Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
  • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to a pharmaceutical combination preparation of LHRH analogs and anti-estrogens with tissue-selective estrogenic action and its use for the treatment of gynecological disorders, in particular for the treatment of endometriosis and fibroids.
• Gynecological disorders or illnesses significantly reduce the quality of life of women and often lead to infertility in addition to sometimes unbearable pain.
• One of the most common diseases of women of childbearing age (5% to 10%) is endometriosis. This is associated with severe pain during menstruation and a limited fertility rate up to sterility. The incidence is also high in the case of the fibroid, a benign tumor in the muscle tissue of the uterus (10% to 25% of women around 30 years of age).
• Fibroids can cause severe abnormal menstrual bleeding (hypermenorrhea), painful menstrual bleeding (dysmenorrhea) or intermenstrual bleeding (metrorrhagia and menorrhagia) and, depending on the situation, also lead to reduced fertility.
• dysmenorrhea caused by endometriosis and fibroids, there are also functional ones (caused by hormonal and vegetative disorders).
• Progestogens that are under the control of the hypothalamic-pituitary system or growth factors (which also include cytokines) play a decisive role.
• These diseases or disorders are generally treated with hormones, such as LHRH analogs (Lemay, A. et al, Fertil. Steril., 41, 863-871 (1984)).
• LHRH analogs Lemay, A. et al, Fertil. Steril., 41, 863-871 (1984)
• some women do not tolerate these without side effects.
• treatment with LHRH agonists leads to side effects such as, for example, hypoestrogenicity (risk of osteoporosis) (Dawood, MY et al, Fertil. Steril.
• Bone density which increases the risk of osteoporosis (Dawood, M.Y. Int. J. Gynecol. Obstet., 40, 29-42, (1993)).
• Other side effects associated with estrogen deprivation are also described by Dawood.
• the invention is therefore based on the object of providing a pharmaceutical combination preparation for the treatment of gynecological disorders, in particular for the treatment of endometriosis or of fibroids, with which a decrease in the bone density is prevented and the disadvantages of previous hormone treatments are avoided.
• a pharmaceutical combination preparation which comprises two active substances, of which the first active substance is an LHRH analogue or a combination of LHRH analogues and the second active substance is an anti-estrogen with tissue-selective estrogenic activity.
• the LHRH analog is an LHRH agonist or antagonist.
• LHRH antagonists and LHRH agonists can be used.
• Preferred LHRH analogs are from the group of the compounds leucorelin, cetrorelix, antide, buserelin, ramorelix, zoladex, 2- (4-acetylaminophenyl) -4,7-dihydro-7- (2-methoxybenzyl) -3- (N-methyl-N-benzylaminomethyl) -4-oxothieno- [2,3-b] pyridine-5-carboxylic acid ethyl ester and 5-benzyol-7- (2,6-di- fluorobenzyl) -4,7-dihydro-3- (N-methyl-N-benzylaminomethyl) -2- (4-propionylamidophenyl) -4-oxothieno [2,3-b] pyridine.
• the active ingredients are usually in separate dosage forms or, in the case of orally bioavailable LHRH antagonists, in a common one
• the LHRH analogs can be administered as single doses or as depot forms.
• a dosage unit contains different amounts of active substance depending on the dosage form.
• 2 ⁇ g-20mg LHRH analog per kg body weight is usually administered.
• the administration can be in solid or liquid form.
• the amounts of the LHRH analogues are 0.02 ⁇ g-2.5mg per kg body weight.
• an isotonic saline or dextrose solution is preferably used, which is optionally adjusted to a pH of 5 to 9, preferably to the pH of the blood, with a buffer.
• Leuprorelin is preferably used orally in a dosage of 2-100 ⁇ g / kg body weight (daily dosage); one tablet preferably contains 0.1 to 5.0 mg leuprorelin.
• the dose for parenteral use is preferably between 0.02 and 1.0 ⁇ g / kg body weight.
• Cetrorelix is preferably used in the form of a physiological saline solution with an active substance amount between 0.1-2.5 mg / kg body weight.
• DE 43 42 092 also describes slow-release formulations from Cetrorelix.
• Buserelin is preferably used in doses of 0.02-l ⁇ g / kg body weight (intravenously), 0.02-2 ⁇ g / kg body weight (subcutaneously), 0.02-10 ⁇ g / kg body weight (intramuscular), 0.1 -50 ⁇ g / kg body weight (intranasal) and
• Zoladex is preferably administered orally with a content of 50 / ⁇ g-20mg / kg body weight and parenterally with a content of 0.2 ⁇ g-100 ⁇ g / kg body weight or with a slow-release system (WO-A 93/24150).
• Antide is administered in an amount of 0.1-2.5 mg / kg body weight.
• Ramoreiix is preferably administered in liposomal form.
• the second active ingredient component of the combination preparation is an anti-estrogen with a tissue-selective estrogenic effect.
• Anti-estrogenic substances are used, among other things, in tumor therapy.
• Anti-oestrogens with tissue-selective estrogenic activity in the sense of the invention are so-called SERMs (selective estrogen-receptor modulators) which exert their partial agonistic estrogenic activity in a tissue- or organ-selective manner.
• SERMs selective estrogen-receptor modulators
• all anti-oestrogens with tissue-selective oestrogenic activity can be used.
• Those selected from the group of raloxifene, droloxifene, centchroman or their derivatives are preferably used.
• Anti-estrogens of the raloxifene type are particularly preferred.
• raloxifene around 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene.
• raloxifene and its derivatives are used to increase bone mass (EP 0 635 270).
• the active substance content of the anti-estrogen used according to the invention is, depending on the form of application, 0.1 ⁇ g-10 mg anti-estrogen per kg body weight with daily application.
• the anti-estrogens can be administered intravenously, subcutaneously, intramuscularly, orally, intranasally or intravaginally. Slow release formulations are also possible. The daily released amount is then also in the above range.
• the LHRH analogue and the anti-estrogen can be administered to the patient simultaneously and / or sequentially in time. Different treatment regimens are possible:
• the LHRH analogue is administered simultaneously with the tissue-selective anti-estrogen over the same period. Administration is possible daily, every 3 days, weekly or once a month over a period of 1 to 6 months. A longer application is also easily possible. For monthly use, a depot formulation is preferred.
• the LHRH analogue is initially administered simultaneously with the tissue-selective anti-estrogen over a certain period of time. Regarding the duration and frequency of administration (daily or at longer intervals), the statements made under 1 apply. The treatment is then continued with the anti-estrogen alone.
• the information given under 1 also applies to the duration and frequency of administration. 3.
• the treatment with the LHRH analogue is carried out and completed over a certain period of time.
• the tissue-selective anti-estrogen is then applied.
• the duration and frequency of use can be selected for each component, as indicated under 1.
• the treatment with the combination preparation according to the invention surprisingly prevents the previously observed LHRH analog-induced decrease in bone density and does not stimulate the growth inhibited endometriosis or stimulate the growth of the normal endometrium in the uterus.
• the pharmaceutical combination preparation according to the invention is particularly suitable for long-term treatment of endometriosis or. Fibroids and other steroid (sex) hormone-dependent diseases are suitable, since on the one hand the side effects normally occurring under LHRH analogs (agonists or antagonists) treatment are avoided and on the other hand lost bone mass is rebuilt (for example when the tissue-selective is administered) Anti-estrogen after stopping LHRH analog treatment). At the same time, the growth inhibition of endometriosis is maintained without the endometrium in the uterus being stimulated.
• LHRH analogs agonists or antagonists
• Variant 1 has proven to be particularly preferred for long-term therapy.
• the pharmaceutical combination preparation according to the invention is produced, for example, by formulating the LHRH analogs and the anti-estrogens with tissue-selective estrogenic activity separately from one another with the customary pharmaceutical carriers, auxiliaries and / or additives, the dosage forms of the individual active ingredients not having to be identical. It is e.g. it is quite possible that one active ingredient of the combination preparation is administered orally, while the other active ingredient is administered subcutaneously or nasally.
• both active ingredients can also be formulated together for oral administration. Separate oral forms of administration are also possible.
• the invention also relates to the packaging unit, which in the case of peptide LHRH analogs comprises at least three components. It contains two active substances, which are made up separately, one of which is an LHRH analogue or a combination of LHRH analogs, and the other of which is an anti-estrogen with tissue-selective estrogenic activity. The third
• Component represents an information note for the simultaneous and / or sequential application of the dosage forms.
• Another object of the invention is the use of an LHRH analog or a combination of LHRH analogs and an anti-estrogen with tissue-selective estrogenic action for the treatment of gynecological disorders, in particular for the treatment of endometriosis and fibroids.
• Endometrial pieces were transplanted into different areas of the abdominal cavity of 60 animals.
• endometriosis foci Four weeks later the development of endometriosis (cystic endometriosis foci) was checked. The animals were then treated for 4 weeks with the LHRH antagonist Antide (0.5 mg / animal every 3 days sc) and raloxifene (3 mg / animal per day po), either alone or in combination of the two compounds. In the end, the size of the endometriosis foci before treatment was compared with the values after 4 weeks of treatment.
• the LHRH antagonist Antide 0.5 mg / animal every 3 days sc
• raloxifene 3 mg / animal per day po
• mice received the LHRH antagonist Antide and raloxifene in parallel for the first 2 weeks and raloxifene alone for the following 2 weeks.
• the doses were chosen as under 1.1.
• Example 1 The same results as in Example 1 could be achieved.

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• Proteomics, Peptides & Aminoacids (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 1996
  • 1996-01-29 DE DE19604231A patent/DE19604231A1/de not_active Ceased
• 1997
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  • 1997-01-29 BR BR9707210A patent/BR9707210A/pt not_active IP Right Cessation
  • 1997-01-29 US US09/117,357 patent/US7309691B2/en not_active Expired - Fee Related
  • 1997-01-29 EP EP97902258A patent/EP0877621A1/de not_active Withdrawn
  • 1997-01-29 JP JP9527295A patent/JP2000505422A/ja not_active Ceased
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  • 1997-01-29 CN CN97191940A patent/CN1209750A/zh active Pending
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• 1998
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• 2001
  • 2001-08-10 US US09/925,419 patent/US20020032156A1/en not_active Abandoned
• 2002
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