United States Patent:  6,083,916

Assignee:  Takeda Chemical Industries, Ltd. (Osaka, JP)

Filed:  March 30, 1998

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

SUMMARY OF THE INVENTION

The present invention has an object to solve the foregoing problems and provide a pharmaceutical product for application to the uterus mucosa, capable of softening the patient's pain as well as reducing the number of administration so as to decrease such a troublesomeness as frequent administration and continuously administering a necessary drug over a prolonged period of time while taking a contraceptive measures.

In order to accomplish the object, the present invention has constructed a pharmaceutical product for application to the uterus mucosa as follows.

A first invention is characterized in that a drug comprising either a peptide having the LH-RH action or an LH-RH antagonist is carried on an intrauterine contraceptive device so as to be able to provide controlled release.

Here the construction of carrying so as to be able to provide controlled release means a construction able to gradually release a carried drug. Concrete examples of such construction can be listed as follows:

A capsule type means for controlled release which comprises covering pharmaceutical particles with a high polymer film and diffusing the pharmaceutical particles gradually through the high polymer film;

A matrix type means for controlled release which comprises dispersing pharmaceutical particles in a high polymer material of a spherical shape or the like and gradually diffusing them from a surface of the high polymer material;

A means for controlled release with the use of an osmotic pressure pump, which comprises a container formed from a semi-permeable membrane and provided with a delivering outlet at one portion thereof and delivers through the outlet a drug accommodated in the container by an osmotic pressure of the moisture invading from around the container;

A means for controlled release which employs a container provided with pores in its peripheral wall instead of the foregoing semi-permeable membrane;

A closure-type means for controlled release which comprises a container accommodating a drug and covered with a closure formed from a biodegradable or soluble high polymer; and

A pulse-type means for controlled release which comprises a plurality of small chambers arranged in series and accommodating a drug, a partition wall of each chamber being made of a biodegradable or soluble high polymer.

However, the construction of carrying so as to be able to provide controlled release according to the present invention is not limited to those means.

When carrying the above drug on the intrauterine contraceptive device (IUD), an excipient or the like additives are mixed if needed. Examples of them are listed below:

Water and polyatomic alcohols as a solvent for dissolving the drug;

Sugar-alcohols, sugars, polysaccharides, gelatinizer and grease as an excipient for dispersing the drug and keeping it dispersed;

Sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters as a surfactant; and

Inorganic salts, organic acid salts, inorganic bases and inorganic acids as a pH regulator or an osmotic pressure regulator.

The above-mentioned IUD may take such a shape as having been widely used up to now. Further, it may be opened instead of being closed in the shape of a ring. Generally, it means an IUD to be fitted in the uterus but may be fitted in the vagina.

A second invention is characterized in that an intrauterine contraceptive device is formed from a biodegradable high polymer and carries a drug so as to be able to provide controlled release of the drug.

Here the biodegradable high polymer means a high polymer material gradually decomposing in vivo. Copolymers of lactic and glycolic acids (PLGA), polymers of lactic acid (PLA), copolymers of butyric and glycolic acids (PBGA), esters of these polymers, a complex consisting of at least two of these polymers or esters and collagen can be listed as its examples but it is not limited to these ones.

Further, besides leuprorelin acetate, an LH-RH agonist and the LH-RH antagonist, for example, the following ones can be used as the above drug:

Follicle Estrogen or Progestogen;

allylestrenol, estradiol benzoate, estriol benzoate, estradiol, estriol, ethinylestradiol, gestnorone caproate, hydroxyprogesterone caproate, estradiol valerate, estrogens conjugated, chlormadinone acetate, medroxyprogesterone acetate, dydrogesterone, estradiol dipropionate, estriol tripropionate, norethisterone, pregnanediol, progesterone, fosfestrol, and mestranol.

Antipyretic, analgestic and anti-inflammatory agents;

actarit, aspirin, aspirin.multidot.ascorbic acid, aspirin.multidot.dialuminate, acetaminophen, acemetacin, alclofenac, alminoprofen, ampiroxicam, amfenac sodium, isopropylantipyrine, ibuprofen, indometacin, indometacin farnesil, ethenzamide, etodolac, epirizole, emorfazone, tiaramide hydrochloride, tinoridine hydrochloride, tramadol hydrochloride, buprenorphine hydrochloride, oxaprozin, obelon, camphor.multidot.sodium salicylate, cleamine A, cleamine S, ketophenylbutazone, ketoprofen, chondroitin sulfate sodium-sodium salicylate, sasapyrine, salicylamide, sodium salicylate, saridon, salsocain, zaltoprofen, simetride.multidot.anhydrous caffeine, eptazocinehydrobromide, ergotamine tartrate.multidot.anhydrous caffeine, butorphanol tartrate, diclofenac sodium, diflunisal, sulindac, sulpyrine, tiaprofenic acid, tenoxicam, tolfenamic acid, tolmetin sodium, nabumetone, naproxen, neo vitacain, piroxicam, phenacetin, fenoprofen calcium, fenbufen, flufenamic acid, flufenamic acid aluminium, flurbiprofen, flurbiprofen axetil, floctafenine, bucolome, pranoprofen, pentazocine, proglumetacin maleate, migrenin, dimetotiazine mesilate, metiazinic acid, mefenamic acid, mofezolac, loxoprofen sodium, lobenzarit disodium, and an extract from inflammatory rabbit skin inoculated by vaccinia virus.

Metabolic inhibitors;

6-mercaptopurine riboside, enocitabine, carmofur, cytarabine, cytarabine ocphosfate, tegafur, tegafur.multidot.uracil, doxifluridine, hydroxycarbamide, fluorouracil, methotrexate, and mercaptopurine.

Alkylating agents;

ifogfamide, nitrogen mustard-N-oxide hydrochloride, nimustine hydrochloride, carboquone, cyclophosphamide, dacarbazine, thiotepa, improsulfan tosilate, busulfan, mitobronitol, melphalan, ranimustine, and estramustine phosphate sodium.

Anti-tumor and antibiotic agents;

actinomycin D, aclarubicin hydrochloride, idarubicin hydrochloride, epirubicin hydrochloride, daunorubicin hydrochloride, doxorubicin hydrochloride, pirarubicin hydrochloride, bleomycin hydrochloride, zinostatin stimalamer, neocarzinostatin, mitomycin C, bleomycin sulfate and peplomycin sulfate.

Anti-tumor plant agents;

etoposide, irinotecan hydrochloride, vincristine sulfate, vindesine sulfate, and vinblastine sulfate.

Other anti-tumor agents;

aceglatone, ubenimex, L-asparaginase, fadrozole hydrochloride hydrate, procarbazine hydrochloride, mitoxantrone hydrochloride, carboplatin, tamoxifen citrate, toremifene citrate, krestin, medroxyprogesterone acetate, cisplatin, schizophyllan, sobuzoxane, tretinoin, nedaplatin, picibanil, flutamide, pentostatin, porfimer sodium, and lentinan.

Anti-endometriosis agents or anti-uterine fibroids agents;

nafarelin acetate, buserelin acetate, dydrogesterone, danazol and ethinylestradiol.multidot.norgestrel.

However, the above drug is not limited to these ones but at least two of them may be compounded when needed.

A third invention comprises defining the drug set forth in the second invention to either a peptide having the LH-RH action or an LH-RH antagonist.

A drug carried on an IUD is gradually released to be continuously absorbed through the uterus mucosa or the vagina mucosa for such a long period of treatment time as, for example, several months once the IUD is put in the uterus. Besides, during this treatment term, the fitted IUD prevents pregnancy.

If the IUD is formed from a biodegradable high polymer, it gradually decomposes by itself while providing controlled release of the drug and will completely decompose after the elapse of an administration term. Therefore, it need not be removed from the living body.

The present 1st to 3rd invention produces the following advantages because it is constructed and functions as mentioned above.

(1) The present invention can administer a necessary drug without giving such a pain as caused by injection and besides can do it continuously over such a prolonged period of time as at least several months if only once fitted. Additionally, since the fitting itself is a contraceptive measures, no other contraceptive measures is needed to result in the possibility of reducing the patient's pain and the troublesomeness such as frequent administration.

(2) The drug administration can be interrupted or changed at an optional time by removing the fitted IUD. Therefore, it is possible to make a proper drug administration depending on the condition of the patient, differently from the conventional technique which employs an injection drug having the property of providing controlled release.

Moreover, the pharmaceutical product for application to the uterus mucosa according to the second or the third invention has the following characteristic:

(3) An IUD being made of a biodegradable high polymer, it is not necessary to remove the IUD from the living body because it is completely decomposed after the elapse of an administration term. Only the fitting of this IUD is sufficient when administering the drug. This can further lessen the troublesomeness experienced when administering the drug.

Claim 1 of 2 Claims

1. An intrauterine contraceptive device which is made from a biodegradable copolymer of lactic acid and glycolic acid and/or a biodegradable polymer of lactic acid, wherein leuprorelin acetate is comprised in the device, said device is applied to a patient for treatment of breast cancer, uterus cancer, endometriosis or central precocious puberty, and the release of the leuprorelin acetate from the device is prolonged.

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