1. Quality Control tests of Transdermal Patches
Dr. Asif Mahmood
Ph.D. (Pharmaceutics), (IUB-Pak)
Faculty of Pharmacy
The University of Lahore-Pakistan
2. TRANSDERMAL PREPARATIONS
• Designed to support the passage of drug substances from the
surface of the skin, through its various layers, and even into the
systemic circulation.
Advantage of TDDS over other delivery systems : 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.
Disadvantage: is that skin has very effective barrier so small molecules which
can easily penetrate are used.
3. • ADVANTAGES
Self administration is possible with these system.
The drug input can be terminated at any point of time by removing
transdermal patch.
Allows effective use of drugs with short biological half-life
Allow administration of drugs with narrow therapeutic window
Provides controlled plasma level of very potent drugs
Drug input can be promptly interrupted when toxicity occurs
• DISADVANTAGES:
Drug or drug formulation may cause skin irritation or sensitization.
Uncomfortable to wear . May not be economical.
4. a) Transfollicular route
Transfollicular route is the shortest pathway that drug has to follow
to reach the systemic circulation that provides a large area for
diffusion of drugs.
b) Transcellular route
Drug delivering through this route passes from corneocytes which
has highly hydrated keratin creating hydrophilic pathway.
The drug passes through the corneocytes of stratum corneum.
c) Intercellular route
In intercellular pathway the drug diffuses through the
continuous lipid matrix present between the cells.
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6. Rate of permeation, dQ/dt, across a skin can be expressed as
dQ/dt = Ps[ cd - cr ]
Where,
dQ/dt – Rate of permeation
Ps – Permeability coefficient
Cd – Concentration in donor compartment
Cr – Concentration in receptor compartment
7. The principle transport mechanism across mammalian skin
is by passive diffusion. The factors influencing and having
differences in transdermal permeability of the stratum
corneum.
Lipid solubility:
At higher concentrations, the rate of penetration of the
alcohols is greatly increased, and does not follow the pattern
of absorption from weak solution.
But, high concentrations may damage the stratum corneum
impairing its 'barrier' properties.
8. Partition coefficient:
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Drugs possessing both water and lipid
solubility are favorably absorbed through the skin.
Transdermal permeability coefficient shows a linear
dependency on partition coefficient. A lipid/water
partition of 1 or greater is generally required for optimal
transdermal permeability.
pH condition:
The extent of dissociation in case of ionic drugs and their
transdermal permeability depends on pH condition of the
skin surface as well as the drug delivery system. Incase of
ephedrine and scopolamine, the transdermal flux of the
drug increases with increasing pH upto 1.2 approximately
1.2 higher than their respective pKa values.
9. These are compounds which promote skin permeability
by altering the skin as a barrier to the flux of a desired
penetrant.
These may conveniently be classified below
i. Solvents
ii. Surfactants
iii. Miscellaneous chemicals
10. The common ingredients which are used for the preparation of TDDS are as
follows.
1. Drug: Drug is in direct contact with release liner. Ex: Nicotine,
Methotrexate.
2. Liners: Protects the patch during storage. Ex: polyester film.
3. Adhesive: Serves to adhere the patch to the skin for systemic delivery of
drug. Ex: Acrylates, Poly-iso-butylene, Silicones.
4. Permeationenhancers: Controls the Release of the drug. Ex: Terpenes,
Terpenoids. Solvents like alcohol, Ethanol, Methanol etc.
5. Backing layer: Protect patch from outer environment. Ex: Cellulose
derivatives, poly vinyl alcohol, Polypropylene Silicon rubber.
6. Polymer matrix: The polymer controls the release of the drug from the
device. Ex: Natural polymers, Synthetic Elastomers, Synthetic Polymers
11. • IdealpropertiesofpolymersforTransdermaldrugdeliverysystem.
The polymer should be stable.
non-reactive with the drug.
easily manufactured and fabricated into the desired product and
inexpensive.
The polymer and its degradation products must be non-toxic or non-
antagonistic to the host.
The mechanical properties of the polymer should not deteriorate excessively
when large amounts of active agent are incorporated into it.
13. Quality control tests for topical
preparations(TDDS)
Physicochemical evaluation
In vitro evaluation
In vivo evaluation
Physicochemical Evaluation
Thickness: The thickness of transdermal film is determined by travelling
microscope, dial gauge, screw gauge or micrometre at different points of the
film.
Uniformity of weight: Weight variation is studied by individually
weighing 10 randomly selected patches and calculating the average weight. The
individual weight should not deviate significantly from the average weight.
14. Drug content determination:
An accurately weighed portion of film (about 100 mg) is dissolved in 100 mL of
suitable solvent in which drug is soluble and then the solution is shaken
continuously for 24 h in shaker incubator. Then the whole solution is sonicated.
After sonication and subsequent filtration, drug in solution is estimated spectro-
photometrically by appropriate dilution
Content uniformity test: 10 patches are selected and content is
determined for individual patches. If 9 out of 10 patches have content between
85% to 115% of the specified value and one has content not less than 75% to
125% of the specified value, then transdermal patches pass the test of content
uniformity. But if 3 patches have content in the range of 75% to 125%, then
additional 20 patches are tested for drug content. If these 20 patches have range
from 85% to 115%, then the transdermal patches pass the test.
15. Moisture content: The prepared films are weighed individually and
kept in a desiccators containing calcium chloride at room temperature for 24 h.
The films are weighed again after a specified interval until they show a constant
weight. The percent moisture content is calculated using following formula.
% Moisture content = Initial weight – Final weight X 100
Moisture Uptake: Weighed films are kept in a desiccator at room
temperature for 24 h. These are then taken out and exposed to 84% relative
humidity using saturated solution of Potassium chloride in a desiccator until a
constant weight is achieved. % moisture uptake is calculated as given below.
% moisture uptake = Final weight – Initial weight X 100
Flatness: A transdermal patch should possess a smooth surface and
should not constrict with time. For flatness determination, one strip is cut from
the centre and two from each side of patches. The length of each strip is
16. Folding endurance: A strip of specific area is to be cut evenly and
repeatedly folded at the same place till it broke. The number of times the film
could be folded at the same place without breaking gave the value of the folding
endurance.
Tensile Strength: One end of the films is kept fixed with the help of
an iron screen and other end is connected to a freely movable thread over a
pulley. The weights are added gradually to the pan attached with the hanging
end of the thread. A pointer on the thread is used to measure the elongation of
the film. The weight just sufficient to break the film is noted.
Water Content: A test for water content should be included .
Microbial Limits: The type of microbial test(s) and acceptance criteria
should be based on the nature of the drug substance, method of manufacture
etc.
Sterility: Depending on the use of the dosage form, e.g., ophthalmic
preparations, sterility of the product should be demonstrated as appropriate
17. Viscosity: Rheological properties such as viscosity of semisolid dosage
forms can influence their drug delivery. Viscosity may directly influence the
diffusion rate of drug at the microstructural level.
Water vapour permeability (WVP) evaluation:
It can be determined with foam dressing method the air forced oven is replaced
by a natural air circulation oven.
Polariscope examination: This test is to be performed to examine
the drug crystals from patch by polariscope. A specific surface area of the piece
is to be kept on the object slide and observe for the drugs crystals to distinguish
whether the drug is present as crystalline form or amorphous form in the patch.
Adhesive properties
Shear Adhesion test: This test is to be performed for the
measurement of the cohesive strength of an adhesive polymer. It canbe
influenced by the molecular weight
Tack properties: It is the ability of the polymer to adhere tosubstrate
18. Peel Adhesion test: In This test, the force required to remove an
adhesive coating form a test substrate is referred to as peel adhesion. A single
tape is applied to a stainless steel plate or a backing membrane of choice and
then tape is pulled from the substrate at a 180° angle, and the force required
for tape removed is measured
Rolling ball test:
19. 2. a. In vitro release studies
The Paddle over Disc: This method is identical to the USP paddle
dissolution apparatus, except that the transdermal system is attached to a disc
or cell resting at the bottom of the vessel which contains medium at 32 ±5°C.
The Cylinder modified USP Basket: This method is similar to
the USP basket type dissolution apparatus, except that the system is attached to
the surface of a hollow cylinder immersed in medium at 32 ±5°C.
The reciprocating disc: In this method patches attached to holders
are oscillated in small volumes of medium, allowing the apparatus to be useful
for systems delivering low concentration of drug.
b. In vitro permeation studies
The amount of drug available for absorption to the systemic pool is greatly
dependent on drug release.
Horizontal-type skin permeation system: This has been
widely used for the evaluation of drug permeation across skin.
20. Franz diffusion cell: The cell is composed of two compartments:
donor and receptor. The receptor compartment has a volume of 5-12ml. The
diffusion buffer is continuouslystirred at 600rpm by a magnetic bar. The
temperature in the bulk of the solution is maintained by circulating
thermostatic water through a water jacket that surrounds
the receptor compartment.
Flow-through diffusion cell: Flow through diffusion cells have the
advantage that they can be used when the drug has lower solubility in the
receptor compartment. This cell can be fully automated and connected directly
to HPLC.
21. 3. In vivo Studies
In vivo evaluations are the true depiction of the drug performance. The
variables which cannot be taken into account during in vitro studies can be
fully explored during in vivo studies. In vivo evaluation of TDDS can be
carried out using animal models human volunteers.
Animal models: The most common animal species used for evaluating
transdermal drug delivery system are mouse, hairless rat, hairless dog,
rabbit, guinea pig etc. Rhesus monkey is one of the most reliable models for
in vivo evaluation of transdermal drug delivery in man.
22. Skin Irritation study
Skin irritation and sensitization testing can be performed on healthy rabbits
(average weight 1.2 to 1.5 kg). The dorsal surface (50cm2) of the rabbit is to be
cleaned and remove the hair from the clean dorsal surface by shaving and
clean the surface by using rectified spirit and the representative formulations
can be applied over the skin. The patch is to be removed after 24 hr. and the
skin is to be observed and classified into 5 grades on the basis of the severity
of skin injury.
Stability studies
Stability studies are to be conducted according to the ICH guidelines by
storing the TDDS samples at 40±0.5°c and 75±5% RH for 6 months. The
samples were withdrawn at 0, 30, 60, 90 and 180 days and analyse suitably
for the drug content.
23. Human models: The final stage of the development of a transdermal
device involves collection of pharmacokinetic and pharmaco-dynamic data
following application of the patch to human volunteers.
Clinical trials have been conducted to assess the efficacy, risk involved, side
effects, patient compliance etc.
Phase I clinical trials are conducted to determine mainly safety in volunteers
and phase II clinical trials determine short term safety and mainly
effectiveness in patients. Phase III trials indicate the safety and effectiveness in
large number of patient population and phase IV trials at post marketing
surveillance are done for marketed patches to detect adverse drug reactions.
Though human studies require considerable resources but they are the best to
assess the performance of the drug.
24. Thank you for your attention
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