8/2/2019 1-s2.0-0168365990901075-main

1/6

Journal of Controlled Release, 12 (1990) 257-263Elsevier Science Pu blisher s B.V.. Amsterda m - Pr inted in The Net her lands

25

EFFECTIVE AND CONTROLLED TRANSDERMAL DELIVERY OF EPHEDRINESanjay K. Jain, Suresh P. Vyas* and V.K. DixitPharmaceutics Laboratory, Department of Pharmaceutical Sciences, Doctor Harisingh Gour Vishwavidyalaya,Sagar (m.p.) 470 003 (India)(Received November 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

Th e present work comp rises the form ulation ano! an evaluation of ephedrin e with a view todeveloping and preparing an ephedrin e releasing system for tran sderm al applications. Eud ragitRL-100 and Eudragit RS-100 were used to prepare pseudolatices and m atrix diffusion drug res-ervoirpatches. These preparations were evalu ated for in vitro release and permeation of th e drugacross hairless m ouse skin. Pseudolatices and a m atrix diffu sion dru g reservoir system (1.0 cm )prepared using Eudragit RL-100 and Eudragit RS-100 in a 60: 40 ratio released the drug at therate of 0.96 and 0.63 m g h- 1 respectively. Th e designedpseudolatices and m atrix diffusion trans-derm al patches were also evalua ted for in vivo perform an ce. Th e drug plasm a profiles were com -pared with t heplasm aprofile obtained followin g the adm inistration of norm al oral m ultiple dosesof ephedrin e hyd rochloride using conventional tablets. After tran sderm al application of half thedose of ephedrin e, as com pared w ith th e conventional dose recom m ended for adm inistrationdu ring 24 h, a constant and com paratively higher dru g blood level could be achieved. Th e m ostpromising in vivo availability of the drug was recorded with selected pseudolatices.

INTRODUCTION

Transdermal drug delivery offers its own ad-vantages over other routes of drug administra-tion. Besides convenience, enhanced and con-trolled therapeutic responses have beenrecorded [ 11. Various types of preparations andmethods employed in the preparation of trans-dermal drug delivery systems have been dis-cussed in the literature [2-51. Two basic phys-ical models that have been used to estimate thedrug release mechanism are the membrane-permeation controlled and the matrix-diffu-sion controlled systems [61. Recently, a topicalpreparation of lidocaine based on pseudolatex*To whom correspondence should be addressed. Ephedrine is an antiasthmatic drug with

has been discussed [ 71. X-ray crystallographicanalysis of the dispersions indicated the ab-sence of a crystalline drug. The pseudolatexdispersion offers the opportunity to produce onthe skin highly substantive, clear, continuousand virtually invisible films containing molec-ularly dispersed drug [ 71.

The present study is an attempt to evaluatethe performance of different Eudragit basedtransdermal preparations of ephedrine. Eudra-git RL-100 and Eudragit RS-100 are copoly-mers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.Eudragit RL-100 is more permeable to waterthan Eudragit RS-100. These systems wereevaluated both in vitro and in vivo.

0168-3659/90/$03.50 0 1990 Elsevier Science Pu blisher s B.V.

8/2/2019 1-s2.0-0168365990901075-main

2/6

short biological half-life, i.e., 3-5.5 h. There-fore, 10 mg of drug is required to be adminis-tered three to four times a day [8]. Frequentdosing is associated with certain problems, suchas insomn ia, trem ors, hypertension, ta chycar-dia, etc. [ 91. The high tr an sderma l p ermeabil-ity of ephedrine was recently recognised, and ath era peut ic system to provide a prolonged con-tinuous transdermal infusion of ephedrine intothe systemic circulation was explored [lo]. Acons ta nt th era peut ic blood level was observedfor 48 h following the application of such asystem.

MATERIALSEphedrine [Burroughs Wellcome (India)

Ltd., Bombay, India]; Eudragit RL-100 andEu dra git RS-100 (used a s received from RohmPh arm a, Darm sta dt, F.R.G.); dibutyl phth al-at e (Flu ka A.-G., Switzerlan d). Tween 80 (po-lyoxyeth ylene sorbita n mono-oleate) an d allother ingredients were of AnalaR grade, andwere used as received from Glindia, a chemicaldivision of Glaxo India Ltd. Bombay, India.

METHODSPreparation of matrix diffusion patch

Polymeric films cont ain ing th e dru g wereprepared by the method described by Iyer andVasavada using mercury as a subst ra te for filmcasting [ 111. The drug reservoir films werecast ed from 10% (w/w) solut ion of polymer s(Eudragit RL-100, Eudragit RS-100 and 80 :20,60 :40,40 :60 and 20 :80 mixtures by weight ofEu dragit RL-100 and Eudr agit RS-100 respec-tively) in acetone. The solut ions included 2%(w/w) of eph edr ine an d 10% (w/w) of dibu tylpht ha late (based on the polymer weight) inacetone. Portions (5 ml) of th e solution werepoured in to glass rin gs (10 cm) on a mer cur ysubstrate. After complete evaporation of the

solvent at 30 C, th e films were rem oved fromth e glass rings and st ored at cont rolled hu mid-ity (R.H. 58% ) and t emper at ur e (28 It_ C ).

One of th e su rfaces of the film was moisten edwith a cetone and a slight ly oversized a luminu mfoil was placed against it. The film was then allowed to dry in air for 24 h and was inspectedfor comp lete sealing between th e two layers. Thealuminum foil, preventing diffusion of the drugwas used as a backing membr ane.

Preparation of pseudolatices

The ephedrine-Eudragit pseudolatices wereprepared by a solvent removal method [ 71. AnEu dr agit (10% w/w)-ephedr ine (2% w/w) solut ion in chloroform was emulsified with anaqueous solution of surfactant (Tween 80,10%w/w). The organic solvent a nd a fra ction of th ewater (ca. 25% w/w of that initially incorpo-rated) were removed. The plasticizer dibutylpht ha lat e (10% w/w based on the polymerweight) was incorporat ed in th e pseudolat ex toimprove the film forming properties of the dispersions. The polymers and their weight frac-tion ratio, drug and plasticizer concentrationsused in the pseudolatex systems were the sameas those used in the preparation of matrix dif-fusion systems.

Determination of drug concentration

The ephedrine concentra tion in both types ofproduct was determined spectrophotometri-tally [ 121. A sample of dried product waweighed and dissolved in methanol. After appropriate dilution with meth an ol, a colour wasdeveloped u sing bromoth ymol blue and th e absorban ce was measu red at 420 nm using a Shima dzu UV 150-02 spectroph otometer . Theephedrine concentra tion was determ ined usinga calibration cur ve prepar ed using stan dard solut ions of differen t kn own concent ra tions oephedrine.

8/2/2019 1-s2.0-0168365990901075-main

3/6

In vitro drug release studiesThe ma tr ix diffusion system (patch) was at -

tached to a glass slide (4.0 x 2.5 cm) us ing sili-cone adhesive (Medical adhesive B, MetroarkPvt . Ltd ., Calcutt a, India). The edges of th e at -tached patch were covered with a silicone lu-brican t (high vacuum grade, Metroark Pvt.Ltd., Calcut ta , India) to prevent drug releasefrom the edges of the system [ 131. This glassplate-membran e assembly was immer sed in 200ml of isotonic phosphat e buffered salin e (PBS )of pH 7.4 ma int ain ed at 37 + 1 C [ 141. The so-lution was stirr ed continuously by means of aperista ltic pum p (Polysta ltic, Watson Mar-low) at a ra te of 30 ml min-. To avoid wat erevaporation, the vessels were kept covered withalu min um foil. Aliquots (5 ml each) were with -dra wn at var ious t ime inter vals (i.e. 1,2,4,6,8,10, 14 and 18 h) and replaced with the samevolume of fresh buffer. The ephedrine concen-tration in these samples was assayed by thespectrophotometric method [ 121.

In the case of pseudolatices, in vitro drug re-lease stu dy was perform ed using a Fr anz diffu-sion cell (Crown Glass Co., New Jersey,U.S.A.). The cont ent s of th e donor compar t-men t (pseudolatices) an d th e receiver com-par tm ent (isotonic P BS of pH 7.4) were sepa-ra ted by cellopha ne mem bra ne (Spectr opore-2membrane, 5000-7000 M.W. cut-off; SpectrumMedical Industries, Los Angeles, CA, U.S.A.)sandwiched between the two compartments.The temperature of the receiver compartmentwas m aint ained at 37 ? 1 o C. At each sam plingtime the solution in the receiver compartmentwas completely withdra wn and replaced withfresh isotonic PBS of pH 7.4.In vitro skin permeation studies

Th e in v i t ro skin permeation of ephedrinefrom prepared matrix diffusion systems andpseudolatices was studied using a Franz diffu-sion cell (Crown Glass Co., New Jersey,U.S.A.). The prepa ra tion wa s app lied directly

to the stratum corneum side of freshly excisedskin from the abdominal region [ 15 ] of a hairless mouse (male, HRS st ra ins, 6-8 weeks oldInternational Scientific Stores, Agra, India). Inth is system, clinical conditions were simu latedby controlling the receiver compartment temperat ure at 37 ? 1 oC while allowing the donorcompa rt ment to be exposed to am bient temp erature (30 C ). the receiver compartment con-ta ined isotonic PBS (pH 7.4). Port ions (1 ml)of buffer solution were withdrawn from the receiver compa rt ment at time int ervals of 1,2,4,8, 12,16,20,24 an d 28 h; th e sa mp les were replaced with an equal volume of fresh isotonicPBS (pH 7.4). The ephedrine concentrationsin these samples were determined spectropho-tometr ically at 420 nm after addition of bromothymol blue [ 121.In vivo absorption studies

The p seudolat ices and a mat rix diffusion system compr ising Eudr agit RL-lOO-Eu dragit RS100 (60:40),2% (w/w)ephedr inea nd lO% (w/w) dibutyl phthalate were selected for in uiuevaluation. The in vitro drug skin permeationrates determined for these systems were approximately equal to the permeation rates requir ed, i.e. 58 pg h-l cm- (as calculat ed andreported by Bhalla and Toddywala [ 161) toachieve an effective plasma concentration.Ther efore, th ese system s were selected for further in uiuoevaluation.

The stu dies were car ried out on n ine health yhuman male volunteers divided into thregroups. These subjects possessed no history ohaving taken any drug during the precedingweek, a s well as during t he st udies. The subjectwere fasted, with water ad libitum, for 12 to 1h prior to administration of the drug.

The first group was given an ephedrine hydr ochlor ide (10 mg) conven tiona l t ab let (DeysMedical Stores, Calcutta, India) orally, foutim es a day at 6 h interval with 200 ml of waterThe second group received a tr an sderma l matrix diffusion patch and the third group th

8/2/2019 1-s2.0-0168365990901075-main

4/6

260

pseu dolatex system (both containing 20 mg ofeph edrine). Both systems were app lied on acleaned 10 cm2 area of the forearm .

Blood samples were collected from each sub-ject after 0 , 1,2,4,6,8,10,12,16,20,24nd 32h. The transdermal prep arations were removed24 h after app lication. the dru g contents of thesamples were determined using a gas-liquidchromatographic method as described byPickup and Paterson [ 171.

After fifteen days a cross-over study w as per-formed by exchan ging the sub jects of differentgroup s for the ap plication of eph edrine trans-derm al prep arations and for oral adm inistra-tion of the conventional tablets.

RESULTS AND DISCUSSIONThe in vitro release profiles recorded for ma-

trix diffusion systems and pseudolatices are20.0 1

_ 15.00E:: 12.5Er IO.0

2.5

0.0 5 IO I5 20 25 30Min l/2

Fig. 1. In uitro drug release profiles of ephedr ine from dif-ferent mat rix diffusion pat ches (1.0 cm). Bar indicates+S.D. (one side deviat ion). (0) Eu RS-100; (m) Eu RS-100:Eu RL-100=80:20; (0) Eu RS-100:Eu RL-100=60:40; (0) Eu RS-100:Eu RL-100=40:60; A EuRS-100:Eu RL-100=20:80; an d (A) Eu RL-100.

E- 12.5-tL lO.O-:G

IO IS

8/2/2019 1-s2.0-0168365990901075-main

5/6

2 6

0 4 12 16 20 24 26 32HOURS

Fig. 3. In uitm dru g perm eation p rofiles of ephedr ine fromdifferent matrix diffusion patches through hairless mouseskin. Bar indicates +S.D. (one side deviation). (q EuRS-loo; (m) Eu RS-lOO:Eu RL-100=80:20; (0) Eu RS-100:Eu RL-100=60:40; (a) Eu RS-100:Eu RL-100=40:60; (A)EuRS -lOO:Eu EL-100=20:80;and (A)Eu RL-100.

24 1 /

_0 4 b Ii 2b i4 2iHOURS

Fig. 4. In vitro drug permeation profiles of ephedrine fromdifferent pseudolatices through hairless mouse skin. Barindicat es +S.D. (onesided eviat ion). (~7) Eu RS-100, (m)Eu RS-1OO:Eu RL-100=80:20; (0) Eu RS-100:Eu RL-100=60:40; (a) Eu Rs-lOO:Eu RL-100=40:60; (A) EuRS-100:Eu RL-100=20:80; an d (A ) Eu RL-100.

shown in Figs. 1 an d 2, resp ectively. Th e dr ugrelease from both types of preparation showeda linear relationship between th e cum ulat iveam oun t of drug released (Q) and t he squ are rootof time (t ). An initial ra pid drug release wasnoted in the case of matrix diffusion systems,whilst in the case of pseudolatices a lag tim e

HOURSFig. 5. Mean ephedrine plasma concentration, ng. ml-( 31S.E.) as a function of time following oral administration and tr an sderm al application. Key: (0 ) ephedr ine hydrochloride conventional tablet (ora l); (0 ) monolith imatrix diffusion patch; (A ) pseudolatices system T=DOing time for conventional tablet.

(ca. 30 min ) was observed. The lag tim e coulbe accoun ted for by the time ta ken by the druto diffuse across the cellophane membran(used to support the pseudolatices ). Similarlythe rapid initial drug release from matrix diffusion syst ems m ay be due to direct exposure oth e system to the diffusion media an d quick r elease of the drug present at the surface. A decrease in the release rate with increasing Eudragit RS-100 cont ent in th e polymer ma tr iwas noted. The slowest release ra te constan t warecorded in the case of the Eudragit RS-100bas ed syst em (0.39 an d 0.60 m g h- cm- fothe matrix diffusion patch and the pseudolatices, respectively; see Table 1) .

Eph edrine released from th e mat rix diffusionpatch and the pseudolatices penetrated thhairless mouse skin and appeared in the receiver comp ar tm ent via a monopha sic zero order pr ocess (Figs. 3 an d 4). Wh en th e sa mpolymer comp osition was used, th e rat e oephedrine permeat ion thr ough h airless mousskin following the application of pseudolati~ewas comparatively higher than the permeationdetermined after the application of matrix diffusion patches (55 an d 65 fig h-l cm- for matrix diffusion patch and pseudolatices, respectively; see Table 1) . The higher permeation ratof ephedrine from pseudolatices could be at

8/2/2019 1-s2.0-0168365990901075-main

6/6

(M.P.) 470 003, India are gratefullyacknowledged.

REFERENCES

J.E. Sha w and S.K. Chan drasekar an, Contr olled top-ical delivery of dru g for syst emic action, Dr ug Metab.Rev., 8 (1978) 223-233.Y.W. Chien, Pharmaceutical considerations of trans-dermal nitroglycerine delivery: the various ap-proaches, Amer. Hear t J., 108 (1984) 207-216.0. Siddiqui, Y. Sun, J.C. Liu and Y.W. Chien, Facili-tat ed transderm al tra nsport of insulin, J. Ph arm. Sci.,76 (1987) 341-345.Y.C. Haun g, P.R. Keshar y an d Y.W. Chien, Impr ove-ment in tr an sderm al bioavailability of nitr oglycerineby formulation design, Drug Dev. Ind. Pharm., 11(1985) 1255-1270.N. Bondor, J. Zupan and S. Selk, Improved deliveryth rough biological m embra ne. VII. Derm al delivery ofcromoglycic acid (Cromolyn) via its prodru g, Int . J .Pharm., 7 (1980) 63-75.W.R. Good, Transderm-nitro controlled delivery ofnitroglycerine via the transdermal route. Drug Dev.Ind. Pharm., 9 (1983) 647-670.S. Buyukyaylaci, Y.M. J oshi, G.E. Peck an d G.S. Ban-kar , in: M. Ander son an d S.W. Kim (Eds.), RecentAdvances in Drug Delivery Systems, Vol. 1, PlenumPress, New York, 1984, pp. 291-307.R.S. Satoskar and S.D. Bhan darka r (Eds.), P harm a-cology and Pharmacotherapeutics, Popular Praka-

910

11

12

13

14

15

16

17

1819

263sha n, Bombay, 7th edn ., 1980, pp. 204-206.Martindale - The Extra Pharmacopoeia, The Pharmaceut ical P ress, London, 28th edn ., 1982, p. 11.J .E. Shaw, SK. Chandr asekara n, A.S. Michaels anL. Tastovich in: H. Maivach (Eds.), Animal Model iDerm at ology, Ch ur chill-Livings&me, Edinbu rgh, 197Chap. 14.B.V. Iyer and R.G. Vasavada, Evaluation of lanolinalcohol films a nd k inetics of triam cinolone acetonidRelease, J . Phar m. Sci., 68 (1979) 783.F. Metsui, J.R. Watson and W.N. French, Use of thacid dye technique for quan titat ion of pha rm aceuticaamines eluted from thin layer chromatograms, JChr omatogr., 44 (1969) 109.S. Borodkin and F .E. Tucker, Dru g release from hydr oxypropyl cellulose-polyvinyl aceta te films, JPh ar m. Sci., 63 (1974) 1359.British P ha rm acopoeia, Vol. II, Ministry of Hea lth anSocial Sciences for Great Britain and Northern Irelan d, 1980, p. A-53.T.J. Fra nz, Percutaneous absorption or the relevancof in. oitro dat a, J. Invest . Derma tol., 64 (1975) 790795.H.L. Bhalla and R.D. Toddywala, transdermal filmof ephedr ine, Dru g Dev. Ind. Ph ar m., 14 (1988) 119131.M.E. Pickup and J.W. Paterson, Determination oephedr ine plasma level by gas liquid chr omatogra phyJ. Pharm. Pharmacol., 26 (1974) 561-562.J.N. Hunt, Gastric emptying and secretion in manPhysiol. Rev., 39 (1959) 491.J .N. Hunt and W.R. Spurgel, Pat tern of emptying oth e hu man stomach, J. Physiol., I13 (1951) 157.