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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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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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