Europaisches Patentamt 19 European Patent Office

Office europeen des brevets © Publication number: 0 500 793 B1

EUROPEAN PATENT SPECIFICATION

@ Date of publication of patent specification © int. ci.5: A61K 9/22, A61K 31/565 03.11.93 Bulletin 93/44

© Application number : 91900649.4

© Date of filing : 12.11.90

© International application number : PCT/US90/06588

@ International publication number : WO 91/07173 30.05.91 Gazette 91/12

@ OSMOTIC, ORAL DOSAGE FORM FOR FERTILITY CONTROL.

© Priority: 16.11.89 US 437480 @ Inventor : WRIGHT, Jeri, Dawn 11732 Betlen Drive Dublin, CA 94568 (US) @ Date of publication of application Inventor : CHILDERS, Jerry, D. 02.09.92 Bulletin 92/36 1259 Ayala Drive, 2 Sunnyvale, CA 94086 (US) (45) Publication of the grant of the patent : Inventor : BARCLAY, Brian, L. 03.11.93 Bulletin 93/44 887 Lois Ave. Sunnyvale, CA 94087 (US) Inventor : WONG, Patrick, S.-L. @ Designated Contracting States : 2030 Cornell Street AT BE CH DE DK ES FR GB GR IT LI LU NL SE Palo Alto, CA 94306 (US) Inventor : ATKINSON, Linda, E. 191 Lucero Way © References cited : Portola Valley, CA 94025 (US) EP-A- 0 232 877 GB-A- 2 010 676 GB-A- 2 189 995 © Representative : Evans, David Charles et al GR-A- 2 371 224 F.J. CLEVELAND & COMPANY 40-43, US-A- 4 327 725 Chancery Lane US-A- 4 372 951 London, WC2A 1JQ (GB) US-A- 4 948 593

© Proprietor : ALZA CORPORATION 950 Page Mill Road P.O. Box 10950 CO Palo Alto California 94303-0802 (US) CO o> h- o o If) Note : Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been LU filed until the opposition fee has been paid (Art. 99(1) European patent convention).

Jouve, 18, rue Saint-Denis, 75001 PARIS 1 EP 0 500 793 B1 2

Description art. Another object of the present invention is to pro- This invention pertains to an osmotic oral dosage vide a dosage form for co-administering an form useful for fertility control. The dosage form pro- and a in a pulsed dose followed by the vides an initial pulsed delivery of a progestogen and 5 rate-controlled delivery of an estrogen over a pro- an estrogen followed by a prolonged delivery of an es- longed period of time for fertility control in a warm- trogen. blooded female. A continuous need exists for fertility control for Another object of the invention is to provide a providing freedom for women to chose when they pharmaceutical^ acceptable dosage form manufac- want to have children. Efforts were made, in the early 10 tured as an osmotic dosage form that makes avail- 1 960's, to satisfy the need for fertility control with the able initially an estrogen and a progestogen followed introduction of the comprising by sustained and controlled delivery of an estrogen. an estrogenic and a progestational steroid. Another object of the invention is to provide a The contraceptive pill used by the prior art comprises novel dosage form manufactured as an osmotic de- a form that delivers the in a bulk, non- ls vice that can administer the steroids estrogen and rate, uncontrolled dose. In one prior art contraceptive progestogen immediately on entering the gastrointes- regimen, a tablet comprising both an estrogen and a tinal tract for passage to a biological receptor site to progestin are administered for about three weeks, produce the desired contraceptive effect, followed by while in another modification a tablet comprising an administering estrogen only to the biological receptor estrogen is administered for about two weeks and a 20 site for the intended effect. tablet comprising an estrogen and progestin are ad- Another object of the invention is to provide an ministered for about a week. The contraceptive ster- osmotic dosage form that comprises two regimens of oids were delivered as an oral tablet devoid of rate- steroid administration in the same dosage form, com- controlled delivery properties because the contra- prising (1) a first regimen that administers a steroid ceptive steroids are practically insoluble in aqueous 25 pair comprising an estrogen and a progestogen and fluids and, accordingly, they do not lend themselves (2) a second regimen that administers an estrogen, for manufacture into a dosage form that administers and wherein the osmotic dosage form substantially the steroids at a controlled and known rate per unit eliminates the unwanted influences of the gastroin- time. testinal environment on the steroids while they reside The contraceptive steroids, moreover, were deliv- 30 in the dosage form, and also provides for instant ad- ered by the prior art in a dose unprotected from the ministration of the steroid by the first regimen and the changing environment of the , controlled, low-dose administration or the steroid dur- with little consideration forthe steroid's pharmacolog- ing the second regimen. ical and physiological effects and the accompanying Another object of the invention is to provide an disadvantages on a recipient. For example, one dis- 35 osmotic dosage form that can delivera progestational advantage associated with the prior art tablet accom- steroid at a pulsed rate of delivery for substantially panies the dose-dumping of estrogen which can lead lessening of the steroid. to gastrointestinal disturbances, , weight-gain, Another object of the invention is to provide an , and an increase in the incidence of thrombo- osmotic dosage form that can deliver an estrogen phelibitis and associated cardiovascular disorders. 40 steroid in small amounts for substantially lessening Also, the prior art tablet does not provide for the fast the incidence of side effects. release of a progestational steroid for avoiding liver Another object of the present invention is to pro- metabolism of the steroid and the subsequent deliv- vide an osmotic dosage form that can deliver a sub- ery of an estrogen in small continuous doses for less- stantially aqueous insoluble estrogen and progesto- ening the incidence of side effects in the recipient. 45 gen pair ata pulsed rate, and then deliver an aqueous The oral contraceptives are disclosed in The Pharma- insoluble estrogen at a controlled and continuous rate cological Basis of Therapeutics, by Goodman and Gil- over time. man, 7th Ed., pages 1430 to 1439 (1985), published Another object of the present invention is to pro- by Macmillian Publishing Company. vide an osmotic dosage form adapted for oral admin- 50 istration of an estrogen and a progestogen, which DISCLOSURE OF OBJECTS OF THE INVENTION dosage form comprises an external pulse released coat comprising an estrogen and a progestogen, and Accordingly, in view of the above presentation, it a compartment comprising a first composition com- is an immediate object of this invention to provide a prising an estrogen and a contacting second expand- dosage form comprising an estrogen and a progesto- 55 able composition, which compositions operate to- gen that can be administered for fertility control, and getherforthe controlled administration of an estrogen which dosage form substantially overcomes the dis- over time. advantages and omissions associated with the prior Another object of the present invention is to pro- 2 3 EP 0 500 793 B1 4 vide a complete oral contraceptive regimen useful for bers. The terms appearing earlier in the specification women of childbearing age which regimen comprises and in the description of the drawing figures, as well an osmotic dosage form and a method of contracep- as embodiments thereof, are further detailed else- tion, the use of which osmotic dosage form and meth- where in the disclosure. od of contraception requires intervention only for ini- 5 tiation of the contraceptive regimen. DETAILED DISCLOSURE OF THE DRAWING Another object of the invention is to provide a FIGURES composition of matter comprising an estrogen, a pro- gestogen and a cellulose , which composition Turning now to the drawing figures in detail, can be externally stored on and dispensed from an os- 10 which drawing figures are examples of the dosage motic device for the purpose of fertility control. form provided by this invention, and which examples Another object of the invention is to provide a are not to be construed as limiting the invention, one contraceptive regimen comprising eighteen to twen- example of the dosage form is illustrated in drawing ty-three dosage forms, which dosage forms deliver a figure 1 and designed by the numeral 10. In drawing pulsed dose of a progestational and estrogenic ster- 15 figure 1, dosage form 10 comprises a body 11 sized, oid followed by a continuous dose of an estrogenic shaped and adapted for into the steroid. gastrointestinal tract of a human. Dosage form 10 Other objects, features, and advantages of the comprises at least one orifice 14 that connects the in- invention will be more apparent to those skilled in the side with the outside of dosage form 10. dispensing arts from the following detailed specifica- 20 In drawing figure 2, dosage form 10 is seen in tion, taken in conjunction with the drawing figures and opened view through 2-2 of drawing figure 1 . In draw- the accompanying claims. ing figure 2, dosage form 10 is manufactured as an osmotic device. The osmotic dosage form 10 com- BRIEF DISCLOSURE OF THE DRAWINGS prises a body 11 . a wall 12, which surrounds and de- 25 fines an internal compartment 1 3. Wall 1 2 comprises In the drawing figures, which are not drawn to at least one exit means 14 that connects internal com- scale but are set-forth to illustrate various embodi- partment 13 with the exterior of dosage form 10. Dos- ments of the invention, the drawing figures are as fol- age form 10 can comprise more than one exit means lows: 14. Wall 12 of dosage form 10 comprises in at least a Drawing figure 1 is a view of a single surface 30 part a semipermeable composition that is permeable of a dosage form adapted and shaped for orally ad- to the passage of an exterior fluid present in the en- ministering a contraceptive pair of steroids followed vironment of use. The composition comprising wall 1 2 by administering a single steroid to the gastrointesti- is substantially inert, and it maintains its physical and nal tract of a warm-blooded female; chemical integrity during the dispensing life of contra- Drawing figure 2 is an opened view of the dos- 35 ceptive steroids from osmotic dosage form 10. The age form of drawing figure 1 through 2-2, wherein phrase, "keeps its physical and chemical integrity," drawing figure 2 depicts the wall of the dosage form means wall 12 does not lose its structure and it does carrying on its exterior surface an aqueous-fluid re- not change chemically during the contraceptive dis- leasable coat comprising an estrogen and a proges- pensing life of dosage form 10. togen pair, or a progestogen, with the compartment 40 Wall 12, in a presently preferred embodiment, of the dosage form comprising an estrogen; comprises a cellulosic polymer composition. The cel- Drawing figure 3 is an opened view of the dos- lulosic polymer comprises a member selected from age form of drawing figure 1 through 2-2 wherein the group consisting of a cellulose , cellulose drawing figure 3 depicts another embodiment com- ether, cellulose ester-ether, cellulose acylate, cellu- prising a pair of steroids releasably carried in the wall 45 lose diacylate, cellulose triacylate, cellulose , of the dosage form; cellulose diacetate and cellulose triacetate. The cel- Drawing figure 4 depicts the release rate of a lulosic comprise a degree of substitution, progestin from an exterior release overcoat on the D.S., on the anhydroglucose unit from greater than O dosage form; up to 3, inclusive. By degree of substitution is meant Drawing figure 5 depicts the quick release of so the average number of hydroxyl groups originally an estrogen from a composition coated onto the ex- present on the anhydroglucose unit comprising the terior surface of the dosage form; and cellulose polymer that are replaced by a substituting Drawing figure 6 depicts the release rate of an group. Exemplary polymers comprise cellulose acet- estrogen from an exterior overcoat and from the inter- ate having a D.S. up to 1 and an acetyl content up to nal compartment of a dosage form over a prolonged 55 21%; cellulose acetate having an acetyl content of period up to eighteen hours. 32% to 39.8%; cellulose diacetate having a D.S. of 1 In the drawings and in the specification, like parts to 2 and an acetyl content of 21% to 35%; cellulose in related drawing figures are identified by like num- triacetate having a D.S. of 2 to 3 and an acetyl content 3 5 EP 0 500 793 B1 6 of 35% to 44.8%, and the like. Other examples com- form 10. prise cellulose propionate having a D.S. of 1 .8, a prop- The contraceptive estrogen steroids possessing content of 39.2% to 45% and a hydroxyl content estrogenic activity present in first layer 1 5 that can be of 2.8% to 5.4%; cellulose acetate butyrate having a dispensed from compartment by dosage form 1 0 to a D.S. of 1 .8, an acetyl content of 1 3% to 1 5% and a bu- 5 warm-blooded female recipient comprise estrogen tyryl content of 34% to 39%; cellulose acetate butyr- steroids 17 represented by dots. The estrogen active ate having an acetyl content of 2% to 29%, a butyryl steroids comprise a member selected from the group content of 1 7% to 53% and a hydroxyl content of 0.5% consisting of , , estradiol to 4.7%; cellulose triacylates having a D.S. of 2.9 to benzoate, , estradiol propionate, 3 such as cellulose trivalerate, cellulose trilaurate, cel- 10 , , ethinyl es- lulose tripalmitate, cellulose trisuccinate, and cellu- tradiol, 17a-ethinyl estradiol , 17a-ethinyl es- lose trioctanoate; cellulose diacylates having a D.S. of tradiol acetate, 17a-ethinyl , 17a- 2.2 to 2.6 such as cellulose disuccinate, cellulose di- ethinyl estradiol ethers, , , es- palmitate, cellulose dioctanoate, cellulose dipentale, trone sulfate, , and estriol -tri- and the like. Additional cellulose polymers that may 15 acetate. Generally, compartment 1 3 comprises about be present in wall 12 comprise ethyl cellulose com- 0.005 milligrams to 0.750 milligrams of an estrogeni- prising an ethoxy group degree of substitution of 1.5 cally-active, fertility-regulating pharmaceutical^ ac- to 3, about 40% to 50% ethoxy content, and a viscos- ceptable steroid, which estrogenic steroid is delivered ity range of 7 to 1 00 centipoises, or higher; a cellulose in small amounts from 0.2 micrograms to 30 micro- ether selected from the group consisting of hydroxy- 20 grams per hour for 8 to 24 nours and usually for 12 to propylcellulose, hydroxypropylmethylcellulose and 24 hours. hydroxyethylcellulose, and the like. In one preferred Estrogenic steroid 17 present in compartment 13 manufacture wall 12 comprises 100 weight percent is present in a composition, wherein estrogenic ster- (wt%) of a cellulosic polymer as disclosed above; in oid 17 is blended with a pharmaceutical^ acceptable another preferred manufacture wall 12 comprises 25 carrier, which carrier comprises from 20 mg to 300 mg from 60 weight percent to 90 weight percent of a mem- of a polyethylene oxide comprising a 50,000 to ber selected from the group consisting of a cellulose 350,000 horizontal molecular weight and identified as acylate, cellulose diacylate and cellulose triacylate horizontal dashes 18, and from 0.05 mg to 75 mg of polymer, from 1 5 to 45 weight percent of an ethyl cel- a polyvinyl pyrrolidone comprising a 8,000 to 65,000 lulose and from 0 to 25 weight percent of a polyethy- 30 molecular weight as identified by slanted dashes 1 9, lene glycol with the total amount of all wall- and from 0 to 8 mg of a lubricant identified by the letter components comprising wall 12 equal to 100 weight Vwith the accompanying number 20 such as magne- percent; and another embodiment comprising 45 to sium stearate, calcium stearate, or the 80 weight percent of a member selected from the like. group consisting of a cellulose acylate, cellulose dia- 35 Second layer 16 comprises, in a presently prefer- cylate and cellulose triacylate, from 15 to 45 weight red embodiment, comprises 20 mg to 300 mg of a percent of an ethyl cellulose, from 0.5 to 25 weight polyethylene oxide comprising a 4,000,000 to percent of a cellulose ether selected from the group 7,500,000 molecular weight as identified by wavy consisting of hydroxypropylcellulose, hydroxyethyl- lines 21 , from 1 mg to 50 mg of an osmotically active cellulose, and hydroxypropylmethylcellulose, and 40 compound such as a member selected from the group from 0 weight percent to 30 weight percent of poly- consisting of sodium chloride, potassium chloride, ethylene glycol, with the total amount of all compo- and the like, as identified by circles 22, from 0.05 mg nents comprising wall 12 equal to 1 00 weight percent. to 35 mg of a hydroxypropylmethylcellulose exhibiting The cellulosic polymers are known in U.S. Pat. Nos. a molecular weight of 9,200 to 30,000 and identified 3,133,132; 3,845,770; 3,916,899 and 4,160,000; and 45 by triangles 23, from 0 mg to 1 00 mg of an acrylic car- in the Handbook of Common Polymers by Scott, J. R. boxyl polymer comprising a molecular weight of and Roff W. J., (1971) published by CRC Press Cleve- 1 ,250,000 to 4,000,000 and identified by squares 24, land, Ohio. and from 0 mg 7.5 mg of a lubricant such as magne- Internal compartment 13 comprises a first- sium stearate, calcium stearate, stearic acid, and the compositional layer 15 and a second-compositional so like, as identified by oval 25. Second layer 16 option- layer 16. The first layer 15 can.be defined optionally ally comprises from 0.10 mg to 5 mg of ferric oxide as a first composition 15, and the second layer 16 and optionally from 0.001 mg to 3 mg of FD & C blue also can be defined optionally as a second composi- lake#1. tion 16. The first layer 15 and the second layer 16 ini- Dosage form 10, as seen in drawing figure 2, tially are in laminar arrangement and they cooperate 55 comprises an exterior coat. Coat 26 is on the exterior with each other and with dosage form 10 for deliver- surface of semipermeable wall 1 2. Coat 26 comprises ing contraceptively effective dose amounts of a con- a composition represented by dots 27, which compo- traceptive estrogen from compartment 13 of dosage sition 27 comprises an estrogenic steroid and a pro- 4 7 EP 0 500 793 B1 8 gestational steroid pair. Composition 27 also compris- oxime, estriol and D-13p-ethyl-17a-ethinyl-17p-hy- es a pharmaceutical^ acceptable steroid carrier se- droxygon-4-en-3-one, estriol succinate and 3-keto- lected from the group consisting of a hydroxypropyl- desogestrel, and desogestrel, estra- methylcellulose, a hydroxypropylethylcellulose, a hy- diol cypionate and gestodene, estradiol benzoate and droxypropylcellulose or a hydroxyethylmethylcellu- 5 medroxyprogesterone acetate, estradiol dipropionate lose and, optionally, a polyethylene glycol, or an op- and , and the like. Coat 26 also tional polyvinyl pyrrolidone, for providing instantly the comprises from 0.15 mg to 100 mg of a member se- release of the contraceptive steroid pair from coat 26 lected from the group consisting of hydroxypropylme- to a female receptor. Coat 26, in operation in the gas- thylcellulose, hydroxypropylethylcellulose, hydroxy- trointestinal tract, dissolves or undergoes dissolution 10 propylcellulose and hydroxyethylmethylcellulose and concurrently therewith delivers the steroids. wherein the cellulose member comprises a 9,000 to Coat 26 comprises at least one of the estrogenic ster- 50,000 molecular weight, from 0 to 50 mg of a poly- oids disclosed earlier in this specification. Coat 26 by ethylene glycol and from 0 to 75 mg of a polyvinylpyr- immediately delivering an estrogenic steroids pro- rolidone comprising a 8,500 to 45,000 molecular vides immediate fertility control, and thereby essen- 15 weight. Coat 26, in operation in gastrointestinal fluid, tially overcomes the time required by dosage form 10 begins to release contraceptive steroid instantly, that to deliver an estrogenic steroid from compartment 1 5. is, when the fluid contacts coat 26. Coat 26 instantly Dosage form 1 0 needs a start-up time for imbibing an releases the steroid pair in from zero to 60 minutes, exterior fluid through wall 12 into compartment 15 to usually from zero to 30 minutes, for immediate pas- activate second layer 16 causing it to expand, push 20 sage of the steroid pair into the systemic circulation and displace the first layer through port 14. of a recipient. Delivery system 10 in another embodi- Coat 26 comprises at least one progestational ment optionally comprises a color overcoat of 0.01 to steroid that is released as a single dose for lessening 1 0 mg of a commercially available blue colorant. Also, metabolism by the liver. Contraceptive steroids pos- delivery system 10 can alternately be encompassed sessing progestational activity present in coat 26 25 with an outer taste-mask preferably consisting of 0 to comprise a member selected from the group consist- 10 mg of a hydroxypropylmethylcellulose. ing of , d-norgestrel, norethindrone, lev- Coat 26 unexpectedly comprises and delivers onorgestrel, norgestimate, , norethis- both an estrogenic and a progestogenic steroid in a terone acetate, norethynodrel, norethindrone acet- deliverable composition for their concomitant contra- ate, 17-hydroxyprogesterone, 17-hydroxyprogester- 30 ceptive effect. It is unexpected and unforeseen that one esters, 19-nor-17-hydroxyprogesterone, 19-nor- an estrogenic steroid and a different progestogenic 17 hydroxyprogesterone esters, 17a-ethinyl-testos- steroid can be coated together and delivered simul- terone, 17a-ethinyl-19-nortestosterone, D-17p-acet- taneously in a contraceptive dose amount. This is so oxy-13p-ethyl-17a-ethinyl-gon-4-en-3-one oxime, d- as estrogenic and the progestogenic steroids each 13p-ethyl- 17a-ethinyl-17p-hydroxygon-4-en-3-one, 35 possess different coating properties, different dis- 13p-ethyl-17p-hydroxygon-4-en-3-one, 13p,17a-die- pensing kinetics, different physical properties, differ- thyl-17p-hydroxygon-4-en-3 one, ethylnodiol diace- ent molecular structure substituents, different solubil- tate, medroxyprogesterone, chlormadione acetate, ities, and different concentrations in the coat. The es- d imet h istrone , 1 7a-et h i nyl- 1 7p-acetoxy- 1 9-noran- trogenic and the progestogenic steroids are present drost-4-en-3-one oxime, 3-keto-desogestrel, deso- 40 in the exterior coat substantially-free of interaction, gestrel, gestodene, gestodene acetate, medroxypro- and they are available for immediate use for their si- gesterone acetate and megestrol, medroxyprogester- multaneous contraceptive effect. one acetate and megestrol acetate, ethinyl estradiol Drawing figure 3 depicts another embodiment and gestodene, ethinyl estradiol and desogestrel, and provided by the invention. In drawing figure 3, dosage the like. 45 form 10 is seen in opened section, and it comprises Coat 26 provides immediate delivery of the con- a wall 12 that surrounds internal compartment 13, traceptive steroid pair for quicker plasma steroid lev- with at least one exit means 14 through wall 12. In- els. Coat 26 generally comprises 10 nanogram to 25 ternal compartment 13 comprises layer 15 compris- milligrams of an estrogen and from 15 nanograms to ing an estrogenic steroid 1 7, a polyethylene oxide 1 8, 150 mg of a progestational steroid. Representative so an optional polyvinylpyrrolidone 19, an optional anti- steroid pairs present in coat 26 are exemplified by oxidant, 28, such as butylated hydroxy toluene or bu- ethinyl estradiol and norethindrone, ethinyl estradiol tylated hydroxyanisole, and a lubricant 20. Internal and norgestrel, ethinyl estradiol and norethisterone, compartment 13 also comprises a second layer 16, ethinyl estradiol and , ethinyl estradiol which layer 16 comprises a polyethylene oxide 21, an and norgestimate, estradiol valerite and levonorges- 55 osmagent 22, a hydroxypropylmethylcellulose 23, an trel, estrone and norethindrone, estradiol propionate optional acrylic carboxyl polymer 24, and a lubricant and ethinyl-19-nortestosterone, estriol and acetoxy- 25. Wall 12 in dosage form 10 in this embodiment 1 3p-et hyl- 1 7a-et h inyl-1 7p-hydroxygon-4-en-3-one comprises steroid composition 27, which steroid com- 5 g EP 0 500 793 B1 10 position is leached by fluid of the gastrointestinal tract ic solvent are mixed into a solid or a semisolid state, from wall 12 in zero to 60 minutes. by conventional methods such as ballmilling, calen- The expression, "exit means 14," as used herein, dering, stirring or rollmilling, and then pressed into a comprises means and methods suitable for the con- preselected layer forming shape. Next, a layer of a trolled metered release of estrogenic steroid from 5 composition comprising an osmopolymer and an op- compartment 13 of dosage form 10. Exit means 14 is tional osmagent are placed in contact with the layer sized and adapted for the metered release of estro- comprising the beneficial estrogenic contraceptive genic steroid from dosage form 10. Exit means 14 in- steroid, and the two layers comprising the compart- cludes at least one passageway, orifice, or the like, ment are surrounded with a semipermeable wall. The through wall 12 for communicating with the contra- 10 layering of the first beneficial controlling estrogenic ceptive steroids dosage in compartment 1 3 of dosage steroid composition and the second osmopolymer form 10. The expression, "at least one passageway," composition can be accomplished by using a two-lay- includes aperture, orifice, bore, pore, porous ele- er tablet press. The wall can be applied by molding, ment, and the like, through which the contraceptive spraying or dipping the pressed shapes into wall steroids can migrate, a hollow fiber, capillary tube, 15 forming compositions. Another preferred technique porous overlay, porous insert, composite semi- that can be used for applying wall 12 is the air sus- permeable contacting microporous insert, or the like. pension coating procedure. This procedure compris- The expression includes also a material that erodes es suspending and tumbling the two layered compo- or is a material that is leached from wall 12 in a fluid sitions in a current of air until the wall-forming com- environment of use to produce at least one passage- 20 position surrounds the layers. The exterior instant re- way in wall 12. Representative materials suitable for lease coat comprising the contraceptive steroid also forming at least one passageway, or a multiplicity of can be formed by using the air technique. passageways, include an erodible polyglycolic acid, The air suspension procedure is well suited for inde- or a polylactic acid member in wall 1 2, a gelatinous fi- pendently forming a wall or an exterior quick-release lament, polyvinyl, alcohol, a leachable material such 25 coat. The air suspension procedure is described in as a fluid removable pore forming polysaccharide, U.S. Pat. No. 2,799,241 ; in J.Am. Pharm. Assoc., Vol. polyol, salts, oxide, or the like. A passageway, or a 48, pp 451-59, (1959); and ibid, Vol. 49, pp 82-84, plurality of passageways can be formed by leaching (1 960). Dosage forming systems 1 0 also can be coat- a material su:h as sorbitol, fructose, maltose, lactose, ed with the wall-forming compositions with a Wur- orthe like, from wall 12. The passageway 14 can have 30 ster® Air Suspension Coater or an Aeromatic® Air any shape such as round, triangular, square, elliptical, Suspension Coater can be used for applying the wall and the like, for assisting in the metered release of or the exterior coat. Other wall and coating techni- the contraceptive steroids from dosage form 1 0. Dos- ques such as pan coating can be used for manufac- age form 1 0 can be constructed with one or more pas- turing the dosage form. In the pan coating system sageway in spaced apart relation, or more than one 35 wall forming or coat forming compositions are depos- passageway on a single surface of dosage form 10. ited by successive spraying of the ingredients around Passageways and equipment for forming passage- the contraceptive steroid accompanied by tumbling in ways are disclosed in Patent Nos. a rotating pan. A pan coater is used to produce a thick- 3,845,770 issued 11/74 to Theeuwes et al; 4,063,064 er wall or a coat. A larger volume of solvent can be issued 12/77 to Saunders etal; and 4,088,864 issued 40 used in a cosolvent system to produce a thinner wall 5/78 to Theeuwes et al. Passageways in osmotic sys- or a coat. Finally, the wall or the coated devices are tems formed by leaching are disclosed in United dried in a forced air oven to free the dosage form of States Patent Nos. 4,200,098 issued 4/80 to Ayer et any solvents. Generally, the wall formed by these al; 4,285,987 issued 8/81 to Ayer et al; 4,309,996 is- techniques will have a preferred thickness of 1 to 25 sued 1/82 to Theeuwes; and 4,320,759 issued 3/82 to 45 mils (0.03 to 0.64 mm) with a presently preferred Theeuwes. thickness of 3 to 10 mils (0.08 to 0.26 mm), and the Dosage form 10 of the present invention is man- exterior coat generally will have a thickness of 0.3 to ufactured by standard techniques. For example, in 8 mils (0.008 to 0.20 mm). Of course, thicker walls are one embodiment a beneficial contraceptive estrogen- encompassed by the invention. Other manufacturing ic steroid is mixed with the pharmaceutical^ accept- so procedures are described in Modern Plastic Encyclo- able osmopolymer that acts as a carrier for the con- pedia, Vol. 46, pp 62-70, (1969); and in Pharmaceut- traceptive estrogenic steroid, and with other compo- ical Sciences, by Remington, 14th Ed., pp 1626- sition forming ingredients and then pressed into a sol- 1978, (1970), published by Mack Publishing Co., id layer possessing dimensions that correspond to Easton, PA. the internal dimensions of the compartment space 55 The osmotically effective compounds, which are adjacent to the passageway. In another manufacture, known also as osmagents, as osmotically effective the beneficial estrogenic contraceptive steroid and solutes, and as osmotic enhancers, useful forthe pur- other composition forming ingredients and a non-tox- pose of this invention, comprise a member selected 6 11 EP 0 500 793 B1 12 from the group consisting of water soluble inorganic screen, dried at room temperature for 16 hours and osmagents and water soluble organic osmagents. passed again through a 20 mesh screen. Finally, 2.5 The osmagents include a member selected from the g of magnesium stearate is added to the granulation group consisting of magnesium sulfate, magnesium and all the ingredients mixed in a rollermill for 1 to 3 chloride, sodium chloride, potassium chloride, lithium 5 minutes. sulfate, lithium chloride, potassium sulfate, choline The second composition is prepared by mixing chloride, and the like. The osmotically effective com- 370.0 g of polyethylene oxide having a molecular pounds are known in United States Pat. No. weight of 4,000,000 with 1 00 g of sodium chloride and 4,177,256 and 4,449,983. the homogeneous blend passed through a 40 mesh Exemplary solvents suitable for manufacturing 10 screen. Then, the just prepared polyethylene oxide, the wall include inert inorganic and organic solvents sodium chloride blend is mixed with 25.0 g of hydrox- t hat do not adversely harm t he materials and t he final ypropylmethylcellulose, having a number average wall. The solvents broadly include a member selected molecular weight of 1 1 ,200, and with 2.5 g of nontoxic from the group consisting of aqueous solvents select- FD & C blue lake #1 for 10 minutes in a mixer. Then, ed from the group consisting of aqueous solvents, al- 15 350 ml of denatured, anhydrous ethanol is added cohols, ketones, esters, ethers, aliphatic hydrocar- slowly to the blending mixture and all the ingredients bons, halogenated solvents, cycloaliphatics, aromat- mixed for an additional 5 minutes. The freshly pre- ics, heterocyclic solvents, and mixtures thereof. Typ- pared wet granulation is passed through a 20 mesh ical solvents include acetone, diacetone alcohol, me- screen, allowed to dry at room temperature for 16 thanol, ethanol, isopropyl alcohol, butyl alcohol, me- 20 hours, and again passed through a 20 mesh screen. thyl acetate, ethyl acetate, isopropyl acetate, n-butyl The screened granulation is mixed with 2.5 g of mag- acetate, methyl isobutyl ketone, methyl propyl ke- nesium stearate in a rollermill for 1 minute. tone, n-hexane, n-heptane, ethylene glycol monoe- A two-layered press is used for forming the thyl ether, ethylene glycol monoethyl acetate, methy- layered arrangement. First, 30 mg of the first compo- lene dichloride, ethylene dichloride, propylene di- 25 sition comprising the contraceptive ethinyl estradiol chloride, water, acetone and water, acetone and me- steroid is added to the press and tamped; then 30 mg thanol, acetone and ethyl alcohol, methylene dichlor- of the second layer forming composition is added to ide and methanol, ethylene dichloride and methanol, the press and the two layers pressed into a contact- and the like. ing layered arrangement. 30 Next, the layers are surrounded with a semi- DETAILED DISCLOSURE OF EXAMPLES OF THE permeable wall. The wall forming composition com- INVENTION prises 70% cellulose acetate, having an acetyl con- tent of 39.8%, 28% ethylcellulose, and 2% polyethy- The following examples are merely illustrative of lene glycol having a molecular weight of 3350. The the present invention and they should not be consid- 35 wall forming composition is dissolved in acetone:wa- ered as limiting the scope of the invention in anyway, ter (90: 1 0 wt:wt) solvent to make a 4% solids solution. as these examples and other equivalents thereof will The wall forming composition is sprayed onto and become apparent to those versed in the art in the light around this bilaminate in an Aeromatic® Air Suspen- of the present disclosure, the drawings and the ac- sion Coater. companying claims. 40 The wall coated bilaminates are dried for 24 hours at room temperature. Then, a 25 mil (0.635 mm) exit EXAMPLE 1 orifice is laser drilled on the contraceptive layer side of the osmotic device. The residual solvent is re- An osmotic dosage form adapted, designed and moved by drying the osmotic system for 48 hours at shaped for delivering contraceptive steroids is manu- 45 50°C and 50% relative humidity. The osmotic sys- factured as follows: first, a contraceptive composition tems are then dried for one hour at 50°C to remove is prepared by passing through a 40 mesh screen the excess moisture. The osmotic systems are over- 456.95 g of polyethylene oxide having a molecular coated on the exterior surface on the semipermeable weight of about 100,000. Then, 40 g of polyvinyl pyr- wall. The overcoat comprises 16% norethindrone rolidone comprising a number average molecular 50 (0.400 mg) and 0.28% ethinyl estradiol (0.007 mg). weight of about 38,000, is added to the polyethylene The steroid pair are dissolved in a solution comprising oxide and the two ingredients mixed for about 1 0 min- 83.72% hydroxypropylcellulose and denatured alco- utes in a conventional mixer. While the two ingre- hol to make a 4% solution. The drug overcoat compo- dients are mixing, a freshly prepared solution of 0.55 sition is sprayed onto and around the laser drilled de- g of ethinyl estradiol dissolved in 250 ml of denatured 55 livery system in an Aeromatic® Air Suspension Coat- anhydrous ethanol is slowly added to the mixer and er. the mixing continued for an additional 10 minutes. Finally, the osmotic systems are given a color The wet granulation is passed through a 20 mesh overcoat consisting of commercially available Opa- 7 13 EP 0 500 793 B1 14 dry® blue, a hydroxypropylmethylcellulose, mixed tradiol rate of release of 2.158 ng/hr from the com- with denatured alcohol:water (90:10 volume:volume) partment, and an exterior coat comprising 0.28% ethi- to make a 5% solution. The color composition is nyl estradiol, 16% norethindrone and 83.72% hydrox- sprayed onto and around the drilled delivery system ypropylcellulose that are released in from zero to 30 in an Aeromatic® Air Suspension Coater. The residual 5 minutes when the steroid-coat is contacted by an ex- solvent is removed by drying for 16 hours at 35°C to ternal fluid. yield the operative osmotic dosage forms. Accompa- nying figure 4 depicts the norethindrone release pat- EXAMPLE 4 tern from the exterior overcoat; accompanying figure 5 depicts the ethinyl estradiol release pattern from 10 The procedure of Example 1 is followed in this ex- the exterior overcoat; and, accompanying figure 6 de- ample to prepare an osmotic dosage form comprising picts the release rate per hour for ethinyl estradiol re- a first, displaceable composition comprising 0.036 mg leased from the exterior overcoat and the compart- of estradiol cypionate, 28.314 mg of polyethylene ox- ment of the dosage form over time. ide, having a 200,000 molecular weight, 1-5 mg of 15 polyvinyl pyrrolidone, and 0.15 mg of magnesium EXAMPLE 2 stearate; a second composition comprising 22.05 mg of polyethylene oxide, having a 4,000,000 molecular The procedure of example 1 is followed in this ex- weight, 6.0 mg of sodium chloride 1-5 mg of hydrox- ample, with all conditions as previously described, ex- ypropylmethylcellulose, having a 11,200 molecular cept for a color overcoat tnat is made as described in 20 weight, 0.30 mg of pharmaceutical^ acceptable blue this example. The osmotic system is given a color dye, and 0.15 mg of magnesium stearate; a wall com- overcoat to enhance its aesthetic appearance. In one prising 5.70 mg of cellulose acetate having a 43.5% manufacture the osmotic systems are coated with a acetyl content, and 0.30 mg of polyethylene glycol; an composition comprising 38.4 g of hydroxypropylme- orifice having a diameter of 20 mils (0.52 mm); and a thylcellulose and 4.27 g of polyethylene glycol 3350 25 releasable exterior coat comprising estradiol cypion- to produce a clear overcoat. In another manufacture ate and levonorgestrel. the osmotic systems are coated with a composition comprising 21 .87 g (10% by wt) of hydroxypropylme- EXAMPLE 5 thylcellulose having a 11,200 molecular weight, 2.46 g (10% by wt) of polyethylene glycol having a 3350 30 An osmotic dosage form comprising means for molecular weight and 0.25 g (1.0% by wt) of FD & C the immediate administration of a progestogenic ster- blue lake #1 dye to produce a blue overcoat. In an op- oid and an estrogenic steroid from an external com- tional manufacture the color overcoat can comprise position, followed by the twenty-four hour administra- hydroxypropylmethyl cellulose and diethyl tion of an estrogenic contraceptive, is prepared ac- mixed with denatured alcohol water (90:10 vol- 35 cording to Example 1. In this example a steroid over- ume:volume) to make a 5% solution. The color com- coat comprising 3.703 g of norethindrone, 0.065 g of position is sprayed onto and around the drilled deliv- ethinyl estradiol and 38.4 g of hydroxypropylmethyl- ery system in an Aeromatic® Air Suspension Coater. cellulose and 4.27 g of polyethylene glycol are dis- The residual solvent is removed by drying for 1 6 hours solved in denatured, anhydrous ethanol and distilled at 25°C to yield the operative osmotic dosage form. 40 water (11 :2 v:v) and sprayed onto the exterior surface of the semipermeable wall, in an Aeromatic® Air Sus- EXAMPLE 3 pension Coater. Immediately following a sealer coat comprising 21.87 g of hydroxypropylmethylcellulose, Following the procedure of Example 1 , an osmot- 2.46 g of polyethylene glycol and 0.25 g of FD & C ic dosage form is prepared comprising a first compo- 45 blue lake #1 dissolved in denatured anhydrous alco- sition which composition comprises 0.033 mg of ethi- hol and distilled water (90:10 v:v) solvent, to make a nyl estradiol, 27.417 mg of polyethylene oxide having 5% solids solution, is sprayed onto the norethindrone a 100,000 molecular weight, 2.4 mg of polyvinyl povi- ethinyl estradiol overcoat. The osmotic systems are done having a molecular weight of 38,000, and 0.15 dried for 16 hours at 35°C to remove residual solvent. mg of magnesium stearate; a second composition 50 The final concentration of the norethindrone in the comprising 22.2 mg of polyethylene oxide having a exterior composition is 0.400 mg, and the final con- 5,000,000 molecular weight, 6 mg of sodium chloride, centration of ethinyl estradiol in the exterior compo- 1-5 mg of a hydroxypropylmethylcellulose having a sition is 0.007 mg. The interior compartment contains 11,200 molecular weight, 0.15 mg of blue dye and the single steroid ethinyl estradiol in a concentration 0.15 mg of magnesium stearate; a semipermeable 55 of 0.033 mg. The total concentration of ethinyl estra- wall comprising 6.65 mg of cellulose acetate, having diol comprising the exterior and the interior compart- a 43.5% acetyl content, and 0.35 mg of polyethylene ment is 0.04 mg. glycol; an orifice diameter of 0.52 mm; and ethinyl es- 8 15 EP 0 500 793 B1 16

EXAMPLE 6 17a-ethinyl-gon-4-en-3-one oxime blended with hy- droxypropylcellulose and hydroxypropylmethylcellu- An osmotic dosage form comprising means for lose. immediately administering an estrogenic steroid and An osmotic dosage form is prepared wherein the a progestogenic steroid from an external composition, 5 external composition comprises 1.5 mg of 13p-ethyl- followed by prolonged administration of an estrogenic 17a-ethinyl-17p-hydroxygon-4-en-3-one, 0.05 mg of contraceptive steroid, is prepared according to Exam- ethinyl estradiol, blended with hydroxypropylcellu- ple 1. In this example, a steroid overcoat comprising lose and hydroxypropylethylcellulose. 0.065 g of estradiol dipropionate, 3.703 g of norethy- nodrel and 4.26 g of Opadry, a hydroxypropylcellu- 10 EXAMPLES 10 lose nontoxic carrier, are dissolved in denatured alco- hol :water (90:20 v:v) and sprayed onto the outer sur- A contraceptive dosage form for oral administra- face of the wall of the osmotic system. Then, a seal tion to a female recipient desiring contraception is pre- coat composition comprising Opadry blue and Opa- pared by following the above procedures. In this ex- dry clear, (3:1 wt:wt), dissolved in denatured alcohol 15 ample the dosage form provided is as follows: a first (90:10 v:v) cosolvent to make a 5% solid solution is contraceptive composition weighing 30 mg and com- sprayed onto the osmotic system comprising estra- prising 0.11 wt% ethinyl estradiol, 94.39 wt% poly- diol dipropionate in the compartment. The osmotic ethylene oxide possessing a 100,000 molecular systems are dried for 16 hours at 35°C to remove the weight, 5 wt% hydroxypropylmethylcellulose pos- residual solvent. The final concentration of the ster- 20 sessing a 11,200 molecular weight, and 0.5 mg of oids in the exterior composition is 0.007 mg of estra- magnesium stearate; a second push composition for diol dipropionate and 0.400 mg of norethynodrel. The applying a force against the first composition for Opadry blue composition comprises hydroxypropyl- pushing it from the dosage form, wherein the second methylcellulose, polyethylene glycol and FD & C blue composition weighs 30 mg and comprises 74 wt% of lake #1. The Opadry clear comprises hydroxypropyl- 25 a polyethylene glycol possessing a 7,500,000 molec- methylcellulose and polyethylene glycol. ular weight, 20 wt% of sodium chloride, 5 wt% of hy- droxypropylmethylcellulose possessing a 11,200 mo- EXAMPLE 7 lecular weight, 0.5 Wt% of FD & C blue like #1 dye, and 0.5 wt% of magnesium stearate. The dosage Following the procedure in Example 1, an osmot- 30 form comprises a semipermeable wall weighing 7.00 ic device is manufactured comprising an external mg, which wall comprises 95 wt% of a cellulose acet- quick release composition comprising estradiol and ate comprising a 43.5% acetyl content and 5 wt% of norgestrel for delivering 0.005 mg of the ethinyl estra- polyethylene glycol possessing a 3350 molecular diol and 0.50 mg of the d,l-norgestrel, an internal first weight. An instant steroid release overcoat is in con- composition comprising 0.035 mg of ethinyl estradiol, 35 tact with the exterior surface of the semipermeable 84.75 weight percent polyethylene oxide having a wall, which instant overcoat comprises 0.70 wt% ethi- 200,000 molecular weight, 10 weight percent hydrox- nyl estradiol, 1.47 wt% norethindrone, 90 wt% hy- ypropylmethylcellulose, having a number average droxypropylmethylcellulose possessing a 11,200 mo- molecular weight of 11,200, and 0.25 weight percent lecular weight and 9.30 wt% of polyethylene glycol magnesium stearate: an internal second composition 40 possessing a 3350 molecular weight. In an optional comprising 64.75 weight percent polyethylene oxide, embodiment a second steroid-free overcoat on the having a 7,500,000 molecular weight, 24 weight per- outermost surface of the dosage form weighs 2.00 cent sodium chloride, 10 weight percent hydroxypro- mg and comprises 90 wt% hydroxypropylmethylcellu- pylmethylcellulose, having a 11,200 number average lose possessing a 11,200 molecular weight and 10 molecular weight, 1 weight percent ferric oxide and 45 wt% of polyethylene glycol possessing a 3350 molec- 0.25 weight percent magnesium stearate; and a sem- ular weight. The dosage form has an 0.52 mm exit ipermeable wall comprising 97 weight percent cellu- passageway. lose acetate having an acetyl content of 39.8% and 3 weight percent polyethylene glycol having a molecu- EXAMPLE 11 lar weight of 4000. The device comprises a 20 mil 50 (0.52 mm) exit orifice. Following the procedure of Example 1 , an osmot- ic dosage form is prepared comprising a first compo- EXAMPLES 8-9 sition consisting essentially of 0.039 mg of ethinyl es- tradiol, 28.31 mg of polyethylene oxide having a An osmotic dosage form is prepared by following 55 100,000 molecular weight, 1.5 mg of hydroxypropyl- the above described manufacturers. In this example, methylcellulose a 11,200 molecular weight, and 0.15 the external composition comprise 0.008 mg of ethi- mg of magnesium stearate; a second composition nyl estradiol, 0.50 mg of D-17p-acetoxy-13p-ethyl- comprising 22.2 mg of polyethylene oxide having a 9 17 EP 0 500 793 B1 18

5,000,000 molecular weight, 6 mg of sodium chloride, ered in a ratio that corresponds to their initial ratio I. 5 mg of a hydroxypropylmethylcellulose having a in the coat for fertility control. II, 200 molecular weight, 0.15 mg of blue dye and 0. 15 mg of magnesium stearate; a wall comprising 4. The osmotic device for delivering the contracep- 6.65 mg of cellulose acetate, having a 43.5% acetyl 5 tive steroids according to claim 1, wherein the content, and 0.35 mg of polyethylene glycol; an orifice dosage form delivers the estrogenic steroid from diameter of 2.0 mils (0.52 mm), and an ethinyl estra- the compartment in from 30 minutes to 24 hours. diol rate of release of 2.1 58 ng/hr, and an exterior aqu- eous releasable coat comprising 0.0825 mg of nore- 5. The osmotic device for delivering the contracep- thindrone and 0.008 mg of ethinyl estradiol. 10 tive steroids according to claim 1, wherein the dosage form continuously administers the estro- EXAMPLE 12 genic steroid by (a) the coat releasing its estro- genic steroid in from zero minutes to 1 hour, and A dosage form is prepared according to the pro- (b) the dosage form administering from the com- cedures of this example for providing a dosage form 15 partment its estrogenic steroid in from 30 minutes comprising a first composition comprising maltroder- to 24 hours. trin, hydroxypropylcellulose and an estrogenic ster- oid, and a second composition comprising sodium 6. The osmotic device for delivering the contracep- carboxymethyl cellulose. tive steroids according to claim 1 , wherein the es- 20 trogenic steroid in the exterior coat is a member selected from the group consisting of estradiol, Claims estradiol valerate, estradiol benzoate, estradiol cypionate, estradiol propionate, estradiol dipro- 1. An osmotic device for delivering contraceptive pionate, estradiol acetate, ethinyl estradiol, ethi- steroids, the osmotic device comprising: 25 nyl estradiol esters, ethinyl estradiol acetate, (a) a wall comprising at least in part a compo- ethinyl estradiol Lenzoate, ethinyl estradiol sition permeable to the passage of fluid, ethers, estrone, estrone acetate, estrone sulfate, which wall surrounds; estriol, estriol succinate and . (b) a compartment; (c) at least one exit passageway that connects 30 7. The osmotic device for delivering the contracep- the exterior of the device with the compart- tive steroids according to claim 1 , wherein the es- ment; trogenic steroid in the interior compartment is a (d) a first composition in the compartment, member selected from.the group consisting of es- said composition comprising a contraceptive- tradiol, estradiol valerate, estradiol benzoate, es- ly effective estrogenic steroid; 35 tradiol cypionate, estradiol propionate, estradiol (e) a second composition in the compartment, dipropionate, estradiol acetate, ethinyl estradiol, said second composition comprising an os- ethinyl estradiol esters, ethinyl estradiol acetate, mopolymer, which composition when the de- ethinyl estradiol benzoate, ethinyl estradiol vice is in operation in the presence of fluid ethers, estrone, estrone acetate, estrone sulfate, that enters the device, increases in dimen- 40 estriol, estriol succinate and estriol triacetate. sions and displaces the first composition through the passageway from the device; 8. The osmotic device for delivering the contracep- and, tive steroids according to claim 1, wherein the (f) a coat on the exterior of the wall, the coat progestogenic steroid in the exterior coat is a comprising a contraceptively effective 45 member selected from the group consisting of amount of an estrogenic steroid and a contra- progesterone, d,l-norgestrel, norethindrone, lev- ceptively effective amount of a progestogenic onorgestrel, norgestimate, 3-keto-desogestrel, steroid. desogestrel, gestodene, , norethynodrel, hydroxyprogesterone, hydroxy- 2. The osmotic device for delivering the contracep- 50 progesterone esters, 1 9-nor-hydroxyprogester- tive steroids according to claim 1, wherein the one, 19-nor-17-hydroxyprogesterone esters, coat when contacted by fluid releases immediate- 17a-ethinyl , 17a-ethinyl-19-nortes- ly the estrogenic steroid and the progestogenic tosterone, D- 1 7p-acetoxy-1 3p-et hyl- 1 7a-et h i- steroid as a contraceptive pair. nyl-gon-4-en-3-one oxime, d-13p-ethyl-17a- 55 ethinyl-17p-hydroxygon-4-en-3- one, 13p-ethyl- 3. The osmotic device for delivering the contracep- 17p-hydroxygon-4-en-3-one, 13p,17p-diethyl- tive steroids according to claim 1 , wherein the es- 17p-hydroxygon-4-en-3-one, ethynodiol diace- trogenic and the progestogenic steroids are deliv- tate, medroxyprogesterone, chlormadione acet- 10 19 EP 0 500 793 B1 20

ate, medroxyprogesterone acetate, megestrol 2. Osmotische Vorrichtung zur Abgabe der emp- acetate, dimethistrone, and 17a-ethinyl-17p- fangnisverhutenden Steroide nach Anspruch 1, acetoxy-1 9-norandrost-4-en-3-one oxime. worin die Beschichtung dann, wenn sie mit Flus- sigkeit in Kontakt kommt, sofort das Estrogen- 9. The osmotic device for delivering the contracep- 5 Steroid und das Gestagen-Steroid als empfang- tive steroids according to claim 1 , wherein the es- nisverhutendes Verbindungspaar freisetzt. trogenic and the progestogenic steroids in the ex- terior coat are selected from the group consisting 3. Osmotische Vorrichtung zur Abgabe der emp- of a contraceptive pair of ethinyl estradiol and fangnisverhutenden Steroide nach Anspruch 1, norethindrone; ethinyl estradiol and d,l-norges- 10 worin das Estrogen-Steroid und das Gestagen- trel; estrone and norethisterone; ethinyl estradiol Steroid in einem Mengenverhaltnis zur Gebur- and 3-keto-desogestrel; ethinyl estradiol and tenkontrolle abgegeben werden, das ihrem an- desogestrel; ethinyl estradiol and gestodene; fanglichen Verhaltnis in der Beschichtung ent- ethinyl estradiol and levonorgestrel; ethinyl es- spricht. tradiol and norgestimate; ethinyl estradiol and 15 17a-ethinyl-19-nortestosterone; ethinyl estradiol 4. Osmotische Vorrichtung zur Abgabe der emp- and 17a-ethinyl testosterone; ethinyl estradiol and fangnisverhutenden Steroide nach Anspruch 1, D-1 7p-acetoxy-1 3p-ethyl-1 7a-ethinyl-gon-4-en-3- worin die Dosisform das Estrogen-Steroid aus one oxime; ethinyl estradiol and d-13p-ethyl-17a- der Kammer in einer Zeit von 30 Minuten bis 24 ethinyl-17p-hydroxygon-4-en-3-one; ethinyl estra- 20 Stunden abgibt. diol and 13p-ethyl-17p-hydroxygon-4-en-3-one; ethinyl estradiol and 13p, 17a-diethyl-17p-hy- 5. Osmotische Vorrichtung zur Abgabe der emp- droxygon-4-en-3-one; and ethinyl estradiol and fangnisverhutenden Steroide nach Anspruch 1, 1 7a-et h i nyl- 1 7p-acetoxy- 1 9- nora nd rost-4-en-3- worin die Dosisform kontinuierlich das Estrogen- one oxime. 25 Steroid abgibt (a) uberdie Beschichtung, die das Estrogen- Steroid in 0 Minuten bis 1 Stunde freisetzt, Patentanspruche und (b) uberdie Dosisform, die das Estrogen-Ste- 1 . Osmotische Vorrichtung zur Abgabe empfangnis- 30 raid aus der Kammer in einer Zeit von 30 Mi- verhutender Steroide, wobei die osmotische Vor- nuten bis 24 Stunden verabreicht. richtung umfalit: (a) eine Wandung, die wenigstens teilweise 6. Osmotische Vorrichtung zur Abgabe der emp- eineZubereitung umfalit, die fur den Durchtritt fangnisverhutenden Steroide nach Anspruch von Flussigkeit durchlassig ist, wobei die 35 1, worin das Estrogen-Steroid in der Aulien- Wandung umgibt beschichtung eine Verbindung ist, die aus der (b) eine Kammer; aus Estradiol, Estradiolvalerat, Estradiolbenzoat, (c) wenigstens einen Austrittsdurchgang, der Estradiolcypionat, Estradiolpropionat, Estradiol- die Aulienumgebung der Vorrichtung mit der dipropionat, Estradiolacetat, , Kammer verbindet; 40 Ethinylestradiolester, Ethinylestradiolacetat, (d) eine erste Zubereitung in der Kammer, wo- Ethinylestradiolbenzoat, Ethinylestradiolether, bei diese Zubereitung ein empfangnisverhu- Estron, Estronacetat, Estronsulfat, Estriol, tend wirksames Estrogen-Steroid umfalit; Estriolsuccinat und Estrioltriacetat bestehenden (e) eine zweite Zubereitung in der Kammer, wo- Gruppe gewahlt ist. bei die zweite Zubereitung ein Osmopolymer 45 umfalit, wobei sich die Zubereitung dann, 7. Osmotische Vorrichtung zur Abgabe der emp- wenn die Vorrichtung in Gegenwart einer fangnisverhutenden Steroide nach Anspruch Flussigkeit, die in die Vorrichtung eintritt, in 1, worin das Estrogen-Steroid in der inneren Funktion ist, hinsichtlich ihrer Dimensionen Kammer eine Verbindung ist, die aus der aus ausweitet und die erste Zubereitung durch so Estradiol, Estradiolvalerat, Estradiolbenzoat, den Durchgang aus der Vorrichtung ver- Estradiolcypionat, Estradiolpropionat, Estradiol- drangt; und dipropionat, Estradiolacetat, Ethinylestradiol, (f) einen Uberzug auf der Aulienseite der Ethinylestradiolester, Ethinylestradiolacetat, Wandung, wobei der Uberzug eine empfang- Ethinylestradiolbenzoat, Ethinylestradiolether, nisverhutend wirksame Menge eines Estro- 55 Estron, Estronacetat, Estronsulfat, Estriol, gen-Steroids und eine empfangnisverhutend Estriolsuccinat und Estrioltriacetat bestehenden wirksame Menge eines Gestagen-Steroids Gruppe gewahlt ist. umfalit. 11 21 EP 0 500 793 B1 22

8. Osmotische Vorrichtung zur Abgabe der emp- roide oestrogenique a action contraceptive; fangnisverhutenden Steroide nach Anspruch 1, (e) une seconde composition dans le compar- worin das Gestagen-Steroid in der Aulienbe- timent, ladite seconde composition compre- schichtung eine Verbindung ist, die aus der aus nant un osmopolymere, laquelle composition Progesteron, d, 1-Norgestrel, Norethindron, 5 lorsque le dispositif fonctionne en presence Levonorgestrel, Norgestimat, 3-Ketodesogestrel, du fluide qui penetre dans le dispositif, voit Desogestrel, Gestoden, Norethisteronacetat, ses dimensions augmenter et deplace la pre- Norethynodrel, Hydroxyprogesteron, Hydroxypro- miere composition a travers le passage a par- gesteronester, 19-Norhydroxyprogesteron, 19- tirdu dispositif; et, Nor-1 7-hydroxyprogesteronester, 1 7a-Ethinylte- 10 (f) un revetement a I'exterieur de la paroi, le stosteron, 17a-Ethinyl-19-nortestosteron, D- revetement comprenant une quantite a action 1 7p-Acetoxy- 1 3p-et hyl- 1 7a-et hinyl-gon-4-en-3- contraceptive d'un steroide oestrogenique et on-oxim, d-13p-Ethyl-17a-ethinyl-17p-hydroxy- une quantite a action contraceptive d'un ste- gon-4-en-3-on, 1 3p-Ethyl-1 7p-hydroxygon-4-en- roide progestogenique. 3-on , 1 3p, 1 7p-Diet hyl- 1 7p-hydroxygon-4-en-3- 15 on, Ethynodioldiacetat, Medroxyprogesteron, 2. Dispositif osmotique pour administrer les steroT- Chlormadionacetat, Medroxyprogesteronacetat, des contraceptifs selon la revendication 1, dans Megestrolacetat, Dimethistron und 17a-Ethinyl- lequel le revetement lorsqu'il entre en contact 1 7p-acetoxy-1 9-norandrost-4-en-3-on-oxim be- avec le fluide libera immediatement le steroide stehenden Gruppe gewahlt ist. 20 oestrogenique et le steroide progestogenique comme paire contraceptive. 9. Osmotische Vorrichtung zur Abgabe der emp- fangnisverhutenden Steroide nach Anspruch 1, 3. Dispositif osmotique pour administrer les steroT- worin das Estrogen-Steroid und das Gestagen- des contraceptifs selon la revendication 1, dans Steroid in der Aulienbeschichtung gewahlt sind aus 25 lequel les steroTdes oestrogenique et progestoge- der Gruppe von Verbindungen, die aus einem nique sont administres selon un rapport qui empfangnisverhutenden Verbindungspaar aus correspond a leur rapport initial dans le revete- Ethinylestradiol und Norethindron, Ethinylestradiol ment pour la maitrise de la fecondite. und d,l-Norgestrel, Estron und Norethisteron, Ethinylestradiol und 3-Ketodesogestrel, Ethinyl- 30 4. Dispositif osmotique pour administrer les steroT- estradiol und Desogestrel, Ethinylestradiol und des contraceptifs selon la revendication 1, dans Gestoden, Ethinylestradiol und Levonorgestrel, lequel la forme posologique administre le steroi- Ethinylestradiol und Norgestimat, Ethinylestradiol de oestrogenique a partir du compartiment en 30 und 17a-Ethinyl-19-nortestosteron, Ethinylestradiol minutes a 24 heures. und 17a-Ethinyltestosteron, Ethinylestradiol und 35 D-17p-Acetoxy-13p-ethyl-17a-ethinyl-gon-4-en- 5. Dispositif osmotique pour administrer les steroT- 3-on- oxim, Ethinylestradiol und d-13p-Ethyl- des contraceptifs selon la revendication 1, dans 17a-ethinyl-17p-hydroxygon-4-en-3-on, Ethinyl- lequel la forme posologique administre de facon estradiol und 13p-Ethyl-17p-hydroxygon-4-en-3- continue le steroide oestrogenique par (a) libera- on, Ethinylestradiol und 13p,17a-Diethyl-17p- 40 tion par le revetement de son steroide oestroge- hydroxygon-4-en-3-on und Ethinylestradiol und nique en zero minutes a 1 heure, et (b) adminis- 1 7a-Ethinyl-1 7p-acetoxy-1 9-norandrost-4-en-3- tration par la forme posologique, a partir du on-oxim gewahlt sind. compartiment, de son steroide oestrogenique en 30 minutes a 24 heures. 45 Revendications 6. Dispositif osmotique pour administrer les steroT- des contraceptifs selon la revendication 1, dans 1 . Dispositif osmotique pour administrer des steroT- lequel le steroide oestrogenique dans le revete- des contraceptifs, le dispositif osmotique compre- ment exterieur est un element choisi dans le grou- nant : 50 pe constitue par I'oestradiol, le valerate d'oestra- (a) une paroi comprenant au moins en partie diol, le benzoate d'oestradiol, le cypionate d'oes- une composition permeable au passage de tradiol, le propionate d'oestradiol, le dipropionate fluide, laquelle paroi entoure; d'oestradiol, I'acetate d'oestradiol, I'ethynyl-oes- (b) un compartiment; tradiol, les esters d'ethynyl-oestradiol, I'acetate (c) au moins un passage de sortie qui relie 55 d'ethynyl-oestradiol, le benzoate d'ethynyl-oes- I'exterieur du dispositif au compartiment; tradiol, les ethers d'ethynyloestradiol, I'oestrone, (d) une premiere composition dans le compar- I'acetate d'oestrone, le sulfate d'oestrone, I'oes- timent, ladite composition comprenant un ste- triol, le succinate d'oestriol et le triacetate d'oes- 12 23 EP 0 500 793 B1 24

triol. xime; d'et hynyl-oestrad iol et de d- 1 3p-et hyl-1 7a- et hynyl- 1 7p-hydroxygon-4-ene-3-one; d'et hy- 7. Dispositif osmotique pour administrer les steroT- nyl-oestradiol et de 13p-ethyl-17p-hydroxygon- des contraceptifs selon la revendication 1, dans 4-ene-3-one; d'ethynyl-oestradiol etde 13p, 17a- lequel le steroide oestrogenique dans le compar- 5 diethyl-17p-hydroxygon-4-ene-3-one; et d'ethy- timent interieur est un element choisi dans le nyl-oestradiol et de 17a-ethynyl-17p-acetoxy-l9- groupe constitue par I'oestradiol, le valerate norandrost-4-ene-3-one-oxime. d'oestradiol, le benzoate d'oestradiol, le cypiona- te d'oestradiol, le propionate d'oestradiol, le di- propionate d'oestradiol, I'acetate d'oestradiol, 10 I'ethynyl-oestradiol, les esters d'ethynyl-oestra- diol, I'acetate d'ethynyl-oestradiol, le benzoate d'ethynyl-oestradiol, les ethers d'ethynyloestra- diol, I'oestrone, I'acetate d'oestrone, le sulfate d'oestrone, I'oestriol, le succinate d'oestriol et le 15 triacetate d'oestriol.

8. Dispositif osmotique pour administrer les steroT- des contraceptifs selon la revendication 1, dans lequel le steroide progestogenique dans le reve- 20 tement exterieur est un element choisi dans le groupe constitue par la progesterone, le d,l-nor- gestrel, la norethindrone, le levonorgestrel, le norgestimate, le 3-ceto-desogestrel, le desoges- trel, le gestodene, I'acetate de norethisterone, le 25 norethynodrel, Medroxyprogesterone, les esters d'hydroxyprogesterone, la 19-nor-hydroxypro- gesterone, les esters de 19-nor-17-hydroxypro- gesterone, la 17a-ethynyl-testosterone, la 17a- ethynyl-19-nor-testosterone, la D-sterone , la 30 17a-et hynyl- 1 9-nor-testosterone, la D-17p-ace- toxy-1 3p-et hyl-1 7a-et hynyl-gon-4-ene-3-one-o xime, la d-13p-ethyl-17a-ethynyl-17p-hydroxy- gon-4-ene-3-one, la 13p-ethyl-17p-hydroxygon- 4-ene-3-one, la 13p, 17p-diethyl-17p-hydroxy- 35 gon-4-ene-3-one , le diacetate d'ethynodiol, la medroxyprogesterone, I'acetate de chlormadio- ne, I'acetate de medroxyprogesterone, I'acetate de megestrol, la dimethistrone, et la 1 7a-ethynyl- 17p-acetoxy-19-norandrost-4-ene-3 -one-oxi- 40 me.

9. Dispositif osmotique pour administrer les steroT- des contraceptifs selon la revendication 1, dans lequel les steroTdes oestrogenique et progestoge- 45 nique dans le revetement exterieur sont choisis dans le groupe constitue par une paire contracep- tive d'ethynyl-oestradiol et de norethindrone; d'ethynyl-oestradiol et de d,l-norgestrel; d'oes- trone et de norethisterone; d'ethynyl-oestradiol 50 et de 3-ceto-desogestrel; d'ethynyl-oestradiol et de desogestrel; d'ethynyloestradiol et de gesto- dene; d'ethynyl-oestradiol et de levonorgestrel; d'ethynyl-oestradiol et de norgestimate; d'ethy- nyl-oestradiol et de 17a-ethynyl-19-nortestoste- 55 rone; d'ethynyl-oestradiol et de 17a-ethynyl-tes- tosterone; d'ethynyl-oestradiol et de D-17p-ace- toxy-1 3p-et hyl-1 7a-et hynyl-gon-4-ene-3-one-o 13 EP 0 500 793 B1

14 EP 0 500 793 B1

FIG.4 200.00-,

LxJ

LU " 0.00H 1 | , 0.00 6.00 TIME(HOURS)

FIG.5 5. 00-,

LU 3= CO CO

0.00- 0.00 6.00 TIME(HOURS)

FIG.6 5.00-

CO

0.00 ■^-T-g- 0.00 18.00 TIME (HOURS) 15