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Pharmaceutical Product for Application to Uterus Mucosa

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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. CM < lo CO Is- oo o a. LU 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: 2 3 EP 0 873 751 A2 4 Water and polyatomic alcohols as a solvent for dis- dium, diflunisal, sulindac, sulpyrine, tiaprofenic ac- solving the drug; id, tenoxicam, tolfenamic acid, tolmetin sodium, Sugar-alcohols, sugars, polysaccharides, gelatiniz- nabumetone, naproxen, neo vitacain, piroxicam, er and grease as an excipient for dispersing the phenacetin, fenoprofen calcium, fenbufen, drug and keeping it dispersed; flufenamic acid, flufenamic acid aluminium, flurbi- Sorbitan fatty acid esters and polyoxyethylene profen, flurbiprofen axetil, floctafenine, bucolome, sorbitan fatty acid esters as a surfactant; and pranoprofen, pentazocine, proglumetacin maleate, Inorganic salts, organic acid salts, inorganic bases migrenin, dimetotiazine mesilate, metiazinic acid, and inorganic acids as a pH regulator or an osmotic mefenamic acid, mofezolac, loxoprofen 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-mercaptopurine riboside, enocitabine, car- be opened instead of being closed in the shape of a ring. mofur, cytarabine, cytarabine ocphosfate, tegafur, Generally, it means an IUD to be fitted in the uterus but 15 tegafur»uracil, doxifluridine, hydroxycarbamide, may be fitted in the vagina. fluorouracil, methotrexate, and mercaptopurine. A second invention is characterized in that an intra- Alkylating agents; uterine contraceptive device is formed from a biode- ifosfamide, nitrogen mustard-N-oxide hydro- gradable high polymer and carries a drug so as to be chloride, nimustine hydrochloride, carboquone, cy- able to provide controlled release of the drug. 20 clophosphamide, dacarbazine, thiotepa, improsul- Here the biodegradable high polymer means a high fan tosilate, busulfan, mitobronitol, melphalan, ran- polymer material gradually decomposing in vivo. Copol- imustine, and estramustine phosphate 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, aclarubicin hydrochloride, ida- ids (PBGA) , esters of these polymers, a complex con- 25 rubicin hydrochloride, epirubicin hydrochloride, sisting of at least two of these polymers or esters and daunorubicin hydrochloride, doxorubicin hydro- collagen can be listed as its examples but it is not limited chloride, pirarubicin hydrochloride, bleomycin hy- to these ones. drochloride, zinostatin stimalamer, neocarzinosta- Further, besides leuprorelin acetate, an LH-RH ag- tin, mitomycin C, 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; etoposide, irinotecan hydrochloride, vincris- Follicle Estrogen or Progestogen; tine sulfate, vindesine sulfate, and vinblastine sul-
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  • WO 2018/218208 Al 29 November 2018 (29.11.2018) W !P O PCT

    WO 2018/218208 Al 29 November 2018 (29.11.2018) W !P O PCT

    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/218208 Al 29 November 2018 (29.11.2018) W !P O PCT (51) International Patent Classification: Fabio; c/o Bruin Biosciences, Inc., 10225 Barnes Canyon A61K 31/00 (2006.01) A61K 47/00 (2006.01) Road, Suite A104, San Diego, California 92121-2734 (US). BEATON, Graham; c/o Bruin Biosciences, Inc., 10225 (21) International Application Number: Barnes Canyon Road, Suite A104, San Diego, California PCT/US20 18/034744 92121-2734 (US). RAVULA, Satheesh; c/o Bruin Bio (22) International Filing Date: sciences, Inc., 10225 Barnes Canyon Road, Suite A l 04, San 25 May 2018 (25.05.2018) Diego, Kansas 92121-2734 (US). (25) Filing Language: English (74) Agent: MALLON, Joseph J.; 2040 Main Street, Four teenth Floor, Irvine, California 92614 (US). (26) Publication Langi English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 62/5 11,895 26 May 2017 (26.05.2017) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 62/5 11,898 26 May 2017 (26.05.2017) US CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (71) Applicants: BRUIN BIOSCIENCES, INC. [US/US]; DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 10225 Barnes Canyon Road, Suite A104, San Diego, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, California 92121-2734 (US).