annual Scientific Session, Booth #848 -- Encapsulation Systems Inc. (ESI) www.encsys.com,
an innovator in controlled delivery systems, announces today that it will showcase the U-Strip Insulin System, a programmable transdermal drug delivery
patch, at the American Diabetes Association's 67th Annual Scientific Session from June 22-26th at Booth #848 at the McCormick Place Convention
Center. This breakthrough technology will provide millions of diabetics with the first wearable, programmable and non-invasive insulin delivery system
that eliminates painful needles and promises improved compliance with the automatic "set-it-and-forget-it" design of the system.
"The U-Strip Insulin Patch is an ultrasonic drug delivery system using an alternating sonic transmission to effect pore dilation and deposit large molecule
drugs into the dermis," says Bruce K. Redding, Jr., President and CEO, Encapsulation Systems, based in Havertown, Pennsylvania. "Although our primary
market is Type 2 diabetics, our insulin delivery transdermal patch is able to deliver a basal and bolus dose of insulin under a programmable regimen to
both Type 1 and Type 2 diabetics."
"While the U-Strip Insulin Patch is in Phase-2 clinical trials and not yet approved for human use by the FDA, I believe the U-Strip will provide a major
breakthrough in the transdermal delivery of insulin for Type 2 diabetics," states Dr. Rex Kessler, endocrinologist and Director of Research at the Kessler
Research Institute in Media, PA. "Compared to insulin injections and continuous subcutaneous delivery systems, transdermal delivery eliminates the pain
associated with these invasive methods. The ultrasonic applicator unit records the dose delivered and stores the information for 60 days. The U-Strip
Insulin Patch enhances patient compliance because of a programmed insulin drug delivery profile and ease of use."
HOW THE U-STRIP INSULIN PATCH WORKS:
The U-Strip is a patent pending drug delivery system consisting of 3 components: the sonic applicator module, the battery strap and the modified
transdermal patch.
-- Transdermal Patch is specially designed to hold the target drug.
-- Sonic Applicator Module is a programmable ultrasonic transmitter that
fits directly above the patch. The ultrasonic transmitter can be
programmed to deliver a constant or pulse of ultrasonic energy, through the
transdermal patch. Ultrasound from the Sonic Applicator Module pushes the
drug (insulin) contained within the patch through the skin.
-- A rechargeable battery system is located within the strap, which holds
the ultrasonic transmitter over the patch.
U-STRIP ADVANTAGES:
The U-Strip offers a number of advantages to both the patient and to medical professionals which include:
-- Non-Invasive - No needles are required with this totally non-invasive
drug delivery system.
-- Safe and effective - U-Strip controls the patient's medication so
there is less change of over/under dosage.
-- Direct bloodstream absorption - This on-demand delivery system
bypasses the stomach and the intestine where drug potency can be destroyed.
-- Individualized drug regimen - Medical professionals can easily
individualize drug regimen tailored for each patient's needs.
-- Easy to Follow - The automatic drug delivery ensures heightened
compliance for pediatric and elderly patients, because there is nothing to
remember and no schedules to follow. Patients simply "Set it and Forget it"
and ensure their drug regimen is more easily followed.
-- Additional Pharmaceutical Applications - The U-Strip technology may
open the door to a number of advanced pharmaceutical delivery applications
for other chronic medical conditions.
BACKGROUND:
The National Diabetes Information Clearinghouse reports that there are "20.8 million children and adults in the United States, or 7% of the population,
who have diabetes," a disease in which the body does not produce or properly use insulin, the hormone needed to convert sugar, starches and other food
into energy needed for daily life. There are two major types of diabetes, Type 1, which results from the body's failure to produce insulin, and Type 2,
which results from insulin resistance (a condition in which the body fails to properly use insulin). Most Americans who are diagnosed with diabetes have
Type 2 diabetes.
Treatment for diabetes varies depending on the type of diabetes one has been diagnosed with, ranging from insulin injections/pumps, which are
sometimes painful, to daily oral drug regimens. For most diabetic patients treatment methods and drug delivery systems can often be cumbersome and
frustrating.
THE FUTURE - U-STRIP INSULIN SYSTEM

The U-Strip™ is a patent pending drug delivery system in Phase-2 clinical trials that is not yet approved for human use by the FDA. However, the
development of a programmable, portable, ultrasonic instrument will extend the number and types of drugs that can be given with the transdermal
patch.
"For almost 20 years we have been the leader in specialty controlled release products for use in food, pharmaceuticals and medical devices," adds
Redding. "However, the U-Strip Insulin System marks a milestone in our company's history by opening the door to a number of advanced pharmaceutical
delivery applications and demonstrates our investment and ongoing commitment in research and development."
ABOUT ENCAPSULATION SYSTEMS INC:
Founded in 1988, Encapsulation Systems Inc. www.encsys.com (ESI) is a private company specializing in the development and commercialization of
specialty controlled release products for use in the food, pharmaceutical and medical device fields. A major innovator of controlled delivery systems since
its inception, ESI has 11 patent applications pending in the United States and internationally and has claimed 57 new inventive concepts regarding the U-
Strip Technology.
B-Roll includes visuals of the U-Strip Insulin patch and interviews with:
Bruce K. Redding, creator of U-Strip Insulin Patch and president/CEO, Encapsulation Systems.
Rex Kessler, M.D. Endocrinologist, Kessler Research Institute, Principal Investigator U-Strip Human Pilot Trial 2
Ms. Bo Michniak-Kohn, Ph.D., Associate Professor Pharmaceutics, Rutgers, State University of New Jersey, U-Strip Scientific Advisory Board Member
FOR B-ROLL - Please call Nancy Tamosaitis, Vorticom Inc. 212.532.2208 or emailnancyt@vorticom.com for b-roll. The launch press release announcing
the company's human pilot trial results is also available by calling 212.532.2208.
Media Contacts:
Nancy Tamosaitis
917.371.4053 (mobile)
212.532.2208 (office)
Email Contact
Carolyn Marquez
347.885.6722 (mobile)
Email Contact
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Transdermal Drug Delivery Technology Revisited: Recent Advances

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Transdermal Drug Delivery Technology Revisited : Recent Advances

By Shreeraj Shah - 10/14/2008

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Conditions in which Transdermal Patches are used 8

Transdermal patch is used when:

The use of transdermal patch is not suitable when:

Brand Name Drug Manufacturer Indications

NicotinellR Nicotine Novartis Pharmacological

MatrifenR Fentanyl Nycomed Pain relief patch

Ortho EvraTM Norelgostromin/ ORTHO-McNEIL Postmenstrual

NuPatch 100 Diclofenac Zydus Cadila Anti Inflammatory

NeuproR Rigotine UCB and Schwarz Pharma early-stage idiopathic

Alora Estradiol TheraTech/Proctol and Postmenstrual

NicodermR Nicotine Alza/GlaxoSmithKline Smoking cessation

Estraderm Estradiol Alza/Norvatis Postmenstrual

Climara Estradiol 3M Pharmaceuticals/Berlex Postmenstrual

Androderm Testosterone TheraTech/GlaxoSmithKline Hypogonadism in

Nitrodisc Nitroglycerin Roberts Pharmaceuticals Angina pectoris

Transderm- ScopR Scopolamine Alza/Norvatis Motion sickness

Nuvelle TS Estrogen/Proge Ethical Holdings/Schering Hormone

Deponit Nitroglycerin Schwarz-Pharma Angina pectoris

Nitro-dur Nitroglycerin Key Pharmaceuticals Angina pectoris

Catapres TTSR Clonidine Alza/Boehinger Ingelheim Hypertension

FemPatch Estradiol Parke-Davis Postmenstrual

Minitran Nitroglycerin 3M Pharmaceuticals Angina pectoris

Climaderm Estradiol Ethical Holdings/Wyeth- Postmenstrual

DuragesicR Fentanyl Alza/Janssen Pharmaceutical Moderate/severe

Fematrix Estrogen Ethical Holdings/Solvay Postmenstrual

Transderm- NitroR Nitroglycerin Alza/Norvatis Angina pectoris

Testoderm TTSR Testosterone Alza Hypogonadism in

OxytrolR oxybutynin Watson Pharma Overactive bladder

Prostep Nicotine Elan Corp./Lederle Labs Smoking cessation

(1)Physiological factors (2) Formulation factors

Electroporation is a method of application of short, high-voltage electrical pulses to the skin.

Patent No. Date Title Information

US741530633 Aug. 19, Transdermal The present invention provides a transdermal

US741374834 Aug. 19, Transdermal A specific dosage regimen of buprenorphine

US739812136 Jul. 8, Iontophoresis An iontophoresis device useful for administering

US739511137 Jul. 1, Transdermal The present invention provides a system for

4. Jacoby, David B., Youngson, R. M., Marshall Cavendish Corporation; Encyclopedia Of

5. Bayarski, Yury; Transdermal Drug Delivery, Transdermal Patches

6. MANAGED CARE April 2004. ©MediMedia USA ,

9. Arcangelo , Virginia P., Peterson, Andrew M.; Pharmacotherapeutics for Advanced

18.Medscape Today journal Available http://www.medscape.com/viewarticle/530060_4

20.Electroporation From Wikipedia, the free encyclopedia

21. Neumann E, Schaefer-Ridder M, Wang Y, Hofschneider PH (1982). "Gene transfer into

24.Sonophoresis From Wikipedia, the free encyclopedia

25.Transdermal patch From Wikipedia, the free encyclopedia

26.Paranjape, Makarand; Biomedical Optics & Medical Imaging, Pain-free diabetic

28.Anandi Krishnan, Pharmainfo.net

30.Watson Pharmaceuticals' OXYTROL(R) Receives Positive Opinion for Approval in the

Excellent article. Can you

Submitted by rkeefer on Fri, 07/03/2009 - 15:47.

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Copyright © 2005 - 2011 Pharmainfo.net.

Not to be confused with dermal patch.

A 21mg dose Nicoderm CQ patch applied to the left arm

Clonidine tablets and transdermal patch

administered scopolaminefor motion sickness.[1][2]

○ 5.5 Vapour Patch

through the membrane.