CN108014343A - A kind of pharmaceutical composition for treating breast cancer and preparation method thereof - Google Patents
A kind of pharmaceutical composition for treating breast cancer and preparation method thereof Download PDFInfo
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- CN108014343A CN108014343A CN201711389010.9A CN201711389010A CN108014343A CN 108014343 A CN108014343 A CN 108014343A CN 201711389010 A CN201711389010 A CN 201711389010A CN 108014343 A CN108014343 A CN 108014343A
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- pharmaceutical composition
- breast cancer
- treating breast
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- methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K31/33—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
Abstract
The present invention relates to field of pharmaceutical preparations, specifically discloses a kind of pharmaceutical composition for treating breast cancer and preparation method thereof.Pharmaceutical composition of the present invention includes the component of following mass percentage：Pa Boxini 26% 30%, lactitol 38% 40%, microcrystalline cellulose 28% 32%, polacrilin potassium 1% 3%, methylcellulose 1% 3%.Said composition is adapted to wet granulation, it 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 pharmaceutical composition for treating breast cancer and its preparation side
Method.
Background technology
Pa Boxini (Palbociclib), entitled 6- acetyl group -8- cyclopenta -5- methyl -2- [5- (the 1- piperazines of chemistry
Base) pyridine -2- bases amino] -8H- pyridos [2-3-d] pyrimidin-7-ones, trade name Ibrance, is that Pfizer develops
A kind of new drug of oral treatment metastatic breast cancer, Pa Boxini is the suppression medicine of cyclin dependent kinase 4,6,
Mainly prevent cell by the G1 phases to S phases and then the synthesis of suppression DNA by suppressing CDK4/6 activity.Clinical experimental study is sent out
Existing, Pa Boxini combines Letrozole to postclimacteric local infiltration patient with breast cancer or the estrogen receptor (ER) diagnosed recently
The positive, the patient of HER-2 feminine genders are highly effective.Pa Boxini obtained U.S.'s food and medication management on 2 3rd, 2015
Office (FDA) approval listing.Food Bureau of Drugs Supervision of the U.S. (FDA) claims the medicine to be a kind of breakthrough medicine, using the teaching of the invention it is possible to provide than present market
On the more lasting drug effect of medicine.
Pabuk former times profit is furnished with 2 pKa values, is respectively 3.9 and 7.4.When pH value is less than 4, solubility is high；PH value is higher than 4
When, drug solubility is remarkably decreased, about 0.009mg/ml.The absolute bioavailability of its conventional capsule agent is about 46%, and
And absorb by whether feeding and influencing, under non-fed conditions, bioavilability is about 13%.Thus, it can be seen that not feeding, cause
The medicine gastric emptying time reduces, and quickly reaches small intestine (physiological pH is higher than 4) and aids reduction drug solubility, and then reduces biology
Availability.
Pa Boxini material flows are poor, and height is required to auxiliary material, can improve its mobility by granulation, the prior art uses
Dry granulation or powder are directly encapsulated, by controlling particle diameter to solve the problems, such as its dissolution.The prior art passes through size controlling, its
Although particle diameter dissolution rate can be improved, inventor is too small for the diameter of aspirin particle of this poor fluidity by many experiments discovery,
Specific surface area is too big, large percentage of the raw material in prescription, causes material of the bulk pharmaceutical chemicals physical state to whole prescription mixture
Property has a great influence, and greatly reduces the mobility of prescription mixture material, causes content uniformity larger, influences industrialization.And
Particle diameter is excessive and its dissolution rate can be produced a very large impact, therefore the control of particle diameter is most important, should meet mobility, again
Meet the requirement of dissolution rate.Although it can also improve mobility using dry granulation, it has formulation and technology more limitation
With require, common material can not dry-pressing；Must use the good good fluidity of compressibility auxiliary material for example Lactis Anhydrous, amylum pregelatinisatum,
Part model microcrystalline cellulose, it is of high cost；Yield in unit time is fewer than wet granulation very much, is not suitable for industrialized production.
Wet granulation is that the liquid in adhesive soaks medicine powder particle surface first, makes to produce 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.
Pa Boxini has sticky strong property after impact, and this viscosity is relevant with the specific surface area of particle diameter, so
Its particle diameter will be controlled in a certain range.It is according to International Patent Application Publication WO2014128588, it is necessary to larger using Pa Boxini
The bulk pharmaceutical chemicals of particle diameter, to improve the production capacity of its physicochemical property and formulation products, but if particle diameter is big, its mobility
With regard to bad satisfaction, in particular by direct powder compression or dry granulation, it is required for controlling less particle diameter to meet molten
The requirement gone out.
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 need supplementary material to be repeatedly 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 particle diameter D903.2-2.8 micron, mobility
It is poor.
CN105213322A discloses pharmaceutical composition prepared by a kind of dry granulation process, it uses inside and outside addition, carries
The problems such as high dissolution rate and stability of product, but dry granulation equally exists low output, poor fluidity.
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, for control particle diameter at 20 microns, medicine is tired pH's 6.0 lower 60 minutes
Product dissolution rate has been further increased to 68.7%.It uses dry granulation, but its particle diameter is too small, and mobility is bad, content uniformity
It is larger, be not suitable for industrialized production, its dissolution rate strengthens PH sensitiveness, in PH>Dissolution rate stability is bad when 4.
CN105748435A discloses a kind of Pabuk former times profit cloth pharmaceutical composition and preparation method thereof, it is 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 screens rational prescription and matches somebody with somebody
Than directly mixing encapsulated technique using supplementary material, the preparation suitable with Yuan Yan companies reference preparation dissolved corrosions can be obtained.
But its particle diameter is excessive, have a great influence to its mixed material, dissolution rate is bad.
CN101001857A, using lactose, cornstarch as filler, adds bonding it discloses a kind of Pa Boxini tablets
Agent (corn starch paste) is pelletized, and 1% magnesium stearate lubrication, tabletting are added after dry.It uses wet granule compression tablet, is formed sediment with corn
Powder adds water that adhesive is made, and obtained composition dissolution rate is low, its particle water content is high, tablet weight variation is big, and stability is poor, related
Content of material is high, dissolution rate is bad.
The present invention obtains the pharmaceutical composition of suitable wet granulation, it uses wet granulation by the screening to auxiliary material
Obtained Dissolution of Tablet 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 pharmaceutical composition of the treatment breast cancer of suitable wet granulation, it uses wet
Dissolution of Tablet made from method granulation is high, impurity content is low, good fluidity, tablet weight variation is small, stability is good, is more suitable for industrializing
Production, in order to realize the object of the invention, the present invention provides following technical solution：
A kind of pharmaceutical composition for treating breast cancer, includes the component of following mass percentage：Pa Boxini 26%-
30%, lactitol 38%-40%, microcrystalline cellulose 28%-32%, polacrilin potassium 1%-3%, methylcellulose 1%-3%.
Preferably, a kind of pharmaceutical composition for treating breast cancer, include the component of following mass percentage：
Pa Boxini 28%, lactitol 39%, microcrystalline cellulose 30%, polacrilin potassium 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, plus disintegration
Agent (sodium carboxymethyl starch, hydroxypropyl cellulose, Ac-Di-Sol, crospovidone) and lubricant (silica,
Magnesium stearate, cataloid, sodium stearyl fumarate, stearic acid), it is made using encapsulated or dry granulation is directly mixed
Composition, although it by controlling raw material particle size control 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 has a great influence the material properties of whole prescription mixture, greatly reduces the flowing of prescription mixture material
Property, cause tabletting tablet weight variation larger, influence 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.
The present invention another goal of the invention be to provide a kind of preparation method for the pharmaceutical composition for treating breast cancer, specifically
Technical solution is as follows：
A kind of preparation method for the pharmaceutical composition for treating breast cancer, 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 stand-by after being cooled to 30 DEG C；
(3) Pa Boxini, lactitol, microcrystalline cellulose, polacrilin potassium are added in wet mixing pelletizer and mixed
Afterwards, prepared adhesive is added, 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 percentage by weight of purified water are 1 in the step (2):19.
Preferably, the step (3) mixing time is 150-180S, stirring frequency 40Hz.
Preferably, the step (4) drying temperature is 60-65 DEG C, drying time 3-4h.
Preferably, the step (4) grain diameter is 280 μm -320 μm.
Preferably, the step (4) granule moisture level is 0.55%-0.65%.
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 component and when contain water in raw material at the same time, the tablet dehydration being pressed into can make solubility 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 presence can increase the plastic deformation of friability particle, reduce elasticity enhancing tablet hardness.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；Pa Boxini Grain size controllings moisture of the present invention is
0.55%-0.65%, both ensure that the hardness of tablet, sticking is 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 materials, granulation
When the binder dosage that adds 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
Change, diamond retention exceed by force, so that particle is larger after dry and relative particle granularity is not easy uniformly, particle is filled out when causing tabletting
Mould is uneven, makes punch pressure skewness, makes punch pressure skewness, and tablet hardness is reduced.On the other hand bond
When agent dosage is insufficient, 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 at the same time with purified water percentage by weight: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 have a great influence 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, a kind of impurity is few, dissolution is high, tablet weight variation is small, the suitable wet granulation technology of hardness to obtaining, its 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, are adapted to wet granulation technology 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.
Embodiment
The following examples will more specifically explain the present invention, but the present invention is not limited only to these implementations
Example, these same 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
Percentage by weight is 1:19, stirring is stand-by after being naturally cooling to 30 DEG C to being completely dissolved；
(3) Pa Boxini, lactitol, microcrystalline cellulose, polacrilin potassium are added in wet mixing pelletizer and mixed
Afterwards, prepared adhesive is added, stirs 150-180S, stirring frequency 40Hz, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 3-4h, whole grain, controls grain diameter
280 μm -320 μm and moisture 0.55%-0.65%；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Embodiment 4
| Composition | The mass percentage (%) of each component |
| Pa Boxini | 28% |
| Lactitol | 41% |
| Microcrystalline cellulose | 30% |
| Polacrilin potassium | 2% |
Pa Boxini, lactitol, microcrystalline cellulose, polacrilin potassium are added in mixer and carry out mixing 4min, directly
Connect tabletting.
Embodiment 5
| Composition | The mass percentage (%) of each component |
| Pa Boxini | 28% |
| Lactitol | 41% |
| Microcrystalline cellulose | 30% |
| Polacrilin potassium | 2% |
(1) mass percentage of component is pressed, weighs each component；
(2) Pa Boxini weighed be crushed into 100 mesh sieves, lactitol, polacrilin potassium cross 60 mesh sieves respectively, then will
It is uniformly mixed, dry granulation；
(3) particle obtained above and microcrystalline cellulose are mixed, tabletting.
Comparative example 1
| Component | Amount |
| Pa Boxini | 50mg |
| Lactose | 80mg |
| Cornstarch (mixing is used) | 10mg |
| Cornstarch (is used) into paste | 8mg |
| Magnesium stearate (1%) | 8mg |
Pa Boxini is mixed with lactose and cornstarch (mixing use), 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
Thing is granulated.Wet granular is set 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
| Component | Dosage (g) |
| Pa Boxini (D90=103 μm) | 125.0 |
| Microcrystalline cellulose | 185.0 |
| Lactose | 93.0 |
| Carboxyrnethyl starch sodium | 27.0 |
| Cataloid | 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
Percentage by weight is 1:19, stirring is stand-by after being naturally cooling to 30 DEG C to being completely dissolved；
(3) Pa Boxini, microcrystalline cellulose, lactose, carboxyrnethyl starch sodium, cataloid are added to wet-mixing system
After being mixed in grain machine, prepared adhesive is added, stirs 150-180S, stirring frequency 40Hz, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 3-4h, whole grain, controls grain diameter
280 μm -320 μm and moisture 0.55%-0.65%；Magnesium stearate is added to 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 |
| Pa Boxini | 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
Percentage by weight is 1:19, stirring is stand-by after being naturally cooling to 30 DEG C to being completely dissolved；
(3) Pa Boxini, microcrystalline cellulose, lactose, sodium carboxymethyl starch, silica are added to wet-mixing granulation
After being mixed in machine, prepared adhesive is added, stirs 150-180S, stirring frequency 40Hz, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 3-4h, whole grain, controls grain diameter
280 μm -320 μm and moisture 0.55%-0.65%；Magnesium stearate is added to be uniformly mixed；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Comparative example 4
| Composition | The dosage of each component |
| Pa Boxini | 1500mg |
| Tartaric acid | 1200mg |
| Microcrystalline cellulose | 840mg |
| Lactose | 345mg |
| Sodium carboxymethyl starch | 210mg |
| Silica | 84mg |
| Magnesium stearate | 21mg |
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Percentage by weight is 1:19, stirring is stand-by after being naturally cooling to 30 DEG C to being completely dissolved；
(3) Pa Boxini, tartaric acid, microcrystalline cellulose, lactose, sodium carboxymethyl starch, silica are added to wet method
After being mixed in mixer-granulator, prepared adhesive is added, stirs 150-180S, stirring frequency 40Hz, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 3-4h, whole grain, controls grain diameter
280 μm -320 μm and moisture 0.55%-0.65%；Magnesium stearate is added to be uniformly mixed；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Comparative example 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
Percentage by weight is 1:19, stirring is stand-by after being naturally cooling to 30 DEG C to being completely dissolved；
(3) by Pa Boxini, microcrystalline cellulose, lactose, sodium carboxymethyl starch (interior to add), magnesium stearate (interior to add), colloidal state
Silica is added in wet mixing pelletizer after mixing, adds prepared adhesive, stirs 150-180S, stirring frequency
For 40Hz, softwood is prepared；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 3-4h, whole grain, controls grain diameter
280 μm -320 μm and moisture 0.55%-0.65%；It is equal to add (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 |
| Pa Boxini | 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
Percentage by weight is 1:19, stirring is stand-by after being naturally cooling to 30 DEG C to being completely dissolved；
(3) Pa Boxini, hydroxyethyl starch sodium, polyvinylpyrrolidone, mannitol, polyoxyethylene sorbitan monoleate are added to wet method
After being mixed in mixer-granulator, prepared adhesive is added, stirs 150-180S, stirring frequency 40Hz, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 3-4h, whole grain, controls grain diameter
280 μm -320 μm and moisture 0.55%-0.65%；Silica is added to be uniformly mixed；
(5) tabletting is carried out using high speed tablet press；
(6) pack.
Comparative example 7
(1) weighed by recipe quantity；
(2) adhesive is prepared：Methylcellulose is added in 80-90 DEG C of purified water, methylcellulose and purified water
Percentage by weight is 1:19, stirring is stand-by after being naturally cooling to 30 DEG C to being completely dissolved；
(3) Pa Boxini, hydroxypropyl methylcellulose, stearic acid, sodium carbonate, microcrystalline cellulose are added to wet-mixing granulation
After being mixed in machine, prepared adhesive is added, stirs 150-180S, stirring frequency 40Hz, prepares softwood；
(4) softwood after granulation is placed in fluid bed dryer, 60-65 DEG C of dry 3-4h, whole grain, controls grain diameter
280 μm -320 μm and moisture 0.55%-0.65%；Magnesium stearate is added to 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 (angle ofrepose) and represented.
Typically 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, flowing
Property 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 have a great influence 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.Measure 3 times altogether, be averaged, the results are shown in Table 1.
2nd, tablet weight variation detects：
Take test sample 20, accurately weighed gross weight, after trying to achieve average piece weight, then weight every accurately weighed respectively,
Per sheet weight with average piece again compared with, 2 must not be more than beyond limit test of weight variation by regulation, and must not have 1 beyond limiting
Spend 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, HPLC measure contents are taken, 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 relative to 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
Control 2 prescription of embodiment and other process conditions constant, adjust drying temperature, drying time in wet granulation technology
And moisture, the influence of measure drying temperature, drying time and moisture to tablet quality, experimental result are shown in Table 2：
Influence experimental result of 2 pellet moisture of table to tabletting
Consider, it is 60-65 DEG C of dry 3-4h to select drying temperature, and it is 0.55%-0.65% to control moisture, 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 stand-by after being naturally cooling to 30 DEG C to being completely dissolved；
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
Methylated cellulose aqueous solution is best as adhesive effect, while has screened methylcellulose and purified water weight percent
Than for 1:19 effects are best, and obtained Dissolution of Tablet is high, impurity content is low, tablet hardness is suitable.
3 adhesive species screening experiment result of table
4 binder concn screening experiment result of table
Consider, select methylated cellulose aqueous solution it is best as adhesive effect, while screened methylcellulose and
Purified water percentage by weight 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
Pa Boxini pharmaceutical compositions described in example 1,2,3,4,6,7,9 and reference substance carry out influence factor experiment.Hot test：Take implementation
Example and comparative examples put 60 DEG C at a temperature of places 10 days, in the 5th day and the 10th day sampling, by stability high spot reviews project into
Row detection.High wet test：Example and reference substance are put and are placed 10 days under RH92.5% ± RH5%, are taken in the 5th day and the 10th day
Sample, is detected by stability high spot reviews project.Strong illumination is tested：Example and comparative examples are placed on equipped with daylight
In the lighting box of lamp, place 10 days, sampled in the 5th day and the 10th day, by stabilization under conditions of illumination is 4500lx ± 500lx
Property 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)
- A kind of 1. pharmaceutical composition for treating breast cancer, it is characterised in that：Include the component of following mass percentage：Pa Boxi Buddhist nun 26%-30%, lactitol 38%-40%, microcrystalline cellulose 28%-32%, polacrilin potassium 1%-3%, methylcellulose 1%-3%.
- A kind of 2. pharmaceutical composition for treating breast cancer according to claim 1, it is characterised in that：Including following quality hundred Divide the component of content：Pa Boxini 28%, lactitol 39%, microcrystalline cellulose 30%, polacrilin potassium 2%, methylcellulose 2%.
- A kind of 3. pharmaceutical composition for treating breast cancer according to claim 1 or 2, it is characterised in that the pharmaceutical composition Tablet is made.
- A kind of a kind of 4. preparation method for the pharmaceutical composition for treating breast cancer as claimed in claim 1, it is characterised in that bag Include 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 Temperature fall It is stand-by after to 30 DEG C；(3) Pa Boxini, lactitol, microcrystalline cellulose, polacrilin potassium is added to after being mixed in wet mixing pelletizer, added Enter prepared adhesive, stir, prepare 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.
- A kind of 5. preparation method of pharmaceutical composition for treating breast cancer according to claim 4, it is characterised in that：Step (2) methylcellulose and the percentage by weight of purified water are 1 in:19.
- A kind of 6. preparation method of pharmaceutical composition for treating breast cancer according to claim 4, it is characterised in that：Step (3) mixing time is 150-180S, stirring frequency 40Hz.
- A kind of 7. preparation method of pharmaceutical composition for treating breast cancer according to claim 4, it is characterised in that：Step (4) drying temperature is 60-65 DEG C, drying time 3-4h.
- A kind of 8. preparation method of pharmaceutical composition for treating breast cancer according to claim 4, it is characterised in that：Step (4) grain diameter is 280 μm -320 μm.
- A kind of 9. preparation method of pharmaceutical composition for treating breast cancer according to claim 4, it is characterised in that：Step (4) granule moisture level is 0.55%-0.65%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711389010.9A CN108014343A (en) | 2017-12-21 | 2017-12-21 | A kind of pharmaceutical composition for treating breast cancer and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711389010.9A CN108014343A (en) | 2017-12-21 | 2017-12-21 | A kind of pharmaceutical composition for treating breast cancer and preparation method thereof |
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| CN108014343A true CN108014343A (en) | 2018-05-11 |
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| CN201711389010.9A Withdrawn CN108014343A (en) | 2017-12-21 | 2017-12-21 | A kind of pharmaceutical composition for treating breast cancer and preparation method thereof |
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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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| CN101351193A (en) * | 2006-01-05 | 2009-01-21 | 特瓦制药工业有限公司 | Dry formulations of aripiprazole |
| CN104887641A (en) * | 2015-04-08 | 2015-09-09 | 上海鲁源医药科技有限公司 | Palbociclib gastric-floating tablet and preparation method thereof |
| 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 | Medicinal preparation of palbociclib and preparing method thereof |
| WO2016193860A1 (en) * | 2015-06-04 | 2016-12-08 | Pfizer Inc. | Solid dosage forms of palbociclib |
| 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 |
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| 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 |
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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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Application publication date: 20180511 |