CN108066303A - A kind of anticancer pharmaceutical composition and preparation method thereof - Google Patents
A kind of anticancer pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN108066303A CN108066303A CN201711495469.7A CN201711495469A CN108066303A CN 108066303 A CN108066303 A CN 108066303A CN 201711495469 A CN201711495469 A CN 201711495469A CN 108066303 A CN108066303 A CN 108066303A
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- pharmaceutical composition
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- anticancer pharmaceutical
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 18
- 239000004744 fabric Substances 0.000 claims abstract description 41
- 235000010981 methylcellulose Nutrition 0.000 claims abstract description 28
- 229920000609 methyl cellulose Polymers 0.000 claims abstract description 26
- 239000001923 methylcellulose Substances 0.000 claims abstract description 26
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229920000881 Modified starch Polymers 0.000 claims abstract description 12
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 12
- 239000000661 sodium alginate Substances 0.000 claims abstract description 12
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 12
- 239000000845 maltitol Substances 0.000 claims abstract description 11
- 235000010449 maltitol Nutrition 0.000 claims abstract description 11
- 229940035436 maltitol Drugs 0.000 claims abstract description 11
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims abstract description 11
- 230000001070 adhesive effect Effects 0.000 claims description 34
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- 238000003756 stirring Methods 0.000 claims description 28
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 32
- 239000002245 particle Substances 0.000 description 25
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
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- 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
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
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- 238000009825 accumulation Methods 0.000 description 3
- 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 3
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- 239000007788 liquid Substances 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 238000012552 review Methods 0.000 description 3
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- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
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- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
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- 235000019890 Amylum Nutrition 0.000 description 1
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
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- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
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- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
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- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
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- 239000002609 medium Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000003821 menstrual periods Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
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- 230000000505 pernicious effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 238000009702 powder compression Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 102220042174 rs141655687 Human genes 0.000 description 1
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- 238000005070 sampling Methods 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
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- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
-
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to field of pharmaceutical preparations, specifically disclose a kind of anticancer pharmaceutical composition and preparation method thereof.Pharmaceutical composition of the present invention includes the component of following mass percentage：Pabuk former times profit cloth 26% 30%, maltitol 30% 36%, pregelatinized starch 30% 40%, sodium alginate 1% 3%, methylcellulose 1% 3%.Said composition is suitble to wet granulation, uses low Dissolution of Tablet height, impurity content made from wet granulation, good fluidity, tablet weight variation is small, stability is good.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of anticancer pharmaceutical composition and preparation method thereof.
Background technology
Breast cancer is one of the most common malignant tumors in women, and incidence accounts for the 7%~10% of the various malignant tumours of whole body,
It is only second to uterine cancer, it has also become threaten the Etiological of WomanHealth.Its morbidity is often related with heredity, and 40~60 years old exhausted
Women's incidence before and after menstrual period is higher.It is that one kind is usually happened at breast galandular epithelium tissue, seriously affects women's body and mind and is good for
Health even one of malignant tumour of threat to life, in recent years, incidence is in the trend risen year by year, and it is pernicious to have leapt to women
The first place of tumour, the incidence in China have been higher by world average level.There are about 1,200,000 women every year in the whole world to suffer from breast cancer, and 50
Ten thousand people die of breast cancer.In developed countries such as West Europe, North Americas, breast cancer incidence accounts for female malignant first place.
Pabuk former times profit cloth (English name：Palbociclib), structural formula is as follows：
Pabuk former times profit cloth is a kind of inhibitor of cell cycle protein dependent kinase (CDK) 4 and 6.Cyclin D1 and
CDK4/6 is the downstream for causing cell proliferation signals access.In vitro, Pabuk former times profit cloth is by blocking cell from cell cycle G1
Phase enters the S phases so as to slow down the cell Proliferation of estrogen receptor (ER)-positive breast cancer cells strain.It is compared to independent medication,
Pabuk former times profit cloth joint estrogen antagonist treatment breast carcinoma cell strain, causes its Retinoblastoma Protein (Rb) phosphorylation
Slow down, as a result E2F expression and signal transmission slow down and growth inhibition acceleration.In vitro, Pabuk former times profit cloth joint estrogen antagonism
Agent treatment ER- positive breast cancer cells strains cause its cell ageing to accelerate, and 6 days can be lasted up to after drug withdrawal.It is multinomial internal
Research shows to treat a kind of ER- positive breast cancer heteroplastic transplantation models in patient source, phase with Pabuk former times profit cloth joint Letrozole
It is compared to for independent medication, can accelerate to inhibit Rb phosphorylations, downstream signal transmission and tumour growth.
Pabuk former times profit cloth material flow is poor, and the prior art is directly encapsulated using dry granulation or powder, passes through control
Grain size solves the problems, such as its dissolution, although grain size dissolution rate can be improved, inventor is had found by many experiments for this
The diameter of aspirin particle of poor fluidity is too small, and specific surface area is too big, and large percentage of the raw material in prescription causes bulk pharmaceutical chemicals physical state
It is affected to the material properties of entire prescription mixture, greatly reduces the mobility of prescription mixture material, cause loading amount
It differs greatly, influences industrialization.And grain size is excessive that its dissolution rate can be produced a very large impact, therefore the control of grain size is to closing weight
Will, mobility should be met, meet the requirement of dissolution rate again.Although it can also improve mobility using dry granulation,
It has formulation and technology more limitation and requirement, and common material can not dry-pressing；The auxiliary material of the good good fluidity of compressibility must be used
It is of high cost such as Lactis Anhydrous, amylum pregelatinisatum, part model microcrystalline cellulose；Yield in unit time is fewer than wet granulation very much,
Be not suitable for industrialized production.
Wet granulation is that the liquid in adhesive soaks drug powder particle surface first, makes to generate adhesion between powder, so
The particle of certain character and size is formed under the action of liquid bridge formation and applied mechanical power afterwards, after drying finally with solid bridge
Form consolidation.Since the product of wet granulation has good appearance, good fluidity, wearability are relatively strong, compressibility is good etc.
A little, being most widely used in medical industry.
Pabuk former times profit is furnished with sticky strong property after impact, and this viscosity is, institute relevant with the specific surface area of grain size
It to be controlled in a certain range with its grain size.According to International Patent Application Publication WO2014128588, it is necessary to use Pabuk former times profit cloth
The bulk pharmaceutical chemicals of greater particle size, to improve the production capacity of its physicochemical property and formulation products, but if grain size is big, stream
Dynamic property, in particular by direct powder compression or dry granulation, is required for controlling smaller grain size that could expire with regard to bad satisfaction
The requirement dissolved out enough.
CN105748435A discloses a kind of Pabuk former times profit cloth pharmaceutical composition and preparation method thereof, by controlling Pabuk
Former times profit cloth raw material particle size size (50 μm~150 μm) with reference to the use preferable auxiliary material of mobility, and is screened rational prescription and is matched somebody with somebody
Than directly mixing encapsulated technique using supplementary material, can obtain and the comparable preparation of Yuan Yan companies reference preparation dissolved corrosion.
But its grain size is excessive, is affected to its mixed material, dissolution rate is bad.
CN106667952A discloses a kind of preparation method of Pabuk former times profit cloth pharmaceutical composition, is first by lactose, crystallite
Cellulose, Pabuk former times profit cloth bulk pharmaceutical chemicals and a part of sodium carboxymethyl starch, magnesium stearate mixing after, dry granulation, then with dioxy
SiClx, remaining sodium carboxymethyl starch, magnesium stearate are mixed to prepare；The uniformity of dosage units and drug substance stable of gained pharmaceutical composition
Property it is good, drug dissolution is high；But use dry granulation yield too low, and supplementary material is needed repeatedly to be added separately to, it is impossible to it is real
Now automatically continuously production is not the optimal selection of modern industrial process, meanwhile, select grain size D903.2-2.8 micron, mobility
It is poor.
CN105816437A discloses a kind of pharmaceutical preparation of Pabuk former times profit cloth and preparation method thereof, by Pabuk former times profit cloth with
After acidic excipient mixing, then it is common crush after be made preparation, control grain size is at 20 microns, drug 60 minutes tired under pH6.0
Product dissolution rate has been further increased to 68.7%.It uses dry granulation, but its grain size is too small, and mobility is bad, content uniformity
It is larger, be not suitable for industrialized production, dissolution rate enhances PH sensibility, in PH>Dissolution rate stability is bad when 4.
The present invention obtains the pharmaceutical composition of suitable wet granulation, uses wet granulation by the screening to auxiliary material
Dissolution of Tablet obtained is high, impurity content is low, good fluidity, tablet weight variation is small, stability is good, is more suitable for industrialized production.
The content of the invention
It is an object of the invention to provide a kind of anticancer pharmaceutical compositions of suitable wet granulation, use wet granulation system
Dissolution of Tablet it is high, impurity content is low, good fluidity, tablet weight variation is small, stability is good, be more suitable for industrialized production, be
Realization the object of the invention, the present invention provide following technical solution：
A kind of anticancer pharmaceutical composition includes the component of following mass percentage：Pabuk former times profit cloth 26%-30%, wheat
Bud sugar alcohol 30%-36%, pregelatinized starch 30%-40%, sodium alginate 1%-3%, methylcellulose 1%-3%.
Preferably, a kind of anticancer pharmaceutical composition, include the component of following mass percentage：Pabuk former times profit
Cloth 28%, maltitol 33%, pregelatinized starch 35%, sodium alginate 2%, methylcellulose 2%.
Preferably, tablet is made in the pharmaceutical composition.
The composition of the prior art is most to use the preferable lactose of mobility, microcrystalline cellulose as filler, in addition disintegration
Agent (sodium carboxymethyl starch, hydroxypropyl cellulose, croscarmellose sodium, crospovidone) and lubricant (silica,
Magnesium stearate, colloidal silicon dioxide, sodium stearyl fumarate, stearic acid), it is made using encapsulated or dry granulation is directly mixed
Composition, although by the way that raw material particle size control is controlled to solve the problems, such as dissolution rate, inventor sends out by many experiments
Too small referring now to the diameter of aspirin particle of this poor fluidity, specific surface area is too big, and large percentage of the raw material in prescription causes raw material
Medicine physical state is affected to the material properties of entire prescription mixture, greatly reduces the flowing of prescription mixture material
Property, it causes tabletting tablet weight variation larger, influences industrialization.The present invention has obtained a kind of good fluidity, miscellaneous by the screening of auxiliary material
Matter content is low, stability is good, dissolution rate is high and may be such that the small composition of tablet weight variation without using lubricant.
Another goal of the invention of the present invention is to provide a kind of preparation method of anticancer pharmaceutical composition, specific technical solution
It is as follows：
A kind of preparation method of anticancer pharmaceutical composition, comprises the following steps：
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, stirs to being completely dissolved, treats nature
It is for use after being cooled to 30 DEG C；
(3) by Pabuk former times profit cloth, maltitol, pregelatinized starch, sodium alginate is added in wet mixing pelletizer mixed
After conjunction, prepared adhesive is added in, stirs, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, dry, whole grain controls grain diameter and moisture；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Preferably, methylcellulose and the weight percent of purified water are 1 in step (2):19.
Preferably, step (3) described mixing time is 100-120S, stirring frequency 35Hz.
Preferably, step (4) described drying temperature is 60-65 DEG C, drying time 2-3h.
Preferably, step (4) described grain diameter is 230 μm -270 μm.
Preferably, step (4) described granule moisture level is 0.44%-0.52%.
There is appropriate water content in particle, be conducive to be suppressed with the tablet of enough hardness.Moisture in particle punch die to
The surface that grain is extruded to particle when being compressed forms film, formed film can play lubricating action improve the transmission of pressure from
And increase the hardness of tablet.Containing water-soluble ingredient and during containing water in raw material simultaneously, the tablet dehydration being pressed into can make it is soluble into
Divide and recrystallize and solid is formed on intergranular frame, increase the hardness of tablet.The particle elasticity that is completely dried is big, plasticity is small, difficult
To be pressed into piece.Suitable moisture reduces elasticity enhancing tablet hardness in the presence of the plastic deformation that can increase friability particle.But if
The water content of particle is too high, both easy sticking in tableting processes, also influences the mobility of particle so as to influence the control of piece weight.
Its particle water content of each kind tablet must be controlled in optimum range；Pabuk former times profit cloth Grain size controlling moisture of the present invention is
0.44%-0.52% both ensure that the hardness of tablet, sticking be not easy in tableting processes, and obtained mobility of particle is good, piece
The method of double differences is different small.
The species and dosage of adhesive are also larger to Index Influences such as grain graininess, hardness, dissolution, related substances, granulation
When the binder dosage that adds in played for the compressibility of the uniformity of granular size, hardness, disintegration and particle it is important
Effect.Binder dosage is more, and saturation degree is higher, and power is combined between particle from pendulum shape, strap shape, capillary to muddy
Variation, diamond retention exceed by force, and so as to which particle is larger after drying and relative particle granularity is not easy uniformly, particle is filled out when causing tabletting
Mould is uneven, is unevenly distributed punch pressure, is unevenly distributed punch pressure, and tablet hardness is reduced.On the other hand bond
During agent dosage deficiency, when compressed, elasticity increase causes slice, thin piece loose, hardness is low to particle.The present invention is by substantial amounts of bonding
Agent species and dosage screening (such as 75% ethanol water, starch slurry, corn starch paste, PVP K30, high substitution hydroxypropyl fiber
Element, gelatine size, sodium carboxymethylcellulose, hydroxypropyl methylcellulose) in, methylated cellulose aqueous solution is best as adhesive effect,
It is 1 that methylcellulose has been screened simultaneously with purified water weight percent:19 effects are best, and obtained Dissolution of Tablet is high, impurity contains
Measure that low, tablet hardness is suitable.
In addition, drying temperature and time are affected to impurity content, dissolution rate and moisture, it is high, molten to cross low moisture content
Go out it is bad, cross high impurity content it is then larger.Other technological parameters, which also have impurity and dissolution rate, to be had a certain impact.
Therefore, to obtain, a kind of impurity is few, it is high to dissolve out, tablet weight variation is small, the suitable wet granulation technology of hardness, work
Skill control is very important.The present invention is screened by substantial amounts of prescription and technology controlling and process, not only obtains suitable wet granulation
Pharmaceutical composition, while using Dissolution of Tablet made from wet granulation is high, impurity content is low, good fluidity, tablet weight variation
It is small, stability is good, be more suitable for industrialized production.
The present invention has the advantages that：
1st, pharmaceutical composition good fluidity, dissolution rate are high, impurity content is low, and wet granulation technology is suitble to prepare.
2nd, preparation method of the present invention is simple and easy to control, is more suitable for industrialized production, and obtained product stability is good.
Specific embodiment
The following examples will make the present invention more specifically to explain, but the present invention is not limited only to these implementations
Example, these similary embodiments are not also limit the invention in any way.
Embodiment 1-3
Preparation method：
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Weight percent is 1:19, stirring is to being completely dissolved, after being naturally cooling to 30 DEG C for use；
(3) Pabuk former times profit cloth, maltitol, pregelatinized starch, sodium alginate are added in wet mixing pelletizer and mixed
After conjunction, prepared adhesive is added in, stirs 100-120S, stirring frequency 35Hz prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 2-3h, whole grain, controls grain diameter
230 μm -270 μm and moisture 0.44%-0.52%；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Embodiment 4
| Composition | The mass percentage (%) of each component |
| Pabuk former times profit cloth | 28% |
| Maltitol | 33% |
| Pregelatinized starch | 35% |
| Sodium alginate | 2% |
Pabuk former times profit cloth, maltitol, pregelatinized starch, sodium alginate are added in mixer and carry out mixing 4min,
Direct tablet compressing.
Embodiment 5
| Composition | The mass percentage (%) of each component |
| Pabuk former times profit cloth | 28% |
| Maltitol | 33% |
| Pregelatinized starch | 35% |
| Sodium alginate | 2% |
(1) mass percentage of component is pressed, weighs each component；
(2) the Pabuk former times profit cloth weighed be crushed into 100 mesh sieves, maltitol, sodium alginate cross 60 mesh sieves respectively, then
It is mixed uniformly, dry granulation；
(3) by particle obtained above and pregelatinized starch mixing, tabletting.
Comparative example 1
| Ingredient | Amount |
| Pabuk former times profit cloth | 50mg |
| Lactose | 80mg |
| Cornstarch (mixing is used) | 10mg |
| Cornstarch (is used) into paste | 8mg |
| Magnesium stearate (1%) | 8mg |
Pabuk former times profit cloth with lactose and cornstarch (mixing use) is mixed, blends uniformly, obtains powder.By cornstarch
(into paste with) be suspended in 6ml water, be thermally formed paste while agitating.Paste is added in mixed powder, will be mixed
Object is granulated.Wet granular is made to be sieved firmly by No.8, it is dry at 50 DEG C.1% magnesium stearate of mixture is lubricated, it is tabletted.
Comparative example 2
| Ingredient | Dosage (g) |
| Pabuk former times profit cloth (D90=103 μm) | 125.0 |
| Microcrystalline cellulose | 185.0 |
| Lactose | 93.0 |
| Carboxyrnethyl starch sodium | 27.0 |
| Colloidal silicon dioxide | 11.0 |
| Magnesium stearate | 9.0 |
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Weight percent is 1:19, stirring is to being completely dissolved, after being naturally cooling to 30 DEG C for use；
(3) Pabuk former times profit cloth, microcrystalline cellulose, lactose, carboxyrnethyl starch sodium, colloidal silicon dioxide are added to wet-mixing
After being mixed in granulator, prepared adhesive is added in, stirs 100-120S, stirring frequency 35Hz prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 2-3h, whole grain, controls grain diameter
230 μm -270 μm and moisture 0.44%-0.52%；Magnesium stearate is added in be uniformly mixed；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Comparative example 3
| Composition | The mass percent (%) of each component |
| Pabuk former times profit cloth | 27.78% |
| Microcrystalline cellulose | 43.48% |
| Lactose | 21.74% |
| Sodium carboxymethyl starch | 5% |
| Silica | 0.5% |
| Magnesium stearate | 1.5% |
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Weight percent is 1:19, stirring is to being completely dissolved, after being naturally cooling to 30 DEG C for use；
(3) Pabuk former times profit cloth, microcrystalline cellulose, lactose, sodium carboxymethyl starch, silica are added to wet-mixing system
After being mixed in grain machine, prepared adhesive is added in, stirs 100-120S, stirring frequency 35Hz prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 2-3h, whole grain, controls grain diameter
230 μm -270 μm and moisture 0.44%-0.52%；Magnesium stearate is added in be uniformly mixed；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Comparative example 4
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Weight percent is 1:19, stirring is to being completely dissolved, after being naturally cooling to 30 DEG C for use；
(3) Pabuk former times profit cloth, tartaric acid, microcrystalline cellulose, lactose, sodium carboxymethyl starch, silica are added to wet
After being mixed in method mixer-granulator, prepared adhesive is added in, stirs 100-120S, stirring frequency 35Hz prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 2-3h, whole grain, controls grain diameter
230 μm -270 μm and moisture 0.44%-0.52%；Magnesium stearate is added in be uniformly mixed；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Comparative example 5
| Composition | Dosage |
| Pabuk former times profit cloth | 125.0g |
| Microcrystalline cellulose | 188.5g |
| Lactose | 94.5g |
| Carboxyrnethyl starch sodium (interior to add) | 13.5g |
| Colloidal silicon dioxide | 6.0g |
| Magnesium stearate (interior to add) | 4.5g |
| Carboxyrnethyl starch sodium (additional) | 13.5g |
| Magnesium stearate (additional) | 4.5g |
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Weight percent is 1:19, stirring is to being completely dissolved, after being naturally cooling to 30 DEG C for use；
(3) by Pabuk former times profit cloth, microcrystalline cellulose, lactose, sodium carboxymethyl starch (interior to add), magnesium stearate (interior to add), glue
State silica is added in wet mixing pelletizer after mixing, adds in prepared adhesive, stirs 100-120S, stirring frequency
Rate is 35Hz, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 2-3h, whole grain, controls grain diameter
230 μm -270 μm and moisture 0.44%-0.52%；It is equal to add in (additional) mixing of carboxyrnethyl starch sodium (additional), magnesium stearate
It is even；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Comparative example 6
| Composition | Dosage |
| Pabuk former times profit cloth | 148.5g |
| Hydroxyethyl starch sodium | 40.5g |
| Polyvinylpyrrolidone | 27.0g |
| Mannitol | 48.0g |
| Polyoxyethylene sorbitan monoleate | 5.4g |
| Silica | 0.6g |
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Weight percent is 1:19, stirring is to being completely dissolved, after being naturally cooling to 30 DEG C for use；
(3) Pabuk former times profit cloth, hydroxyethyl starch sodium, polyvinylpyrrolidone, mannitol, polyoxyethylene sorbitan monoleate are added to wet
After being mixed in method mixer-granulator, prepared adhesive is added in, stirs 100-120S, stirring frequency 35Hz prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 2-3h, whole grain, controls grain diameter
230 μm -270 μm and moisture 0.44%-0.52%；Silica is added in be uniformly mixed；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Comparative example 7
| Supplementary material | G/100 pieces |
| Pabuk former times profit cloth | 7.5 |
| Hydroxypropyl methylcellulose | 13.125 |
| Stearic acid | 7.5 |
| Sodium carbonate | 3.75 |
| Microcrystalline cellulose | 5.25 |
| Magnesium stearate | 0.375 |
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Weight percent is 1:19, stirring is to being completely dissolved, after being naturally cooling to 30 DEG C for use；
(3) Pabuk former times profit cloth, hydroxypropyl methylcellulose, stearic acid, sodium carbonate, microcrystalline cellulose are added to wet-mixing system
After being mixed in grain machine, prepared adhesive is added in, stirs 100-120S, stirring frequency 35Hz prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 2-3h, whole grain, controls grain diameter
230 μm -270 μm and moisture 0.44%-0.52%；Magnesium stearate is added in be uniformly mixed；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
1 composition mobility of experimental example, tablet weight variation and dissolution rate detection
Detection method：
1st, mobility-detected：
The mobility of solid can not be expressed with single characteristic value, commonly used angle of repose (angleofrepose) and represented.It is logical
Refer to the maximum angular that the free inclined-plane of powder accumulation horizon and horizontal plane are formed.Angle of repose is smaller, and frictional force is smaller, mobility
It is better, it is considered that good fluidity during θ≤30 degree, whens θ≤40 degree can meet the need for liquidity in production process.Powder
Mobility is affected to the weight differential of the preparations such as granule, capsule, tablet and normal operating.
Inventor uses injection method：Powder is slowly added into above funnel, the material leaked out from funnel bottom is in level
The inclination angle of coniform accumulation body is formed on face.It measures 3 times altogether, is averaged, the results are shown in Table 1.
2nd, tablet weight variation detects：
Take test sample 20, accurately weighed total weight, after acquiring average piece weight, then weight every accurately weighed respectively,
Per sheet weight with average piece again compared with, must not be more than 2 beyond limit test of weight variation by regulation, and must not have 1 beyond limiting
It spends 1 times (tablet weight variation limit ± 7.5%), the results are shown in Table 1.
3rd, dissolution rate detects
With reference to dissolution method (two the second methods of annex XC of Chinese Pharmacopoeia version in 2015), PH4.0 acetic acid is separately added into
Salting liquid, PH6.8 phosphate solutions, rotating speed are 50 turns per minute, 37 DEG C ± 0.5 DEG C of temperature, 180min after dispensing,
240min is sampled, and samples 10ml, immediately mutually synthermal, same volume the dissolution medium of supplement.Sample is through 0.45um water system micropores
Filter membrane filtration (when medium is PH6.8 phosphate solutions or aqueous solution, selects 0.8um miillpore filters), discards primary filtrate 3ml,
Subsequent filtrate is taken, HPLC measures content, and calculates the every accumulation stripping quantity in different time.
1 composition mobility of table, tablet weight variation and dissolution rate detection
In conclusion the composition of the present invention is good compared with prior art mobility of particle, tablet weight variation is small, tablet dissolution
Degree is high.
Influence experiment of 2 granule moisture level of experimental example to tabletting
It controls 2 prescription of embodiment and other process conditions constant, adjusts drying temperature, drying time in wet granulation technology
And moisture, the influence of drying temperature, drying time and moisture to tablet quality is measured, experimental result is shown in Table 2：
Influence experimental result of 2 pellet moisture of table to tabletting
Consider, select drying temperature as 60-65 DEG C of dry 2-3h, control moisture as 0.44%-0.52%, both
It ensure that the hardness of tablet, sticking be not easy in tableting processes, obtained mobility of particle is good, and tablet weight variation is small.
3 adhesive species of experimental example and concentration screening experiment
Control 2 prescription of embodiment and other process conditions constant, adjustment adhesive species and dosage, measure tablet hardness,
Impurity content and dissolution rate, experimental result are shown in Table 3 and table 4：
Adhesive 1：Methylcellulose is added in 80-90 DEG C of purified water, the weight hundred of methylcellulose and purified water
Divide than being 1:19, stirring is to being completely dissolved, after being naturally cooling to 30 DEG C for use；
Adhesive 2：75% ethanol water
Adhesive 3：5% starch slurry
Adhesive 4：Cornstarch (is suspended in 6ml water, be thermally formed paste while agitating) by corn starch paste.
Adhesive 5：5% PVP K30 aqueous solution
Adhesive 6：5% hydroxypropylcellulose ethanol solution
Adhesive 7：5% gelatine size
Adhesive 8：5% sodium carboxymethylcellulose
Adhesive 9：5% hydroxypropyl methylcellulose
3 adhesive species screening experiment result of table
4 binder concn screening experiment result of table
Consider, select methylated cellulose aqueous solution best as adhesive effect, at the same screened methylcellulose with
Purified water weight percent is 1:19 effects are best, and obtained Dissolution of Tablet is high, impurity content is low, tablet hardness is suitable.
4 influence factor of experimental example is tested
By 2015《Chinese Pharmacopoeia》Two annex XIXC bulk pharmaceutical chemicals are with pharmaceutical preparation stability test guideline to implementing
Pabuk former times profit cloth pharmaceutical composition described in example 1,2,3,4,6,7,9 and reference substance carries out influence factor experiment.Hot test：Take reality
Apply example and comparative examples put 60 DEG C at a temperature of place 10 days, sampled in the 5th day and the 10th day, by stability high spot reviews project
It is detected.High wet test：Example and reference substance were put and are placed 10 days under RH92.5% ± RH5%, in the 5th day and the 10th day
Sampling, is detected by stability high spot reviews project.Strong illumination is tested：Example and comparative examples were placed on equipped with day
In the lighting box of light lamp, in illumination to be placed 10 days under conditions of 4500lx ± 500lx, sampled in the 5th day and the 10th day, by steady
Qualitative high spot reviews project is detected；Influence factor result of the test is shown in Table 5.
5 influence factor result of the test of table
In conclusion the composition of the present invention uses, Dissolution of Tablet made from wet granulation is high, impurity content is low, stablizes
Property is good.
Claims (9)
1. a kind of anticancer pharmaceutical composition, it is characterised in that：Include the component of following mass percentage：Pabuk former times profit cloth
26%-30%, maltitol 30%-36%, pregelatinized starch 30%-40%, sodium alginate 1%-3%, methylcellulose
1%-3%.
2. a kind of anticancer pharmaceutical composition according to claim 1, it is characterised in that：Including following mass percentage
Component：Pabuk former times profit cloth 28%, maltitol 33%, pregelatinized starch 35%, sodium alginate 2%, methylcellulose 2%.
3. a kind of anticancer pharmaceutical composition according to claim 1 or 2, it is characterised in that piece is made in the pharmaceutical composition
Agent.
4. a kind of a kind of preparation method of anticancer pharmaceutical composition as described in claim 1, which is characterized in that including following step
Suddenly：
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, stirs to being completely dissolved, treats Temperature fall
It is for use after to 30 DEG C；
(3) by Pabuk former times profit cloth, maltitol, pregelatinized starch, sodium alginate is added to mixed in wet mixing pelletizer after,
Prepared adhesive is added in, stirs, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, dry, whole grain controls grain diameter and moisture；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
5. a kind of preparation method of anticancer pharmaceutical composition according to claim 4, it is characterised in that：First in step (2)
Base cellulose and the weight percent of purified water are 1:19.
6. a kind of preparation method of anticancer pharmaceutical composition according to claim 4, it is characterised in that：Step (3) is described
Mixing time is 100-120S, stirring frequency 35Hz.
7. a kind of preparation method of anticancer pharmaceutical composition according to claim 4, it is characterised in that：Step (4) is described
Drying temperature is 60-65 DEG C, drying time 2-3h.
8. a kind of preparation method of anticancer pharmaceutical composition according to claim 4, it is characterised in that：Step (4) is described
Grain diameter is 230 μm -270 μm.
9. a kind of preparation method of anticancer pharmaceutical composition according to claim 4, it is characterised in that：Step (4) is described
Granule moisture level is 0.44%-0.52%.
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| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
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| WO2016193860A1 (en) * | 2015-06-04 | 2016-12-08 | Pfizer Inc. | Solid dosage forms of palbociclib |
| CN105213322A (en) * | 2015-10-30 | 2016-01-06 | 南京正大天晴制药有限公司 | Pharmaceutical composition prepared by a kind of dry granulation process |
| CN105213346A (en) * | 2015-11-02 | 2016-01-06 | 北京泰德制药股份有限公司 | A kind of pharmaceutical composition containing cinacalcet hydrochloride and preparation method thereof |
| CN105816437A (en) * | 2016-03-29 | 2016-08-03 | 深圳市华力康生物医药有限公司 | A pharmaceutical preparation of palbociclib and its preparation method |
| CN106667952A (en) * | 2016-12-12 | 2017-05-17 | 河南润弘制药股份有限公司 | Palbociclib pharmaceutical composition and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
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Application publication date: 20180525 |