Note: Descriptions are shown in the official language in which they were submitted.
~47gZ
The present invention relates to a vaginal ~iny -~
Canadian Application No. 237,945 filed October 20,
1975 and assigned to the applicants, describes a vaginal ring ; -
device which comprises a support-ring, if desired formed with
one or more recesses in which an elastomer material containing
a pharmacologically active substance is so located that the
material has an exposed surface, the elastomer material being
an LTV-silicone elastomer. ,
The present invention is an improvement in or
modification of the ring described in application No. 237j945,
wherein the support-ring has a crescent- or kidney-shaped
or ellipsoidal cross-section or is formed as a hollow profile
ring which is closed or open on the inner side or as a hollow
ring which is closed or open on the inner side or as a hollow
ring having a circular or crescent- or kidney-shaped cross-section
or as a core-Jacketed compound ring or as a sandwich body~
Throughout the Specification, including the claims, references
to the cross-section of a ring are to be understood as references
to the cross-section, taken in a plane containing the axis of ~
..
the ring that lies on one side oE the said axis. ~;
As the support-ring in a general sense determines the
shape of the vaginal ring, the external features apply AlSO ` ~:
to the vaginal ring of the invention.
Vaginal rings, which contain gestagenically active
steroid hormones or a combination of gestagenically and
oestrogenically active medicaments and which prevent conception
with or without inhibiting ovulation, are used when pharmaceutical
preparations for oral administration containing such active -
' :..~
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.. - .. - . - ~ - . . - - . . -
~IV1~79Z
substances are not to be used for a wide variety of reasons, for
example, wnere the person concerned has an aversion to taking a
tablet. Vaginal rings also have the advantage that a woman is
relieved of the necessity of having to take tablets daily. It is
a ring-shaped structure simple to apply which is introduced into -
the vagina and is well tolerated by women. As compared with the
known intra-uterine pessaries and capsules applied subcutaneously,
they have the further advantage that at any time they can be re-
moved and reinserted by the woman.
Vaginal rings made from synthetic plastics, especially ~ ~ -
those based on silicone elastomers which are obtained from RTV-
silicone rubber two~component compositions (Contraception 8 (1973)
651) or which are based on silicone rubber hot vulcanizates (Ster-
oids 21 (1973) 325), and which contain pharmacol~ogically active
substances such, for example, as steroid hormones, are known
(Fertil. Steril. 21 (1970) 99; Amer. J. Obstet. Gynecol. 113
; (1972) 927; Contraception 8 (6) (1973) 561; DT OS 1,~900,196).
The active substance is released from the synthetic plastics
carrier over a long period and is absorbed by the vaginal mucosa.
;: :
The steroid hormones contained in the hitherto known ~ -
vaginal rlngs have been exclusively those having a gestagenic
action. Depending on the magnitude of the rate of release of
the active substance bv the vaginal rings, there is produced by
their use protection against conception with or without the
inhibition of ovulation.
However, contraceptives in the form of hitherto known `
vayinal rings have disadvantages. Inter alia, they are based on
RTV (room temperature vulcanizing)-silicone rubber two-component
compositions which, as is known, have poor mechanical properties.
The mechanical properties of RTV-vulcanizates must first be im-
proved by the addition of fillers. These fillers, however, may
impair the release of active substance from the vaginal ring. A ~
. ~'
-- 3 --
,.. :'''.
z :::
few of the known vaginal rlngs are made by the vulcanization of
suspensions of active substance in RTV-silicone rubber two-
component compositions in the appropriate shapes. The active
substances are released from this type of vaginal ring during
the period of use in quantities that decrease considerably with
time (Contraception 8 (1973) 561).
Considerable differences in the dosage of active sub- ~ -
stance inevitably result in qualitative and quantitative differ~
ences in the biological or contraceptive action and also in the
nature and magnitude of undesired side effects during the period
of use of the vaginal rings. Known vaginal rings, which contain
the active ingredient homogeneously suspended in the synthetic ,
plastics base, have a total weight of from around 6.0 to 15.0
grams. If the active substance is to be released from these
vaginal rings during the period of use in a quantity sufEicient ~ ;
for the desired action, they must contain in the region of from
5 to 30% by weight of the active substance. In relation to the ;
quantity of active substance released during the period of use,
this is an uneconomically high content of the substance in the
~20 device.
Furthermore, no method is yet known for regulating the
magnitude of the rate of release desired for a particular pharma-
cologically active substance from such vaginal rings based on
silicone elastomer.
Some of the known vaginal rings are based on synthetic
plastics that are physiologically not entirely unobjectionable.
Thus, Eor the manuEActure of some vaginal rings there have been ;~
used RTV-silicone rubber two-component compositions containing
tin compounds as vulcanization accelerators which have a toxic
action on the living organism (Amer. J. Obstet. Gynecol. 113
(1972) 927).
There are also known vaginAl rings, which like those
-- 4
,
.. . . . ~ . . .
Z ..
for the treatment of prolapse, are provided with a metal spring.
These vaginal rlngs are relatively stiff and their use may lead
to erosions of the mucous membrane in the region of the postero-
lateral vault of the vagina (Amer. Med. Ass. 208 (1969) 949).
Specification No. 1,264,732 describes devices which consist of a
medicament-containing capsule on a ring of silicone rubber. How-
ever, owing to their construction such devices are ill suited ~or
mass production and they also lack practicability in use.
The problem with which the present invention is concerned
is to provide a vaginal ring which contains a pharmacologically
active substance, wherein the active substance or substances is/are
released over a period of at least three weeks, preferably a
longer period, in a regular and constant quantity necessary for
producing the biological action desired, and which avoid or mini-
mise the above-mentioned disadvantages of the hitherto known
vaginal rings.
A preferred construction of vaginal ring of the inven- i~
tion comprises a support-ring having one or two pocket-shaped
recesses extending round it to receive active-substance-containing
rings based on LTV-silicone elastomers fitting into these recesses.
This preferred vaginal ring o~ the invention comprises
the following parts:
The ~upport-rin~ proper havin~ one or two recesses and
~n inner or outer ring containing a pharmacologically active sub-
stance ortwo such active-substance-containing rings together,
which are fitted into the pocket-like recesses of the support-
ring. The recesses in the support-ring may extend parallel to
one another on the outer edge of the support-ring. Corresponding
to the dimensions of the active-substance-containing rings, the
recesses optionally also have different depths or widths.
The medicament-containing rings advantageously have a
circular cross-section, but the cross-section may also have the
- lO~gZ
shape of a segmen-t of a circle. The dimensions of the support-
ring and of the active-substance-containing rings are so chosen
that the lines of contact of the outer or inner edge of the
support-ring with the medicament-containing ring are situated, in
a radiall~ outward direction with respect to the cross-section
of the ring, beyond the centre line of the medicament-containing
ring in the case of a circular cross-section or the centre line ~ -~
of the circle forming the segment in the case of a cross-section
having the shape of a segment of a circle. In this way the ; `
. .. .
medicament-containing rings are positively located in the pocket- ;
shaped recesses of the support-ring.
By a pharmacologically active substance there is to be
understood herein a substance capable of having an effect on a
living organism. The pharmacologically ackive substance (also
referred to ~erein simply as "the active substance") is prefer~
ably a medicament, the term medicament being understood herein
to include not only substances capable of curing or preventing
disease, but also other substances capable of having beneficial `-~
...
~ effects in animal (including human) organisms.
Several forms of vaginal ring devices constructed in ;
accordance with the invention will now be described, by way of
example, with reference to the accompanying drawings, in which:
Fig. 1 shows a section through a support-ring having ~,~
a crescent-shapedcross-section having a height a and a maximum ~
wall thickness b, the wall thickness being taken in a radial ~;
direction with respect to the ring as a whole; `~
Fig. 2 shows a section through a support-ring having
a hollow crescent-shaped cross-section;
Fig. 3 shows a section taken through a hollow profile
ring;
Fig. 4 shows a section taken through a hollow proflle
ring which is open at its inner side;
'
-- 6 --
'
1~3~ 9Z
Fig. S shows a section taken through a support ring,
which was made by the sandwich mode of construction;
Fig. 6 shows a section taken through a support-ring
having A circular cross-section, which is hollow;
Fig. 7 shows a section taken through a support-ring
~hich consists of a combina~ion of a synthetic plastics material
in the core with another synthetic plastics material in the
form of a jacket;
Fig. 7a shows a section taken through a modified form
of the ring shown in Fig. 7;
Fig. 8 shows a section taken through a hollow support- ~ ;
ring which is open on its inner side;
Fig. 9 shows a section taken through a support-ring
of ellipsoidal cross-section; and
Fig. 10 shows a section taken through a ho}low support-
ring of ellipsoidal cross-section.
Referring to the accompanying drawings, the form of ring -
shown in Fig. 1 comprises a support-ring 1 of crescent-shaped or
kidney-shaped cross-section, an oestrogen-containing part-ring 2
and a gestagen-containing part-ring 3. The two part-rings 2 and
3 each extend a part of the way round the outer circumference of
the support-ring 1.
The second form of ring, which is shown in ~ig. 2,
differs from the ring shown in Fig. 1 in that the support-rihg
4 is of hollow (instead of solid) crescent-shaped or kidney-
shaped cross-section and in that the two part-rings 2 and 3
are replaced by a single gestagen-containing ring 5.
The third form of ring, which is shown in Fig. 3, com-
prises a support-ring, which is indicated generally by the refer-
ence numeral 6, and which is of hollow circular cross-section
with the main, outer tubular member 7 being connected to an inner
tubular member 8 by walls 9 which, seen in cross-section, extend
:
" , ~. . ~.......... . , ~
radially. Extending side-by-side around the outer circumference
of the outer tubul~r memher 7 are an oestrogen-containing ring 10
and a gestayen-containing ring 11.
The fourth form of ring, which is shown in Fig. 4, com-
prises a double-walled support-ring, which is indicated gener- ~
ally by the reference numeral 12, and which is of generally circu- ~ ;
lar cross-section except tha~ it is open in the region of its
inner circumference, thereby giving access to a hollow annular
region 13. The support-ring 12 is also provided wit~ radially
extending internal walls or partitions 14. A gestagen-containing
ring 15 extends round the outer circumference of the support-ring `
12.
The fifth form of ring, which is shown in Fig. S, com- ;
prises a support-ring, which is indicated generally by the refer-
ence numeral 16, and which is of circular cross-section. The
support-ring 16 is made up of a core portion 17 surrounded by a
tubular jacket portion 18. A gestagen-containing ring 19 is
;;. ' ' '.
located in a recess which extends round the outer circumference
of the tubular jacket portion 18.
2Q The sixth form of ring, which is shown in Fig. 6, ; ~`~
comprises a support-ring 20, which is of hollow circular cross- ~ `
section and which is formed with two grooves which extend side-
by-side round the outer circumference o~ the support-ring. The
smaller of the two grooves contains an oestrogen-containing ring `
21 and the larger of them contains a gestagen-containing ring 22.
The seventh form of ring, which is shown in Fig. 7
comprises a support-ring, which is indicated generally by the ;~`
reference numeral Z3, and~which is of circular cross-section.
The support-riny 23 is made up of a core portion 24 surrounded by
a tubular jacket portion 25. The portion 25 is formed with two ~ ;`
grooves which extend round its outer circumference. The smaller
of the two grooves contains an oestrogen-containing ring 26 and
the larger of them contains a gestagen-containing ring 27.
The eighth form of ring, which is shown in ~ig. 7a,
comprises a support-ring, which is indicated generally by the
reference numeral 28, and which is of circular cross-section.
The support-ring 28 is made up o~ a core portion 29 surrounded
by a tubular jacket portion 30. The portion 30 is formed with
a groove which extends round its outer circumference. The groove
contains a gestagen-containing ring 31 around which there extends
an oestrogen-containing ring 32.
The ninth form of ring, which is shown in Fig. 8,
cornprises a hollow support-ring 33, which is of generally circular
cross-section, but which is formed with an opening extending round
the inner circumference of the ring. A groove extending round
the outer circumference of the support-ring 33 houses a gestagen-
containin~ ring 34.
The tenth orm of ring, which is shown in Fig. 9, com-
prises a support-ring 35, which is of elliptical cross-section.
Two grooves extend side-by-side round the outer circumference of
the support-ring 35, the larger groove housing a gestagen-contain-
ing ring 36 and the smaller groove housing an oestrogen-containing
ring 37.
The eleventh form of ring, which is shown in Fig.10,
comprises a support-ring 38, which is of hollow elliptical cross-
section. Extending round the out~r circumerence o~ the support-
ring 38 is a groove which houses a gestagen-containing ring 39.
The support-ring may consist of any physiologically
tolerable synthetic plastics, provided that it has sufficient
strength and elasticity. Suitable synthetic plastics are, for
example, organo-polysiloxane elastomers such, for example, as
LTV-dimethyl-polysiloxane elastomer, heat vulcanized dimethyl-
polysiloxane elastomers, polyamides, natural and synthetic
rubber, polyesters, polytetrafluorethylene and polyethylenes,
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which may be worked up in known manner into moulded bodies, for
example, by injection-moulding or castings.
~nother preferred construction o~ the inv~ntion is one ~ '~
in which there are vulcanised on to a support-ring of LTV-silicone
elastomer rings based on LTV-silicone elastomer which contain a
pharmacologically active substance.
This construction is composed of the following parts:
A support-ring proper having one or two layers contain- ;,~
ing a pharmacologically active substance and which are vulcanized
' 10 on to the inner and/or the outer edge of the support-ring.
1~ The active-substance-containing layers have a cross-
~,~ section of a part of an annulus. The dimensions of the support-
~ . .. .
ring and of the vulcanized-on outer and inner active-substance- ' -' ~
. , .
,` containing rings are so chosen that the outer and inner vulcanized- ;`~
on active-substance-containing rings, respectively, of the
support-ring do not make contact with each other. The layers ; ,
containing a pharmacologically active substance may extend round
: .:
the whole support-ring or be vulcanized-on in pre,ferably circum-
l ferentially extending sections. ,~'
-¦`20 The vaginal rings of the invention have an average size
of 0.5 to 20 cm, and the size depends on the purpose of use. In
the case of small mammals, such as dogs, the size o~ the ring is ',
smaller than in the case of larger mammals, such as horses and , ,
cows. In the case oE vaginal rings for women, the external ,'
l diameter is about 5 to 10 cm and, for example, in the case of
'I rhesus monkeys it is about 2 to 3 cm. The diameter of the cross-
section o~ the ring is 5 to 15 mm, and preferably 7 to 10 mm.
The support-ring and the active-substance-containing ,~
1 rings or vulcanized-on layers are made from ]cnown LTV-silicone
,l, 30, elastomers. Silicone elastomers of the LTV-type and organo-
,'1 ~ . ~-,
polysiloxane two-component moulding compositions of the LTV-type -~
~low temperature vulcanizing type) and the ingredients of these
' ,.'` ' ~ ~'
- 10 -
~ -'
~ ... . .
9Z
compositions are known, for example, from German Auslegeschriften
1,171,641 and 1,900,969, German Offenlegungsschrift 1,940,124 U.S.
Specifications Nos. 2,823,218, 3,159,601, 3,159,662 and 3,220,972.
There are suitable, for example LTV-silicone elastomer
two-component compositions which consist of 89-91% of linear
dimethyl-polysiloxane containing a maximum of 0.5 mol-% of methyl-
vinyl-siloxane units and 9~ of dimethyl-polysiloxane contain-
ing SiH-bonds and having a molecular weight of 500 to 1,000 which
contain up to 3 SiH-bonds, and are vulcanized in the presence of
platinum or a platinum compound such, for example as hexachloro-
platinic acid, (LTV-silicone elastomer A); LTV-silicone elastomer ;
two-component compositions which contain 85 to 89% of dimethyl-
polysiloxane having a maximum of 0.5 mol-% of methyl-vinyl-siloxane .
units, 5-6% of dimethyl-polysiloxane containing Si-H-bonds, 5-10
of a dimethyI-polysiloxane resin having a cross-linking and rein-
~orcing action and containing a maximum of 1.2 mol-% of methyl-
vinyl-siloxane units, and are vulcanized, for example with a ~. .
platinum compound as catalyst (LTV-silicone elastomer B); and LTV-
silicone elastomer two-component moulding compositions containing
dime~hyl-polysiloxane copolymer (LTV-silicone elastomer C). .
The LTV-silicone elastomer C is preferably used in the ~:
case of pharmacologically active substances having one or more
unsaturated groups in the molecule and comprises:-
I. 20-100 parts by weight of an organo-polysiloxane having
a viscosity of 500-200,000 cSt (at 25C) and the general
formula:
R R R
CH2 = CHSiO - - SiO - ~ Si - CH = CH2 ~ ~
~ R R R ~ :
in which R represents an alkyl (preferably methyl) and/ .
or aryl radical and _ represents a whole number from 200
to 1600.
-- 1 1 --
l~i8~2
II. 1-50 parts, preferably 10-35 parts, by weight of an
organo-polysiloxane copolymer comprising:
(a) (R') 3sioo 5-units,
(b) (R')2(vi)Sioo 5-units, and
(c) SiO2-units,
in which R' represents a monovalent organic radical
. - . .
; containing no unsaturated groups and at least 50~ of
R' are m~thyl radicals, and the ratio a+b/c is 0.4 `~
` - 1.5 (preferably 0.6 - 1.0) and the ratio b/c is ~ ~ -
- 0.02 - 0.5 (preferably 0.05 - 0.15).
III. 5-15 parts by weight of an organo-hydrogen-polysiloxane ;
of the general formula
:, . . . .
RllaHbsio4-a-b
2 ~ ~
in which R'' represents a monovalent radical containing ;`
no unsaturated groups and the ratio a:b has a ~alue of
0.5 - 10 (preferably 1.0 - 5) and the sum a+b is equal
to 1 to 2.5, and at least three hydrogen atoms are pre-
l ~ sent bound to different Si-atoms per molecule, which
'20~ contains 50-500 mol-% of the unsaturated groups present
in components I and II on Si-H-bonds, and a ~;
IV catalytic quantity of platinum or a platinum compound. I
The alkyl and/or aryl radicals R present in component I
may contain up to 10 carbons atoms. There may be mentioned for
example, methyl, ethyl, propyl, isopropyl, butyl, octyl, tertiary-
amyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tolyl, xylyl,
beznyl, chlorophenyl, ayanomethyl and 3,3,3-trifluoropropyl radicals. ;
The residues R' and Rli present in components I and II
are identical or different and represent alkyl radicals containing
up to 8 carbon atoms, and preferably those containing up to 3 ;
carbon atoms. There may be mentioned, for example, methyl, ethyl
and _-propyl.
:: ~
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- ~015~4~3;2
The constituents I, II and IV form one component of the
LTV-organo-polysiloxane two-component moulding composition and
constituent III is the second component having a cross-linking
action.
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- 12a - ~
..... . . . .. . . ... . .. . . . . . .. .. . .. . . .. .. . . . . . .
4~79Z
~,
For the purpose ~ retarding hardenin~ ou~ at room
temperature, component I or the m~xture of components I, II and
IV or I, II, III and IV, contain metal ions, for example, copper ;
~ .
(II) ions, in a quantity of 2.00 to 75 parts by weight of metal
ions for each part by weight of platinum. -
Although the vulcanization of the organo-polysiloxane
. . ~ .
moulding compositions in the presence of noble metal catalysts ~
; ~
can also be carried out at room temperature or body temperature,
it is especially advantageous to carry out the vulcanization
at a temperature within the range of from 40 to 120C. The
, .
vulcanization time of the catalyzed mixture is 1 to 6 hours ;~
at a temperature within the range of from 60 to 120C. For
pre-vulcanization the mixture may be heated at a higher temperature
for a short time, for example, up to 150~C for 1 - 10 minutes, ;
but a maximum of 15 minutes.
The platinum component IV of the moulding composikion
may be used in one of the forms that are described in the
literature for catalysing the reaction between silicon-bound
hydrogen residues and silicon~bQund vinyl residues. There may
-. ,
~20 be~mentioned metallic~platinum ~ se or platinum on carrier
substances, such, for example, as silica gel or carbon powder,
or hexachloropIatinic acid and platinum salks such, for example,
as platinum carbonyl dichloride Pt CO Cl2 and platinum dicarbonyl
dichloride Pk~CO)2Cl2. All these plakinum compounds can be
used as vulcanization catalysts. However, pure hexachloroplatinic
acid has the disadvan~ge that it is relatively difficultly
901uble in organo-silicon compounds that contain silane groupings.
Platinum compounds that are used as catalysts in solid form cause ~ ;
the cross-linking reaction to kake place very slowly and in a
manner difficult to regulate, and also the reaction itself can be
more easily interrupted than is to be expected when the comparable
catalysts are used in solukion, Hexachloroplakinic acid used as
.
-13-
,~....... . . . . . .
~)84 7~Z
a catalyst ~s therefore dissolved preferably in ~sopropanol,
and Pt CO C12 and Pt(C0)2C12 are dissolved in a vinyl group-
containing diorgano-polysiloxane containing 10 to 15 mol-%
of vinyl groups. There must be used at least 0.1 part by weight
of platinum per million parts by weight of components I and II.
As impurities in the moulding compositions can poison such small -`
amounts of catalyst, there are preferably used 10 to 40 parts
per million of platinum. Larger quantities of platinum do not
impair the reaction.
In a special construction of the vaginal ring device
of the invention there is used as the same LTV-silicone elastomer
both for the support-ring and also the pharmacologically active-
substance-containing ring. ~ `
In a special construction of the support-ring used for
the vaginal ring device of the invention, the support-ring comprises
a foamed silicone rubber having closed pores. For this purpose
there is added to the vulcanizing mixture in a finely divided
form an agent that evaporates during the vulcanization such, for
example, as a hydrocarbon such, for example, as pentane or heptane
and a halogenated hydrocarbon such, for example, as methylene
chloride, monofluorodichloromethane, dichloro-fluoromethane or
trichloro-trifllloroethane. '.
The vulcanizates obtained rom these organo-polysiloxane
two-component moulding compositions are inactive towards nonionic
lipophilic medicaments, are physiologically tolerable to the living
organism, and are not absorbed thereby.
, . ~ . .
The pharmacologically active substances present in the ~ ;
elastomer material, for example, elastomer rings, are preferably
active substances having a hormonal activity such, for example,
as oestrogens and gestagens. There may be mentioned, for example,
3-methoxy-17~ethinyl-1,3,5(10) oestratrien~17-ol (mestranol),
3-hydroxy~1,3,5(10) oestratrien~l7~one (oestrone), 17~oestradiol,
~ ,
:
-14-
oestriol and eth.~nyl-oestradiol and also 4~pregnen-3,20-dione
~progesterone), d-13~ethyl 17~ ethinyl~17~hydroxy-4-gonen-3-one
(d-norgestrel) and esters thereof, 17a ethinyl-l9-nortestosterone
(norethisterone) and esters thereo~, 6-chloro-17-hydroxy-la,2~-
methylene-pregna-4,6-dien-3,20-dione (cyproterone) and esters ~:
thereof, 19-nor-hydroxyprogesterone and esters thereof, 6-chloro- ~ :~
17-acetoxy-pregna-4,6-dien-3,20-dione tchloromadinone acetate),
15,16a-methylene- and 15,16~-methylene-17~-hydroxy-18-methyl-17a- ~ :
ethinyl-4-oestren-3-one, 17~_acetoxy-6~-methyl-progesterone ~:
(medroxy-progesterone acetate~ and 9~,10a-pregna-4,6-dien-3,20-
dione (dydrogesterone).
As pharmacologically active substances there come into
consideration all medicaments, especially those that are non-
ionic and lipophilic. Thus, there are also suitable neuroleptics :~
such, for example, as butyrophenone derivatives, for example,
haloperidol, or bacteriostatics and fungistatics such, for example,
as nystatin or metronidazole, for incorporation in the silicone ~
elastomer. .. - .
The quan~.ty of pharmacologically active substance
incorporated in the LT~-silicone elastomer is 10 to 60% by
weil.ght and in each particular case depends on the specific
active substance or combination of active substances. For
example, there may be mentioned the following total dosages:
Cyproterone acetate: 200 to 1000 mg
D-norgestrel: 100 to 500 mg
Ethinyl-oestradi~l: 20 to 100 mg i:
Oestradiol: 20 to 90 mg
Mestranol: 50 to 100 mg
Ethinyl-nortestosterone acetate:150 to 950 mg ~ .
,
Oestrone: 10 to 80 mg .;
Oestriol: 15 to 70 mg
Progesterone: 250 to 900 mg
.
--15--
7~'~
Norethisterone: 100 to 600 mg
Cyproterone: 100 to 900 mg
Norhydroxyprogesterone: 2s0 to 950 mg
Chloromadinone acetate: 170 to 850 mg
15,16~-methylene- and 15,16~-
methylene-17~-hydroxy-18-methyl-
17~-ethinyl-4-oestren-3-one: 50 to 750 mg
Dydrogesterone: 100 to 550 mg
Metronidazole: 300 to 950 mg
Thus, it is possible for the ~uter elastomer section
or ring to contain only a gestagen and the inner section or ring
an oestrogen, or vice versa. Gestagens or oestrogens may be
used, for example, in combination with bactericides.
The total quantity of acti~e substance in the LTV-
silicone elastomer is so chosen that during the desired period
a predetermined constant quantity is released per day. Examples
are as follows:
Cyproterone acetate: 300 to 1000 ~gm/d `~
D-norgestrel: 30 to 250 ~gm/d
Ethinyl-oestradiol: 30 to 60 ~gm/d
Oestradiol: 20 to 150 ~gm/d ~;
Mestranol: 20 to 100 ~gm/d
Ethinyl-nortestosterone acetate:300 to 1000 ~gm/d
One construction of the vaginal ring o~ the invention
is for use in preventing conception. A contraceptive e~fect
based on inhibitlng ovulation may be achieved within the period
of use of the vaginal ring of the inventlon when it releases,
~or example, daily between 130 and 250 ~gm of d-norgestrel and
30 to 50 ~gm of ethinyl-oestradiol or between 800 and 1000
~gm of cyproterone acetate and 30 to 50 ~gm of ethinyl-oestradiol. ~
Vaginal rings that contain inthe active-substance-containing ;
inner and outer sections or rings agents that are active against
protozoa such, for example, as metronidazole and optionally
oestrogens, are especially suitable ~or the treatment of
~ -16-
': , . '?
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trichomoniasis, The ~edicament is incorporated in the LTv-
silicone rubber base used ~or maklng the ring contatning the
active substance. For thls purpose the active substance is
disintegrated or finely ground, optionally rnicronised, mixed
with an LTV-silicone rubber two component composition to form a
suspension free from air bubbles, moulded into rings, and
vulcanized by heating, preferabl~ at 40 - 120~C.
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The-actlve-substance~containing rings have, in the
case of the outer ring, a diameter of 0.5 to 8.0 mm, preferahly
1.5 to 5.0 mm and, in the case of the inner ring, a diameter
of 0.3 to 2.0 r~n, pre~erably 0.4 to 1.6 mm.
The active-substance~containing rings may be built
up wholly or partially on the matrix principle. However, the
active-substance-containing rings may instead consist of a
core containing an active substance and an outer sheath of
silicone elastomer of any desired layer thickness which is free
from active substance or lower in concentration of the active
substance than in the core, or, conversely, it may consist of an
enclosing layer o~ elastomer and a core-member low in active
substance. Such a sheath which is lower in concentration of
the active substance over a core higher in concentration of
active subs*ance in which the acti~e substance is preponderantly
in suspension is obtained, or example, by subjecting a pre-
paration built up on the matrix principle to an extraction for
a short time with a suitable solvent such, for example, as
ethanoI/water 1/1 (vol./vol.).
The sections or rings containing the active substance
are inserted in the pocket-shaped recesses in the support-ring, ;
and if desired adhesively secured in the recesses by the use
of a catalysed L'rV-silicone elastomer two-component component
composition and subsequent vulcanization, or moulded on the
pre-vulcanized support-ring and vulcanized together with the
support-ring.
The supp~rt-ring and the active-substance-containing
outer and/or inner ring or section, joined or adhesively secured
together, form the vaginal ring device proper.
For producing a coating or layer containing a
pharmacologically active substance on the support-ring the -
active substance is likewise incorporated in the LTV-silicone
'.
-17-
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elastomer base. For this purpose the actlve substance is finely
ground, if desired micronised, mixed with and LTV-silicone
elastomer two-component composition to form a suspension, applied
as a layer by means of the multi-colour injection moulding
technique to the pre-vulcanized support ring, and vulcanized ~ ~
by h~ating, preferably at 40 - 120C. ~ .
It may also be of advantage to add to the suspengion
containing the active substance and silicone elastomer an
auxiliary substance such~ for example, as tenside, anti-forming
agent, a solubiliser or absorption-retarder, or a mi~ture of `~
any two or more of such substances, in order to impart the
desired physical properties to the moulded body. Furthermore,
there also come into consideration lnert auxiliary substances
such, for example, as highly dispersed silicon dioxide, which
give the ring the desired mechanical properties.
The medicament-contain~ng coatings, when vulcanized
on to the outer surface of the support-ring, have a thickness
of 0.1 to 5.0 mm, and preferably 0.5 to 3.0 mm, and, when
vulcanized on to the inner surface of the support-ring, a thick-
ness of 0.1 to 3.0 mm, and preferably 0.5 to 2.0 mm.
The active-substance~containing coatings are preferably
built up wholly or partially on the matrix prin~iple.
As, during the vulcanization of the LTV-silicone
elastomer two-component composition, no by-products are formed
a subse~uent heat treatment of the hardened product is unnecessary.
The va~inal ring devices of the invention have the
advantage that the pharmacologically active substance or
substances are released therefrom relatively regularly and in
constant amounts over a long period within the limits of the ~;
.:
dosage necessary for the desired biological action, for example,
for inhibiting ovulation. They have a further advantage that
the quantity of the active substance that has to be incorporated -
-18-
z
in a single such contracept~ve can be ~uch smaller than in the
case of the known va~lnal rings.
The va~inal ring devices of the invention based on
LTV-silicone elastomer have a materially reduced tendency to
crumble under mechanical stress. When introduced into the
body they are not so easily damaged as are vaginal rings based
on RTV-elastomers, which contain or improviilg the mechanical
properties moxe or less defined mixtures of active fillers
having known disadvantageous(propertles towards the pharmacologi-
cally active substance. ;~
With the vaginal ring device of the invention there `~`
can be successfully used many active substances that could not
be successfully used with the hithertQ known and usual carrier
materials in the known vaginal rings.
The vaginal rings made in accordance with the invention
can be sterilised in saturated steam under pressure at 120C,
without undergoing undesired changes,
The following Examples illustrate the invention:
~ EXAMPLE 1
A support-ring intended to receive two medicament-
containing rings is produced by the hollow body klast method
in the form of a tubular i^ing ~see Fig. 6) of polyethylene/
vinyl acetate copolymerisate ~LUPOLEN ~ V 3520 K/BASF) having
the following dimensions:
External diameter 60 mm, internal diameter 44 mm and diameter of
the hollow space in the cross~section of the ring 3 mm. The
support~ring is provided with two pocket-shaped recesses extending
around it, which are intended to receive medicament-containing ,~
rings as shown in Fig. 6. One medicament-containing ring has a -
diameter of 2.0 mm, and the other medicament-containing ring has
a diameter of 1.0 mm. The va~inal ring, after insertion of the
medicament~containing rings, has in the plane of insertion of
-19- ; ~' '
.~ .
Z
thoce rings a d1ameter of the rIng cross-section of 8.5 mm.
The medicament~conta~ning ~ng having a dlameter of
2 mm is formed from a suspension of 5 parts by weight of D-nor-
gestrel, 15 parts by weight of hlghly dispersed silicon dioxide
rendered water-repellent (AEROSIL O ~972/DEGUSSA) and 8 parts
by weight of very finely pulverised magnesium oxide, in 72
parts by wei~ght of LTV-organo-polysiloxane two-component moulding
composition A, is pre-vulcanized by heating for 1 1/2 minutes
at 120C., and is vulcanized by ~eating for 3 hours at 80C The
LTV-organo-polysiloxane two-component moulding composition A
consists of 75 parts by weight of a polydimethyl siloxane vinyl-
terminally blocked at both ends having a viscosity of 50,000
cSt at 25C., 25 parts by weight of a copolymer having the
composition: 40 mol-% of SiO2-units, 45 mol~% of (CH3)-SiOo 5-units,
15 mol-% of Vi(CH3)2SiOo 5-units, 8 parts by weight of an SiH-
component consisting of: 16.6 mol~ of (CH3) 3SlOo 5-units, 33.4
mol-% of (CH3)2SiO-units, 50 mol-% o CH3HSiO-units and 52 ppm
of platinum in the form of a solution of 1~ strength of Pt(CO)2C1
calculated on the quantity of dimethyl-polysiloxane vinyl-terminally
blocked at both ends.
The other medicament-containing ring is produced from
a homogeneous suspension of 3 parts by weight o~ ethinyl-
~estradiol and 26 parts by weight o highly dispersed silicon
dioxide rendered water-repellent (~EROSIL ~ R972/DEGUSSA) in 71
parts by weight of LTV-organopolysiloxane two-component mouldihg
composition B by moulding, pre-vulcanizing at about 120C for
1 1/2 minutes and vulcanizing for two hours at 105C. The LTV-
organo-polysiloxane two-component moulding composition B consists
of 82.5 parts by weight of a poly~imethylsiloxane vinyl-terminally
blocked at both ends having a viscosity of 1000 cSt at 25C.,
15 parts by weight of a copolymer of the composition: 40 mol-~
of SiO2-units, 45 mol-% of (CH3)3Sioo 5-units, 15 mol-~ of Vi(CH3)2
-20-
~38~
SiOo 5-units, 7.0 parts by wei~ht of an SiH-component consisting
of: 38 mol-% of S~O2-un~ts, 29 mol~% of (CH3)3SlQo 5-units,
33 mol-% of (CH3)2HSiOo 5-units and 40 ppm of platinum in the
form of a solution of 2~ strength o~ H2PtC16 in isopropanol
(calculated on the quantity of polydlmethylsiloxane vinyl-
terminally blocked at both ends).
The medicament-containing rings are inserted inthe
suppo~t-ring and with this are a constituent of the vaginal ring.
EXAMPLE 2
.
From dimethyl-polysiloxane moulding composition `~
(SILASTIC ~ 4600/DOW CORNING) is formed by moulding, pre~
vulcanizing at 150C for 5 minutes and vulcanizing for one hour
at 120C., a tubular material having a kidney-shaped cross-
section and a diameter of 9 mm and an internal diameter o~ 5 mm,
which has a pocket-shaped recess of 1.5 mm on its outer surface.
Sections of this tubular material are moulded with the use of
catalysed SILATIC ~ 4600 to form hollow rubber rings (see Fig. 2)
as support-rings, and vulcanized for 30 minutes while heating
at 130C. The support-rings have an external diameter of 60 mm
and an internal diameter of 42 mm and the pocket-shaped recess
extends along its outer surface to receive a medicament-containing
ring having a diameter of 2 mm. This outer ring containing D-
norgestrel i5 prepared from the moulding composition mentioned
in Example 1 in the manner given therein, and is inserted in the
support-ring.
EXAMPLE 3
A vaginal ring containing D-norgestrel is produced in
a three-stage process in the form of a combination vulcanizate ;
of a support-ring with the ring components containing D-norgestrel
(see Fig. 5). The support~ring of this vaginal rlng is moulded
by the sandwich~injection mouldln~ process with a groove (not shown)
extending round it from polyisobutylene having an average
-21-
... .
79Z
molecular weIght o~ about 2,700,000 (~PANOL~ B 150/BASF) as the
core and LTV-sillc~ne rubher two-component composition B (as
described in Example 1) in admixture with 20 parts by weight
of highly dispersed silicon dioxide rendered water-repellent
(AEROSIL ~ R972/DEGUSSA) as the outer layer. The dimensions
of the support-ring are: External diameter 62 mm, internal
diameter 4~ mm, the groove extending round it to receive the
D-norgestrel-containing outer ring: 1 mm deep, 3 mm wide.
The D-norgestrel-containing ring component.is formed
from the moulding composition described in Example 1 bs7 injection
into the groove extending round the support-ring and connected
to the outer layer of the support-ring by subsequent pre-
vulcanization for 1.2 minutes at 115C followed by vulcanization
for two hours at 110C. This ring component has a cross-section'
the shape of a segment of a circle and at its outer edge a
radius of curvature of 120 mm.
_AMPLE 4
A vaginal ring containing D-norgestrel and ethinyl-
oestradiol is made in the form of a compound vulcanizate having ;
a kidney-shaped cross-section ~see Fig. 1) by the multi-colour
injection-moulding technique. The ring has an external diameter ;
of 60 mm. The distances a and b are 7.6 mm and 2.8 mm, respective-
ly. There are injected on to the support-ring component in
succession at the outer edge the D-norgestrel-containing and
ethinyl-oestradiol-containing components, pre-vulcanized by
heating for 2 minutes at 115C~, removed from the mould and
~ulcanized outside the mould by heating for 2 hours at 80C.
The support-ring component is produced from a mixture of 23 parts
by weiaht of highly dispersed silicon dioxide (AEROSIL ~ R972/
DEGUSSA) and 77 parts by weight of the LTV-silicone rubber two-
component composition A described in Example 1.
The D-norgestrel-containing ring component 2 mm in
-22-
, ~ .
Z
diameter projects 0.6 mm, shaped as the segment of a circle,
from the outer edge o~ the support~ring. It consists of a
mixture of 24 parts by weight o~ hi~hly dispersed silicon dioxide,
8 parts by weight of micronised D-~norgeskrel and 68 parts by
weight of catalysed LTV-silicone rubber base (SILOPREN O 3008/BAYER).
The ethinyl-oestradiol-containing ring component having
a diameter of 1 mm projects 0.4 mm, shaped as the segment of a
circle, from the outer edge of the support-ring. It contains per
100 parts by weight 10 parts by weight of micronised ethinyl-
oestradiol and 21 parts by weight of highly dispersed silicon ~;
dioxide in addition to 69 parts by weight of LTV-organo-poly-
siloxane moulding composition consisting of 75 parts by weight
of a polydimethyl-siloxane vinyl-terminally blocked at both ends
having a viscosity of 1000 cSt at 25C., 25 parts by weight of
a copolymer of the composition: 40 mol-~ of SiO2-units, 45 mol-% ;
of (CH3)2SiOo 5-units, 15 mol-% of Vi(CH3)2 SiOo 5-units, 8 parts
by weight of an Si-H-component consisting of 16.6 mol-% of
(CH3~3SiOo 5-units, 33.4 mol-~ of (CH3)2SiO~units, 50.0 mol-%
of CH3HSiO-units and 10 ppm of platinum (calculated on the
total mixture, in the form of a solution of 2% strength of H2PtC16
in isopropanol).
EXAMPLE 5
A vaginal ring containing ethinyl.-oestradiol as well
as ethinyl-nortestosterone acetate is made in the form of a
mechanical combination of an ethylene-vinyl acetate copolymer- -
isate (~LATHON Q 3180/DU PONT) as a hollow profile ring having
two medicament-containing band~rings of LTV-silicone elastomer
base fitting into grooves extending round it (see Fig. 3). `
The support-ring is formed from hollow profile sections
by welding their ends and has an external diameter of 64 mm
and an internal diameter of 44 mm, stay and wall thicknesses
of 1.5 mm, and has its outer edge grooves extending round it that ;~
:, ';~ ~..
.
-23-
. ' .
i~4~2
are 1 mm deep and 3 mm ~ide, and 1 mm deep and 1 mm wide,
respectively, The ethtnyl-nortestosterone acetate-c~ntaining
ring component, 1 mm th~ck and 3 mm wide and having an internal .-
diameter of 62 mm, is formed rom a mixture of 10 parts by
weight of micronised ethinyl~nortestosterone acetate and 22 parts
by weight of highly dispersed silicon dioxide in 68 parts by
weight of an LTV-organo-polysiloxane two-component moulding
composition consisting of 75 parts by weight of a polydimethyl-
siloxane vinyl-terminally blocked at both ends and having a
viscosity of 1000 cSt at 25C., 25 parts by weight of a copolymer
having the composition: 40 mol~% of SiO2-units, 45 mol-~ of (CH3)
2SiOo 5-units, 15 mol-% of vi(CH3)2Sioo 5-units, 8 parts by
weight of an Si-H-component consisting of 16.6 mol-% of (CH3)3
SiOo 5-units, 33.4 mol-% of (CH3)2SiO-units, 50.0 mol-% of
CH3HSiO-units and 30 ppm of platinum (calculated on the total
mixture~ in the form of a solution of 1% strength of Pt(CO)2C12
dissolved in an open-chained vinyl group-containing dimethyl- ;
polysiloxane containing 12 mol-% of vinyl groups) and 5 parts
by weight, calculated on the parts by weight of platinum, of Cu-
(II)-ions, and is then vulcanized at 105~C.
The ethinyl-oestradiol-containing ring component is
1 mm thick and 1 mm wide and has an internal diameter of 58 mm,
and is moulded from ~he composition described in ~xample 4 and
vulcanized by being heated at 80C.
EXAMPLE 6
A vaginal ring containing 15,16~-methylene-17~-hydroxy- :~
18-methyl-17~-ethinyl-4-oestren-3-one as well as oestriol has : :~
the following structure:
A solid soft rubber ring based on natural rubber having
an external diameter.of 36 mm and a diameter of the ring cross- . ;
section of 6.6 mm is used as the lnserted member and is jacketed ~ :
by injection-moulding with a 1.2 mm thick layer of LTV-silicone
-24-
. . .
~ 479Z
rubber (see Fig 7). The silicone rubber layer has on the outer
edge of the ring two 0.5 mm deep ~rooves having widths of 1.6
and 3.0 mm respectlvely. This ring is the support-riny for -two-
medicament-containing rings of which the cross-section is the . ~ ;
shape of a segment of a circle, which are mechanically connected
to the support-ring. The jacketing of the soft rubber ~ing is .
carried out with the LTV organo~polysiloxane two-component
moulding composition A described in Example 1 and vulcanized at
130~C.
The vaginal component containing 10 parts by wei.ght of ;
micronised 15,16a-methylene-17~-hydroxy-18-methyl-17~-ethinyl-4-
oestren-3-one, having a chord length of 3.0 mm, is made on the
basis of a mixture consistiny of 20 parts by weight of highly
dispersed sil.icon dioxide (~EROSIL ~ 200) and 70 parts by weight .
of the LTV-silicone rubber two-component composition B described
in Example 1.
The vaginal component containing oestriol, having in
cross-section the shape of a $egment of a circle, and a chord ..
length of 1.6 mm, is produced from a mixture of 12 parts by
weight of micronised oestriol, 19 parts by weight of highlY ;
dispersed sillcon dioxide and 69 parts by weight of the above ;:
described LTV-silicone rubber two-component composition B by ~ .
moulding and vulcanizing for three hours at 90C.
EXAMPLE 7
A vaginal ring.containing D~norgestrel and ethinyl-
oestradiol takes the form o~ a compound vulcanizate of support-
ring and two components partially jacketing the support-ring and
separately containing the medicaments and which are chemically ;
connected with the ring (see Fig. 7a). The core of the support- ~ .
ring is made of rubber-like polyurethane in the form of a solid `:-~
ring having a groove extending round its outer surface, which is
1.5 mm deep and 3 mm wide and an outer diameter of 60 mm and a :.
, :. ~ .
-25-
.-' ~ .
... . . ,- . . .. . .. . .. . , , ~ . .. . . . . .
1~ 2
diameter of the rin~ Qf 8 ~. Th~s support~ring core is provided
with ~ coating 1 5 m~ thick by repeated immersion in a solution
of 20% strength of the catalysed LTV-silicone rubber two-component
composition B (see Example 1) in methylene chloride and ~he
coating is pre-vulcanized Eor two minutes at 125C and vulcanized
at 130C ~or one hour.
The groove in this support~ring, which in injection-
moulding functions as the insertion part, is filled by the process
of two-colour injection moulding with the composition containing
D-norgestrel descrihed in Example 4, and pre-vulcanized for 1 1/2
minutes at 110C. On this band containing D-norgestrel extending
round the outer edge of the vaginal ring is centrally injection
moulded with the moulding composition containing ethinyl-oestradiol
of Example 1 a round cord having a diameter of 1 mm, and pre-
vulcanized for two minutes at 1104C. The vaginal ring so prepared
is vulcanized by being heated for one hour at 110C.
EXAMPLE 8
Vaginal rings containing D-norgestrel are made with
the use o~ the support-ring described in Example 7 by vulcanizing-
on the moulding composition containin~ D-norgestrel described
in Example 1 in the groove of the support-ring (see Fig. 7a).
EXAMPLE 9
A vaginal ring containing D~norgestrel and ethinyl-
oestradiol is made in the ~orm o~ a mechanical combination o~ a
support-ring having an ellipsoidal cross-section (see Fig. 9,
a = 2 mm, b -- 3.5 mm) and two recesses o~ 0.8 and 1.4 mm,
respectively, e~tending round the outer edge at a distance apart
of 1.5 mm, and a width of groove of 1.0 and 2.0 mm, respectively,
with a medicament-containing ring having in cross-section the
shape of a segment of a circle fitting into each of these grooves. ;~
The support-ring is injection moulded with ethylene-vinyl acetate
copolymerisate (ALATHON ~ 3185/DU PONT). The ring component ~:
-26- -
. . .
.... . . ..
1084~5~Z ~ ~
conta~ning D norgestrel is m~ulaea ~xo~ the compositior~ given
in Example 1 and vulcanized for 90 mlnutes at 110C.
The r:ing cornponent containing ethinyl-oestradiol ls
moulded from the composition given in Example 1 and vulcanized
by heating at 105~C.
EXAMPLE 10 ~:
A vaginal ring containing 4-pregnen-3/20-dione (progest-
erone) is made in the form of a combination vulcanizate consisting
of a support-ring having a groove extending along its outer edge ..
in which the ring component containing progesterone is vulcanized.
The support-ring is a hollow ring provided with an opening 2 mm ; ~.
wide at its inner edge (see Fig. 8) The ring has an external :;
diameter of 60 mm, an internal diameter of 42 mm and in cross .;
section an internal diameter of 5 mm, The groove extending round . :
the outer edge of the ring is l.S mm deep and 3 mm wide. `~
The support-ring is formed from a mixture of 20 parts :
by weight of highly dispersed silicon dioxide and 80 parts by
weight of LTV-silicone rubber two-component composition B, of
which the composition is given in Example 1, and pre-vulcanized
at 120C. This support~ring is used in a second stage of the pro-
cess like an insert part, in the groove of which, extending round
it, is in~ection moulded the moulding composition containing
progesterone. This moulding composition consists o lS parts
by weight o ~icronised progesterone and 20 parts by weight of high~
ly dispersed silicon dioxide in the LTV-silicone rubber two-
component composition A (or composition see Example 1). After . :~
the injection moulding, it is pre-vulcanized in the groove of the .
hollow ring by heating at 90C. The medicament-containing ring
is then vulcanlzed by being heated for two hours at 80C.
The progesterone-containin~ ring component of the ;`~
vaginal ring present as a combination vulcanizate is converted .
by a four.stage im~erslon process ~ntQ ~ medicament-carrier ::~
~`
-27-
'~',
Z
having a jack~t p~or in act~ve substance u~n a core rich in
acti~e substance. In addition the vaginal ring is kept in
succession in ethanol alcohol o~ 90% strength ~or 10 minutes
and 5 minut~s, of 70% strength for 5 minutes and of 50% strength
for 5 minutes.
EXAMPLE 11
A vaginal ring containing 17a-acetoxy-6a-methyl-
progesterone (medroxyprogesterone acetate) is made in the form
of a mechanical combination of a support ring having a groove
extending round its outer edge to receive a ring component
containing medroxyprogesterone acetate (see Fig. 10). The
support-ring is a hollow ring having an ellipsoidal cross-section
it has an external diameter of 60 mm, an internal diameter of
42 mm, a wall thickness of 3 mm and is formed from ethylene/vinyl
acetate copolymer (ALATHON O 3185/DU PONT) by the hollow body
blast process, and has a groove of 1.5 mm depth and 2.S mm
widtlh extending round its ouber edge.
The medroxyprogesterone acetate-containing component
is separately injection moulded from a mixture of 20 parts by
weight of micronised medroxyprogesterone acetate, 11 parts by
weight of highly dispersed silicon dioxide and 69 parts by
weight of LTV-silicone rubber two~component composition B
(for composition see Example 1) and ~ulcanized at 100~C.
EX~M~LE 12
A va~inal ring containing 15,16~~methylene-17~-hydroxy-
l~-methyl-17~-ethinyl-4-oestren-3-one is made in the form of
a mechanical combination of a support ring open at its inner -
edge, which is moulded in the form of a hollow profile ring
(see Fig. 4) from polyethylene/vinyl acetate copolymerisate
(LUPOLEN V 3520 K / BASF) having a groove 2 mm wide and 1 mm
deep extending round its outer edge to receive the medicament- ;
containing band~ring.
' ' ''':
-28~
' ' ' ,'~
7g~
The support~rirlg .~S Eormed ~rom hollow profile sections
by welding the ends and has an external diameter of 62 mm, an
internal diame-ter of 40 mm, and ~ stay and wall thi.ckness of
1.5 mm.
The medicament-con-taining band-ring is made from a
mixture of 8 parts by wei~ht of 15,16~ methylene-17~-hydroxy-
18-methyl-17~-ethinyl-4-oestren-3-one, 19 parts by weight of
highly dispersed silicon dioxide and 73 parts by weigh-t of LTV-
silicone rubber composition B, of which the composition is given
in Example 1, and vulcanized by being heated for three hours ~ :
at 90C.
.:
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