CN105534940B - A kind of diclofenac sodium extended action tablet composition and preparation method thereof - Google Patents
A kind of diclofenac sodium extended action tablet composition and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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Abstract
The present invention relates to drug field, in particular to a kind of diclofenac sodium extended action tablet and preparation method thereof.The present invention is using wax material as adhesive, using ion exchange resin as framework material, using the unerodible matrix sustained release tablets of hot melt packing technology production, Mechanism of Drug Release is more reasonable, it is not discharged substantially in stomach, C14H10Cl2NNaO2 is substantially reduced to the irritation of human stomach, avoids patient's stomachache, burn feeling, acid reflux, the side effects such as poor, nausea of receiving.In addition; hot melt packing technology can make C14H10Cl2NNaO2 ingredient excitatory disposably be rolled into spheroidal particle by wax material adhesive; avoid the ill-effects such as the intense stimulus benefit of respiratory tract, eyes that C14H10Cl2NNaO2 dust generates producers in granulation, mixing, tabletting, packaging process; the physical and mental health for being conducive to operator is also beneficial to the protection of environment.
Description
Technical field
The present invention relates to drug field, in particular to a kind of diclofenac sodium extended action tablet and preparation method thereof.
Background technique
C14H10Cl2NNaO2 is a kind of non-steroidal anti-inflammatory analgesics derived from phenylacetic acid class, and the mechanism of action is to inhibit epoxy
Change enzymatic activity, to block conversion of the arachidonic acid to prostaglandin.Meanwhile it can also promote arachidonic acid and glycerol three
Rouge combines, and reduces the arachidonic acid concentration of endocellular liberation, and inhibits the synthesis of leukotriene indirectly.Diclofenac sodium extended action tablet
Domestic, external listing is for many years, significant in efficacy, and dosage form is suitable for.
C14H10Cl2NNaO2, chemical name are [o- (2,6-DCA)] sodium phenylacetate, and molecular formula is
C14H10Cl2NNaO2, molecular weight 318.13, molecular structural formula is as shown in formula I:
Diclofenac is pale yellow crystals, odorless, soluble easily in water, the non-polar organic solvents such as ethyl alcohol, it is a kind of derivative
It, can be by inhibiting peroxidase activity, so that arachidonic acid be blocked to convert in the non-steroidal anti-inflammatory analgesics of phenylacetic acid class
Prostaglandin；Meanwhile it can also promote arachidonic acid and triglyceride (triacylglycerol) to combine, and reduce the flower of endocellular liberation
Raw tetraene acid concentration, and inhibit the generation of the products such as leukotriene, bradykinin to play antipyretic-antalgic and anti-inflammatory effect indirectly.
Rheumatism and rheumatoid arthritis are a kind of common disease and frequently-occurring disease, can all be occurred in all age group crowd,
Disease incidence increases with the age and is risen, and the disease incidence of 55~64 years old age bracket crowd is about 29%, 64 years old or more age bracket crowd
Disease incidence is up to 49%.In the U.S., which is considered as endangering one of five big diseases of human health, it makes millions of patients
Life and work ability is lost, serious person can make the lost of life 10~15 years, or even directly result in death.The number provided according to WHO
Word shows that the whole world has 1% people to suffer from rheumatism and rheumatoid arthritis, treats the annual growth of the health care expenditures of the disease
It is 7%.China at present only the disease incidence of rheumatoid arthritis just up to 5%.Left and right, rheumatism and patient with rheumatoid arthritis
Number totals over 10,000,000 people.Currently, anti-arthritic drugs market scale in China's is about 2,000,000,000~2,500,000,000 yuans, year
Growth rate is 6% or so, it is contemplated that was up to 3,000,000,000 yuans by 2018, wherein retail pharmacies will occupy comparable market part
Volume.And antirheumatic and medicine for treating rheumatoid arthritis will account for the share in anti-arthritic drugs market 40%~50% or so.Treatment
Rheumatism and rheumatoid arthritis are the most universal with non-steroid anti-inflammatory drug application.Such types of drugs is more, has more than 20, often
There are 5~6 kinds, and Diclofenac has become the choice drug of antirheumatic and rheumatoid arthritis with its unique curative effect.
Currently, C14H10Cl2NNaO2 oral slow-releasing preparation is largely spansule and sustained-release tablet, sustained-release tablet is divided into solidifying
Three kinds of glue-type, erosion type, unerodible matrix sustained release tablets forms, and most of the country be hydrogel matrix slow-release tablet,
Erodible matrix sustained release tablets are oral slow at present, controlled release preparation main Types, account for about listing matrix tablet kind 60%~
70%, production technology has wet granulation technology, direct tablet compressing technique, or is coated and is produced using film controlled-releasing technology.
But existing production method and there are the shortcomings that:
1, the adhesive that diclofenac sodium extended action tablet wet granulation takes water as a solvent is pelletized, and is sustained release with cellulose family
Material, the granulation of normal wet granulating process meets water electrode and easily forms the micelle being not easy in dispersion, and particle obtained is uneven,
Wet granular processed is extremely difficult；One-step palletizing particle is as flakes, loosely, unstable and be unfavorable for production operation.
2, when diclofenac sodium extended action tablet wet granulation is pelletized using organic solvent (such as: ethyl alcohol), pelletization heat production is big,
Particle after drying is very rigid, is not easy to whole grain, and granulation process chieftain is more, and chieftain is hard to recycle, and leads to yield even
It is lower；Particle and fine powder content difference are big, and differential pressure is big between the piece release piece being pressed into and piece, release between batches
Difference is big, unstable product quality；Meanwhile organic solvent is inflammable and explosive, there are production safety hidden danger.
3, powder uniformly mixed during diclofenac sodium extended action tablet direct tablet compressing due to main ingredient, slow-release material and other
The difference and compressibility of material density are different, main ingredient, slow-release material and unclassified stores have the tendency that during decline it is separated, this
There is the phenomenon that being unevenly distributed, the piece release piece and piece that are pressed into main ingredient, slow-release material and unclassified stores between like-particles
Between differential pressure it is big, release difference between batches is big, unstable product quality.
4, all there is dust from flying in production process, and C14H10Cl2NNaO2 dust is to granulation, mixing, tabletting, packaging personnel
Respiratory tract, eyes be difficult to be resistant to by intense stimulus, be unfavorable for the physical and mental health of operator.
5, the diclofenac sodium extended action tablet of domestic listing is substantially gel-type and erodible matrix sustained release tablets, releases in stomach
Dissolution is put, C14H10Cl2NNaO2 has irritation to stomach, so that patient generates stomachache, burn feeling, acid reflux, the secondary work of poor, nausea etc. of receiving
With.
Summary of the invention
In view of this, the present invention provides a kind of diclofenac sodium extended action tablet and preparation method thereof.The present invention provides one kind
The formula of diclofenac sodium extended action tablet and its industrialization production technology of preparation improve production efficiency, have a stomachache after reduction medication
Side effect, while creatively disposably C14H10Cl2NNaO2 is wrapped up, eliminate its to the respiratory tract of operator and
Eye irritation, which is shed tears, waits adverse reactions, is conducive to personal safety and protection environment.
C14H10Cl2NNaO2 causes the side effect of patient's stomach, respiratory tract, eye mucosa to be that drug nature determines, the present invention
Diclofenac sodium extended action tablet made of technology can not only be substantially reduced its gastric irritation side effect, can also avoid in production process
The ill-effects such as the intense stimulus of respiratory tract, eyes that C14H10Cl2NNaO2 dust generates producers, are conducive to operator
Physical and mental health, be also beneficial to the protection of environment.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides a kind of diclofenac sodium extended action tablets, are grouped as by the group of following mass parts:
In some specific embodiments of the invention, adhesive described in diclofenac sodium extended action tablet provided by the invention
For wax material；The wax material is one or both of glycerin monostearate, hexadecanol, spermaceti, hydrogenated vegetable oil
Above mixture.
In some specific embodiments of the invention, skeleton material described in diclofenac sodium extended action tablet provided by the invention
Material is the ion exchange resin admixture of one or both of kayexalate, polacrilin potassium, polacrilin or more.
In some specific embodiments of the invention, filler described in diclofenac sodium extended action tablet provided by the invention
More than one or both of hydroxypropul starch, sucrose, lauryl sodium sulfate, superfine silica gel powder, polyvinylpyrrolidone
Mixture.
In some specific embodiments of the invention, lubricant described in diclofenac sodium extended action tablet provided by the invention
For the mixture of one or both of magnesium stearate, sucrose fatty ester.
In some specific embodiments of the invention, coating agent described in diclofenac sodium extended action tablet provided by the invention
For Opadry.
In other specific embodiments of the invention, a kind of diclofenac sodium extended action tablet provided by the invention, by such as
The group of lower mass parts is grouped as:
In other specific embodiments of the invention, a kind of diclofenac sodium extended action tablet provided by the invention, by such as
The group of lower mass parts is grouped as:
In other specific embodiments of the invention, a kind of diclofenac sodium extended action tablet provided by the invention, by such as
The group of lower mass parts is grouped as:
In other specific embodiments of the invention, a kind of diclofenac sodium extended action tablet provided by the invention, by such as
The group of lower mass parts is grouped as:
In other specific embodiments of the invention, a kind of diclofenac sodium extended action tablet provided by the invention, by such as
The group of lower mass parts is grouped as:
In other specific embodiments of the invention, a kind of diclofenac sodium extended action tablet provided by the invention, by such as
The group of lower mass parts is grouped as:
In other specific embodiments of the invention, a kind of diclofenac sodium extended action tablet provided by the invention, by such as
The group of lower mass parts is grouped as:
In other specific embodiments of the invention, a kind of diclofenac sodium extended action tablet provided by the invention, by such as
The group of lower mass parts is grouped as:
The present invention also provides the preparation methods of the diclofenac sodium extended action tablet, and the component of formula ratio is taken to heat package.
In some specific embodiments of the invention, the temperature that package is heated described in the preparation method is 45~65
DEG C, the time of the hot melt package is 5~25min.
In other specific embodiments of the invention, heated described in the preparation method package temperature be 45~
65 DEG C, it is specifically as follows 55~65 DEG C, 58~63 DEG C, 45~55 DEG C or 55~62 DEG C；The time of the hot melt package specifically may be used
Think 5~15min, 10~25min, 8~18min or 5~16min.
In some specific embodiments of the invention, the preparation method is that taking C14H10Cl2NNaO2, framework material, bonding
After agent, filler mixing, 45~65 DEG C, high shear agitation 5-25min are heated to, forms similar ball after carrying out hot melt package
Shape particle, after whole grain of being then sieved, with 5~15min of mix lubricant, tabletting, coating obtain diclofenac sodium extended action tablet.
Specifically, the time with mix lubricant can be 10min, 3min or 8min.
In some specific embodiments of the invention, sieving was 20 meshes described in the preparation method, after cooling
After 18 meshes.
The present invention passes through the raw material for changing diclofenac sodium extended action tablet and auxiliary material composition ratio and preparation process, using hot melt
Package production technology is pelletized, and is disposably effectively wrapped up C14H10Cl2NNaO2, then carries out tabletting, be then coated
Industrialization production technology.
Beneficial effects of the present invention:
1, the present invention is using ion exchange resin as framework material, and wax material is adhesive, using hot melt packing technology
The unerodible matrix sustained release tablets of production, Mechanism of Drug Release is more reasonable, does not discharge substantially in stomach, hence it is evident that reduces C14H10Cl2NNaO2
To the irritation of stomach, patient is avoided to generate stomachache, burn feeling, acid reflux, the side effects such as poor, nausea of receiving.
2, C14H10Cl2NNaO2 is carried out spheroidal particle is disposably made using wax material hot melt in process of production
Effective package, avoid in granulation, mixing, tabletting, packaging process C14H10Cl2NNaO2 dust and breathing generated to producers
The ill-effects such as the intense stimulus in road, eyes are conducive to the physical and mental health of operator, and the safety for being also beneficial to production environment is protected
Shield.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 is the preparation technology flow chart of diclofenac sodium extended action tablet provided by the invention.
Specific embodiment
The invention discloses a kind of diclofenac sodium extended action tablet and preparation method thereof, those skilled in the art can use for reference this
Literary content, is suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications are to art technology
It is it will be apparent that they are considered as being included in the present invention for personnel.Method and application of the invention has passed through preferably
Embodiment is described, related personnel obviously can not depart from the content of present invention, in spirit and scope to side as described herein
Method and application are modified or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
The present invention provides a kind of diclofenac sodium extended action tablets, are calculated in mass percent, comprising:
Wherein:
Main ingredient: C14H10Cl2NNaO2
Framework material: polacrilin potassium (Amberlite IRP88), kayexalate (Amberlite IRP69),
Polacrilin (Amberlite IRP64)
Adhesive: glycerin monostearate, hexadecanol, spermaceti, hydrogenated vegetable oil
Filler: hydroxypropul starch, sucrose, lauryl sodium sulfate, superfine silica gel powder, polyvinylpyrrolidone.
Lubricant can be the mixture of one or both of magnesium stearate, sucrose fatty ester or more.
Coating agent is Opadry.
The preparation process of above-mentioned diclofenac sodium extended action tablet are as follows: take C14H10Cl2NNaO2, framework material, adhesive, filler
After sieving, it is put into hot melt package granulator and heats up after mixing heating, 45-65 DEG C of temperature controlling range, high shear agitation
5-25 minutes, the package of drug, granulation, round as a ball primary completion, hot melt formed spheroidal particle after wrapping up, then 20 mesh mistake
Sieve, after 18 mesh sieves after cooling, after 5~15min of mix lubricant then is added, it is fragrant to obtain double chlorine for tabletting and coating
Sour sodium sustained release tablets.
The present invention passes through the raw material and auxiliary material composition ratio and preparation process for changing diclofenac sodium extended action tablet, using hot melt
Package production technology is pelletized, and is disposably effectively wrapped up C14H10Cl2NNaO2, then carries out tabletting, or then wrap
The industrialization production technology of clothing.
The present invention provides a kind of formula of diclofenac sodium extended action tablet and its industrialization production technologies of preparation, improve life
Efficiency is produced, the side effect having a stomachache after medication is reduced
The present invention eliminates its dust and exhales operator by disposably wrapping up C14H10Cl2NNaO2, pelletizing, round as a ball
It inhales to stimulate and have difficulty in breathing and shed tears etc. and is unfavorable for the factor of production, be conducive to personal safety and protection environment.
Preparation method high production efficiency provided by the invention, safe operation is simple, is suitble to industrial industrialization.
The present invention is using ion exchange resin as framework material, using wax material as adhesive, using hot melt packing technology
The unerodible matrix sustained release tablets of production, Mechanism of Drug Release is more reasonable, does not discharge substantially in stomach, hence it is evident that reduces C14H10Cl2NNaO2
To the irritation of stomach, so that patient generates stomachache, burn feeling, acid reflux, the side effects such as poor, nausea of receiving.
C14H10Cl2NNaO2 is carried out spheroidal particle is disposably made using wax material hot melt in process of production
Effectively package, drug and the package of auxiliary material, granulation, round as a ball primary completion, avoid in granulation, mixing, tabletting, packaging process
The ill-effects such as the intense stimulus of respiratory tract, eyes that C14H10Cl2NNaO2 dust generates producers, conducive to operator's
Physical and mental health is also conducive to the protection of environment.
Raw materials used and reagent can be purchased by market in diclofenac sodium extended action tablet provided by the invention and preparation method thereof
?.
Below with reference to embodiment, the present invention is further explained:
Embodiment 1
Formula:
Preparation process:
1, C14H10Cl2NNaO2 1000g, kayexalate 1060.5g, glycerin monostearate 385.5g are accurately weighed,
Hydroxypropul starch 385.5g, superfine silica gel powder 40g, magnesium stearate 60g are spare.
2, C14H10Cl2NNaO2, kayexalate, hydroxypropul starch, superfine silica gel powder is taken to be put into hot melt package granulator mixed
It closes 5 minutes, the heating that heats up then is added after glycerin monostearate continuess to mix 3 minutes, it is 55-65 DEG C of temperature controlling range, high
Fast shear agitation 5-15 minutes, spheroidal particle is formed after carrying out hot melt package, then 20 mesh sieve, after 18 after cooling
Then mix lubricant 10min is added up to mesosome in mesh sieve.
3, tabletting, specification 0.1g answer tabletting weight 303mg, specification 75mg to answer tabletting weight 227.3mg.
Embodiment 2
Formula:
Preparation process:
1, C14H10Cl2NNaO2 1000g, polacrilin 640g, hexadecanol 806.5g, sucrose 613.5g, micro mist are accurately weighed
Silica gel 50g, magnesium stearate 40g, Opadry 76g are spare.
2, it takes C14H10Cl2NNaO2, polacrilin, hexadecanol, sucrose, superfine silica gel powder to be put into hot melt package granulator and mixes 5 points
Heat up heating after clock, 58-63 DEG C of temperature controlling range, high shear agitation 10-25 minutes, forms class after carrying out hot melt package
Like spherical particle, then 20 mesh sieve, after 18 mesh sieves after cooling, be then added mix lubricant 10min obtain it is intermediate
Body.
3, tabletting, specification 0.1g answer tabletting weight 315mg, specification 75mg to answer tabletting weight 236.3mg.
4, it is coated, diclofenac sodium extended action tablet is made after being coated with Opadry.
Embodiment 3
Formula:
Preparation process:
1, C14H10Cl2NNaO2 1000g, polacrilin potassium 358g, hydrogenated vegetable oil 442g, sucrose 1076g are accurately weighed, is gathered
Vinylpyrrolidone 114g, superfine silica gel powder 60g, Opadry 78g are spare.
2, C14H10Cl2NNaO2, polacrilin potassium, sucrose, polyvinylpyrrolidone, superfine silica gel powder is taken to be put into hot melt package system
Grain machine mixes 5 minutes, is then added after hydrogenated vegetable oil continuess to mix 3 minutes to heat up and heat, and 45-55 DEG C of temperature controlling range,
High shear agitation 8-18 minutes, carry out forming spheroidal particle after hot melt package, then 20 mesh sieve, after cooling after
Then 18 mesh sieves mix 3min and obtain intermediate.
3, tabletting, specification 0.1g answer tabletting weight 305mg, specification 75mg to answer tabletting weight 228.8mg.
4, it is coated, diclofenac sodium extended action tablet is made after being coated with Opadry.
Embodiment 4
Formula:
Preparation process:
1, C14H10Cl2NNaO2 1000g, kayexalate 282g, spermaceti 462.5g are accurately weighed, sucrose 1180g, ten
Sodium dialkyl sulfate 10g, superfine silica gel powder 26g, sucrose fatty ester 94g, Opadry 78.5g are spare.
2, C14H10Cl2NNaO2, kayexalate, sucrose, lauryl sodium sulfate, superfine silica gel powder is taken to be put into hot melt packet
It wraps up in granulator to mix 5 minutes, the heating that heats up then is added after spermaceti continuess to mix 3 minutes, it is 55-62 DEG C of temperature controlling range, high
Fast shear agitation 8-18 minutes, spheroidal particle is formed after carrying out hot melt package, then 20 mesh sieve, after 18 after cooling
Mesh sieve, and sucrose fatty ester is added, it then mixes 8min and obtains intermediate.
3, tabletting, specification 0.1g answer tabletting weight 305.7mg, specification 75mg to answer tabletting weight 229.3mg.
4, it is coated, diclofenac sodium extended action tablet is made after being coated with Opadry.
Embodiment 5
Formula:
Preparation process:
1, C14H10Cl2NNaO2 1000g, polacrilin potassium 461.5g, spermaceti 312.5g, sucrose 1084g, poly- second are accurately weighed
Alkene pyrrolidone 115g, superfine silica gel powder 45g, magnesium stearate 32g, Opadry 75g are spare.
2, C14H10Cl2NNaO2, polacrilin potassium, sucrose, polyvinylpyrrolidone, superfine silica gel powder is taken to be put into hot melt package system
Grain machine mixes 5 minutes, and the heating that heats up then is added after spermaceti continuess to mix 3 minutes, 55-62 DEG C of temperature controlling range, cuts at a high speed
Stirring 5-16 minutes is cut, spheroidal particle is formed after carrying out hot melt package, then 20 mesh sieve, after 18 meshes after cooling
Whole grain, mix lubricant 10min is then added obtains mesosome.
3, tabletting, specification 0.1g answer tabletting weight 305mg, specification 75mg to answer tabletting weight 228.8mg.
4, it is coated, diclofenac sodium extended action tablet is made after being coated with Opadry.
Embodiment 6
Formula:
Preparation process:
1, C14H10Cl2NNaO2 1000g, polacrilin potassium 526g, glycerin monostearate 781.5g, sucrose are accurately weighed
422g, polyvinylpyrrolidone 225.5g, superfine silica gel powder 40g, magnesium stearate 55g, Opadry 75g are spare.
2, it takes C14H10Cl2NNaO2, sucrose, polyvinylpyrrolidone, superfine silica gel powder to be put into hot melt package granulator and mixes 5 points
Clock, then plus D glycerin monostearate continues to mix 3 minutes after heat up heating, 55-62 DEG C of temperature controlling range, high speed shear
Stirring 5-16 minutes forms spheroidal particle after carrying out hot melt package, and then 20 mesh sieve, whole after 18 meshes after cooling
Then mix lubricant 10min is added up to mesosome in grain.
3, tabletting, specification 0.1g answer tabletting weight 305mg, specification 75mg to answer tabletting weight 228.8mg.
4, it is coated, diclofenac sodium extended action tablet is made after being coated with Opadry.
Embodiment 7
Formula:
Preparation process:
1, C14H10Cl2NNaO2 1000g, kayexalate 320g, hexadecanol 510g, sucrose 1045g are accurately weighed, is gathered
Vinylpyrrolidone 105g, superfine silica gel powder 35g, magnesium stearate 33g, Opadry 76g are spare.
2, C14H10Cl2NNaO2, kayexalate are taken, sucrose, polyvinylpyrrolidone, superfine silica gel powder are put into hot melt packet
It wraps up in granulator to mix 5 minutes, is then added after hexadecanol continuess to mix 3 minutes to heat up and heat, 55-62 DEG C of temperature controlling range,
High shear agitation 5-16 minutes, carry out forming spheroidal particle after hot melt package, then 20 mesh sieve, after cooling after
Then mix lubricant 10min is added up to mesosome in 18 mesh sieves.
3, tabletting, specification 0.1g answer tabletting weight 305mg, specification 75mg to answer tabletting weight 228.8mg.
4, it is coated, diclofenac sodium extended action tablet is made after being coated with Opadry.
The inspection of the diclofenac sodium extended action tablet provided by the invention of embodiment 8
1, related substance
The finely ground powder for the diclofenac sodium extended action tablet for taking embodiment 1 to the embodiment 7 under content determination item to prepare is appropriate (about
It is equivalent to C14H10Cl2NNaO2 0.1g), it is accurately weighed, it sets in 100ml measuring bottle, adds methanol appropriate, make within sonic oscillation 10 minutes double chlorine
Fragrant acid sodium dissolution, lets cool, with methanol dilution to scale, shakes up, be centrifuged, take supernatant as test solution；
Diethyl phthalate 5mg separately is taken, sets in 200ml measuring bottle, methanol is added to make to dissolve, test solution is added in precision
1ml is shaken up with methanol dilution to scale, as contrast solution.
It is measured according to high performance liquid chromatography (two V D of annex of Chinese Pharmacopoeia version in 2010).With octadecylsilylated key
Conjunction silica gel is filler, with -4% glacial acetic acid solution of methanol (65:35) for mobile phase；Detection wavelength is 254nm.
It takes C14H10Cl2NNaO2 reference substance appropriate, the solution in every 1ml containing about 1mg is made with water, the solution is taken to be exposed to purple
Irradiated 15 minutes under outer smooth lamp (254nm), take 20 μ l, inject liquid chromatograph, record chromatogram, with C14H10Cl2NNaO2 peak phase
To occurring an impurity peaks at retention time about 0.8, the separating degree between impurity peaks and C14H10Cl2NNaO2 peak should be not less than 6.0, reason
5000 should be not less than by calculating by plate number by C14H10Cl2NNaO2 peak.
20 μ l of contrast solution is taken, liquid chromatograph is injected, adjusts detection sensitivity, makes the about full amount of C14H10Cl2NNaO2 peak height
The 20% of journey；It is accurate again to measure test solution, each 20 μ l of contrast solution, it is injected separately into liquid chromatograph, record chromatogram is extremely
2 times of main peak retention time, if any impurity peaks in test solution, chromatographic peak except diethyl phthalate and its before
Outside, the peak (impurity III) for being 1.2~1.3 if any relative retention time, peak area are not greater than contrast solution multiplied by after 0.5
Main peak area (0.5%), other single impurity peak areas are not greater than contrast solution main peak area (0.5%), each impurity peaks face
Long-pending and (impurity III is based on the peak area after correction) is not greater than 2 times (1.0%) of contrast solution main peak area.Test solution
Any peak less than 0.1 times of contrast solution main peak area is negligible in chromatogram.
2, release
The diclofenac sodium extended action tablet that Example 1 is prepared to embodiment 7, according to drug release determination method (Chinese Pharmacopoeia 2010
Two annex of year version, Ⅹ the first method of D), using dissolution method (two annex of Chinese Pharmacopoeia version in 2010, Ⅹ the first method of C)
Device, using water (or other media) 900ml as dissolution medium, revolving speed is 100 turns per minute, is operated according to methods, through 2 hours, it is 4 small
When, 8 hours, take solution 10ml respectively, and mutually synthermal, same volume dissolution medium is replenished in time, filter, precision measures continuous
Filtrate 2ml sets in 10ml measuring bottle, is diluted with water to scale, shakes up, according to UV-VIS spectrophotometry (Chinese Pharmacopoeia 2010
Year two IV A of annex of version), absorbance is measured respectively at the wavelength of 276nm；Separately take C14H10Cl2NNaO2 reference substance appropriate, it is accurate
Weighed, being dissolved in water and quantifying dilution is made in every 1ml containing about the solution of 15 μ g, is measured in the same method.Every is calculated separately in difference
The burst size of time.This product every 2 hours, 4 hours with 8 hours burst sizes should be respectively labelled amount 30%~55%,
50%~80% and 80% or more, regulation should all be met.
Release Dependence Results are shown in Table 1~table 4.
The present invention and the former dissolution curve measurement result for grinding sample in 1 pH7.0 purified water of table
Sustained release tablets of the present invention and the former dissolution curve measurement result for grinding sample in 2 pH7.4 phosphate buffer solution of table
The present invention and the former dissolution curve measurement result for grinding sample in 3 pH4.5 acetate buffer solution of table
The present invention and the former dissolution curve measurement result for grinding sample in 4 pH1.0 hydrochloric acid solution of table
Conclusion: diclofenac sodium extended action tablet prepared by the present invention is in pH1.0 hydrochloric acid solution, pH7.0 purified water, pH7.4
Phosphate buffer and pH4.5 acetate buffer carry out release profiles comparison: diclofenac sodium extended action tablet is molten in pH1.0 hydrochloric acid
It is not discharged substantially in liquid, pH4.5 acetate buffer, intense irritation will not be generated to stomach；In pH7.0 purified water, pH7.4
Phosphate buffer release 2 hours should all meet regulation ratio with 8 hours burst sizes, while discharge at 16-20 hours for 4 hours
Amount meets the requirement of sustained release preparation close to 100%.
3, assay is measured according to high performance liquid chromatography (two V D of annex of Chinese Pharmacopoeia version in 2010).
Chromatographic condition and system suitability are filler with octadecylsilylated bonded silica gel, with -4% ice of methanol
Acetum (70:30) is mobile phase, Detection wavelength 276nm.It takes C14H10Cl2NNaO2 reference substance appropriate, every 1ml is made with water
In solution containing about 1mg, take the solution to be exposed under ultraviolet lamp (254nm) and irradiate 15 minutes, take 20 μ l, inject liquid phase color
Spectrometer records chromatogram, with C14H10Cl2NNaO2 peak relative retention time about 0.8 at there are an impurity peaks, impurity peaks and double chlorine
Separating degree between fragrant acid sodium peak should be not less than 4.0.
Prepare diclofenac sodium extended action tablet 20 of measuring method Example 1 to embodiment 7, it is accurately weighed, it is finely ground, it is accurate
It is appropriate (being approximately equivalent to C14H10Cl2NNaO2 50mg) to weigh fine powder, sets in 200ml measuring bottle, adds 70% methanol solution appropriate, ultrasound vibration
It swings 15 minutes, lets cool, with 70% methanol dilution to scale, mix, filtration takes subsequent filtrate as test solution.Precision measures
10 μ l inject liquid chromatograph, record chromatogram.Separately take C14H10Cl2NNaO2 reference substance appropriate, it is accurately weighed, add 70% methanol molten
The solution for diluting and being made in every 1ml containing 0.25mg is solved and quantified, is measured in the same method.By external standard method with calculated by peak area to get.
4, accelerated test:
Diclofenac sodium extended action tablet sample made from the embodiment of the present invention 1 to 7 is taken, is placed in stabilization by commercially available back (plastic-aluminum)
Property tester, is placed 6 months under conditions of 40 ± 2 DEG C of temperature, relative humidity 75 ± 5%.After setting-out the 1st, 2,
3, it samples within 6 months, measures the character, release, related substance, content of sample in accordance with the law, be compared with the result of 0 day sample.
Test result is shown in Table 5.
5 diclofenac sodium extended action tablet accelerated test result (40 ± 2 DEG C, RH75 ± 5%) of table
5, keep sample test for a long time:
Diclofenac sodium extended action tablet made from the embodiment of the present invention 1 to 7 is taken, by commercially available back (plastic-aluminum) in temperature 25 ± 2
DEG C, under conditions of relative humidity RH60 ± 10%, respectively at the 0th, 3,6,9,12 month sample, in accordance with the law measure sample character,
Release, related substance, content, are compared with the result of 0 day sample.Long-term test results are shown in Table 6 within 12 months.
6 diclofenac sodium extended action tablet long-term test results of table (25 ± 2 DEG C, RH60 ± 5%)
It is above-mentioned the results showed that diclofenac sodium extended action tablet prepared by the present invention was in 6 months accelerated tests and 12 months
The indices that long term test measures meet regulation and 0 day result compares, and character, related substance, content, release etc. are
No significant difference (P > 0.05).
9 comparative test of embodiment
1, the comparative analysis of production efficiency
2, the comparative analysis of side effect
The side effect of stomach caused by C14H10Cl2NNaO2, respiratory tract, eye mucosa is that drug nature determines, skill of the present invention
Diclofenac sodium extended action tablet made of art can be substantially reduced its gastric irritation side effect, can also avoid C14H10Cl2NNaO2 dust pair
The ill-effects such as the intense stimulus of respiratory tract, eyes that producers generate, are conducive to the physical and mental health of operator, also favorably
In the protection of environment.
Diclofenac sodium extended action tablet made of the technology of the present invention can reduce medicining times, easy to use, improve clothes for patients
The compliance of medicine, especially suitable for needing the patients with chronic diseases of medication for a long time；Simultaneously blood concentration can be made steady, avoid or
Adverse drug reaction is reduced, effective treatment to disease is more advantageous to.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (5)
1. a kind of diclofenac sodium extended action tablet, which is characterized in that be grouped as by the group of following mass parts:
Preparation method are as follows: after taking C14H10Cl2NNaO2, framework material, adhesive, filler mixing, be heated to 45~65 DEG C, height
Fast 5~25min of shear agitation carries out hot melt package, forms spheroidal particle, whole grain of being then sieved, with mix lubricant 5~
After 15min, tabletting, coating obtain diclofenac sodium extended action tablet；
Described adhesive is wax material；The wax material is glycerin monostearate, hexadecanol, spermaceti, hydrogenated vegetable oil
One or both of more than mixture；
The framework material is the ion of one or both of kayexalate, polacrilin potassium, polacrilin or more
Exchanger resin mixture.
2. diclofenac sodium extended action tablet according to claim 1, which is characterized in that the filler be hydroxypropul starch,
Mixture more than one or both of sucrose, lauryl sodium sulfate, superfine silica gel powder, polyvinylpyrrolidone.
3. diclofenac sodium extended action tablet according to claim 2, which is characterized in that the lubricant is magnesium stearate, sugarcane
The mixture of one or both of sugar fatty acid ester.
4. diclofenac sodium extended action tablet according to claim 3, which is characterized in that the coating agent is Opadry.
5. diclofenac sodium extended action tablet according to claim 4, which is characterized in that being sieved described in preparation method was
20 meshes, after 18 meshes after cooling.
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