CN105232503A - Hydrochloric acid dapoxetine tablet - Google Patents
Hydrochloric acid dapoxetine tablet Download PDFInfo
- Publication number
- CN105232503A CN105232503A CN201510827956.3A CN201510827956A CN105232503A CN 105232503 A CN105232503 A CN 105232503A CN 201510827956 A CN201510827956 A CN 201510827956A CN 105232503 A CN105232503 A CN 105232503A
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- CN
- China
- Prior art keywords
- dapoxetine hydrochloride
- dapoxetine
- hydrochloric acid
- dextrin
- sheet according
- Prior art date
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- USRHYDPUVLEVMC-FQEVSTJZSA-N dapoxetine Chemical compound C1([C@H](CCOC=2C3=CC=CC=C3C=CC=2)N(C)C)=CC=CC=C1 USRHYDPUVLEVMC-FQEVSTJZSA-N 0.000 title claims abstract description 85
- 229960005217 dapoxetine Drugs 0.000 title claims abstract description 85
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000004375 Dextrin Substances 0.000 claims abstract description 27
- 229920001353 Dextrin Polymers 0.000 claims abstract description 27
- 235000019425 dextrin Nutrition 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000002245 particle Substances 0.000 claims abstract description 7
- 239000007962 solid dispersion Substances 0.000 claims abstract description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 238000007907 direct compression Methods 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 18
- 229930195725 Mannitol Natural products 0.000 claims description 18
- 239000000594 mannitol Substances 0.000 claims description 18
- 235000010355 mannitol Nutrition 0.000 claims description 18
- 239000000741 silica gel Substances 0.000 claims description 17
- 229910002027 silica gel Inorganic materials 0.000 claims description 17
- 239000008187 granular material Substances 0.000 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- 239000000945 filler Substances 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 4
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 3
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 239000013078 crystal Substances 0.000 abstract description 36
- 238000004090 dissolution Methods 0.000 abstract description 15
- 238000000338 in vitro Methods 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 4
- 239000000470 constituent Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- 238000000034 method Methods 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000000872 buffer Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 5
- 239000012738 dissolution medium Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000007774 longterm Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 206010036596 premature ejaculation Diseases 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- UJTTUOLQLCQZEA-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-(4-hydroxybutyl)carbamate Chemical compound C1=CC=C2C(COC(=O)NCCCCO)C3=CC=CC=C3C2=C1 UJTTUOLQLCQZEA-UHFFFAOYSA-N 0.000 description 1
- 239000005696 Diammonium phosphate Substances 0.000 description 1
- 206010021703 Indifference Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 1
- 235000019838 diammonium phosphate Nutrition 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- LTUDISCZKZHRMJ-UHFFFAOYSA-N potassium;hydrate Chemical compound O.[K] LTUDISCZKZHRMJ-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a hydrochloric acid dapoxetine tablet and belongs to the field of medicine production new technologies, in particular to the hydrochloric acid dapoxetine tablet and a preparation method thereof. Hydrochloric acid dapoxetine serves as the main constituent, and the tablet is obtained through direct tabletting of hydrochloric acid dapoxetine solid dispersion particles and auxiliary materials; a preparation method of the hydrochloric acid dapoxetine solid dispersion particles comprises the steps of mixing hydrochloric acid dapoxetine with organic solvent for forming a clear solution, and then adding the clear solution to dextrin for conducting pelleting. The weight ratio of hydrochloric acid dapoxetine and dextrin is 1 to 2-15, and the organic solvent is one or more out of ethanol, acetic acid, ethyl acetate and acetone. By means of the hydrochloric acid dapoxetine tablet, the influence of crystal form difference on preparations is eliminated, and the obtained hydrochloric acid dapoxetine tablet is good in in-vitro dissolution, safe and stable.
Description
Technical field
The invention belongs to medicine and manufacture new technical field, be specifically related to a kind of dapoxetine hydrochloride sheet and a kind of preparation method thereof.
Background technology
Dapoxetine (INN, trade name Priligy), be exclusively used in treatment prospermia of males (PE), this is a kind of medicine namely needing type, and be the first oral medicine (tablet) of the type for the treatment of premature ejaculation that goes through in the world so far, belong to century-old medicine enterprise, Italian first pharmaceutical factory---the product of Mei Nalini company.Be suitable for crowd be 18-64 year male.The initial dose recommended for all patients is 30mg, needs within 1 to 3 hour, to take in the precontract of sexual life.If the satisfied not and side effect of effect is still within tolerance interval after taking 30mg, dosage can be increased to the 60mg of maximum recommended dosage.Recommend maximum dosage frequency of utilization be every 24 hours once.
Dapoxetine hydrochloride chemistry (S)-N, N-dimethyl-3-(naphthyl-1-oxygen base)-phenylpropyl alcohol semicarbazide hydrochloride by name.Structural formula is as follows:
Dapoxetine hydrochloride has similar pharmacological action to other SSRIs, initial dapoxetine is that research is for antidepressant medicine, but and other SSRIs unlike, dapoxetine pharmacokinetics shows that its oral absorption is fast, the half-life is short, excretion is fast, becomes the medicine being suitable for taking and taking treatment premature ejaculation.The curative effect of dapoxetine is random at five, obtains certainly in 3 clinical trial phases of placebo, and these five tests have male more than 6000 and their companion participates in, and this is largest so far, the most comprehensive clinical trial about premature ejaculation medicine.Dapoxetine is one species specific, and the selective serotonin reuptake inhibitor that short-term works, only has and just take when required, namely within 1-3 hour before each sexual intercourse, takes, instead of all needs every day to take.
Dapoxetine hydrochloride is that white is to off-white powder; This product is easily molten in methanol, ethanol, slightly soluble in dichloroethanes, almost insoluble in water.Dapoxetine hydrochloride is BCSII compounds, and poorly soluble is the key factor affecting clinical efficacy difference.There is multiple crystal formation in dapoxetine hydrochloride, the dissolubility difference of different crystal forms is comparatively large, and exists between crystal formation and the phenomenon transformed.
The crystal formation situation of the product that it is prepared all is not mentioned in document US5068432 and US6025517.Patent US5292962 is substantially identical with preparation process disclosed in WO2008035358, but does not carry out sign explanation to its crystal formation.The crystal formation that WO2013075669 reports prepared by patent US5292962, WO2008035358 is all crystal form A, and WO2013075669 has applied for the patent of crystal form B and unformed crystalline substance.Wherein, 2 θ values of the XRPD collection of illustrative plates of crystal form A are: 6.33,8.92,14.42,15.11,16.34,16.65,16.95,17.84,18.93,19.18,20.70,20.93,21.16,22.73,23.82,25.34,26.66,27.80,29.03,29.52.2 θ values of the XRPD collection of illustrative plates of crystal form B are: 6.29,8.84,14.33,15.06,16.28,16.38,16.61,16.89,17.78,18.87,20.62,20.76,21.10,21.82,22.69,23.78,25.30,26.66,27.75,28.46,28.97,29.48,30.19,31.22.CN104496829A discloses crystal form A and crystal form B stability, the stability of crystal form A and crystal form B is all poor, as crystal form A in 100 DEG C of baking ovens one week, show it by XRD and become crystal form B, as crystal form B 15 days under light illumination, show it by XRD and become crystal form A, this unstability of crystal form A and crystal form B is to the processing of preparation, store, transport proposes more harsh requirement, finally makes the manufacturing cost of product and use cost remain high.The dissolubility indifference of crystal form A, crystal form B two crystal formation, is in water almost insoluble.
CN104496829A discloses novel crystal forms of a kind of dapoxetine hydrochloride and preparation method thereof and application, it has found Dapoxetine hydrochloride crystal form C, and 2 θ of the XRPD collection of illustrative plates of crystal C are followed successively by: 14.21 ± 0.2,14.94 ± 0.2,16.48 ± 0.2,18.70 ± 0.2,20.51 ± 0.2,22.55 ± 0.2,23.61 ± 0.2,25.11 ± 0.2,28.85 ± 0.2,29.35 ± 0.2.Crystal C good stability, be not easily converted into crystal form A, B, but poorly soluble, water insoluble.
CN103130661B discloses a kind of crystal, amorphous substance and preparation method thereof of dapoxetine hydrochloride, it has found dapoxetine hydrochloride amorphous substance, and amorphous substance dissolubility is good, slightly water-soluble, but amorphous substance poor stability, room temperature places crystal form A after month.
The difference of crystal formation directly has influence on the external solubility of dapoxetine hydrochloride sheet.CN103735525B adopts micronization technology and adds exhibiting high surface activating agent in the formulation to avoid the difference of crystal formation on the impact of preparation dissolution, by by dapoxetine hydrochloride size controlling at 0.5 ~ 20um and add sodium lauryl sulphate, successfully eliminate the difference of crystal formation to the impact of preparation dissolution, but when long term test (25 DEG C, 40RH%) 12 months, the dapoxetine hydrochloride sheet adopting CN103735525B method to make has occurred that dissolution drops to the phenomenon of limit.The gastrointestinal reaction added when increasing oral hydrochloride dapoxetine sheet of exhibiting high surface activating agent sodium lauryl sulphate simultaneously, heavy dose of poloxamer easily causes the reversion of gastrointestinal tract mucous water oil environment, thus causes vomiting of exerting one's utmost effort.
Therefore develop and a kind ofly can evade the impact of crystal formation difference on preparation, In Vitro Dissolution is good, the dapoxetine hydrochloride sheet of safety and stability is imminent.
Summary of the invention:
In view of the deficiencies in the prior art, the object of the invention is to be studied by lot of experiments, solve crystal formation difference to the impact of preparation, provide that a kind of In Vitro Dissolution is good, the dapoxetine hydrochloride sheet of safety and stability and preparation method thereof.
Compared with prior art, the dapoxetine hydrochloride sheet tool of the employing solid dispersal that the present invention relates to has the following advantages and marked improvement: (1) production technology is simple, and easy to operate, yield is high, can realize the large production of industrialization; (3) dapoxetine hydrochloride and dextrin exist in the mode of solid solution, and dissolution in vitro is high, reach disintegrate and stripping is complete; (4) preparation release is affected by environment little, and In Vitro Dissolution curve is steady, and differences between batches are little; (5) after long-term placement, dissolution in vitro does not decline.
The object of the invention is following scheme realize:
Dapoxetine hydrochloride sheet is formed by dapoxetine hydrochloride solid dispersion particles and adjuvant direct compression; Described dapoxetine hydrochloride solid dispersion particles is prepared from as follows: dapoxetine hydrochloride and organic solvent are formed settled solution, then joins in dextrin and granulate.The weight ratio of dapoxetine hydrochloride and dextrin is 1: 2-15.The weight ratio of dapoxetine hydrochloride and dextrin more preferably 1: 8-10.Described organic solvent be selected from ethanol, acetic acid, ethyl acetate, acetone one or more.
Described accessory package containing filler and lubricant, filler be selected from lactose, starch, microcrystalline Cellulose, mannitol, pregelatinized Starch and calcium hydrogen phosphate one or more.Filler is preferred mannitol further.Described lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci, sodium stearyl fumarate.
The preparation method of described dapoxetine hydrochloride sheet, is characterized in that comprising following steps: just dapoxetine hydrochloride and organic solvent form settled solution, then join in dextrin and granulate, dry, forms with adjuvant direct compression.The dapoxetine hydrochloride sheet prepared by preparation method of described dapoxetine hydrochloride sheet.
Accompanying drawing explanation
Fig. 1 is embodiment 6, embodiment 7, embodiment 8, embodiment 13, embodiment 14, embodiment 15, embodiment 16, embodiment 170 days external stripping curve investigation figure (dissolution medium: pH3.8 citrate-phosphate disodium hydrogen buffer).
Fig. 2 is embodiment 6, embodiment 7, embodiment 8, embodiment 13, embodiment 14, embodiment 15, embodiment 16, long-term In Vitro Dissolution curve investigation in the June figure (dissolution medium: pH3.8 citrate-phosphate disodium hydrogen buffer) of embodiment 17.
Detailed description of the invention
The dapoxetine hydrochloride sheet that the present invention obtains has that method is simple, good stability, and dissolution is high, feature evident in efficacy.Following implementation the present invention, but do not limit the present invention in any way.
Embodiment 1:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with mannitol, micropowder silica gel, magnesium stearate, direct compression forms.
Embodiment 2:
Prescription:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with mannitol, micropowder silica gel, magnesium stearate, direct compression forms.
Embodiment 3:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with mannitol, micropowder silica gel, magnesium stearate, direct compression forms.
Embodiment 4:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with mannitol, micropowder silica gel, magnesium stearate, direct compression forms.
Embodiment 5:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with mannitol, micropowder silica gel, magnesium stearate, direct compression forms.
Embodiment 6:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with mannitol, micropowder silica gel, magnesium stearate, direct compression forms.
Embodiment 7:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with mannitol, micropowder silica gel, magnesium stearate, direct compression forms.
Embodiment 8:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with mannitol, micropowder silica gel, magnesium stearate, direct compression forms.
Embodiment 9:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol are mixed to form settled solution, then joins in dextrin and granulates, dry, forms with mannitol, micropowder silica gel, magnesium stearate direct compression.
Embodiment 10:
Prescription:
Method for making: dapoxetine hydrochloride and acetic acid are mixed to form settled solution, then joins in dextrin and granulates, dry, and after mixing with starch, lactose, micropowder silica gel, magnesium stearate, direct compression forms
Embodiment 11:
Prescription:
Method for making: dapoxetine hydrochloride and ethyl acetate, acetone are mixed to form settled solution, then join in dextrin and granulate, dry, after mixing with microcrystalline Cellulose, mannitol, Pulvis Talci, sodium stearyl fumarate, direct compression forms
Embodiment 12:
Prescription:
Method for making: dapoxetine hydrochloride and ethanol, acetone are mixed to form settled solution, then join in dextrin and granulate, dry, after mixing with pregelatinized Starch, calcium hydrogen phosphate, micropowder silica gel, sodium stearyl fumarate, direct compression forms.
Embodiment 13:
Prescription:
Method for making: direct compression after dapoxetine hydrochloride, dextrin, mannitol, micropowder silica gel, magnesium stearate mixing is formed.
Embodiment 14:
Prescription:
Method for making: direct compression after dapoxetine hydrochloride, dextrin, mannitol, micropowder silica gel, magnesium stearate mixing is formed.
Embodiment 15:
Prescription:
Method for making: direct compression after dapoxetine hydrochloride, dextrin, mannitol, micropowder silica gel, magnesium stearate mixing is formed.
Embodiment 16:
Prescription:
Method for making: direct compression after dapoxetine hydrochloride, dextrin, mannitol, micropowder silica gel, magnesium stearate mixing is formed.
Embodiment 17: implement by embodiment 3 disclosed in CN103735525B.
Embodiment 18: the dapoxetine hydrochloride sheet adopting embodiment 6, embodiment 7, embodiment 8, embodiment 13, embodiment 14, embodiment 15, embodiment 16, embodiment 17 method to make is carried out 0 day and the investigation of long term test In Vitro Dissolution in June curve.
In Vitro Dissolution dissolution determination condition is as follows:
Dissolution testing conditions:
Dissolution medium: pH3.8 citrate-phosphate disodium hydrogen buffer (take monohydrate potassium 2.88g and disodium hydrogen phosphate dodecahydrate 4.7g, the 1000ml that adds water makes dissolving)
Medium volume: 900ml
Rotating speed: 50rpm
Chromatographic condition and system suitability:
Chromatographic column: octadecylsilane chemically bonded silica is filler (particle diameter 5 μm)
Column temperature: 30 DEG C
Mobile phase: 0.02mol/L diammonium phosphate buffer (with phosphoric acid adjust pH to 5.0)-acetonitrile (40: 60)
Flow velocity: 1.0ml/min
Determined wavelength: 230nm
Sample size: 10 μ l
Number of theoretical plate: be not less than 5000 by dapoxetine peak
Prepared by solution:
Reference substance solution: take dapoxetine hydrochloride reference substance appropriate, accurately weighed, add mobile phase and dissolve and quantitatively dilute the solution made about containing 44 μ g in every 1ml;
Need testing solution: get dissolution test gained solution, filter, subsequent filtrate is as need testing solution.
Assay method:
Get this product 6, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC second methods) and high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD), precision measures reference substance solution and each 10 μ l of need testing solution, injection liquid chromatography respectively, record chromatogram, by external standard method with the stripping quantity of the every sheet of calculated by peak area.Stripping curve table is drawn according to often some stripping quantity.Measurement result is in table 1, table 2; Fig. 1, Fig. 2.Result shows that the dapoxetine hydrochloride sheet adopting the present invention to implement can solve the crystal formation announced in WO2008035358, WO2013075669, CN104496829A, CN103130661B and affect dapoxetine hydrochloride sheet; The dapoxetine hydrochloride sheet adopting the present invention to implement is better than and carries out enforcement dapoxetine hydrochloride sheet by embodiment 3 disclosed in CN103735525B.
Table 10 day external stripping curve investigation table (dissolution medium: pH3.8 citrate-phosphate disodium hydrogen buffer)
| 5min | 15min | 20min | 30min | 45min | |
| Embodiment 6 | 90％ | 95％ | 96％ | 97％ | 97％ |
| Embodiment 7 | 89％ | 96％ | 96％ | 97％ | 97％ |
| Embodiment 8 | 91％ | 96％ | 96％ | 96％ | 98％ |
| Embodiment 13 | 21％ | 47％ | 56％ | 75％ | 81％ |
| Embodiment 14 | 26％ | 51％ | 64％ | 78％ | 83％ |
| Embodiment 15 | 13％ | 17％ | 21％ | 26％ | 29％ |
| Embodiment 16 | 85％ | 94％ | 96％ | 96％ | 97％ |
| Embodiment 17 | 43％ | 67％ | 81％ | 92％ | 96％ |
Table 2 is In Vitro Dissolution curve investigation table in June (dissolution medium: pH3.8 citrate-phosphate disodium hydrogen buffer) for a long time
| 5min | 15min | 20min | 30min | 45min | |
| Embodiment 6 | 89％ | 94％ | 97％ | 96％ | 98％ |
| Embodiment 7 | 91％ | 95％ | 985 | 98％ | 98％ |
| Embodiment 8 | 90％ | 94％ | 975 | 98％ | 98％ |
| Embodiment 13 | 23％ | 51％ | 61％ | 75％ | 82％ |
| Embodiment 14 | 17％ | 45％ | 60％ | 73％ | 79％ |
| Embodiment 15 | 14％ | 18％ | 24％ | 25％ | 31％ |
| Embodiment 16 | 36％ | 59％ | 64％ | 77％ | 79％ |
| Embodiment 17 | 21％ | 43％ | 57％ | 72％ | 85％ |
Claims (9)
1. a dapoxetine hydrochloride sheet, is characterized in that: formed by dapoxetine hydrochloride solid dispersion particles and adjuvant direct compression; Described dapoxetine hydrochloride solid dispersion particles is prepared from as follows: dapoxetine hydrochloride and organic solvent are formed settled solution, then joins in dextrin and granulate, and the weight ratio of dapoxetine hydrochloride and dextrin is 1: 2-15.
2. dapoxetine hydrochloride sheet according to claim 1, is characterized in that: the weight ratio of dapoxetine hydrochloride and dextrin is 1: 8-10.
3. dapoxetine hydrochloride sheet according to claim 1, is characterized in that: described organic solvent be selected from ethanol, acetic acid, ethyl acetate, acetone one or more.
4. the dapoxetine hydrochloride sheet according to any one of claim 1-3, is characterized in that: described accessory package is containing filler and lubricant.
5. dapoxetine hydrochloride sheet according to claim 4, is characterized in that: described filler be selected from lactose, starch, microcrystalline Cellulose, mannitol, pregelatinized Starch and calcium hydrogen phosphate one or more.
6. dapoxetine hydrochloride sheet according to claim 4, is characterized in that: described filler is mannitol.
7. dapoxetine hydrochloride sheet according to claim 4, is characterized in that: described lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci, sodium stearyl fumarate.
8. the preparation method of the dapoxetine hydrochloride sheet according to any one of claim 1-3, it is characterized in that comprising following steps: dapoxetine hydrochloride and organic solvent are formed settled solution, then join in dextrin and granulate, dry, form with adjuvant direct compression.
9. the dapoxetine hydrochloride sheet prepared by preparation method of dapoxetine hydrochloride sheet according to claim 8.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107536821A (en) * | 2016-06-29 | 2018-01-05 | 康普药业股份有限公司 | A kind of dapoxetine hydrochloride sustained release preparation |
| CN110833530A (en) * | 2019-12-12 | 2020-02-25 | 盖天力医药控股集团制药股份有限公司 | Dapoxetine hydrochloride orally disintegrating tablet and preparation method and application thereof |
| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013180675A1 (en) * | 2012-05-28 | 2013-12-05 | Mahmut Bilgic | Tablet formulation comprising dapoxetine |
| WO2014027981A2 (en) * | 2012-08-17 | 2014-02-20 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Effervescent tablet formulations of dapoxetine and a pde5 inhibitor |
| CN103735525A (en) * | 2014-02-12 | 2014-04-23 | 江苏仁寿药业有限公司 | Dapoxetine tablets and preparation method thereof |
| CN104546724A (en) * | 2013-10-12 | 2015-04-29 | 博瑞生物医药技术(苏州)有限公司 | Solid dispersion of antifungal agent |
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2015
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013180675A1 (en) * | 2012-05-28 | 2013-12-05 | Mahmut Bilgic | Tablet formulation comprising dapoxetine |
| WO2014027981A2 (en) * | 2012-08-17 | 2014-02-20 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Effervescent tablet formulations of dapoxetine and a pde5 inhibitor |
| CN104546724A (en) * | 2013-10-12 | 2015-04-29 | 博瑞生物医药技术(苏州)有限公司 | Solid dispersion of antifungal agent |
| CN103735525A (en) * | 2014-02-12 | 2014-04-23 | 江苏仁寿药业有限公司 | Dapoxetine tablets and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107536821A (en) * | 2016-06-29 | 2018-01-05 | 康普药业股份有限公司 | A kind of dapoxetine hydrochloride sustained release preparation |
| CN110903203A (en) * | 2018-09-14 | 2020-03-24 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN110903203B (en) * | 2018-09-14 | 2022-11-18 | 天津药物研究院有限公司 | Dapoxetine hydrochloride crystal and preparation method and application thereof |
| CN110833530A (en) * | 2019-12-12 | 2020-02-25 | 盖天力医药控股集团制药股份有限公司 | Dapoxetine hydrochloride orally disintegrating tablet and preparation method and application thereof |
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| CN105232503B (en) | 2018-01-05 |
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