chapter i: introduction

CHAPTER I: INTRODUCTION 1.1

Overview of Transdermal Drug Delivery System: Transdermal Drug Delivery System (TDDS) a novel drug delivery system is the dosage

form to deliver therapeutically active compound to the body through the skin. TDDS has a lot of advantages over oral drug delivery system such as avoiding first pass metabolism, increase therapeutic efficacy, self-administration, and controlled delivery of drug molecule over a longer period of time (such as 7 Days) to keep constant steady state plasma concentration. Due to its advantages over oral drug delivery, TDDS is becoming more promising choice of drug delivery system for new drug molecule. Currently, there are 35 approved products in the market for TDDS, which is producing $4.3 billion revenue. TDDS can provide controlled release of drug and also allowed continuous input and eliminate pulse entry in the systematic circulation.1 1.1.1

Advantages of TDDS:2,3

1. Avoid First Pass metabolism 2. Self-administration 3. Elude the fluctuation in drug plasma concentration level 4. Greater patient compliance due to elimination of multiple dosing regimen 5. Removal of patch at any time, due to side effects 6. Avoidance of GI incompatibility



1

7. Steady and optimum Plasma concentration obtained with reducing side effects 8. Enhance therapeutic efficacy and patient compliance. 1.1.2

Type of TDDS:4,5

1) Reservoir type of TDDS: The reservoir TDDS system has drug reservoir embedded in the pouch system. This pouch system has release liner on one side and backing membrane on the other side. Mostly the pouch is filled with liquid or semisolid type of drug formulation. The reservoir form of TDDS has an adhesive layer on peripheral of the patch system or the adhesive can be embedded in the patch system. (Fig.1.1) 2) Matrix type of TDDS: Matrix type of TDDS is further divided in two types a) Drug in Adhesive and b) Drug Matrix in Adhesive. Drug is suspended or solubilized in adhesive itself and coated on the backing layer, called Drug in Adhesive type TDDS. Here the polymer itself act as an adhesive, so there is no need for extra adhesive layer for affixing patch on to the skin. In Drug Matrix in adhesive type of TDDS, drug is solubilized or suspended in polymer. Here the polymer is not adhesive in nature and to affix the patch on the skin another layer of adhesive is applied on the polymer drug matrix patch. (Fig. 1.1) 1.1.3

Basic Components of TDDS:6

1. Polymer 2. Drug 3. Solubilizer/plasticizer 4. Permeability Enhancers

2

5. Pressure sensitive Adhesive 6. Backing laminate 7. Release liner

Fig. 1.1 Different Types of Transdermal Patches7

3

1.1.4

Diffusion Process in TDDS

TDDS is follow the passive diffusion process to transport drug molecules from TDDS system (Having high concentration of drug) to systematic circulation (low concentration of drug). There are two diffusion process is going on in the TDDS system. 1) Diffusion through the polymer and 2) Diffusion through the skin. 1) Diffusion through the polymer: Diffusion through polymer solutions and gels have been studied for decades by the use of various techniques such as gravimetry8, membrane permeation9, fluorescence10 and dynamic light scattering11. The studies have resulted in a better knowledge on polymer morphology and structure12, transport phenomena13 and recently the controlled release of drug from polymers. In addition, these studies have led to theoretical description of the diffusion of solvent and/or solutes in polymer solution and gels.14-16 There are numerous models have been proposed till now based on various theories such as the obstruction effects, the hydrodynamic interaction and the free volume theory17. (Fig.1.2)

Fig. 1.2: Polymer-Drug Interaction



4

2) Diffusion through Skin: It is a valid generalization to state that the stratum corneum allows no substance to penetrate easily and allows all substance to enter slightly. According to structure of the skin, the drugs are possibly traveled through the following pathway to reach the systemic circulation. 1) The appendages (Shunt Pathway): a) Hair follicles, b) Sebaceous gland and, 2) Transepidermal penetration: a) Transcellular route, b) Intercellular route. The penetration through appendages pathway mainly depends on following factors: 1) No. of horny cell layers available and b) Thickness of the horny layer. Lipid soluble compounds diffuse through the sebum filled follicles, in which sebum might be worked as a vehicle for lipophilic drugs which has high affinity, resulting in high partitioning coefficient for release into the skin. Sweat ducts comprise a tiny fraction of the surface and cannot play an important role in lipophilic drug flux profile but certain water soluble electrolytes and drugs can freely enter into the skin through water filled sweat channels. The transepidermal penetration is mainly achieved by either transcellular or intercellular pathway. Most of the lipophilic drugs travel through either of these routes. Fig.1.3 showed the different drug penetration pathway in the skin.18,19



5

Fig. 1.3: Stratum Corneum and Route of Penetration. 1.1.5

Thermodynamics of Skin Permeation The mechanism of skin permeation of water soluble and lipid soluble non-electrolytes are

demonstrated by means of thermodynamic parameters, such as, activation energy (Ea), preexposed factor (A-), enthalpy (H) and entropy (S). 20 1.1.5.1 Activation energy of Skin Permeation The skin permeation of non-electrolytes, such as alkanols was reported to be an energy requiring process and follow the Arrhenius relationship: )*

𝐽𝑠𝑠 = 𝐴𝑒 ((+,)



(1)

6

For hydrophilic alkanols (C5), the activation energy is constant and 16.5 ± 0.1 kcal/mol is required for their permeation through hydrated stratum corneum. On the other hand, for the lipophilic alkanols (G”, and both independent of frequency; lower tan d values (G”) to a dominant elastic solid-like behavior (G”>G’). This cross over point is also called the sol-gel point or the characteristics modulus and can be used in gel rheology to correspond to the change of behavior from a more solid-like to liquid-like. The cross over point may be related to the interaction between particles. All the formulations are same except permeability enhancers (carbon chain length in



99

fatty acids), it means particle interaction is different for all formulation and give different sol-gel point for different permeability enhancers. Fig. 3.11 showed complex modulus (G*) vs. temperature profile for formulation; this can be used to predict the storage stability of different formulations. FO-25_T0 showed minimum changes in complex modulus and also phase angle remains high during storage period (Fig. 3.11-D). This indicates FO-25_T0 has a stable shelf life as observed. Other formulations are more sensitive to temperature change, which indicates a shorter shelf life than that of FO-25_T0. The higher the gelling temperature at a given formulation can be explained by the collision probability of polymer chains is higher even at high temperature thereby increasing the probability of polymer solvent interaction and thus network formation and gelation at higher temperature. Difference in gel points may be used to explain the relative rate of breaking. The gel point is the change from liquid to solid like behavior. The lower the gel point, the shorter the breaking time may be needed under the same conditions. For the different fatty acids, the temperature sweep test can be used to rank the time of breaking between different formulations and can be used as a consistency test. Table 3.12 shows an example of using the gel point to evaluate the breaking time of formulations having different permeability enhancers, storage time and homogenization speed. The temperature sweep test can be used as a predictive tool for a gel breaking.130



100

(A)

45

T0

T1

T2

Cross-Over Temperature (C)

40 35 30 25 20 15 10 5 0 FO-25

FL-25

FC-25

FT-25

FLAB-25

FLG90-25

F-25

Permeability Enhancers

(B)

70

25000

20000

15000

Cross-Over Temperatue (C)

60 50 40 30 20 10 0 FO

FL

FC

FT

FLAB

Permeability Enhancers



101

FLG90

F

(C)

50

T0

T1

T2

Cross-Over Temperature (C)

45 40 35 30 25 20 15 10 5 0 25000

20000

15000

Homoginization Speed (RPM)

F-25_T0 (D)

70 60

Modulsu (Pa)

50 40 30

G'

20

G"

10 0 0

10

20

30

40

50

60

70

80

90

Temperature (C)

Fig: 3.9: (A) Effect of Storage period and Permeability enhancers on the Cross-Over Temperature, (B) Effect of homogenization speed and Permeability enhancers on the CrossOver Temperature, (C) Effect of storage period and homogenization speed on the CrossOver Temperature, (D) Representative graph of Temperature Sweep.



102

Table 3.12: Cross Over Temperature (Modulus) of Formulations

Formulation



Cross-Over Temperature (°C) (Modulus Pa) T0

T1

T2

FO-25

30.1 (13.8)

37.6 (18.8)

36.6 (19.4)

FL-25

32.7 (15.1)

36.5 (16.8)

35.4 (18.5)

FC-25

27.5 (13.6)

34.8 (19.7)

33.4 (19.0)

FT-25

40.1 (14.8)

32.5 (17.1)

34.3 (18.3)

FLAB-25

38.5 (15.7)

34.3 (17.0)

38.4 (18.2)

FLG90-25

30.2 (13.9)

41.3 (19.2)

37.9 (22.5)

F-25

37.9 (18.5)

37 (19.1)

35.9 (24.6)

FO-20

28.4 (13.6)

43.7 (19.1)

FL-20

54.7 (14.0)

29.7 (13.4)

36.1 (17.0)

FC-20

33.4 (13.9)

35.5 (15.8)

43.5 (20.3)

FT-20

49.9 (13.0)

25.9 (13.8)

60.6 (31)

FLAB-20

46.3 (18.5)

31.7 (14.6)

43.2 (20.9)

FLG90-20

24.7 (12.6)

34.8 (16.8)

39.3 (17.8)

F-20

29.4 (14.9)

41.6 (19.8)

46.0 (23.3)

FO-15

28.3 (12.8)

36.8 (16.6)

37.2 (18.2)

FL-15

39.8 (11.9)

30.1 (14.7)

38.8 (22.9)

FC-15

28.4 (13.1)

32.1 (15.7)

34.1 (17.3)

FT-15

59.5 (10.9)

23.1 (13.3)

33.6 (24.3)

FLAB-15

32.1 (12.9)

35.2 (14.7)

38.3 (21.2)

FLG90-15

27 (11.6)

32.3 (14)

26.9 (41.4)

F-15

40.8 (18.3)

39.6 (18.4)

41.3 (26.8)

103

(A)

T0

T1

T2

Temperature Loop Area (Pa/C)

600 500 400 300 200 100 0 FO-25

FL-25

FC-25

FT-25

FLAB-25

FLG90-25

F-25

Permeability Enhancers

(B)

25000

700

20000

15000

Temperature Loop Area (Pa/C)

600 500 400 300 200 100 0 FO

FL

FC

FT

FLAB

Permeability Enhancers



104

FLG90

F

(C)

25000

Temperature Loop Area (Pa/C)

450

20000

15000

400 350 300 250 200 150 100 50 0 T0

T1

T2

Storage Period (Days)

F-25_T0

90

Complex Modulus (Pa)

80 70 60 50 40 30 20 10 0 0

10

20

30

40

50

60

70

80

90

Temperature (C)

Fig: 3.10: (A) Effect of Storage period and Permeability enhancers on the Temperature Loop Area, (B) Effect of homogenization speed and Permeability enhancers on the Temperature Loop Area, (C) Effect of storage period and homogenization speed on the Temperature Loop Area, (D) Representative graph of Temperature Ramp.

105

Table 3.13: Temperature Loop Area of Formulations

Temperature Loop Area (Pa/°C)

Formulation



T0

T1

T2

FO-25

215.91

194.61

147.66

FL-25

330.32

47.04

58.13

FC-25

337.6

194.51

153.84

FT-25

412.15

144.61

138.91

FLAB-25

480.65

228.06

31.31

FLG90-25

247.92

99.56

54.13

F-25

389.04

258.33

13.13

FO-20

204.99

117.18

1160.52

FL-20

316.85

197.93

711.69

FC-20

356.5

125.1

87.83

FT-20

418.84

196.99

517.49

FLAB-20

643.44

245.95

6.28

FLG90-20

222.87

130.16

459.66

F-20

428.04

215.08

62.33

FO-15

329.41

146.24

101.18

FL-15

344.49

124.94

248.5

FC-15

349.88

211.81

212.81

FT-15

455.47

96.33

60.81

FLAB-15

534.89

208.83

48.69

FLG90-15

271.80

164.93

152.38

F-15

424.22

206.28

139.28

106

(A) 80 FO-25_T0

Complex Modulus (G* Pa)

70 60

F-25_T0

50

FO-20_T0

40 F-20_T0

30

FO-15_T0

20 10

F-15_T0

0 0

10

20

30

40

50

60

70

80

90

Temperature (C)

(B) FO-20_T0

Complex Modulus (G* Pa)

80 70

FL-20_T0

60

FC-20_T0

50

FT-20_T0

40

FLAB-20_T0

30 FLG90-20_T0

20

F-20_T0

10 0 0

10

20

30

40

50

Temperature (C)



107

60

70

80

90

(C) 120

Complex Modulus (G* Pa)

100 80

FO-15_T0 F-15_T0

60

FO-15_T1 F-15_T1

40

FO-15_T2 20

F-15_T2

0 0

10

20

30

40

50

60

70

80

90

Temperature (C)

Fig. 3.11: Effect of Homogenization Speed (A), Permeability Enhancers (B) and Storage Period (C) on the complex modulus (G*) during Temperature sweep. 3.8

Diffusion study A modified Franz-diffusion cells were used in our studies, in which drug leaves an unstirred

donor compartment, crosses through a membrane of thickness h and cross sectional area A, and accumulates in a stirred receiver compartment for which sink conditions were maintained. For this type of steady-state diffusion, we can use Fick’s First law, which is as follows: 131,132 𝐽=

tG

(33)

u∗tw

Where, J = Flux (µg cm-2 hr-1)



108

A= Cross sectional area of membrane (cm2) tG tw

=Amt of drug permeated vs. time (µg/hr.)

From, experimental point of view, the flux can be calculated by utilizing equation 34,

J=

Slope

(34)

Diffuison area

Where, Slope = resultant slope of

tG tw

vs. time

Diffusion area = A = 1.77 cm2 The movements of the diffusing particles are dependent on the concentration gradient i.e. tV tH

across the membrane. So, we can write above equation as follows. z{

J = −D( )

(35)

z|

Where D= Diffusion Coefficient of a penetrant (cm2/hr) tV tH

= concentration gradient.

If a cellulose membrane/Human cadaver skin separates the two compartments of a diffusion cell with cross section area A and thickness h, and if the concentration in the membrane on the donor and on the receptor sides are C1 and C2 respectively than equation 1 and 3 can be combined and re-written as follows:

J=



z} ~∗z•

= D

{P({W €

109

(36)

The concentrations C1 and C2 within the membrane ordinarily are not known but can be replaced by the partition coefficient multiplied by the concentration Cd on the donor side or Cr on the receiver side, which is given by as follows: {P

K =

=

{z

{W

(37)

{‚

So, we can write equation 36 and 37, z}

= DAK

z•

{z({‚

(38)

€

We maintain the sink conditions in receptor medium throughout the experiment, and so Cd>>>Cr, from that it was assuming Cr≈ 0 Hence, equation 38 is re-written to, tG tw

=

„u…V𝑑 †

= 𝑃𝐴𝐶𝑑

(39)

Where,

𝑃=

…„

(40)

†

So,

P=

dM

1

Adt

Cd

(41)

Form equation 33 and 39,

P=

Jss

(42)

Cd

110

The Diffusion Coefficient was calculated from the slope obtained by plotting amount of drug permeated as a function of square root of time. The formula used to calculate diffusion coefficient is as follows:132

D=Πx

Slope

2

(43)

2

4 x A x C02

Where, A = cross section area of membrane (1.77 cm2) C0 = concentration in donor compartment (µg/ml) Slope = resultant slope of amount permeated vs. square root of time Moreover, we calculated the lag time (tLag) by plotting the amt release vs. time graph. Here we calculated the tLag from the diffusion coefficient found from the equation 44,

tLag =

h2

(44)

6D

Also lag time can be calculated using the permeability coefficient according to equation 45,

tLag =

h

(45)

6P

Where, tLag = lag time (hr) h = Thickness of the membrane (cm) D = Diffusion coefficient (cm2/hr) P = Permeability coefficient (cm/hr)



111

3.8.1

Diffusion through Human Cadaver skin Based on the previous experience, different fatty acids and other well-known permeability

enhancing agents were opted as permeability enhancers; these contain C10, C12, and C18 carbon chain in their structure. Such as Oleic acid (C18), Lauric acid (C12), Capric acid (C10), TranscutolP, Labrasol, Luroglycol-90. Earlier, the human cadaver skin was removed from the -80 °C of temperature and immediately put in phosphate buffer saline of pH 7.4. It was kept in the saline for about an hour to properly hydrate. The receptor compartment was filled with 100% phosphate buffer saline with 0.01% sodium azide and kept it for an hour to achieve 32 °C temperature of the receptor medium. In this case, samples were withdrawn at time interval of 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 60 and 72 hrs. Every time 0.5 ml of sample was withdrawn from the receptor medium and replaced by same amount of 100% PBS with 0.01% sodium azide solution. Samples were analyzed by HPLC at 230 nm wavelength. Every time the thickness of the skin was measured using vernule calepuse, and it was observed 0.30 ± 0.02 mm. In addition, by decreasing the carbon chain of enhancer the permeation of ECO was increased. This behavior can be due to more polar molecules of enhancers available to interact with the lipid of SC. All the data is the average of the three experiments. All physicochemical parameters such as Flux (J), permeability coefficient (P), diffusion coefficient (D), were calculated from equation 34, 40 and 43 respectively. 3.8.2

Effect of Enhancers: The data presented in Table 3.14 and Fig. 3.12, 3.13, with different permeation enhancers

in gel formulation (5% ECO + 1% Klucel-HF) were experimented with human cadaver skin, the best results were obtained with Capric acid (8%) and Lauric acid (8%). Capric acid is C10 saturated

112

fatty acid. As can be seen in Table 3.14 and Fig. 3.12, 3.13, the flux of ECO is increasing with decreasing the carbon chain length of fatty acids. This can be clarified by following mechanisms. Capric acid is hydrophilic as compare to other higher carbon chain containing fatty acids. Previous publication showed that capric acid is more soluble in polar solvents as compare to other hydrophobic fatty acids. Furthermore, PG with capric acid showed higher permeability as compare to other fatty acids.56,57 Capric acid is a hydrophilic fatty acid. Data illustrated that it has very small lag time as compare to the other permeability enhancers. During the uptake process, decanoic acid seems to increase transcellular permeability by perturbing membrane lipid, their disordering potency increasing with chain length. In addition, the sodium salt of fatty acids forms micelles in aqueous solution. The critical micelle concentration (CMC) of these systems decreases with increasing chain length. Above the CMC, increases in the absorption enhancing effect with increasing concentration of free enhancers. 133,134,135



113

(A)

250

T0

T1

T2

Flux (ug/cm2/Hr)

200

150

100

50

0 FO-25

FL-25

FC-25

FT-25

FLAB-25

FLG90-25

F-25

Permeability Enhancers

(B)

250

25000

20000

15000

FLux (ug/cm2/Hr)

200

150

100

50

0 FO

FL

FC

FT

FLAB

Permeability Enhancers



114

FLG90

F

(c)

6

25000

20000

15000

Flux (ug/cm2/Hr)

5 4 3 2 1 0 T0

T1

T2

Storage Period (Days)

Fig: 3.12: (A) Effect of Storage period and Permeability enhancers on the Flux Profile, (B) Effect of homogenization speed and Permeability enhancers on the Flux Profile, (C) Effect of storage period and homogenization speed on the Flux Profile,

(A)

Cumulative Amt of ECO/are (ug/cm2)

10000 9000 8000 7000

FC-25_T0

6000

FLAB-25_T0

5000

FL-25_T0

4000

FLG90-25_T0

3000

F-25_T0

2000

FO-25_T0

1000

FT-25_T0

0 0



10

20

30 40 Time (Hr)

115

50

60

70

Cumulative Amt of ECO/area (ug/cm2)

(B)

10000 9000 8000

FC-20_T0

7000

FLAB-20_T0

6000 5000

FL-20_T0

4000

FLG90-20_T0

3000

F-20_T0

2000

FO-20_T0

1000

FT-20_T0

0 0

10

20

30

40

50

60

70

Time (Hr)

(C)

Cumulative Amt of ECO/area (ug/cm2)

7000 6000

FC-15_T0

5000

FLAB-15_T0

4000

FL-15_T0 3000

FLG90-15_T0

2000

F-15_T0

1000

FO-15_T0 FT-15_T0

0 0

10

20

30

40

50

60

70

Time (Hr)

Fig: 3.13: Cumulative amount of ECO permeated through Human cadaver skin vs Time profile for formulations prepared at 25000 RPM (A), 20000 RPM (B) and 15000 RPM (C) for different enhancers.



116

Table 3.14: Flux Profile of Formulations (n=3) Flux (µg/cm2/hr) ± S.D. Formulation



T0

T1

T2

FO-25

23.17 ± 4.66

12.05 ± 3.79

11.44 ± 0.58

FL-25

185.6 ± 4.70

184.05 ± 5.51

167.87 ± 22.68

FC-25

205.58 ± 5.17

183.04 ± 4.23

181.76 ± 11.75

FT-25

34.57 ± 21.73

2.35 ± 2.95

1.97 ± 1.59

FLAB-25

4.19 ± 1.80

2.13 ± 0.5

0.52 ± 0.37

FLG90-25

59.16 ± 5.86

29.09 ± 20.06

25.77 ± 4.68

F-25

5.06 ± 2.27

2.29 ± 0.65

2.25 ± 0.60

FO-20

9.34 ± 3.59

6.86 ± 1.99

6.31 ± 2.17

FL-20

164.43 ± 25.0

161.52 ± 15.61

141.26 ± 16.81

FC-20

193.55 ± 7.28

188.2 ± 20.99

184.35 ± 16.62

FT-20

0.95 ± 1.06

0.45 ± 0.23

0.33 ± 0.09

FLAB-20

4.93 ± 4.51

0.5 ± 0.27

0.41 ± 0.25

FLG90-20

49.34 ± 26.09

29.03 ± 17.96

16.51 ± 4.70

F-20

1.91 ± 2.67

1.49 ± 0.76

0.84 ± 0.97

FO-15

8.18 ± 6.55

6.79 ± 3.0

4.02 ± 1.44

FL-15

132.05 ± 25.95

130.15 ± 34.95

92.12 ± 18.92

FC-15

179.66 ± 32.43

174.95 ± 23.30

131.55 ± 33.08

FT-15

0.25 ± 0.11

0.18 ± 0.19

0.12 ± 0.02

FLAB-15

1.4 ± 0.06

1.07 ± 1.27

0.49 ± 0.09

FLG90-15

38.13 ± 15.13

31.43 ± 6.99

8.2 ± 5.19

F-15

1.29 ± 0.94

1.12 ± 1.42

0.26 ± 0.11

117

CHAPTER IV 4.0

Conclusion Scale-up process for Transdermal formulations are very difficult. Rheological studies of

Transdermal formulations can help to solve some challenges during manufacturing scale-ups. During QbD principle application, homogenizations speed comes under critical process parameters (CPP), while diffusion and storage period is called critical quality attributes (CQA). Throughout the research, we had tried to see the effect of CPP and CQA on the rheological properties of the gel formulations. Furthermore, It is well-known that transdermal drug release is specially based on the diffusion process of drug molecules into the formulation components. And rheological properties affect the diffusion process of the drug molecules, Such as Viscosity inversely proportional to the diffusion co-efficient. Here, we tried to evaluate the mechanical properties of the transdermal gels in the presence of the permeability enhancers and also at different storage period and mixing speed. Rheological studies of the gels showed that permeability enhancers, processing parameters and storage period was affecting the microstructure systems organized in the gels. Moreover, the microstructure of the polymers also affected the diffusion process of the drug. During In-vitro study, ECO was diffusing from polymer entangled system and also from the skin membrane. As the cohesive energy of the gel system increased the diffusion of drug in polymer entangled system was decreased and the flux of ECO also decreased. Increase of cohesive energy demonstrated that the interaction of polymer-drug, or polymerenhancer was increased and it required higher amount of energy to break the bonds. Furthermore, temperature sweep data also validated this assumption by decreasing in loop area during temperature cycle and also increased the cross over point of G’ and G”. Oleic acids exhibited very stable microstructure as compare to other fatty acids. These rheological studies indicated that



118

knowledge of rheological properties during product development can be helpful during storage stability profiling and selecting processing parameters for manufacturing scale. Application of Time Temperature Superposition was helpful to evaluate the thermorhelogical properties of the transdermal gels. It was found that all the transdermal gels prepared at different mixing speed or with different permeability enhancers were thermorheologically simple and can apply TTS principle. TTS principle was useful to evaluate the thermal properties of final formulations such as glass transition temperature, thermal expansion co-efficient and fraction volume free volume of the formulations. It is very difficult to measure the glass transition temperature of formulation using DSC or any other techniques. Using frequency sweep, we can measure the modulus at different temperature and then by applying TTS principle, we can extend the frequency range using polymer free volume theory. Moreover, It can help us to evaluate the viscoelasticity of the formulation at different time periods.



119

CHAPTER V: REFRENCES 1.

Chhetri A., and Kumar Dey B., “An Overview on Transdermal Drug Delivery”, Indo American Journal of Pharmaceutical Research, 2016, 6(7), 6073-6091

2.

El-Kattan A., Asbill C., and Haidar S., “Transdermal Testing: Practical Aspects and Methods”, PSTT, 2000, 3(12), 426-430

3.

Yeoh T., “Master Class Designing Non-Invasive Skin Mediated Therapies II”, [2016], [August], [5], [Paramus], [NJ]

4.

Bathe R., Kapoor R., “Transdermal drug delivery system: formulation, development and evaluation- An overview”, International Journal of Biomedical and Advance Research, 2015, 6(1), 1-10

5.

Ashok kumar J., Pullakandam N., Prabu S. L., and Gopal V., “Transdermal Drug Delivery System: An Overview”, International Journal of Pharmaceutical Sceience Review and Research, 2010, 3(2), 49-54

6.

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