Transdermal Drug Delivery System with Enhanced Skin Permeability

Chapter 21

Transdermal Drug Delivery System with Enhanced Skin Permeability Yie W. Chien and Chia-Shun Lee

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Controlled Drug Delivery Research Center, Rutgers—The State University of New Jersey, College of Pharmacy, Busch Campus, Piscataway, NJ 08854

A new generation of transdermal drug delivery (TDD) system was developed to contain one or more skin permeation enhancers in the surface adhesive coating layers. This TDD system has been found, experimentally, to release the enhancers to the surface of stratum corneum to modify the skin's barrier properties, prior to the controlled delivery of the active drug. The extent of enhancement in skin permeability appears to be dependent upon the chemical structure of drug to be delivered transdermally as well as the type and the concentration of enhancer used. The mechanism of skin permeation enhancement have been explored and are analyzed in this report.

Continuous infusion This

intravenous

has

mode

been

of

"first-pass" and a and

administration elimination

monitored of

control

drug

direct of

delivery

its of

the

is

of

a of

levels

in

into

the

patients

and

can

the

close

hepatic

prolonged,

body.

Therefore,

systemic

both

the

circulation

such

therefore,

of

delivery.

provide

However,

and,

rate

drug

constant,

the

levels.

risks

of

bypassing

infusion

drug

programmed mode

maintaining

drug

certain

the

Recently,

there

intravenous

drug

potential drug

To

as

drug

delivery

at

superior

capable

well

circulating of

a

mode

of

necessitates

medical

supervision

medication.

delivery

of

as

be

intravenous

entails

hospitalization

of

to

therapeutically-effective closely

advantages

of

administration

considered

is

a

growing

infusion

can

hazards,

by

using

administration

to

provide

into

the

systemic

accomplish

systemically

the

effective

recognition be

closely

the

intact

a

circulation

goals

of

drugs,

that

the

duplicated, skin

continuous

as

benefits without

the

portal

transdermal

drug

(_1 ).

transdermal several

controlled

transdermal

drug

0097-6156/87/0348-0281 $06.00/0 © 1987 American Chemical Society

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

delivery delivery

CONTROLLED-RELEASE TECHNOLOGY


282

(TDD) systems have r e c e n t l y been d e v e l o p e d t o d u p l i c a t e the b e n e f i t s of continuous i n t r a v e n o u s drug infusion. The evolution of TDD systems began w i t h the development o f s c o p o l a m i n e - r e l e a s i n g TDD system (Transderm-Scop® by A l z a ) f o r 72-hr p r o p h y l a x i s o f motioninduced nausea (_2). The s u c c e s s f u l marketing of n i t r o g l y c e r i n r e l e a s i n g TDD systems (Deponit® by Pharma-Schwarz/Lohmann, N i t r o disc® by S e a r l e , Nitro-Dur® by Key, and Transderm-Nitro® by C i b a ) , as w e l l as isosorbide dinitrate-releasing TDD system (Frandol® tape by T o a e i y o , Yamanouchi) f o r once-a-day m e d i c a t i o n o f a n g i n a p e c t o r i s (3,4) have e s t a b l i s h e d TDD systems as an a c c e p t a b l e dosage form. Most r e c e n t l y , r e g u l a t o r y a p p r o v a l has been o b t a i n e d f o r a clonidine-releasing TDD system (Catapres-TTS® by Boehringer Ingelheim) f o r weekly t h e r a p y o f h y p e r t e n s i o n (4·) and an e s t r a d i o l r e l e a s i n g TDD system (Estraderm® by C i b a ) f o r twice-a-week treatment of postmenopausal symptoms (_5 ). It has drug d e l i v e r y fits: 1) 2)

3) 4)

5)

6) 7)

been offers

recognized that transdermal one or more o f the f o l l o w i n g

rate-controlled p o t e n t i a l bene-

Avoidance o f the r i s k s and the i n c o n v e n i e n c e s o f i n t r a venous t h e r a p y . P r e v e n t i o n o f the v a r i a t i o n i n a b s o r p t i o n and metabolism, as w e l l as the p o t e n t i a l i r r i t a t i o n a s s o c i a t e d w i t h o r a l drug a d m i n i s t r a t i o n . C o n t i n u i t y of drug a d m i n i s t r a t i o n , p e r m i t t i n g the use of a drug w i t h s h o r t b i o l o g i c a l h a l f - l i f e . Efficacy can be a c h i e v e d w i t h reduced d a i l y dosage o f drug by c o n t i n u i n g drug i n p u t and b y p a s s i n g h e p a t i c f i r s t pass e l i m i n a t i o n . L e s s chance o f o v e r - o r u n d e r - d o s i n g as the r e s u l t o f p r o l o n g e d , preprogrammed d e l i v e r y o f drug a t the r e q u i r e d therapeutic rate. Provision of a s i m p l i f i e d t h e r a p e u t i c regimen, leading to a b e t t e r p a t i e n t c o m p l i a n c e . Ability t o e a s i l y t e r m i n a t e the m e d i c a t i o n , as needed, by s i m p l y removing the TDD system from the s k i n s u r f a c e .

Interest i n the potential biomedical applications of the r a t e - c o n t r o l l e d t r a n s d e r m a l drug a d m i n i s t r a t i o n i s f u r t h e r demons t r a t e d by the s u b s t a n t i a l i n c r e a s e i n r e s e a r c h and development a c t i v i t i e s i n many h e a l t h c a r e i n s t i t u t i o n s ( 3 , 6 , 7 ) . The p o t e n t i a l drug c a n d i d a t e s e v a l u a t e d have ranged from the a n t i - h y p e r t e n s i v e , antianginal, anti-histamine, anti-inflammatory, analgesic, antia r t h r i t i c , s t e r o i d a l to c o n t r a c e p t i v e drugs. I t has been e s t i m a t e d by m a r k e t i n g a n a l y s i s e x p e r t s t h a t over 10% o f the drug p r o d u c t s w i l l be marketed i n TDD systems w i t h i n the next 5 y e a r s . However, i t has been i n c r e a s i n g l y r e c o g n i z e d t h a t not e v e r y drug can be administered t r a n s d e r m a l l y at a r a t e sufficiently h i g h enough t o a c h i e v e a b l o o d l e v e l t h a t i s t h e r a p e u t i c a l l y benef i c i a l f o r systemic medication. An i n c r e a s i n g number o f b i o m e d i c a l r e s e a r c h e r s working i n the f i e l d s o f t r a n s d e r m a l drug delivery


21.

CHIEN AND LEE

Transdermal Drug Delivery System

have g r a d u a l l y d i s c o v e r e d the p o t e n t i a l systemic medications (6,7).

limitations

283 of transdermal

As an example o f a p o t e n t i a l l i m i t a t i o n , the drugs listed i n F i g u r e 1 have r a t h e r low m o l e c u l a r weights and r e l a t i v e l y s i m i l a r in molecular size. However, t h e i r skin permeation rates vary as much as 100 f o l d s (2 mcg/cm /hr f o r f e n t a n y l v s . 200 mcg/cm /hr for ephedrine). This difference i n skin p e r m e a b i l i t y w i l l be r e f l e c t e d i n the s i z e o f TDD system r e q u i r e d t o d e l i v e r t h e e f f e c t i v e d a i l y dose ( T a b l e I ) . A TDD system h a v i n g a d r u g - r e l e a s i n g s u r f a c e a r e a o f 90 cm i s e x p e c t e d t o be r e q u i r e d f o r the d e l i v e r y o f d i e t h y l c a r b a m a z i n e a t a d a i l y dose o f 215 mg/day. From the s t a n d p o i n t o f p r a c t i c a l a p p l i c a t i o n s , a TDD system o f t h i s size would n o t be n e i t h e r d e s i r a b l e n o r e c o n o m i c a l . 2

2


2

To deliver a therapeutically-effective dose transdermally u s i n g a TDD system w i t h a r e a s o n a b l e s i z e ( e . g . , _< 20 c m ) , the b a r r i e r p r o p e r t i e s o f the s k i n f o r drug permeation must be overcome to e f f e c t i v e l y deliver the drugs t r a n s d e r m a l l y a t a c o n t r o l l e d rate. The f o l l o w i n g approaches have been shown t o p o t e n t i a l l y d e c r e a s e the s k i n ' s b a r r i e r p r o p e r t i e s and enhance the t r a n s d e r m a l permeation o f the drugs (8): 2

1)

2)

3)

P h y s i c a l approach a) Iontophoresis b) U l t r a s o n i c energy c) Thermal energy d) S t r i p p i n g o f s t r a t u m corneum e) H y d r a t i o n o f s t r a t u m corneum Chemical approach a) Synthesis of l i p o p h i l i c analogs b) D e l i p i d i z a t i o n o f s t r a t u m corneum c) C o - a d m i n i s t r a t i o n o f s k i n permeation enhancer B i o c h e m i c a l approach a) S y n t h e s i s o f b i o c o n v e r t i b l e prodrugs b) C o - a d m i n i s t r a t i o n o f s k i n metabolism i n h i b i t o r s

Development of Skin Permeation Enhancers-releasing TDD System The s k i n p e r m e a b i l i t y o f drugs has been r e p o r t e d l y improved by treating the s t r a t u m corneum s u r f a c e w i t h an a p p r o p r i a t e skin p e r m e a t i o n enhancer. Representatives of p o t e n t i a l skin permeation enhancers a r e l i s t e d i n Chart I . In this investigation, t h e concept o f promoting the s k i n permeability o f drugs by s k i n permeation enhancers i s a p p l i e d i n the p r a c t i c e o f t r a n s d e r m a l c o n t r o l l e d drug d e l i v e r y by d e v e l oping a skin-permeation-enhancing (SPE) Transdermal D e l i v e r y System (_9 ). In b r i e f , the SPE-transdermal d e l i v e r y system i s f a b r i c a t e d by f i r s t d i s p e r s i n g drug, l i k e s t e r o i d , homogeneously, as m i c r o r e s e r v o i r s , i n the s i l i c o n e e l a s t o m e r m a t r i x . F o l l o w i n g the c r o s s l i n k i n g and c u r i n g o f the d r u g - d i s p e r s e d polymer m a t r i x i n the d e v i c e maker, t h e d r u g - r e l e a s i n g s u r f a c e was then c o a t e d with


284


Di»thylcorbomoiin»

Eph»drin«

NitroglycTin

ÇON(C,H,),

HOCHCHNHCH

CH,-ON0 I CH-ONO, I

Ο

2

ι

(200M9/cm /hr)

Scopo|omin»


CH -OW0 2

(lOO p g / c m V h r )

2

(13 pg/cmVhr) F—itpnyl

Chlorph»nironnin« CH CH N(CH ) 2

2

2

3

2

CH CH CON-^ 3

CH OH

^-CH CH ~C H

2

a

2

t

s

2

OOCCH C.H

O r

some

1.

(3.5 p g / c m V h r )

Chemical

representative

Table I:

CI

S

(3.8 p g / c m V h r )

Figure

C.H,

Comparison

structure

drugs

(Data

and adapted

(2 /cm /hr)

skin

permeation

of

i n Skin Permeation Rate and Required TDD Size

Skin

Effective Daily

Rate )

Treatment

1

(mg/cm /day) 2

Ephedrine

4.8

Diethylcarbamazine

2.4

Fentanyl

0.048

1) Data c a l c u l a t e d

rate

f r o m R e f e r e n c e 13).

Permeation Drugs

2

Me

Nasal congestion Filariasis infection Postoperative analgesia

TDD

Dose ^

Size

(mg/day)

(cm )

150-400 (oral) 215 (oral) 0.6-2.4 (i.m.)

31.3-83.3

2

2

89.6

from R e f e r e n c e 13

2) Data from R e f e r e n c e 12


12.5-50

21.

CHIEN AND LEE


285

multi-laminates of skin permeation enhancer-containing adhesive by lamination technique (Figure 2 ) .

silicone


This new type of transdermal drug delivery system i s capable of releasing one or a combination of two or more skin permeation enhancers to the stratum corneum surface in order to modify the skin's barrier properties ( 1 0 ) , p r i o r to the controlled delivery of the active drug, and the skin becomes more permeable to the drug (Figure 3 ) . In v i t r o skin permeation studies i n a hydrodynamically wellcalibrated skin permeation c e l l (Figure 4) demonstrated that simple pharmaceutical excipients, l i k e capric acid (a saturated straightchain fatty acid), can substantially enhance the trandermal permeation rate of progesterone. The time lag i s s i g n i f i c a n t l y reduced, while the zero-order skin permeation rate p r o f i l e i s maintained (Figure 5 ) . The same phenomena have also been observed with other types of enhancers examined. The extent of enhancement can be expressed as a parameter, c a l l e d enhancement factor, which is calculated from the following relationship: „ , ^ Enhancement Factor

(Normalized skin permeation rate) (Normalized skin permeation rate) r

, enhancer ^ control

It i s interesting to note that the enhancement of skin permeation of drugs by fatty acid i s dependent upon the a l k y l chain length (Figure 6 ) . In addition, the e s t e r i f i c a t i o n of the carboxy l i c acid group reduces the effectiveness of fatty acids i n skin permeation enhancement. The type of enhancer used and i t s concent r a t i o n in the adhesive coating also play an important role in the extent of skin permeation (Figure 7 ) . In addition to progesterone, which i s r e l a t i v e l y skin permeable, the propyl esters of myristic acid (a long-chain saturated fatty acid) and of o l e i c acid (a long-chain unsaturated fatty acid) are also capable of promoting the rate of skin permeation for the less permeable s t e r o i d a l drugs (Table II). The skin permeation rates for the s t e r o i d a l anti-inflammatory agents, l i k e hydrocortisone, nonsteroidal anti-inflammatory drugs, l i k e indomethacin, and estrogenic steroids, l i k e e s t r a d i o l , have a l l been substantially enhanced. The effectiveness of skin permeation enhancer appears to be dependent upon i t s location in the TDD system. The extent of skin permeation enhancement i s greater when the enhancer i s incorporated in the adhesive layer (Table III). In addition to the esters of saturated and unsaturated fatty acids, azone and decylmethyl sulfoxide are also very e f f e c t i v e in enhancing the skin permeability of drugs (Table II and Figure 6). Results appear to suggest the possible existence of a r e l a t i o n ship between the skin permeability enhancement of a drug, molecular structure of the drug, as well as the type of enhancer used. The skin permeability can be further improved by incorporating


286


Chart

I . S k i n P e r m e a t i o n Enhancer

1) Azone

3

N-CH (CH ) CH 2

2

I 0

)

Decyl Methyl Sulfoxide

CH

3

2) Oleic Acid

CH (CH ),CH

3

2

2

3

4) Capric Acid

Ο

Ο

HO —


Used

H

O

CH (CH ) CH -CH 2

2

5

2

— CH

2

(CHj) CH 7

3

CH (CH ) CH -CH 3

Drug - impermeable b a c k i n g laminate

2

6

2

)

Drug r e s e r v o i r / p o l y m e r i c

SPE-releasing

adhesive

matrix multilaminate

Drug (s) E n h a n c e r (s) Figure 2. The c r o s s - s e c t i o n a l view o f a s k i n - p e r m e a b i l i t y e n h a n c i n g TDD system, showing v a r i o u s major s t r u c t u r a l com ponents .


21.

CHIEN AND LEE

STRATUM CORNEUM ! Downloaded by UNIV LAVAL on September 22, 2015 | http://pubs.acs.org Publication Date: September 4, 1987 | doi: 10.1021/bk-1987-0348.ch021

287


F i g u r e 3. An expanded diagram t o enhancing the s k i n permeation of one o r more enhancers t o s k i n s u r f a c e characteristics o f s t r a t u m corneum delivery of a therapeutically active

PAPILLARY LAYER ! CAPILLARY ! NETWORK

ILOOD CIRCULATION ! !

i l l u s t r a t e the concept o f drugs by f i r s t releasing t o m o d i f y the p e r m e a b i l i t y p r i o r t o the c o n t r o l l e d drug.



288


DONOR COMPARTMENT

AIR I 4

Figure 4. Diagrammatic i l l u s t r a t i o n of a hydrodynamically well-calibrated skin permeation c e l l (reproduced from Ref. 11). The c e l l consists of two compartments in vertical arrangement: A donor compartment, which i s exposed to an ambient condition and a receptor compartment, which i s maintained at 37°C by c i r c u l a t i n g a thermostated water through the water-jacket. The solution hydrodynamics i n the receptor compartment i s kept at constant by a Tefloncoated starhead magnet rotating at 600 rpm by a synchronous motor mounted d i r e c t l y underneath the c e l l mounting block. One unit of the skin-permeation enhancing (SPE) Transdermal Therapeutic System i s sandwiched between the donor and receptor compartments with i t s SPE-releasing adhesive layer i n intimate contact with the stratum corneum surface and the skin permeation p r o f i l e s were characterized by sampling the receptor solution at regular i n t e r v a l s , for up to 32 hours, and assaying the samples by a s t a b i l i t y - i n d i c a t i n g HPLC method.



21.

CHIEN AND L E E

Figure

5.

progesterone rated

fatty

Enhancement by acid,

289


various

in

the

skin

concentrations

released

from

the

permeation of

capric

adhesive

profiles acid,

coating

a

layer.


of satu-


290

•

CH (CH >nC00H 3

2

Ο CH (CH )nC00C H7 2

3


S

3

30

NUMBER OF CH GROUP (n) 2

F i g u r e 6. Dependency o f t h e enhancement f a c t o r f o r t h e s k i n permeation o f p r o g e s t e r o n e on t h e a l k y l c h a i n l e n g t h o f s a t u r a t e d f a t t y a c i d s w i t h maximum enhancement a t n=6, and t h e e f f e c t o f e s t e r i f i c a t i o n on s k i n permeation enhancement. 50 Decyl Methyl Sulfoxide

Ο

Azone -Ο—Capric

Acid

ζ LU 5

LU

Ο Ζ

4?---©

·©

10

15

Oleic Acid

< Σ Ζ

5

ENHANCER

CONC.

20

( %m ) m

2

F i g u r e 7. Dependency o f enhancement f a c t o r f o r t h e s k i n perme a t i o n o f p r o g e s t e r o n e on t h e c o n c e n t r a t i o n o f v a r i o u s skin permeation enhancers.


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CHIEN AND LEE

Table


291

I I : Enhancement of Skin Permeability of Various Drugs by Different Types of Enhancers ^ 3


Drugs

Progesterone Estradiol Indomethacin Hydrocortisone

Skin Permeation Rate (mcg/cm^/day)

36.72 29.29 9.36 1.10

± 10.32 ± 24.48 ± 0.08 ± 0.12

Enhancement Factor propyl myristate

propyl oleate

Azone

Decylmethyl sulfoxide

4.56 9.33 3.77 4.57

5.36 14.62 4.67 5.01

5.96 20.17 14.49 61.30

11.04 12.59 15.67 25.23

a) Unit concentration of enhancer i n the adhesive

layer = 3.2 mg/cm

2

3

Table I I I : E f f e c t of the Location of Skin Permeation Enhancer ^ on the Enhancement of Progesterone Permeability

Location

Polymer matrix Adhesive f i l m

Skin Permeation Rate (meg/cm^/day)

34.6 ± 0.5 36.7 ± 10.3

Enhancement Factor propyl myristate

propyl oleate

Azone

Decylmethyl sulfoxide

2.67 4.56

4.05 5.36

2.56 5.96

3.81 11.04

a) The same amount of an enhancer was incorporated either i n the drug-containing polymer matrix or i n the drug-free adhesive film.


292


a combination of two or more different types of enhancers i n the adhesive layer, such as the combination of azone with o l e y l acetate, or reduced, such as the combination of azone with propyl oleate (Table IV).


Mechanisms of Skin Permeation Enhancement Transdermal delivery of drugs and other small molecules through the skin can be regarded as consisting of a process of dissolution and molecular d i f f u s i o n through a composite structure. The p r i n c i pal barrier to d i f f u s i o n i s the stratum corneum. A simplistic two-phase model has been proposed, which describes the stratum corneum as a hydrophilic protein gel dispersing i n a continuous l i p i d matrix (Figure 8). The penetrant molecules must migrate through by dissolution and Fickian d i f f u s i o n (13). If this two-phase model (Figure 8) i s v a l i d , d e l i p i d i z a t i o n of the stratum corneum, which dissolves away the l i p i d matrix, by organic solvent, from the skin composite structure (14), should improve the skin permeability of drugs. Results from the d e l i p i d i z a t i o n studies indicated that the enhancers releasing from the adhesive coating of SPE-Transdermal Delivery System s t i l l enhance the permeation of progesterone across the d e l i p i d i z e d skin with constant permeation p r o f i l e and reduced time lag (Figure 9). The extent of skin permeation enhancement i s dependent upon the type of enhancer released. The same phenomena were also observed (Figure 10) when the stratum corneum layer was t o t a l l y removed by stripping technique (15). The results appear to suggest that the skin permeation enhancers studied also promote the permeation of progesterone across the hydrophilic viable skin of epidermis and dermis. The results summarized i n Table V indicate that i n the control system (contains no skin permeation enhancer), the skin permeation rate of progesterone increases by 143% when stratum corneum i s delipidized. The enhancement i s 843% when the stratum corneum is t o t a l l y eliminated. As a low surface concentration of enhancer (3 mg/cm^) i s incorporated into the adhesive coating, the enhancing effect on the permeation across the d e l i p i d i z e d skin shows no statistical difference among the enhancers studied. A l l four types of skin permeation enhancers were observed to promote the permeation of progesterone across the intact skin. Azone and o l e i c acid are more e f f e c t i v e than capric acid and decylmethyl sulfoxide in enhancing the permeation rate of progesterone across the intact skin, which i s approximately the same as that across the stripped skin. However, the rates of permeation across the intact and d e l i p i d i z e d skin, under the effect of capric acid and decylmethyl sulfoxide, are rather similar i n magnitude. The results suggest that azone and o l e i c acid may promote the skin permeation of progesterone v i a the l i p i d matrix pathway, while capric acid and decylmethyl sulfoxide may enhance the permeability of the hydrophilic protein gel to the transport of progesterone, a l i p o p h i l i c molecule.


21.

CHIEN AND LEE


293

Table IV: Skin Permeability Enhancement of Indomethacin by Combination of Permeation Enhancers 3

Skin Permeation Enhancers ^

Azone " "

Azone propyl oleate o l e i c acid o l e y l alcohol o l e y l acetate mono-olein

"


11

Azone " "

14.49 8.44 13.47 15.25 18.96 7.19

myristyl alcohol propyl myristate myristyl N, Ndimethylamide

11

a

Enhancement Factor

5.10 8.98 12.02

^ U n i t concentration of enhancer i n the adhesive layer = 3.2 mg/cm^ (Equal concentration for #1 and #2 enhancers) Stratum Corneum

1

"p7

1

Τ P.

Lipid Matrix

ΊΓ Ph

+

(P,)

Hydrophilic Protein Gel

(P ) h

Hydrodynamic Diffusion Layer

Figure 8. Diagrammatic i l l u s t r a t i o n of the two-phase model which describes the stratum corneum as a hydrophilic protein gel dispersing i n a continuous l i p i d matrix.


294



S

0

8

16 Time

24

32

40

(hours)

F i g u r e 9. P e r m e a t i o n p r o f i l e s o f p r o g e s t e r o n e a c r o s s a d e l i p i d i z e d s k i n and t h e e f f e c t o f v a r i o u s s k i n p e r m e a t i o n e n h a n c e r s . Keys: Control device (C) and e n h a n c e r - r e l e a s i n g d e v i c e (Aazone, O A - o l e i c a c i d , C A - c a p r i c a c i d , DMS-Decylmethyl sulfoxide).



21.

CHIEN

A N D L E E


Time

(hours)

Figure 10. Permeation p r o f i l e s of progesterone across a stripped skin (no stratum corneum) and the effect of various skin permeation enhancers. Keys: Control device (C) and enhancer-releasing device (A-azone, OA-oleic acid, CA-capric acid, DMS-Decyl methyl sulfoxide).


296


Table V : E f f e c t of Enhancers on Permeation Rate of Progesterone Across Various Skin Structures

Enhancers

N o r m a l i z e d S k i n P e r m e a t i o n Rate

1)

2

(mcg/cm /hr ± S.D.)


Intact Control

Skin

Stripped Skin^

Delipidized Skin 2 )

0.28 (±0.05)

0.40 (±0.07)

2.36 (±0.68)

sulfoxide

8.40 5.32 2.23 2.19

(±2.64) (±1.25) (±0.86) (±0.93)

2.69 3.94 2.08 2.40

(±1.11) (±1.26) (±0.62) (±0.40)

6.46 (±1.07) 6.67 (±1.20) 4.22 (±0.30) 4.48 (±0.49)

sulfoxide

9.15 5.58 7.91 11.26

(±2.35) (±1.87) (±1.85) (±0.73)

3.30 3.64 5.20 12.50

(±0.72) (±0.79) (±0.47) (±4.21)

4.87 6.47 6.17 7.75

2

A)

3 mg/cm Azone Oleic acid Capric acid Decylmethyl

B)

2

15 mg/cm Azone Oleic acid Capric acid Decylmethyl

The s k i n p e r m e a t i o n r a t e a f t e r c o r r e c t i n g the v a r i a t i o n p e r m e a t i o n r a t e a c r o s s the r e f e r e n c e s k i n .

Stratum corneum s u r f a c e was p r e - e x t r a c t e d w i t h o r g a n i c f o r 4 hours ( R e f e r e n c e 1 4 ) .

Stratum corneum s u r f a c e was removed by 25x s t r i p p i n g 15).

(±0.53) (±1.65) (±1.04) (±3.08)

i n skin

solvent

(Reference


21. CHIEN AND LEE


297


As the c o n c e n t r a t i o n o f enhancer i n the a d h e s i v e l a y e r i n c r e a s e s by 5 f o l d s , the s k i n p e r m e a t i o n r a t e o f p r o g e s t e r o n e a c r o s s the i n t a c t s k i n i n c r e a s e s u b s t a n t i a l l y f o r c a p r i c a c i d and d e c y l m e t h y l s u l f o x i d e , but n o t f o r azone and o l e i c a c i d . The d e l i p i d ization of stratum corneum s i g n i f i c a n t l y a f f e c t s the e n h a n c i n g e f f e c t o f azone on the s k i n p e r m e a t i o n r a t e o f p r o g e s t e r o n e , but not on t h a t o f d e c y l m e t h y l s u l f o x i d e . The e f f e c t o f d e l i p i d i z a t i o n on the e n h a n c i n g c a p a c i t y o f c a p r i c a c i d and o l e i c a c i d i s r e l a t i v e l y s m a l l (Table V ) . To gain a better u n d e r s t a n d i n g o f the mechanisms involved in the enhancement o f s k i n permeation, the enhancement factor f o r the enhanced p e r m e a t i o n o f p r o g e s t e r o n e a c r o s s v a r i o u s skin s t r u c t u r e s a t low and h i g h enhancer c o n c e n t r a t i o n s has been c a l c u l a t e d ( T a b l e s VI & V I I ) . The d a t a i n d i c a t e d t h a t as the a d h e s i v e layers contain low c o n c e n t r a t i o n of skin permeation enhancer, the permeation a c r o s s the i n t a c t s k i n i s i n c r e a s e d by 30 f o l d s f o r azone and 19 f o l d s f o r o l e i c a c i d . T h i s enhancement i s s u b s t a n t i a l l y greater than the enhancement o f the p e r m e a t i o n a c r o s s t h e delipidized skin. However, t h e a p p r o x i m a t e l y 8 - f o l d enhancement f o r b o t h c a p r i c a c i d and d e c y l m e t h y l s u l f o x i d e i s n o t s t a t i s t i c a l l y d i f f e r e n t from t h a t a c r o s s the d e l i p i d i z e d s k i n . For the permeation across the d e l i p i d i z e d s k i n , the e f f e c t i v e n e s s i n enhancement showed no s t a t i s t i c a l d i f f e r e n c e among the f o u r enhancers used. The r e s u l t s a p p a r e n t l y s u g g e s t e d t h a t a t low enhancer concentration, the enhancement i n the s k i n p e r m e a t i o n o f p r o g e s t e r o n e by c a p r i c a c i d and d e c y l m e t h y l s u l f o x i d e appears t o r e s u l t from an improved permeation across the h y d r o p h i l i c protein g e l pathway alone. However, azone and o l e i c a c i d must a l s o a c t on the f a t t y m a t r i x pathway, which y i e l d s additional enhancement. In the case o f o l e i c a c i d , the c o n t r i b u t i o n o f l i p o p h i l i c f a t t y m a t r i x pathway t o the o v e r a l l s k i n p e r m a t i o n enhancement o f p r o g e s t e r o n e i s about the same as t h e h y d r o p h i l i c p r o t e i n g e l pathway. In t h e case o f azone, the f a t t y m a t r i x pathway c o n t r i b u t e s a p p r o x i m a t e l y 80% o f the t o t a l enhancement o f s k i n p e r m e a t i o n o f p r o g e s t e r o n e as compared t o 20% c o n t r i b u t i o n from t h e p r o t e i n g e l pathway. As the s u r f a c e concentration o f enhancer i n the a d h e s i v e coating increased, the mechanism o f s k i n p e r m e a t i o n enhancement showed some changes as r e f l e c t e d i n the r e l a t i v e contribution o f f a t t y m a t r i x and p r o t e i n g e l pathways ( T a b l e V I I ). The b e h a v i o r f o r azone and o l e i c a c i d a t h i g h c o n c e n t r a t i o n was o b s e r v e d t o be i d e n t i c a l t o t h a t a t low c o n c e n t r a t i o n (compare t h e d a t a i n T a b l e s VI and V I I ). On the o t h e r hand, c a p r i c a c i d and d e c y l m e t h y l s u l f o x i d e showed a d u a l e f f e c t on the h y d r o p h i l i c protein g e l and a l s o on the l i p o p h i l i c f a t t y m a t r i x . I n the case o f c a p r i c a c i d , the o v e r a l l enhancement i n the p e r m e a t i o n o f p r o g e s t e r o n e was i n c r e a s e d by 354%, i n which t h e p r o t e i n g e l pathway and f a t t y m a t r i x pathway c o n t r i b u t e approximately equally ( w i t h enhancement f a c t o r o f 15.3 v s . 13.0). In the case o f d e c y l m e t h y l s u l f o x i d e , the o v e r a l l enhancement was improved by 515% (40.2 v s . 7.8). The enhancement i s p r i m a r i l y the r e s u l t o f i n c r e a s e s (521%) i n the permeation enhancement across the h y d r o p h i l i c protein gel ( w i t h enhancement f a c t o r o f 31.25 a t h i g h enhancer concentration


298


Table VI : Enhancement i n Progesterone*-) Permeability Across Various Skin Structures (at low enhancer cone.)

Enhancers ^

Enhancement

2

Factor-*)

(mean

±

S.D.)

Delipidized


Intact

Skin

Stripped

Skin )

Skin )

4

5

Azone

30.0 ( ± 9 . 4 )

6.73 ( ± 2 . 7 7 )

2.74

(±0.45)

Oleic acid Capric acid Decylmethyl

19.0 8.0 7.8

9.85 5.20 6.00

2.83 1.79 1.90

(±0.51) (±0.13) (±0.21)

sulfoxide

"^107o d r u g

loading

in

polymer

(±4.5) (±3.1) (±3.3)

(±3.15) (±1.55) (±1.00)

matrix

2) 3 mg/cm

3)

of

2

Calculated

adhesive

polymer

by:

„ . Enhancement

„ Factor

skin

permeation

rate)

= 77: — : — — (Normalized skin

(Normalized

—: permeation

— rate;

v

, enhancer ^ control Ί

4) Stratum

corneum

surface

^Stratum

corneum

was

was

removed

pre-extracted

with

by

technique

stripping

organic

solvent

Table VII : Enhancement i n Progesterone*-) Permeability Across Various Skin Structures (at high enhancer cone.)

Enhancers )

Enhancement

2

Factor-*)

(mean

±

Delipidized Intact

Skin

32.7 ( ± 8 . 4 ) 19.9 28.3 40.2

drug

loading

in

polymer

Skin )

4

Oleic acid Capric acid Decylmethyl

"^10%

Stripped

Skin )

Azone

sulfoxide

S.D. )

(±6.7) (±6.6) (±2.6)

5

8.25 (± 1.80) 9.10 13.00 31.25

( ± 1.97) (± 1.17) (±10.5)

2.06

(±0.22)

2.74 2.61 3.28

(±0.70) (±0.44) (±1.31)

matrix

2) 15

3)

mg/cm

2

Calculated

of

adhesive

polymer

by:

_ m Enhancement

__ Factor

skin

permeation

rate)

= -7— — : — — (Normalized skin

(Normalized

: permeation

τ rate;

r

, enhancer ^ control

4) Stratum

corneum

surface

~* S t r a t u m

corneum

was

was

removed

pre-extracted

with

by

technique

stripping

organic

solvent


21.

CHIEN AND LEE


299


v s . 6.00 at low enhancer c o n c e n t r a t i o n ) . The a n a l y s i s a p p a r e n t l y s u g g e s t s t h a t at h i g h enhancer c o n c e n t r a t i o n , d e c y l m e t h y l s u l f o x i d e exerts i t s e n h a n c i n g e f f e c t o n l y on the h y d r o p h i l i c p r o t e i n gel pathway, whereas azone, o l e i c a c i d and c a p r i c a c i d have a d u a l a c t i o n on b o t h the h y d r o p h i l i c p r o t e i n g e l and lipophilic fatty m a t r i x pathways. The d u a l a c t i o n on t h e s e pathways i s about the same f o r c a p r i c a c i d , a s a t u r a t e d f a t t y a c i d , and f o r o l e i c a c i d (a n o n - s a t u r a t e d f a t t y a c i d ) . On the o t h e r hand, azone a c t s p r e f e r e n t i a l l y on the l i p o p h i l i c f a t t y m a t r i x pathway. I t i s i n t e r e s t i n g t o n o t e t h a t at b o t h low and h i g h enhancer concentrations, the enhancing e f f e c t on the p e r m e a t i o n o f p r o g e s t e r one a c r o s s the v i a b l e s k i n , i . e . s t r i p p e d s k i n ( w i t h no stratum corneum), shows no s t a t i s t i c a l d i f f e r e n c e among a l l f o u r e n h a n c e r s . The enhancement f a c t o r was o b s e r v e d t o be s u b s t a n t i a l l y smaller than t h a t f o r i n t a c t and d e l i p i d i z e d s k i n ( T a b l e VI and V I I ). Conclusions By d e l i v e r i n g s k i n p e r m e a t i o n enhancer from the a d h e s i v e polymer, which c o a t s the drug-releasing surface o f the t r a n s d e r m a l drug d e l i v e r y system, the s k i n p e r m e a b i l i t y o f drugs can be s u b s t a n t i a l l y enhanced. The e x t e n t o f enhancement appears t o be dependent upon the c h e m i c a l s t r u c t u r e o f drug to be d e l i v e r e d t r a n s d e r m a l l y and the type and c o n c e n t r a t i o n o f enhancer used. Considering the s t r a t u m corneum as the composite structure o f h y d r o p h i l i c p r o t e i n g e l and l i p o p h i l i c f a t t y m a t r i x , the mechanisms o f s k i n p e r m e a t i o n enhancement were i n v e s t i g a t e d u s i n g p r o g e s t e r o n e as the model p e n e t r a n t and azone, c a p r i c a c i d , o l e i c a c i d and decylmethyl sulfoxide as the model e n h a n c e r s . The results g e n e r a t e d t o date c o n c l u d e d t h a t d e c y l m e t h y l s u l f o x i d e i s an enh a n c e r which promotes the s k i n p e r m e a b i l i t y o f drugs by preferent i a l l y a f f e c t i n g the h y d r o p h i l i c p r o t e i n g e l pathway. Azone a c t s p r i m a r i l y on the l i p o p h i l i c f a t t y m a t r i x pathway w i t h some e f f e c t s on the h y d r o p h i l i c p r o t e i n g e l m a t r i x . Capric a c i d , a saturated f a t t y a c i d , promotes the p e r m e a t i o n v i a h y d r o p h i l i c p r o t e i n gel pathway a t low c o n c e n t r a t i o n and a l s o v i a l i p o p h i l i c f a t t y m a t r i x pathway at h i g h c o n c e n t r a t i o n . O l e i c a c i d , a non-saturated f a t t y a c i d , enhances the p e r m e a t i o n through b o t h p r o t e i n g e l and fatty m a t r i x pathways e q u a l l y . Acknowledgments The authors wish to express t h e i r a p p r e c i a t i o n t o Ms. M. f o r her a b l e a s s i s t a n c e i n p r e p a r a t i o n o f t h i s m a n u s c r i p t .

Boslet

Literature Cited 1)

Shaw, J. E.; Chandrasekaran, S. K.; Campbell, P.; J. Invest. Dermatol., 1976, 67, 677. 2) Shaw, J. E.; Chandrasekaran, S. K.; Drug Metab. Rev., 1978, 8, 223.



300


3) 1982 Industrial Pharmaceutical R & D Symposium on Transdermal Controlled Release Medication, Rutgers' College of Pharmacy, Piscataway, New Jersey, January 14 & 15, 1982. Proceedings published in Drug Develop. Ind.Pharm.,1983, 9, 497-744. 4) World Congress of Clinical Pharmacology Symposium on Transder mal Delivery of Cardiovascular Drugs, Washington, D. C., August 5, 1983. Proceedings published in Am. Heart J . , 1984, 108, 195-236. 5) Good, W. R.; Powers, M. S.; Campbell, P.; Schenkel, L.; J. Cont. Release, 1985, 2, 89-97. 6) 1985 International Pharmaceutical R & D Symposium on Advances in Transdermal Controlled Drug Administration for Systemic Medications, Rutgers University, College of Pharmacy, June 20 & 21, 1985. 7) Symposium on Problems and Possibilities for Transdermal Drug Delivery, The Schools of Medicine and Pharmacy, University of California, San Francisco, California, February 2-3, 1985. 8) Chien, Y. W.; Proc. 13th International Symposium on "Controlled Release of Bioactive Materials", 1986, p. 23-24. 9) Chien, Y. W.; Lee, C. S.; United States and International patents (pending). 10) Chien, Y. W.; Lee, C. S.; Abs. Academy of Pharmaceutical Sciences' 39th National Meeting and Exposition 1985, pp. 109. 11) Keshary, P. R.; Huang, Y. C.; Chien, Y. W.; Drug Develop. & Ind. Pharm., 1985, 11, 1213-1254. 12) Osol, Α.; Remington's Pharmaceutical Sciences, 16th edition, Mack, Easton, Pennsylvania (1980). 13) Michaels, A. S.; Chandrasekaran, S. K.; Shaw, J. E.; AIChE Journal, 1975, 21, 985. 14) Doshi, U. B.; Chiang, C. C.; Tojo, K.; Chien, Y. W.; Proc. 13th International Symposium on "Controlled Release of Bio active Materials, 1986, p. 138. 15) Durrheim, H.; Flynn, G. L.; Higuchi, W. I.; Behl, C. R.; J. Pharm. Sci., 1980, 69, 781 RECEIVED

November 13, 1986


Transdermal Drug Delivery System with Enhanced Skin Permeability

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