formulasi tablet vaginal

7/26/2019 Formulasi Tablet Vaginal

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DRUG DEVELOPMENT AND I NDUSTRI AL PHARMACY, 14 8), 1013-1021 1988)

FORMULATI ON OF A FOAMI NG VAGI NAL TABLET

AND

SUPPOSI TORY

Eugene L. Par r ot t

Di vi s i on of Phar maceut i cs

Col l ege of Phar macy, Uni ver si t y of I owa

I owa Ci t y , I A 5 2 2 4 2

ABSTRACT

For mul at i ons f or a f oam ng, sper m ci dal vagi nal t abl et and a

f oam ng, sper m ci dal supposi t ory ar e pr esent ed. Some phar maceut i cal

char act eri st i cs pecul i ar t o bot h dosage f orms were measured.

A

si mpl e met hod

i s

suggest ed

f o r

t he eval uat i on of t he quant i t y and

col l apse r es i s t ance of t he f oam

I NTRODUCTI ON

Recent l y ef f or t has been di r ect ed t o cont r acept i ve pr oduct s.

I n t he i ndi vi dual f am l y pl anned par ent hood f r equent l y pr ot ect s

t he heal t h of t he mot her and i mpr oves t he car e of t he chi l dr en.

I n t he Uni t ed St at es t he t r end t owar d sel f car e i s havi ng an

i mpact on nonpr escr i pt i on cont r acept i ve use.

nat i ons t her e

i s

a need f or cont r acept i ve dosage f or ms t hat ar e

I n t he t hi r d wor l d

r eadi l y sel f - adm ni s te r ed, i nexpens i ve and r el at i vel y ef f i c i ent .

Vagi nal cont r acept i ves cont ai n a s per m ci de and are desi gned

t o hol d t he sper m ci de wi t hi n t he vagi na and pr i mar i l y agai nst

t he cer vi x. The

FDA

Advi sor y Panel on Nonpr escr i pt i on Cont r acep-

t i ves consi der s menf egol , nonoxynol - 9 and oct oxynol as saf e and

1013

Copyright

1988

by Marcel Dekker Inc.

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1014 PARROTT

ef f ect i ve sper m ci des ( Cat egor y I )

(1).

The maj or i t y of vagi nal

cont r acept i ves cont ai n nonoxynol - 9.

Vagi nal cr eams and j el l i es t end to be messy, pr ovi de l ubr i ca-

t i on and ar e easi l y r emoved i f t hey ar e wat er sol ubl e. J el l i es

t end t o spr ead unevenl y i n t he vagi na. Foam pr oduci ng dosage f orms

ar e pr ef er r ed as excessi ve l ubr i cat i on and l eakage f r omt he vagi na

are m ni mal , and t he f oam adheres t o t he vagi nal wal l s and t en-

ac i ous l y cover s t he cer v i cal

0 s

Aerosol di spenser s have t he di s-

advant age t hat t hey ar e bul ky, and t he user cannot t el l when t he

di spenser i s al most empt y. Thus, t he f oam ng supposi t or y and

vagi nal t abl et appear t o be usef ul dosage f or ms as t hey ar e con-

veni ent t o use, por t abl e and t he user knows how many uni t s r emai n.

The f oam ng vagi nal cont r acept i ve i s desi gned

s o

t hat when i nsert ed

hi gh i nt o t he vagi na wi t hi n

10

m nut es i t wi l l have f or med a mechani -

cal l y s t r ong f oam t hat wi l l bl ock the cer v i cal openi ng f or an hour .

I f pr operl y empl oyed wi t h a condom t he ef f i ci ency of t he combi na-

t i on r i val s t hat of t he or al cont r acept i ves .

EXPERI MENTAL

Mat er i al s . Nonoxynol - 9 ( I pegal

CO- 630)

was donat ed by G F Corpor a-

t i on, Wayne,

N. J .

Mi c r oc r ys t al l i ne cel l ul ose, anhydr ous c i t r i c ac i d,

hydr ous l act ose, magnes i um st ear at e, pol yet hyl ene gl ycol s , col l oi dal

s i l i con di oxi de, sodi umbi car bonat e, sodi um l aur yl sul f at e and sodi um

st arch gl ycol at e wer e USP/ NF gr ade.

Pr epar at i on of Tabl et s .

wer e pr epar ed usi ng a s i ngl e punch t abl et pr ess f i t t ed wi t h

f l at - f aced, bevel l ed edge punches havi ng a di amet er

of 12. 7 mm.

The

f ormul at i on was:

Tabl et s cont ai ni ng

50

mg of nonoxynol - 9

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FORMULATI ON OF A FOAMI NG VAGI NAL TABLET AND

SUPPOSI TORY

1015

mg/ t ab

Nonoxynol - 9 50

Col l oi dal s i l i c on di oxi de 32

Hydr ous l act ose 316

Anhydr ous ci t r i c aci d 125

Sodi um bi car bonat e 142

Sodi um st ar ch gl ycol at e

50

Sodi um l aur y l s ul f at e 5

Magnesi um st erat e 6

Mi c r oc r yst al l i ne cel l ul os e

7 9

The col l odi al s i l i con di ox i de was wet t ed wi t h

50

al cohol . The

nonoxynol - 9 was di ssol ved i n

50

al cohol . The sol ut i on was added

t o t he col l oi dal s i l i con di ox i de i n a pl anet ar y m xer and bl ended

unt i l uni f or m

The mass was pass ed t hr ough a 12- mesh sc r een f i t t ed

i n an os ci l l at i ng gr a nul at or .

The wet gr anul es wer e dr i ed over ni ght

i n an ai r oven at

55 60C.

The dr i ed gr anul at i on was passed t hr ough

a 30- mesh scr een and pl aced i nt o a V- bl ender .

The ci t r i c ac i d,

l act ose and m cr ocr yst al l i ne cel l ul ose wer e added to t he V- bl ender

and bl ended f or 10 m nut es. The sodi um bi carbonat e and sodi um st ar ch

gl ycol at e wer e added t o t he V- bl ender and bl ended f or

10

m nut es .

The sodi um l aur yl

sul f at e and magnesi um st ear at e wer e added t o

t he

V- bl ender . The compl et e f or mul at i on was bl ended f or 5 m nut es . The

gr anul at i on was compr essed i nt o t abl et s.

Pr epar at i on of Suppos i t or i es .

The f or mul at i on f or t he suppos i t or i es

pr epar ed by t he f usi on met hod was:

Nonoxynol - 9

Mi c r oc r yst al l i ne cel l ul os e

Sodi um l aur y l s ul f at e

Anhydr ous c i t r i c ac i d

Sodi um bi car bonat e

Pol yet hy l ene gl ycol 6000

Pol yet hy l ene gl ycol

4

m g /

SUPP

100

100

1

103. 5

86. 25

840

1 0 7 0

The pol yet hyl ene gl ycol s wer e f used at

7OOC.

The nonoxynol - 9 and

t he m crocr ys t al l i ne cel l ul ose wer e uni f or m l y bl ended i n a

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1016 PARROTT

p lane t a ry mixer , and then added to t he fused po lye thy lene g lyc o l s .

The sodium lau ry l s u l fa te , c i t r i c ac i d and sodium b ica rbona te

were added t o th e fused mixt ure. The complete formu lat ion was

s t i r r e d ge nt ly fo r 10 minutes a t 70OC. The mass was poured i n t o

room temp eratu re aluminum molds. Af te r congeali ng, th e supposi-

t o r i e s were removed from t h e molds and packaged i n cardbo ard

b o x e s wi t h d i v i d e r s .

Ap par atu s. The bottom of a t e s t tub e wi th a 15.87 mm i n s i d e d i a -

meter was f l a t t en ed us ing

len gth of th e tube was ca

br at ed tub e was suspended

t u r e b a th a t 37 f 0.1OC.

of 12.7

mm

was cut from a

an oxygen to rc h . Employing pi pe ts th e

i b r a t e d i n terms of volume. The c a l i -

f rom a r in g s ta nd i n a const ant tempera-

1 .0 g rubber c y l in de r wi th a d iamete r

rub ber st op pe r. By means of a n a t t a c h e d

thr ead , which was a l igne d by two lengt hs of g l as s tubing , th e

weight could be ge nt ly lowered onto t he su rf ac e of th e foam

(Figure 1 ) .

d i s t i l l e d wate r a t 7 O C were p i p e t t e d i n t o t h e t u b e.

form was dropped i n t o th e tub e, and th e times were recorded for

th e foam t o expand t o var iou s volumes (s ee Table 1) . Af t er 10

minutes the weight was p laced on th e s ur fa ce of th e foam, and th e

volume of t h e foam and t i m e were recorded u n t i l th e foam no longer

s u pp o r te d t h e we i gh t which t h e n s e t t l e d t o t h e bo tt om o f t h e t u b e .

F or t a b l e t s 2 . 0 m l and f o r s u p p o s i t o r i e s 4 0 m l of

The dosage

Di s i n te gr a t i on was conducted w i thou t d i sk s i n th e USP d i s -

i n t e g r a t i o n a p p a r a t u s .

s o l u t i o n ap p a ra t us 2 o pe r a t i ng a t 5 rpm using 500 m l o f d i s -

t i l l e d water a t 37OC. Samples were pe r i od ic a l ly withdrawn by

Dissolution was conducted in t h e USP di s -

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FORMULATI ON OF A FOAMI NG VAGI NAL TABLET AND SUPPOSI TORY

1017

a f i l t er - t i pped pi pet and anal yzed spect r ophot omet r i cal l y at

216

nm f or nonoxynol - 9.

RESULTS ND

DI SCUSSI ON

Foam ng Tabl et . The aver age wei ght of 20 t abl et s was

818

mg, and

t he r ange was f r om806 t o

830

mg. The t abl et s met t he speci f i cat i ons

of

t he Wei ght Vari at i on Test

USP MI 2 ) .

2E

har dness t est er t he aver age har dness of

20

t abl et s was 4 . 2 kp.

W t h 6 t abl et s i n the di s i nt egr at i on appar at us wi t hout di sks t he

di s i nt egr at i on occur r ed wi t hi n 3 m nut es. The pH

of 100

m of

di st i l l ed wat er i n whi ch one t abl et had di ssol ved was 4. 9, whi ch

appr oxi mat es t he cl i ni cal l y desi r ed pH

of

t he vagi nal f l ui d. I n

t he

USP

di ssol ut i on appr at us

2

usi ng 500 m of di s t i l l ed wat er at

37OC

and a speed of

50

rpm t he t abl et d i ssol ved wi t hi n 4 m nut es .

I n t er ms used t o phar maceut i cal l y char act er i ze a t abl et , t he vagi nal

t abl et appear ed accept abl e.

A s measur ed by a Schl euni ger

Cl i ni cal l y a copi ous

and mechani cal l y st r ong f oam i s r equi r ed

t o f or m a pr ot ect i ve bar r i er cont ai ni ng t he sper m ci de over t he

cer v i c al

0 s A s

a devel opment al t ool

t o

compar e var i ous f or mul a-

t i ons, t he appar at us shown i n Fi gur e was used t o measur e t he

vol ume of f oam pr oduced i n

10

m nut es, and t hen by use of a

1 . 0

g

wei ght p l aced on t he sur f ace of t he f oam i t s r esi st ance t o col l apse

was det er m ned. Si x t abl et s wer e consi der ed t o be t he m ni mum

number t o pr ovi de a val i d t est

(3 ) .

t he maxi mum vol ume

2 2

m) of f oamwas at t ai ned at appr oxi mat el y

6

m nut es af t er whi ch t he vol ume r eceded. When at 10 m nut es

t he 1. 0 g wei ght was pl aced on t he sur f ace of t he f oam i t r e-

qui r ed appr oxi mat el y 9 m nut es bef ore t he f oam had col l apsed t o

t he ext ent t hat t he wei ght set t l ed to t he bot t om of t he t ube.

The dat a are gi ven i n Tabl e

1.

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1 18

- T h r e a d

X

1 0 m m

g l a s s

t u b i n g

C I a m p s

PARROTT

I

g w e i g h t

- - .

6 X 1 5 0 m m

t e s t t u b e

37O

B a t h

R i n g

s t a n d

F i gur e

1.

Apparat us or t he eval uat i on of a f oam

Foam ng Supposi t or y.

The aver age wei ght of 20

supposi t or i es pr epar ed

usi ng t hr ee mol ds was 2 . 4 2 g, and t he r ange was f r om2. 30 t o 2 . 5 4

g .

The col l apse or f r act ur e l oad

of

2 . 7 kg assured an adequat e f i r mness

f or i ns er t i on 4 ) . W t h 6 suppos i t or i es i n t he di s i nt egr at i on

appar at us wi t hout di sks

no

suppos i t or y exi s t ed af t er 20 m nut es .

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FORMULATION OF FOAMING VAGINAL TABLET AND SUPPOSITORY

1019

TABLE

Quantity and Collapse Resistance o f

Foam from a Vaginal Tablet

a

Volume of Foam, mL Time min

3.0 0.39 (0.04)b

5.5 0.60 (0.02)

8 .0 0 .93

(0 .12 )

10.5

1.44 (0 .21)

13.0 2.00 (0.26 )

15.5

18.0

20.5

22.0

15.5

13 OC

8 . 0

5 . 5

3 .0

0

2.57 (0.33)

3 .42 (0 .04)

4.60

(0.53)

5.82

(0.64)

8.20

(0.50)

9.06

(0.50)

11.05 (0.66)

12.01

(0.86)

14.24

(1.06)

19.70 (2.90)

a

bstandard deviation

average of

6

tablets

1.0 g

weight placed

on

foam at 10 minutes

TABLE 2

Dissolution Profile

of

Nonoxynol-9

from a Spermicidal Suppository

Time, min Percent Dissolved

3 28 . 0

6 36.0

9 64.8

12 81.2

15

93.5

18 97.8

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1 2

PARROTT

TABLE 3

Quant i t y and Col l apse Resi st ance

of Foam f r om a Suppos i t or y

Vol ume of Foam mL

Ti me, a m n

1 . 0

1 . 5

1 .6

1 . 4

1 . 2

1 . 0

2.91 (0 .68)b

5 .21 (0 .42)

7 .58 (1 .91)

12 .73 (1 .91)

15.34 (2 .28)

19 .46c(1 .07)

30.00

a

bst andard devi at i on

aver age of

6

suppos i t or i es

C

supposi t or y r esi due aver age

44

mg

The pH of

100

m of di st i l l ed wat er i n whi ch one supposi t or y had

di ssol ved was

4 . 2 .

500

m

of di s t i l l ed wat er at

37OC

and a

speed of

50

r pm 90 of

t he nonoxynol - 9 di ssol ved wi t hi n

20

m nut es . t ypi c al r es ul t i s

shown i n Tabl e

2 .

I n t he

USP

di ssol ut i on appar at us 2 usi ng

The maxi mum vol ume

(1 . 6

m) of f oam was at t ai ned at appr oxi -

mat el y

8

m nut es as shown i n Tabl e

3.

At

30

m nut es when t he t est

was t erm nat ed appr oxi mat el y 98 of t he supposi t or y was di ssol ved.

I f at

10

m nut es t he

1 . 0

g wei ght was pl aced on t he sur f ace of t he

f oam i t set t l ed t o the bot t om of t he t ube wi t hi n

5

seconds as t he

f oam col l apsed.

These f oam char act er i st i cs wer e compar ed t o a

CONCLUSI ON

A f or mul t i on f or a f oam ng sper m ci dal supposi t or y and a

f oam ng vagi nal t abl et ar e gi ven.

Thei r pr opert i es were eval uat ed

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FORMULATION OF A FOAMING VAGINAL TABLET AND SUPPOSITORY

1021

by st andar d met hods and compar ed al t hough t he dosage f or ms ar e

di f f er ent .

Fromthe

f or mul at i on vi ewpoi nt bot h appear t o have

accept abl e phar maceut i cal char act er i st i cs.

For most vagi nal cont r acept i ves i t i s di r ect ed t hat i n-

ser t i on occur at l eas t 10 m nut es pr i or t o i nt er cour se. Thus ,

i t i s l ogi cal t o eval uat e a pr oduct i n t er ms of t he quant i t y of

f oamproduced and i t s col l apse r esi st ance at t hat t i me.

A

si mpl e

commer ci al ef f er vescent supposi t or y (I nt ercept TM) , whi ch pr oduced

a f oampr ocess i ng a maxi mumvol ume of 1. 0 m at appr oxi mat el y

7

m nut es and whi ch di d not suppor t t he 1. 0

g

wei ght .

appar at us i s suggest ed f or t hi s eval uat i on. I n compar i ng an

exper i ment al and a commer ci al supposi t or y t o an exper i ment al

vagi nal t abl et , t he t abl et f or mul at i on pr oduced appr oxi mat el y a

t enf ol d gr eat er vol ume of f oam whi ch col l apsed l ess r eadi l y t han

t he f oam f r om t he supposi t or i es. Fr om t he devel opment al vi ew-

poi nt t he t abl et f ormul at i on may be an accept abl e candi dat e f or

cl i ni cal s t udy.

REFERENCES

1.

Feder al Regi s t er , 4 5 , 8 2 0 1 4 - 4 9 ( Dec. 1 2 ,

1 9 8 0 .

2 . The Uni t ed St at es Phar macopei a, 20t h r ev. , Mack Publ i shi ng

C o .

Eas t o n, Pa. , 1 9 8 0 , p. 9 9 0 .

3 R. M

Fung and

E. L.

Par r ot t ,

J

Phar m Sci . ,

6 9 , 4 39 1 9 8 0 ) .

4

E . L .

Par r ot t ,

J .

Phar m Sc i . ,

60 8 6 7 1 9 7 1 ) .

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