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Europaisches Patentamt (19) European Patent Office Office europeeneen des brevets £P 0 873 751 A2

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) intci.e: A61K9/22, A61K 38/09 28.10.1998 Bulletin 1998/44

(21) Application number: 98302622.0

(22) Date of filing: 03.04.1998

(84) Designated Contracting States: (72) Inventors: AT BE CH CY DE DK ES Fl FR GB GR IE IT LI LU • Nonomura, Muneo MC NL PT SE Toyonaka-shi, Osaka (JP) Designated Extension States: • Futo, Tomomichi AL LT LV MK RO SI Yodogawa-ku, Osaka-shi, Osaka (JP) • Shimizu, Hisayoshi (30) Priority: 04.04.1997 J P 86191/97 Takatsuki-shi, Osaka (JP)

(71) Applicant: TAKEDA CHEMICAL INDUSTRIES, Ltd. (74) Representative: Marlow, Nicholas Simon Osaka-shi, Osaka-fu (JP) Reddie & Grose 16, Theobalds Road London WC1X8PL (GB)

(54) Pharmaceutical product for application to uterus mucosa

(57) A drug comprising either a peptide having the several months to be continuously absorbed through the LH-RH action or an LH-RH antagonist is carried on an uterus mucosa or the vagina mucosa. This construction intrauterine contraceptive device (IUD) so as to be able makes it possible to reduce the patient's pain and such to provide controlled release. Once the IUD is put in the a troublesomeness as frequent drug administration and uterus, the carried drug is gradually released over such continuously administer a necessary drug over a pro- a prolonged period of treatment time as, for example, longed period of time while taking a contraceptive meas- ures.

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Printed by Jouve, 75001 PARIS (FR) 1 EP 0 873 751 A2 2

Description foregoing problems and provide a pharmaceutical prod- uct for application to the uterus mucosa, capable of sof- BACKGROUND OF THE INVENTION tening the patient's pain as well as reducing the number of administration so as to decrease such a troublesome- 1 . Field of the Invention s ness as frequent administration and continuously ad- ministering a necessary drug over a prolonged period The present invention relates to a pharmaceutical of time while taking a contraceptive measures. product for application to the uterus mucosa, which car- In order to accomplish the object, the present inven- ries a drug comprising a peptide having the luteinizing tion has constructed a pharmaceutical product for appli- hormone releasing hormone (hereafter referred to only 10 cation to the uterus mucosa as follows. as 'LH-RH') action, an LH-RH antagonist or the like on A first invention is characterized in that a drug com- an intrauterine contraceptive device (hereafter referred prising either a peptide having the LH-RH action or an to as 'IUD') and is adjusted to be able to administer the LH-RH antagonist is carried on an intrauterine contra- drug over a prolonged period of time while taking a con- ceptive device so as to be able to provide controlled re- traceptive measures by being fitted in the uterus or the 15 lease. like. Here the construction of carrying so as to be able to provide controlled release means a construction able 2. Description of the Prior Art to gradually release a carried drug. Concrete examples of such construction can be listed as follows: In order to treat breast cancer, uterus cancer, en- 20 dometriosis or central precocious puberty, an LH-RH A capsule type means for controlled release which agonist, i.e. a peptide having the LH-RH action, and an comprises covering pharmaceutical particles with a LH-RH antagonist or the like are administered. Howev- high polymer film and diffusing the pharmaceutical er, these drugs can be hardly absorbed through the al- particles gradually through the high polymer film; imentary canal, so that there exist as conventional drugs 25 A matrix type means for controlled release which for administration an injection drug to be administered comprises dispersing pharmaceutical particles in a by injection and a vaginally administered drug to be ab- high polymer material of a spherical shape or the sorbed through the vagina mucosa rapidly, for example, like and gradually diffusing them from a surface of as disclosed in Japanese Patent Publication No. Hei the high polymer material; 5-24129. 30 A means for controlled release with the use of an osmotic pressure pump, which comprises a con- 3. Problems Presented by the Prior Art tainer formed from a semi-permeable membrane and provided with a delivering outlet at one portion The injection drug causes pain to a patient when thereof and delivers through the outlet a drug ac- administered and besides has to be administered for a 35 commodated in the container by an osmotic pres- long time so as to cure the above-mentioned diseases. sure of the moisture invading from around the con- Therefore, either of the above drugs required so fre- tainer; quent administration that it was troublesome. A means for controlled release which employs a In order to solve this problem, a drug having the container provided with pores in its peripheral wall property of providing controlled release is prepared as 40 instead of the foregoing semi-permeable mem- an injection drug by forming it into microcapsules and brane; the like so as to lengthen its administration interval to, A closure-type means for controlled release which for example, four weeks or the like. However, this way comprises a container accommodating a drug and entails a problem that the patient cannot be relieved covered with a closure formed from a biodegrada- from the pain the patient experiences when the drug is 45 ble or soluble high polymer; and administered and besides the drug cannot be interrupt- A pulse-type means for controlled release which ed nor changed once it is administered. comprises a plurality of small chambers arranged Additionally, the patient should not become preg- in series and accommodating a drug, a partition wall nant because the therapy for the above-mentioned dis- of each chamber being made of a biodegradable or eases is likely to exert a bad influence on an embryo, so soluble high polymer. Consequently, there was caused a problem that the pa- tient must undergo a non-hormone contraceptive treat- However, the construction of carrying so as to be ment such as fitting an IUD separately from the admin- able to provide controlled release according to the istration of the above drug. present invention is not limited to those means. 55 When carrying the above drug on the intrauterine SUMMARY OF THE INVENTION contraceptive device (IUD), an excipient or the like ad- ditives are mixed if needed. Examples of them are listed The present invention has an object to solve the below:

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Water and polyatomic alcohols as a solvent for dis- dium, , , sulpyrine, tiaprofenic ac- solving the drug; id, , , sodium, Sugar-alcohols, sugars, polysaccharides, gelatiniz- , , neo vitacain, , er and grease as an excipient for dispersing the , calcium, , drug and keeping it dispersed; , flufenamic acid aluminium, flurbi- Sorbitan fatty acid esters and polyoxyethylene profen, axetil, floctafenine, bucolome, sorbitan fatty acid esters as a surfactant; and , , maleate, Inorganic salts, organic acid salts, inorganic bases migrenin, dimetotiazine mesilate, metiazinic acid, and inorganic acids as a pH regulator or an osmotic , , sodium, pressure regulator. 10 lobenzarit disodium, and an extract from inflamma- tory rabbit skin inoculated by vaccinia virus. The above-mentioned IUD may take such a shape Metabolic inhibitors; as having been widely used up to now. Further, it may 6- riboside, enocitabine, car- be opened instead of being closed in the shape of a ring. mofur, , cytarabine ocphosfate, , Generally, it means an IUD to be fitted in the uterus but 15 tegafur»uracil, , , may be fitted in the vagina. , , and mercaptopurine. A second invention is characterized in that an intra- Alkylating agents; uterine contraceptive device is formed from a biode- , -N-oxide hydro- gradable high polymer and carries a drug so as to be chloride, hydrochloride, , cy- able to provide controlled release of the drug. 20 clophosphamide, , , improsul- Here the biodegradable high polymer means a high fan tosilate, , , , ran- polymer material gradually decomposing in vivo. Copol- imustine, and sodium. ymers of lactic and glycolic acids (PLGA), polymers of Anti-tumor and antibiotic agents; lactic acid (PLA), copolymers of butyric and glycolic ac- actinomycin D, hydrochloride, ida- ids (PBGA) , esters of these polymers, a complex con- 25 rubicin hydrochloride, hydrochloride, sisting of at least two of these polymers or esters and hydrochloride, hydro- collagen can be listed as its examples but it is not limited chloride, hydrochloride, hy- to these ones. drochloride, zinostatin stimalamer, neocarzinosta- Further, besides leuprorelin acetate, an LH-RH ag- tin, , bleomycin sulfate and peplomycin onist and the LH-RH antagonist, for example, the follow- 30 sulfate. ing ones can be used as the above drug: Anti-tumor plant agents; , hydrochloride, vincris- Follicle Estrogen or Progestogen; tine sulfate, sulfate, and sul- allylestrenol, estradiol benzoate, estriol ben- fate. zoate, estradiol, estriol, ethinylestradiol, gestnor- 35 Other anti-tumor agents; one caproate, hydroxyprogesterone caproate, es- aceglatone, ubenimex, L-, tradiol valerate, estrogens conjugated, chlormadi- fadrozole hydrochloride hydrate, hy- none acetate, medroxyprogesterone acetate, dy- drochloride, hydrochloride, carbopla- drogesterone, estradiol dipropionate, estriol tripro- tin, tamoxifen citrate, toremifene citrate, krestin, pionate, norethisterone, pregnanediol, progester- 40 medroxyprogesterone acetate, , schizo- one, fosfestrol, and mestranol. phyllan, sobuzoxane, , nedaplatin, pici- Antipyretic, analgestic and anti-inflammatory banil, flutamide, , , and agents; lentinan. actarit, , aspirin»ascorbic acid, aspi- Anti-endometriosis agents or anti-uterine fibroids rin»dialuminate, acetaminophen, , al- 45 agents; clofenac, , , so- nafarelin acetate, buserelin acetate, dydro- dium, isopropylantipyrine, , , gesterone, danazol and ethinylestradioknorgestrel. indometacin farnesil, , , epiri- zole, emorfazone, tiaramide hydrochloride, tinorid- However, the above drug is not limited to these ones ine hydrochloride, hydrochloride, bu- 50 but at least two of them may be compounded when prenorphine hydrochloride, , obelon, needed. camphor», cleamine A, cleamine A third invention comprises defining the drug set S, ketophenylbutazone, , chondroitin forth in the second invention to either a peptide having sulfate sodium»sodium salicylate, sasapyrine, sali- the LH-RH action or an LH-RH antagonist. cylamide, sodium salicylate, saridon, salsocain, A drug carried on an IUD is gradually released to , simetride»anhydrous caffeine, epta- be continuously absorbed through the uterus mucosa or zocinehydrobromide, ergotamine tartrate»anhy- the vagina mucosa for such a long period of treatment drous caffeine, tartrate, so- time as, for example, several months once the IUD is

3 5 EP 0 873 751 A2 6 put in the uterus. Besides, during this treatment term, action in a biodegradable high polymer 3 and molding it the fitted IUD prevents pregnancy. to a predetermined shape of IUD 4 by a casting mold. If the IUD is formed from a biodegradable high pol- When such IUD 4 is fitted in the uterus, the biode- ymer, it gradually decomposes by itself while providing gradable high polymer 3 gradually decomposes and at controlled release of the drug and will completely de- 5 the same time the drug 2 provides controlled release to compose after the elapse of an administration term. be efficiently absorbed through the uterus mucosa over Therefore, it need not be removed from the living body. a prolonged period of time. The present 1st to 3rd invention produces the fol- And after the elapse of a predetermined period of lowing advantages because it is constructed and func- time, for example, three months, while the drug 2 carried tions as mentioned above. 10 on the IUD 4 is completely released, the IUD 4 itself dis- appears from the uterus with the whole biodegradable (1) The present invention can administer a neces- high polymer 3 decomposed. sary drug without giving such a pain as caused by Then another new IUD 4 carrying the drug 2 is fitted injection and besides can do it continuously over in the uterus to continue the treatment. such a prolonged period of time as at least several is Notably, it is possible to interrupt the treatment at months if only once fitted. Additionally, since the fit- an optional time by taking the IUD 4 away from the uter- ting itself is a contraceptive measures, no other con- us. When changing the amount and term for controlled traceptive measures is needed to result in the pos- release as well as the kind of the drug, a new IUD 4 sibility of reducing the patient's pain and the trou- carrying a desired drug so as to be able to provide con- blesomeness such as frequent administration. 20 trolled release of the drug for a desired period of time is (2) The drug administration can be interrupted or fitted in the uterus after the old IUD 4 has been removed changed at an optional time by removing the fitted from the uterus. IUD. Therefore, it is possible to make a proper drug administration depending on the condition of the pa- Example 1 tient, differently from the conventional technique 25 which employs an injection drug having the property 596 mg of leuprorelin acetate, an LH-RH agonist of providing controlled release. and 94 mg of gelatine were dissolved in 0.5 g of water Moreover, the pharmaceutical product for ap- to prepare an aqueous solution. Meanwhile, 4.78 g of plication to the uterus mucosa according to the sec- 75/25 (w/w) copolymer of lactic and glycolic acids hav- ond or the third invention has the following charac- 30 ing a molecular weight of about 1 4,000 (PLGA) was dis- teristic: solved in 8.0 g of dichloromethane. Then this solution (3) An IUD being made of a biodegradable high pol- was added to the above aqueous solution to prepare a ymer, it is not necessary to remove the IUD from the W/O emulsion and cool it to 19°C. living body because it is completely decomposed Next, this emulsion was dispersed into 1 liter of after the elapse of an administration term. Only the 35 0. 1 % PVA solution preliminarily cooled to 1 9°C to there- fitting of this IUD is sufficient when administering the by make a (W/0)/W emulsion. This (W/0)/W emulsion drug. This can further lessen the troublesomeness was dried in water for three hours to volatilize the dichlo- experienced when administering the drug. romethane. Thereafter, the resulting microcapsules were scavenged through centrifugation and freeze BRIEF DESCRIPTION OF THE DRAWINGS 40 dried. Thus dried microcapsules were heat molded by a Fig. 1 is a sectional view of a pharmaceutical prod- casting mold to obtain a pharmaceutical product for ap- uct for application to the uterus mucosa, showing a plication to the uterus mucosa in a desired shape of I UD. first embodiment; This pharmaceutical product continued to release Fig. 2 is a view corresponding to Fig. 1 and showing 45 leuprorelin acetate in the uterus over a period of at least a second embodiment; and one month. Fig. 3 is a view corresponding to Fig. 1 and showing a modification of the second embodiment. Example 2

DETAILED DESCRIPTION OF PREFERRED 50so 433 mg of leuprorelin acetate was dissolved in 0.5 EMBODIMENT g of water to prepare an aqueous solution. Meanwhile, 3.83 g of poly-lactic acid (PLA) having a molecular First Embodiment weight of 1 7,000 was dissolved in 6.4 g of dichlorometh- ane. This solution was added to the above aqueous so- A pharmaceutical product 1 for application to the 55 lution to prepare a W/O emulsion and cool it to 15°C. uterus mucosa according to a first embodiment of the Next, this emulsion was dispersed into 1 liter of present invention as shown in Fig. 1 was formed by dis- 0.1% PVA solution preliminarily cooled to 15°C to make persing a drug 2 such as a peptide having the LH-RH a (W/0)/W emulsion. Then this (W/0)/W emulsion was

4 7 EP 0 873 751 A2 8 dried in water for three hours. The resulting microcap- one month. sules were scavenged through centrifugation and freeze dried. Thereafter, they were compression molded Second Embodiment to a desired shape of IUD by a casting mold. The obtained pharmaceutical product for applica- 5 A pharmaceutical product 1 for application to the tion to the uterus mucosa continued to release leuprore- uterus mucosa according to a second embodiment of lin acetate in the uterus over a period of at least three the present invention as shown in Fig. 2 comprises a months. drug 2 enclosed in a diffusion controlled film 5 made of a high polymer material such as, for example, a copol- Example 3 10 ymer of ethylene and vinyl acetate and then supported by silicon elastomer 6 or the like to be formed into an 500 mg of leuprorelin acetate was dissolved in 50 IUD 4. g of water to prepare an aqueous solution. Meanwhile, The drug 2 carried on the IUD 4 gradually passes 4.5 g of copolymer of butyric and glycolic acids having through the diffusion controlled film 5 and diffuses to be a molecular weight of about 18,500 (PBGA) was dis- is absorbed through the uterus mucosa. Since the trans- solved in 10 g of dichloromethane. This solution was mission and diffusion of the drug decrease after a pre- added to the above aqueous solution to prepare a W/O determined period of time has elapsed, this IUD 4 is re- emulsion. moved from the uterus and a new IUD 4 is fitted if the Next, this emulsion was vacuum dried in a casting administration is continued. mold and compression molded to a desired shape of 20 IUD. The obtained pharmaceutical product for applica- Example 6 tion to the uterus mucosa continued to release leuprore- lin acetate in the uterus over a period of at least one 500 mg of leuprorelin acetate and 4.5 g of PLA hav- month. ing a molecular weight of about 25,000 were dissolved 25 in 1 0 g of dichloromethane. This solution was dispersed Example 4 into 1 liter of 0. 1 % PVA solution to prepare an O/W emul- sion. 5 g of leuprorelin acetate was dissolved in 50 g of This O/W emulsion was dried in water for three water to prepare an aqueous solution. Meanwhile, 45 g hours. The resulting microcapsules were scavenged of PLGA having the same grade as that used in Example 30 through centrifugation and freeze dried. The dried sub- 1 was dissolved in 100 g of dichloromethane. This so- stance was suspended in silicon oil. This suspension lution was added to the above aqueous solution to pre- was enclosed in a film made of a copolymer of ethylene pare a W/O emulsion. and vinyl acetate and supported by silicon elastomer to Next, this emulsion was dried at a temperature of obtain a pharmaceutical product for application to the 40°C under a condition of 100 to 300 Torr by a vacuum 35 uterus mucosa formed in a desired shape of IUD. drier. The resulting dried product was ground by a turbo- This pharmaceutical product continued to release counter jet mill. The thus ground substance was accom- leuprorelin acetate in the uterus over a period of at least modated in a casting mold and heat molded to obtain a three months. pharmaceutical product for application to the uterus mu- The IUD 4 may take the shape of the modification cosa in a desired shape of IUD. 40 shown in, for example, Fig. 3 or other shapes as far as The obtained product continued to release leu- they don't cause any abnormality to the living body when prorelin acetate in the uterus over a period of at least fitted. one month. Needless to say, the drug to be used is not limited to those shown in Examples 1 to 6. The term within Example 5 45 which the drug can be administered for controlled re- lease in the uterus can be suitably fixed to, for example, 4.5 g of 55/45 (w/w) copolymer of lactic and glycolic at least six months by controlling the amount and deliv- acids, PLGA having a molecular weight of about 20,000 ery speed of the drug to be carried as far as it does not was dissolved in 10 g of dichloromethane. 0.5 g of cis- cause any abnormality to the living body. platin, an antineoplastic (anticancer) agent was added 50 to this solution so as to suspend it therein homogene- ously with ultrasonic. Claims This suspension was accommodated in a casting mold and vacuum dried at room temperature to obtain 1 . A controlled release drug delivery device for admin- a pharmaceutical product for application to the uterus 55 istering a pharmaceutical to the uterine mucosa mucosa in a desired shape of IUD. which comprises: The obtained pharmaceutical product continued to release cisplatin in the uterus over a period of at least an intrauterine contraceptive device; and

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a pharmaceutical carried on the intrauterine ters, inorganic salts, organic acid salts, inorganic contraceptive device, bases or inorganic acids.

wherein the pharmaceutical comprises a peptide 11. A delivery device according to any preceding claim having luteinising hormone-releasing hormone ac- s in which the intrauterine contraceptive device is bi- tivity or luteinising hormone-releasing hormone an- odegradable. tagonist activity. 1 2. A controlled release drug delivery device for admin- 2. A delivery device according to claim 1 in which the istering a pharmaceutical to the uterine mucosa pharmaceutical comprises leuprorelin acetate. 10 which comprises:

3. A delivery device according to claim 1 or 2 in which a biodegradable intrauterine contraceptive de- the pharmaceutical is accommodated in the intrau- vice; and terine contraceptive device and in which the phar- a pharmaceutical carried on the intrauterine maceutical can diffuse out of the intrauterine con- 15 contraceptive device. traceptive device. 13. A delivery device according to claim 12 in which the 4. A delivery device according to any preceding claim pharmaceutical comprises a peptide having lutein- in which the pharmaceutical is in a pharmaceutical^ ising hormone-releasing hormone activity or lutein- acceptable excipient, carrier or diluent. 20 ising hormone-releasing hormone antagonist activ- ity. 5. A delivery device according to claim 4 in which the carrier comprises a capsule which accommodates 14. A delivery device according to claim 12 or 13 in the pharmaceutical and which is permeable to it. which the intrauterine contraceptive device is of a 25 biodegradable high polymer. 6. A delivery device according to claim 4 in which the carrier comprises a matrix in which the pharmaceu- 15. A delivery device according to claim 14 in which the tical is dispersed, the pharmaceutical being able to biodegradable high polymer comprises at least one diffuse from the matrix. of a copolymer of lactic acid and , a pol- 30 ymer of lactic acid, a copolymer of butyric acid and 7. A delivery device according to claim 4 in which the glycolic acid, esters of those said polymers or a carrier comprises an osmotic pressure pump, the complex comprising at least two of said polymers osmotic pressure pump comprising: or esters and collagen.

a container which accommodates the pharma- 35 16. A delivery device according to any of claims 12 to ceutical and which is formed from a semi-per- 1 5 in which the pharmaceutical comprises leuprore- meable membrane; lin acetate. a delivery outlet which can release the pharma- ceutical from the container as water enters the 17. A pharmaceutical productfor application to the uter- container through the semi-permeable mem- 40 us mucosa characterised in that a drug (2) compris- brane. ing either a peptide having the LH-RH action or an antagonist is carried on an intrauterine contracep- 8. A delivery device according to claim 4 in which the tive device (4) so as to be able to provide controlled carrier comprises a container which accommodates release. the pharmaceutical and in which a wall of the con- 45 tainer is biodegradable or soluble. 18. A pharmaceutical productfor application to the uter- us mucosa characterised in that an intrauterine con- 9. A delivery device according to claim 4 in which the traceptive device (4) is formed from a biodegrada- carrier comprises a plurality of chambers arranged ble high polymer (3), a drug (2) being carried on the in series, each chamber accommodating the phar- so intrauterine contraceptive device (4) so as to be maceutical, the partition walls of each chamber be- able to provide controlled release. ing biodegradable or soluble. 19. A pharmaceutical productfor application to the uter- 10. A delivery device according to any of claims 4 to 9 us mucosa as set forth in claim 1 8, wherein the drug in which the excipient or diluent comprises at least 55 (2) is either a peptide having the LH-RH action or one of water, alcohols, sugar-alcohols, sugars, an LH-RH antagonist. polysaccharides, gelatinizer, grease, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid es-

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