Journal

of Controlled Release, 12 (1990) 257-263 Elsevier Science Publishers B.V.. Amsterdam - Printed in The Netherlands

257

EFFECTIVE AND CONTROLLED TRANSDERMAL Sanjay K. Jain, Suresh P. Vyas* and V.K. Dixit
Pharmaceutics Laboratory, Department Sagar (m.p.) 470 003 (India) (Received November

DELIVERY OF EPHEDRINE

of Pharmaceutical Sciences, Doctor Harisingh Gour Vishwavidyalaya,

17, 1988; accepted in revised form October 3 1, 1989)

Key words: ephedrine; pseudolatices; matrix diffusion path; in vivo, in vitro system evaluation; transdermal delivery

The present work comprises the formulation ano! an evaluation of ephedrine with a view to developing and preparing an ephedrine releasing system for transdermal applications. Eudragit RL-100 and Eudragit RS-100 were used to prepare pseudolatices and matrix diffusion drug reservoirpatches. These preparations were evaluated for in vitro release and permeation of the drug across hairless mouse skin. Pseudolatices and a matrix diffusion drug reservoir system (1.0 cm) prepared using Eudragit RL-100 and Eudragit RS-100 in a 60: 40 ratio released the drug at the rate of 0.96 and 0.63 mg h- 1respectively. The designedpseudolatices and matrix diffusion transdermal patches were also evaluated for in vivo performance. The drug plasma profiles were compared with theplasmaprofile obtained following the administration of normal oral multiple doses of ephedrine hydrochloride using conventional tablets. After transdermal application of half the dose of ephedrine, as compared with the conventional dose recommended for administration during 24 h, a constant and comparatively higher drug blood level could be achieved. The most promising in vivo availability of the drug was recorded with selected pseudolatices.

INTRODUCTION

Transdermal drug delivery offers its own advantages over other routes of drug administration. Besides convenience, enhanced and controlled therapeutic responses have been recorded [ 11. Various types of preparations and methods employed in the preparation of transdermal drug delivery systems have been discussed in the literature [ 2-51. Two basic physical models that have been used to estimate the drug release mechanism are the membranepermeation controlled and the matrix-diffusion controlled systems [ 61. Recently, a topical preparation of lidocaine based on pseudolatex
*To whom correspondence should be addressed.

has been discussed [ 71. X-ray crystallographic analysis of the dispersions indicated the absence of a crystalline drug. The pseudolatex dispersion offers the opportunity to produce on the skin highly substantive, clear, continuous and virtually invisible films containing molecularly dispersed drug [ 71. The present study is an attempt to evaluate the performance of different Eudragit based transdermal preparations of ephedrine. Eudragit RL-100 and Eudragit RS-100 are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. Eudragit RL-100 is more permeable to water than Eudragit RS-100. These systems were evaluated both in vitro and in vivo. Ephedrine is an antiasthmatic drug with a

0168-3659/90/$03.50

0 1990 Elsevier Science Publishers B.V.

short biological half-life, i.e., 3-5.5 h. Therefore, 10 mg of drug is required to be administered three to four times a day [8]. Frequent dosing is associated with certain problems, such as insomnia, tremors, hypertension, tachycardia, etc. [ 91. The high transdermal permeability of ephedrine was recently recognised, and a therapeutic system to provide a prolonged continuous transdermal infusion of ephedrine into the systemic circulation was explored [lo]. A constant therapeutic blood level was observed for 48 h following the application of such a system.

solvent at 30 C, the films were removed from the glass rings and stored at controlled humidity (R.H. 58% ) and temperature (28 It_ C ). 2 One of the surfaces of the film was moistened with acetone and a slightly oversized aluminum foil was placed against it. The film was then allowed to dry in air for 24 h and was inspected for complete sealing between the two layers. The aluminum foil, preventing diffusion of the drug, was used as a backing membrane.
Preparation of pseudolatices

MATERIALS

Ephedrine [Burroughs Wellcome (India) Ltd., Bombay, India]; Eudragit RL-100 and Eudragit RS-100 (used as received from Rohm Pharma, Darmstadt, F.R.G.); dibutyl phthalate (Fluka A.-G., Switzerland). Tween 80 (polyoxyethylene sorbitan mono-oleate) and all other ingredients were of AnalaR grade, and were used as received from Glindia, a chemical division of Glaxo India Ltd. Bombay, India.

METHODS Preparation of matrix diffusion patch

The ephedrine-Eudragit pseudolatices were prepared by a solvent removal method [ 71. An Eudragit (10% w/w)-ephedrine (2% w/w) solution in chloroform was emulsified with an aqueous solution of surfactant (Tween 80,10% w/w). The organic solvent and a fraction of the water (ca. 25% w/w of that initially incorporated) were removed. The plasticizer dibutyl phthalate (10% w/w based on the polymer weight) was incorporated in the pseudolatex to improve the film forming properties of the dispersions. The polymers and their weight fraction ratio, drug and plasticizer concentrations used in the pseudolatex systems were the same as those used in the preparation of matrix diffusion systems.
Determination of drug concentration

Polymeric films containing the drug were prepared by the method described by Iyer and Vasavada using mercury as a substrate for film casting [ 111. The drug reservoir films were casted from 10% (w/w) solution of polymers (Eudragit RL-100, Eudragit RS-100 and 80 : 20, 60 : 40,40 : 60 and 20 : 80 mixtures by weight of Eudragit RL-100 and Eudragit RS-100 respectively) in acetone. The solutions included 2% (w/w) of ephedrine and 10% (w/w) of dibutyl phthalate (based on the polymer weight) in acetone. Portions (5 ml) of the solution were poured into glass rings (10 cm) on a mercury substrate. After complete evaporation of the

The ephedrine concentration in both types of product was determined spectrophotometritally [ 121. A sample of dried product was weighed and dissolved in methanol. After appropriate dilution with methanol, a colour was developed using bromothymol blue and the absorbance was measured at 420 nm using a Shimadzu UV 150-02 spectrophotometer. The ephedrine concentration was determined using a calibration curve prepared using standard solutions of different known concentrations of ephedrine.

In vitro drug release studies

The matrix diffusion system (patch) was attached to a glass slide (4.0 x 2.5 cm) using silicone adhesive (Medical adhesive B, Metroark Pvt. Ltd., Calcutta, India). The edges of the attached patch were covered with a silicone lubricant (high vacuum grade, Metroark Pvt. Ltd., Calcutta, India) to prevent drug release from the edges of the system [ 131. This glass plate-membrane assembly was immersed in 200 ml of isotonic phosphate buffered saline (PBS ) of pH 7.4 maintained at 37 + 1 C [ 141. The solution was stirred continuously by means of a peristaltic pump (Polystaltic, Watson Marlow) at a rate of 30 ml min-. To avoid water evaporation, the vessels were kept covered with aluminum foil. Aliquots (5 ml each) were withdrawn at various time intervals (i.e. 1,2,4,6,8, 10, 14 and 18 h) and replaced with the same volume of fresh buffer. The ephedrine concentration in these samples was assayed by the spectrophotometric method [ 121. In the case of pseudolatices, in vitro drug release study was performed using a Franz diffusion cell (Crown Glass Co., New Jersey, U.S.A.). The contents of the donor compartment (pseudolatices) and the receiver compartment (isotonic PBS of pH 7.4) were separated by cellophane membrane (Spectropore-2 membrane, 5000-7000 M.W. cut-off; Spectrum Medical Industries, Los Angeles, CA, U.S.A.) sandwiched between the two compartments. The temperature of the receiver compartment was maintained at 37 ? 1 oC. At each sampling time the solution in the receiver compartment was completely withdrawn and replaced with fresh isotonic PBS of pH 7.4.
In vitro skin permeation studies

to the stratum corneum side of freshly excised skin from the abdominal region [ 15 ] of a hairless mouse (male, HRS strains, 6-8 weeks old, International Scientific Stores, Agra, India). In this system, clinical conditions were simulated by controlling the receiver compartment temperature at 37 ? 1 oC while allowing the donor compartment to be exposed to ambient temperature (30 C ). the receiver compartment contained isotonic PBS (pH 7.4). Portions (1 ml) of buffer solution were withdrawn from the receiver compartment at time intervals of 1,2,4, 8, 12,16,20,24 and 28 h; the samples were replaced with an equal volume of fresh isotonic PBS (pH 7.4). The ephedrine concentrations in these samples were determined spectrophotometrically at 420 nm after addition of bromothymol blue [ 121.
In vivo absorption studies

The in vitro skin permeation of ephedrine from prepared matrix diffusion systems and pseudolatices was studied using a Franz diffusion cell (Crown Glass Co., New Jersey, U.S.A.). The preparation was applied directly

The pseudolatices and a matrix diffusion system comprising Eudragit RL-lOO-Eudragit RS100 (60:40),2% (w/w)ephedrineandlO% (w/ w) dibutyl phthalate were selected for in uiuo evaluation. The in vitro drug skin permeation rates determined for these systems were approximately equal to the permeation rates required, i.e. 58 pg h-l cm- (as calculated and reported by Bhalla and Toddywala [ 161) to achieve an effective plasma concentration. Therefore, these systems were selected for further in uiuo evaluation. The studies were carried out on nine healthy human male volunteers divided into three groups. These subjects possessed no history of having taken any drug during the preceding week, as well as during the studies. The subjects were fasted, with water ad libitum, for 12 to 14 h prior to administration of the drug. The first group was given an ephedrine hydrochloride (10 mg) conventional tablet (Deys Medical Stores, Calcutta, India) orally, four times a day at 6 h interval with 200 ml of water. The second group received a transdermal matrix diffusion patch and the third group the

260

pseudolatex system (both containing 20 mg of ephedrine). Both systems were applied on a cleaned 10 cm2 area of the forearm. Blood samples were collected from each subject after 0, 1,2,4,6,8,10,12,16,20,24 32 and h. The transdermal preparations were removed 24 h after application. the drug contents of the samples were determined using a gas-liquid chromatographic method as described by Pickup and Paterson [ 171. After fifteen days a cross-over study was performed by exchanging the subjects of different groups for the application of ephedrine transdermal preparations and for oral administration of the conventional tablets. RESULTS AND DISCUSSION The in vitro release profiles recorded for matrix diffusion systems and pseudolatices are
20.0

12.5-

t L : G lO.O-

IO

IS

20

<
25 30

Min /a Fig. 2. In vitro drug release profiles of ephedrine from different pseudolatices side deviation). 100=80:20; (0) (1.0 cm*). Bar indicates + S.D. (one RLEu RL(0)

(0) Eu RS-100; (m) Eu RS-100:Eu

_
0

15.0

RS-100:Eu RL-100=40:60; (A) 100 = 20 : 80; and ( A ) Eu RL-100.

::
E r

12.5

IO.0

TABLE 1 Release rate constant (K,) and permeation rate constant (K,) of matrix diffusion transdermal patches and pseudolatices of different polymer combinations. Polymer ratio Drug content, ERL: ERS mg crnm2 Release rate UC), mg h- cm- MDT PS 1.20 1.02 Permeation rate (K,), fig h- crnm2 MDT 75 70 PS 80 75

2.5

0.0 5 IO I5 20 25 30

Min l/2 Fig. 1. In uitro drug release profiles of ephedrine from different matrix diffusion patches (1.0 cm). Bar indicates +S.D. (one side deviation). (0) Eu RS-100; (m) Eu RS100:Eu RL-100=80:20; (0) Eu RS-100:Eu RL100=60:40; (0) Eu RS-100:Eu RL-100=40:60; A Eu RS-100:Eu RL-100=20:80; and (A) Eu RL-100.

lo:o 8:2

1.82 1.80

1.05 0.81

6:4 4:6 2:8 0:lO

1.95 1.98 1.96 1.97

0.63 0.57 0.48 0.39

0.96 0.81 0.75 0.60

55 45 35 30

65 55 45 40

ERL: Eudragit RL-100; ERS: Eudragit RS-100; MDT: matrix diffusion transdermal patch; PS: pseudolatex.

261

12

16 HOURS

20

24

26

32

HOURS

3. In uitm drug permeation profiles of ephedrine from different matrix diffusion patches through hairless mouse skin. Bar indicates +S.D. (one side deviation). ( q ) Eu RS-loo; (m) EuRS-lOO:EuRL-100=80:20; (0) EuRS100:Eu RL-100=60:40; (a) Eu RS-100:Eu RL100=40:60; (A)EuRS-lOO:EuEL-100=20:80;and (A) Eu RL-100.
Fig. 24

Fig. 5. Mean ephedrine plasma concentration, ng. ml- ( 31S.E.) as a function of time following oral administration and transdermal application. Key: (0 ) ephedrine hydrochloride conventional tablet (oral); (0 ) monolithic matrix diffusion patch; (A ) pseudolatices system T=DOSing time for conventional tablet.

Ii
HOURS

2b

i4

2i

Fig. 4. In vitro drug permeation profiles of ephedrine from different pseudolatices through hairless mouse skin. Bar indicates +S.D. (onesidedeviation). (~7) EuRS-100, (m) Eu RS-1OO:Eu RL-100=80:20; (0) Eu RS-100:Eu RL100=60:40; (a) EuRs-lOO:EuRL-100=40:60; (A) Eu RS-100:Eu RL-100=20:80; and (A ) Eu RL-100.

shown in Figs. 1 and 2, respectively. The drug release from both types of preparation showed a linear relationship between the cumulative amount of drug released (Q) and the square root of time (t ). An initial rapid drug release was noted in the case of matrix diffusion systems, whilst in the case of pseudolatices a lag time

(ca. 30 min) was observed. The lag time could be accounted for by the time taken by the drug to diffuse across the cellophane membrane (used to support the pseudolatices ). Similarly, the rapid initial drug release from matrix diffusion systems may be due to direct exposure of the system to the diffusion media and quick release of the drug present at the surface. A decrease in the release rate with increasing Eudragit RS-100 content in the polymer matrix was noted. The slowest release rate constant was recorded in the case of the Eudragit RS-100 based system (0.39 and 0.60 mg h- cm- for the matrix diffusion patch and the pseudolatices, respectively; see Table 1) . Ephedrine released from the matrix diffusion patch and the pseudolatices penetrated the hairless mouse skin and appeared in the receiver compartment via a monophasic zero order process (Figs. 3 and 4). When the same polymer composition was used, the rate of ephedrine permeation through hairless mouse skin following the application of pseudolati~es was comparatively higher than the permeation determined after the application of matrix diffusion patches (55 and 65 fig h-l cm- for matrix diffusion patch and pseudolatices, respectively; see Table 1) . The higher permeation rate of ephedrine from pseudolatices could be at-

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(M.P.) 470 003, acknowledged.

India

are

gratefully

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