CN104188951B - A kind of diacetyl rhein compositions and preparation method thereof - Google Patents
A kind of diacetyl rhein compositions and preparation method thereof Download PDFInfo
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- CN104188951B CN104188951B CN201410476377.4A CN201410476377A CN104188951B CN 104188951 B CN104188951 B CN 104188951B CN 201410476377 A CN201410476377 A CN 201410476377A CN 104188951 B CN104188951 B CN 104188951B
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Abstract
The invention provides a kind of diacetyl rhein compositions and preparation method thereof.Described diacetyl rhein compositions, it is characterized in that, be made up of following raw material in parts by weight: diacetyl rhein: 1 weight portion, poloxamer: 0.01 0.1 parts, sodium benzoate: 0.001 0.1 parts, filler: 0.3 6 parts, disintegrating agent: 0 0.5 parts, binding agent: 0.01 0.5 parts, wetting agent: 0 0.8 parts and lubricant: 0.01 0.5 parts.The present invention not only can increase the dissolubility of this medicine, improves the bioavailability of medicine, it is also possible to alleviates produced side effect after patient takes medicine.
Description
Technical field
The present invention relates to a kind of diacetyl rhein compositions and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Diacetyl rhein, chemical name 4,5-diacetyl-9,10-dihydro-9,10-dioxy-2-anthracene carboxylic acid, it is commonly called as double vinegar auspicious
Cause, in water, acid neutralize in common solvents insoluble, dissolve in dimethyl sulfoxide and DMF, meet alkali liquor and easily divide
Solve.Diacetyl rhein can induce Chondrogenesis, have pain relieving, antiinflammatory and antipyretic effect；There is suppression IL-1, matrix metal egg
White enzymes (MMP) etc. generate, and do not suppress prostaglandin to synthesize；Osteoarthritis is had the effect delaying disease process, is used for treating bone
Arthritis and relevant disease.Laxativeness is that application diacerein treats modal side reaction (incidence rate about 7%), typically can
Occur in initial several days after the treatment, in most cases automatically can disappear along with continual cure.The incidence rate of Upper abdominal pain
For 3-5%, n or V is then less than 1%.
Diacetyl rhein preparation the most on sale is mainly hard capsule, remaining adjuvant be mainly composed of breast
Sugar, cross-linking sodium carboxymethyl cellulose, PVP K30, silicon dioxide and magnesium stearate.For treating joint disease (osteoarthritis
And relevant disease).Diacetyl rhein is extremely difficult is dissolved in water and acid, therefore when oral administration, it is impossible to be completely absorbed, as allusion quotation
The NSAID (non-steroidal anti-inflammatory drug) of type, this medicine has certain gastrointestinal toxicity because not exclusively absorbing.Its modal side reaction is
Diarrhoea (incidence rate is about 7%), Upper abdominal pain, Nausea and vomiting, urine flavescence etc., have a strong impact on patient over the course for the treatment of
Enthusiasm.
Secondly, its metabolite chrysophanic acid pharmacokinetic parameter in human body of diacerein is predominantly: Drug-time curve
Lower area AUC(0-t)For (24927.7 ± 15869.8) μ g h L-1, area under the drug-time curve AUC(0-∞)For (25961.7 ±
16592.5)μg·h·L-1；Peak concentration of drug CmaxFor (4352.8 ± 2415.4) μ g h L-1；Peak time tmaxFor (2.3 ±
0.8)h；Terminal elimination half-life t1/2For (4.4 ± 0.9) h.Its drug release rate belongs to normality release, its peak time and half
Phase of declining is the shortest.It is the most insoluble in water, and peak time is shorter, and to directly result in this drug bioavailability low.
Various derivant, pharmaceutical composition and pharmaceutical preparation is had pointed out to improve diacetyl rhein in existing patent
Other insoluble in or be only slightly soluble in the character of medicine of water.EP-A-243,968 patent describes water miscible diacetyl Radix Et Rhizoma Rhei
Acid potassium salt, this salt can be used for preparing the compositions of parenteral administration.EP-A-598,337 patent describe include insoluble in or
Being only slightly soluble in the compositions of the active constituents of medicine of water, this active component is to mix in cross linked polymer, surfactant and oil,
This compositions can improve bioavailability.US-A-5,225,192 patents describe the method preparing fast dissolving pharmaceutical, the party
Method includes mixing in cross-linked polymer particle by medicine, and this polymer beads does not dissolves in but can swell in water, makes described medicine
Thing contacts with organic solvent, is then vacuum dried.Although said method improves the bioavailability of medicine, but does not alleviate
Patient's misery in side effect.
CN101032476A patent describes and diacetyl rhein is formed after certain process a kind of pharmacy shape
Acceptable salt in formula, uses dispersible carrier material and other adjuvants, prepares effectively one-tenth with solvent-fusion method or abrasive micropowder
Divide dispersion, then drop pill made by condensing agent, improve the bioavailability of medicine.CN102406635A patent describes two
The cyclodextrin of acetyl rhein compound and derivant and preparation method thereof, reduce the toxic and side effects of medicine, but above-mentioned side
Method operation complexity, requires higher to preparation technology in process of production, and production cost is higher, it is difficult to carry out the big life of industrialization
Produce.
Summary of the invention
It is an object of the invention to for above not enough, it is an object of the invention to provide a kind of diacetyl rhein compositions and
Its preparation method, not only can increase the dissolubility of this medicine, improves the bioavailability of medicine, it is also possible to alleviate after patient takes medicine
Produced side effect, solves problems of the prior art.
To achieve these goals, the invention provides a kind of diacetyl rhein compositions, it is characterised in that by following
Raw material in parts by weight is made:
Preferably, described filler is one or several in starch, lactose, dextrin, microcrystalline Cellulose and mannitol.
Preferably, described disintegrating agent is polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose and crosslinked carboxymethyl fecula sodium
In one or several.
Preferably, described binding agent is one or several in polyvinylpyrrolidone and sodium carboxymethyl cellulose.
Preferably, described wetting agent is one or several in distilled water and ethanol solution.
Preferably, described lubricant is magnesium stearate, silicon dioxide, PEG400, polyethylene glycol 6000 and Talcum
One or several in powder.
Present invention also offers the preparation method of above-mentioned diacetyl rhein compositions, it is characterised in that concrete steps
Including: weighing each raw material in proportion, the consumption of wherein said wetting agent is not 0, and part or all of solid material is crossed 80-
150 mesh sieves or do not sieve, join in other raw materials mixed by the mixture of wetting agent or wetting agent and binding agent, described
Other raw materials in do not comprise lubricant, soft material processed, cross 20-40 mesh sieve wet granulation, 40-80 DEG C is dried, after 20-60 mesh sieve
Granulate, adds lubricant, mixing；It is distributed into granule, loads and make capsule, or tablet made by tabletting.
Present invention also offers the preparation method of above-mentioned diacetyl rhein compositions, it is characterised in that concrete steps
Including: weighing each raw material in proportion, the consumption of wherein said wetting agent is not 0, and part or all of solid material is crossed 80-
150 mesh sieves or do not sieve, use fluid bed or fluid bed granulator or one-step-granulating method, by wetting agent or wetting agent and binding agent
Mixture joins in other raw materials mixed, and does not comprise lubricant, boiling granulating, air inlet temperature in other described raw materials
Spending 40 DEG C-80 DEG C, be dried after granulation, sieve granulate, adds lubricant, mixing；It is distributed into granule, loads and make capsule,
Or tabletting makes tablet.
Present invention also offers the preparation method of above-mentioned diacetyl rhein compositions, it is characterised in that concrete steps
Including: weighing each raw material in proportion, the consumption of wherein said wetting agent is 0, and part or all of solid material is crossed 80-150
Mesh sieve or do not sieve, by all raw material mix homogeneously；Dry granulating machine is used directly to pelletize in the mixture of gained, after granulate,
It is distributed into granule, loads and make capsule, or directly use compressing dry granulation machine to be pressed into tablet in the mixture of gained.
Compared with prior art, the invention has the beneficial effects as follows:
Compositions prepared by the present invention with sell in the market compared with types of drug, the molten of medicine can be significantly improved
Out-degree, reduces the intestinal degradation of diacetyl rhein, increases the transmembrane transport of diacetyl rhein, alleviates the stomach after patient takes medicine
Gastrointestinal toxicity, Clinical practice obtains good result, especially can reduce diarrhoea and occur..Its purposes is: be used for suppressing IL-1,
Matrix metalloproteinases (MMP) etc. generate, and promote transforming growth factor (TGF)-β and cartilage synthesis.
The present invention obtained diacetyl rhein compositions, no matter the side effect after dissolution or patient's medication is anti-
Feedback display, all than on market, existing preparation has raising in various degree.From analysis of dissolution, reach dissolution in 5 minutes
More than 90%, and the diacerein capsule of import only has about 70% dissolution in 5 minutes, just reaches more than 90% after 10 minutes.
Equally, comparing the side effect after patient takes medicine, on market, for diarrhoea, (incidence rate is about its modal side reaction of existing preparation
7%), the incidence rate of Upper abdominal pain is the phenomenon that 3-5%, n or V are then less than 1%, have urine to turn yellow once in a while；And diethyl
Acyl chrysophanic acid compositions is after being taken by volunteer, and the incidence rate of its diarrhoea and Upper abdominal pain is only 1%, almost or does not slightly have
The phenomenons such as Nausea and vomiting and urine flavescence.As can be seen here, the diacetyl rhein compositions of the present invention and commercially available diacerein glue
Capsule is compared, and dissolution is significantly improved, it is easier to enters people's body-internal-circulation, and significantly reduces the gastrointestinal tract poison of patient after taking
Property, bring Gospel to patient, have obviously clinical advantage.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.In addition, it is to be understood that after having read the content that the present invention lectures, people in the art
The present invention can be made various changes or modifications by member, and these equivalent form of values fall within the application appended claims equally and limited
Scope.
Embodiment 1
A kind of diacetyl rhein compositions, is made up of following raw material in parts by weight:
Its preparation method is: weigh each raw material in proportion, and each solid material is crossed 100 mesh sieves, takes diacetyl rhein, pool
Luo Shamu, sodium benzoate, lactose, polyvinylpolypyrrolidone, polyvinylpyrrolidone, silicon dioxide mix homogeneously, be then poured into grooved
In mixer, stirring is simultaneously introduced purified water, soft material processed, crosses 40 mesh sieves and pelletizes, be dried 2 hours by granule 60 DEG C subsequently, takes out
Let cool after granule to room temperature, cross 40 mesh sieve granulate, carry out granule by the magnesium stearate of the granule calculating addition 1% after granulate total
Mixed, the granule after finally always mixing carries out capsule filling, bubble-cap, packaging, makes capsule.
Embodiment 2
A kind of diacetyl rhein compositions, is made up of following raw material in parts by weight:
Its preparation method is:
Weighing each raw material in proportion, sieve respectively 80 mesh by diacetyl rhein, poloxamer, sodium benzoate.By poly-second
Alkene pyrrolidone is dissolved in the ethanol solution of 10%.Use fluid bed granulator, by diacetyl rhein, poloxamer, benzene first
Acid sodium, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose are put in fluid bed granulator and are mixed, and open blower fan, intake air temperature control
10% ethanol solution of polyvinylpyrrolidone, at 70 DEG C, is sprayed into boiling granulating in fluid bed granulator by system, 60 DEG C of dry 2h,
Grain crosses 60 mesh sieves, adds PEG6000 mixing, fills capsule, packaging.
Embodiment 3
A kind of diacetyl rhein compositions, is made up of following raw material in parts by weight:
Weigh each raw material in proportion, above-mentioned material is directly mixed, directly use compressing dry granulation machine to be pressed into tablet, bubble
Cover, packaging.
Embodiment 4
A kind of diacetyl rhein compositions, is made up of following raw material in parts by weight:
Its preparation method is: weigh each raw material in proportion, and each solid material is crossed 100 mesh sieves, takes diacetyl rhein, pool
Luo Shamu, sodium benzoate, lactose, polyvinylpyrrolidone, silicon dioxide mix homogeneously, be then poured in trough type mixing machine, stir
Mix and be simultaneously introduced purified water, soft material processed, cross 40 mesh sieves and pelletize, subsequently granule 60 DEG C is dried 2 hours, take out let cool after granule to
Room temperature, crosses 40 mesh sieve granulate, carries out granule by the magnesium stearate of the granule calculating addition 1% after granulate and always mixes, finally will always mix
After granule carry out capsule filling, bubble-cap, packaging, make capsule.
For investigating the dissolution characteristic of diacetyl rhein compositions prepared by the present invention, embodiment 1-4 is obtained by the present invention
Diacetyl rhein hard capsule and tablet, as follows with commercial preparation dissolution study comparing result:
Dissolution determination method:
Take this product, with phosphate buffer (pH 7.0) 900ml as solvent, be 100 turns of stirrings per minute with rotating speed, in accordance with the law
Operation, through 30 minutes time, takes solution about 10ml, filters, and precision measures subsequent filtrate 5ml, puts in 50ml measuring bottle, adds phosphate-buffered
Liquid (pH 7.0) is diluted to scale, shakes up.According to spectrophotography (annex IVA), at the wavelength of 259nm, measure trap.Separately
Take appropriate commercially available diacerein preparation as reference substance, make every 1ml containing about diacerein 5 with phosphate buffer (pH 7.0)
The solution of μ g, as reference substance solution, is measured in the same method, and calculates the stripping quantity of every.
Dissolution results is shown in Table 1
Three kinds of compositionss of table 1 preparation contrast with the dissolution of commercial preparation
Result shows, compositions prepared by the present invention in 20min dissolution all more than 80%, the soonest, and molten at 30min
Out-degree is all more than 90%, but consistent with the stripping curve of commercial preparation, meets country's requirement to imitation medicine Conformance Assessment.
For investigating the bioavailability situation of diacetyl rhein compositions prepared by the present invention, the present invention selects 12 to be good for
Health volunteer, according to carrying out double-dummy design in random table, often organizes three people, and after single-dose, dosage is 50mg, when measuring different
Blood drug level under between, investigates pharmacokinetic parameter by compartment model simulation.The results are shown in Table 2:
Three kinds of compositionss of table 2 preparation contrast with the pharmacokinetic parameter of commercial preparation
Result shows, compositions area under the drug-time curve AUC prepared by the present invention(0-t) andCmax apparently higher than commercial preparation,
Half-life is also obviously prolonged.Compositions bioavailability prepared by the present invention relative to commercial preparation significantly improve 30% with
On, there is significant difference.
The safety that the diacetyl rhein compositions prepared for investigating the present invention uses, embodiment 1-3 is obtained by the present invention
The diacetyl rhein hard capsule arrived and tablet, carry out safety comparative study with commercial preparation.
Select some and meet the volunteer of regulation, often organize 20 people, after being respectively divided into 4 groups, take the medicine of corresponding group
Thing, takes medicine 3 weeks continuously, every day 1 time, each one (50mg/ grain), investigates and takes the impact on volunteer of this drug side effect.
The results are shown in Table 2.
Result shows, the side effect of compositions prepared by the present invention significantly reduces, and the compliance of volunteer significantly improves.
By the enforcement of the present invention, improve the internal dissolubility of diacetyl rhein, increase and absorb, improve biological profit
Expenditure, decreases its gastrointestinal side effect, has good clinical effectiveness.
Claims (9)
1. a diacetyl rhein compositions, it is characterised in that be made up of following raw material in parts by weight:
。
2. diacetyl rhein compositions as claimed in claim 1, it is characterised in that described filler be starch, lactose,
One or several in dextrin, microcrystalline Cellulose and mannitol.
3. diacetyl rhein compositions as claimed in claim 1, it is characterised in that described disintegrating agent is the poly-dimension of crosslinking
One or several in ketone, cross-linking sodium carboxymethyl cellulose and crosslinked carboxymethyl fecula sodium.
4. diacetyl rhein compositions as claimed in claim 1, it is characterised in that described binding agent is polyvinyl pyrrole
One or several in alkanone and sodium carboxymethyl cellulose.
5. diacetyl rhein compositions as claimed in claim 1, it is characterised in that described wetting agent is distilled water and second
One or several in alcoholic solution.
6. diacetyl rhein compositions as claimed in claim 1, it is characterised in that described lubricant be magnesium stearate,
One or several in silicon dioxide, PEG400, polyethylene glycol 6000 and Pulvis Talci.
7. the preparation method of the diacetyl rhein compositions according to any one of claim 1-6, it is characterised in that specifically walk
Suddenly including: weigh each raw material in proportion, the consumption of wherein said wetting agent is not 0, and part or all of solid material is crossed 80-
150 mesh sieves or do not sieve, join in other raw materials mixed by the mixture of wetting agent or wetting agent and binding agent, described
Other raw materials in do not comprise lubricant, soft material processed, cross 20-40 mesh sieve wet granulation, 40-80 DEG C is dried, after 20-60 mesh sieve
Granulate, adds lubricant, mixing；It is distributed into granule, loads and make capsule, or tablet made by tabletting.
8. the preparation method of the diacetyl rhein compositions according to any one of claim 1-6, it is characterised in that specifically walk
Suddenly including: weigh each raw material in proportion, the consumption of wherein said wetting agent is not 0, and part or all of solid material is crossed 80-
150 mesh sieves or do not sieve, use fluid bed or fluid bed granulator or one-step-granulating method, by wetting agent or wetting agent and binding agent
Mixture joins in other raw materials mixed, and does not comprise lubricant, boiling granulating, air inlet temperature in other described raw materials
Spending 40-80 DEG C, be dried, 50-70 DEG C of dry 0.5-2h after granulation, sieve granulate, adds lubricant, mixing；It is distributed into granule,
Capsule is made in filling, or tablet made by tabletting.
9. the preparation method of the diacetyl rhein compositions according to any one of claim 1-6, it is characterised in that specifically walk
Suddenly including: weigh each raw material in proportion, the consumption of wherein said wetting agent is 0, and part or all of solid material is crossed 80-
150 mesh sieves or do not sieve, by all raw material mix homogeneously；Dry granulating machine is used directly to pelletize in the mixture of gained, granulate
After, it is distributed into granule, loads and make capsule, or directly use compressing dry granulation machine to be pressed into tablet in the mixture of gained.
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| CN105012247A (en) * | 2015-08-21 | 2015-11-04 | 上海慈瑞医药科技有限公司 | Diacerein composition and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101015541A (en) * | 2007-02-25 | 2007-08-15 | 上海慈瑞医药科技有限公司 | Diacetyl rhein dropping pills and its preparing process |
| CN101032476A (en) * | 2006-03-10 | 2007-09-12 | 刘德海 | Medical combination including rhein or diacetylrhein and the preparing method thereof |
| WO2009118589A2 (en) * | 2008-03-24 | 2009-10-01 | Wockhardt Research Centre | Orally disintegrating compositions of rhein or diacerein |
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2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032476A (en) * | 2006-03-10 | 2007-09-12 | 刘德海 | Medical combination including rhein or diacetylrhein and the preparing method thereof |
| CN101015541A (en) * | 2007-02-25 | 2007-08-15 | 上海慈瑞医药科技有限公司 | Diacetyl rhein dropping pills and its preparing process |
| WO2009118589A2 (en) * | 2008-03-24 | 2009-10-01 | Wockhardt Research Centre | Orally disintegrating compositions of rhein or diacerein |
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Address after: 200240 Shanghai city Minhang District Jianchuan Road No. 951 Building 5 floor 2 Room 203 Patentee after: Shanghai pharmaceutical Polytron Technologies Inc Address before: 200240 Shanghai city Minhang District Jianchuan Road No. 951 Building 5 floor 2 Room 203 Patentee before: Shanghai Cirui Pharmaceutical Sci. & Tech. Co., Ltd. |