Transdermal Formulation and Evaluation of Timolol Maleate

7/26/2019 Transdermal Formulation and Evaluation of Timolol Maleate

1/6

Transdermal formulation and evaluation of timolol maleate.

Saraf Swarnlata*, Saraf S1, and Dixit V.K. 2

1Institute of Pharmac, Pt. !avishan"ar Shu"la #niversit, !ai$ur %&'( )2 +1+

2De$artment of Pharmaceutical Sciences, Dr. .S. 'our V.V., Sa-ar, .P.

*e/mail0 swarnlatasarafrediffmail.com

Summar

Transdermal deliver of timolol meliate was tried for 3oth reservoir as well as matrix

sstem. The $hsicall sta3le $atches re-ardin- dru- contents, tensile stren-th, tou-hness

and 4VT were found for PV51+ and 62 formulation. 7oth $atches follows diffusioncontrolled dru- $ermeation and hi-h $ermeation with PV51+ while reservoir sstem

follows 8ero order $ermeation "inetics.

Introduction

Timolol maleate is a 3eta adrenoce$tor/3loc"in- a-ent used in treatment ofcardiovascular diseases li"e mocardial infarction, an-ina $ectoris, h$ertension,

res$irator com$lications and mi-raine. It is 9/1+ times $otent than $ro$ranolol 1. The

main limitation of thera$eutic effectiveness of timolol maleate is its hi-her fre:uenc of

dru- dosin- and short 3iolo-ical half/life, hi-h first $ass meta3olism and $oor3ioavaila3ilit 3 oral route. . It is ra$idl a3sor3ed from -astrointestinal tract with $ea"

$lasma concentration of ;/1+ n-< ml after 1 hr2, it is meta3oli8ed u$ to 9+= in liver witha mean half/life of 2.+/2.; hr.>, thus necessitatin- fre:uent administration of lar-er dosesto maintain thera$eutic dru- level. Therefore, To maintain effective $lasma concentration

and to avoid su3 thera$eutic and toxic concentration, a continuous deliver of timolol

maleate is re:uired. The transdermal route is, therefore, a 3etter alternative, to achieveconstant $lasma level, which additionall warrants less fre:uent dose re-ime.

The $resent stud has 3een selected transdermal deliver sstem to achieve maximum

thera$eutic 3enefit.

5T6!I5?S 5@D 6TADS

'ift sam$le of timolol maleate %T( was o3tained from &adila 5nti3iotics ?td.,

5hamda3ad. drox $ro$l methlcellulose was $rocured from 4arner industan ?td.,dera3ad. Di3utl $hthalate, ethl cellulose, $olvinl alcohol %PV5(, 6P6S 3uffer,

$rocured from Si-ma &hemical &o. St. ?ocus o, #S5. 5ll other chemicals and re-ent

used were of analtical rea-ent -rade.


2/6

Ba3rication of matrix diffusion $atches

atrix $atches were casted) on mercur usin- stainless steel rin-s havin- inner diameter

of 1.; cm and thic"ness +.; cm were used for holdin- the $olmer solution on mercursurface. Two t$e of $olmer $atches were $re$aredC P& and 6& com3ination and

with PV5. The $olmer solutions were $re$ared 3 dissolvin- P& 1+= ands 6& 1+

= se$aratel in methanol/ chloroform %101( mixture. 7oth solutions were mixed to-etherin com3ination of 10, 209, >0, )0E and ;0; res$ectivel usin- 1= di3utl $hthalate as

$lastici8er. 5 wei-hed amount of dru- is dis$ersed in $olmer mixture then $oured in

rin- $laced on mercur surface in $etri dish at a uniform $lace and solvent eva$oration

was controlled 3 convein- with funnel. 5fter eva$oration of the solvent, the film wasta"en out from the metal rin- 3 shar$ "nife and $reserve in aluminum foil. Similar

$rocedure was ado$ted to $re$are PV5 matrix $atch $re$aration havin- $olmer

concentration of ;, 1+.and 1;= in water with +.;= -lcerin as $lastici8er.

Phsical characteri8ation

Thic"ness of $olmeric $atch was measured 3 usin- a dial -au-e %ercer, 6n-land(,havin- least count of +.++2 mm. To maintain its sha$e, enou-h hardness is re:uired to

resist inde$endence or $enetration was determined 3 allFs method) and calculated as a

functional wei-ht. In order to determine the elon-ation as a tensile stren-th, the

$olmeric $atch was $ulled 3 means of a $ulle sstemC wei-hts were -raduall addedto the $an to increase the $ullin- force till the $atch was 3ro"en. The elon-ation i.e. the

distance traveled 3 the $ointer 3efore 3rea" of the $atch was noted with the hel$ of

ma-nifin- -lass on the -ra$h $a$er;, the tensile stren-th was calculated as "-< cm2. The$resence of moisture ma not affect the hardness of $atch in the normal environmental

conditions, 3ut it ma affect in exa--erated conditions. The $olmer $atches were cut,

wei-hed and $laced in a humidit cham3er maintained at E9= ! for 2 h fore:uili3rium. 5fter 2 h $olmer $atch were ta"en out and wei-ht accuratel. The

difference 3etween initial and final wei-ht was com$uted as $ercenta-e moisture

a3sor3ed. The water va$or transmission %4VT( from the film was calculated 3

&rowfold and 6smeric formula E. It was determined at 2;G 2+& at E9=!. 'lasswei-hin- 3ottles of e:ual diameter %2.; cm( and hei-ht %;.+ cm( were used as 4VT cells.

5 wei-ht :uantit of anhdrous calcium chloride was ta"en u$ to 1+ mm hei-ht in each

cell and a thin laer of silicon adhesive -rease a$$lied over the 3rim then $atch was$laced on 3rim and adhesive was allowed to set for ; minutes. The cells are accuratel

wei-hed and "e$t in humidit cham3er maintained at E9= ! for 2) h. 5fter 2) h, the

cells were a-ain wei-hed and an increase in wei-ht was considered as a :uantitativemeasure of the moisture transmitted throu-h the $atch. Dru- distri3ution studies0 The

distri3ution of dru- in $olmer $atch effect the release rate. It was studied

microsco$icall with the hel$ of ?iet8 icrosco$e to o3serve uniform distri3ution of

dru- in $atch.


3/6

Sta3ilit studies0

Sta3ilit studies of all $atches were $erformed at different stora-e condition 3measurin- tensile stren-th, moisture content and dru- content %s$ectro$hotometric

method(. The measurement were carried out 3 "ee$in- the $atches at different

conditions of tem$erature 29+&, >;+& and ;++& and relative humidit of >+=, ;+=, E9= for stora-e $eriod of three months at room tem$erature %2;H1+&(. The $atches, which

maintained uniformit, sha$e, tou-hness, dru- content and flexi3ilit at all tem$erature

and !, were selected for further $ermeation studies.

S"in Pre$aration0

The full thic"ness human cadaver s"in was washed with $urified water after removal of

all su3cutaneous fat and hairs and cut in to $ieces for ex$erimental use. The s"in $ieceswere soa"ed in 6P6S 3uffer and store in free8er at >++& until used. ust 3efore the

ex$eriment, it was thawed at room tem$erature and chec"ed for an microsco$ical

dama-e.

In vitro dru- $ermeation studies0

5 dru- $ermeation stud was carried out with dru- solution in 6P6S 3uffer $.) and

sta3le $atches throu-h human cadaver s"in usin- modified "ieshr/ chein diffusion cells.The concentration of dru- "e$t similar in dru- solution in 6P6S 3uffer and $atches to

com$are $ermeation $rofile. The Patches and dru- solution were "e$t on stratum cornium

side of cells and this $atch / s"in / com$lex sandwiched 3etween donor and rece$torcom$artment. The receivin- com$artment contains 3lan" 1+.+ ml of 6P6S 3uffer $

.) and touches the dermal side of the s"in. The whole of the assem3l was "e$t on

ma-netic stirrer, which thermostaticall controlled at >G 2o& at 1++ r$m. Sam$les were

withdrawn at $re set time interval from the receivin- com$artment and anal8eds$ectro$hotometricall at 2) nm usin- shimad8u/1E+1 #V/ visi3le s$ectro$hotometer.

The fresh 3uffer in receivin- com$artment was re$laced after each withdrawal. The

$ermeation studies determined for $eriod of ) h. and calculated as cumulative $ercentdru- $ermeated.

!esults


4/6

In $resent studies, the $olmer and $lastici8er choice for $atch $re$aration were 3ased on

no interaction with dru- and 6P6S 3uffer with considera3le sta3ilit. Various

com3inations of $olmers hdrox $ro$l methl cellulose %P&( and ethl cellulose%6&( and various concentration of $olvinl alcohol were tried for $atch $re$aration and

evaluated for $hsical studies %Ta3le 1(.Bormula ti on &ode Polmer #sed Polmer &ore Thic"ness ardness Tensi le s tren-th 4VT -m


5/6

The $ermeation $rofile of dru- from 3oth $atches 62 and PV51+ when $lotted,3etween

$ermeation data a-ainst s:uare root of time shows linear relationshi$ indicatin- dru-

$ermeation followed i-uhi e:uation %Bi-.2(.

The $ermeation $rofile data of $atches were $lotted in lo- values with time, the slo$e

value comes near to +.)G+.+1SD % +.;(, su--estin- dru- $ermeation is controlled 3

diffusion within the matrix rather than 3 s"in.4hen we com$are 3oth $atches, the PV51+ sstem $rovide hi-her 1.;9 G +.2+ SD =

dru-< cm2 of $ermeation rather than 62, i.e., +.9 G+.2+ = dru-< cm2 in )h of $eriod.

&onclusion

The studies su--est that 3oth reservoir as well as matrix sstem of transdermal deliver

of T is $ossi3le. The reservoir sstem followed 8ero order while the matrix sstem


6/6

followed first order release $rofile. 5mon- 3oth matrix sstems PV51+ $atch have more

$ermea3ilit than 62 $atch.

!eferences

1. @a$olian, ?. 5., Smith, !. ?., Proceed. Int. Sm$, &ontrolled !elease 7ioact. ater.,

1, &ontrolled !eleased Societ Inc. #S5 1+, 53st. @o. D22+.

2. !emin-ton Pharmaceutical Sciences, 19th 6d., ar" Pu3lishin- &om$an,Pennslvania, 1+, P 1EE.

>. VermeLi P. ,. Pharm. Pharmacol, 19, ;+,;>.

). Sciarria, . ., Patel, S. P., . Pharm. Sci., 1;, E), 129.

;. 5llen, D. ., Deerco . D., Kwan, K. &., . Pharm. Sci., 12, E1, 1+.E. &rawford, !. !., 6smerian, A. K., . Pharm. Sci., 11, E+, >1).

Birst Pu3lished Be3ruar )th 2++Ehtt$0

Transdermal Formulation and Evaluation of Timolol Maleate

Documents

Transcript of Transdermal Formulation and Evaluation of Timolol Maleate