CN106866546A

CN106866546A - Solid dispersions of flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof

Info

Publication number: CN106866546A
Application number: CN201510910546.5A
Authority: CN
Inventors: 张席妮; 熊志刚; 周涛; 资春鹏; 涂福荣
Original assignee: Changzhou Ainuo New Rui Pharmaceutical Co Ltd
Current assignee: Changzhou Ainuo New Rui Pharmaceutical Co Ltd
Priority date: 2015-12-10
Filing date: 2015-12-10
Publication date: 2017-06-20

Abstract

A kind of unformed flibanserin, it is characterised in that the characteristic peak without flibanserin in X-ray powder diffraction spectrum.A kind of unformed flibanserin pharmaceutically acceptable salt, it is characterised in that without the characteristic peak of flibanserin salt in X-ray powder diffraction spectrum.A kind of preparation method of the unformed shape of unformed flibanserin or its pharmaceutically acceptable salt and its solid dispersions and its manufacture method with pharmaceutic adjuvant, wherein, flibanserin or its pharmaceutically acceptable salt are unformed shape.The solid dispersions stability and favorable dispersibility of flibanserin of the invention or its pharmaceutically acceptable salt and pharmaceutic adjuvant, increased flibanserin or the dissolution rate of its salt, it is more beneficial for improving the absorption of the bioavilability and body of pharmaceutical preparation to medicine, under the conditions of accelerated test, good physics and chemical stability can be kept.The preparation method of unformed solid dispersions of the invention is simple to operate, with low cost, favorable reproducibility, it is easy to accomplish, it is adapted to industrial production.

Description

The solid dispersions of flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant and Its preparation method

Technical field

The invention belongs to field of pharmaceutical preparations, and in particular to a kind of unformed flibanserin and unformed flibanserin hydrochloric acid Salt, further relates to the solid dispersions of a kind of unformed flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant, relates to again And it is a kind of containing unformed flibanserin or its pharmaceutically Pharmaceutical composition of acceptable salt and pharmaceutic adjuvant and its preparation Method.

Background technology

Flibanserin（Flibanserin）, chemical entitled 3- [2- [4- [4- (trifluoromethyl) phenyl] piperazine -1- bases] second Base] -1H- 2-ketone benzimidaozoles are a kind of medicines for improving female libido of German Boehringer Ingelheim company exploitation. Flibanserin mainly acts on two kinds of neurotransmitters for helping to evoke sexual desire in brain.Wherein the first mediator is dopamine, It controls the reward of brain and happy center, and people can be helped to improve the interest to sexual behaviour.Second noradrenaline Element, the part that it reacts mainly for responsible control notice in brain and to environment, can help people by notice collection In to sex partner.Clinical research shows that it has obvious therapeutic effect to Pre-menopausal Women hyposexuality.

Although flibanserin is evident in efficacy, but still there are some defects.Patent PCT/EP02,08466 disclose fluorine The polymorphs form of Ban Selin free alkalis：Polymorph A and Polymorph B；Patent PCT/IN2009/000347 is disclosed Nine kinds of crystal formations of flibanserin hydrochloride：Form I、Form II、Form III、Form IV、Form V、Form VI、Form VII, Form VIII and Form IX, but and have no unformed report.What the medicine was used for preparation is flibanserin free alkali, Although polymorphs form is thermodynamically stable crystal formation, stable type is good, and solubility of the crystal formation in water is extremely low, and its is extremely low Water solubility had a strong impact on the bioavilability of medicine.

The solid forms of medicine directly affect the rate of dissolution of bulk drug, the dissolution rate of preparation and bioavilability, in order to The bioavilability of medicine is improved, consumption is reduced, is reduced toxic and side effect, it will usually develop the new solid forms of medicine, therefore, Develop the solid form that the drug solubility is more preferable, bioavilability is higher and just seem necessary.

The solid forms of medicine in addition to crystalline state, also unformed state, the unformed state of medicine is used as solid matter A kind of specific form, there is important purposes in medicine preparation.Unformed shape medicine not only can be widely applied to medicine system In agent, and can be made with excellent by multiple technologies means and the stability of method raising unformed shape medicine The medicine of quality.

Because not enough and unformed active constituents of medicine of the flibanserin in terms of bioavilability is in terms of pharmaceutical preparation Good application prospect, find new unformed flibanserin and preparation method thereof and just seem very necessary.

The content of the invention

Divide with the solid of pharmaceutic adjuvant it is an object of the invention to provide a kind of flibanserin or its pharmaceutically acceptable salt Prose style free from parallelism and preparation method thereof, obtains the flibanserin of the unformed shape of stability and favorable dispersibility or its is pharmaceutically acceptable Salt and the solid dispersions of pharmaceutic adjuvant, increased flibanserin or the dissolution rate of its salt, and the preparation method does not receive drying process Limitation, also do not limited by solvent species and quantity of solvent, it is easy to operate, it is with low cost, it is easy to accomplish, be capable of achieving industry metaplasia Produce.

In order to achieve the above object, technical scheme is as follows：

A kind of unformed flibanserin, preparation method comprises the following steps：

1）After flibanserin is dissolved with solvent, solution temperature is -50 ~ 150 DEG C, forms the solution of containing flibanserin, wherein, fluorine Ban Selin is 0.001 ~ 100 with the weight ratio of solvent:1；

2）Removing step 1）Solvent in the solution for obtaining, or by step 1）The solution for obtaining is lowered the temperature rapidly, or is quickly added Enter poor solvent, carry out crystallization, obtain the unformed form of flibanserin.

Also, step 1）The solvent is selected from containing less than 12 alcohols, phenols, ethers, halogenated hydrocarbons, ketone, the aldehyde of carbon atom At least one in class, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water, step 2）The method for removing solvent includes：Evaporation, vacuum Evaporation, spray drying, freeze-drying, hot-melt extruded, filtering, centrifugation or agitated thin film.

A kind of unformed flibanserin hydrochloride, preparation method comprises the following steps：

1）After flibanserin hydrochloride is dissolved with solvent, solution temperature is -50 ~ 150 DEG C, forms containing flibanserin hydrochloride Solution, wherein, flibanserin hydrochloride is 0.001 ~ 100 with the weight ratio of solvent:1；

2）Removing step 1）Solvent in the solution for obtaining, or by step 1）The solution for obtaining is lowered the temperature rapidly, or is quickly added Enter poor solvent, carry out crystallization, obtain the unformed form of flibanserin hydrochloride.

The solid dispersions of a kind of flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant, the solid dispersions bag Containing flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant, both weight ratios are 1:0.1 ~ 100, wherein, it is described Flibanserin or its pharmaceutically acceptable salt are unformed shape, in the X-ray powder diffraction spectrum of the solid dispersions, The characteristic peak of the crystal without flibanserin or its salt after the background peaks of deduction pharmaceutic adjuvant.

Further, the pharmaceutic adjuvant be selected from diluent, lubricant, adhesive, disintegrant, surfactant, into membrane material At least one in material, coating material and capsule material.

Preferably, described pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol, Ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethylcellulose calcium are adjacent Phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic acid tree Fat, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, carboxylic first At least one in base sodium starch, dextrin, PEO, shitosan, chitosan, ion exchange resin and collagen.

The preparation method of the solid dispersions of flibanserin of the invention or its pharmaceutically acceptable salt and pharmaceutic adjuvant, Comprise the following steps：

1) flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant are mixed, is heated to pharmaceutic adjuvant melting；Wherein, fluorine Ban Selin or its pharmaceutically acceptable salt and the weight ratio of pharmaceutic adjuvant are 1:0.1~100；

2) cooled down after being well mixed, mixture is crushed, obtain the flibanserin or its pharmaceutically acceptable salt of unformed shape With the solid dispersions of pharmaceutic adjuvant.

Preferably, step 1）Described in pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP, Polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxylic first Base cellulose phthalate, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, Polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, friendship At least one in connection starch, sodium carboxymethyl starch, dextrin, PEO, shitosan, chitosan and collagen.

The present invention provides another flibanserin or its pharmaceutically acceptable salt with the solid dispersions of pharmaceutic adjuvant Preparation method, comprises the following steps：

1) flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is -50 ~ 150 DEG C, the solution or suspension of containing flibanserin or its salt and pharmaceutic adjuvant are formed, wherein, flibanserin or its is pharmaceutically acceptable The weight ratio of salt and solvent be 0.001 ~ 100:1, the weight of flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant Than being 1:0.1~100；

2) removing step 1）Solvent in the solution or suspension that obtain, obtain unformed shape flibanserin or its pharmaceutically The solid dispersions of acceptable salt and pharmaceutic adjuvant.

Preferably, step 1）Described in pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP, Microcrystalline cellulose, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, sodium carboxymethylethyl Cellulose, carboxymethylcellulose calcium phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetic acid It is ester succinate, polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pre- Gelling starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, shitosan, chitosan, ion exchange resin and At least one in collagen.

Solid dispersions in the present invention refer to mixture, compound, copolymer, co-precipitate, eutectic, solid dispersion Body, solvate and hydrate.

Flibanserin of the invention or its pharmaceutically acceptable salt and the solid dispersions of pharmaceutic adjuvant, use Cu-K α Radiation, spy of the background peaks without flibanserin crystalline state that pharmaceutic adjuvant is deducted to spend in the X-ray powder diffraction spectrum that 2 θ are represented Peak is levied, shows that flibanserin or its pharmaceutically acceptable salt are unformed state.Flibanserin is generally used in the prior art Crystalline state, have no the report of its unformed shape.Normally due to the orderly and periodic arrangement of amorphous material molecule, reduce point The energy of sub- interphase interaction, energy is relatively low, and flibanserin of the invention or its pharmaceutically acceptable salt are unformed shape, Molecule is in height disordered state, and the surface free energy of material is bigger, and the molecule in solid matter is compared with crystalline solid material Molecule has energy higher, it is easier to disperse, and increases its dissolution rate, improves flibanserin or the bioavilability of its salt.

After be well mixed for flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant by the present invention, " solid point is used Powder " method, is intercepted drug molecule by the polymer network structure of pharmaceutic adjuvant, suppresses the generation of crystallization, makes it keep dividing Dissipate and unformed state.The present invention is using being widely used, the pharmaceutic adjuvant that cheap, dissolubility is good, these pharmaceutic adjuvants with Flibanserin or its pharmaceutically acceptable salt mix, and the technology such as cooperation evaporation, spray drying, freeze-drying and hot-melt extruded can To obtain the amorphous forms of flibanserin or its pharmaceutically acceptable salt, increase flibanserin of the present invention or it pharmaceutically may be used The stability of the unformed shape of flibanserin or its pharmaceutically acceptable salt in the solid dispersions of the salt of receiving.

The present invention selects pharmaceutically widely used, cheap auxiliary material, obtains flibanserin or it pharmaceutically may be used The salt of receiving and the solid dispersions of pharmaceutic adjuvant, it is easy to develop pharmaceutical formulation, preparation method of the invention does not receive drying process Limitation, also do not limited by solvent species and quantity of solvent, it is easy to operate, it is with low cost, it is easy to accomplish, be capable of achieving industry metaplasia Produce.

Compared with prior art, the beneficial effects of the invention are as follows：

1) the unformed flibanserin and unformed flibanserin hydrochloride that prepared by the present invention have preferable stability, with crystalline substance Type is compared, and with solubility and dissolution rate higher, is more beneficial for absorption of the body to medicine, improves the biological utilisation of medicine Degree, allows medicament to preferably play clinical disease treatment effect.

2) the unformed flibanserin or its salt that prepared by the present invention have high degree of dispersion with the solid dispersions of pharmaceutic adjuvant Property and stability, after solid pharmaceutical preparation is made, by disintegration can make drug particle degree of scatter more preferably, dispersion and dissolution rate Faster, the absorption of medicine is conducive to.Therefore, the dissolution rate of unformed state medicine substantially increases, and is more beneficial for body to medicine Absorption, improve medicine bioavilability, allow medicament to preferably play clinical disease treatment effect.

3) flibanserin or its pharmaceutically acceptable salt of unformed state of the invention disperse with the solid of pharmaceutic adjuvant The preparation method of body is not limited by drying process, is not also limited by solvent species and quantity of solvent, easy to operate, low cost It is honest and clean, it is easy to accomplish, it is capable of achieving industrialized production.

4) flibanserin or its salt of unformed state prepared by the present invention are accelerating with the solid dispersions of pharmaceutic adjuvant Under experimental condition（40 ± 2 DEG C, humidity 75% ± 5%）, good physical stability and chemical stability can be kept.Therefore, this hair It is bright to have broad application prospects.

Brief description of the drawings

Fig. 1 is the X-ray powder diffraction figure of the unformed flibanserin of the embodiment of the present invention 1.

Fig. 2 is the X-ray powder diffraction figure of the unformed flibanserin hydrochloride of the embodiment of the present invention 2.

Fig. 3 is the X-ray powder of the solid dispersions of the unformed flibanserin and PVP-K30 of the embodiment of the present invention 3 Last diffraction pattern.

Specific embodiment

Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention does not receive following implementation The limitation of example.

X-ray powder diffraction figure of the present invention is gathered on Ultima IV x-ray diffractometers.It is of the present invention X-ray powder diffraction method parameter it is as follows：

X-ray powder parameter：Cu-Kα

Kα（Å）：1.5418

Voltage：40 kilovolts

Electric current：40 milliamperes

Divergent slit：Automatically

Scan pattern：Continuously

Sweep limits：From 2.0 to 60.0 degree

Sampling step length：0.0200 degree

Sweep speed：60 degrees/min

Embodiment 1

By flibanserin（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings molten clear. Above-mentioned solution is cooled to rapidly -10 DEG C, white solid is separated out, filtering is dried, and obtains unformed flibanserin free alkali, X- Ray powder diffraction pattern is as shown in figure 1, without the characteristic peak of flibanserin crystal formation in X-ray powder diffraction figure.

Embodiment 2

By flibanserin hydrochloride（50 milligrams）It is dissolved in ethanol（600 microlitres）And water（600 microlitres）In, mixing is stirred at 40 DEG C Uniformly.Above-mentioned solution is slowly concentrated to dryness in a rotary evaporator, white solid is obtained, unformed flibanserin hydrochloric acid is obtained Salt, X-ray powder diffraction figure are as shown in Fig. 2 without the characteristic peak of flibanserin hydrochloride Form in X-ray powder diffraction figure.

Embodiment 3

By flibanserin hydrochloride（5 grams）And PVP K30（10 grams）Add water（300 milliliters）In, it is heated to 60 DEG C of stirrings molten Clearly.Above-mentioned solution is dried with JISL mini spray dryers LSD-48,60 DEG C of inlet temperature, 50 DEG C of outlet temperature is maintained, received Collection outlet material, obtains white solid, and further vacuum drying obtains unformed flibanserin hydrochloride with PVP-K30 Solid dispersions.X-ray powder diffraction figure is as shown in figure 3, in the X-ray powder diffraction figure of the solid dispersions, deduct medicine With the characteristic peak without flibanserin hydrochloride Form after the background peaks of auxiliary material.

Embodiment 4

By flibanserin hydrochloride（1 gram）With HPMC E50（0.2 gram）It is added to water（10 milliliters）In, it is heated to 40 DEG C stirring is molten clear.By above-mentioned solution freeze-drying, white solid is obtained, i.e., unformed flibanserin hydrochloride is fine with hydroxypropyl The solid dispersions of dimension element E50, in the X-ray powder diffraction figure of the solid dispersions, deduct nothing after the background peaks of pharmaceutic adjuvant The characteristic peak of flibanserin hydrochloride Form.

Embodiment 5

By flibanserin（1 gram）And PEG 8000（50 grams）Melting is heated to, room temperature is quickly cooled under stirring, obtain white Color solid.Above-mentioned solid is crushed, the solid of white powdery solids, i.e., unformed flibanserin and PEG 8000 is obtained Dispersion, in the X-ray powder diffraction figure of the solid dispersions, without flibanserin crystal formation after the background peaks of deduction pharmaceutic adjuvant Characteristic peak.

Embodiment 6

By flibanserin（1 gram）And PEG20000（100 grams）240 DEG C are heated to, are well mixed, be quickly cooled to room temperature, Obtain white solid.Above-mentioned solid is crushed, white powdery solids are obtained, i.e., unformed flibanserin and polyethylene glycol 10000 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct free-floride after the background peaks of pharmaceutic adjuvant The characteristic peak of Ban Selin crystal formations.

Embodiment 7

By flibanserin（1 gram）, normal propyl alcohol（20 grams）And liposome（4 grams）Mixture be heated to 90 DEG C, stirring, mixing is equal It is even, it is evaporated in vacuo and removes solvent, be cooled to room temperature and obtain white solid, i.e., unformed flibanserin disperses with the solid of liposome Body, in the X-ray powder diffraction figure of the solid dispersions, deducts the spy without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant Levy peak.

Embodiment 8

By flibanserin hydrogen salt hydrochlorate（1 gram）, methyl alcohol（20 grams）With methacrylic acid copolymer A types（4 grams）Mixture heating To 50 DEG C, stirring is molten clear, is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains white solid, i.e., unformed flibanserin hydrochloric acid Salt and the solid dispersions of methacrylic acid copolymer A types, in the X-ray powder diffraction figure of the solid dispersions, deduct medicinal Without the characteristic peak of flibanserin hydrochloride Form after the background peaks of auxiliary material.

Embodiment 9

By flibanserin（1 gram）, normal propyl alcohol（20 grams）And ethyl cellulose（2 grams）Mixture be heated to 30 DEG C, stirring, mixing Uniformly, it is evaporated in vacuo and removes solvent, be cooled to room temperature and obtain white solid, i.e., unformed flibanserin is consolidated with ethyl cellulose Body dispersion, it is brilliant without flibanserin after the background peaks of deduction pharmaceutic adjuvant in the X-ray powder diffraction figure of the solid dispersions The characteristic peak of type.

Embodiment 10

By flibanserin hydrochloride（1 gram）, methyl alcohol（20 grams）With hydroxypropyl cellulose SSL（4 grams）Mixture be heated to 30 DEG C, Stirring is molten clear, is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains white solid, i.e., unformed flibanserin hydrochloride and hydroxypropyl The solid dispersions of base cellulose SSL, in the X-ray powder diffraction figure of the solid dispersions, deduct the background peaks of pharmaceutic adjuvant Afterwards without the characteristic peak of flibanserin hydrochloride Form.

Embodiment 11

By flibanserin hydrochloride（1 gram）, methyl alcohol（20 grams）, water（10 grams）And polyvinyl acetate（4 grams）Mixture be heated to 30 DEG C, stir molten clear, be evaporated in vacuo and remove solvent, be cooled to room temperature and obtain white solid, i.e., unformed flibanserin hydrochloride With the solid dispersions of polyvinyl acetate, in the X-ray powder diffraction figure of the solid dispersions, the background of pharmaceutic adjuvant is deducted Without the characteristic peak of flibanserin hydrochloride Form behind peak.

Embodiment 12

By flibanserin（50 milligrams）With polyacrylic resin Eudragit L100（100 milligrams）It is added to methyl alcohol（750 is micro- Rise）, stir molten clear at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, i.e., it is unformed The solid dispersions of flibanserin hydrochloride and polyacrylic resin Eudragit L100, the X-ray powder of the solid dispersions Last diffraction pattern as shown in Fig. 2 in X-ray powder diffraction figure deduct pharmaceutic adjuvant background peaks after the spy without flibanserin crystal formation Levy peak.

Embodiment 13

By flibanserin（50 milligrams）With polyacrylic resin Eudragit S100（5 milligrams）It is added to methyl alcohol（4 milliliters）And second Acetoacetic ester（1 milliliter）, stir molten clear at -30 DEG C.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white is obtained solid Body, stirring is lower to separate out white solid, i.e., unformed flibanserin disperses with the solid of polyacrylic resin Eudragit S100 Body, in the X-ray powder diffraction figure of the solid dispersions, deducts the spy without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant Levy peak.

Embodiment 14

By flibanserin（50 milligrams）With carbopol Carbomer 940（50 milligrams）It is added to methyl alcohol（4 milliliters）With tetrahydrochysene furan Mutter（1 milliliter）, it is uniformly mixed at -30 DEG C.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white is obtained solid Body, the lower solid dispersions for separating out white solid, i.e., unformed flibanserin and carbopol Carbomer 940 of stirring, this is consolidated In the X-ray powder diffraction figure of body dispersion, the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant is deducted.

Embodiment 15

By flibanserin（50 milligrams）With pregelatinized starch Pharma-Gel（100 milligrams）It is added to methyl alcohol（4 milliliters）And water（1 Milliliter）, it is well mixed at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, under stirring Separate out the solid dispersions of white solid, i.e., unformed flibanserin and Pharma-Gel pregelatinized starch, the solid dispersions X-ray powder diffraction figure in, deduct pharmaceutic adjuvant background peaks after the characteristic peak without flibanserin crystal formation.

Embodiment 16

By flibanserin（50 milligrams）With side chain crosslinked starch high（50 milligrams）It is added to methyl alcohol（4 milliliters）And water（1 milliliter）, room The lower stirring of temperature is molten clear, and above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtains white solid, and stirring is lower to separate out white Solid, i.e., the solid dispersions of unformed flibanserin and side chain crosslinked starch high, the X-ray powder of the solid dispersions spreads out Penetrate in figure, deduct the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant.

Embodiment 17

By flibanserin（50 milligrams）With sodium carboxymethylcellulose SCMC（500 milligrams）It is added to dimethyl sulfoxide (DMSO)（5 milliliters）, room The lower stirring of temperature is molten clear.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, i.e., unformed fluorine class color Woods and the solid dispersions of sodium carboxymethylcellulose SCMC, in the X-ray powder diffraction figure of the solid dispersions, deduct medicinal Without the characteristic peak of flibanserin crystal formation after the background peaks of auxiliary material.

Embodiment 18

By flibanserin（50 milligrams）And chitosan（500 milligrams）It is added to ethanol（5 milliliters）, stir molten clear at room temperature, will Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtains white solid, i.e., unformed flibanserin and chitosan Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, without flibanserin after the background peaks of deduction pharmaceutic adjuvant The characteristic peak of crystal formation.

Embodiment 19

By flibanserin（50 milligrams）With sodium carboxymethyl starch Explotab（500 milligrams）It is added to ethanol（5 milliliters）, at room temperature Be uniformly mixed, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e., unformed fluorine class color Woods and the solid dispersions of sodium carboxymethyl starch Explotab, in the X-ray powder diffraction figure of the solid dispersions, deduct medicine With the characteristic peak without flibanserin crystal formation after the background peaks of auxiliary material.

Embodiment 20

By flibanserin（50 milligrams）With alginates E401（500 milligrams）It is added to ethanol（5 milliliters）, stirring mixing is equal at room temperature It is even.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, i.e., unformed flibanserin and alginates The solid dispersions of E401, in the X-ray powder diffraction figure of the solid dispersions, deduct free-floride after the background peaks of pharmaceutic adjuvant The characteristic peak of Ban Selin crystal formations.

Embodiment 21

By flibanserin（50 milligrams）With carboxymethylcellulose calcium phthalic acid ester Agucoat CPD（5 grams）It is suspended in methyl alcohol（30 Milliliter）, it is heated to 50 DEG C and is uniformly mixed.By above-mentioned solution, concentration removes most of solvent rapidly in a rotary evaporator, Filtering, dries, and obtains white solid, i.e., unformed flibanserin and carboxymethylcellulose calcium phthalic acid ester Agucoat CPD Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct floride-free class's color after the background peaks of pharmaceutic adjuvant The characteristic peak of woods crystal formation.

Embodiment 22

By flibanserin（50 milligrams）With carragheen E407（500 milligrams）It is suspended in methyl alcohol（30 milliliters）, it is heated to 50 DEG C of stirrings Well mixed, by above-mentioned solution, concentration removes most of solvent rapidly in a rotary evaporator, and filtering is dried, and obtains white solid The solid dispersions of body, i.e., unformed flibanserin and carragheen E407, in the X-ray powder diffraction figure of the solid dispersions, Deduct the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant.

Embodiment 23

By flibanserin（50 milligrams）And shitosan（5 grams）It is suspended in methyl alcohol（50 milliliters）, it is heated to 50 DEG C and is uniformly mixed. By above-mentioned solution, concentration removes most of solvent rapidly in a rotary evaporator, and filtering is dried, and obtains white solid, i.e., without fixed Type flibanserin and the solid dispersions of shitosan, in the X-ray powder diffraction figure of the solid dispersions, deduct pharmaceutic adjuvant Background peaks after the characteristic peak without flibanserin crystal formation.

Embodiment 24

By flibanserin（30 milligrams）With polyacrylic resin Eudragit E100（30 milligrams）It is dissolved in normal propyl alcohol（600 microlitres） And N,N-dimethylformamide（600 microlitres）In, it is heated to 50 DEG C and stirs molten clear, above-mentioned solution is cooled to 10 DEG C, separate out white Color solid, filtering is dried, and obtains the solid dispersions of unformed flibanserin and polyacrylic resin Eudragit E100, In the X-ray powder diffraction figure of the solid dispersions, the feature without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant is deducted Peak.

Embodiment 25

By flibanserin（30 milligrams）With collagen Peptan（300 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And acetonitrile（600 Microlitre）In, it is heated to 50 DEG C of stirrings molten clear.Above-mentioned solution is cooled to 10 DEG C, white solid is separated out, filtering is dried, and obtains nothing Sizing flibanserin and the solid dispersions of collagen Peptan, in the X-ray powder diffraction figure of the solid dispersions, detain Except the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant.

Embodiment 26

By flibanserin（30 milligrams）With gummy Galactosol（300 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And methyl alcohol（600 Microlitre）In, it is heated to 50 DEG C of stirrings molten clear.Above-mentioned solution is cooled to 10 DEG C, white solid is separated out, filtering is dried, and obtains nothing Sizing flibanserin and the solid dispersions of natural gum Galactosol, in the X-ray powder diffraction figure of the solid dispersions, detain Except the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant.

Embodiment 27

By flibanserin hydrochloride（30 milligrams）With hydroxypropyl methylcellulose phthalate HPMCP（30 milligrams）It is added to second Alcohol（750 microlitres）And water（750 microlitres）, it is heated to 80 DEG C and is uniformly mixed.Above-mentioned solution is rapid in a rotary evaporator Concentration removes solvent, obtains white solid, i.e., unformed flibanserin hydrochloride and hydroxypropyl methylcellulose phthalate The solid dispersions of HPMCP, in the X-ray powder diffraction figure of the solid dispersions, deduct free-floride after the background peaks of pharmaceutic adjuvant The characteristic peak of Ban Selin hydrochloride Forms.

Embodiment 28

By flibanserin hydrochloride（30 milligrams）With ion exchange resin Amberlite IR-120（300 milligrams）It is added to ethanol （750 microlitres）And water（750 microlitres）, it is heated to 80 DEG C and is uniformly mixed.Above-mentioned solution is rapid dense in a rotary evaporator Contracting removes solvent, obtains brown solid, i.e., unformed flibanserin hydrochloride and ion exchange resin Amberlite IR-120 Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct floride-free class's color after the background peaks of pharmaceutic adjuvant The characteristic peak of woods hydrochloride Form.

Embodiment 29

By flibanserin（30 milligrams）And caprolactone（300 milligrams）It is added to ethanol（750 microlitres）And water（750 is micro- Rise）, it is heated to 80 DEG C and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains brown The solid dispersions of solid, i.e., unformed flibanserin and caprolactone, the X-ray powder diffraction of the solid dispersions In figure, the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant is deducted.

Embodiment 30

By flibanserin（30 milligrams）With dextrin Maltrin M100（300 milligrams）It is added to ethanol（750 microlitres）And water（750 Microlitre）, it is heated to 80 DEG C and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains palm fibre The solid dispersions of color solid, i.e., unformed flibanserin and dextrin Maltrin M100, the X-ray powder of the solid dispersions In last diffraction pattern, the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant is deducted.

Embodiment 31

By flibanserin hydrochloride（30 milligrams）With sodium carboxymethylcellulose SCMS（3 milligrams）It is added to water（30 milliliters）, heating It is uniformly mixed to 100 DEG C.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains white solid, i.e., The solid dispersions of unformed flibanserin hydrochloride and sodium carboxymethylcellulose SCMC, the X-ray powder of the solid dispersions In diffraction pattern, the characteristic peak without flibanserin hydrochloride Form after the background peaks of pharmaceutic adjuvant is deducted.

Embodiment 32

By flibanserin hydrochloride（30 milligrams）And beta-schardinger dextrin（30 milligrams）It is added to methyl alcohol（300 microlitres）And water（300 is micro- Rise）, stir molten clear at room temperature.By above-mentioned solution in a rotary evaporator rapidly concentration remove solvent, obtain white solid, i.e., without Sizing flibanserin hydrochloride and the solid dispersions of beta-schardinger dextrin, in the X-ray powder diffraction figure of the solid dispersions, detain Except the characteristic peak without flibanserin hydrochloride Form after the background peaks of pharmaceutic adjuvant.

Embodiment 33

By flibanserin（30 milligrams）With sodium carboxymethylcellulose SCMC（30 milligrams）It is added to methyl alcohol（300 microlitres）And water（60 Microlitre）, it is uniformly mixed at 60 DEG C.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains white solid The solid dispersions of body, i.e., unformed flibanserin and sodium carboxymethylcellulose SCMC, the X-ray powder of the solid dispersions In diffraction pattern, the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant is deducted.

Embodiment 34

By flibanserin（5 milligrams）With PEO Polyox WSR301（60 milligrams）It is added to methyl alcohol（300 microlitres）And water （60 microlitres）, it is uniformly mixed at 60 DEG C.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains white The solid dispersions of solid, i.e., unformed flibanserin and PEO Polyox WSR301, the X- of the solid dispersions is penetrated In line powder diagram, the characteristic peak without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant is deducted.

Embodiment 35

By flibanserin（30 milligrams）With polyvinyl alcohol EG-40（60 milligrams）It is added to methyl alcohol（300 microlitres）And water（60 microlitres）, Stir molten clear at 60 DEG C, concentration removes solvent rapidly in a rotary evaporator by above-mentioned solution, obtains white solid, i.e., unformed Flibanserin and the solid dispersions of polyvinyl alcohol EG-40, in the X-ray powder diffraction figure of the solid dispersions, deduct medicinal Without the characteristic peak of flibanserin crystal formation after the background peaks of auxiliary material.

Embodiment 36

By flibanserin（50 milligrams）With HPMC acetate succinate Agoat MG（2 grams）It is added to ethanol （10 milliliters）And water（2 milliliters）, it is uniformly mixed at 80 DEG C, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, White solid is obtained, i.e., unformed flibanserin disperses with the solid of HPMC acetate succinate Agoat MG Body, in the X-ray powder diffraction figure of the solid dispersions, deducts the spy without flibanserin crystal formation after the background peaks of pharmaceutic adjuvant Levy peak.

Embodiment 37

By flibanserin（50 milligrams）And carboxymethylethylcellulose（2 grams）It is added to ethanol（10 milliliters）And water（1 milliliter）, 80 Be uniformly mixed at DEG C, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e., unformed fluorine Ban Selin and the solid dispersions of carboxymethylethylcellulose, in the X-ray powder diffraction figure of the solid dispersions, deduct medicine With the characteristic peak without flibanserin crystal formation after the background peaks of auxiliary material.

Embodiment 38

By flibanserin（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings molten clear. Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, unformed flibanserin free alkali is obtained.X- Without the characteristic peak of flibanserin crystal formation in ray powder diffraction pattern.

Embodiment 39

By flibanserin（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings molten clear. 10 milliliters of toluene are added into above-mentioned solution, drying under reduced pressure after filtering obtains unformed flibanserin.X-ray powder diffraction Without the characteristic peak of flibanserin crystal formation in figure.

Embodiment 40

By flibanserin（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings molten clear. Above-mentioned solution is directly carried out into freeze-drying, unformed flibanserin free alkali is obtained.Floride-free class in X-ray powder diffraction figure The characteristic peak of color woods crystal formation.

Embodiment 41

By flibanserin（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings molten clear. Above-mentioned solution is dried with JISL mini spray dryers LSD-48, inlet temperature 60 is maintained^oC, outlet temperature 50^oC, collect out Mouth material, obtains white solid, and further vacuum drying obtains unformed flibanserin free alkali.In X-ray powder diffraction figure Characteristic peak without flibanserin crystal formation.

Embodiment 42

By flibanserin hydrochloride（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings It is molten clear.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, unformed flibanserin is obtained and is dissociated Alkali.Without the characteristic peak of flibanserin hydrochloride Form in X-ray powder diffraction figure.

Embodiment 43

By flibanserin hydrochloride（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings It is molten clear.10 milliliters of toluene are added into above-mentioned solution, drying under reduced pressure after filtering, obtain unformed flibanserin free alkali.X- Without the characteristic peak of flibanserin hydrochloride Form in ray powder diffraction pattern.

Embodiment 44

By flibanserin hydrochloride（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings It is molten clear.Above-mentioned solution is directly carried out into freeze-drying, unformed flibanserin free alkali is obtained.Nothing in X-ray powder diffraction figure The characteristic peak of flibanserin hydrochloride Form.

Embodiment 45

By flibanserin hydrochloride（50 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And water（900 microlitres）In, it is heated to 60 DEG C of stirrings It is molten clear.Above-mentioned solution is directly dried with JISL mini spray dryers LSD-48, inlet temperature 60 is maintained^oC, outlet temperature 50^oC, outlet material is collected, white solid is obtained, further vacuum drying obtains unformed flibanserin hydrochloride.X-ray powder Nothing carrys out that characteristic peak for hydrochloride Buddhist nun's crystal formation in diffraction pattern.

Embodiment 46：Unformed flibanserin hydrochloride is tested with the influence factor of PVP K30 solid dispersions

Material：The solid dispersions of the unformed flibanserin hydrochloride of the gained of embodiment 1 and PVP K30

Table 1：

Table 1 is illustrated：Unformed flibanserin hydrochloride under high temperature, super-humid conditions, places 10 with PVP K30 solid dispersions My god, relevant material is separated out without significantly changing without flibanserin crystal of hydrochloride.

Embodiment 47：Unformed flibanserin hydrochloride is tested with the influence factor of PVP K30 solid dispersions

Experiment condition：Temperature 40^oC±2^oC, humidity 75% ± 5%

Table 2：

Table 2 is illustrated：Unformed flibanserin hydrochloride under the conditions of accelerated test, places 6 with PVP K30 solid dispersions Month, relevant material is separated out without significantly changing without flibanserin crystal of hydrochloride.

The unformed solid dispersions of flibanserin of the invention or its pharmaceutically acceptable salt and pharmaceutic adjuvant, its dissolution rate Substantially increase, be more beneficial for improving the bioavilability of medicine, allow medicament to preferably play clinical disease treatment effect, should Amorphous article is under the conditions of accelerated test（40 ± 2 DEG C, humidity 75% ± 5%）, good physical stability and chemistry can be kept steady It is qualitative.

Claims

1. a kind of unformed flibanserin.

2. a kind of unformed flibanserin, it is characterised in that the characteristic peak without flibanserin in X-ray powder diffraction spectrum.

3. a kind of preparation method of unformed flibanserin, comprises the following steps：

After flibanserin is dissolved with solvent, solution temperature is -50 ~ 150 DEG C, forms the solution of containing flibanserin, wherein, fluorine class Color woods is 0.001 ~ 100 with the weight ratio of solvent:1；It is characterized in that, solvent is selected from alcohols, phenols, ethers, halogenated hydrocarbons, ketone At least one in class, aldehydes, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water.

4. removing step 1）Solvent in resulting solution, or the solution that will be obtained is lowered the temperature rapidly, or is rapidly joined not Good solvent, carries out crystallization, obtains the unformed form of flibanserin.

5. characterized in that, the method for removing solvent is selected from：Evaporation, vacuum evaporation, spray drying, freeze-drying, hot-melt extruded, At least one in filtering, centrifugation or agitated thin film.

6. a kind of unformed flibanserin pharmaceutically acceptable salt, including hydrochloride, sulfate, maleate, fumarate, Methane sulfonates etc..

7. a kind of unformed flibanserin pharmaceutically acceptable salt, including hydrochloride, sulfate, maleate, fumarate, Methane sulfonates etc., it is characterised in that without the characteristic peak of flibanserin salt in X-ray powder diffraction spectrum.

8. a kind of preparation method of unformed flibanserin pharmaceutically-acceptable salts, comprises the following steps：

After flibanserin salt is dissolved with solvent, solution temperature is -50 ~ 150 DEG C, forms the solution of containing flibanserin salt, wherein, Flibanserin salt is 0.001 ~ 100 with the weight ratio of solvent:1；It is characterized in that, solvent is selected from alcohols, phenols, ethers, halo At least one in hydrocarbon, ketone, aldehydes, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water.

9. removing step 1）Solvent in resulting solution, or the solution that will be obtained is lowered the temperature rapidly, or is rapidly joined not Good solvent, carries out crystallization, obtains the unformed form of flibanserin salt.

10. characterized in that, the method for removing solvent is selected from：Evaporation, vacuum evaporation, spray drying, freeze-drying, hot melt are squeezed Go out, filter, being centrifuged or agitated thin film at least one.

The solid dispersions of a kind of 11. flibanserins or its pharmaceutically acceptable salt and pharmaceutic adjuvant, it is characterised in that described Solid dispersions include flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant, and both weight ratios are 1:0.1 ~ 100, Wherein, described flibanserin or its pharmaceutically acceptable salt are unformed shape, the X-ray powder of the solid dispersions In difraction spectrum, the characteristic peak without flibanserin or its salt crystal after the background peaks of pharmaceutic adjuvant is deducted.

12. flibanserins according to claim 11 or its pharmaceutically acceptable salt disperse with the solid of pharmaceutic adjuvant Body, it is characterised in that at least one in the pharmaceutic adjuvant is selected from diluent, lubricant, adhesive, disintegrant, surface work At least one in property agent, filmogen, coating material and capsule material.

13. flibanserins according to claim 11 or its pharmaceutically acceptable salt disperse with the solid of pharmaceutic adjuvant Body, it is characterised in that at least one in the pharmaceutic adjuvant is selected from HPMC, hydroxypropyl cellulose, PVP, Polyethylene glycol, ethyl cellulose, microcrystalline cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, sodium carboxymethylethyl Cellulose, carboxymethylcellulose calcium phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetic acid It is ester succinate, polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pre- Gelling starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, shitosan, chitosan, ion exchange resin and At least one in collagen.

The preparation method of the solid dispersions of a kind of 14. flibanserins or its pharmaceutically acceptable salt and pharmaceutic adjuvant, including Following steps：

Flibanserin or its pharmaceutically acceptable salt are mixed with pharmaceutic adjuvant, pharmaceutic adjuvant melting is heated to；Wherein, fluorine class Color woods or its pharmaceutically acceptable salt and the weight ratio of pharmaceutic adjuvant are 1:0.1~100；

Cooled down after well mixed, the mixture that will be obtained is crushed, obtain the flibanserin of unformed shape or its is pharmaceutically acceptable Salt and pharmaceutic adjuvant solid dispersions.

The solid dispersions of 15. flibanserins according to claim 14 or its pharmaceutically acceptable salt and pharmaceutic adjuvant Preparation method, it is characterised in that the pharmaceutic adjuvant be selected from diluent, lubricant, adhesive, disintegrant, surfactant, At least one in filmogen, coating material and capsule material.

The solid dispersions of 16. flibanserins according to claim 14 or its pharmaceutically acceptable salt and pharmaceutic adjuvant Preparation method, it is characterised in that described pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP, gather Ethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl It is cellulose phthalate, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, poly- Acrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinking Starch, sodium carboxymethyl starch, dextrin, PEO, shitosan, chitosan and collagen, cyclodextrin, lactose, gala At least one in sugar, PEARLITOL 25C, sorbierite, xylitol, urea.

The preparation method of the solid dispersions of a kind of 17. flibanserins or its pharmaceutically acceptable salt and pharmaceutic adjuvant, including Following steps：

Flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is -50 ~ 150 DEG C, Form the solution or suspension of containing flibanserin or its pharmaceutically acceptable salt and pharmaceutic adjuvant, wherein, flibanserin or its Pharmaceutically acceptable salt is 0.001 ~ 100 with the weight ratio of solvent:1, flibanserin or its pharmaceutically acceptable salt and medicine It is 1 with the weight ratio of auxiliary material:0.1~100；

Removing step 1）Solvent in the solution or suspension that obtain, obtain unformed shape flibanserin or its can pharmaceutically connect The salt and the solid dispersions of pharmaceutic adjuvant received.

The solid dispersions of 18. flibanserins according to claim 17 or its pharmaceutically acceptable salt and pharmaceutic adjuvant Preparation method, it is characterised in that the pharmaceutic adjuvant be selected from diluent, lubricant, adhesive, disintegrant, surfactant, At least one in filmogen, coating material and capsule material.

The solid dispersions of 19. flibanserins according to claim 17 or its pharmaceutically acceptable salt and pharmaceutic adjuvant Preparation method, it is characterised in that described pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP, gather Ethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl It is cellulose phthalate, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, poly- Acrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinking Starch, sodium carboxymethyl starch, dextrin, PEO, shitosan, chitosan, ion exchange resin and collagen, ring paste At least one in essence, lactose, galactolipin, PEARLITOL 25C, sorbierite, xylitol, urea.

The solid dispersions of 20. flibanserins according to claim 17 or its pharmaceutically acceptable salt and pharmaceutic adjuvant Preparation method, it is characterised in that step 1）The solvent is selected from containing less than 12 alcohols, phenols, ethers, the halos of carbon atom At least one in hydrocarbon, ketone, aldehydes, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water；Step 2）The method for removing solvent includes： Evaporation, vacuum evaporation, spray drying, freeze-drying, hot-melt extruded, filtering, centrifugation or agitated thin film.

21. a kind of Pharmaceutical compositions, it is characterised in that the Pharmaceutical composition contains unformed flibanserin and two kinds or two kinds More than pharmaceutically acceptable auxiliary material, at least one in the pharmaceutic adjuvant is selected from diluent, lubricant, adhesive, collapses At least one in solution agent, surfactant, filmogen, coating material and capsule material.

22. Pharmaceutical compositions according to claim 21, it is characterised in that in the pharmaceutic adjuvant in the Pharmaceutical composition At least one be selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose, microcrystalline cellulose Element, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethylcellulose calcium phthalic acid Ester, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic resin, poly- carboxylic Ethene, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, CMS Sodium, dextrin, PEO, shitosan, chitosan, collagen, cyclodextrin, lactose, galactolipin, PEARLITOL 25C, sorb At least one in alcohol, xylitol, urea.

23. claim 17-18 it is any as described in composition, for preparing treatment Pre-menopausal Women hyposexuality medicine Purposes.

A kind of 24. Pharmaceutical compositions, it is characterised in that the Pharmaceutical composition contain unformed flibanserin solid dispersions and At least one pharmaceutically acceptable auxiliary material.