CN106667952A - Palbociclib pharmaceutical composition and preparation method thereof - Google Patents
Palbociclib pharmaceutical composition and preparation method thereof Download PDFInfo
- Publication number
- CN106667952A CN106667952A CN201611141522.9A CN201611141522A CN106667952A CN 106667952 A CN106667952 A CN 106667952A CN 201611141522 A CN201611141522 A CN 201611141522A CN 106667952 A CN106667952 A CN 106667952A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- former times
- magnesium stearate
- pabuk former
- percent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a palbociclib pharmaceutical composition and a preparation method thereof and belongs to the technical field of medicines. The pharmaceutical composition is prepared from the following components in percentage by mass: 27.00 percent to 28.50 percent of palbociclib, 21.00 percent to 22.5 percent of lactose, 42.50 percent to 44.00 percent of microcrystalline cellulose, 4.5 percent to 5.5 percent of sodium carboxymethyl starch, 0.5 percent to 0.8 percent of silicon dioxide and 1.2 percent to 2.0 percent of magnesium stearate. In the pharmaceutical composition, the palbociclib is used as an active component, the lactose and the microcrystalline cellulose are used as a filling agent, the sodium carboxymethyl starch is used as an efficient disintegrating agent, the silicon dioxide is used as a flow aid and the magnesium stearate is used as a lubricant; main and auxiliary materials have good compatibility and the medicine has good stability; all the components are matched with one another and have a coordinating effect; the obtained pharmaceutical composition has a good dissolution effect and a high dissolution degree, and can be sufficiently absorbed so that the curative effect is improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of Pabuk former times profit cloth pharmaceutical composition, one is also related to
Plant the preparation method of Pabuk former times profit cloth pharmaceutical composition.
Background technology
Pabuk former times profit cloth (Palbociclib), Chinese chemical name is：6- acetyl group -8- cyclopenta -5- methyl -2- { [5-
(piperazine -1- bases) pyridine -2- bases] amino }-pyrido [2,3-d] pyrimidine -7 (8H) -one, English language Chemical is entitled：6-acetyl-
8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-pyrido[2,3-
D] pyrimidin-7 (8H)-one, shown in its structural formula such as following formula (I)：
Pabuk former times profit cloth is a kind of inhibitor of cell cycle protein dependent kinase 4 and 6 (CDK4/6).Cyclin
White D1 and CDK4/6 is the downstream molecules of signal path, and cell can be caused to breed.In testing in vitro, Pabuk former times profit cloth can hinder
Only cell cycle changes from trophophase (G1 phases) to the DNA replication dna phase (S1 phases), so as to reduce or slow down ER ER+-
The cell propagation of anode breast carcinoma cell strain.Pabuk former times profit cloth and antiestrogen use in conjunction process breast cancer cell line,
Retinoblastoma Protein (Rb) phosphorylation can be reduced, so as to cause E2F expression and signal transmission to reduce, growth inhibited
Accelerate.Pabuk former times profit cloth joint antiestrogen acts in vitro ER+Breast cancer cell line, can increase cell ageing, and
The effect can continue until 6 days after medicine is removed.In vivo study shows that Pabuk former times profit cloth and a kind of patient of letrozole combination treatment come
The ER- positive breast cancer heteroplastic transplantation models in source, can accelerate the suppression to Rb phosphorylations, downstream signal and tumour growth to make
With.
Modern preparations are according to factor designs such as clinical application demand, pharmaceutical properties, patient's compliance, commercial production levels
Suitable dosage form.It is orally one of administering mode that patient is most willing to accept, wherein capsule is the most frequently used peroral dosage form, tool
Have production automation degree higher, yield is big, low cost, carry, transport, taking convenience the advantages of.But, existing Pabuk former times
The not high problem of sharp cloth capsule generally existing dissolution, causes crude drug to be fully absorbed, and lessens the curative effect.
The content of the invention
It is an object of the invention to provide a kind of Pabuk former times profit cloth pharmaceutical composition, with higher dissolution.
Second object of the present invention is to provide a kind of preparation method of Pabuk former times profit cloth pharmaceutical composition.
In order to realize object above, the technical solution adopted in the present invention is：
A kind of Pabuk former times profit cloth pharmaceutical composition, the component comprising following mass percent：Pabuk former times profit cloth 27.00%~
28.50%th, Lactose 21.00%~22.5%, Microcrystalline Cellulose 42.50%~44.00%, carboxymethyl starch sodium 4.5%~
5.5%th, silicon dioxide 0.5%~0.8%, magnesium stearate 1.2%~2.0%.
Preferably, described Pabuk former times profit cloth pharmaceutical composition, the component comprising following mass percent：Pabuk former times profit cloth
27.78%th, Lactose 21.74%, Microcrystalline Cellulose 43.48%, carboxymethyl starch sodium 5%, silicon dioxide 0.5%, magnesium stearate
1.5%.
Preferably, the Lactose is Lactose TABLETTOSE 80；The Microcrystalline Cellulose is Microcrystalline Cellulose TYPE
101.The compressibility and mobility of Lactose TABLETTOSE 80 is preferable.Select the type microcrystalline celluloses of TYPE 101 of JRS companies
Element, can improve the mixing uniformity with principal agent.
Lactose can affect the mobility of powder body with Microcrystalline Cellulose different ratio, so as to have influence on the mix homogeneously of principal agent
Property, have influence on medicament contg and dissolution rate.Preferably, Lactose and the mass ratio of Microcrystalline Cellulose are 1:2.
The pharmaceutical composition is capsule.
In the Pabuk former times profit cloth pharmaceutical composition of the present invention, Pabuk former times profit cloth is active component (principal agent or major ingredient)；Lactose
It is filler with Microcrystalline Cellulose, Lactose is a kind of excellent filler；Microcrystalline Cellulose is that cellulosic sections are hydrolyzed and obtained
The less crystallinity cellulose of the degree of polymerization, with good compressibility and stronger adhesion, with Lactose with the use of having
Good filling effect, Microcrystalline Cellulose is also done binding agent and is used in oral capsule in addition to the effect of filler.Carboxymethyl
Starch Sodium is superdisintegrantes, and the compatibility with principal agent is good, and it has good mobility to be easily mixed, and compressibility is preferably, receives
The impact of hydrophobic auxiliary (such as magnesium stearate) is less.Silicon dioxide light weight, is fluidizer.Magnesium stearate is lubricant.
The Pabuk former times profit cloth pharmaceutical composition of the present invention, using the Lactose of Pabuk former times profit cloth and specified quantitative, Microcrystalline Cellulose,
Carboxymethyl starch sodium, silicon dioxide, magnesium stearate are compounded, and the compatibility is good between main ingredient, and medicine has good stablizing
Property；Each component cooperates, coordinative role, and gained pharmaceutical composition has good result of extraction, and dissolution is high, is conducive to filling
Divide and absorb, improve curative effect.
A kind of preparation method of above-mentioned Pabuk former times profit cloth pharmaceutical composition, comprises the following steps：
1) by Lactose, Microcrystalline Cellulose, Pabuk former times profit cloth crude drug and account for pharmaceutical composition gross weight 2.70%~
3.30% carboxymethyl starch sodium premix after, add account for pharmaceutical composition gross weight 0.80%~1.20% magnesium stearate mix
Close, obtain compound；
2) by step 1) gained compound carry out dry granulation, obtain particulate material；
3) by remaining carboxymethyl starch sodium, silicon dioxide add step 2) gained particulate material in mix after, add surplus
Remaining magnesium stearate is always mixed, and obtains final product described pharmaceutical composition.
Step 1) in, the prior eye mesh screen of mistake 65 of the Lactose；The prior eye mesh screen of mistake 80 of the Pabuk former times sharp cloth crude drug；Institute
State the prior mesh sieve of mistake 50 of Microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate.
The rotating speed of the premix is 20~30r/min, and the time of premix is 15~20min；After adding magnesium stearate, mixing
Rotating speed be 20~30r/min, time of mixing is 2~4min.Medicament mixed uniformity RSD of gained compound is less than
2.0%.
Step 2) in, dry granulation is carried out using dry granulating machine, conditional parameter is：Pressure height is limited to 600psi, lower bound
For 400psi；Feeding speed is 15~20Hz, tabletting 15~20Hz of frequency, and pelletize 20~25Hz of frequency；Granulation mesh size be
1.0~1.2mm.After using above-mentioned condition parameter, made particle size distribution is more uniform, and feeding speed is with tabletting frequency in proportion
Increase, do not change particle properties.
Step 3) in, the prior mesh sieve of mistake 50 of the carboxymethyl starch sodium, silicon dioxide, magnesium stearate.
Step 3) in, add carboxymethyl starch sodium, after silicon dioxide, the rotating speed of mixing is 20~30r/min, mixing when
Between for 6~9min (medicament mixed uniformity RSD be less than 2.0%)；After adding magnesium stearate, total mixed rotating speed is 20~30r/
Min, the time of mixing is 3~5min.Add the incorporation time after magnesium stearate short, do not affect drug-eluting.
By step 3) gained pharmaceutical composition load capsule shells in, obtain final product the capsule of the pharmaceutical composition.
The preparation method of the Pabuk former times profit cloth pharmaceutical composition of the present invention is first by Lactose, Microcrystalline Cellulose, Pabuk former times profit
After cloth crude drug and a part of carboxymethyl starch sodium, magnesium stearate mixing, dry granulation, then with silicon dioxide, remaining carboxylic first
Base Starch Sodium, magnesium stearate are mixed to prepare；The uniformity of dosage units and medicine stability of gained pharmaceutical composition is good, drug dissolution
It is high；Dry granulation reduces the operation such as granulate after adding wetting agent to pelletize, be dried and being dried compared with wet granulation in operation, shorten
In man-hour, improve production efficiency；The preparation method process is simple, it is easy to operate, it is adapted to large-scale industrial production.
Description of the drawings
Fig. 1 is the preparation method process chart of the Pabuk former times profit cloth medicament composition capsule agent of embodiment 1.
Specific embodiment
With reference to specific embodiment, the present invention is further illustrated.
In specific embodiment, particle size distribution D of Pabuk former times used sharp cloth crude drug90：3.2~2.8 μm, D50：1.5
~1.2 μm.The particle size distribution is detected using Winner 2000ZD laser particle size analyzers；The particle size distribution represents final
For the crude drug particle diameter distribution of Medicine prescription.
Embodiment 1
The Pabuk former times profit cloth pharmaceutical composition of the present embodiment, is made up of the component of following mass percent：Pabuk former times profit cloth
27.78%th, Lactose 21.74%, Microcrystalline Cellulose 43.48%, carboxymethyl starch sodium 5% (in granule 3%, granule outer 2%), two
Silicon oxide 0.5%, magnesium stearate 1.5% (1.0%, granule outer 0.5% in granule).
Aforementioned pharmaceutical compositions are made into capsule, specification：75mg active component/grain capsule；In batches：10000.This reality
The preparation method of the Pabuk former times profit cloth medicament composition capsule agent of example is applied, is comprised the following steps (technological process is as shown in Figure 1)：
1) Pabuk former times profit cloth crude drug is crossed into 65 eye mesh screens, it is standby；Lactose (TABLETTOSE 80) is crossed into 80 eye mesh screens,
It is standby；Microcrystalline Cellulose (TYPE 101), carboxymethyl starch sodium, magnesium stearate, silicon dioxide are crossed respectively 50 eye mesh screens, it is standby
With；
2) by the Lactose (TABLETTOSE 80) of 587g, the Microcrystalline Cellulose (TYPE 101) of 1174.00g, 750.00g
Pabuk former times profit cloth crude drug and the carboxymethyl starch sodium of 81.00g add in trough type mixing machine, premixed with the rotating speed of 25r/min
After closing 15min, the magnesium stearate of 27.00g is added, continue to mix 3min with the rotating speed of 25r/min, obtain compound；Compound
Medicament mixed uniformity RSD be less than 2.0%；
3) the hydraulic pressure height for setting dry granulating machine is limited to 600psi, and lower bound is 400psi；Feeding speed 20Hz, tabletting
Frequency 20Hz, frequency 25Hz of pelletizing；Granulation dusting cover screen distance is 1.0mm；
By step 2) gained compound pours dry granulating machine into and obtains and carry out in loading hopper dry granulation, obtains particulate material；
4) by the carboxymethyl starch sodium of 54.00g, the silicon dioxide of 13.50g and step 3) gained particulate material be placed in grooved mix
In conjunction machine, with the rotating speed mixing 6min (medicament mixed uniformity RSD is less than 2.0%) of 25r/min, the Hard Fat of 13.5g is added
Sour magnesium, continues to mix 3min with the rotating speed of 25r/min, obtains final product pharmaceutical composition；
5) gained pharmaceutical composition is pressed into specification requirement using Autocapsulefillingmachine to load in No. 2 capsule shells, obtains final product
Capsule.
Inner packing：Manual bottling is carried out according to 21/bottle (to be wrapped from oral stable medicinal polythene bottle with high density
Dress).Sealed with automatic electromagnetic sensing aluminium foil sealing machine after bottling, checked once every 10min, seen sealing leak；Patch
Good label.
Embodiment 2
The Pabuk former times profit cloth pharmaceutical composition of the present embodiment, is made up of the component of following mass percent：Pabuk former times profit cloth
27.78%th, Lactose 21.74%, Microcrystalline Cellulose 43.48%, carboxymethyl starch sodium 5% (in granule 3%, granule outer 2%), two
Silicon oxide 0.5%, magnesium stearate 1.5% (1.0%, granule outer 0.5% in granule).
Aforementioned pharmaceutical compositions are made into capsule, specification：100mg active component/grain capsule；In batches：10000.This
The preparation method of the Pabuk former times profit cloth medicament composition capsule agent of embodiment, comprises the following steps：
1) Pabuk former times profit cloth crude drug is crossed into 65 eye mesh screens, it is standby；Lactose (TABLETTOSE 80) is crossed into 80 eye mesh screens,
It is standby；Microcrystalline Cellulose (TYPE 101), carboxymethyl starch sodium, magnesium stearate, silicon dioxide are crossed respectively 50 eye mesh screens, it is standby
With；
2) by the Lactose (TABLETTOSE 80) of 782.60g, the Microcrystalline Cellulose (TYPE 101) of 1565.30g,
The Pabuk former times profit cloth crude drug of 1000.00g and the carboxymethyl starch sodium of 108.00g are added in trough type mixing machine, with 25r/min's
After rotating speed premixing 15min, the magnesium stearate of 36.00g is added, continue to mix 3min with the rotating speed of 25r/min, must be mixed
Material；Medicament mixed uniformity RSD of compound is less than 2.0%；
3) the hydraulic pressure height for setting dry granulating machine is limited to 600psi, and lower bound is 400psi；Feeding speed 15Hz, tabletting
Frequency 15Hz, frequency 20Hz of pelletizing；Granulation dusting cover screen distance is 1.0mm；
By step 2) gained compound pours dry granulating machine into and obtains and carry out in loading hopper dry granulation, obtains particulate material；
4) by the carboxymethyl starch sodium of 72.00g, the silicon dioxide of 18.00g and step 3) gained particulate material be placed in grooved mix
In conjunction machine, with the rotating speed mixing 6min (medicament mixed uniformity RSD is less than 2.0%) of 25r/min, the Hard Fat of 18.00g is added
Sour magnesium, continues to mix 3min with the rotating speed of 25r/min, obtains final product pharmaceutical composition；
5) gained pharmaceutical composition is pressed into specification requirement using Autocapsulefillingmachine to load in No. 1 capsule shells, obtains final product
Capsule.
Inner packing：Manual bottling is carried out according to 21/bottle (to be wrapped from oral stable medicinal polythene bottle with high density
Dress).Sealed with automatic electromagnetic sensing aluminium foil sealing machine after bottling, checked once every 10min, seen sealing leak；Patch
Good label.
Embodiment 3
The Pabuk former times profit cloth pharmaceutical composition of the present embodiment, is made up of the component of following mass percent：Pabuk former times profit cloth
27.78%th, Lactose 21.74%, Microcrystalline Cellulose 43.48%, carboxymethyl starch sodium 5% (in granule 3%, granule outer 2%), two
Silicon oxide 0.5%, magnesium stearate 1.5% (1.0%, granule outer 0.5% in granule).
Aforementioned pharmaceutical compositions are made into capsule, specification：125mg active component/grain capsule；In batches：10000.This
The preparation method of the Pabuk former times profit cloth medicament composition capsule agent of embodiment, comprises the following steps：
1) Pabuk former times profit cloth crude drug is crossed into 65 eye mesh screens, it is standby；Lactose (TABLETTOSE 80) is crossed into 80 eye mesh screens,
It is standby；Microcrystalline Cellulose (TYPE 101), carboxymethyl starch sodium, magnesium stearate, silicon dioxide are crossed respectively 50 eye mesh screens, it is standby
With；
2) by the Lactose (TABLETTOSE 80) of 978.30g, the Microcrystalline Cellulose (TYPE 101) of 1956.60g,
The Pabuk former times profit cloth crude drug of 1250.00g and the carboxymethyl starch sodium of 135.00g are added in trough type mixing machine, with 25r/min's
After rotating speed premixing 15min, the magnesium stearate of 45.00g is added, continue to mix 3min with the rotating speed of 25r/min, must be mixed
Material；Medicament mixed uniformity RSD of compound is less than 2.0%；
3) the hydraulic pressure height for setting dry granulating machine is limited to 600psi, and lower bound is 400psi；Feeding speed 20Hz, tabletting
Frequency 20Hz, frequency 25Hz of pelletizing；Granulation dusting cover screen distance is 1.0mm；
By step 2) gained compound pours dry granulating machine into and obtains and carry out in loading hopper dry granulation, obtains particulate material；
4) by the carboxymethyl starch sodium of 90.00g, the silicon dioxide of 22.50g and step 3) gained particulate material be placed in grooved mix
In conjunction machine, with the rotating speed mixing 6min (medicament mixed uniformity RSD is less than 2.0%) of 25r/min, the Hard Fat of 22.50g is added
Sour magnesium, continues to mix 3min with the rotating speed of 25r/min, obtains final product pharmaceutical composition；
5) gained pharmaceutical composition is pressed into specification requirement using Autocapsulefillingmachine to load in No. 0 capsule shells, obtains final product
Capsule.
Inner packing：Manual bottling is carried out according to 21/bottle (to be wrapped from oral stable medicinal polythene bottle with high density
Dress).Sealed with automatic electromagnetic sensing aluminium foil sealing machine after bottling, checked once every 10min, seen sealing leak；Patch
Good label.
Embodiment 4
The Pabuk former times profit cloth pharmaceutical composition of the present embodiment, is made up of the component of following mass percent：Pabuk former times profit cloth
28.5%th, Lactose 21.25%, Microcrystalline Cellulose 42.5%, carboxymethyl starch sodium 5.5% are (in granule outside 3.3%, granule
2.2%), silicon dioxide 0.8%, magnesium stearate 1.45% (0.97%, granule outer 0.48% in granule).
Aforementioned pharmaceutical compositions are made into capsule, specification：75mg active component/grain capsule；In batches：10000.This reality
The preparation method of the Pabuk former times profit cloth medicament composition capsule agent of example is applied, is comprised the following steps：
1) Pabuk former times profit cloth crude drug is crossed into 65 eye mesh screens, it is standby；Lactose (TABLETTOSE 80) is crossed into 80 eye mesh screens,
It is standby；Microcrystalline Cellulose (TYPE 101), carboxymethyl starch sodium, magnesium stearate, silicon dioxide are crossed respectively 50 eye mesh screens, it is standby
With；
2) by the Lactose (TABLETTOSE 80) of formula ratio, Microcrystalline Cellulose (TYPE 101), Pabuk former times profit cloth crude drug
Add in trough type mixing machine with the carboxymethyl starch sodium for accounting for pharmaceutical composition gross weight 3.30%, premixed with the rotating speed of 20r/min
After closing 20min, add and account for the magnesium stearate of pharmaceutical composition gross weight 0.97%, continue to mix 4min with the rotating speed of 20r/min,
Obtain compound；Medicament mixed uniformity RSD of compound is less than 2.0%；
3) the hydraulic pressure height for setting dry granulating machine is limited to 600psi, and lower bound is 400psi；Feeding speed 20Hz, tabletting
Frequency 20Hz, frequency 25Hz of pelletizing；Granulation dusting cover screen distance is 1.2mm；
By step 2) gained compound pours dry granulating machine into and obtains and carry out in loading hopper dry granulation, obtains particulate material；
4) by remaining carboxymethyl starch sodium, silicon dioxide and step 3) gained particulate material be placed in trough type mixing machine, with
The rotating speed mixing 9min (medicament mixed uniformity RSD is less than 2.0%) of 20r/min, adds remaining magnesium stearate, with 20r/
The rotating speed of min continues to mix 5min, obtains final product pharmaceutical composition；
5) gained pharmaceutical composition is pressed into specification requirement using Autocapsulefillingmachine to load in No. 2 capsule shells, obtains final product
Capsule.
Inner packing：Manual bottling is carried out according to 21/bottle (to be wrapped from oral stable medicinal polythene bottle with high density
Dress).Sealed with automatic electromagnetic sensing aluminium foil sealing machine after bottling, checked once every 10min, seen sealing leak；Patch
Good label.
Embodiment 5
The Pabuk former times profit cloth pharmaceutical composition of the present embodiment, is made up of the component of following mass percent：Pabuk former times profit cloth
27.2%th, Lactose 22%, Microcrystalline Cellulose 44%, carboxymethyl starch sodium 4.5% (in granule 2.7%, granule outer 1.8%), two
Silicon oxide 0.5%, magnesium stearate 1.8% (1.2%, granule outer 0.6% in granule).
Aforementioned pharmaceutical compositions are made into capsule, specification：75mg active component/grain capsule；In batches：10000.This reality
The preparation method of the Pabuk former times profit cloth medicament composition capsule agent of example is applied, is comprised the following steps：
1) Pabuk former times profit cloth crude drug is crossed into 65 eye mesh screens, it is standby；Lactose (TABLETTOSE 80) is crossed into 80 eye mesh screens,
It is standby；Microcrystalline Cellulose (TYPE 101), carboxymethyl starch sodium, magnesium stearate, silicon dioxide are crossed respectively 50 eye mesh screens, it is standby
With；
2) by the Lactose (TABLETTOSE 80) of formula ratio, Microcrystalline Cellulose (TYPE 101), Pabuk former times profit cloth crude drug
Add in trough type mixing machine with the carboxymethyl starch sodium for accounting for pharmaceutical composition gross weight 2.70%, premixed with the rotating speed of 30r/min
After closing 15min, add and account for the magnesium stearate of pharmaceutical composition gross weight 1.20%, continue to mix 3min with the rotating speed of 30r/min,
Obtain compound；Medicament mixed uniformity RSD of compound is less than 2.0%；
3) the hydraulic pressure height for setting dry granulating machine is limited to 600psi, and lower bound is 400psi；Feeding speed 15Hz, tabletting
Frequency 15Hz, frequency 20Hz of pelletizing；Granulation dusting cover screen distance is 1.0mm；
By step 2) gained compound pours dry granulating machine into and obtains and carry out in loading hopper dry granulation, obtains particulate material；
4) by remaining carboxymethyl starch sodium, silicon dioxide and step 3) gained particulate material be placed in trough type mixing machine, with
The rotating speed mixing 6min (medicament mixed uniformity RSD is less than 2.0%) of 30r/min, adds remaining magnesium stearate, with 30r/
The rotating speed of min continues to mix 3min, obtains final product pharmaceutical composition；
5) gained pharmaceutical composition is pressed into specification requirement using Autocapsulefillingmachine to load in No. 2 capsule shells, obtains final product
Capsule.
Inner packing：Manual bottling is carried out according to 21/bottle (to be wrapped from oral stable medicinal polythene bottle with high density
Dress).Sealed with automatic electromagnetic sensing aluminium foil sealing machine after bottling, checked once every 10min, seen sealing leak；Patch
Good label.
In specific embodiment, capital equipment used is as shown in table 1.
The list of main equipment of table 1
| Production equipment | Model | Manufacturer | Device parameter |
| Trough type mixing machine | CH-20 | Liaoning Xiang An pharmaceutical machines company limited | 10-13kg/ time |
| Laboratory dry granulating machine | HCG-25B | Beijing Hua Hongjin cities commerce and trade company limited | 1-5kg/ hours |
| Autocapsulefillingmachine | NJP400 | Zhejiang Ruian Yong Chuan Machinery Co., Ltd.s | 400/minute |
| Automatic electromagnetic senses aluminium foil sealing machine | GLF-1300 | Beijing Long Xianghua cities plant equipment company limited | 100-250 bottles/minute |
In the preparation method of above-described embodiment, always mixed granule can fill up capsule shells, it is to avoid content uniformity when capsule is filled
The risk for transfiniting.
In following experimental examples, without component, the same embodiment of consumption and preparation method part (the specification 75mg correspondence for specializing
Embodiment 1, specification 100mg correspondence embodiment 2, specification 125mg correspondence embodiment 3).
The crude drug of experimental example 1. is detected
1.1 crude drug physicochemical properties
In specific embodiment, Pabuk former times profit cloth crude drug used, shown in structural formula such as following formula (I)：
Character：It is faint yellow to yellow powder.
pKa：PKa=7.4 (the secondary nitrogen of piperazine), 3.9 (pyridine nitrogens).
Crystal formation：A types.The crystal formation of crude drug is on the content and uniformity of dosage units of medicine without impact；A types be compared with stable crystal form,
On medicine stability and dissolution without impact.
Draw moist and chemical stability：Crude drug slightly draws moist；Crude drug stability data show its powder high temperature,
It is more stable under high humidity；Medicine slightly draw it is moist do not affect medicine stability, nor affect on the medicament contg uniformity and dissolution.
1.2 crude drug dissolubility at various ph values
Dissolubility (crude drug particle size distribution of the Pabuk former times profit cloth crude drug in different pH medium is investigated herein：D90For 3.1
μm, D50For 1.4 μm).As a result it is as shown in table 2.As a result show that crude drug dissolubility is reduced, as medium pH as medium pH increases
Its dissolubility is decreased obviously during more than 4.0.Pabuk former times profit cloth is pH dependent drugs.
Dissolubility of the Pabuk former times of the table 2 profit cloth in different pH value media
| PH value | 1.0 | 2.0 | 3.0 | 4.0 | 4.5 | 5.1 | 6.8 | Water |
| Dissolubility (mg/ml) | 31.89 | 6.19 | 2.31 | 0.70 | 0.18 | 0.12 | 0.0022 | 0.0066 |
1.3 density and mobility
Heap density, tap density and the angle of repose of 6 batches of Pabuk former times profit cloth crude drug are tested, and calculates meansigma methodss, as a result such as
Under：
Heap density：0.210g/ml；Tap density：0.500g/ml；Angle of repose：52.1°。
The main ingredient compatibility experiments of experimental example 2.
Herein the adjuvant of selection and principal agent are carried out into compatibility, placed at different conditions, by investigating having for principal agent
Material is closed, the main ingredient compatibility is investigated.
Sample combination：1) principal agent and filler (Lactose, Microcrystalline Cellulose) mass ratio 1:1 combination；2) principal agent and disintegrating agent
(carboxymethyl starch sodium) mass ratio 10:1 combination；3) principal agent and fluidizer (silicon dioxide) mass ratio 10:1 combination；4) principal agent with
Lubricant (magnesium stearate) mass ratio 10:1 combination.
Placement condition：60 DEG C of high temperature, illumination 4500lx ± 500lx, high humidity RH92.5% ± RH5%；Sampling time point：0
My god, 5 days, 10 days；Testing index：Relevant material, increasing weightlessness, character.As a result it is as shown in table 3.
The main ingredient compatibility experiments result of table 3
From table 3 it can be seen that principal agent and each adjuvant place 10 days under the conditions of 60 DEG C of high temperature, high humidity RH92.5%, not
Detection known impurities, maximum unknown impuritie content and total impurities were not changed significantly with 0 day ratio；Principal agent and principal agent and adjuvant
Compatibility sample is placed 10 days under illumination condition, is increased slightly than maximum unknown impuritie and total impurities with 0 day, but impurity is all in limit
In the range of degree；The each adjuvant of Comprehensive Experiment as shown by data is good with the crude drug compatibility.
The adjuvant of experimental example 3 and consumption are investigated
Result is investigated according to the dissolution of crude drug particle diameter, selection there are the medium pH4.0 Acetate Solutions for distinguishing power as adjuvant
Consumption screens medium.Dissolution determination method is：The winding of glue capsule rustless steel iron wire is taken from, according to dissolution method (China
Pharmacopeia two annex X the second methods of C of version in 2010), pH4.0 Acetate Solution 900ml are added, rotating speed is 50 turns per minute, temperature
37 DEG C ± 0.5 DEG C, the different time points sampling after dispensing samples 10ml, immediately mutually synthermal, same volume the dissolution of supplement
Medium.0.45 μm of water system miillpore filter filtration of sample Jing, discards just filtrate 3ml, in taking subsequent filtrate 1ml to 10ml measuring bottles, plus phase
Medium is answered to be settled to scale, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia two A of annex IV of version in 2010), in 259nm
Wavelength at mensuration absorbance, calculate content, and calculate the accumulative dissolution of each time point.
3.1 Lactose and Microcrystalline Cellulose ratio are investigated
The Lactose ratio collocation different with Microcrystalline Cellulose, to powder body compressibility, mobility, density, dissolution etc. shadow is produced
Ring.Therefore, the prescription of the Lactose shown in table 4 and Microcrystalline Cellulose different proportion is investigated.As a result as shown in Table 5,6.
The different filler ratio prescription compositions of table 4
Particle properties after the different proportion filler dry granulation of table 5
Impact (medium of the filler ratio of table 6 to drug-eluting：PH4.0 Acetate Solutions)
From experimental result, 20141022-2 batch of capsule (Lactose:Microcrystalline Cellulose is 2:1) in medium pH4.0 acetic acid
The dissolution of front 10min is considerably slower than 20141022-1 batch of (Lactose in saline solution:Microcrystalline Cellulose is 1:1) criticize with 20141022-3
(Lactose:Microcrystalline Cellulose is 1:2), 20141022-1 and 20141022-3 batch of dissolved corrosion no significant difference, Lactose in prescription
The dissolution of medicine is affected during large percentage；20141022-3 batch of (Lactose:Microcrystalline Cellulose is 1:2) made mobility of particle is compared with it
Its two batches is good, and the lower fine powder of sieve is also relatively fewer.Accordingly, the present invention selects Lactose:Microcrystalline Cellulose mass ratio is 1:2.
Additional consumption affects on drug-eluting in 3.2 carboxymethyl starch sodium
The interior effect with disintegrating agent is the disintegrate for promoting dry granulation to be made pellet, so that drug-eluting；Additional disintegrate
The effect of agent is to promote capsule shells disintegrate rupture by disintegrating agent imbibition, so that drug-eluting, both consumptions can shadow
The dissolution to medicine is rung, additional consumption in disintegrating agent is investigated by experiment.
Capsule 's content weight and additional disintegrating agent quality consumption 2.00% are fixed first, are investigated interior plus carboxymethyl starch sodium and are used
Amount, institute's residual quantity Lactose and Microcrystalline Cellulose are with 1:2 ratio polishings (as shown in table 7).As a result it is as shown in table 8.
Add different amounts prescription composition in the disintegrating agent of table 7
Add different amounts drug-eluting data (medium in the disintegrating agent of table 8：PH4.0 Acetate Solutions)
From dissolution results, when interior plus carboxymethyl starch sodium consumption is 2.00%, drug-eluting is substantially slack-off,
Dissolved corrosion no significant difference when consumption is 4.00% and 3.00%, illustrates to add 3.00% disintegrating agent to can reach in granule
The quickly disintegrated effect of granule is made, therefore interior plus carboxymethyl starch sodium consumption selects 3.00%.
It is determined that on the basis of the interior consumption with disintegrating agent, investigating impact of the additional disintegrating agent consumption to drug-eluting.It is additional
Disintegrating agent investigates level：0.50%th, 1.00%, 2.00% and 3.00%.Made capsule is investigated in medium pH4.0 Acetate Solutions
In stripping curve.As a result it is as shown in table 9.
Impact (medium of the additional consumption of the disintegrating agent of table 9 to drug-eluting：PH4.0 Acetate Solutions)
From above dissolution data, when additional disintegrating agent consumption is 0.50% (20141028-1 batch) and 1.00%
Drug-eluting is substantially slack-off when (20141028-2 batch)；When additional disintegrating agent consumption be 2.00% (20141027-2 crowd) and
2 batches of capsule dissolved corrosion no significant differences when 3.00% (20141028-3 batch), can medicine Fast Stripping, therefore additional disintegrate
Agent consumption is defined as 2.00%.
The experiment by more than determines additional consumption, respectively 3.00% He in the carboxymethyl starch sodium of the present invention
2.00%.
Impact of the 3.3 magnesium stearate consumptions to drug-eluting
Magnesium stearate is hydrophobic lubricant, and for the medicine of slightly solubility, its consumption size can affect the dissolution of medicine.
There is the phenomenon of roll banding wheel when adding 0.50% magnesium stearate roll compacting in the dry granulation plus in material, when its consumption is increased to
When 1.00%, rolling does not relatively smoothly glue the phenomenon of wheel, and interior plus magnesium stearate consumption is defined as into 1.00%.
The additional consumption of magnesium stearate is less, when capsule is filled it is possible that the phenomenon of viscous filling bar；But its consumption compared with
Dissolution high and that medicine may be affected.Therefore need to investigate the additional consumption of magnesium stearate.Primarily look at magnesium stearate
Impact of the different amounts to drug-eluting, determines additional magnesium stearate research on maximum utilized quantity, when later stage capsule is filled if there is viscous
Bar phenomenon, can externally add magnesium stearate consumption to be adjusted in the range of research on maximum utilized quantity.
Additional magnesium stearate investigates level：0.50%th, 1.00%, 2.00% and 3.00%.As a result it is as shown in table 10.
Impact (medium of the additional consumption of the magnesium stearate of table 10 to drug-eluting：PH4.0 Acetate Solutions)
From dissolution data, when additional magnesium stearate consumption is 3.00% (20141030-3 batch) before 15min dissolutions
Substantially slack-off, additional magnesium stearate consumption is 0.50% (20141027-2 batch), 1.00% (20141030-1 batch) and 2.00%
Dissolution no significant difference when (20141030-2 batch), illustrates that when additional magnesium stearate consumption is more than 3.0% medicine can be affected
Dissolution, the additional magnesium stearate research on maximum utilized quantity of this product is 2.00%.The consumption of additional magnesium stearate is during pilot scale sample preparation
0.50%, filling process is more smooth, and without finding to glue the phenomenon of bar is filled, therefore the additional magnesium stearate consumption of this product is defined as
0.50%.
The embodiment of experimental example 4. gained pharmaceutical composition testing result
4.1 detection method
1) heap density, tap density：Using graduated cylinder measurement method, graduated cylinder is placed on electronic balance presses " peeling " key first,
Sample is slowly added to weigh to obtain sample quality in graduated cylinder, the volume indicated according to graduated cylinder calculates the heap density of sample；Then
By material jolt ramming, the volume observed after jolt ramming, tap density is calculated.
2) mobility：Mobility of particle is studied, with angle of repose as inspection target.Total mixed granule is poured slowly into solid
In funnel above circular culture dish, a diameter of D of culture dish, mixed material flows out from funnel, until particle packing
To overflowing from plate edge.The height H on the summit of granuloplastic cone to plate edge is measured, angle of repose can be by under
Formula is calculated：Tan α=2H/D, α=arctg (2H/D)；Determine 2 times, averaged.
3) particle size distribution：Sieve method.The granule about 50.0g after total mixing is taken, weighed weight puts the upper strata of 24 mesh sieves
(lower floor with it is secondary be 65 mesh sieves, 120 mesh sieves and sieve bottom), keep horizontality sieve, left and right come and go, be afraid of to make a call to 3 minutes when sieving.
Granule on 24 mesh is taken with secondary, powder on powder and sieve bottom on granule, 120 mesh on 65 mesh, weighed weight calculates its proportion
(%).
4) granule content is always mixed：With Pabuk former times profit cloth capsule content assay method.Precision weighs appropriate always mixed granule (about phase
When in Pabuk former times profit cloth 25mg), in putting 50ml measuring bottles, plus 0.1mol/L hydrochloric acid-acetonitrile (80:20) appropriate, ultrasound 5 minutes is put
It is cooled to room temperature, plus 0.1mol/L hydrochloric acid-acetonitrile (80:20) scale is diluted to, is shaken up, filtered；Precision measures subsequent filtrate 2ml, puts
In 25ml measuring bottles, with 0.1mol/L hydrochloric acid-acetonitrile (80:20) scale is diluted to, is shaken up, as need testing solution.Precision is measured
20 μ l inject chromatograph of liquid, record chromatogram.Separately take Pabuk former times profit cloth reference substance appropriate, it is accurately weighed, plus 0.1mol/L salt
Acid-acetonitrile (80:20) dissolve and be quantitatively diluted to solution of every 1ml containing about 40 μ g, be measured in the same method.By external standard method in terms of peak area
Calculate, obtain final product.
5) stripping curve examines measure：Take reference preparation and embodiment gained capsule is each 6, twined with rustless steel iron wire respectively
Around, according to dissolution method (Chinese Pharmacopoeia two annex X the second methods of C of version in 2010), be separately added into pH1.0 hydrochloric acid solutions,
PH4.0 Acetate Solutions, pH6.8 phosphate solutions and each 900ml of water, rotating speed is 50 turns per minute, 37 DEG C ± 0.5 DEG C of temperature,
Different time points sampling after dispensing, samples 10ml, immediately mutually synthermal, same volume the dissolution medium of supplement.Sample
0.45 μm of water system miillpore filter filtration of product Jing is (when medium is pH6.8 phosphate solutions or aqueous solution, from 0.8 μm of micropore filter
Film), just filtrate 3ml is discarded, subsequent filtrate is taken, HPLC determines content, and calculates per accumulation stripping quantity in different time.
Wherein, shown reference preparation information is as shown in table 11.
The reference preparation of table 11
4.2 testing result：Testing result is as shown in table 12,13.
The embodiment particle detections of table 12
The embodiment of table 13 compares with the actual dissolution data of reference preparation
Knowable to experimental result, the capsule and reference preparation of embodiment 1-3 is in pH1.0 hydrochloric acid solutions, pH4.0 acetate
Dissolved corrosion in solution, pH6.8 phosphate solutions, water is more consistent, and there is the capsule of embodiment 1-3 preferable dissolution to imitate
Really.
4.3 embodiments material relevant with reference preparation compares
The embodiment of table 14 material relevant with reference preparation compares
Conclusion：Embodiment material relevant with reference preparation does not detect known impurities, and other single impurity and total impurities are equal
In the range of bound requirements.
The crude drug granularity of experimental example 5 is investigated
Pabuk former times profit cloth water solublity is poor, and capsule made by varigrained raw material is likely to can the presence of difference on dissolution
It is different.Using same preparation technology prepared by capsule to different grain size crude drug, and the dissolution to made capsule, content etc. are examined
Survey.
Detect raw materials used particle diameter distribution with Winner 2000ZD laser particle size analyzers first.As a result 15 be see the table below.
The crude drug particle diameter distribution of table 15
The different grain size crude drug property midbody particle property of table 16
| Lot number | Heap density (g/ml) | Tap density (g/ml) | Angle of repose (°) | Content (%, mg/mg) |
| 20141016-1 | 0.652 | 0.858 | 34.9 | 27.96 |
| 20141016-2 | 0.647 | 0.863 | 34.9 | 27.20 |
| 20141016-3 | 0.649 | 0.854 | 34.3 | 27.53 |
The granule that 3 kinds of granularity crude drug are prepared using same dry granulation process, heap density, tap density and mobility it
Between without notable difference, always mixed powder content is also in acceptability limit.It is preferable in dry-pressing pelletization sheet stock formability, and nothing
The viscous phenomenon for rolling wheel.
The investigation of stripping curve is carried out to capsule prepared by different grain size crude drug.As a result it is as shown in table 17.
Impact of the crude drug granularity of table 17 to drug-eluting
Test result indicate that, the dissolution of the granularity of crude drug on medicine is influential, when crude drug granularity is larger
(D9036.695 μm, D5010.463 μm) drug-eluting slows down, but adopt mean particle size D90- 16.300 μm, D50- 2.685 μm and
D90- 2.895 μm, D5020141016-2 batch and 20141016-3 of -1.285 μm of crude drug preparations criticizes capsule in 4 kinds of media
Dissolution difference is not obvious.Illustrate crude drug particle size range in D90For 2.895~16.300 μm, D50For 1.285~2.685 μm
In the range of drug-eluting is not affected.Therefore, D is selected90：3.2~2.8 μm, D50：1.5~1.2 μm, the particle size range is represented
Eventually for the particle diameter distribution of the raw material of this product.
The technique of the preparation method of experimental example 6 is investigated
The comparison of wet granulation and dry granulation：Dry granulation is reduced plus wetting agent system compared with wet granulation in operation
Grain, be dried and be dried after the operation such as granulate, man-hour can be shortened, therefore select the present invention to select dry granulation process.
Dry granulation process parameter is investigated
The preparation technology of dry granulation is that the powder body of crude drug and filler is compressed under high pressure into thin slice, by system
The prepared dry particl of grain, is then always mixed with additional material again, is obtained and always mix powder and be filled capsule.It is corresponding in each step
Technological parameter may all influence whether the qualitative attribute of medicine.
Hybrid technique is investigated before 6.1 dry granulations
Can the crude drug stronger for this poor fluidity of Pabuk former times profit cloth, electrostatic, successfully be prepared by dry granulation
Content single-size, depends greatly on the blend step before dry granulation.
Weigh Lactose, Microcrystalline Cellulose and pour trough type mixing machine into, then weigh crude drug again and carboxymethyl starch sodium is poured into
In trough type mixing machine, static mixer rotating speed is 25rpm, respectively at 10min, 15min and 20min at the top of material pot, middle part
Mixing homogeneity is measured by sampling with bottom, the mixing homogeneity of each time point is detected.To avoid the over-lubrication of magnesium stearate,
Magnesium stearate is added to continue to mix 3min after the completion of above-mentioned mixing.As a result shown in table 18.
The different mixing time point mix homogeneously degrees of data of table 18
It can be seen from different time points mix homogeneously degrees of data, fixed trough type mixing machine rotating speed 25rpm, during mixing 10min
Medicament mixed uniformity RSD is respectively less than 5.0% more than 2.0%, 15min and 20min RSD, illustrates that mixing 15min~20min can
Ensure that medicament mixed is uniform, be to save incorporation time before process time lab scale craft dry granulation to select 15min.
6.2 dry granulation process are investigated
1) Pabuk former times profit cloth capsule dry granulation device therefor is HCG-25B type laboratory dry granulating machines in embodiment.
The Hydraulic Equipment is generally located on 3~4MPa, about 435psi~580psi, is adjusted according to the situation of the piece for processing, one
As be less than 5MPa, about 725psi, by hydraulic pressure control in the range of 400psi~600psi, can ensure the shaping of slip
Property, so being fixed to hydraulic pressure, upper limit 600psi, lower limit 400psi.
2) feeding speed and tabletting speed speed have influence on the hardness of sheet stock, accelerate feeding speed and slow down tabletting speed,
Sheet stock hardness can be increased.The aperture of screen cloth and speed affect the size and granularity of granule during granulation.
Investigate granulation fine screen mesh mesh number and be respectively 1.0mm, 1.2mm, 1.5mm to grain graininess and the impact of capsule dissolution.
As a result as shown in table 19,20.
Particle size distribution after the different screen cloth granulations of table 19
The particle diameter distribution of granule after being pelletized from different screen clothes, when mesh size is 1.0mm, grain graininess mainly collects
In between 24 mesh sieves and 65 mesh sieves, on 24 mesh sieves and 120 now total amount be 22.3%；When mesh size is 1.2mm, 24 mesh
Coarse granule increases on sieve, and granule great majority are concentrated between 24 mesh sieves and 65 mesh sieves, on 24 mesh sieves and 120 now total amount be
47.9%, the increase of granular size difference；When mesh size is 1.5mm, granule is mainly the coarse granule on 24 mesh sieves, and granule is big
Little difference is also more apparent；Mesh size is bigger, and granule is more on 24 mesh sieves, made granular size when fine screen mesh particle diameter is 1.0mm
It is more uniform.
The different granulation screen cloth capsule dissolution data of table 20
From dissolution data, when screen cloth of pelletizing is 1.5mm, capsule dissolution is slack-off, glue when aperture is 1.0 and 1.2mm
Capsule dissolution no significant difference.Capsule dissolution zero difference when screen cloth particle diameter is 1.0mm or 1.2mm, but using made of 1.0mm screen clothes
Grain granularity is more uniform, it is determined that fine screen mesh mesh number is 1.0mm during granulation.
The investigation of feeding speed and tabletting speed：Feeding speed and tabletting speed (with frequency representation) can affect sheet stock
Hardness, when feeding speed is fast, when tabletting speed is slow, sheet stock hardness increases；Feeding speed is slow, when tabletting speed is fast, sheet stock hardness
It is reduced by, qualified sheet stock can be made when both reach the speed of coordination.So while investigate feeding speed and tabletting speed, with
Grain graininess and capsule dissolution monitor made sheet stock hardness (as shown in table 21).As a result as shown in table 22,23.
The dry granulation parameter of table 21 investigates level
| Lot number | 20141109-1 | 20141109-2 | 20141109-3 |
| Feeding speed* | 20 | 15 | 10 |
| Tabletting speed* | 10 | 15 | 20 |
| Granulation speed* | 20 | 20 | 20 |
Note *：Herein speed representation electric machine frequency, does not represent rotating speed.
The feeding speed of table 22 and tabletting speed investigate result
When feeding speed is 2 times of tabletting speed, it is 1 that No. 2 are sieved upper granule than both speed：Increase when 1, under No. 7 sieves
Fine powder amount also increases, hard when illustrating the sheet stock hardness when feeding speed is 2 times of tabletting speed compared with both with uniform velocity；Work as tabletting
When speed is 2 times of feeding speed, sheet stock is imperfect, relatively thin, and fine powder is many after granulation, and mobility of particle is poor, no longer carries out
Dissolution.
The different feeding speeds of table 23 and tabletting speed dissolution data (medium：PH4.0 Acetate Solutions)
From dissolution data, the made capsule dissolution when feeding speed is 20Hz, and tabletting speed is 10Hz is considerably slower than
Both are made capsule dissolution during 15Hz at frequency, illustrate that, when feeding speed is too fast, sheet stock hardness can increase, so as to have influence on
Capsule dissolution.It is thus determined that for feeding speed be 15Hz, tabletting speed be 15Hz, both speed 1:1.
6.3 incorporation times are investigated
The optimal incorporation time of additional material and the granule after dry granulation is investigated, to reduce principal agent uneven wind is mixed
Danger.
Weigh the additional material carboxymethyl starch sodium of granule and silicon dioxide is poured in trough type mixing machine together with granule and fixed
Mixer rotating speed is 25rpm, respectively at 3min, 6min and 9min at the top of material pot, that middle part and bottom are measured by sampling mixing is equal
Evenness, detects the mixing homogeneity of each time point.As a result it is as shown in table 24.
The different mixing time point mix homogeneously degrees of data of table 24
It can be seen from different time points mix homogeneously degrees of data, fixed trough type mixing machine rotating speed 25rpm, medicine during mixing 3min
Thing mixing homogeneity is respectively less than 2.0% more than 2.0%, 6min and 9min RSD, illustrates that mixing 6min~9min can ensure medicine
Mix homogeneously, be save process time lab scale craft always do time selection 6min.
6.4 magnesium stearate incorporation times are investigated
Magnesium stearate causes after capsule shells dissolving content not with granule incorporation time is long can form hydrophobic powder bed
Can disperse, the dissolution of medicine may be influenced whether, therefore magnesium stearate incorporation time need to be investigated.As a result such as the institute of table 25
Show.
The magnesium stearate of table 25 difference incorporation time capsule dissolution data (medium：Ph4.0 Acetate Solutions)
From dissolution data, when magnesium stearate mixes 3min and 5min, self-control capsule dissolution trend is consistent, without substantially
Difference；When magnesium stearate incorporation time is 8min, the dissolution rate of 15min is substantially slack-off before capsule, illustrates that magnesium stearate mixes
Time is to a certain extent influential on capsule dissolution.To reduce the process time and reducing the wind of magnesium stearate over-mixed
Danger, the incorporation time for selecting magnesium stearate is 3min.
Claims (10)
1. a kind of Pabuk former times profit cloth pharmaceutical composition, it is characterised in that：Component comprising following mass percent：Pabuk former times profit cloth
27.00%~28.50%, Lactose 21.00%~22.5%, Microcrystalline Cellulose 42.50%~44.00%, carboxymethyl starch sodium
4.5%~5.5%, silicon dioxide 0.5%~0.8%, magnesium stearate 1.2%~2.0%.
2. Pabuk former times according to claim 1 profit cloth pharmaceutical composition, it is characterised in that：Comprising following mass percent
Component：Pabuk former times profit cloth 27.78%, Lactose 21.74%, Microcrystalline Cellulose 43.48%, carboxymethyl starch sodium 5%, silicon dioxide
0.5%th, magnesium stearate 1.5%.
3. Pabuk former times according to claim 1 and 2 profit cloth pharmaceutical composition, it is characterised in that：The pharmaceutical composition is glue
Wafer.
4. a kind of preparation method of Pabuk former times as claimed in claim 1 profit cloth pharmaceutical composition, it is characterised in that：Including following
Step：
1) Lactose, Microcrystalline Cellulose, Pabuk former times profit and are accounted for into pharmaceutical composition gross weight 2.70%~3.30% at cloth crude drug
After carboxymethyl starch sodium premix, the magnesium stearate mixing for accounting for pharmaceutical composition gross weight 0.80%~1.20% is added, obtain mixed
Close material；
2) by step 1) gained compound carry out dry granulation, obtain particulate material；
3) by remaining carboxymethyl starch sodium, silicon dioxide add step 2) gained particulate material in mix after, add remaining
Magnesium stearate is always mixed, and obtains final product described pharmaceutical composition.
5. the preparation method of Pabuk former times according to claim 4 profit cloth pharmaceutical composition, it is characterised in that：Step 1) in,
The prior eye mesh screen of mistake 65 of the Lactose；The prior eye mesh screen of mistake 80 of the Pabuk former times sharp cloth crude drug；The Microcrystalline Cellulose, carboxylic first
The prior mesh sieve of mistake 50 of base Starch Sodium, magnesium stearate.
6. the preparation method of Pabuk former times according to claim 4 profit cloth pharmaceutical composition, it is characterised in that：The premix
Rotating speed is 20~30r/min, and the time of premix is 15~20min；After adding magnesium stearate, the rotating speed of mixing is 20~30r/
Min, the time of mixing is 2~4min.
7. the preparation method of Pabuk former times according to claim 4 profit cloth pharmaceutical composition, it is characterised in that：Step 2) in,
Dry granulation is carried out using dry granulating machine, conditional parameter is：Pressure height is limited to 600psi, and lower bound is 400psi；Feeding speed
For 15~20Hz, tabletting 15~20Hz of frequency, pelletize 20~25Hz of frequency；Granulation mesh size is 1.0~1.2mm.
8. the preparation method of Pabuk former times according to claim 4 profit cloth pharmaceutical composition, it is characterised in that：Step 3) in,
The prior mesh sieve of mistake 50 of the carboxymethyl starch sodium, silicon dioxide, magnesium stearate.
9. the preparation method of Pabuk former times according to claim 4 profit cloth pharmaceutical composition, it is characterised in that：Step 3) in,
After adding carboxymethyl starch sodium, silicon dioxide, the rotating speed of mixing is 20~30r/min, and the time of mixing is 6~9min；Add
After magnesium stearate, total mixed rotating speed is 20~30r/min, and the time of mixing is 3~5min.
10. the preparation method of the sharp cloth pharmaceutical composition of Pabuk former times according to any one of claim 4-9, its feature exists
In：By step 3) gained pharmaceutical composition load capsule shells in, obtain final product the capsule of the pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611141522.9A CN106667952A (en) | 2016-12-12 | 2016-12-12 | Palbociclib pharmaceutical composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611141522.9A CN106667952A (en) | 2016-12-12 | 2016-12-12 | Palbociclib pharmaceutical composition and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106667952A true CN106667952A (en) | 2017-05-17 |
Family
ID=58868734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611141522.9A Pending CN106667952A (en) | 2016-12-12 | 2016-12-12 | Palbociclib pharmaceutical composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106667952A (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108014343A (en) * | 2017-12-21 | 2018-05-11 | 孟斯琴 | A kind of pharmaceutical composition for treating breast cancer and preparation method thereof |
| CN108066303A (en) * | 2017-12-31 | 2018-05-25 | 湖南博隽生物医药有限公司 | A kind of anticancer pharmaceutical composition and preparation method thereof |
| CN108066312A (en) * | 2017-12-29 | 2018-05-25 | 山东裕欣药业有限公司 | A kind of Pa Boxini pharmaceutical compositions and preparation method thereof |
| WO2019056163A1 (en) * | 2017-09-19 | 2019-03-28 | 浙江华海药业股份有限公司 | N-formyl palbociclib and preparation method therefor and use thereof, and palbociclib preparation and quality control method therefor |
| JP2020132535A (en) * | 2019-02-14 | 2020-08-31 | ニプロ株式会社 | Tablets and manufacturing method thereof |
| CN112274493A (en) * | 2020-11-18 | 2021-01-29 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of pipera cypress xili capsule |
| CN114246841A (en) * | 2020-09-24 | 2022-03-29 | 南京济群医药科技股份有限公司 | Composition and medicine of piperazine isethionate and quinapride |
| CN114246872A (en) * | 2020-09-24 | 2022-03-29 | 南京济群医药科技股份有限公司 | Process method and composition for improving liquidity of pipariril isethionate |
| JP2022542533A (en) * | 2020-07-09 | 2022-10-05 | 上海博志研新薬物技術有限公司 | Brivaracetam pharmaceutical composition, its production method and application |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2016
- 2016-12-12 CN CN201611141522.9A patent/CN106667952A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (16)
| 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 |
| WO2019056163A1 (en) * | 2017-09-19 | 2019-03-28 | 浙江华海药业股份有限公司 | N-formyl palbociclib and preparation method therefor and use thereof, and palbociclib preparation and quality control method therefor |
| CN110997666A (en) * | 2017-09-19 | 2020-04-10 | 浙江华海药业股份有限公司 | N-formyl palbociclib, preparation method and application thereof, palbociclib preparation and quality control method thereof |
| CN108014343A (en) * | 2017-12-21 | 2018-05-11 | 孟斯琴 | A kind of pharmaceutical composition for treating breast cancer and preparation method thereof |
| CN108066312A (en) * | 2017-12-29 | 2018-05-25 | 山东裕欣药业有限公司 | A kind of Pa Boxini pharmaceutical compositions and preparation method thereof |
| CN108066303A (en) * | 2017-12-31 | 2018-05-25 | 湖南博隽生物医药有限公司 | A kind of anticancer pharmaceutical composition and preparation method thereof |
| JP7211136B2 (en) | 2019-02-14 | 2023-01-24 | ニプロ株式会社 | Tablet and manufacturing method thereof |
| JP2020132535A (en) * | 2019-02-14 | 2020-08-31 | ニプロ株式会社 | Tablets and manufacturing method thereof |
| JP2022542533A (en) * | 2020-07-09 | 2022-10-05 | 上海博志研新薬物技術有限公司 | Brivaracetam pharmaceutical composition, its production method and application |
| JP7423013B2 (en) | 2020-07-09 | 2024-01-29 | 上海雲晟研新生物科技有限公司 | Brivaracetam pharmaceutical composition, its manufacturing method and application |
| CN114246841A (en) * | 2020-09-24 | 2022-03-29 | 南京济群医药科技股份有限公司 | Composition and medicine of piperazine isethionate and quinapride |
| CN114246872A (en) * | 2020-09-24 | 2022-03-29 | 南京济群医药科技股份有限公司 | Process method and composition for improving liquidity of pipariril isethionate |
| CN114246841B (en) * | 2020-09-24 | 2024-02-02 | 南京济群医药科技股份有限公司 | Composition and medicine of isethionic acid piperdine Bai Xi |
| CN114246872B (en) * | 2020-09-24 | 2024-02-06 | 南京济群医药科技股份有限公司 | Technological method and composition for improving fluidity of isethionic acid piperazine Bai Xili |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
| CN112274493A (en) * | 2020-11-18 | 2021-01-29 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of pipera cypress xili capsule |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106667952A (en) | Palbociclib pharmaceutical composition and preparation method thereof | |
| CN105748435B (en) | A kind of Pabuk former times benefit cloth pharmaceutical composition and preparation method thereof | |
| CN102266307B (en) | Valsartan capsules and preparation method thereof | |
| CN104306344B (en) | A kind of Azilsartan tablet and preparation technology thereof | |
| CN104586804B (en) | A kind of preparation method of the Letrozole piece of good stability | |
| CN105663062B (en) | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof | |
| CN108553433A (en) | A kind of Azilsartan piece and preparation method thereof | |
| CN108066312A (en) | A kind of Pa Boxini pharmaceutical compositions and preparation method thereof | |
| CN107320456A (en) | 2-acetylamino-2-deoxy-D-glucose capsule preparations and preparation method thereof | |
| CN108498470A (en) | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof | |
| CN112023056B (en) | Fluconazole pharmaceutical composition and preparation method thereof | |
| CN105596341B (en) | A kind of amber love song Ge Lieting solid pharmaceutical preparations and preparation method | |
| CN107951850A (en) | A kind of malic acid card is won for the preparation method of Buddhist nun's piece | |
| CN109953966A (en) | A kind of pharmaceutical composition and preparation method thereof containing Rui Boxini | |
| CN111000812B (en) | Preparation method of lacosamide tablets | |
| CN114366757A (en) | Compound polyethylene glycol electrolyte and preparation method thereof | |
| CN108014343A (en) | A kind of pharmaceutical composition for treating breast cancer and preparation method thereof | |
| CN112315931A (en) | Pentoxyverine citrate tablet and preparation method thereof | |
| CN112691084A (en) | Pharmaceutical composition and preparation method thereof | |
| CN109512796A (en) | Method for filling paracetamol capsules | |
| CN105078913B (en) | A kind of Irbesartan Tablets and preparation method thereof | |
| CN103893185B (en) | A kind of valsartan and Hydrochlorothiade dispersible tablet and preparation method thereof | |
| CN102846579B (en) | Valsartan medicinal capsule and preparation method thereof | |
| CN105982901A (en) | Propranolole hydrochloride and hydrochlorothiazide tablets and preparation method thereof | |
| CN115105505B (en) | Norfloxacin pharmaceutical composition and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170517 |