CN115444827B - Pharmaceutical composition and preparation method thereof - Google Patents
Pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN115444827B CN115444827B CN202110634909.2A CN202110634909A CN115444827B CN 115444827 B CN115444827 B CN 115444827B CN 202110634909 A CN202110634909 A CN 202110634909A CN 115444827 B CN115444827 B CN 115444827B
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- pharmaceutical composition
- dapoxetine hydrochloride
- agent
- film forming
- forming agent
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 30
- 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 claims abstract description 75
- 229960005217 dapoxetine Drugs 0.000 claims abstract description 75
- 239000002994 raw material Substances 0.000 claims abstract description 47
- 239000000843 powder Substances 0.000 claims abstract description 41
- 239000002245 particle Substances 0.000 claims abstract description 30
- 239000011248 coating agent Substances 0.000 claims abstract description 29
- 238000000576 coating method Methods 0.000 claims abstract description 29
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000000945 filler Substances 0.000 claims abstract description 8
- 239000000796 flavoring agent Substances 0.000 claims abstract description 8
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 8
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 239000000853 adhesive Substances 0.000 claims abstract description 4
- 230000001070 adhesive effect Effects 0.000 claims abstract description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 238000007873 sieving Methods 0.000 claims description 13
- 229920003081 Povidone K 30 Polymers 0.000 claims description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 11
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 11
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 229960001021 lactose monohydrate Drugs 0.000 claims description 8
- 108010011485 Aspartame Proteins 0.000 claims description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 7
- 239000000605 aspartame Substances 0.000 claims description 7
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 7
- 235000010357 aspartame Nutrition 0.000 claims description 7
- 229960003438 aspartame Drugs 0.000 claims description 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- 229960002920 sorbitol Drugs 0.000 claims description 7
- 235000010356 sorbitol Nutrition 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 5
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 4
- 244000099147 Ananas comosus Species 0.000 claims description 4
- 235000007119 Ananas comosus Nutrition 0.000 claims description 4
- 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 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 4
- 229960004998 acesulfame potassium Drugs 0.000 claims description 4
- 239000000619 acesulfame-K Substances 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 229960001855 mannitol Drugs 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 229920003080 Povidone K 25 Polymers 0.000 claims description 3
- 229940100487 povidone k25 Drugs 0.000 claims description 3
- 244000144730 Amygdalus persica Species 0.000 claims description 2
- 235000006040 Prunus persica var persica Nutrition 0.000 claims description 2
- 235000013399 edible fruits Nutrition 0.000 claims description 2
- 239000008369 fruit flavor Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 19
- 235000019640 taste Nutrition 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 8
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 235000019658 bitter taste Nutrition 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 26
- 238000004090 dissolution Methods 0.000 description 17
- 239000006191 orally-disintegrating tablet Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 12
- 239000011812 mixed powder Substances 0.000 description 11
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- 229920003134 Eudragit® polymer Polymers 0.000 description 5
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000873 masking effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
Abstract
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition and a preparation method thereof. The pharmaceutical composition comprises: dapoxetine hydrochloride, a film forming agent, a filling agent, a disintegrating agent, an adhesive, a lubricant and a flavoring agent, wherein the particle size D 90 of the dapoxetine hydrochloride is as follows: the dapoxetine hydrochloride powder is coated by a powder coating direct tabletting method through a film forming agent with the weight ratio of the film forming agent of 15-30 percent, wherein the thickness of the film forming agent is 80-120 mu m. The film forming agent is selected and added in a mode of obviously covering up the bitter taste of the dapoxetine hydrochloride to improve the taste of the medicine, and the stability of the raw material medicine in the preparation can be improved to improve the quality of the product. In addition, the drug release can be obviously improved and the absorption of the drug in the human body can be accelerated by controlling the particle size of the dapoxetine hydrochloride. The pharmaceutical composition disclosed by the invention has the advantages of simple preparation process, low cost, convenience in administration, quick response and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, relates to a pharmaceutical composition and a preparation method thereof, and in particular relates to an oral solid preparation containing dapoxetine hydrochloride and a preparation method thereof.
Background
Dapoxetine hydrochloride is white to off-white crystalline powder, is easy to oxidize, has the chemical name of (S- (+) -N, N-dimethyl-a- [2- (naphthoxy) ethyl ] phenylpropanamine hydrochloride, and has the following structural formula:
Dapoxetine hydrochloride is a selective 5-hydroxytryptamine reuptake inhibitor (SSRIs). Similar to other SSRIs, dapoxetine was originally studied as an antidepressant, but unlike other SSRIs, dapoxetine has shown its kinetics with rapid absorption, short half-life and rapid excretion, making it a suitable drug for PE treatment when taken.
In the prior art, the disclosed dapoxetine tablet is mostly prepared by adopting a wet granulation process, but the wet granulation process has more steps and more complex parameters, the parameters in the granulation process are not easy to control, and the practical operability is poor.
The dapoxetine tablet disclosed in CN108853072A, CN103735525B has complex preparation process, and ethanol is introduced in the granulating process, so that the problem of solvent residue is easily caused. Patent CN201510827956.3 discloses a preparation process of directly tabletting dapoxetine hydrochloride and auxiliary materials after preparing solid dispersion, and the tablet prepared by the process has the advantages of quick dissolution and quick release, but organic solvent is used in the process, the problems of solvent residue and the like are also required to be concerned in the later stage, the process is complex, and the practical operability is not high.
Dapoxetine hydrochloride is bitter and astringent, is easily dissolved in methanol and ethanol, is almost insoluble in water, and has hygroscopicity. Therefore, the method for improving the taste of the dapoxetine hydrochloride drug and the solubility and stability of the drug has important significance for researching clinical medicinal dapoxetine hydrochloride.
Disclosure of Invention
In order to solve the technical problems, the invention provides the pharmaceutical composition containing dapoxetine hydrochloride, which has the advantages of simple preparation process, obvious taste masking, high stability, good quality, convenient use and obvious effect.
It is also an object of the present invention to provide a process for the preparation of the pharmaceutical composition.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
The invention discloses a pharmaceutical composition, which comprises dapoxetine hydrochloride, a film former, a filler, a disintegrating agent, an adhesive, a lubricant and a flavoring agent, and comprises the following specific components in percentage by weight:
dapoxetine hydrochloride 30% -60%
15-30% Of film forming agent
40-65% Of filler
10-20% Of disintegrating agent
2% -5% Of adhesive
1% -4% Of lubricant
0.5 To 1 percent of flavoring agent
The research shows that the particle size of the dapoxetine hydrochloride influences the mixing uniformity and the in-vitro release rate of the product. According to some embodiments of the invention, the uncrushed raw material disintegrates more slowly; after the raw materials are crushed, the disintegration time is obviously shortened. Through a great deal of experimental researches, the method has the advantages that when the grain diameter D 90 of the dapoxetine hydrochloride is controlled to be 80-120 mu m, the layering phenomenon of the medicine in the powder mixing process can be effectively avoided, the fluidity of the raw medicine is improved, the mixing uniformity and dissolution of the medicine are improved, the release of the medicine is improved, and the absorption of the medicine in a human body is accelerated. Therefore, in order to ensure the mixing uniformity and the in-vitro release rate, the particle size D 90 of the dapoxetine hydrochloride in the pharmaceutical composition disclosed by the invention is required to be controlled within 80-120 mu m, and the raw materials can be crushed, ground and the like to control the particle size range.
On the other hand, the invention discloses that the dapoxetine hydrochloride is coated by adopting the film forming agent with the content of 15% -30%, and according to some embodiments of the invention, the processed dapoxetine hydrochloride is coated by powder, so that the taste can be well masked, the stability of the orally disintegrating tablet can be improved, and the growth of related substances can be reduced. The film forming agent is selected without affecting the drug dissolution, but the coating weight is too high to facilitate disintegration and release. Therefore, the film forming agent with a certain content is selected to influence not only the compliance of patients, but also the dissolution performance of medicines. In the pharmaceutical composition disclosed by the invention, the film forming agent is preferably selected from one or more of hydroxypropyl methyl cellulose, eudragit I100 and hydroxypropyl cellulose SL-type.
According to some embodiments of the invention, the filler in the above pharmaceutical composition is selected from one or more of lactose monohydrate, microcrystalline cellulose, mannitol, sorbitol.
According to some embodiments of the present invention, the disintegrating agents are different, have a significant effect on dissolution rate and disintegration time, and the disintegrating agents in the above pharmaceutical composition are preferably one or more of self-crosslinking povidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose.
According to some embodiments of the invention, the binder in the above pharmaceutical composition is preferably selected from one or more of povidone K30, povidone K25.
According to some embodiments of the invention, the lubricant described in the above pharmaceutical composition is preferably one or more of magnesium stearate, talc, silica.
According to some embodiments of the invention, the flavoring agent in the above-mentioned pharmaceutical composition is preferably selected from one or more of aspartame, acesulfame potassium, fruit flavors.
According to some embodiments of the invention, the fruit essence in the above pharmaceutical composition is preferably selected from one or more of peach essence, orange essence, pineapple essence.
The invention also provides a preparation method of the pharmaceutical composition according to the technical scheme, and according to some embodiments of the invention, the invention discloses a preparation process of directly tabletting after powder coating, and tabletting after uniformly mixing coated pharmaceutical powder and proper auxiliary materials. Compared with the traditional wet granulation and powder direct compression process, the powder coating tabletting has the advantages of: the preparation process is simple, and the industrial production cost is reduced; (2) The taste masking is obvious, and the product quality and the taste of the product are improved; (3) convenient use and quick absorption; and (4) the product quality is high and the stability is good.
The preparation method of the pharmaceutical composition disclosed by the invention comprises the following specific steps:
Step (1): crushing the dapoxetine hydrochloride raw material, and sieving the crushed dapoxetine hydrochloride raw material with a 80-mesh sieve to control the particle size D 90 of the dapoxetine hydrochloride raw material to be 80-120 mu m;
step (2): coating the raw materials obtained by micronization in the step (1) with a film forming agent in a fluidized bed;
Step (3): uniformly mixing the coated particles obtained in the step (2) with a filler, a disintegrating agent and a binder to obtain premixed particles;
Step (4): and (3) adding a lubricant and a flavoring agent into the premixed particles obtained in the step (3) to carry out total mixed tabletting.
The beneficial effects of the invention are as follows:
1) The film forming agent is selected and added in a manner that not only can obviously cover the bitter taste of the dapoxetine hydrochloride to improve the taste of the medicine, but also can increase the stability of the raw material medicine in the preparation and improve the quality of the product;
2) The particle diameter D 90 of the dapoxetine hydrochloride is controlled to be 80-120 mu m, so that the release of the medicine can be obviously improved, and the absorption of the medicine in a human body can be accelerated;
3) Compared with the commercial products, the pharmaceutical composition dapoxetine hydrochloride tablet provided by the invention has the advantages of quick release, high stability, simple preparation process, low cost and convenience in administration, and can better mask the bitter taste of the dapoxetine hydrochloride.
Drawings
Fig. 1 is a graph of the particle size detection of dapoxetine hydrochloride raw material.
Fig. 2 is a graph comparing dissolution data of the disclosed examples and comparative examples.
FIG. 3 is a graph showing the increasing trend of degraded impurities under the acceleration conditions of examples and comparative examples.
Detailed Description
The technical scheme of the invention is further described below by specific examples, but the invention is not limited thereto.
Experimental materials:
Experimental facilities:
The detection method comprises the following steps:
① The method for measuring the disintegration time limit adopts the method for detecting the oral disintegrating tablet under the item of the method for detecting the disintegration time limit of 0921 in the section 4 of Chinese pharmacopoeia 2020;
② The dissolution rate measurement method adopts the second method of the dissolution rate and release rate measurement method of the 4 th edition of the "Chinese pharmacopoeia" 2020 edition.
Example 1
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
The preparation process comprises the following steps:
1. pretreatment: sieving untreated dapoxetine hydrochloride raw material with a 40-mesh screen to remove caking, and controlling the grain size to be 160-200 mu m;
2. Premixing: premixing a dapoxetine hydrochloride raw material and microcrystalline cellulose, sorbitol, low-substituted hydroxypropyl cellulose and povidone K30 for 10 minutes;
3. Total mixing: adding prescribed amounts of magnesium stearate and aspartame to the premix powder and mixing for an additional 5 minutes;
4. tabletting: tabletting the mixed powder obtained in the step3, wherein the hardness is 20N.
Example 2
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
The preparation process comprises the following steps:
1. pretreatment: crushing the dapoxetine hydrochloride raw material, and then sieving the crushed dapoxetine hydrochloride raw material with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. Premixing: premixing a dapoxetine hydrochloride raw material and microcrystalline cellulose, sorbitol, low-substituted hydroxypropyl cellulose and povidone K30 for 10 minutes;
3. Total mixing: adding prescribed amounts of magnesium stearate and aspartame to the premix powder and mixing for an additional 5 minutes;
4. tabletting: tabletting the mixed powder obtained in the step3, wherein the hardness is 20N.
Example 3
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
The preparation process comprises the following steps:
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: powder coating is carried out on the raw materials by adopting a hydroxypropyl methyl cellulose aqueous solution;
3. premixing: premixing the coated powder with microcrystalline cellulose, sorbitol, low-substituted hydroxypropyl cellulose and povidone K30 for 10 minutes;
4. Total mixing: adding prescribed amounts of magnesium stearate and aspartame to the premix powder and mixing for an additional 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Example 4
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
The preparation process comprises the following steps:
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: powder coating is carried out on the raw materials by adopting a hydroxypropyl methyl cellulose aqueous solution;
3. premixing: premixing the coated powder with microcrystalline cellulose, sorbitol, low-substituted hydroxypropyl cellulose and povidone K25 for 10 minutes;
4. Total mixing: adding prescribed amounts of magnesium stearate and aspartame to the premix powder and mixing for an additional 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Example 5
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
Preparation process
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: powder coating is carried out on the raw materials by adopting a hydroxypropyl methyl cellulose aqueous solution;
3. premixing: premixing the coated powder with microcrystalline cellulose, sorbitol, low-substituted hydroxypropyl cellulose and povidone K30 for 10 minutes;
4. Total mixing: adding prescribed amounts of magnesium stearate and aspartame to the premix powder and mixing for an additional 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Example 6
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
Preparation process
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: coating the raw materials with Eudragit I100 powder;
3. Premixing: premixing the coated powder with lactose monohydrate, mannitol, low-substituted hydroxypropyl cellulose and povidone K30 for 10 minutes;
4. total mixing: adding the prescribed amount of silicon dioxide and orange essence into the premixed powder, and continuously mixing for 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Example 7
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
Preparation process
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: coating the raw materials with Eudragit I100 powder;
3. Premixing: premixing the coated powder with lactose monohydrate, mannitol, low-substituted hydroxypropyl cellulose and povidone K30 for 10 minutes;
4. total mixing: adding the prescribed amount of silicon dioxide and orange essence into the premixed powder, and continuously mixing for 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Example 8
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
Preparation process
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: powder coating is carried out on the raw materials by adopting hydroxypropyl cellulose SL;
3. premixing: premixing the coated powder with lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and povidone K30 for 10 minutes;
4. Total mixing: adding the prescribed amount of talcum powder and pineapple essence into the premixed powder, and continuously mixing for 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Example 9
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
Preparation process
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: powder coating is carried out on the raw materials by adopting hydroxypropyl cellulose SL;
3. premixing: premixing the coated powder with lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and povidone K30 for 10 minutes;
4. Total mixing: adding the prescribed amount of talcum powder and pineapple essence into the premixed powder, and continuously mixing for 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Example 10
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
Preparation process
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: powder coating is carried out on the raw materials by adopting hydroxypropyl cellulose SL;
3. Premixing: premixing the coated powder with lactose monohydrate, microcrystalline cellulose, crospovidone and povidone K30 for 10 minutes;
4. total mixing: adding prescribed amount of talcum powder and acesulfame potassium into the premixed powder, and continuously mixing for 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Example 11
Dapoxetine hydrochloride orally disintegrating tablets (batch 1000 tablets)
Preparation process
1. Pretreatment: crushing the dapoxetine hydrochloride raw material, and sieving with a 80-mesh sieve, wherein the particle size is controlled to be 80-120 mu m;
2. coating: the hydroxypropyl cellulose SL is used for carrying out powder coating on the raw materials;
3. premixing: premixing the coated powder with lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and povidone K30 for 10 minutes;
4. total mixing: adding prescribed amount of talcum powder and acesulfame potassium into the premixed powder, and continuously mixing for 5 minutes;
5. Tabletting: tabletting the mixed powder obtained in the step 4, wherein the hardness is 20N.
Performance testing
Test example 1 determination of mixing uniformity
The method for measuring the mixing uniformity comprises the following steps: after the three-dimensional mixer is totally mixed, 3 samples are respectively taken from 3 different positions (an upper layer, a middle layer and a lower layer) of the material in the mixing hopper, the content is measured, the mixing uniformity of the different positions is calculated, and the RSD is not more than 5%.
The mixing uniformity judgment standard is that RSD is less than or equal to 3 percent and is regarded as excellent, RSD is less than or equal to 5 percent and is regarded as qualified, and RSD is more than 5 percent and is regarded as unqualified. Comparative example 1 is Priligy (Dapoxetine Hydrochloride Tablets)
The results of the uniformity of mixing are shown in Table 1.
TABLE 1 results of uniformity of mixing measurements
"- -" Indicates no corresponding detection parameter.
As shown in the table above, the particle diameter D 90 of the raw material of dapoxetine hydrochloride which is not crushed is 160-200 μm, and the mixing uniformity of the example 1 is not satisfactory; when the particle size D 90 of the processed dapoxetine hydrochloride raw material is 80-120 mu m, the mixing uniformity of the examples 2-11 meets the requirement, and the flowability of the raw material is improved and the mixing uniformity results are excellent for the examples 3-11 after the raw material is coated.
Test example 2 mouthfeel test
The dapoxetine orally disintegrating tablets of examples 1 to 11 and comparative example 1 were subjected to taste testing, and the test results are shown in the following table.
Table 2 mouthfeel test results
From the above table, it can be seen that: examples 5,7,9, 10, 11 are better tasting, satisfying patient compliance, while comparative examples with lower coating weight gain, and comparative example 1 are less tasting, bitter, dry, and less compliant. Therefore, the problem of the bitter taste of dapoxetine hydrochloride can be effectively solved by increasing the dosage of the film forming agent in the prescription.
Test example 3 dissolution test
Dissolution measurements were performed for examples 1-11 and comparative example 1. Experimental method according to the dissolution assay, an aqueous medium was selected, volume 250ml, rotational speed 25rpm, n=12. The results were as follows:
TABLE 3 dissolution test results
As can be seen from the above table, the samples of examples 1-11 all dissolved out rapidly and completely. The dissolution comparison of examples 1 and 2 shows that the particle size of the raw material has a significant effect on dissolution, and the dissolution comparison and mouthfeel comparison of examples 2 and 3 show that coating the raw material powder is effective in taste masking and has a small effect on dissolution of the sample; examples 10 and 11 show that the dissolution rate is significantly affected by different types of disintegrants; examples 6 and 7 show that coating the material with Eudragit I100 improves the taste and masks the bitter taste, but the dissolution is slower than other examples, and the coating weight gain is too high to facilitate disintegration release.
Test example 4 disintegration time test
A method for measuring the disintegration time limit comprises the steps of taking one tablet of the tablet, placing the tablet into a test tube containing 2mL of water at 37 ℃, visually observing the tablet to disintegrate until the tablet is not hard, recording the time as the disintegration time, rapidly adding 5mL of water along the wall of the test tube, immediately pouring the water into a beaker covered with a 26-mesh sieve (688 mu m), repeatedly measuring 6 tablets, and completely passing the test tube to evaluate the tablet disintegrating effect. Comparative example 1 is Priligy (Dapoxetine Hydrochloride Tablets). The above examples and comparative examples were tested and the test results are shown in the following table:
Table 4 disintegration time measurement results
As can be seen from the above table, in example 1, the uncrushed raw material disintegrated more slowly; in the embodiment 2, after the raw materials are crushed, the disintegration time is obviously shortened; example 3 the material was crushed and coated with less impact on disintegration time; example 4, changing the binder type, has less effect on disintegration time; examples 5,6,7,8 and 9 have great influence on disintegration time by changing the types and weight of the film forming agent; examples 10, 11 change the type of disintegrant, with a significant impact on disintegration time; examples 6 and 7 the starting materials were coated with Eudragit I100 and the disintegration time was significantly prolonged.
Test example 5 stability test
Samples of inventive examples 2-11 and comparative example 1 were taken and placed under accelerated conditions (40 ℃ + -2 ℃/75% RH+ -5% RH) for preliminary stability investigation. Comparative example 1 is Priligy (Dapoxetine Hydrochloride Tablets).
TABLE 5 comparison of 6 month stability acceleration for examples 2-11 with comparative example 1
As can be seen from the table, the dapoxetine hydrochloride orally disintegrating tablet disclosed by the invention has the characteristics that the dapoxetine hydrochloride is crushed and coated, so that the taste can be well masked, the stability of the orally disintegrating tablet can be improved, the growth of related substances is reduced, the dissolution of raw materials can be accelerated by controlling the particle size of the raw materials to be 80-120 mu m, the drug absorption is accelerated, the preparation process is simple, the stability is good, the cost is low, the administration is convenient, the effect on male premature ejaculation indication is quick, and the like.
Claims (7)
1. A pharmaceutical composition, comprising: dapoxetine hydrochloride, a film forming agent, a filling agent, a disintegrating agent, an adhesive, a lubricant and a flavoring agent, wherein the particle size D 90 of the dapoxetine hydrochloride is as follows: the pharmaceutical composition is prepared by coating dapoxetine hydrochloride with powder through a film forming agent, wherein the film forming agent is selected from hydroxypropyl cellulose SL type, the weight ratio of the film forming agent to the pharmaceutical composition is 22.5%, and the disintegrating agent is selected from crosslinked povidone.
2. A pharmaceutical composition according to claim 1, wherein the filler is selected from one or more of lactose monohydrate, microcrystalline cellulose, mannitol, sorbitol.
3. A pharmaceutical composition according to claim 1, wherein the binder is selected from one or more of povidone K30, povidone K25.
4. A pharmaceutical composition according to claim 1, wherein the lubricant is selected from one or more of magnesium stearate, talc, silica.
5. A pharmaceutical composition according to claim 1, wherein the flavouring agent is selected from one or more of aspartame, acesulfame potassium, fruit flavors.
6. The pharmaceutical composition of claim 5, wherein the fruit essence is selected from one or more of peach essence, orange essence, pineapple essence.
7. A method of preparing a pharmaceutical composition according to any one of claims 1-6, comprising the steps of:
Step (1): crushing the dapoxetine hydrochloride raw material, and sieving the crushed dapoxetine hydrochloride raw material with a 80-mesh sieve to control the particle size D 90 of the dapoxetine hydrochloride raw material to be 80-120 mu m;
step (2): coating the raw materials obtained in the step (1) with a film forming agent in a fluidized bed powder manner;
Step (3): uniformly mixing the coated particles obtained in the step (2) with a filler, a disintegrating agent and a binder to obtain premixed particles;
Step (4): and (3) adding a lubricant and a flavoring agent into the premixed particles obtained in the step (3) to carry out total mixed tabletting.
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