Transdermal drug delivery system

2

Transdermal Therapeutic Systems

Diffusion of the medication (drug) through skin into

the systemic circulation for distribution and

therapeutic effect

Most TDD systems use passive delivery

3

13.1 Advantages of TTS’s13.1 Advantages of TTS’s

1. Eliminates oral absorption variables.

2. Eliminates first-pass metabolism

3. Provides controlled constant drug.

4. Can accommodate potent drugs

5. Permits self-administration

6. Non-invasive (no needles or injections)

7. Improves patient compliance

8. Easy treatment termination

4

Limitations of TDD Systems

• Poor diffusion of large molecules

• Skin irritation

5

• Therapeutic indication• Desired drug delivery profile

- Dose level, duration, etc.• Skin adhesion profile• Application site• Ease of application• Patch size, shape, appearance, comfort• Wear period• Packaging• Patch disposal• Patch cost

TDD System Design Factors

6

Process of transdermal permeation.

7

BASIC COMPONENTS OF TDDS 1.Polymer matrix

2.The drug 3.Permeation enhancers 4.Other excipients1.Polymer matrixIdeal polymer ٠MWT,and chemical functionality of the polymer should not affect the

diffusivity of drug and its release ٠stable ٠non reactive ٠easily manufactured ٠easily fabricated into desired product ٠inexpensive ٠degaradation product must be non toxic or non antagonistic to the host ٠ should retain its mechanical properties when the large amount of drug is loaded in to it

8

Polymers used in TDDS• Natural polymers

– Cellulose derivatives– Zein– Gelatin– Shellac– Waxes– Proteins– Gums– Natural rubbers– starch

• Synthetic elastomers --polybutadiene --hydrin rubber --polysiloxone --silicone rubber --nitrile --acrylonitrile --butyl rubber --styrene butadiene rubber --neoprine etc.

• Synthetic polymers PVA,PVC,PE,PP,Poly amide,Poly acrylate,Polyurea,PVP,PMMA,Epoxy etc.

9

2. Suitable drug candidate• Physico chemical properties of drug

– Should have MW less than 1000 daltons(800-1000)– Should have affinity for both lipophilic and hydrophilic phases– Should have low melting pont

• Biological properties of drug– Should be potent(less than 20mg)– Half life should be short– Must not induce a cutaneous irritant or allergic response– Drugs which degrade in the GI tract or inactivated by hepatic

first pass effect are suitable candidate– Tolerance to the drug must not develop – Drugs which has to be administered for a longer period of time

can be formulated – Drugs which cause adverse effects to non target tissues can

also be formulated

10

3.PERMEATION ENHANCERS(to enhance stratum corneum permeability)

• Solvents Increases penetration by swelling the polar pathway transport or fluidising lipids Eg.water,ethanol,methanol,DMS,homologs of methyl sulphoxide,dimethyl

acetamide,and DMF,2-pyrrolidone,N-methyl,2-pyrrolidone,laurocapram,PG,glycerol,silicone fluids,isopropyl palmitate.

• Surfactants Enhances the polar pathway transport of hydrophilic drugs• Anionic surfactants Dioctyl sulpho succinate,SLS,deco decylmethyl sulphoxide etc.• Non ionic surfactants Pluronic F127,Pluronic F68,etc.• Bile salts Sodium taurocholate,sodium deoxy cholate,sodium tauroglycocholate.• Binary systems Propylene glucol-oleic acid and 1,4-butane diol-linoleic acid• Miscellaneous Urea-hydrating and keratolytic agent,N,N-dimethyl-m-toluamide,calcium

thioglycolate,anti cholinergic agents• Potential permetion enhancers Euclyptol,di-o-methyl-ß-cyclodextrin and soyabean casein

11

Permeability Coefficient Is the Critical Predictor of Transdermal Delivery

Transport = Flux = (mg/cm2/sec) = P x A x (Cd – Cr)

Permeability Coefficient = P = D x K (cm/sec) h

Where A = Surface area of patchD = Diffusivity of drug in membrane (skin)K = Partition coefficient (patch/skin)C = Concentration in donor or receptor

(patch or skin)h = Thickness of membrane (skin)

12

4.OTHER EXCIPIENTS• AdhesivesIdeal properties• Should not irritate or sensitize the skin or affect normal functions of the skin• Should adhere to the skin aggressively• Should be easily removed• Should not leave an un washable residue on the skin• Should have an intimate contact with the skin • Should be compatible with the drug,excipients and permeation enhancers• Permeation of drug should not be affected• Backing membraneIdeal properties• Flexible and provide good bond to the drug reservoir• Prevent drug from leaving the dosage form• Should be impermeable• E.g.metallic plastic laminate,plastic backing with absorbent pad and

occlusive base plate,adhesive foam pad with occlusive base plate.

13

• Liner: Protects the drug during storage and is removed prior to use

• Drug

• Adhesive: Serves to bind the components of the patch to the skin

• Membrane: Controls the release of the drug from the reservoir in certain types of patches

• Backing: Protects the patch from the outer environment.

14

Formulation of TDDS1.Membrane-moderated or permeation controlled TDDS

• Drug reservoir(homogenous dispersion of drug with polymeric matrix or suspension of drug in un leachable viscous liquid medium such as silicone fluid) is encapsulated within drug impermeable metallic plastic laminate and a rate controlling polymeric membrane(ethylene vinyl acetate co polymer)

• The cross sectional view of this system is shown in the following Fig.1

15

Reservoir Patches

• The reservoir system has a drug layer that is separate from the adhesive.

16

Film Backing

Drug Layer

Protective Peel Strip (removed prior to use)

skin

Schematic Drawing of the Reservoir type of patch.

Rate-controlling Membrane

Contact Adhesive

17

• Drug molecule are permitted to release through this rate controlling membrane

• A thin layer of silicone or poly acrylate adhesive may be applied to the external surface of the rate controlling membrane to achieve intimate contact of the TDDS and the skin surface

• Release rate of this TDDS depends upon the polymer composition,permeability co efficient and thickness of the rate cotrolling membrane and adhesive

• The intrinsic rate of drug release from this TDDS is calculated by the following formula.1

CR

dQ/dt= -------------------- 1/Pm+1/Pa

18

Where

CR-con.of drug in the reservoir compartment

Pm-permeability co efficient of rate controlling polymeric membrane Pa- permeability co efficient of adhesive

For microporous membrane Km/r. Dm

Pm = -------------------- hm

Ka/m. Da

Pa = -------------------- ha

Substituting these values in formula.1, it becomes

Km/r .Ka/m .Dm.Da

dQ/dt= ---------------------------------------------CR

Km/r. Dm.ha + Ka/m. Da. hm

19

Where• Km/r --partition co-efficient of drug between membrane and reservoir

• Ka/m --partition co-efficient of drug between adhesive and membrane

• Dm --diffusion co-efficient of drug in the membrane

• Da -- diffusion co-efficient of drug in the adhesive

Example of this system are

1.Nitro glycerin releasing TDDS (Transderm-Nitro/ciba,USA)for once a day medication in angina pectoris

2.Scopolamine releasing TDDS (Transderm-Scop/ciba,USA)for 72 hrs.prophylaxis of motion sickness

3. Estradiol releasing TDDS (Estraderm/ciba)for treatment of menopausal syndrome

4. Clonidine releasing TDDS (Catapres/Boehringer Ingelheim)for 7 day therapy of hyper tension

5. Prostaglandin-derivatives TDDS

20

2.Adhesive diffusion/dispersion-controlled TDDS

Drug reservoir• homogenous dispersion of drug with adhesive polymer(poly(isobutylene) or

poly acrylate)

• Then spreading of this medicated adhesive polymer on flat sheet of drug impermeable metallic plastic backing to form thin drug reservoir layer

• On top of the drug reservoir layer,thin layers of rate controlling adhesive polymer of specific permeability and constant thickness are applied to produce an adhesive diffusion/dispersion-controlled TDDS

• The cross sectional view of this system is shown in the following Fig.2

21

Drug in Adhesive Patches

• A system in which the drug is incorporated directly into the adhesive, rather than into a separate layer. Usually used for smaller molecular weight compounds.

• These can be either a single layer or multi-layer.

• Sometimes referred to as the “matrix type patch”

22

Film Backing

Drug/Adhesive Layer

Protective Liner (removed prior to use)

skin

Schematic Drawing of the Matrix (Drug-in-Adhesive) type of patch.

23

• The rate of drug release in this system is defined by

Ka/r.Da

dQ/dt= -----------------CR

ha

WhereKa/r-partition co-efficient of drug bw adhesive layer and reservoir layer

Da-diffusion co-efficient of drug in the adhesive layer

ha-thickness of adhesive layer

Examples for this system1.Iso sorbide dinitrate-releasing TDDS 2.Verapamil releasing TDDS

24

• 3.Matrix diffusion-controlled TDDS

Drug reservoir

• homogenous dispersion of drug with hydrophilic or lipophilic polymer matrix by any one of the following methods

• Homogenous dispersion of finely ground drug particles with liquid polymer or highly viscous base polymer followed by cross linking of polymer chains

• Homogenous mixing of drug solid with rubbery polymer at an elevated temperature

• Dissolving the drug and polymer in a common solvent follwed by solvent evaporation in a mould at an elevated temperature or under vaccum.

• Medicated polymer is moulded in to desired surface area and controlled thickness

• This medicated polymer disc is pasted on to an occlusive base plate with impermeable plastic backing

• Then the adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc

25

• the rate of drug release from this sytem is defined as

A Cp DpDq/dt = [ ---------------------] 1/2

2t where

A initial drug loading doseCp and Dp are solubility and diffusivity of drug in poymer matrix

the rate of drug release from this system at steady state is defined as

Q/t1/2= [(2A-Cp) Cp Dp] 1/2

26

Example of this system are

1.Nitro glycerin releasing TDDS (Nitro-Dur and Nitro-Dur II /Key pharmaceuticals,USA)

2. Estradiol di acetate releasing TDDS

3. Verapamil releasing TDDS

The cross sectional view of this system is shown in the following Fig.3

27

4.Micro reservoir type/micro sealed dissolution- controlled TDDS

Combination of the reservoir and matrix diffusionDrug reservoir•suspension of drug with aqueous solution of water soluble liquid polymer

•Homogenous dispersion of drug suspension in a lipophilic polymer(silicone elastomer)

•As a result discrete un leachable microscopic spheres of drug reservoir is formed which is stabilized by cross linking

•Medicated polymer is moulded in to desired surface area and controlled thickness and it is coated with a layer of bio compatible polymer to modify mechanism and rate of drug release

•This medicated polymer disc is pasted on to an occlusive base plate with impermeable plastic backing

•Then the adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc

Example of this system are

1.Nitro glycerin releasing TDDS (Nitrodisc /searle,USA)

The cross sectional view of this system is shown in the following Fig.4

1.Nitro glycerin releasing TDDS (Nitro-Dur and Nitro-Dur II /Key pharmaceuticals,USA)

2. Estradiol di acetate releasing TDDS

3. Verapamil releasing TDDS

28

29

Products on the market, or in development include:

• Clonidine• Works as an agonist of adrenaline at the

presynaptic α2 adrenergic

• Product name = Catapres-TTS®

• used to treat hypertension

30

• Ethinylestradiol (EO) and norelgestromin (N)• Product name = Ortho-Evra®

• Used for Contraception• Type of patch = Drug-in-Adhesive

• Frequency of application = weekly

31

• Fentanyl

• Product Name = Duragesic®

• Used for: Analgesia• Type of Patch = Drug-in-Adhesive• Frequency of Application = Weekly

32

• Lidocaine• Product Name = Lidoderm®

• Used for: analgesia of postheretic neuralgia (PHN), a painful condition caused by the varicella zoster virus (herpes zoster = shingles)

• Type of Patch = Reservoir• Frequency of Application = Daily

33

• Nicotine

• Product name = Habitrol®, Nicoderm – CQ®, Nicotrol®, Prostep®

• Used for: Smoking cessation

• Frequency of administration = Daily

34

• Nitroglycerin• Works by producing nitric oxide (NO), which then acts as

a vasodilator• Product Names = Nitro-Dur®, Transderm-Nitro®

• Used for: Angina• Type of Patch = Nitro-Dur is Drug-in-adhesive Nitrodisc is reservoir• Frequency of administration = Daily

35

• Estradiol• Product Name = Alora®, Climara®, Esclim®,

Estraderm®, FemPatch®, Vivelle®, Vivelle-DOT®

• Used for: Hormone replacement• Type of Patch: Drug-in-adhesive• Frequency of application = weekly

36

• Estradiol + Norethindrone• Product name = CombiPatch®

• Used for: Hormone Replacement

37

• Oxybutynin• Works as competitive antagonist of the

muscarinic acetycholine receptor• Product name = Oxytrol®

• Used for: Overactive bladder (antispasmodic)• Type of Patch: Drug-in-adhesive• Frequency of application = twice a week

38

• Scopolamine• Works as competitive antagonist of acetylcholine

at the muscarinic receptor• Product Name = Transderm Scop®

• Used for: Motion Sickness

39

• Testosterone

• Product Names = Androderm®, Testoderm TTS®, Testoderm®

• Used for: Hypogonadism

40

• Lidocaine + Epinephrine

• Product name = Lidosite

• Used for: Dermal anesthesia

• Type of Patch = Reservoir, iontophoretic.

Epinephrine acts as vasoconstrictor, thus prolonging the duration of action of lidocaine (by delaying resorption) at the site

41

Manufacturer Trade name Drug Strength available

Ciba

Estraderm Estradiol 25 μg, 50 μg, 100 μg

Transderm-Scop Scopolamine 1.5 mg

Transderm-Nitro Nitroglycerin 0.1 mg, 0.2 mg

Janssen Duragesic Fentanyl 25 μg, 50 µg, 100 μg

Basel Habritol Nicotine 21 μg

Parke-Davis Nicotrol Nicotine 21 μg

Lederle Prostep Nicotine 21 μg

42

TTS Available in market

Large scale mfg of TTS

43

Physical parameters Evaluation of adhesiveIn-vitro testingIn-vivo assessmentCutaneous metabolismStability studiesEvaluation of skin reactions.

Evaluation Parameters

09/30/14 43

44

Thickness

09/30/14 44

45

Weight variation

09/30/14 45

46

Folding endurance

09/30/14 46

47

Moisture content

09/30/14 47

% Moisture content = Initial weight – Final weight X 100 Final weight

Moisture content

% Moisture content = Initial weight – Final weight X 100 Final weight

48

Moisture uptake

09/30/14 48

% moisture uptake = Final weight – Initial weight X 100 Initial weight

49

Flatness

09/30/14 49

% constriction = I1 – I2 X 100 I1

I2 = Final length of each stripI1 = Initial length of each strip

50

Drug content

09/30/14 50

51

Water Vapor Transmission studies

09/30/14 51

52

Evaluation of adhesive

1} Peel adhesion properties

09/30/14 52

It is the force required to remove adhesive from test substrate.

53

2} Tack properties

It is the ability of the polymer to adhere to substrate with little contact pressure.

2.1} Thumb tack test

2.2} Rolling ball tack test

09/30/14 53

54

2.3}Quick-stick (or peel-tack) test

09/30/14 54

55

2.4} Probe tack test

09/30/14 55

56

3} Shear strength properties

09/30/14 56

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

57

Tensile strength

09/30/14 57

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

F - the force required to break a - width of film b - thickness of film L - length of film l - elongation of film at break point

58

In-vitro testing

The Paddle over Disc

The Cylinder modified USP Basket

The reciprocating disc

Diffusion Cells e.g. Franz Diffusion Cell and its modification

Keshary- Chien Cell

09/30/14 58

59

In-vitro testing

Importance

(1)Defining skin permeation kinetic studies using a diffusion cell system and cadaver skin during the drug development process.

(2) in vitro drug release kinetics, to be used for batch-to-batch release and as a compendial test.

09/30/14 59

Preparation of skin for permeation studies

• Intact Full thickness skin

• Separation of epidermis from full thickness skin:

60

61

K-C cell for permeation studies

09/30/14 61

62

Effect of skin uptake metabolism

63

64

In-vivo assessment

1} Animal model

Mouse, hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig

09/30/14 64

65

In-vivo assessment

2} Human model

. Phase I clinical trials are conducted to determine mainly safety in volunteers.

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.

Phase IV trials at post marketing surveillance are done for marketed patches to detect adverse drug reactions.

09/30/14 65

Skin irritation studies

• Group I was served as normal, without any treatment.

• Group II, control, was applied with marketed adhesive tape.

• Group III Transdermal systems (blank)• Group IV Transdermal systems (drug

loaded)• Group V standard irritant .

66

Contact dermatitis

67

Evaluation of skin reactions.

09/30/14 67

68

Stability studies

09/30/14 68

Study Storage conditions Time period

Temperature Relative humidity

Long Term 25°C± 2°C OR

30°C± 2°C

60%± 5% OR

65%± 5%

12 months

Intermediate 30°C± 2°C 65%± 5% 6 months

Accelerated 40°C± 2°C 75%± 5% 6 months

69

70

APPLICATIONS

09/30/14 70

71

The Past

• 3000 BC--Pharmaceuticals and plasters first recorded in Babylonia.

• 1500 BC--Plasters recorded in the Ebers Papyrus (Egypt).

• Plasters made by physicians or pharmacists at the time of dispensing

09/30/14 71

72

The Past

• Used for topical and deep tissues• Counterirritants, protective dressings, belladonna,

salicylic acid, flaxseed, mustard, • Adhered to skin with stiff ointments, waxes,

melted waxes and rubber resins, kaolin• Applied hot, could absorb water • Backings made of cloth or animal skin

Plasters, Poultices and CeratesPlasters, Poultices and Cerates

09/30/14 72

73

The Past: Adhesives

Example of plaster formula (1909)

Rubber 20 grams

Petrolatum 20 grams

Lead Plaster 960 grams

To make, 1000 gramsAdd any one of the following Belladonna Leaves,

Oleoresin of Capsicum, Mercury, Opium, Soap

09/30/14 73

74

The Past

The last 150 years:• Electrically assisted applications first occurred

in late 1800s and in early 1900s.• Rubber became available in the 1800s• Nitroglycerin was applied topically as an

ointment for delivery to the bloodstream in the 1950 to present.

• Belladonna, capsicum, mustard and salicylic acid plasters

09/30/14 74

The Past

75

The Present Day

• 1970-- Alza Research (US) began first development of the modern transdermal

• 1980-- Scopolamine first transdermal reached US

• 2002– Many Rx and non-RX products in US market.

• Transdermals deliver drugs from a few hours up to 7 days.

09/30/14 75