CN101443011A - Use of flibanserin for the treatment of post-menopausal sexual desire disorders - Google Patents
Use of flibanserin for the treatment of post-menopausal sexual desire disorders Download PDFInfo
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- CN101443011A CN101443011A CNA2007800169605A CN200780016960A CN101443011A CN 101443011 A CN101443011 A CN 101443011A CN A2007800169605 A CNA2007800169605 A CN A2007800169605A CN 200780016960 A CN200780016960 A CN 200780016960A CN 101443011 A CN101443011 A CN 101443011A
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- menopause
- lifelong
- acquired
- flibanserin
- libido
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Abstract
The invention relates to the use of flibanserin for the preparation of a medicament for the treatment of post-menopausal Sexual Desire Disorders.
Description
The present invention relates to the purposes in the medicine of flibanserin dysaphrodisia after preparation is used for the treatment of menopause.
Invention is described
Chemical compound 1-[2-(4-(3-trifluoromethyl-phenyl) piperazine-1-yl) ethyl]-2,3-dihydro-1H-benzimidazolyl-2 radicals-ketone (flibanserin, flibanserin) be that form with its hydrochlorate is disclosed among European patent application EP-A-526434, and have following chemical constitution.
Flibanserin demonstrates 5-HT
1AAnd 5-HT
2-receptor has affinity.Therefore it is a kind of for example promising therapeutic agent of depression, schizophrenia and anxiety neurosis of multiple disease for the treatment of.
Technical term " property disease " comprises dysaphrodisia, sexual excitation obstacle, orgasm disorder disease, dyspareunia, because the sexual dysfunction that general medicine condition of illness causes, material induction type sexual dysfunction and the sexual dysfunction of certain illustrated (Diagnostic and Statistical Manual of MentalDisorders not, the 4th edition, Text Revision, Washington DC, American PsychiatricAssociation, 2000).
The present invention relates to randomly as the form of free alkali, the last acceptable acid-addition salts of pharmacology and/or randomly be used for the treatment of the purposes of the medicine of postmenopausal women dysaphrodisia in preparation as the flibanserin of the form of its hydrate and/or solvate.
Term " treatment menopause after hyposexuality (Hypoactive) disease " waits the implication with " treating postmenopausal women hyposexuality obstacle " etc. in the present invention.
Can be observed the advantageous effect of flibanserin, no matter all the life existence or acquired dysaphrodisia are " general type (generalized type) " or " situational type (situational type) ", no matter and cause of disease origin (combination of organ (health and drug-induced), psychology (owing to psychological factor), organ (health and drug-induced) and psychology (owing to psychological factor), or unknown).Term " lifelong (lifelong) " is meant that described dysaphrodisia of the present invention promptly exists from initial from sexual function.Term " acquired (acquired) " is meant only back generation during one section normal sexual function of dysaphrodisia of the present invention." general type " is meant that described property disease of the present invention is not limited to stimulation, situation or the companion of some types." situational type " is applicable to that described property disease of the present invention is confined to stimulation, situation or the companion of some types.Owing to the hypotype of " psychological factor " be applicable to judge psychological factor outbreak, the order of severity of sexual disorders, worsen or keep in have important function, and general medicine situation and material do not have in the cause of disease of sexual disorders and do the time spent.At last, the hypotype owing to " blocking factor " is applicable to 1) judge psychological factor outbreak, the order of severity of property disease, worsen or keep in have effect; And 2) also judge that general medicine situation or used material can cause but (Diagnosticand Statistical Manual of Mental Disorders when being not sufficient to become the reason of sexual disorders, the 4th edition, the text revised edition, WashingtonDC, American Psychiatric Association, 2000).
Therefore, for example term " hyposexuality obstacle after the lifelong menopause " is meant that the postmenopausal women hyposexuality obstacle that exists, term " hyposexuality obstacle after the acquired menopause " are meant the postmenopausal women hyposexuality obstacle that afterwards takes place during one section normal sexual function when sexual function is initial.As if though there is obvious contradiction in wording " lifelong menopause after ", it is interpreted as the disease diagnosed after the menopause, show that by medical history in fact this disease promptly exists from initial from sexual function.
Therefore, in a preferred embodiment, the present invention relates to flibanserin and randomly be free alkali, the form of the last acceptable acid-addition salts of pharmacology and/or randomly be the purposes of the form of hydrate and/or solvate, it is to be used to prepare a kind of medicine that is used for the treatment of the disease that is selected from: hyposexuality obstacle (lifelong post-menopausal Hypoactive Sexual DesireDisorder) after the lifelong menopause, sexual aversion disorder (lifelong post-menopausal Sexual AversionDisorder) after the lifelong menopause, sexual anesthesia (lifelong post-menopausal loss of sexualdesire) after the lifelong menopause, hyposexuality (lifelong post-menopausal lack of sexual desire) after the lifelong menopause, libido reduces (lifelong post-menopausal decreased sexual desire) after the lifelong menopause, libido is subjected to press down (lifelong post-menopausal inhibited sexual desire) after the lifelong menopause, libido forfeiture (lifelong post-menopausal loss of libido) after the lifelong menopause, hyposexuality (lifelongpost-menopausal frigidity) after libido obstacle (lifelong post-menopausal libido disturbance) and the lifelong menopause after the lifelong menopause.
Especially be preferably according to the present invention randomly as the form of free alkali, the last acceptable acid-addition salts of pharmacology and/or randomly as the flibanserin of the form of hydrate and/or solvate, be used for the treatment of purposes in the medicine of the disease that is selected from following each disease in preparation: after the lifelong menopause after hyposexuality obstacle, the lifelong menopause after sexual aversion disorder, the lifelong menopause after sexual anesthesia, the lifelong menopause after hyposexuality, the lifelong menopause libido reduce and lifelong menopause after libido be subjected to press down.
In especially preferred embodiment, the present invention relates to randomly as the form of free alkali, the last acceptable acid-addition salts of pharmacology and/or randomly as the flibanserin of the form of hydrate and/or solvate, be used for the treatment of purposes in the medicine that is selected from following disease in preparation: after the lifelong menopause after hyposexuality obstacle, the lifelong menopause after sexual anesthesia and the lifelong menopause libido reduce.
In another embodiment preferred, the present invention relates to randomly as free alkali, the form of the last acceptable acid-addition salts of pharmacology and/or randomly as the flibanserin of the form of hydrate and/or solvate is used for the treatment of purposes in the medicine that is selected from following each disease in preparation: hyposexuality obstacle after the acquired menopause, sexual aversion disorder after the acquired menopause, sexual anesthesia after the acquired menopause, hyposexuality after the acquired menopause, libido reduces after the acquired menopause, libido is subjected to press down after the acquired menopause, libido forfeiture after the acquired menopause, hyposexuality after libido obstacle and the acquired menopause after the acquired menopause.
In addition, be preferably flibanserin according to the present invention, randomly be the form of free alkali, the last acceptable acid-addition salts of pharmacology and/or randomly be the form of hydrate and/or solvate, be used for the treatment of purposes in the medicine that is selected from following disease in preparation: libido reduces after hyposexuality, the acquired menopause after sexual anesthesia, the acquired menopause after sexual aversion disorder, the acquired menopause after hyposexuality obstacle, the acquired menopause after the acquired menopause, libido is subjected to press down after the acquired menopause.
In particularly preferred embodiments, the present invention relates to flibanserin, randomly be the form of free alkali, the last acceptable acid-addition salts of pharmacology and/or randomly be the form of hydrate and/or solvate, be used for the treatment of purposes in the medicine that is selected from following disease in preparation: after the acquired menopause after hyposexuality obstacle, the acquired menopause after sexual anesthesia and the acquired menopause libido reduce.
In addition, the present invention relates to the general or situation hypotype of arbitrary above-mentioned disease and/or owing to psychological factor or owing to the blocking factor hypotype.
Flibanserin is randomly with the form of free alkali form, pharmaceutically useful acid-addition salts and/or randomly use with the form of hydrate and/or solvate.Suitably acid-addition salts comprises the addition salts that for example is selected from following acid formation: succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, Loprazolam, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid.Also can use the mixture of above-mentioned acid-addition salts.In the above-mentioned acid-addition salts, hydrogen chlorate and hydrobromate, especially the hydrogen chlorate is preferred.If flibanserin uses with free alkali form, then it preferably uses with the form as disclosed flibanserin polymorph A among the WO 03/014079.
Flibanserin, randomly with the form of free alkali, the last acceptable acid-addition salts of pharmacology and/or randomly use with the form of hydrate and/or solvate, it can be mixed in the pharmaceutical preparation of routine of solid, liquid and spray form.The form that said composition is can be for example oral to be fit to, rectum, parenteral or intranasal suck exists, and preferred form comprises for example capsule, tablet, coated tablet, ampoule, suppository and nasal spray.
Active component can be mixed into excipient or the carrier that routine is used for pharmaceutical composition, for example Talcum, arabic gum, lactose, gelatin, magnesium stearate, corn starch, aqueous or nonaqueous solvent, polyvinylpyrrolidone, semisynthetic fatty glyceride, benzalkonium chloride, sodium phosphate, EDTA, polysorbate80.Advantageously, said composition can be configured to dosage unit, each dosage unit is suitable for providing the active component of single dose.Dosage range applicatory is between every day 0.1 to 400mg, preferably between 1.0 to 300mg, is more preferably between 2 to 200mg.Each dosage unit can contain 0.01 easily to 100mg, is preferably 0.1 to 50mg.
Every day is to patient's administration 1 time, 2 times, 3 times or 4 dosage forms.Chemical compound of the present invention preferably is administered three times or below three times every day, and more preferably one or twice, a period of time continuously.
Preferably, reach evening in the morning, more preferably be administered once morning (25 or 50mg flibanserin) and evening once (25 or 50mg flibanserin), most preferably only evening once (50 or 100mg flibanserin), a period of time continuously to patient's dosage.For improving the toleration of short time, but half target dose of administration.
Therefore side effect such as calmness is not remarkable.
Suitable tablet can pass through, for example with active substance and known excipient, for example inert diluent such as calcium carbonate, calcium phosphate or lactose, disintegrating agent such as corn starch or alginic acid, binding agent such as starch or gelatin, lubricant such as magnesium stearate or Talcum and/or postpone releasing agent such as carboxymethyl cellulose, cellulose acetate-phthalate, or polyvinyl acetate mixes and makes.This tablet also can comprise several layers.
Correspondingly, coated tablet can be coated with by the sheet heart of the such tablets that will make and be covered with the material that is generally used for tablet coating, but for example power ketone (collidone) or Lac (shellac), arabic gum, Talcum, titanium dioxide or sugar prepare.In order to realize slow release or prevent incompatibility that this sheet heart also can comprise many layers.Similarly, tablet coating can comprise many layers and reach slow release, perhaps uses the above-mentioned excipient of mentioning that is used for tablet.
According to the present invention, the syrup or the elixir that contain active substance or its combination can comprise sweetener in addition, for example glucide, cyclamate (cyclamate), glycerol or sugar and flavour enhancer, for example flavoring agent such as Rhizoma et radix valerianae element (vanilline) or Citrus extract.They also can comprise suspension adjuvants or thickening agent such as sodium carboxymethyl cellulose, and wetting agent is the condensation product of aliphatic alcohol and oxirane for example, or antiseptic such as p-Hydroxybenzoate.
Injection solution for example adds the alkali metal salt of antiseptic such as p-Hydroxybenzoate or stabilizing agent such as ethylenediaminetetraacetic acid, and is transferred in injection vials or the ampoule according to the conventional method preparation.
The capsule that comprises one or more active substances or active substance combination for example can prepare by following method: active substance and inert carrier such as lactose or Sorbitol are mixed, and they are packed in the gelatine capsule.
Suitable suppository for example can prepare by mixing with the carrier that provides for this purpose such as neutral fat or Polyethylene Glycol or derivatives thereof.
Following examples are the present invention to be described and unrestricted its scope:
The example of pharmaceutical preparation
A)
Tablet Each sheet
Flibanserin 100mg
Lactose 240mg
Corn starch 340mg
Polyvinylpyrrolidone 45mg
Magnesium stearate
15mg
740mg
Active substance, lactose and some corn starchs of wearing into fine-powdered are mixed together.Mixture is sieved, moistening with the aqueous solution of polyvinylpyrrolidone then, knead, wet granulation and dry.This granule, remaining corn starch and magnesium stearate are sieved and mix.Mixture is pressed into the tablet of suitable shape and size.
B)
Tablet Each sheet
Flibanserin 80mg
Corn starch 190mg
Lactose 55mg
Microcrystalline Cellulose 35mg
Polyvinylpyrrolidone 15mg
Carboxymethyl starch sodium 23mg
Magnesium stearate
2mg
400mg
Active substance, some corn starchs, lactose, microcrystalline Cellulose and the polyvinylpyrrolidone of wearing into fine-powdered are mixed together, mixture are sieved, and be processed to form granule, be dried and sieve with remaining corn starch and water.Add carboxymethyl starch sodium and magnesium stearate and mixing, mixture is suppressed to form the tablet of suitable size.
C)
Coated tablet Each coated tablet
Flibanserin 5mg
Corn starch 41.5mg
Lactose 30mg
Polyvinylpyrrolidone 3mg
Magnesium stearate
0.5mg
80mg
Active substance, corn starch, lactose and polyvinylpyrrolidone are fully mixed, and water is moistening.With the lumps thing of moistening screen cloth by the 1mm mesh size, in about 45 ℃ of dryings, and then with granule by identical screen cloth.After magnesium stearate is sneaked into, in tablet machine, be pressed into the convex surface tablet label of diameter 6mm.The tablet heart of preparation is thus applied the coating of being made up of sugar and Talcum basically by known method.With the coated tablet wax polishing of making.
D)
Capsule Each capsule
Flibanserin 150mg
Corn starch 268.5mg
Magnesium stearate
1.5mg
420mg
With material and corn starch mixing and moistening with water.The lumps thing of moistening is sieved and drying.Dried granules is sieved and mix with magnesium stearate.The mixture of making is adorned in the hard gelatin capsule of No. 1 size.
E)
Ampoule solution
Flibanserin 50mg
Sodium chloride 50mg
Water for injection 5ml
Itself pH or to choose wantonly at pH be under the 5.5-6.5, active substance is soluble in water, and add sodium chloride make its etc. open.Under apyrogeneity, the solution that obtains is filtered, this filtrate is transferred in the ampoule under aseptic condition, then with its sterilization and sealing by fusing.
F)
Suppository
Flibanserin 50mg
Hard fat
1650mg
1700mg
Tristearin is melted.Under 40 ℃ with powdered active substance homodisperse.It is cooled to 38 ℃ and be poured in the chilly suppository mould.
Claims (16)
1. flibanserin, randomly be the form of its free alkali, the last acceptable acid-addition salts of pharmacology and/or randomly be the form of its hydrate and/or solvate, the purposes after preparation is used for the treatment of women (lifelong or acquired) menopause in the medicine of dysaphrodisia.
2. purposes as claimed in claim 1, it is characterized in that after this menopause that dysaphrodisia is selected from that libido reduces after hyposexuality after sexual anesthesia after sexual aversion disorder after hyposexuality obstacle after the lifelong menopause, the lifelong menopause, the lifelong menopause, the lifelong menopause, the lifelong menopause, after the lifelong menopause libido be subjected to press down, hyposexuality after libido obstacle and the lifelong menopause after the libido forfeiture after the lifelong menopause, lifelong menopause.
3. purposes as claimed in claim 1 or 2 is characterized in that after this menopause that dysaphrodisia is selected from that libido reduces after hyposexuality after sexual anesthesia after sexual aversion disorder after hyposexuality obstacle after the lifelong menopause, the lifelong menopause, the lifelong menopause, the lifelong menopause, the lifelong menopause, libido is subjected to press down after the lifelong menopause.
4. purposes as claimed in claim 1, it is characterized in that after this menopause that dysaphrodisia is selected from that libido reduces after hyposexuality after sexual anesthesia after sexual aversion disorder after hyposexuality obstacle after the acquired menopause, the acquired menopause, the acquired menopause, the acquired menopause, the acquired menopause, after the acquired menopause libido be subjected to press down, hyposexuality after libido obstacle and the acquired menopause after the libido forfeiture after the acquired menopause, acquired menopause.
5. as claim 1 or 4 described purposes, it is characterized in that after this menopause that dysaphrodisia is selected from that libido reduces after hyposexuality after sexual anesthesia after sexual aversion disorder after hyposexuality obstacle after the acquired menopause, the acquired menopause, the acquired menopause, the acquired menopause, the acquired menopause, libido is subjected to press down after the acquired menopause.
6. each described purposes in the claim as described above is characterized in that dysaphrodisia is general hypotype after this menopause.
7. each described purposes in the claim as described above is characterized in that dysaphrodisia is the situation hypotype after this menopause.
8. each described purposes in the claim as described above, it is characterized in that this menopause after dysaphrodisia owing to psychological factor.
9. each described purposes in the claim as described above is characterized in that dysaphrodisia is owing to blocking factor after this menopause.
10. each described purposes in the claim as described above, it is characterized in that flibanserin is the form use of going up acceptable acid-addition salts with the pharmacology, wherein said pharmacology goes up acceptable acid-addition salts and is selected from by following sour formed salt: succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, Loprazolam, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid, citric acid and composition thereof.
11. each described purposes in the claim is characterized in that flibanserin is to use with the form of free alkali as described above.
12. purposes as claimed in claim 11 is characterized in that flibanserin is that this polymorph A uses dsc measurement to have about 161 ℃ fusing point with the form use of the polymorph A of free alkali.
13. each described purposes in the claim is characterized in that flibanserin is the dosage range use with every day 0.1 to 400mg as described above.
14. each described purposes in the claim is characterized in that flibanserin uses one or twice every day, uses a period of time continuously as described above.
15. each described purposes in the claim as described above is characterized in that flibanserin reaches in the morning to use evening, more preferably morning once (25 or 50mg flibanserin) and evening once (25 or 50mg flibanserin).
16. each described purposes in the claim as described above is characterized in that flibanserin only uses once (50 or 100mg flibanserin) at night, uses a period of time continuously.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US74681706P | 2006-05-09 | 2006-05-09 | |
| US60/746,817 | 2006-05-09 | ||
| US60/830,987 | 2006-07-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101443011A true CN101443011A (en) | 2009-05-27 |
Family
ID=40727096
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800169605A Pending CN101443011A (en) | 2006-05-09 | 2007-05-07 | Use of flibanserin for the treatment of post-menopausal sexual desire disorders |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101443011A (en) |
| UA (1) | UA97950C2 (en) |
| ZA (1) | ZA200808104B (en) |
-
2007
- 2007-05-07 UA UAA200813663A patent/UA97950C2/en unknown
- 2007-05-07 CN CNA2007800169605A patent/CN101443011A/en active Pending
-
2008
- 2008-09-22 ZA ZA200808104A patent/ZA200808104B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200808104B (en) | 2009-07-29 |
| UA97950C2 (en) | 2012-04-10 |
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