CN107362148A - A kind of pharmaceutical composition for treating tumour and its preparation method and application - Google Patents
A kind of pharmaceutical composition for treating tumour and its preparation method and application Download PDFInfo
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- CN107362148A CN107362148A CN201710623181.7A CN201710623181A CN107362148A CN 107362148 A CN107362148 A CN 107362148A CN 201710623181 A CN201710623181 A CN 201710623181A CN 107362148 A CN107362148 A CN 107362148A
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- 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
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
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- 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
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- 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
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- 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
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Abstract
The present invention provides a kind of pharmaceutical composition and its preparation method and application,Described pharmaceutical composition includes Fu Linuota and pharmaceutically acceptable auxiliary material,The pharmaceutically acceptable auxiliary material includes filler,Adhesive,Disintegrant and lubricant,The present invention coordinates Fu Linuota by using pharmaceutically acceptable auxiliary material,It is uniform and stable to reach grain graininess,With very fast dissolution feature,To improve the purpose of Fu Linuota antitumous effect,Fluid bed top spray method of granulating is utilized in preparation process,So that grain graininess is uniform and stable,Mixed especially by specifically selecting a part of filler filler slurry is made with binder solution as spray liquid,Another part filler mixes with unclassified stores in the form of dry powder is used as fluidised bed material,Grain graininess is allowed better control over by spray liquid spray,Improve particle properties,Improve stability,Increase the dissolution rate of preparation,And simple process is controllable,Improve the protective to personnel.
Description
Technical field
The invention belongs to field of medicine preparing technology, be related to a kind of pharmaceutical composition for treating tumour and preparation method thereof and
Using.
Background technology
Tumour (tumor) is the second largest killer for the serious threat human life and health for being only second to cardiovascular and cerebrovascular disease.Mesh
Before, the incidence of disease of China's malignant tumour is increased with annual 2.5% speed, and death rate average annual growth about 1.3%, chemotherapy has turned into
One of important means of Multimodality Therapy of Malignant Tumors.Vorinostat (SAHA), chemistry it is entitled " N- hydroxy-ns '-phenyl suberoyl
Amine ", it is a kind of histon deacetylase (HDAC) inhibitor, can be with inhibition of histone deacetylase (HDAC) activity, and then promote
Enter the acetylation of histone, finally suppress growth of cancer cells, induction Carcinoma cell differentiation and apoptosis.Treatment is aggravated, continues and recurred
A kind of or invalid skin T cell lymphoma (CTCL, NHL) after being treated with two kinds of systemic medications.Its by
U.S. FDA is ratified to be used to treat T-cell lymphoma,cutaneous.
In addition to energy killing tumor cell some chemotherapy side effects also occur, as leucocyte and blood are small in traditional intravenous injection
Plate decline, anorexia, Nausea and vomiting, alopecia etc., complication occurs in more than 30% patient, such as endovenitis or blood
Bolt phlebitis etc..Oral chemotherapy can then avoid many side effects.Therefore suitable oral Vorinostat preparation is developed very
It is necessary.
Vorinostat, slightly molten in methyl alcohol, the slightly soluble in ethanol or isopropanol are almost insoluble in dichloromethane or water.
Belong to insoluble anti-tumor medicament.The preparation method of this medicine, which has directly to mix, at present fills capsule, stream of this technique to supplementary material
Dynamic property, granularity requirements are very high, and the meticulous difficulty to filling process of raw material is larger, and raw material is excessively slightly very big on dissolution influence, and powder
Protection of the dust storm dew to personnel is unfavorable.
CN101874793A discloses a kind of Vorinostat solid preparation, consisting of bulk drug Vorinostat and medicinal auxiliary
Material, pharmaceutic adjuvant is filler, disintegrant and lubricant, it is characterised in that the weight of Vorinostat and filler ratio is 1:0.9-
4.5, the weight ratio of Vorinostat and disintegrant is 1:The weight ratio of 0.0834-0.4170, Vorinostat and lubricant is 1:
0.0166-0.0830.The dissolution rate of the Vorinostat solid preparation reached more than 80%, up to 90% or so at 45 minutes.
But for Vorinostat preparation, higher dissolution rate is desired to have to reach better effect.
Therefore, it is necessary to develop a kind of technology, Vorinostat pharmaceutical composition is prepared, can solve the problem that the dissolution rate of preparation,
Improve the feasibility of technique, the technique for increasing the protection to operating personnel.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the invention to provide a kind of pharmaceutical composition and preparation method thereof and should
With.
To use following technical scheme up to this purpose, the present invention：
On the one hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes Fu Linuota and pharmaceutically may be used
The auxiliary material of receiving, the pharmaceutically acceptable auxiliary material include filler, adhesive, disintegrant and lubricant.
In the present invention, Fu Linuota is coordinated by using pharmaceutically acceptable auxiliary material, it is equal to reach grain graininess
Even stabilization, there is very fast dissolution feature, to improve the purpose of Fu Linuota antitumous effect.
Preferably, the filler in starch, microcrystalline cellulose or lactose any one or at least two group
Close, preferred starch.
Preferably, in described pharmaceutical composition, relative to 100 parts by weight Fu Linuota, the dosage of the filler is
170-230 parts by weight, such as 170 parts by weight, 180 parts by weight, 190 parts by weight, 200 parts by weight, 210 parts by weight, 220 parts by weight
Or 230 parts by weight.
Preferably, described adhesive in hydroxypropyl methylcellulose, PVP k30 or starch any one or at least two
The combination of kind, preferably hydroxypropyl methylcellulose.
Preferably, in described pharmaceutical composition, relative to 100 parts by weight Fu Linuota, the dosage of described adhesive is
3-10 parts by weight, such as 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight or 10 weights
Measure part.
Preferably, in described pharmaceutical composition, the weight percentage of described adhesive is 0.5-5%, such as
0.5%th, 0.8%, 1%, 1.5%, 1.8%, 2%, 2.3%, 2.5%, 2.8%, 3%, 3.5%, 4%, 4.5% or 5%, it is excellent
Select 2-3%.Granulation uniformity and preparation stability of the dosage for solvent of adhesive are surprised to find that in the present invention, especially
It is that dissolution characteristic has considerable influence, only just be can guarantee that under suitable binder dosage with faster dissolution rate,
Preferably to improve the therapeutic effect of medicine.
Preferably, the disintegrant is selected from sodium carboxymethyl starch, PVPP, low-substituted hydroxypropyl cellulose or crosslinking
In sodium carboxymethylcellulose any one or at least two combination, preferred low-substituted hydroxypropyl cellulose.
Preferably, in described pharmaceutical composition, relative to 100 parts by weight Fu Linuota, the dosage of the disintegrant is
6-15 parts by weight, such as 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, 11 parts by weight, 12 parts by weight, 13
Parts by weight, 14 parts by weight or 15 parts by weight.
Preferably, the lubricant is in silica, magnesium stearate, Compritol 888 ATO, talcum powder or stearic acid
Any one or at least two combination.
Preferably, in described pharmaceutical composition, relative to 100 parts by weight Fu Linuota, the dosage of the lubricant is
1.5-10 parts by weight, such as 1.5 parts by weight, 1.8 parts by weight, 2 parts by weight, 2.5 parts by weight, 3 parts by weight, 3.5 parts by weight, 4 weights
Measure part, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight or 10 parts by weight.
In the present invention, the component of following parts by weight is included as optimal technical scheme, described pharmaceutical composition：
In the composition of the pharmaceutical composition of preferable treatment tumour of the present invention, by for specific filler,
The selection of adhesive, disintegrant and lubricant, enable to starch, hydroxypropyl methylcellulose, low-substituted hydroxypropyl methylcellulose and hard
Fatty acid magnesium preferably coordinates with active constituents of medicine Fu Linuota, the performance of collaboration enhancing preparation, can promote Fu Linuota medicines
Compositions have more preferable stability, faster dissolution rate, preferably play therapeutic effect.
Preferably, the formulation of the pharmaceutical composition for the treatment of tumour of the present invention includes granule, tablet or capsule,
Preferred tablet.
On the other hand, the invention provides the preparation method of pharmaceutical composition as described above, methods described is using fluidisation
Bed top spray granulation, the described method comprises the following steps：
(1) filler slurry is made in a part of filler, filler slurry and binder solution is mixed to get spray
Liquid；
(2) it is placed in fluid bed after remaining filler is mixed with Fu Linuota, disintegrant, after preheating material, sprays into
The spray liquid that step (1) obtains, granulation and drying are carried out simultaneously, sieve, dry particl is made；
(3) mix lubricant is added in the dry particl obtained to step (2), obtains described pharmaceutical composition.
The present invention using fluid bed top spray pelletize, by spray liquid in pelletization and fluid bed material it is specific
Selection, that is, utilize and filler slurry and adhesive is made in a part of filler is mixed to get spray liquid, another filler with
Fu Linuota, disintegrant mixing are used as fluidised bed material, and such mode can make it that medicament composition granule performance is more excellent
To change, granule regularizing, particle size distribution scope is narrower, uniform and stable, and can also improve the dissolution characteristic of pharmaceutical composition,
So that dissolution is faster.
Preferably, step (1) is described is made filler slurry by a part of filler and refers to fill out a part in formula ratio
Agent is filled to carry out disperseing filler slurry is prepared with purified water.
Preferably, the mass percent concentration of the filler slurry is 6-13%, for example, 6%, 6.3%, 6.5%,
6.8%th, 7%, 7.5%, 7.8%, 8%, 8.5%, 8.8%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%,
12.5% or 13%.If filler slurry concentration is too dilute, shaping particles are poor, if filler slurry concentration is too high,
The spray of slurry and binder solution is then influenced whether, the blocking of spray head can be caused, and spray can not be smoothly completed.
Preferably, step (1) described adhesive solution is that adhesive is dissolved or dispersed in purified water to be configured to bond
Agent solution.Preferably, the concentration of described adhesive solution is 8-10%, for example, 8%, 8.3%, 8.5%, 8.8%, 9%,
9.3%th, 9.5%, 9.8% or 10%, bonding dynamics is inadequate if the concentration of binder solution is too low, causes particle not steady enough
It is fixed, the spray of slurry and binder solution is influenced whether if the excessive concentration of binder solution, the stifled of spray head can be caused
Plug, and spray can not be smoothly completed.
Preferably, step (2) described preheating material is that material is preheated into 40-50 DEG C, for example, 40 DEG C, 43 DEG C, 45 DEG C, 48
DEG C or 50 DEG C.
Preferably, during step (2) described granulation, the running parameter setting of fluid bed is as follows：Throttle opening is 100%, wind
Unit frequency is 15~30Hz (such as 15Hz, 18Hz, 20Hz, 22Hz, 24Hz, 26Hz, 28Hz or 30Hz), EAT is 60~
80 DEG C (such as 60 DEG C, 62 DEG C, 65 DEG C, 68 DEG C, 70 DEG C, 73 DEG C, 75 DEG C, 78 DEG C or 80 DEG C), leaving air temp are 20~40 DEG C of (examples
Such as 20 DEG C, 23 DEG C, 25 DEG C, 28 DEG C, 30 DEG C, 33 DEG C, 35 DEG C, 38 DEG C or 40 DEG C), temperature of charge be 30~50 DEG C (such as 30 DEG C,
33 DEG C, 35 DEG C, 38 DEG C, 40 DEG C, 43 DEG C, 45 DEG C, 48 DEG C or 50 DEG C), atomizing pressure be 0.10~0.40MPa (such as
0.10MPa, 0.15MPa, 0.20MPa, 0.25MPa, 0.30MPa, 0.35MPa or 0.40MPa), wriggling revolution speed be 10~
70rpm (such as 10rpm, 15rpm, 18rpm, 20rpm, 25rpm, 30rpm, 35rpm, 40rpm, 45rpm, 50rpm, 55rpm,
60rpm, 65rpm or 70rpm).
Preferably, step (2) sieving was 20-24 mesh (such as 20 mesh, 21 mesh, 22 mesh, 23 mesh or 24 mesh) screen cloth.
Preferably, the step (3) is prepared into corresponding formulation after mix lubricant is added, in addition to by mixture
Step.
Preferably, mixture is carried out tabletting, film coating is made by the step (3) after mix lubricant is added
Tablet.
As the preferred technical solution of the present invention, described pharmaceutical composition includes Fu Linuota, starch, hypromellose
When element, low-substituted hydroxypropyl methylcellulose and magnesium stearate, the preparation method of described pharmaceutical composition comprises the following steps：
(1) starch size is made in a part of starch in formula ratio, starch size and hydroxypropyl methylcellulose solution is mixed
Conjunction obtains spray liquid；
(2) by remaining starch and Fu Linuota, low-substituted hydroxypropyl methylcellulose and it is placed in fluid bed, preheating material
Afterwards, the spray liquid that step (1) obtains is sprayed into, granulation and drying carry out, sieve, dry particl is made simultaneously；
(3) magnesium stearate mixing is added in the dry particl obtained to step (2), obtains described pharmaceutical composition.
On the other hand, the application the invention provides pharmaceutical composition as described above in antineoplastic is prepared.
Relative to prior art, the invention has the advantages that：
(1) present invention coordinates Fu Linuota by using pharmaceutically acceptable auxiliary material, uniform to reach grain graininess
It is stable, there is very fast dissolution feature, to improve the purpose of Fu Linuota antitumous effect.
(2) present invention in preparation process by utilizing fluid bed top spray method of granulating so that and grain graininess is uniform and stable,
Mixed especially by specifically selecting a part of filler filler slurry is made with binder solution as spray liquid,
Another part filler mixes with unclassified stores in the form of dry powder is used as fluidised bed material, is sprayed by spray liquid more preferable
Ground controls grain graininess, improves particle properties, improves stability, increases the dissolution rate of preparation, and simple process is controllable, improves
To the protective of personnel.
Embodiment
Technical scheme is further illustrated below by embodiment.Those skilled in the art should be bright
, the embodiment be only to aid in understand the present invention, be not construed as to the present invention concrete restriction.
Embodiment 1
In this embodiment, the formula of pharmaceutical composition is as follows：
Using fluid-bed marumerization technique, add in a starch part, starch slurry and hydroxypropyl methylcellulose is made in a part
Solution, which mixes, is used as spray liquid, and step is as follows：
(1) 50g starch is carried out disperseing starch size, the mass percent concentration of the starch size is made with purified water
For 13%, weigh the hydroxypropyl methylcellulose of recipe quantity and purified water is made into hydroxypropyl methylcellulose solution (concentration 10%), will form sediment
Slurry material and hydroxypropyl methylcellulose solution are mixed to get spray liquid；
(2) it is placed in after remaining starch is mixed with Fu Linuota, low-substituted hydroxypropyl methylcellulose in fluid bed, 40-50
After DEG C preheating material, the spray liquid that step (1) obtains is sprayed into, granulation and drying are carried out simultaneously, sieving, dry particl are made；
(3) magnesium stearate mixing is added in the dry particl obtained to step (2), tabletting, obtains described pharmaceutical composition
Tablet.
Wherein, during step (2) described granulation, the running parameter setting of fluid bed is as follows：
| Running parameter | Granulating stage control range |
| Throttle opening | 100% |
| Blower fan frequency (Hz) | 15~30 |
| EAT (DEG C) | 60~80 |
| Leaving air temp (DEG C) | 20~40 |
| Temperature of charge (DEG C) | 30~50 |
| Atomizing pressure/MPa | 0.10~0.40 |
| Wriggling revolution speed/rpm | 10~70 |
Embodiment 2
In this embodiment, the formula of pharmaceutical composition is as follows：
| Composition | Unit dose/mg | Percentage/% |
| Fu Linuota | 100 | 31.25 |
| Starch | 199.2 | 62.25 |
| Hydroxypropyl methylcellulose | 6.4 | 2.0 |
| Low-substituted hydroxypropyl cellulose | 12.8 | 4.0 |
| Magnesium stearate | 1.6 | 0.5 |
Using fluid-bed marumerization technique, add in a starch part, starch slurry and hydroxypropyl methylcellulose is made in a part
Solution, which mixes, is used as spray liquid, and step is as follows：
(1) 30g starch is carried out disperseing starch size, the mass percent concentration of the starch size is made with purified water
For 10%, weigh the hydroxypropyl methylcellulose of recipe quantity and purified water is made into hydroxypropyl methylcellulose solution (concentration 10%), will form sediment
Slurry material and hydroxypropyl methylcellulose solution are mixed to get spray liquid；
(2) it is placed in after remaining starch is mixed with Fu Linuota, low-substituted hydroxypropyl methylcellulose in fluid bed, 40-50
After DEG C preheating material, the spray liquid that step (1) obtains is sprayed into, granulation and drying are carried out simultaneously, sieving, dry particl are made；
(3) magnesium stearate mixing is added in the dry particl obtained to step (2), tabletting, obtains described pharmaceutical composition
Tablet.
Wherein, during step (2) described granulation, the running parameter setting of fluid bed is as follows：
| Running parameter | Granulating stage control range |
| Throttle opening | 100% |
| Blower fan frequency (Hz) | 15~25 |
| EAT (DEG C) | 70~80 |
| Leaving air temp (DEG C) | 25~35 |
| Temperature of charge (DEG C) | 40~50 |
| Atomizing pressure/MPa | 0.10~0.30 |
| Wriggling revolution speed/rpm | 20~60 |
Embodiment 3
In this embodiment, the formula of pharmaceutical composition is as follows：
| Composition | Unit dose/mg | Percentage/% |
| Fu Linuota | 100 | 31.25 |
| Starch | 196 | 61.2% |
| Hydroxypropyl methylcellulose | 9.6 | 3.0 |
| Low-substituted hydroxypropyl cellulose | 12.8 | 4.0 |
| Magnesium stearate | 1.6 | 0.5 |
The pharmaceutical composition prepared using fluid-bed marumerization technique, a starch part are added with dry powder, and a part is formed sediment
Powder, which is made starch slurry and mixed with hydroxypropyl methylcellulose solution, is used as spray liquid, and step is as follows：
(1) 25g starch is carried out disperseing starch size, the mass percent concentration of the starch size is made with purified water
For 6%, weigh the hydroxypropyl methylcellulose of recipe quantity and purified water is made into hydroxypropyl methylcellulose solution (concentration 8%), by starch
Slurry and hydroxypropyl methylcellulose solution are mixed to get spray liquid；
(2) it is placed in after remaining starch is mixed with Fu Linuota, low-substituted hydroxypropyl methylcellulose in fluid bed, 40-50
After DEG C preheating material, the spray liquid that step (1) obtains is sprayed into, granulation and drying are carried out simultaneously, sieving, dry particl are made；
(3) magnesium stearate mixing is added in the dry particl obtained to step (2), tabletting, obtains described pharmaceutical composition
Tablet.
Wherein, during step (2) described granulation, the running parameter setting of fluid bed is as follows：
| Running parameter | Granulating stage control range |
| Throttle opening | 100% |
| Blower fan frequency (Hz) | 15~25 |
| EAT (DEG C) | 70~80 |
| Leaving air temp (DEG C) | 25~35 |
| Temperature of charge (DEG C) | 40~50 |
| Atomizing pressure/MPa | 0.10~0.30 |
| Wriggling revolution speed/rpm | 20~60 |
Embodiment 4
The embodiment difference from Example 1 is only that the formula of described pharmaceutical composition is as follows：
The selection of its preparation method and process conditions is same as Example 1.
Embodiment 5
The embodiment difference from Example 1 is only that the formula of described pharmaceutical composition is as follows：
| Composition | Unit dose/mg | Percentage/% |
| Fu Linuota | 100 | 31.15 |
| Starch | 210 | 65.42 |
| Hydroxypropyl methylcellulose | 3 | 0.93 |
| Low-substituted hydroxypropyl cellulose | 6 | 1.9 |
| Magnesium stearate | 2 | 0.6 |
The selection of its preparation method and process conditions is same as Example 1.
Comparative example 1
In the comparative example, the formula of pharmaceutical composition is same as Example 1, the difference is that this comparative example uses wet granulation
Prepared, step is as follows：
(1) premix：Whole starch, Fu Linuota, low-substituted hydroxypropyl cellulose are placed in mixer successively, unlatching is stirred
Mix (150 ± 20rpm), mix 5min,
(2) wet granulation：Weigh the hydroxypropyl methylcellulose of recipe quantity and purified water is made into hydroxypropyl methylcellulose solution.Stirring
Mix after at the uniform velocity adding binder solution under (150 ± 20rpm) state, in stirring (150 ± 20rpm) shearing (1500 ± 50rpm)
Under state, pelletize 3min.Cross 16 mesh sieve whole grains.
(3) fluidized drying：Fluidized bed drying is carried out according to following parameter, particle drying weightlessness ＜ 3.5% (survey by quick moisture
Determine instrument measure：105 DEG C, 3min) in the range of when can stop drying.
| Running parameter | Granulating stage control range |
| Throttle opening | 100% |
| Blower fan frequency (Hz) | 15~30 |
| EAT (DEG C) | 60~80 |
| Leaving air temp (DEG C) | 20~40 |
| Temperature of charge (DEG C) | 30~50 |
(4) it is mixed eventually：Add magnesium stearate, mixing velocity：12 ± 2rpm, incorporation time 4min, tabletting, obtain medicine mixing
The tablet of thing.
Comparative example 2
In the comparative example, the formula of pharmaceutical composition is same as Example 2, the difference is that using fluid bed in this comparative example
When one-step palletizing technique prepares pharmaceutical composition, starch all adds into fluid bed and is used as material in the form of dry powder.Prepare
Step is as follows：
(1) weigh the hydroxypropyl methylcellulose of recipe quantity and purified water is made into hydroxypropyl methylcellulose solution as spray liquid；
(2) successively whole starch, Fu Linuota, low-substituted hydroxypropyl cellulose mixing 5min are placed in fluidisation after mixing
In bed, after preheating material, the spray liquid that step (1) obtains is sprayed into, granulation and drying carry out, sieve, dry particl is made simultaneously；
(3) magnesium stearate mixing is added in the dry particl obtained to step (2), tabletting, obtains described pharmaceutical composition
Tablet.
Wherein, during step (2) described granulation, the running parameter setting of fluid bed is same as Example 2.
Pharmaceutical composition prepared by embodiment and comparative example is subjected to dissolution determination.Assay method is paddle method, with
1000ml 0.1mol/L hydrochloric acid solutions are dissolution medium, rotating speed 75rpm, carry out dissolution measure, and embodiment 1-5 and
Comparative example 1-4 measurement result is summarized in table 1.
Table 1
| 5min | 10min | 15min | 30min | 45min | 60min | |
| Embodiment 1 | 42.3% | 85.3% | 102.5% | 102.0% | 102.8% | 102.0% |
| Embodiment 2 | 40.8% | 83.6% | 100.4% | 101.5% | 102.6% | 102.1% |
| Embodiment 3 | 38.5% | 70.8% | 88.4% | 98.3% | 100.4% | 101.1% |
| Embodiment 4 | 33.7% | 74.3% | 87.4% | 98.6% | 101.2% | 100.8% |
| Embodiment 5 | 32.9% | 72.3% | 88.0% | 98.8% | 101% | 101.5% |
| Comparative example 1 | 27.6% | 69.4% | 86.3% | 98.0% | 101.4% | 102.4% |
| Comparative example 2 | 35.0% | 75.3% | 89.5% | 100.3% | 101.5% | 102.0% |
From the data in table 1, it can be seen that from embodiment 1 and the result of comparative example 1, under prescription same case, Fu Linuota is used
Fluid-bed marumerization dissolution is better than normal wet granulating process；From embodiment 2 and the result of comparative example 2, prescription is mutually sympathized with
Under condition, during Fu Linuota uses fluid-bed marumerization, a starch part is dry plus a part is added with starch slurry, and it is combined
The dissolution of thing is better than the dry fluid-bed marumerization added of starch.It can be seen from embodiment 1 and embodiment 4-5 contrast
In the case of other conditions identical, the dissolution that the content of adhesive can be to drug combination preparation produces bigger influence, real
When to apply in example 1 binder content be 2%, hence it is evident that the dissolution knot of the drug combination preparation prepared better than embodiment 4 and embodiment 5
Fruit.
The size distribution that embodiment 1-3 and comparative example 1-2 is carried out to dry particl compares.Assay method is sieve method, respectively
Sieved using 20 mesh, 40 mesh, 60 mesh, 80 mesh, 100 eye mesh screens, measurement result is shown in Table 2.
Table 2
As shown in Table 2, the dry particl broad particle distribution when using the wet granulation described in comparative example 1, thick
Grain is more.And use embodiment 1-5 and the fluid-bed marumerization described in comparative example 2 dry particl particle size distribution narrower,
It is uniform and stable, more conducively follow-up tablet forming technique feasibility and stability.
Applicant states, the present invention by above-described embodiment come illustrate pharmaceutical composition and preparation method thereof of the present invention and
Using, but the invention is not limited in above-described embodiment, that is, do not mean that the present invention has to rely on above-described embodiment and could implemented.
Person of ordinary skill in the field replaces it will be clearly understood that any improvement in the present invention to the equivalent of raw material selected by the present invention
Change and the addition of auxiliary element, the selection of concrete mode etc., all fall within protection scope of the present invention and it is open within the scope of.
Claims (10)
1. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes Fu Linuota and pharmaceutically acceptable auxiliary
Material, the pharmaceutically acceptable auxiliary material include filler, adhesive, disintegrant and lubricant.
2. pharmaceutical composition according to claim 1, it is characterised in that the filler is selected from starch, microcrystalline cellulose
In lactose any one or at least two combination, preferred starch；
Preferably, in described pharmaceutical composition, relative to 100 parts by weight Fu Linuota, the dosage of the filler is 170-
230 parts by weight.
3. pharmaceutical composition according to claim 1 or 2, it is characterised in that described adhesive be selected from hydroxypropyl methylcellulose,
In PVP k30 or starch any one or at least two combination, preferred hydroxypropyl methylcellulose；
Preferably, in described pharmaceutical composition, relative to 100 parts by weight Fu Linuota, the dosage of described adhesive is 3-10
Parts by weight；
Preferably, in described pharmaceutical composition, the weight percentage of described adhesive is 0.5-5%, preferably 2-3%.
4. according to the pharmaceutical composition any one of claim 1-3, it is characterised in that the disintegrant is selected from carboxymethyl
Any one in sodium starch, PVPP, low-substituted hydroxypropyl cellulose or Ac-Di-Sol or at least two
The combination of kind, preferably low-substituted hydroxypropyl cellulose；
Preferably, in described pharmaceutical composition, relative to 100 parts by weight Fu Linuota, the dosage of the disintegrant is 6-15
Parts by weight.
5. according to the pharmaceutical composition any one of claim 1-4, it is characterised in that the lubricant is selected from titanium dioxide
In silicon, magnesium stearate, Compritol 888 ATO, talcum powder or stearic acid any one or at least two combination, it is preferably stearic
Sour magnesium；
Preferably, in described pharmaceutical composition, relative to 100 parts by weight Fu Linuota, the dosage of the lubricant is 1.5-
10 parts by weight.
6. according to the pharmaceutical composition any one of claim 1-5, it is characterised in that described pharmaceutical composition is included such as
The component of lower parts by weight：
Preferably, the formulation of the pharmaceutical composition for the treatment of tumour of the present invention includes granule, tablet or capsule, preferably
Tablet.
7. the preparation method of the pharmaceutical composition according to any one of claim 1-6, it is characterised in that methods described is adopted
Pelletized, the described method comprises the following steps with fluid bed top spray：
(1) filler slurry is made in a part of filler, filler slurry and binder solution is mixed to get spray liquid；
(2) it is placed in after remaining filler is mixed with Fu Linuota, disintegrant in fluid bed, after preheating material, sprays into step
(1) spray liquid obtained, granulation and drying are carried out simultaneously, sieve, dry particl is made；
(3) mix lubricant is added in the dry particl obtained to step (2), obtains described pharmaceutical composition.
8. preparation method according to claim 7, it is characterised in that described a part of filler is made of step (1) is filled out
Agent slurry is filled to refer to carry out disperseing filler slurry is prepared with purified water by a part of filler in formula ratio；
Preferably, the mass percent concentration of the filler slurry is 6-13%；
Preferably, step (1) described adhesive solution be by adhesive be dissolved or dispersed in purified water prepare composite adhesives it is molten
Liquid；
Preferably, the concentration of described adhesive solution is 8-10%；
Preferably, step (2) described preheating material is that material is preheated into 40-50 DEG C；
Preferably, during step (2) described granulation, the running parameter setting of fluid bed is as follows：Throttle opening is 100%, blower fan frequency
Rate is 15~30Hz, and EAT is 60~80 DEG C, and leaving air temp is 20~40 DEG C, and temperature of charge is 30~50 DEG C, atomization pressure
Power is 0.10~0.40MPa, and wriggling revolution speed is 10~70rpm；
Preferably, step (2) sieving was 20-24 eye mesh screens；
Preferably, the step (3) is after mix lubricant is added, in addition to mixture is prepared into the step of corresponding formulation
Suddenly；
Preferably, mixture is carried out tabletting, tablet is made in film coating by the step (3) after mix lubricant is added.
9. the preparation method according to claim 7 or 8, it is characterised in that described pharmaceutical composition includes Fu Linuota, formed sediment
When powder, hydroxypropyl methylcellulose, low-substituted hydroxypropyl methylcellulose and magnesium stearate, the preparation method of described pharmaceutical composition include with
Lower step：
(1) starch size is made in a part of starch in formula ratio, starch size and hydroxypropyl methylcellulose solution is mixed
To spray liquid；
(2) by remaining starch and Fu Linuota, low-substituted hydroxypropyl methylcellulose and it is placed in fluid bed, after preheating material,
The spray liquid that step (1) obtains is sprayed into, granulation and drying carry out, sieve, dry particl is made simultaneously；
(3) magnesium stearate mixing is added in the dry particl obtained to step (2), obtains described pharmaceutical composition.
10. application of the pharmaceutical composition according to any one of claim 1-6 in antineoplastic is prepared.
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