DE2616064A1 - VAGINAL RING III - Google Patents

Description

Berlin, April 9, 1976

• Χ '

V A G I N A L R I N G III 2616064

Addition to patent application P 2 * t 50 IO7.3

In the patent application P 2k 50 107 ·.? a vaginaling has been described, which consists of a support ring made of plastic with one or two circumferential sack-shaped depressions for receiving drug-containing agents that fit into these depressions. Rings on the basis of silicone elastomer.

In a further embodiment of the invention according to patent application P 2k 50 IO7.3, the support ring has a kidney-shaped or ellipsoidal cross-section or is a closed or inwardly open hollow profile ring or as a closed or inwardly open hollow ring or as a hollow ring with a circular or kidney-shaped cross-section or as a core-encased composite ring or designed as a sandwich body.

Since the support ring is by and large the shape of the vaginal ring constitutes, the external features therefore also apply to the inventive Vaginal ring.

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709842/0468

Board of Directors: Dr. Herbert Asmis ■ Dr. Christian Bruhn Hans-Jürgen Hamann Postal address: SCHERING AG D-1 Berlin 65 Postfach 65 0311 Dr Heinz-Hannse-Karl Otto Millel Menscheid Dr. Horst VViUoI postal check account: Berlin-West 1173-101. Dankl.-irxa. '. L 100 1001D

Chairman of the Supervisory Board: Dr. Eduard v. Schwartzkoppc-n Berliner Commerzban !; Au, Berlin. Account no. luS 7CCf 00.Bankl '.- i :: - a! il HO

Company headquarters: Gerlin and Betykainen Berlin Disronto-Canl. AG, f erlin. Koito no. 241 / iOOS. 6-inch number 100 Λλ

Commercial register: AG Charloltenburg93HP.B233 u AG Kamen HRB 0061 Berliner Handels-Pesollscliaft - · Frankfurter Bani -, Berlin, Kon'.ö no. 14-36 ?. ßanhiCilzah! 10320200

SCHERING AG

Intellectual Property

Vaginal rings, the progestogen we-ksaine steroid hormones or a combination of progestogen and estrogen-acting drug substances included with or without Ovulationsheramung prevent conception, llieten useful if Arzneiformeri to be not applied for oral application containing these active ingredients for various reasons , for example if there is an unwillingness to take a tablet. Vaginal rings also have the advantage that women are freed from the compulsion to take tablets every day. It is an easy-to-apply ring-shaped structure that is inserted into the vagina. They are well tolerated by women. Compared to the known intrauterine devices and subdermally applied capsules, they still have the advantage that they can be removed and reinserted by the woman at any time.

709842/0468

Board of Directors: Dr. Herbert Asmls Dr. Christian Bruhn Hans-Jürgen Hamann Postal address: SCHERING AG D-1 Berlin 65 - Postfach 65 0311 Dr. Heinz Hannse · Karl Otto Mitlelstenscheid · Dr. Horst Witzel Postscheck account: Berlin-West 1175-101, bank code 10010010

SiS? AG (ÄTnl S ^ HPB ^ "Afi Kamen HRB00G1 Berliner Handols ^ esoHschal. - IJanMurtor Bank -, Ber.in.

SuHER [NGAQ

- α "·· - '■ · GoviorMirlier Kotl.ii.scimtü;

Vag in a Irin go made of plastic, in particular those based on silicone elastomers, which are obtained from RTV silicone rubber two-component liquid (Cont.i-aceptJ.on 8 (197.3) 651) or on the basis of silicone rubber hot-vulcanized materials (steroids _2JL (1973) 325) which contain arzaieiinittel active substance ev / ie Stex'oidhoi-niono are known per se (Fertil. Steril. J21 (1970) 99 i Ainer. J. Obbstet. Gynecol ", 113 (1972) 927; Contraception fl> (G) (1973) 56 * 1; DT OS 1,900,196). The medical agent is released from the plastic stick over a longer period of time and is absorbed through the vaginal mucosa.

The steroid hormones contained in the well-known vaginal rings are exclusively those with a gestational effect. Dependent on on the amount of active substance release ex'ate of the vaginal rings vii-d by adding or without them a. Conception protection achieved.

So far Ko7itrazeptiva known in the form of \ ^r aginalringen h \ ben however disadvantages. They are manufactured, among other things, on the basis of IITV silicone rubber two-component liners, whose poor mechanical properties are known. The bio-mechanical properties of the RTV vulcanizates have to go through first

709842/0468

ORIGINAL! NSFEDTiT

SCH ^ RiNGAG

GoweiiiUciicr KociU'i '-. Ti.tiiz

the. Addition of. Fill. "St of fön vorl) (: fj. ^! ; F; rt. These fillers can, however, influence the release of active ingredient from the vaginal ring in two parts ch.uk- Zweikomponent s ma s α s. produced in ent spr ο eh end forms "the Arzneiuiittelwirkstof f ο be delivered from this type vaginal ring in the application π Ke i dream in time greatly reducing amounts (Contraception 8, (1973 ) 561)

Significant differences in the dosage of the Arzneimittolwirkstoffe have MPACT necessarily qualitative and quantitative differences in the biological or contraceptive Y. ^T and uncrvTÜnschter in the nature and extent of side effects in the period of application of A'aginalringc "ur result» contacts vaginal rings, the homogeneously the drug in the plastic base in suspension have a total weight of approx. 6.0 to 15.0 g. If the active pharmaceutical ingredient is to be released from these vaginal rings during the application period in the amount sufficient for the desired effect, then they MUST contain approx. 5 to 30 g of active pharmaceutical ingredient. In relation to the amount of active pharmaceutical ingredients released during the period of use, this is an uneconomical high ex-content

709842/0468

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of active ingredient in the Ai'zncjform.

No other seduction is known to date, the height of the Influence of drugs and active ingredients for a certain reason Medicinal active ingredient in such vaginal rings to be adjusted on silicone-based bases.

Previously known vaginal rings cords partly based on physiological not possible; harmless · plastics made. Thus, from RTV-SiIikoi) kautscJhuk ~ Zv; eikonrponei: iteii · - massßii, which contained tin compounds as vulcanization agents, are used for the production of vagina ringon. The vulcanization accelerators have a toxic effect on the living organism (Amer.J.Obstet.Gynecol. 113 (1972) 927).

Are also known Vaginalringc, which is similar to deaien are Prolcipsbeluiiidluiig with a Metallfedex "\ ^r erselien. This vaginal rings are relatively rigid. For its application, it may 2U Sclileinihauterosioneii in the region of the vaginal vault posteralateraIen come (Amor .Mod.Ass. 208 (1969) 9 (19) GB PS 1,264,732 describes devices which order from a capsule containing medicinal products on a plastic ring made of silicone rubber

709842/0468

OuI {u, .i vivo; / <, '.}.

GevoiMicIier ReclitsachuU.

bad for series production due to their construction suitable. These rings also lack practicality in use.

The invention was based on the object of providing vaginal rings containing active pharmaceutical ingredients which contain the active ingredients Over several weeks, but at least three weeks, regularly and consistently in the aim of achieving the desired Release the amount required for biological effects and overcome the aforementioned disadvantages of known vaginal rings.

The object according to the invention is achieved by clicking on a support ring made of plastic, one or two rings or ring sections made of plastic, containing drugs

LTV = /

Basis of ^ iliconelastoiner applies «

A preferred embodiment of the vaginal ring according to the invention consists of a support ring with one or two circumferential sack-shaped depressions for inclusion in these depressions Matching drug-containing rings based on LTV silicone elastomer.

This vaginal ring according to the invention consists of the following Part en z \ isamines:

709842/0468

all ,: iVV3 r \ Commercial legal cl »·;

From the plastic support ring with one or two Vt and the drug-containing inner and / or outer rings: which fitted into the sack-shaped recess of the support ring will. The depressions in the support ring can, however, both run parallel on the outer edge of the support ring3. The depressions may also have different depths depending on the dimensions of the drug-containing rings or width.

The drug-containing rings preferably have a circular cross-section. But the cross-section can also be in the shape of a segment of a circle. The dimensions of the support ring and the active ingredient-containing rings are chosen so that the contact points of the outer and inner edge .des support ring with the active ingredient-containing ring above the center line of the active ingredient-containing ring with a circular cross-section bzA-r. the center line of the section forming the section Circle lies in a circular section-shaped cross-section. This is a favorable fixation of the 'active ingredient-containing rings reached in the sack-shaped depressions of the support ring.

709842/0468 - ⁶

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SCHERING AG

Intellectual Property

According to the invention, the support ring can have different shapes, which also differ in their manufacturing process can.

Fig. 1 shows a section through a support ring with kidney-shaped Cross-section with the height a and the maximum wall thickness b

Fig. 2 shows a section through a support ring with a kidney-shaped Cross-section that is hollow on the inside

Fig. 3 shows a section through a hollow profile ring

Fig. K shows a section through a hollow profile ring which is open on the inside

Fig. 5 shows a section through a support ring according to the sandwich construction was made

Fig. 6 shows a section through a support ring with a circular Cross-section that is hollow on the inside

Fig. 7 shows a section through a support ring from consists of a composite of a plastic in the core with another plastic as a sheath

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709842/0468

SChERiNa AQ

Commercial Rechii- ^ ctiut:

- 6-dr-

Fig. 8 shows a section through a hollow Snpportring, which is open inwards

Fig. 9 shows a section through a support ring with an ellipsoidal cross-section

Fig. 10 shows a section through a hollow support ring with ellipsoidal cross-section

The soup ring can be made from any physiologically harmless one Order plastic as long as it has sufficient strength and elasticity. Plastics such as, for example, are suitable Orgauopolysiloxane elastomers such as LTV-Diinethylpolyciloxaneelastomer, hot vulcanized dirnethylpolysiloxane elastomers, Polyamides, natural and synthetic rubber, polyester, Polytetrafliioräthylen and Polyäthylen, which are known in per se Way, for example processed by injection molding or casting to form the molded body will.

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709842/0468

SCHERING AG

Intellectual Property

Another preferred embodiment is that one on a support ring made of LTV-Siliconelnstomor drug-containing active ingredients Rings based on LTV silicone elastomer on vulcanized.

This vaginal ring according to the invention is composed of the following Share together:

Vulcanize the actual support ring with one or two drug-containing layers on the inside and / or aii the outer edge of the support ring.

The drug-containing layers have one circular section. The dimensions of the support ring and the vulcanized on the active ingredient Rings are chosen so that the vulcanized layers on the outer or inner edge of the support ring do not touch. The active ingredient-containing layers can enclose or include the entire support ring or else be vulcanized in sections.

The original vaginal rings have an average size of 0.5 to 20 cm, the size depending on the application. In smaller mammals, such as dogs, the ring size will be smaller than in larger mammals, such as horses and cows. dei vaginal rings for women is the Außendurchme.sBor about 5 to 10 era and, for example cm in rhesus monkeys about 2 to third the diameter of the Kiugquorschnitts is 5 to l'J mm, preferably 7 mm to 10 degrees.

709842/0468 -8-

Commercial i; cr'il: .sc: Ii ^: i; r

The support ring and the active ingredient-containing rings or vulcanized !!. Layers are produced on the basis of LTV silicone elastomers known per se. Organopolysiloxaii two-component film compositions of the LTV type (low temperature vulcanisi.rig type) and. Components of these materials are known, for example, from DTAS 1.171.64-1 and 1.900.965, DT OS 1.940 * 124, USP 2.823.218, 3.159VOOl ₁ 3.159.662 and 3.220.972. . ''''.''

For example, two-component LTV silicone rubber compositions are suitable which contain 89-91% linear, at most 0.5 mol 3 Sill formations contain, exist and are catalyzed with platinum or platinum compounds such as Ilexachlorcplatinsäuro (LTV silicone elastomer A), LTV SiI ikonkaut school - two-component compounds, the 85 to 89 Ά diniethylpolysiloxane with a maximum of 0.5 mol ~ 6 methylvinylsiloxane units, 5-6 % dimethyliiolysiloxane with Si-II bonds., 5-10 % of a crosslinking and reinforcing effect. Dinuithylpoly «iloxanharzes with a maximum of 1.2 mol.

709842/0468 " ⁹ "

Gi'V / vtWidur Rc; dit;.:. Diub:

Containing I / r \ ^r -Si3.ikonkautiJc1i \ uc - Zvoikompommtcmf oriMmassen (LTV silicone elastomer C). . . .

The preferred for drug mix-kütof Te with unsaturated LTV-Silioonelastomor C used in chemical structure consists of

I. 20 ~ 100 GeAV. Parts of an Organopcü-yHiloxane with a - .. viscosity of 500 ~ 200,000 cGt (at 25 ° C) and the general formula:. . · '' ·

. R.
ι R.
I. . R.
I. CH = CH CH r = CILSiO - - SiO - I.
, C-; _
I. I.
R. I.
R. R.

where R is an alkyl (preferably methyl) and / or Aryl radical, and η a whole number from 200 to l600 is,. ·.; ._-

II. Consisting of 0-50 parts by weight of an organopolysiloxane copolymer the end: . ".. -;

a) (R ') "SiO, .- units" "■ ···'. '

b) (R ¹ ) _o (vi) Si0 " _r units xuid · '·

c) SiO units,. · ·. ·

wherein R 'is monovalent organic _t Gruxipen no unsaturated radicals containing dai-sets and at least 50% of R ¹ are methyl radicals and the vrobei Vei-hültnifs

70984.2 / 0A68. ". ■ - 10«

OfM IS ";". Rr, ι ·· - λ / -λ

ο ^. - ■! 11. - ί "ι i ι ν -j"', ι ■ ν-; \

a-ib / c 0.4 - 1.5 (vorjsugini'Gxsö 0.6 - 1 _ν θ) and the ratio b / c 0.02 - 0.5 (preferably 0.05 - 0.15) amounts to. ... '-

III »5-15 Gev. ', - parts of an Oi-gajiohydi-ogcnpolysiloxniifj der a 11 κ is a formula .- · ■. '.. ".

R ^{1 f} II. SiO,

a b fl-a ~ b

where R '' represents a monovalent, non-unsaturated radical and the ratio of a: b has a value of 0.5-10 (preferably 1.0-5) and the sum of a + b equals 1 to 2, 5 and where there are at least three hydrogen atoms bonded to different Si atoms per molecule, the 50-500 Μο1 · -? - ο of the unsaturated groups contained in components I) and II). at. Contains Si-II bonds, and eijjor

IV. Catalytic amount of platinum or a pia tin. link.

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^709842/0468

QpI-IiZDiKι.- ·· / \. ^ Oi !! ..- fm Ve; /

The alkyl tuide / or Ary.1 rest-c contained in convonent I R contain up to & u 3.0 carbon atoms

For example, the methyll, ethyl, Propyl ™, iso-propyl, butyl, octyl ₁ tert-Amy.l-, cyclopontyl,
Cyclohexyl, phenyl, naphthyl · -, tolyl, xylyl ₄ Denzyl-, chlorophenyl, Cyanometbyl- and 3 _s 3, 3 ~ Tr ± £ luorproi ^ yl.

^{The radicals R 1} and R ″ contained in components I and II are identical or different and denote alkyl radicals with up to 8 carbon atoms, preferably with
up to 3 carbon atoms. Examples include methyl, ethyl and n-propyl,

The components I ₁ II and IV form a component of the LTV organopolysiloxane Zweilcoinponenten-Pox-iumasse, the
Part III the interlinking wirlcendo broad component

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709842/0468

■ 'SGHEMiNGAQ

The component X or the mixture of the * components I, II and IV or I, II, III and IV can be used for delayed curing at room temperature for metal ions, for example copper (II) ions, in an amount of 2 ₅ 6l to Contain 75 parts by weight of Metallioiien per part by weight of platinum.

Although the vulcanization of the Orgaiiopolyxloxanformmassen in the presence of the noble metal catalyst can also take place at room temperature, vulcanization at a slightly elevated temperature is particularly advantageous. The \ ^r ulkanisationszeit the catalyzed mixture is 1 to 6 hours at 6θ to 120 C. To the mixture may also be heated Anvulk'anisieren higher in the short term, for example up to 150 C for 1-10 minutes, but not more than 15 minutes.

The platinum component, component IV of the molding compound, can in itself be used in one of the known forms which catalyze the reaction between silic intimate water residues and silicon-bonded vinyl residues. Mention may be made of metallic platinum per se or platinum on carriers, such as silica gel or coble powder, or ilcxachloroplatinic acid and platinum salts, such as platinum carbonyl dichloride Pt CO Cl ₀ and platinum dicarbonyl dichloride Pt (CO) _n -Cl. All of these platinum compounds are used as a catalyst

709842/0468. "

SΓ ":" Ίfr, f / ■ - * r .-- \ Goytediltchoi- Utirfftsschtil.-:

., - IV < 2ö16üo4

useful. Pure Hoxachloroplatiiicäure has the disadvantage that it is poorly soluble in organocalcium compounds containing silane groups. Platinum compounds, which are used in solid form as catalysts, allow the decomposition process to be very slow and difficult to regulate run, just as the reaction as such can be more easily interrupted than is to be expected when using comparable catalysts in Lö / jung. Hexachloroplatinic acid is therefore preferably dissolved in isopropanol, Pt CO Cl ₂ and Pt (CO) ₂ Cl _{3 dissolved} in a vinyl group-containing diorgano-olysilo: _s containing 10 to 15 mol% vinyl groups, dissolved, used as a catalyst. At least O must be ₁ I parts by weight "platinum on 1 Mill. Parts by weight used by I and II. Because impurities can poison in the Forum Assen dera'rtig small amounts of catalyst are used preferably 10 to 'OK ppm platinum. Larger Platinmcngen not interfere with the reaction .

A special embodiment of the according to the invention ring consists in the fact that one is made for the support ring as well as for the arzned-agent-containing ring Plastic uses the same LTV silicone elastomer.

A special embodiment of the support ring rib used for the vaginal ring according to the invention is that the Support ring made from a foamed silicone rubber

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709842/0468

closed pores. II: i.erz, u denotes an agent in finely divided form into the vulcanizing mixture, such as carbon, hydrogen, like pentane or heptane and halogenated carbon, such as methyleneichloride, moleofluorodichloromethane , Trichlorofluorometal and triclilortrifluoroethane, which evaporates during the ulcanization.

The Vullcanizatc obtained from these OrganoiDolysiloxan-Ziieikompononten-Formiüassen are inactive against ionogenic lipophilic active pharmaceutical ingredients and are toxic to them . living organism _t-tolerated and are not absorbed by ihin.

The active ingredients contained in the drug-containing hinge - ». Η are preferably active ingredients with hormonal activity, such as, for example, estrogens and gestagens. Examples include 3-hatoxy-17a-ethinyl-1.3-5 (1 °) -estratriene-17-0I (Mesti-aiiol), 3-hydroxy-l. 3, 5 (10) -estratrien-17-one (estrone), 17ß-estradiol, estriol and ethinyl estradiol as well as 4-pregnen-3.20-dione (progesterone), d-13-ethyl-17a-ethinyl-17ß-hyclro> ry -4-gonen-3-one (d-norgestrel) and its ester, 17a-ethynyl-19-nortestosterone (norethisterone) and its ester, 6-chloro-17-hydroxy-la. 2a-me tliylen-pregna-4. 6-dien-3. 20-dione (cyproterone) and its esters, 19-nor »hydroxyprogestcron and its esters, 6-chloro-17-acetoxy-pregna- ^/ i.6 ~ diene-3.20-dione (chloriuiidinone acetate), Jan.

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7098A2 / 0A68

COP?

-Ό! 11.J-IiJVO. ΓW

Iiiitlic; Ri: dil: .stlu: t;

Methylene and 15.16i. \ - j-kitbylene-17β-hydroxy-lft-inotbyl-17 "- eth. Iiiyl-'j-8streii-3-cm, 17a-aceto :: ty-6a-nietbyl -pro £ eKteron (Medroxy-progestcj-onacetai.) and 9ß "lOo: -l ^{J regna-;} J. 6-dicn-3.20 dione (dydrogesterone).

All pharmaceuticals come in as ai-sci-drug active ingredients iufrage, solicit

they are n.non-ionogenic.uvnc'l lij ^ ophil. So- are too. ' Nenroleptika ific Butyrophenondcrivatc ,. Suitable for I -Ialoidcridol or "Dakterio- bsiwT" fiingistntica, like nystatin or Hetj.-onidaz-.ol, i ~ incorporation in the silicone elastomer.

The amount incorporated in the LTV silicone class is 10-60 % and is individually dependent on the specific active ingredient or content. For example, the following total dosages may be mentioned:

Cypi-oterone acetate:. 200 to 1000 mg

• D-norgestrel: 100 to 500 mg

Ethinylöotradiol: 20 to 100 mg

Estradiol:. '"20 to 90 mg

Mestranol: '. 50 to 100 mg

Athinylnortestostcronacetat: 1. ^ 0 to 950 mg

Oestrone :. 10 to ÖO mg

Estriol:. 15 to? 0 mg

70.88.42 / 0468 - ¹⁵ * "

wrlO-illM-C? /\O

Progesterone: 250 to 900 mg ""

Norethii; teron:. 100 to 600 mg

Cypx-otcron: '100 to 900 mg

Noi-hydroxyprogestcron: 250 to 950 mg

Chlormadine acetate: 170 to 850 mg 15th lCxx-Mothylen- and 15 elfiB-l-fctliylen-iy ^ -liydroiry-lB- "

inothyl ~ 17o: -äthinyl- ^/ i-ö.stren-3-oii: '50 to 750 mg

Dehydration:. 100 to 550 mg

Motronidazole: 300 to 950 mg

So it is easily possible that the outer ring only a progestin, while the inner ring contains an estrogen or the other way around. Progestins or estrogens can 2..B. combined be applied with bactericides. '

The total amount of active ingredient in the LTV silicone elastomer is eo measured that over the desired period of time a certain constant amount delivered per day wx3rd. These are in individual for example: ',

- .. Cyproterone acetate: 300 to 1000 ig / d

D. norgestrel: 30 to 25Ο μg / d

Athinylösti-adiol: 30 to 60 fig / d

Estradiol: 20 to 150 ig / d

Hestraa.'ol: '20 to "100 (tg / d

Athinylnortestosterone acetate: 300 to 1000 ig / d.

709842/0468

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. . 2516064

An embodiment of the erfiiulmi'j ;;; according to ■ {.n. Vng: inalr.uigos consists in tlaß diosor for ICoiiacptiov.;: Vc3 .-) iü r.ung oln ^ or.rty.t becomes. A green contraceptive effect! to.i? er Ολί;!;. t ± uii: i ~ hcminung is achieved in the applicationiizoitrrnua dos cv-Cxinungri ^ cinäßon vaginal rings, if this l> cif,} -. ic.l..svicii-o properly between 130 and 250 μg d-Norgostrel _uml 'jO to 50 ; tr; Athinyl-Ö £ 5ti-adiol or BOO and 1000 pg Cypro tero.ua ce tat and 30 and 50 ug ethinyl estradiol releases. -Vaginalrin ^ e, the. in the inner or outer rings containing active substances With - !: cl against. Protozoa such as meti-onidazole and possibly oestrogens, are particularly suitable for the treatment of trichoinoninrine. The active pharmaceutical ingredient is incorporated into the LTV silicone rubber base for the manufacture of the drug-containing ring. For this purpose the active ingredient is x.urkleinert or finely ground, possibly mikonisiert mixed with an LTV _r ~ 5iliconkäutschuk two-component mass to a bubble-free Suqiennion, formed into rings and overheat Εχ-through, at vorzugsi.'eise ^l k0 - 120 ° C, vulcanized.

The drug active substance-containing rings have in the case of the outer ring mm a diameter of 0.5 to B ₁ O, preferably up to 5) 0 1.5 mm, and in the case of the inner ring mm a diameter of 0.3 to 2.0, preferably 0, 4 to 1.6 mm.

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709842/0468 COPY

(λι .- .. 'l! blicht:! 1

i-cill. ·; · (.-! ΐ! (ν

The v; ir) is 1 ο ff 11 a 1 ti j ¹ ; on Hinge. <; ind f,; ms odei "tc-.i.Iv.'c: i.« * · na dom Matrixpriir ^ ip built The "Wix-ki ^ tof fh.-iltigcu Jtingci can r.lier micli from a v / lrkctof flialtigou grain and oir / o low-active ingredient outer jox-on silicone olciütoinerhüllc order bcliobigor layer thickness oclojr tungekelirt. au /; one of. oincr <i iiuittelivirksto l '£ ~ Eli \ r, toincrschiclit-uiiirgcimnun and cimy.n

Kernctück Tjo.tüoIjci? .. A Bolchci

arz; noini: LttelA \ ^r ir3ci. »torrcirine shell over ciincin to drug

active ingredient enriched. If the active ingredient is predominantly suiipeijcliar, one obtains, for example, the extraction of the medicinal product / waterl / l

- The cirzneimittelwirkstoffhaltigen rings gegobcoien- into the bag-shaped A ^r ertiefungen of Supportringc "o5.ngclcgt, '"

- if necessary, with the aid of catalyzed I / TV silicone kuutnchuk two-component debt collection and subsequently ex- vulcanization glued on one side into the depressions of the support ring or onto the vulcanized support rings are formed and assembled with the .Support ring vulcanized.

The support ring - the drug-active ingredient-containing outer and / or inner ring form, joined together or glued, the real one. Vaginal ring.

■ fc

To produce the drug- active ingredient-containing coating on the protective ring, the active ingredient is also incorporated into the LTV silicone rubber base. For this purpose, the material

709842/0468 - eat -

GOF /

finely ground, gj; f. mihroin u: iert, i: r; .t cinci- LTV-Siliconkautr.clmk · - Zweikoiup »> mintcni! iau. ^r ; o υλχ oinor suspension mixed, with the use of the chrome color. '.

It can also Kvcckniä / iig soin that KunGt · '■' suspension with a Hilfsötoff such as surfactant ^ AntiscUaum- .. 'medium, Soluhilisator and or Kcsorptionsverzögcrei- to ver - set "'" · "j to the molding govünschtc physical to give Eigonschr.ftc. Furthermore lconur.cn. but also inert JJiIf s ~ ■ materials, such as colloidal silica, infaragc that give the ring the desired mechanical properties.

In the case of vulcanization on the outer edge of the suction portion, the medicament-containing coatings have a layer thickness of 0.1 to 5.0 mm, preferably 0.5 to 3.0 mm, and in the case of vulcanization, the inner edge of the support ring a layer thickness of 0.1 to 3.0 mm, preferably 0.5 to 2.0 mm.. ·. '..

The active ingredient-containing coatings are wholly or partially after the Matrixpi ~ in.zip built up.

Since the vulcanization of the LTV - silicone rubber two-. Components that no by-products are formed a subsequent heat treatment of the hardened product superfluous.

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709842/0468

COPY

f || I | / _h r:

The Vaginalri.Dge according to the invention have the a'ortoil that the active pharmaceutical ingredients from them for a longer period of time Zeitj.-aum within the limits of the desired biological Wii'kuijg, e.g. Dosionuig necessary for ovul ationsheinuumg, delivered regularly and consistently "ϊΐ-cx-den. You have in addition, the advantage that the amount of active ingredient, incorporated into a single such contraceptive must have been, can be much gex-inger than with the known vaginal rings. - "*"

The inventive vaginal rings based on LTV-Siliconclastonior do not crumble with mechanical

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709842 / 04.68

Su ϋ · Ι <ii \ IG / v3

Gbwim 1j 11L ΐ ι L- r lic

Stress * They are not so easy when introduced into the body κ, ι damage vie vagina irin «; c on the basis of UTV-131as tomer on, the more or less defined mixtures of nktiA'cr l'iillstoffc with the brownish disadvantageous properties Medicinal products for the improvement of mechanical properties.

With your invention according to the vaginal ring, many medicinal products can be used f e success λ-eich hasty et ^ t verdcn that with • the previously known and customary carrier materials were not to be used in the well-known Vag.InaIringon.

The vaginal glands that can be produced according to the invention are fully saturated, geüpaiintem V7asserd «-: unpf at 120 C ntoril :! «: Ί crlmr, without experiencing unonmiiachtc changes.

The following examples are intended to explain the invention.

7098A2 / OAB8 '- 20 ..

" ³ COPY

SCHERING AG

Intellectual property law - MT-

Beis piel 1

A support ring intended to accommodate two drug-containing pendants was produced as a tubular ring (see FIG. 6) from polyamide / vinyl acetate copolymer (LUPOLEN ^V - ^y V 3520 K / DASP) with the following dimensions: 60 mm Outside diameter, kk mm inside diameter and now 3 diameter of the cavity in the ring cross-section. The support ring is provided with two circumferential sack-shaped depressions, which are intended to receive an outer and inner ring containing active ingredients. The drug-containing outer ring has a diameter of 2.0 mm, the drug-containing inner ring has a diameter of 1.0 ram. The vaginal ring has the active ingredients after it has been inserted. In the insertion plane, the ring cross-section had a diameter of 8.5

The drug-containing outer ring with a diameter of 2.0 mm is made from a suspension of 5 parts by weight D-norgestrel, 15 parts by weight of hydrophobized, highly dispersed silicon dioxide (AEROSIL'R972 / DEGUSSA) and 8 parts by weight of finely powdered magnesium oxide in 72 parts by weight of LTV organopolysiloxane two-component molding compound A formed by heating for 1½ minutes

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709842/0468

SCHERHMG AG

Intellectual Property-

vulcanized to 120 C and vulcanized by heating to 8O C for 3 hours. The LTV organopolysiloxane two-component form A consists of 75 parts by weight of a polydiraethylsiloxane that is vinyl-terminated on both sides and has a viscosity of 50,000 cSt at 25 ° C, 25 parts by weight of a copolymer with the composition: 40 mol% SiO _o units, k $ mol% (CH) -SiO units, 15 MoI-Ji

Vi (CH) SiO units, 8 parts by weight of a SiII- j> ti. U, ρ

Component consisting of: 16.6 mol-? 4 (CH) SiO units,

jj ^υ t j

33.4 mol% (CH 2) SiO units, 50 mol% 6 CH HSiO units j " j

and 52 ppm of platinum in the form of a 1% solution of Pt (CO) ₀ Cl based on the proportion of dimethylpolysiloxane with vinyl end-stopping).

The drug-containing inner ring is made of a homogeneous suspension of 3 parts by weight of ethinyl estradiol and 26 parts by weight of hydrophobized, highly dispersed silicon dioxide (AEROSIL®fc972 / DEGUSSA) in 71 parts by weight LTV organopolysiloxane two-component molding compound D by means of molded, vulcanized for 1 l / 2 minutes at approx. 120 ° C and vulcanized for two hours at 10 ° C. the LTV organopolysiloxah two-component molding compound B consists from 82.5 parts by weight of a double-sided vinyl end-stopped

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709842/0463

SCHERIN ¹ G AG

_ op _ commercial training

Polydimethylsiloxanes with a viscosity of 1000 cSt at 25 ° C., 15 parts by weight of a copolymer of the composition: 40 mol% SiO units, 45 mol% (CH,), SxO _n _-. Units, 15 MoI-Ji Vi (CH) SiO. Units, 7.0 parts by weight of an SiH component consisting of: 30 mol% SiO-

Ut

Units, 29 mol% (CH) SiO _n units, 33 mol%

(CII.) _O HSi0 "units and kO ppm platinum in the form of a 3 2 0.5

2% solution of H PtCl / - in isopropanol (based on the proportion of polydimethylsiloxane that is vinyl-terminated on both sides).

The drug-containing rings are placed in the support ring inserted and are part of the vaginal ring with this.

Example 2

From dimethylpolysiloxane molding compound (SILASTIC ^ 4600 / DOW CORNING), by molding, vulcanizing for 5 minutes at 150 C and vulcanizing for 1 hour at 120 C, tubing material with a diameter of 9 is now at 5 nim width, which has a sack-shaped depression of 1, 5 mm. Sections of this hose material are formed into hollow rubber rings (see FIG. 6) as support rings using catalyzed SILASTIC ^ 4600 and then through

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709842/0488

SCHERiMG AG

Intellectual Property

Vulcanized to I3O C for 30 minutes. The support rings have a diameter of 60 mm and an inner diameter of ^; 12 mm and a sack-shaped recess running around the outer edge for receiving a drug-containing ring with a diameter of 2 mm. This D-norgestrel-containing outer ring is produced from the molding compound indicated in Example 1 as indicated there and inserted into the support ring.

Example 3

A vaginal ring containing D-norgestrel is made in a three-step process as composite vulcanizate of a support ring the D-norgestrel-containing ring component produced (cf. Fig. 5). The support ring of this vaginal ring is made in a sandwich injection molding process with circumferential notch made of polyisobutylene with an average molecular weight of approx. 2,700,000 (OPPANOL®B 150 / BASF) as a core and LTV silicone rubber two-component composition B (as in example 1

20 parts by weight described) in a mixture with / hydrophobized, highly dispersible

persem silicon dioxide (AEROSIL ^ ÜO ^ / DEGUSSA) as the outer layer shaped. The dimensions of the support ring are:

62 mm outside diameter, Wh mm inside diameter, circumferential

709842/0468

SCHERIMG AG

Intellectual Property

Notch for receiving the outer ring containing D-norgestrel:.! mm deep, 3 ^inches wide.

The D-norgestrel containing Kingkoiiiponeiito is ixus described in Beisijiol 1 l ^f ARMM; xsn, fi by injecting into the circumferential Kerbiuig of Supportringess formed and by subsequently Anvulkaiiisioren during 1.2 minutes bui 115 C, and subsequent curing for 2 hours at 110 C connected to dor outer layer of the support ring, this ring component has a part-circular cross-section and the outer edge of a au liölbungsradius of 120 mm.

Example 4

A vaginal ring containing D-norgestrel and ethyl-estradiol is used as a composite canisate with a kidney-shaped cross-section (see Fig. 1) in the multi-color injection molding technique manufactured. The ring has an outside diameter of 60 mm. The distances a and b are 7 »6 and 2.8 mm, respectively. To be on the support ring component one after the other on the outer edge the D-norgestrel- and ethinylestradiol-containing components are sprayed on by heating at II5 C for 2 minutes

709842/0468

SCHERiKG AQ

Intellectual Property

vulcanized, defornit and outside the porin Vulcanized to 80 C for 2 hours.

The support ring component is made from a mixture of 23 Parts by weight of highly dispersed silicon dioxide (AEROSIL ~ K972 / DEGUSSA) and 77 parts by weight of the LTV silicone rubber two-component kinases described in Example 1.

The D-norgestrel-containing ring component with a diameter of 2 mm stands out in the shape of a section of a circle from the outer edge of the support ring. It consists of a mixture of 2k parts by weight of highly dispersed silicon dioxide, 8 parts by weight of micronized D-norgestrel and 68 parts by weight of catalyzed LTV silicone elastomer base (SILOPREiI ^ 3008 / BAYER).

The ring component containing ethinyl estradiol with a diameter of 1 mm stands out 0.4 mm in the shape of a circular segment Outer edge of the support ring. It contains 10 parts by weight of micronized ethinyl estradiol in 100 parts by weight and 21 parts by weight of highly disperse silicon dioxide in addition to 69 parts by weight of LTV organopolysiloxane molding compound Consists of 75 parts by weight of a polydimethylsiloxane with a viscosity of 1000, which is vinyl-terminated on both sides cSt at 25 C, 25 parts by weight of a copolymer of

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709842/0468

Commercial RecatSEcfiuis

Composition: 4O mol-? 6 SiO units, 45 mol-? I

id

) SiO ,, ₀ --Einheiten, 15 mole% Vi (CH _) _"r SiO_ units, 8 parts by weight of an Si-H-Koraponsnte consisting of 16.6 mol% (CH _) _ _r SiO. - units, 33.4 mol -? * (CH "> SiO units, 50.0 mol ~? I CH HSiO units and 10 ppm platinum (based on the total mixture in the form of a 2% solution of H PtCl / - in isopropanol).

Example 5

A ethinyl estradiol next Athinylnortestosteronacetat containing vaginal ring is used as a mechanical bond one of ethylene \ ^r inylacetat-Copolynierisat · (ALATHON® 3180 / DU PONT) as a hollow profile ring with circumferential at the outside edge notches made Support ring with two matching in the notches drug active substance-containing band rings on LTV silicone elastomer base (see. Fig. 3) produced.

The support ring is made from hollow profile sections by welding the ends with an outer diameter of 64 ram and inner diameter of 44 mm, web and wall thicknesses of 1.5 mm with one each on the outer edge Imtn deep and 3 mm wide and 1 mm deep and 1 mm wide with a circumferential notch. The ethynyl norestosterone acetate-containing ring

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7G98A2 / 0468

SCi-ERINQ AO

Commercial

component is 1 mm thick and 3 min wide with a clear width of 62 mm from a mixture of 10 parts by weight of microiiized ÄthinylnortGstosteroiiacetafc and 22 parts by weight of highly dispersed silicon dioxide in 68 parts by weight of an LTV organopolysiloxane two-component molding compound consisting of 75 parts by weight of a both sides vinyl-Polydiniethylsiloxans a viscosity of 1000 cSt at 25 ° C, 25 Gov. parts of a copolymer having the composition: hQ MoI Jo SiO units, h5 mol% (CH) SiO _n. units, 15 mol-% Vi ( CII_) _o Si0_ units, 8 parts by weight of a Si-H component ordering of 16.6 mol% (CH) SiO units, 33 mol% ^l t (CH) SiO units, 50.0 mol% of CH HSiO units and 30 ppm of platinum (based on the total mixture in the form of a 1% solution of Pt (CO) Cl in an open-chain dimethylpolysiloxane containing vinyl groups, containing 12 mol - '/ i vinyl groups dissolved) and 5 parts by weight, based on the parts by weight of platinum , Cu (II) ions g eformed and then vulcanized at 105 C.

The ring component containing ethynylate radiol becomes 1 mm strong and 1 mm wide with a clear width of 5 ° " formed from the mass described in the example '± and

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709842/0468

SOHERiNG m

Commercial rechiaichuiz

vulcanized by heating to 00 C.

Example 6

A vaginal ring containing 15, 16a-methyl-17ß-hydroxy-18-methyl-17a-ithinyl-4-estren-3-one nr.boii estriol
has the following structure:

A massive soft £, uiiimiririg on Basic by N.-iturkautschvik with an outer diameter of 36 mm and a diameter of 6.6 now ; Riiig cross-section is used as an insert and in the
Injection molding process encased with a 1.2 mm thick LTV-SiJ llror.-gumiiiisehicht (see Fig. 7) . 0, f5 uini
deep notches of 1.6 or 3 _% 0 mm width on «This ring is slipport ring for two drug-containing substances
Rings with a circular cross-section, which are mechanically connected with iln-i. The sheathing of the soft guium ringes is carried out with the LTV organo}) oleosiloxane two-component mold A described in Example 1 and vulcanization at 130.degree.

The 10 parts by weight of micronized 15, 16a-methylcn-17β ~ hydroxy-18-niethyl-17Ä ~ äthinyl-'t-esti'en-3-one. containing

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709842/0468

SCHERING AQ

Commercial college

/ring

Vaginal component is now based on tendon length with 3 »O a mixture consisting of 20 parts by weight of highly disperse silicon dioxide (AEROSIL ^ 200) and 70 parts by weight of the two-component LTV silicone rubber described in Example 1 se B made. The vaginal ring component containing estriol with a circular segment Cross-section and a chord length of 1.6 mm is made from a mixture of 12 god.-Bearings micronizedera Estriol, 19 parts by weight of fumed silica and 69 parts by weight of the two-part LTV silicone rubber composition described above B produced by molding and vulcanizing at 90 ° C. for 3 hours.

Example 7

A vaginal ring containing D-norgestrel and ethynylestradiol provides a composite vulcanizate of support ring and two containing the active pharmaceutical ingredients separately, the support ring is partially encased by components (see. ..Fig. 7) · The core of the slipport ring is made of rubber-like Polyurethane as a full ring with a notch on the outer edge that is 1.5 mm deep and 3 mm wide and with an outer diameter of 60 mm and a ring

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709842/0488

lutlüvCi / Av;

tM ^ Jibücher Peth-SbdwU

portringkci-n

diameter of 8 mis, made. This supp is obtained by repeated immersion in a solution the catalyzed LTV silicone rubber - two-component mass B (see example 3.) in methylene chloride and Vulcanizing of the coating for 2 minutes at 125 ° C and 1 hour vulcanization at I30 C with a 1.5 ™ » thick cover.

The notch of this support ring, which functions as an insert in the injection molding, is used in the process of the multi-color injection molding with the k in example. D-norgestrel-containing compound described and vulcanized for 1 l / 2 minutes at 110 C. In the center of this tape containing D-Korgestrel around the outer edge of the vaginal ring, a round tube with a diameter of 1 mm is sprayed from the molding compound containing ethinyl estradiol from Example 1 and vulcanized at 110 ° C. for 2 minutes. The prefabricated vaginal ring is vulcanized by heating it to 110 C for one hour.

Example 8

D-norgestrel-containing vagina.!. Rings are used of the support ring described in Example 7 by vulcanization the D-norgestrel described in Example 1

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709842/0488

SCHERE AG

χι-

containing molding compound into the SupportriiigV.c-rbe represents (see. Fig. 7).

iel 9

A D-Noi-gestrol and ethinyl estradiol contains; *! tender vaginal ring becomes a. ··; Suppoz'tringes with an ellipsoidal cross-section (cf. Fig. 9 "a - 2 mm, b = 3" 5 now) and 5iwei on the outer corner at a distance of 1. } mm circumferential depressions of 0.8 or 0.8 mm. 1. k mm boi a width of the notch of 1.0 or 2.0 run; with the ring with a circular section-shaped cross-section that fits into these notches and contains one active pharmaceutical ingredient. The support ring is injection-molded from ethylene-vinyl acetate copolymer (ALATHON® 3185 / DU PONT). The D-Norgestrel

containing ring component is formed from the composition given in ßebeispiel 1 and vulcanized for ^{90 minutes at Ii 1 OC.}

The atinylostradiol-containing Ringkornponeri Io is from the Shaped mass specified in Example 1 and heated by heating vulcanized to IO5 C.

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709842/0468

Ho if; ρ i ο 1 .10

A Ί- Pregneii ~ 3 · 2O-d; i on (progesterone) containing.-r vaginal ring v.'ird alii Verbumivulkanisnt a supportrin * · ^; . ^r : r.'iit on the outer edge uulaufondej · Kti'bo, into which the ! '{ingkoinpoiifintö containing the Prc-f ez tcro / i is vulcanized, hergosiellc. The Supportrin.fi is a hollow ring provided with an opening 2 mm wide on the inner edge (see Fig. 8). The Rii; t »; mm has a Aufiendux'chiuoi! £ or of fiO mm, Iiaicndurchii.osfier of kZ and in cross section an internal diameter of 3 tntn * The n \\ King the outer edge circumferential groove is l _t 5 Him deep "and now wide.

The support ring is made from a mixture of 20 parts by weight highly dispersed silicon uradioxide and 80 geiv. -Share LTV — silicone rubber two-grain]) onGiitenasse U, its composition given in Example 1, molded at 120.degree

one

vulcanized. Diesel ¹ support ring Λν-ird is used in the second process stage like an insert wedge, into whose circumferential notch the molded mask containing progesterone is injected. This molding compound consists of 15 parts by weight inilcronized in progesterone and 20 parts by weight of hoclidisperse silicon dioxide in the LTV silicone rubber two-coraponite compound A (composition see example 1). After being injected into the hollow ring notch, it is heated to 90 ° C

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7 0 9 8 4 2/0468 ° * ^iGINAL

Et ... ,, ti! ve * / Λ \;:. ^:

vulcanized. The drug-containing ring is then heated to 80 C for 2 hours . 1 β lex * t.

The progest.eronha3.tige Ringkornponento des als Vei'buml- » Vulcanized present vaginal ring is made in a four-stage en-Tp with low active ingredient * shell on -active ingredient-rich core überex * Tühr. For this purpose, the vaginal ring is successively 10 minutes and 5 minutes in 90 °, 5 minutes 70% and 5 minutes Leave 50 tiger ethanol alcohol.

Example 13

A 17ct-Acetox3r-6a-methyl-progeste3 "on (Medroxyprogesteronacetat) containing vaginal ring is a mechanical composite of a support ring with circumferential on the outer edge Notch zixr inclusion of the medroxyprogesterone acetate Ring component manufactured (see. Fig. 10). The support ring is a hollow ring with an ellipsoidal cross-section, has a Outside diameter of 60mm, an inside diameter of 42mm, a wall thickness of 3 mm and is made from ethylene / vinyl acetate copolymer (ALATHON® 3185 / DU PONT) in the blow molding process formed with a notch of 1.5 mm deep and 2.5 "" wide on the outer edge.

709842/0468

- 3A--

The medroxyprogesterone acetate-containing component is separately from a mixture of 20 GeYi.-parts of niilcronisiGr Medroxyprogesterone acetate, 11 parts by weight Silicon dioxide and 69 parts by weight of LTV-Silikonkautsclmk-Zwoikomponentonmas.se B (composition see episode 3.) hosed down uiid vulcanized at 100 C.

Example 1 2

A vaginal ring containing 15.-16ß-methylene-17ß-hydroxy-18-methyl-17a-ethinyl-4-estren-3-one is used as a mechanical bond of a support ring which is open at the inner edge and which is designed as a hollow profile ring (see Fig k) is formed from polyethylene / vinyl acetate copolymer (LUPOLEN V 3520 K / BASF) with a circumferential notch on the outer edge of 2 mm width and 1 mm depth to accommodate the drug-containing band ring. The support ring is made from hollow profile sections by welding the ends with an outer diameter of 62 mm, an inner diameter of k0 mm and has a web and wall thickness of 1.5 mm.

The drug-containing band ring is made from a Mixture of 8 parts by weight 15. 16β-llethylene-17β-hydroxy-

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709842/0468

Industrial protection

18-methyl-17a-et] iinyl-4-ustrcn-3 ~ ijn, 19 parts by weight highly disperse silicon dioxide and 73 parts of LTV silicon rubber wet B, whose affiliation is fiotzujit; for example 1 is indicated, shaped and heated up by 3 stiindigcs 90 C vulcanized.

709842/0468

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Claims (1)

WtbHsr iieclitsschuU Claim Further design of the vaginal ring according to patent application P 2k 50 107-3, characterized in that the support ring or the vaginal ring has a nierenföriaigen or ellipsoidal cross-section or that the support ring as a closed or inwardly open hollow profile ring or as a closed or inwardly open hollow ring or is designed as a hollow ring with a circular single or kidney-shaped cross-section or as a core-coated composite ring or as a sandwich body. - 37 - 709 8 42/0 468 ^{OR! GINAL} erected ORIGINAL INSPECTED Board of Directors: Dr. t'crbort Asmis - Dr. Christian Bruhn HansJüiijsn Hamann Postal address: SCMHRING AG D-1 Berlin 65 Poslftrii C5 0311 Dr. Heinz Hannsc Karl Otto Miltalsler.scheidDf.Horst Witzul PoElsehcck account: Grrl: n-Wesl 1175-101. Bnnfcleit7i, H 1C0 IQJ10 Chairman of the Aulsiriitsrat: Dr. Eduard v. SchivarUkoppcn Berliner Conimcr ^ baiil: AC3, Berlin. Account no. 103 / 001r?;. Bankieit /. _t iil 1Cß-! viü0 SiU of the company: Btrlin and Dergkamen Berliner Discunto-rJ.-v !: AG, Berlin. Kanto no ^^ / 'V.'.?. Pnnkleitz number 1.W; «ü0 Handolsrefjister: AG Charlottenburg 93 ΗΠΒ2Β3 and AG Kamen MRU00G1 Berliner Handc-I ^ -Co ^ -Ilscliali - rrankfjrtor Bank · -, Berlin. Konlo-Nr.1-1 -3ο3. ElJiiklcil number 10023200