CN108721231A - The method for preparing Oxiracetam oral disintegrated preparation with fluidized bed granulation tabletting - Google Patents
The method for preparing Oxiracetam oral disintegrated preparation with fluidized bed granulation tabletting Download PDFInfo
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- CN108721231A CN108721231A CN201710250351.1A CN201710250351A CN108721231A CN 108721231 A CN108721231 A CN 108721231A CN 201710250351 A CN201710250351 A CN 201710250351A CN 108721231 A CN108721231 A CN 108721231A
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
The present invention provides a kind of preparation methods of Oxiracetam oral disintegrated preparation, using Oxiracetam and acetic acid hydroxymethyl-propyl cellulose succinate in absolute ethyl alcohol spray-dried solid dispersions obtained as active constituent, it is aided with the auxiliary materials such as filler, disintegrant, adhesive, corrigent, lubricant, is made through fluidized bed granulation tabletting.Mobility of particle of the present invention is good, tableting processes tablet without fragmentation, softening or it is viscous it is puckery rush phenomenon, the Oxiracetam oral disintegrated preparation stability of preparation is good, and sample is good in taste, long shelf-life.Preparation method of the present invention is simple, is suitble to industrialized production.
Description
Technical field
The present invention relates to oral disintegrated preparations containing Oxiracetam, and in particular to a kind of to prepare Aura with fluidized bed granulation tabletting
The method of western smooth oral disintegrated preparation.
Background technology
Oxiracetam (CAS No.：62613-82-5), it is to synthesize anti-lack in 1974 by Italian history Bick Qie Mu companies
Oxygen class cereboactive drug (compound is disclosed in US4118396) has pyrazolidone class formation, is the analog of Piracetam, is one
The new hydroxy-amino-butyric acid cyclic derivatives of kind.It can pass through the specific central nervous pathway of blood-brain barrier stimulation；It can promote phosphorus
Phatidylcholine and phosphatidyl ethanolamine synthesis, selectively activate cerebral cortex function, improve cerebrum metabolism；Adenylate can be activated
Kinase increases atriphos (ATP) synthesis and energy storage, improves the ratio of ATP/ adenosine diphosphate (ADP)s (ADP) in brain,
The synthesis of protein and nucleic acid in brain is set to increase；Clinically be used for cerebral injury and its caused neurological deficit, memory with
The treatment of disturbance of intelligence.Oxiracetam structure is as follows：
About oxiracetam preparation, clinically mainly there are injection, capsule and conventional tablet at present.Injection, directly
It connects and quickly enters human body, the protection of no human body normal physiological barrier, if therefore dosage is improper or the too fast or drug quality of injection is deposited
In problem, it is possible to bring harm to patient, or even cause the consequence that can not be retrieved；In addition injection pain, cannot be by patient
Self-administer, injection site generate that scleroma and intravenous injection are existing when to cause vascular inflammation all be clinical application important to ask
Topic.Thus, consider in drug safety, preferentially selects oral preparation (such as capsule, tablet).The Aura of clinical application at present
There are apparent drawbacks for western smooth oral preparation (capsule or tablet)：On the one hand, either capsule or conventional tablet work
Slowly, bioavilability is low；On the other hand, the patient for taking Oxiracetam is mostly the elderly, and this kind of patient is usually for drug
Dysphagia takes oxiracetam capsule agent, conventional tablet is inconvenient.
Oral disnitegration tablet, can under the conditions of anhydrous in oral cavity fater disintegration, enter alimentary canal with swallowing act；With it is common
Preparation is compared, and has the advantages that convenient to take, absorption is fast, bioavilability is high, small to alimentary canal mucous membrane irritation.Through looking into, about
Oxiracetam is mixed select the development of body Orally disintegrating there is no literature reported on.Rivers Wang Li et al. are disclosed in Chinese patent CN101766595A
A kind of levo-oxiracetam oral disnitegration tablet, it is auxiliary with levo-oxiracetam, sodium carboxymethyl starch, croscarmellose sodium etc.
Material is made by adhesive of water.Inventor has found under study for action, and the oral disnitegration tablet prepared using the above method, pharmacodynamics effect is not
Stablize, fractions of active ingredient decomposes under one's belt, it is difficult to effectively be absorbed by enteron aisle, to substantially reduce pharmacological activity, simultaneously also
Increase security risks.Thus, develop that new to prepare Oxiracetam oral disintegrated preparation technology very necessary.
Invention content
In order to solve the disadvantage that in the prior art, the purpose of the present invention is to provide a kind of Oxiracetam oral disintegrated preparations
Preparation method, using Oxiracetam solid dispersions as active constituent, with auxiliary material through fluidized bed granulation tabletting be made.
Unless otherwise specified, number of the present invention is parts by weight, and the percentage is mass percent.
The object of the present invention is achieved like this：
A kind of preparation method of Oxiracetam oral disintegrated preparation, by Oxiracetam solid dispersions and pharmaceutic adjuvant through stream
Change bed pelletizing press sheet to be made, it is characterised in that：The Oxiracetam solid dispersions are by 1 part of Oxiracetam and 2-10 parts of acetic acid
Then hydroxymethyl-propyl cellulose succinate uniform dissolution is sprayed in 10-30 parts of absolute ethyl alcohols in spray dryer
Mist drying is made；The inlet air temperature of the spray drying is l20 DEG C~165 DEG C, 65~90 DEG C of leaving air temp.
Oxiracetam oral disintegrated preparation of the present invention, solid dispersions containing Oxiracetam, disintegrant, adhesive, corrigent,
Also contain appropriate filler or/and lubricant when necessary.
An embodiment according to the present invention, oral disintegrated preparation solid dispersions containing Oxiracetam of the present invention 55~
92%, filler 0~20%, disintegrant 3~25%, adhesive 1~10%, corrigent 1~3%, lubricant 0~5%, with matter
Measure percentages.
An embodiment according to the present invention, adhesive of the present invention is the adhesive of this field routine, described
Adhesive is preferably ethyl alcohol, starch slurry, sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methyl fibre
The combination of one or more of dimension element, polyvinylpyrrolidone.An embodiment according to the present invention, disintegration of the present invention
Agent be preferably one kind in dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium or
Several combinations.An embodiment according to the present invention, corrigent of the present invention are preferably Sucralose, xylitol, peace
The mixing of one or more of match honey, essence.
An embodiment according to the present invention, filler of the present invention is the filler of this field routine, described
Filler be preferably microcrystalline cellulose (MCC), starch (Starch), pregelatinized starch, lactose, mannitol, sorbierite and
It is one or more in crospovidone (PVPP).An embodiment according to the present invention, lubricant of the present invention are preferable
It is the combination of one or more of superfine silica gel powder, magnesium stearate, talcum powder.
It is found in research, it is also the same to prepare Oxiracetam solid oral disintegrating preparations using fluid-bed marumerization pressed disc method
Existing defects, technology controlling and process is bad to make material powders be not easy to reach fluidized state, cause plug nozzle and filter bag, simultaneously also
Particle obtained may be caused to have color spot or grain size bigger than normal, be unevenly distributed, to influence the dissolution and absorption of drug.
Preferably, fluidized bed granulation of the present invention is that fluid bed is added in Oxiracetam solid dispersions, filler, disintegrant
In granulator, air inlet mixing, wherein inlet air temperature are 25~65 DEG C, are 800~1250m into airspeed3/ hour；Increase air inlet
Temperature sprays into binder solution by the way of top spray or side spray, is mixed under conditions of lasting air inlet, is dry, obtaining Aura
Western smooth solid dispersion particles, wherein into airspeed be 1080~1500m3/ hour, inlet air temperature are 45~109 DEG C, described viscous
The penetrating speed of mixture solution is 10~30mL/ minutes.
Inventor also found that before fluidized bed granulation is hydrojet, dry material is vulnerable to electrostatic and is adhered to fluidisation
In bed wall and on filter bag, these materials sticked cannot participate in pelletizing, and the uniformity of particle and yield is caused to receive influence.
It is furthermore preferred that fluidized bed granulation of the present invention is that fluidisation is added in Oxiracetam solid dispersions, filler, disintegrant
In bed granulator, air inlet mixing, wherein inlet air temperature are 45~60 DEG C, are 950~1150m into airspeed3/ hour；Increase into
Air temperature sprays into binder solution by the way of top spray or side spray, is mixed under conditions of lasting air inlet, is dry, obtaining Austria
La Xitan solid dispersion particles, wherein into airspeed be 1200~1350m3/ hour, inlet air temperature is 70~100 DEG C, described
The penetrating speed of binder solution is 10~30mL/ minutes；Described adhesive solution is the polyethylene pyrrole of a concentration of 5%-20%
Pyrrolidone or carboxymethylcellulose sodium solution, in terms of quality volumn concentration g/mL.
An embodiment according to the present invention, the preparation method of Oxiracetam oral disintegrated preparation of the present invention, including Austria
Preparation, material sieving, fluidized bed granulation and the tableting step of La Xitan solid dispersions, which is characterized in that use following steps：
(1), the preparation of solid dispersions
1 part of Oxiracetam medicinal chemicals and 2-10 parts of acetic acid hydroxymethyl-propyl cellulose succinate uniform dissolution in
It in 10-30 parts of absolute ethyl alcohols, is then spray-dried in spray dryer, wherein the inlet air temperature being spray-dried is l28
DEG C~162 DEG C, 72~95 DEG C of leaving air temp；By after drying Oxiracetam solid dispersions crush to get；
(2), material is sieved
Oxiracetam solid dispersions, filler, disintegrant, corrigent, lubricant after crushing is crossed into 100 mesh respectively
Sieve, it is spare；
(3), fluidized bed granulation
Oxiracetam solid dispersions, filler, disintegrant are added in fluidised bed granulator, air inlet mixing, wherein into
Air temperature is 30~60 DEG C, is 950~1150m into airspeed3/ hour；Inlet air temperature is increased, by the way of top spray or side spray
Binder solution is sprayed into, is mixed under conditions of lasting air inlet, is dry, obtaining Oxiracetam solid dispersion particles, wherein into
Airspeed is 1200~1350m3/ hour, inlet air temperature are 60~100 DEG C, the penetrating speed of described adhesive solution is 10~
30mL/ minutes；Described adhesive solution is the polyvinylpyrrolidone or carboxymethylcellulose sodium solution of a concentration of 5%-20%,
In terms of quality volumn concentration g/mL；
(4), tabletting
Oxiracetam solid dispersion particles prepared by fluid bed, rotation is put into lubricant and corrigent after mixing
It is tabletted in rotatable tablet press machine, turntable 15~30r/min of rotating speed, stuffing pressure be 30~40N, depth of fill be 10~
20mm。
Advantageous effect：
The present invention provides a kind of preparation method of Oxiracetam oral disintegrated preparation, the Aura west prepared with ad hoc approach
Smooth solid dispersions are active constituent, are aided with the auxiliary materials such as filler, disintegrant, adhesive, corrigent, lubricant, through fluid bed
Pelletizing press sheet is made.The present invention can under the conditions of anhydrous (or the only a small amount of water presence) fater disintegration in oral cavity, with swallowing
Act the children or gerontal patient that dysphagia is very suitable for into alimentary canal.The present invention is to live with Oxiracetam solid dispersions
Property ingredient prepare oral disintegrated preparation, and using Oxiracetam, mixed to select body bulk pharmaceutical chemicals be that active constituent prepares Orally disintegrating system merely
Agent is compared, and is greatly reduced drug degree of decomposition in stomach, is improved Drug safety and validity；Meanwhile the present invention is with Austria
La Xitan solid dispersions are active constituent, and the mobility of particle through fluidized bed granulation is more preferable, and more conducively galenic pharmacy technique needs.
The present invention prepares Oxiracetam oral disnitegration tablet by fluidized bed granulation method, passes through a series of ginsengs such as inlet air temperature, intake velocity
Several control, material powders are not easy to reach fluidized state in effective solution fluid bed granulation, cause plug nozzle and
Filter bag and particle obtained have color spot or grain size bigger than normal, and the technical issues of being unevenly distributed, the fluid bed granulate of preparation is thin
Small uniform, hardness is moderate, and tablet weight variation is small.By further state modulator, solve dry material be vulnerable to electrostatic and
The problem of being adhered in fluidisation bed wall and influencing the uniformity and yield of particle on filter bag, while mobility of particle is good, pressure
Piece process tablet without fragmentation, softening or it is viscous it is puckery rush phenomenon, ensure that being smoothed out for fluidized bed granulation.Aura prepared by the present invention
Western smooth oral disintegrated preparation, stability is good, and sample is good in taste, long shelf-life.Preparation method of the present invention is simple, is suitble to industrialization
Production.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
In invention is further explained, it should not be understood as limiting the scope of the invention, person skilled in art can
To make some nonessential modifications and adaptations to the present invention according to aforementioned present invention content.Those of ordinary skill in the art can join
It examines Higher Education Publishing House Pan Weisan and edits 2006 editions《Industrial pharmacy》And medicinal fluidised bed granulator JB/T20014-
2011 implement the present invention.Fluid-bed marumerization machine of the present invention, spray dryer are well known to those of ordinary skill in the art
Equipment, wherein embodiment are provided using granulator and spray dryer by Shandong Singapore and Malaysia drugs manufacture equipment Co., Ltd.The present invention
Medicinal chemicals Oxiracetam used, is provided by Chongqing Fuan Pharmaceutical Co., Ltd., purity 99.5%；Reagent of the present invention is city
Product is sold, wherein acetic acid hydroxymethyl-propyl cellulose succinate is provided by the bio tech ltd Wei Kang.
(1), the preparation of Oxiracetam solid dispersions
Embodiment 1
18 parts of absolute ethyl alcohols are taken, under stirring, 1 part of Oxiracetam medicinal chemicals and 6 parts of acetic acid methylols are added
Then propyl cellulose succinate, stirring are spray-dried to dissolving in spray dryer, spray drying into wind-warm syndrome
Degree is l45 DEG C~148 DEG C, 78~80 DEG C of leaving air temp；By after drying Oxiracetam solid dispersions crush to get.
Embodiment 2
25 parts of absolute ethyl alcohols are taken, under stirring, 1 part of Oxiracetam medicinal chemicals and 5 parts of acetic acid methylols are added
Then propyl cellulose succinate, stirring are spray-dried to dissolving in spray dryer, spray drying into wind-warm syndrome
Degree is l50 DEG C~152 DEG C, 85~88 DEG C of leaving air temp；By after drying Oxiracetam solid dispersions crush to get.
Embodiment 3
10 parts of absolute ethyl alcohols are taken, under stirring, 1 part of Oxiracetam medicinal chemicals and 2 parts of acetic acid methylols are added
Then propyl cellulose succinate, stirring are spray-dried to dissolving in spray dryer, spray drying into wind-warm syndrome
Degree is l25 DEG C~130 DEG C, 62~68 DEG C of leaving air temp；By after drying Oxiracetam solid dispersions crush to get.
Embodiment 4
30 parts of absolute ethyl alcohols are taken, under stirring, 1 part of Oxiracetam medicinal chemicals and 10 parts of acetic acid methylols are added
Then propyl cellulose succinate, stirring are spray-dried to dissolving in spray dryer, spray drying into wind-warm syndrome
Degree is l62 DEG C~165 DEG C, 88~90 DEG C of leaving air temp；By after drying Oxiracetam solid dispersions crush to get.
Embodiment 5
20 parts of absolute ethyl alcohols are taken, under stirring, 1 part of Oxiracetam medicinal chemicals and 7 parts of acetic acid methylols are added
Then propyl cellulose succinate, stirring are spray-dried to dissolving in spray dryer, spray drying into wind-warm syndrome
Degree is l35 DEG C~138 DEG C, 72~75 DEG C of leaving air temp；By after drying Oxiracetam solid dispersions crush to get.
(2), the preparation of the oral disintegrated preparation of solid dispersions containing Oxiracetam
Embodiment 6
Prescription：Oxiracetam solid dispersions 70g, microcrystalline cellulose 6g, sodium carboxymethyl starch 8g prepared by embodiment 1,
Low-substituted hydroxypropyl cellulose 8g, polyvinylpyrrolidone 8g, Sucralose 1g, magnesium stearate 1g.
Preparation method：
(1) dispensing：By Oxiracetam solid dispersions, microcrystalline cellulose, sodium carboxymethyl starch, low substituted hydroxy-propyl fiber
Element, polyvinylpyrrolidone, Sucralose, magnesium stearate sieve with 100 mesh sieve respectively, spare；
(2) fluidized bed granulation：Oxiracetam solid dispersions, filler, disintegrant are added in fluidised bed granulator, into
Wind mixes, and wherein inlet air temperature is 48 DEG C, is 1000m into airspeed3/ hour；Inlet air temperature is increased, is sprayed by the way of top spray
Enter binder solution, is mixed under conditions of lasting air inlet, is dry, Oxiracetam solid dispersion particles being obtained, wherein entering the wind
Rate is 1280m3/ hour, inlet air temperature are 82 DEG C, and the penetrating speed of described adhesive solution is 20mL/ minutes；The bonding
Agent solution is a concentration of 15% polyvinylpyrrolidone ethanol solution, in terms of quality volumn concentration g/mL；
(3) tabletting
Oxiracetam solid dispersion particles prepared by fluid bed, rotation is put into lubricant and corrigent after mixing
It is tabletted in rotatable tablet press machine, turntable rotating speed 22r/min, stuffing pressure 35N, depth of fill 15mm.
The Oxiracetam solid dispersions prepared using embodiment 1 is active constituents, the prescription and technique of reference embodiment 6,
Embodiment 7-11 is run according to the parameter of the following table 1, prepares Oxiracetam oral disintegrated preparation, wherein embodiment 11 is that comparison is implemented
Example 1.
1 embodiment 7-11 Oxiracetam oral disnitegration tablet preparation technology parameters of table
With reference to the technique of embodiment 6, embodiment 12-17 is run according to the prescription of the following table 2, prepares Oxiracetam Orally disintegrating
Preparation.The active constituent of embodiment 12-16 is the Oxiracetam solid dispersions prepared in embodiment 1-5, such as is implemented in table 2
Example 1 shows that active constituent is solid dispersions prepared by embodiment 1.Embodiment 17 is comparative example 2, active constituent
Body bulk pharmaceutical chemicals (not carrying out solid dispersions preparation) are selected for Oxiracetam is mixed.
The Oxiracetam oral disnitegration tablet preparation prescription of 2 embodiment 12-17 of table
(3) quality evaluation of Oxiracetam oral disintegrated preparation of the present invention
Embodiment 18
Oxiracetam oral disintegrated preparation of the present invention is investigated into graininess and compressibility, disintegration time, mouthfeel etc..
Experiment 1：At graininess and compressibility inspection
So that material to be measured is freely fallen from the fixed funnel of sustained height, accumulation body formed on the disk that radius is r,
Until material is overflowed from disk border, the height h of accumulation body is measured, replication 3 times is averaged, and is labeled as hIt is average, i.e. hIt is average
=(h1+h2+h3)/3 calculates arctan (hIt is average/ r), if arctan (hIt is average/ r) 35 ° of <, and 25 ° of >, that is, think that particle is equal
It is even, it is conducive to industrialized production.It is suppressed with the tablet press machine of same model, by hardness control within the scope of 35-50N.Emphasis
It checks hardness, and has seen whether the abnormal conditions such as fragmentation, softening or viscous puckery punching.
Experiment 2：Disintegration time limited checks
It takes 2mL water (37 DEG C) to be placed in 5mL test tubes, sample prepared by above-described embodiment is added, start timing, until all collapsing
It is shattered into independent fine particle, stops timing, records disintegration time, test tube needs to stand in disintegrating procedue, takes 6 progress every time
Detection, takes its average value.
Experiment 3：Mouthfeel inspection
Healthy volunteer 6 is chosen, sample prepared by above-described embodiment is placed on lingual surface and starts timing, until in the oral cavity
Whole disintegration start-stops stop timing, record disintegration time, and experience slice, thin piece and be placed in certainly in mouth to the feeling in oral cavity after complete disintegration,
Such as sweet tea/hardship, whether there is or not grittiness etc.；Specific evaluating result see the table below 3.
The performance measurement result of 3 Oxiracetam oral disintegrated preparation of table
.Oxiracetam oral disintegrated preparation prepared by embodiment 6-10,12-16, fluid bed granulate fine uniform, angle of repose
Between 30-35 degree, good fluidity, tableting processes tablet without fragmentation, softening or it is viscous it is puckery rush phenomenon, tablet weight variation is small, is made
Oral disnitegration tablet hardness in 30-40N, be very suitable for production, transport, packaging, storage；Disintegration time limited 25-35S, it is good in taste,
Without sand type.It is found during preparing oral disnitegration tablet using fluid bed, different technique can cause prodigious difference, such as
Inlet air temperature and intake volume and adhesive control are bad, particulate brittleness can be caused big, bulk density and mobility are small, partial particulate
Outer dry interior wet, color is deeper, and the oral disnitegration tablet of preparation has slight sand type, disintegration time slightly long (embodiment 11).It will be above-mentioned
Oxiracetam oral disnitegration tablet prepared by embodiment 6-10,12-16, in 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10%
Long-term stable experiment is carried out under part, is detected respectively at March, June, September, December, 18 months, 36 months six time points respectively, sample
Moral character shape, content, related substance meet regulation.
Embodiment 19
Investigate release conditions of the Oxiracetam oral disintegrated preparation of the present invention in gastric juice and in intestinal juice.
1. simulate the gastric juice
0.1mol/L hydrochloric acid solution 900ml are measured, are injected in stripping rotor, heating makes solution temperature be kept for 37 ± 0.5 DEG C, determines
Amount precision weighs 6 parts of Oxiracetam oral disintegrated preparation sample in embodiment 6-17, and input turns in basket, and machine is with rotating speed
100rpm is operated, and is sampled respectively at 10min, 30min, 60min, 90min, 120min, through 0.8um micropore water phase filter membrane mistakes
Filter is completed from sampling to filtration in 30s, and sample measures absorbance at 276nm wavelength, and using coordinative solvent as blank pair
According to by external standard method calculating Oxiracetam dissolution percentage.Drug release situation of the Oxiracetam oral disintegrated preparation in simulate the gastric juice
It see the table below 4.
The release conditions of Oxiracetam oral disintegrated preparation prepared by 4 embodiment 6-17 of table in gastric juice
| 10min | 30min | 60min | 90min | 120min | |
| Embodiment 6 | 3.11% | 3.72% | 4.44% | 4.58% | 4.79% |
| Embodiment 7 | 3.05% | 3.51% | 4.16% | 4.40% | 4.53% |
| Embodiment 8 | 3.30% | 3.70% | 4.04% | 4.25% | 4.49% |
| Embodiment 9 | 3.20% | 3.76% | 4.33% | 4.45% | 4.77% |
| Embodiment 10 | 3.35% | 3.83% | 4.26% | 4.41% | 4.60% |
| Embodiment 11 | 5.25% | 6.78% | 7.32% | 8.55% | 9.76% |
| Embodiment 12 | 3.08% | 3.50% | 4.15% | 4.41% | 4.60% |
| Embodiment 13 | 3.43% | 3.92% | 4.55% | 4.69% | 4.83% |
| Embodiment 14 | 3.44% | 3.90% | 4.57% | 4.68% | 4.80% |
| Embodiment 15 | 3.37% | 3.81% | 4.20% | 4.39% | 4.55% |
| Embodiment 16 | 3.25% | 3.70% | 4.11% | 4.35% | 4.54% |
| Embodiment 17 | 25.89% | 49.55% | 74.11% | ---------- | ---------- |
.From the point of view of simulate the gastric juice releases the drug situation, the Oxiracetam oral disintegrated preparation of embodiment 6-10,12-16 preparation
Drug release amount is more than that 3%, 30min-120min drug release rates are gradually reduced within 10min, and always drug release amount is no more than 5% to 120min.
It can be seen that the Oxiracetam solid dispersions that prepare of present invention burst size in simulate the gastric juice is few.It is prepared by embodiment 11 (comparative example 1)
Oxiracetam oral disintegrated preparation 120min always drug release amount close to 10%.Oxiracetam prepared by embodiment 17 (comparative example 2)
Oral disintegrated preparation, drug release amount is more than 70% within 60min.
2. simulated intestinal fluid
Phosphate buffer (pH=6.8) 900ml is measured, is injected in stripping rotor, heating makes solution temperature keep 37 ± 0.5
DEG C, quantitative precision weighs 6 parts of Oxiracetam oral disintegrated preparation sample in embodiment 6-17, and input turns in basket, machine after
Reforwarding turns 60min, and is sampled respectively at 5min, 10min, 15min, 30min, 45min, 45min, 60min, passes through immediately
0.8um micropore water phase membrane filtrations are completed from sampling to filtration in 30s, and sample measures absorbance at 276nm wavelength, and
Using coordinative solvent as blank control, calculates Oxiracetam by external standard method and dissolve out percentage.Oxiracetam oral disintegrated preparation is in mould
Drug release situation in quasi- intestinal juice see the table below 5.
The release conditions of Oxiracetam oral disintegrated preparation prepared by 5 embodiment 6-17 of table in intestinal juice
| 5min | 10min | 15min | 30min | 45min | 60min | |
| Embodiment 6 | 12.30% | 30.81% | 62.15% | 84.08% | 90.04% | 92.55% |
| Embodiment 7 | 13.10% | 32.02% | 64.82% | 85.03% | 90.65% | 92.30% |
| Embodiment 8 | 11.53% | 30.11% | 62.56% | 80.57% | 88.48% | 91.33% |
| Embodiment 9 | 12.80% | 33.05% | 65.13% | 82.64% | 89.06% | 91.90% |
| Embodiment 10 | 12.54% | 32.53% | 65.10% | 82.78% | 88.15% | 90.97% |
| Embodiment 11 | 12.36% | 31.88% | 54.13% | 76.55% | 80.04% | 82.92% |
| Embodiment 12 | 15.30% | 34.02% | 67.80% | 85.11% | 89.60% | 92.66% |
| Embodiment 13 | 11.07% | 30.14% | 62.10% | 80.50% | 87.33% | 91.11% |
| Embodiment 14 | 12.80% | 33.14% | 65.03% | 82.77% | 89.06% | 90.88% |
| Embodiment 15 | 12.44% | 32.63% | 65.10% | 82.38% | 88.40% | 90.57% |
| Embodiment 16 | 12.30% | 31.08% | 64.33% | 86.64% | 90.11% | 92.93% |
| Embodiment 17 | 15.22% | 33.52% | 67.88% | 85.03% | 90.65% | 95.37% |
.From the point of view of simulated intestinal fluid releases the drug situation, the Oxiracetam oral disintegrated preparation of embodiment 6-10,12-16 preparation
It is more than 80%, 60min drug release amounts is more than 90% that drug release amount, which is more than 60%, 30min drug release amounts, within 15min.It can be seen that present invention system
Standby Oxiracetam solid dispersions discharge rapidly in simulated intestinal fluid.
Claims (8)
1. a kind of preparation method of Oxiracetam oral disintegrated preparation, by Oxiracetam solid dispersions and pharmaceutic adjuvant through fluidisation
Bed pelletizing press sheet is made, it is characterised in that：The Oxiracetam solid dispersions are by 1 part of Oxiracetam and 2-10 parts of acetic acid hydroxyl
Then methylpropylcelluloses succinate uniform dissolution is spray-dried in 10-30 parts of absolute ethyl alcohols in spray dryer
It is made；The inlet air temperature of the spray drying is l20 DEG C~165 DEG C, 65~90 DEG C of leaving air temp.
2. method as described in claim 1, it is characterised in that：The oral disintegrated preparation solid dispersions containing Oxiracetam 55~
92%, filler 0~20%, disintegrant 3~25%, adhesive 1~10%, corrigent 1~3%, lubricant 0~5%, with quality percentage
Than meter.
3. method as claimed in claim 2, it is characterised in that：Described adhesive be ethyl alcohol, starch slurry, sodium carboxymethylcellulose,
One or more of hydroxypropyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone combine；Institute
State disintegrant be dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, one kind in croscarmellose sodium or
Several combinations；The corrigent is the mixing of one or more of Sucralose, xylitol, acesulfame potassium, essence.
4. method as claimed in claim 2, it is characterised in that：The filler is microcrystalline cellulose（MCC）, starch
（Starch）, pregelatinized starch, lactose, mannitol, sorbierite and crospovidone（PVPP）In it is one or more；The profit
Lubrication prescription is the combination of one or more of superfine silica gel powder, magnesium stearate, talcum powder.
5. such as any one of claim 1-4 the methods, it is characterised in that：The fluidized bed granulation is by Oxiracetam solid point
Granular media, filler, disintegrant are added in fluidised bed granulator, and air inlet mixing, wherein inlet air temperature are 25~65 DEG C, into airspeed
For 800~1250m3/ hour；Inlet air temperature is increased, binder solution is sprayed by the way of top spray or side spray, in lasting air inlet
Under conditions of mixing, dry, obtain Oxiracetam solid dispersion particles, wherein into airspeed be 1080~1500m3/ hour,
Inlet air temperature is 45~109 DEG C, and the penetrating speed of described adhesive solution is 10~30mL/ minutes.
6. such as any one of claim 1-4 the methods, it is characterised in that：The fluidized bed granulation is by Oxiracetam solid point
Granular media, filler, disintegrant are added in fluidised bed granulator, and air inlet mixing, wherein inlet air temperature are 45~60 DEG C, into airspeed
For 950~1150m3/ hour；Inlet air temperature is increased, binder solution is sprayed by the way of top spray or side spray, in lasting air inlet
Under conditions of mixing, dry, obtain Oxiracetam solid dispersion particles, wherein into airspeed be 1200~1350m3/ hour,
Inlet air temperature is 70~100 DEG C, and the penetrating speed of described adhesive solution is 10~30mL/ minutes；Described adhesive solution is
The polyvinylpyrrolidone or carboxymethylcellulose sodium solution of a concentration of 5%-20%, in terms of quality volumn concentration g/mL.
7. method as claimed in claim 5, it is characterised in that：The fluidized bed granulation is by Oxiracetam solid dispersions, fills out
Fill agent, disintegrant be added fluidised bed granulator in, air inlet mixing, wherein inlet air temperature be 45~60 DEG C, into airspeed be 950~
1150m3/ hour；Inlet air temperature is increased, binder solution is sprayed by the way of top spray or side spray, in the condition of lasting air inlet
Lower mixing, drying, obtain Oxiracetam solid dispersion particles, wherein into airspeed be 1200~1350m3/ hour, into wind-warm syndrome
Degree is 70~100 DEG C, and the penetrating speed of described adhesive solution is 10~30mL/ minutes；Described adhesive solution is a concentration of
The polyvinylpyrrolidone or carboxymethylcellulose sodium solution of 5%-20%, in terms of quality volumn concentration g/mL.
8. such as any one of claim 1-4 the methods, including the preparation of Oxiracetam solid dispersions, material sieving, fluidisation
Bed granulation and tableting step, which is characterized in that use following steps：
（1）, solid dispersions preparation
1 part of Oxiracetam medicinal chemicals and 2-10 parts of acetic acid hydroxymethyl-propyl cellulose succinate uniform dissolution are in 10-
In 30 parts of absolute ethyl alcohols, be then spray-dried in spray dryer, wherein the inlet air temperature being spray-dried be l28 DEG C~
162 DEG C, 72~95 DEG C of leaving air temp；By after drying Oxiracetam solid dispersions crush to get；
（2）, material sieving
Oxiracetam solid dispersions, filler, disintegrant, corrigent, lubricant after crushing is sieved with 100 mesh sieve respectively, it is standby
With；
（3）, fluidized bed granulation
Oxiracetam solid dispersions, filler, disintegrant are added in fluidised bed granulator, air inlet mixing, wherein into wind-warm syndrome
Degree is 30~60 DEG C, is 950~1150m into airspeed3/ hour；Inlet air temperature is increased, is sprayed by the way of top spray or side spray
Binder solution mixes under conditions of lasting air inlet, is dry, Oxiracetam solid dispersion particles being obtained, wherein into wind speed
Rate is 1200~1350m3/ hour, inlet air temperature are 60~100 DEG C, and the penetrating speed of described adhesive solution is 10~30mL/
Minute；Described adhesive solution concentration is the polyvinylpyrrolidone or carboxymethylcellulose sodium solution of 5%-20%, with mass body
Product percentage composition g/mL meters；
（4）, tabletting
Oxiracetam solid dispersion particles prepared by fluid bed, are put into rotatably after mixing with lubricant and corrigent
Tabletted in tablet press machine, turntable 15~30r/min of rotating speed, stuffing pressure is 30~40N, and depth of fill is 10~20mm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710250351.1A CN108721231A (en) | 2017-04-17 | 2017-04-17 | The method for preparing Oxiracetam oral disintegrated preparation with fluidized bed granulation tabletting |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710250351.1A CN108721231A (en) | 2017-04-17 | 2017-04-17 | The method for preparing Oxiracetam oral disintegrated preparation with fluidized bed granulation tabletting |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108721231A true CN108721231A (en) | 2018-11-02 |
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ID=63924132
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710250351.1A Withdrawn CN108721231A (en) | 2017-04-17 | 2017-04-17 | The method for preparing Oxiracetam oral disintegrated preparation with fluidized bed granulation tabletting |
Country Status (1)
| Country | Link |
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| CN (1) | CN108721231A (en) |
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2017
- 2017-04-17 CN CN201710250351.1A patent/CN108721231A/en not_active Withdrawn
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Application publication date: 20181102 |