NZ577761A - Pharmaceutical preparation for the alleviation of endometriosis - Google Patents
Pharmaceutical preparation for the alleviation of endometriosisInfo
- Publication number
- NZ577761A NZ577761A NZ577761A NZ57776108A NZ577761A NZ 577761 A NZ577761 A NZ 577761A NZ 577761 A NZ577761 A NZ 577761A NZ 57776108 A NZ57776108 A NZ 57776108A NZ 577761 A NZ577761 A NZ 577761A
- Authority
- NZ
- New Zealand
- Prior art keywords
- dng
- therapy
- endometriosis
- dienogest
- bone
- Prior art date
Links
- 201000009273 Endometriosis Diseases 0.000 title claims abstract description 29
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 12
- AZFLJNIPTRTECV-FUMNGEBKSA-N dienogest Chemical compound C1CC(=O)C=C2CC[C@@H]([C@H]3[C@@](C)([C@](CC3)(O)CC#N)CC3)C3=C21 AZFLJNIPTRTECV-FUMNGEBKSA-N 0.000 claims abstract description 24
- 229960003309 dienogest Drugs 0.000 claims abstract description 23
- 229940127557 pharmaceutical product Drugs 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 14
- 230000037182 bone density Effects 0.000 claims description 12
- 230000004097 bone metabolism Effects 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 206010060800 Hot flush Diseases 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 208000024891 symptom Diseases 0.000 claims description 5
- 239000000262 estrogen Substances 0.000 claims description 4
- 229940011871 estrogen Drugs 0.000 claims description 4
- 210000000988 bone and bone Anatomy 0.000 claims description 3
- 239000006213 vaginal ring Substances 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 2
- 229940044953 vaginal ring Drugs 0.000 claims description 2
- 206010030247 Oestrogen deficiency Diseases 0.000 claims 2
- 208000006386 Bone Resorption Diseases 0.000 claims 1
- 230000024279 bone resorption Effects 0.000 claims 1
- 238000012332 laboratory investigation Methods 0.000 claims 1
- 239000000583 progesterone congener Substances 0.000 description 15
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 230000002280 anti-androgenic effect Effects 0.000 description 8
- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 description 7
- 229960001616 chlormadinone acetate Drugs 0.000 description 7
- 229960000978 cyproterone acetate Drugs 0.000 description 7
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 7
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 230000004075 alteration Effects 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 229960004338 leuprorelin Drugs 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000004821 effect on bone Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 206010013935 Dysmenorrhoea Diseases 0.000 description 2
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229920003080 Povidone K 25 Polymers 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000001548 androgenic effect Effects 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 229960004400 levonorgestrel Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 231100000647 material safety data sheet Toxicity 0.000 description 2
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010000084 Abdominal pain lower Diseases 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 208000004483 Dyspareunia Diseases 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 229940086944 depo-subq provera Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- CHNXZKVNWQUJIB-CEGNMAFCSA-N ethisterone Chemical class O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 CHNXZKVNWQUJIB-CEGNMAFCSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 210000004197 pelvis Anatomy 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Disclosed is the use of 17alpha-Cyanomethyl-17-beta-hydroxyestra-4,9-diene-3-one (Dienogest) for the manufacture of a pharmaceutical product for monophasic continuous administration of 2 mg Dienogest daily for at least 169 days or 25 weeks to several years to treat endometriosis.
Description
New Zealand Paient Spedficaiion for Paient Number 577761
PHARMACEUTICAL PREPARATION FOR THE ALLEVIATION OF
ENDOMETRIOSIS
Technical field
The invention relates to a pharmaceutical composition for lessening endometriosis without reducing the bone density, which comprises a progestogen having 10 antiandrogenic activity in a daily dose which does not exceed twice the ovulation-inhibitory dose, together with one or more pharmaceutically acceptable excipients/carriers. The invention also embodies a monophasic product which has no negative effect on bone 15 metabolism. This product is therefore suitable for long-term use. Nevertheless, the use of progestogens having antiandrogenic activity in the above dose for manufacturing a pharmaceutical product for the prophylaxis and/or therapy of endometriosis without a 20 negative effect on bone metabolism and thus a reduction in bone density makes it possible to keep the side effects known for conventional pharmaceutical compositions, such as, for example, hot flushes, acne, alteration in the lipid profile, within tolerable 25 limits.
Prior art
Endometriosis is a chronic gynecological disorder 30 occurring primarily in 5-20% of women of childbearing age. Endometriosis is defined in the specialist literature as the occurrence of endometrium or endometrium-like tissue outside the cavity of the uterus. Typical symptoms of the endometriotic disorder 3 5 are dysmenorrhea, dyspareunia and pain on defecation. Endometriosis patients frequently complain of pain in the pelvic region. Lower abdominal pain occurring in the 2nd half of the cycle, followed by a painful period and subsequent freedom from symptoms until the middle
WO 2008/104342 PCT/EP2008/001451
of the following cycle, frequently suggest an endometriotic disorder, but permanent pain is not uncommon either. However, about 30-40% of patients with endometriosis have no symptoms. The disorder is then 5 found only by chance in connection with other diagnostic measures. In about 50-60%, the diagnosis "suffering from endometriosis" is made as a chance diagnosis when seeking an explanation for sterility.
It is known from the specialist and patent literature to treat endometriosis medically with danazole, a derivative of 17a-ethynyltestosterone, GnRH agonists, progestogen/estrogen combinations or progestogen-alone products.
US 6,569,845 discloses the treatment of angiogenic disorders with dienogest in a daily dose of 0.5 to 10 mg. Corresponding pharmaceutical compositions provided as examples, which could also be widely used
2 0 for the treatment of endometriosis, have a dienogest content of 4 00 mg to 2 g.
Moore, C. et al., The treatment of endometriosis, Drugs of Today 1999, 35 (Suppl C) : 41-52 investigated the 25 efficacy of dienogest in the treatment of endometriosis in clinical studies compared with the treatment regimen with danazole or GnRH agonists. 2 mg of dienogest were administered each day for 24 weeks to those affected by endometriosis. The result of the treatment is 30 comparable with the result of a treatment with danazole or GnRH agonists. Up to 90% of those affected reported irregular bleeding, but none reported intolerable bleeding. The efficacy of the standard treatment with danazole is curtailed by significant androgenic
3 5 effects, whereas GnRH agonists are connected with
"menopausal symptoms".
Schweppe, K.-W, Stellenwert der Gestagene, Zentralbl
WO 2008/104342 PCT/EP2008/001451
Gynakol 2003, 125: 276-280 states that low estrogen levels are to be found on continuous oral progestogen treatment (for example with medroxyprogesterone acetate, dienogest, dydrogesterone, lynestrenol in a daily dose of 5 mg to 20 mg, referred to as low-dose and categorized as effective principle for treating endometriosis-related symptoms). Spotting and irregular bleeding are frequent results. This forces an increase in the dose and/or addition of estrogen. Recurrence rates long-term are above 50%.
A safety data sheet of 2005 on a medroxyprogesterone acetate product indicates that progestogen-alone products may exert an adverse effect on bone density, especially on long-term treatment. By contrast, some progestogens combined with estrogens exert a positive influence on bone metabolism.
A further safety data sheet, NDA 21-584, FDA 22.03.2005, on depo-subQ provera 104™
(medroxyprogesterone acetate i.m. - 104 mg/0.65 ml) indicates that women using this product suffer a loss of bone mineral density which increases with the duration of use of the product and is no longer completely reversible.
Knauthe, R and Habenicht U.F., Levonorgestrel has beneficial effects, Exp Clin Endocrinol diabetes 106 (1998) Suppl 1: 37 showed in 1998 that in this connection the partial androgenic effect of a progestogen (levonorgestrel) and not the progestational activity is decisive for this positive influence on bone metabolism. Moreover, Kuhl, H., Klimakterium, Postmenopause und Hormonsubstitution, 3rd edition, Bremen, UNI-MED, 2006, 117 emphasizes that certain progestogens are effective via their partial androgenic effect. Kuhl further states that androgens considerably enhance the positive effect of estrogens on bone
density.
Description of the invention
The object of the invention is a pharmaceutical composition having a steroidal content which is as low as possible for lessening endometriosis, the intention being that the composition does not at the same time exert a negative influence on bone density/bone 10 metabolism.
It has now been found that it is possible to achieve alleviation of endometriosis without reducing the bone density by a pharmaceutical composition with a low 15 hormonal dosage, specifically a progestogen having antiandrogenic activity whose daily dose does not exceed twice the ovulation-inhibitory dose, and one or more pharmaceutically acceptable excipients/carriers.
2 0 At the same time, the pharmaceutical composition and use thereof or the corresponding monophasic product, besides alleviating endometriosis, surprisingly achieves no negative influence on bone metabolism, so that no decrease/reduction in bone density is to be
2 5 found.
Nevertheless, the pharmaceutical composition and the use thereof or the corresponding monophasic product surprisingly keeps the side effects known for
3 0 conventional medicaments for the treatment of endometriosis, e.g. hot flushes, alteration in the lipid profile, within tolerable limits.
The progestogens having antiandrogenic activity which 3 5 are used according to the invention are dienogest, cyproterone acetate or chlormadinone acetate.
The daily dose of dienogest not exceeding twice the
WO 2008/104342 PCT/EP2008/001451
ovulation-inhibitory dose does not exceed 2 mg. Cyproterone acetate or chlormadinone acetate are also employed according to the invention in a daily dosage not exceeding twice the ovulation-inhibitory dose. The 5 ovulation-inhibitory dose of dienogest and of cyproterone acetate is 1 mg, and that of chlormadinone acetate is 1.7 mg.
The daily dose of the progestogens may be once not more 10 than twice the ovulation-inhibitory dose or twice the same dose not exceeding half the ovulation-inhibitory dose.
The object is also achieved according to the invention 15 by a pharmaceutical composition comprising daily dose units which are packed separately and can be removed singly and which are introduced into a pack unit for a period of 28 or 30 consecutive days, where the daily dose units comprise not more than 2 mg of dienogest or
2 0 an equivalent amount of cyproterone acetate or chlormadinone acetate together with one or more pharmaceutically acceptable excipients/carriers.
The pack units are preferably 2 blister packs each with 25 14 or 15 daily dose units.
It has been found that the pharmaceutical composition, which is suitable for the prophylaxis and/or therapy of endometriosis, surprisingly exerts no negative effect 30 on bone metabolism and bone density, and the lipid profile. The pharmaceutical composition is therefore surprisingly suitable for long-term administration, especially with a continuous administration of the dosage forms for a period of at least 169 days or 25
3 5 weeks up to several years, preferably more than
2 years.
The object is also achieved according to the invention
RECEIVED at IPONZ on 24 March 2011
- 6 - (followed by page 6A)
by a kit which comprises at least 28, preferably 30, daily dose units not exceeding twice the ovulation-inhibitory dose of a progestogen having a partial antiandrogenic effect, preferably dienogest,
cyproterone acetate or chlormadinone acetate, together with one or more pharmaceutically acceptable excipients/carriers.
The present invention further relates to the use of progestogens having antiandrogenic activity in a daily dose which does not exceed twice the ovulation-inhibitory dose for manufacturing a pharmaceutical product for the prophylaxis and/or therapy of endometriosis, it having been found that, surprisingly, no negative influence on bone metabolism, and thus no decrease in bone density, is to be found. At the same time, the side effects known for conventional medicaments for the treatment of endometriosis, e.g. hot flushes, alteration in the lipid profile, are kept within tolerable limits.
The present invention particularly relates to the use of 17a-Cyanomethyl-17-beta-hydroxyestra-4,9-diene-3-one (Dienogest) for the manufacture of a pharmaceutical product for monophasic continous administration of 2 mg Dienogest daily for at least 169 days to treat endometriosis.
A further particular embodiment of the present invention is the use of 17a-Cyanomethyl-17-beta-hydroxyestra-4,9-diene-3-one (Dienogest) for the manufacture of a pharmaceutical product for the treatment of endometriosis wherein the pharmaceutical preparation is formulated for monophasic continuous administration of 2 mg of Dienogest daily for at least 169 days.
RECEIVED at IPONZ on 24 March 2011
6A (followed by page 7)
The pharmaceutical product may be in the form of tablets, capsules, coated tablets, wafers, transdermal therapeutic systems, ampoules, suppositories, gels, ointments, implants, vaginal rings or nasal spray. In this connection, the daily dose of progestogen delivered by the non-oral forms of the pharmaceutical product, such as transdermal therapeutic system, ampoule, suppository, gel, ointment, implant, vaginal ring or nasal spray, is equivalent to the daily dose unit not exceeding twice the ovulation-inhibitory dose for the oral forms.
The invention further relates to a monophasic product for alleviating endometriosis which includes at least
Received at IPONZ on 12 December 2011
7
28 dosage units, preferably 30 dosage units, where appropriate in each case 2 blister packs of 14 or 15 dosage units, each comprising a progestogen having 5 antiandrogenic activity with not more than twice the ovulation-inhibitory dose, selected from dienogest, cyproterone acetate or chlormadinone acetate.
The invention also relates to a monophasic product for 10 alleviating endometriosis and without a negative influence on bone metabolism and thus a reduction in bone density which includes the above dosage units, each comprising a progestogen having antiandrogenic activity with not more than twice the ovulation-15 inhibitory dose, selected from dienogest, cyproterone acetate or chlormadinone acetate, where the dosage units are administered continuously for at least 169 to more than 730 days.
The monophasic product is suitable for the prophylaxis and/or therapy of endometriosis, and lessens endometriosis, but does not have a negative influence on bone metabolism/bone density and keeps both the known side effects related to endometriosis therapy 25 (reduced bone density, hot flushes, altered lipid profile) within tolerable limits. It is therefore suitable for long-term therapy.
Exemplary embodiments
Example 1
Tablets with the following composition are produced: Dienogest, micronized 2.000 mg min. 99% < 20 fxm, 100% < 30 [i.m Lactose monohydrate Microcrystalline cellulose Potato starch
62.800 mg 18.000 mg 3 6.000 mg
Received at IPONZ on 12 December 2011
8
Povidone K 25 Magnesium stearate Talc
Crospovidone
8.100 mg 1.350 mg 4.050 mg
2.700 mg
Dienogest is employed micronized with an average particle size of 20 p.m and mixed with lactose monohydrate, microcrystalline cellulose and potato 5 starch. The povidone K 25 is sprayed in during the granulation. After drying and admixing of talc, crospovidone and magnesium stearate, the mixture of substances is compressed to tablets with a diameter of 7 mm and a mass of 135 mg.
Example 2
In a clinical study, 252 women with endometriosis 15 diagnosed at laparoscopy were treated over a period of 6 months either with the GnRH agonist leuprorelin acetate (LA) 3.75 mg s.c. every 4 weeks or with 2 mg/d of the progestogen dienogest (DNG) orally. 128 patients were randomized to the LA group and 124 patients to the 20 DNG group. The efficacy of the respective therapy was examined inter alia by means of a scale of pain (visual analogue scale, VAS) to be completed by the patient. At the end of the treatment, both comparison groups showed a similar reduction in pain compared with the start of 25 the study (-47.5 mm for DNG; -46.0 mm for LA). Statistical analysis showed non-superiority of DNG over LA.
In addition, common side effects of hormonal therapy 30 methods for endometriosis were recorded:
Alterations in the menstrual bleeding occurred in both treatment groups, frequently as absence of period or in the form of slightly irregular bleeding - but these led 35 to discontinuation of the therapy in only a few
Claims (5)
1. The use of 17a-Cyanomethyl-17-beta-hydroxyestra-4, 9-5 diene-3-one (Dienogest) for the manufacture of a pharmaceutical product for monophasic continuous administration of 2 mg Dienogest daily for at least 169 days or 25 weeks to several years, to treat endometriosis.
2. The use according to claim 1 or 2 wherein the monophasic continuous administration is for at least 25 weeks. 15
3. The use according to claim 3 wherein the monophasic continuous administration is for more than 2 years.
4. The use according to any one of claims 1-4 wherein 20 the pharmaceutical product is a vaginal ring.
5. A use according to claim 1, substantially as herein described or exemplified. 25
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07004202A EP1977752A1 (en) | 2007-03-01 | 2007-03-01 | Pharmaceutical composition for reducing endometriosis |
| PCT/EP2008/001451 WO2008104342A1 (en) | 2007-03-01 | 2008-02-23 | Pharmaceutical preparation for the alleviation of endometriosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ577761A true NZ577761A (en) | 2012-03-30 |
Family
ID=38045772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ577761A NZ577761A (en) | 2007-03-01 | 2008-02-23 | Pharmaceutical preparation for the alleviation of endometriosis |
Country Status (18)
| Country | Link |
|---|---|
| EP (2) | EP1977752A1 (en) |
| JP (1) | JP2010520159A (en) |
| KR (1) | KR20090119829A (en) |
| CN (1) | CN101583364A (en) |
| AU (1) | AU2008221012A1 (en) |
| BR (1) | BRPI0806598A2 (en) |
| CA (1) | CA2673936A1 (en) |
| CO (1) | CO6190606A2 (en) |
| CR (1) | CR10912A (en) |
| DO (1) | DOP2009000171A (en) |
| EA (1) | EA200900829A1 (en) |
| EC (1) | ECSP099482A (en) |
| MA (1) | MA31162B1 (en) |
| MX (1) | MX2009007259A (en) |
| NZ (1) | NZ577761A (en) |
| SV (1) | SV2009003324A (en) |
| TN (1) | TN2009000263A1 (en) |
| WO (1) | WO2008104342A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101874806A (en) * | 2009-04-29 | 2010-11-03 | 北京本草天源药物研究院 | Dienogest solid preparation |
| CN102670519B (en) * | 2011-03-16 | 2014-06-11 | 重庆莱美药业股份有限公司 | Quickly-dissolvable dienogest oral preparation and preparation method thereof |
| CN103304619B (en) * | 2013-06-08 | 2015-12-02 | 西藏海思科药业集团股份有限公司 | A kind of Dienogest compound |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4426601A1 (en) * | 1994-07-27 | 1996-02-01 | Schering Ag | Use of a combination product containing a competitive progesterone antagonist and a progestogen for the manufacture of a medicament for the treatment of endometriosis or Leiomyomata uteri |
| EP1535618A1 (en) * | 2003-11-26 | 2005-06-01 | Schering Aktiengesellschaft | Pharmaceutical preparation for continuous hormonal treatment over a period of longer than 21-28 days comprising two estrogen and/or progestin compositions |
| MY151322A (en) * | 2004-04-30 | 2014-05-15 | Bayer Ip Gmbh | Management of breakthrough bleeding in extended hormonal contraceptive regimens |
| DE102004026679A1 (en) * | 2004-05-28 | 2005-12-15 | Grünenthal GmbH | Hormonal contraceptive containing a combination of ethinylestradiol and chlormadinone acetate |
| EP1655031A1 (en) * | 2004-10-08 | 2006-05-10 | Schering AG | Use of dienogest in fixed extended cycle hormonal contraceptives |
-
2007
- 2007-03-01 EP EP07004202A patent/EP1977752A1/en not_active Withdrawn
-
2008
- 2008-02-23 NZ NZ577761A patent/NZ577761A/en not_active IP Right Cessation
- 2008-02-23 AU AU2008221012A patent/AU2008221012A1/en not_active Abandoned
- 2008-02-23 EA EA200900829A patent/EA200900829A1/en unknown
- 2008-02-23 KR KR1020097014169A patent/KR20090119829A/en not_active Application Discontinuation
- 2008-02-23 BR BRPI0806598-5A patent/BRPI0806598A2/en not_active IP Right Cessation
- 2008-02-23 JP JP2009551120A patent/JP2010520159A/en active Pending
- 2008-02-23 EP EP08707797A patent/EP2059248A1/en not_active Ceased
- 2008-02-23 CN CNA2008800023330A patent/CN101583364A/en active Pending
- 2008-02-23 CA CA002673936A patent/CA2673936A1/en not_active Abandoned
- 2008-02-23 WO PCT/EP2008/001451 patent/WO2008104342A1/en active Application Filing
- 2008-02-23 MX MX2009007259A patent/MX2009007259A/en unknown
-
2009
- 2009-06-24 TN TNP2009000263A patent/TN2009000263A1/en unknown
- 2009-07-03 SV SV2009003324A patent/SV2009003324A/en not_active Application Discontinuation
- 2009-07-03 CO CO09068629A patent/CO6190606A2/en not_active Application Discontinuation
- 2009-07-03 CR CR10912A patent/CR10912A/en unknown
- 2009-07-03 EC EC2009009482A patent/ECSP099482A/en unknown
- 2009-07-03 DO DO2009000171A patent/DOP2009000171A/en unknown
- 2009-08-04 MA MA32138A patent/MA31162B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP2059248A1 (en) | 2009-05-20 |
| ECSP099482A (en) | 2009-08-28 |
| AU2008221012A1 (en) | 2008-09-04 |
| CA2673936A1 (en) | 2008-09-04 |
| TN2009000263A1 (en) | 2010-10-18 |
| EP1977752A1 (en) | 2008-10-08 |
| CN101583364A (en) | 2009-11-18 |
| DOP2009000171A (en) | 2009-08-31 |
| CR10912A (en) | 2009-08-13 |
| JP2010520159A (en) | 2010-06-10 |
| CO6190606A2 (en) | 2010-08-19 |
| SV2009003324A (en) | 2009-10-02 |
| MX2009007259A (en) | 2009-07-10 |
| MA31162B1 (en) | 2010-02-01 |
| WO2008104342A1 (en) | 2008-09-04 |
| EA200900829A1 (en) | 2010-02-26 |
| KR20090119829A (en) | 2009-11-20 |
| BRPI0806598A2 (en) | 2014-05-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PSEA | Patent sealed | ||
| LAPS | Patent lapsed |