MXPA01008772A - Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleeding - Google Patents
Use of sex hormones to obtain a nasal pharmaceutical composition that is useful in the treatment of undesirable uterine bleedingInfo
- Publication number
- MXPA01008772A MXPA01008772A MXPA/A/2001/008772A MXPA01008772A MXPA01008772A MX PA01008772 A MXPA01008772 A MX PA01008772A MX PA01008772 A MXPA01008772 A MX PA01008772A MX PA01008772 A MXPA01008772 A MX PA01008772A
- Authority
- MX
- Mexico
- Prior art keywords
- estradiol
- nasal
- pharmaceutical composition
- treatment
- progestogen
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 206010046788 Uterine haemorrhage Diseases 0.000 title claims abstract description 10
- 239000003163 gonadal steroid hormone Substances 0.000 title abstract description 12
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 20
- 229960005309 Estradiol Drugs 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 229920000858 Cyclodextrin Polymers 0.000 claims description 11
- 239000000583 progesterone congener Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 229960003851 Estradiol Hemihydrate Drugs 0.000 claims description 3
- VIKNJXKGJWUCNN-XGXHKTLJSA-N Norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 claims description 3
- 229960000993 norethisterone Drugs 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- NPAGDVCDWIYMMC-IZPLOLCNSA-N Nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 229960004719 nandrolone Drugs 0.000 claims 1
- 206010018987 Haemorrhage Diseases 0.000 description 5
- 230000000740 bleeding Effects 0.000 description 5
- 231100000319 bleeding Toxicity 0.000 description 5
- 239000007921 spray Substances 0.000 description 4
- -1 17β- (estradiol) Chemical class 0.000 description 3
- 206010030247 Oestrogen deficiency Diseases 0.000 description 3
- 230000009245 menopause Effects 0.000 description 3
- 239000007922 nasal spray Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 239000000186 progesterone Substances 0.000 description 3
- 229940097496 Nasal Spray Drugs 0.000 description 2
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Syngestrets Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 230000003466 anti-cipated Effects 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- 150000000319 19-nortestosterones Chemical class 0.000 description 1
- 229940030486 ANDROGENS Drugs 0.000 description 1
- ZUQAPLKKNAQJAU-UHFFFAOYSA-N Acetylenediol Chemical compound OC#CO ZUQAPLKKNAQJAU-UHFFFAOYSA-N 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 229960001616 Chlormadinone Acetate Drugs 0.000 description 1
- 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 1
- JWAHBTQSSMYISL-MHTWAQMVSA-N Demegestone Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(C)[C@@]1(C)CC2 JWAHBTQSSMYISL-MHTWAQMVSA-N 0.000 description 1
- RPLCPCMSCLEKRS-BPIQYHPVSA-N Desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 description 1
- JGMOKGBVKVMRFX-HQZYFCCVSA-N Dydrogesterone Chemical compound C1=CC2=CC(=O)CC[C@@]2(C)[C@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 JGMOKGBVKVMRFX-HQZYFCCVSA-N 0.000 description 1
- 229940011871 Estrogens Drugs 0.000 description 1
- 229960003399 Estrone Drugs 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Etivex Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 229960005352 Gestodene Drugs 0.000 description 1
- SIGSPDASOTUPFS-XUDSTZEESA-N Gestodene Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](C=C4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 SIGSPDASOTUPFS-XUDSTZEESA-N 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Hiestrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- HCFSGRMEEXUOSS-JXEXPEPMSA-N Medrogestone Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(C)[C@@]1(C)CC2 HCFSGRMEEXUOSS-JXEXPEPMSA-N 0.000 description 1
- IIVBFTNIGYRNQY-YQLZSBIMSA-N Nomegestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 IIVBFTNIGYRNQY-YQLZSBIMSA-N 0.000 description 1
- KIQQMECNKUGGKA-NMYWJIRASA-N Norgestimate Chemical compound O/N=C/1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(OC(C)=O)C#C)[C@@H]4[C@@H]3CCC2=C\1 KIQQMECNKUGGKA-NMYWJIRASA-N 0.000 description 1
- 229940053938 Norgestrel Drugs 0.000 description 1
- 229940030490 PROGESTOGEN SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM Drugs 0.000 description 1
- 208000001685 Postmenopausal Osteoporosis Diseases 0.000 description 1
- WWYNJERNGUHSAO-XUDSTZEESA-N Previfem 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 1
- 229940095055 Progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- QFFCYTLOTYIJMR-XMGTWHOFSA-N Promegestone Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@@](C(=O)CC)(C)[C@@]1(C)CC2 QFFCYTLOTYIJMR-XMGTWHOFSA-N 0.000 description 1
- 229940030484 SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM ESTROGENS Drugs 0.000 description 1
- 229960003604 Testosterone Drugs 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 201000000736 amenorrhea Diseases 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229960003473 androstanolone Drugs 0.000 description 1
- 230000000295 complement Effects 0.000 description 1
- 230000002254 contraceptive Effects 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001853 demegestone Drugs 0.000 description 1
- 229960004976 desogestrel Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229960004913 dydrogesterone Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940046080 endocrine therapy drugs Estrogens Drugs 0.000 description 1
- 229940046079 endocrine therapy drugs Progestogens Drugs 0.000 description 1
- 230000001667 episodic Effects 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
- 229960000606 medrogestone Drugs 0.000 description 1
- 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 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- 210000004914 menses Anatomy 0.000 description 1
- 230000003821 menstrual periods Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 229960004190 nomegestrol acetate Drugs 0.000 description 1
- 229960000417 norgestimate Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 229960001584 promegestone Drugs 0.000 description 1
- 230000001568 sexual Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000008738 uterine disease Diseases 0.000 description 1
Abstract
The invention relates to the use of a sex hormone to obtain a pharmaceutical composition that is suitable for nasal administration in order to treat undesirable uterine bleeding phenomena in women.
Description
USE OF SEXUAL HORMONES TO OBTAIN A COMPOSITION
NASAL PHARMACEUTICAL THAT IS USEFUL IN THE TREATMENT OF
UNSUITABLE UTERINE BLEEDING
The present invention relates to the use of sex hormones to obtain a pharmaceutical composition suitable for administration by the nasal route which is useful in the treatment of the phenomenon of undesirable uterine bleeding in women. In therapies that require the administration of sex hormones, uterine bleeding is very often seen outside of anticipated normal periods. Sex hormones can be administered in the treatment of disorders caused by estrogen deficiency and by symptoms of estrogen deficiency associated especially with artificial or natural menopause. These estrogen deficiencies are equally implicated in the occurrence of post-menopausal osteoporosis and in the phenomenon of brain aging and cardiovascular disorders. On the other hand, sex hormones are also administered in several doses for contraceptive purposes or in the treatment of amenorrhea that is not associated with menopause. The pharmaceutical compositions containing sex hormones currently available to the medical profession are compositions that are suitable for oral administration (tablets), transcutaneous administration (gels transdermal systems), parenteral administration (intramuscular injections, implants) or vaginal administration (creams, gels. ..). In a certain number of cases, these various types of treatment cause uterine, episodic or systematic bleeding, outside of the anticipated periods of menstruation,. The problem caused by this phenomenon of bleeding is that it causes concern among patients, who can not by themselves make a distinction between a side effect associated with the treatment and the onset of a uterine disorder. This phenomenon results in the attending physician requesting several kinds of complementary investigations in order to determine the cause of the bleeding. When bleeding is simply associated with treatment, patients then want to return to other types of treatment or prefer to discontinue treatment. In this way, bleeding seems to be one of the main causes of treatment abandonment. At present, all available types of treatment result in compliance difficulties, which to date have only been partially improved by the currently available pharmaceutical forms. Now, the Applicant has discovered that the use of sex hormones to obtain a pharmaceutical composition that is suitable for administration by the nasal route has surprisingly facilitated the treatment of uterine bleeding observed outside the
menstrual periods. This surprising effect, achieved by nasal administration, has not been observed with the other formulations currently available to the medical profession. The improvement is completely more significant
and of interest, since it demonstrates long-term effectiveness, being possible, however, that the treatment be extended for several years. Among the sex hormones that can be used in pharmaceutical compositions according to
In the invention, there may be mentioned, without limitation, natural estrogen steroids such as 17β- (estradiol), estrone and its derivatives, synthetic steroid estrogens, such as ethinyl estradiol, progestogens, such as progesterone,
pregnanes derived from progesterone or 17a-OH-progesterone, such as dydrogesterone, chlormadinone acetate, medrogesterone, medroxyprogesterone acetate, norpregnanes, such as demegestone, promegestone, nomegestrol acetate or 19-nortestosterone compounds, such as norethisterone, diacetate of ethynediol, norgestrel, lovonorgestrel, desogestrel, gestodene or norgestimate, or androgens, such as testosterone or dihydrotestosterone. Preferred sex hormones for the present invention are estradiol and mixtures of estradiol / progestogen. Pharmaceutical compositions suitable for nasal administration of sex hormones are more specifically those that contain one or more sex hormones at doses that vary as a function of the patient's requirements, and a cyclodextrin. Preferably, the pharmaceutical compositions according to the invention are characterized in that the cyclodextrin is a partially methylated cyclodextrin. A preferred composition according to the invention is one which contains extradiol or a mixture of estradiol / progestogen and a cyclodextrin partially methylated and randomly.
When the composition contains a progestogen, the preferred progestogen is norethisterone. The preferred use according to the invention of the pharmaceutical compositions is in the treatment of undesirable uterine bleeding during menopause. By way of non-limiting example, a pharmaceutical composition suitable for nasal administration of estradiol was prepared and clinically tested in order to observe the treatment of the phenomenon of uterine bleeding in menopausal women. The composition is a solution that contains
0. 21 g of estradiol hemihydrate, 2.10 g of random and partially methylated cyclodextrin, 0.9 g of sodium chloride and purified water (add 100 ml), after adjusting the pH of the solution to 6. The solution was packed in a bottle equipped with a distribution pump that allows nasal sprays of 0.07 ml to be distributed. Each spray thus distributes a 150 μl dose of estradiol hemihydrate.
Clinical Studies: Clinical studies were conducted in a population of patients who have been post-menopausal for at least 10 years. The patients were divided into groups that, during a 28 day cycle, were given either: a nasal estradiol composition of the kind described hereinabove (estradiol spray) and an oral placebo composition, or an oral formulation of estradiol and a nasal placebo composition (placebo spray). In each group, patients were administered with a progestogen for at least 10 to 14 days per cycle at the recommended doses for each product. The treatments were given according to a randomization code and lasted 3, 6 or 12 months. The daily dose administered for the nasal spray form is 300 μg of estradiol (2 sprays per day), which corresponds to a dose of 2 mg when the administration is carried out by the oral route.
Results: In the course of clinical studies, it was observed that uterine bleeding in patients in the group treated with nasal spray of estradiol was approximately 30% less frequent than in patients treated with an oral form of estradiol.
Claims (9)
- CLAIMS 1. The use of estradiol in obtaining a pharmaceutical composition suitable for administration by the nasal route to treat the phenomenon of undesirable uterine bleeding in women.
- 2. The use according to claim 1, characterized in that the estradiol is used in admixture with a progestogen.
- 3. The use according to claim 2, characterized in that the progestogen is a compound of 19-nortestosterone.
- 4. The use according to claim 3, characterized in that the progestogen is norethisterone.
- 5. The use according to either claim 1 or claim 2, characterized in that the composition suitable for nasal administration contains estradiol or a mixture of estradiol / progestogen and a cyclodextrin.
- 6. The use according to claim 5, characterized in that the cyclodextrin present in the nasal composition is a partially methylated cyclodextrin.
- The use according to claim 6, characterized in that the partially methylated cyclodextrin present in the nasal composition is randomly methylated.
- 8. The pharmaceutical composition suitable for administration by the nasal route according to either claim 1 or claim 2, characterized in that it occurs in the form of an aqueous solution containing estradiol or a mixture of estradiol / progestogen and a random cyclodextrin and partially methylated.
- 9. The pharmaceutical composition according to claim 8, characterized in that it contains 0.21 g of estradiol hemihydrate, 2.10 g of random and partially methylated cyclodextrin and 0.9 g of sodium chloride for a quantity of purified water sufficient to obtain a total volume of solution of 100 ml, the pH of the solution that is adjusted to 6.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR99/04022 | 1999-03-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01008772A true MXPA01008772A (en) | 2002-05-09 |
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