CN1712041A - Chinese medicial powder injection for treating arthritis and preparation thereof - Google Patents
Chinese medicial powder injection for treating arthritis and preparation thereof Download PDFInfo
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- CN1712041A CN1712041A CN 200410049948 CN200410049948A CN1712041A CN 1712041 A CN1712041 A CN 1712041A CN 200410049948 CN200410049948 CN 200410049948 CN 200410049948 A CN200410049948 A CN 200410049948A CN 1712041 A CN1712041 A CN 1712041A
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- injectable powder
- radix
- rhizoma rhei
- injection
- chrysophanic acid
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Abstract
A Chinese medicine in the form of powder injection for treating arthritis is prepared from the water-insoluble chrysophanic acid through chemical modifying to become water-soluble one and freeze drying.
Description
Technical field
The present invention relates to a kind of Chinese medicine pharmaceutical formulation.Specifically, the present invention relates to the Radix Et Rhizoma Rhei hydrochlorate is the injectable powder of active component, is used for the treatment of arthritis, comprises osteoarthritis, rheumatism and rheumatoid arthritis.
Background technology
Osteoarthritis, rheumatic arthritis and rheumatoid arthritis are the higher joint diseases of sickness rate, with the former is example, sickness rate is about 10% of total population, to the patient more than 60 years old, have the patient more than 50% to be affected, to the women below 45 years old, the sickness rate of 45 years old to 60 years old and over-65s is respectively 2%, 30% and 68%; Then be respectively 3%, 24.5% and 58% for the male.Along with aged tendency of population, the ratio that morbidity population accounts for total population will get more and more.
The medicine of treatment osteoarthritis mainly contains steroidal class and non-steroidal anti-inflammatory drug at present. and the untoward reaction of steroidal anti-inflammatory drugs is known by people.Also there are a lot of untoward reaction in cyclooxygenase-2 inhibitors in the nonsteroidal antiinflammatory drug (COX), can cause digestive tract hemorrhage as oral and injection, and especially the old people more is easy to generate untoward reaction, and this is very disadvantageous for the old disease occurred frequently of this class of osteoarthritis.
Chrysophanic acid is a kind of dissociated anthraquinone chemical compound that extracts from comprise plants such as Chinese herb rhubarb, and its structural formula is:
Its chemical name is 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-2-anthracene carboxylic acid.Chrysophanic acid also can obtain by synthetic method, and this chemical compound is water-soluble hardly.
Patent IT1098332 has announced that chrysophanic acid and diacetyl rhein have the activity of treatment of arthritis as a kind of interleukin (IL)-1 inhibitor.But in patent IT1098332, chrysophanic acid is not proposed the treatment that is applied to osteoarthritis, thinks that it has adsorption to goldbeater's skin, thinks that in addition chrysophanic acid has the diarrhoea effect, and the suggestion derivant-diacetyl rhein of chrysophanic acid.But studies show that the main adverse reaction of oral diacetyl rhein still is diarrhoea, incidence rate is 29.7%.And think that the Radix Et Rhizoma Rhei series products causes diarrhoea and melena, may be relevant with intestinal cancer.So the necessary new preparation that to avoid such untoward reaction of producing.People have done a large amount of effort for this reason.
In order to reduce with the chrysophanic acid diarrhoea untoward reaction of the oral formulations that is raw material, patent US6124358 discloses a kind of method that improves oral chrysophanic acid and diacetyl rhein bioavailability by the raw material micronization; EP0809995 discloses a kind of gel preparation of chrysophanic acid to reduce the method that the diarrheal order of severity takes place and lowers diarrheal.But above patent disclosure all is oral formulations, is difficult to avoid fully suffering from diarrhoea this untoward reaction.
Patent EP0243968 discloses water miscible diacetyl rhein salt, and this chemical compound can be used as articular cavity inner injecting and administering preparations, but the manufacturing cost of diacetyl rhein salt is 3 times of the Radix Et Rhizoma Rhei hydrochlorate, has increased financial burden to the patient.
At present, also not disclosing any both at home and abroad is the injection of the treatment of arthritis of main component with the Radix Et Rhizoma Rhei hydrochlorate.
Goal of the invention:
Because chrysophanic acid can directly extract from some Chinese herbal medicine and obtain, low price, in order to overcome the problem of untoward reaction such as the chrysophanic acid oral administration caused in the prior art diarrhoea, melena, the inventor is through research, successfully having prepared with the Radix Et Rhizoma Rhei hydrochlorate is arthritic injectable powder of being used for the treatment of of active component, keeping under the prerequisite of curative effect, significantly reducing production costs and suffer from diarrhoea incidence rate of adverse reaction.
Summary of the invention:
The invention provides a kind of injectable powder of treatment of arthritis, it is characterized by with the Radix Et Rhizoma Rhei hydrochlorate as active component.The acceptable salt of physiology that Radix Et Rhizoma Rhei hydrochlorate according to the present invention is a chrysophanic acid.Wherein in a kind of scheme, the Radix Et Rhizoma Rhei hydrochlorate can be represented with following structural formula:
Wherein M represents alkali metal, alkaline-earth metal, or other organic base residue.
M represents Na in than specific embodiment, K, Ca, Mg etc.
The present invention is a kind of injectable powder that contains the Radix Et Rhizoma Rhei hydrochlorate, and it is by the Radix Et Rhizoma Rhei hydrochlorate, the PH regulator, and antioxidant and sterile water for injection are made through lyophilization.
The preparation method of Radix Et Rhizoma Rhei hydrochlorate injectable powder is specific as follows: (1) joins a certain amount of Radix Et Rhizoma Rhei hydrochlorate in the sterile water for injection and (uses CO
2Saturated in advance), the solution (2) that forms 0.5-6.0% is got antioxidant (0.1-0.2%) in addition, uses CO
2Saturated water for injection dissolving, add in the above-mentioned solution, with the pH value regulator regulate pH value (3) between 6.0-8.5 add to the full amount of water for injection (4) add the pin activated carbon of 0.02%-0.1%, fully stir, spread two-layer sterilization filter paper filtering with aseptic suction funnel, after G6 sintered filter funnel fine straining (5) the filtrate passed examination of reuse through sterilizing, packing, aseptic sealing by fusing both gets behind frozen drying.
Injectable powder of the present invention also can directly be regulated pH value to 6.0-8.5 with chrysophanic acid through the pH value regulator, makes whole dissolvings, according to the formulation method of routine, makes freeze-dried powder then.In the method, preferably pH value is adjusted to 7.5-8.5.
Arthritis phalangeal osteoarthritis, rheumatoid arthritis and rheumatic arthritis of the present invention.The Radix Et Rhizoma Rhei hydrochlorate injectable powder of treatment of arthritis of the present invention is particularly suitable for treating osteoarthritis.
The Radix Et Rhizoma Rhei hydrochlorate injectable powder of treatment of arthritis of the present invention can be used for intramuscular injection, intravenous injection, articular cavity local injection.
In one embodiment, be used for the each 10-50 milligram of muscle or intravenous injection Radix Et Rhizoma Rhei hydrochlorate, every day 1-3 time; Be used for intra-articular injection, weekly, each 20-40 milligram Radix Et Rhizoma Rhei hydrochlorate, continuous 5 weeks.
In a preferred embodiment, be used for the each 20 milligrams of chrysophanic acid sodium of muscle or intravenous injection, every day secondary; Be used for intra-articular injection, weekly, each 20 milligrams of chrysophanic acid sodium, continuous 5 weeks.
Employed antioxidant can be vitamin C in preparation, sodium sulfite, cysteine etc.The pH value regulator can use NaOH, acetic acid, Na
2CO
3, and the commonly used PH regulator in other this area etc.And in preparation, also can use the adjuvant of other this area preparation injectable powder commonly used.
Chrysophanic acid can obtain by chemical method is synthetic, also can be by the plant extract that contains chrysophanic acid is obtained, and as the chrysophanic acid that extracts in the Radix Et Rhizoma Rhei as supply of commodities, its purity is more than 98%, the tannin passed examination.
The acceptable salt of physiology that Radix Et Rhizoma Rhei hydrochlorate of the present invention is a chrysophanic acid.The acceptable salt of the physiology of chrysophanic acid can be the salt of chrysophanic acid and alkali, for example slaine, ammonium salt or organic base addition salts.Preferred example is alkali metal salt (for example sodium salt or a potassium salt), alkali salt (for example magnesium salt or calcium salt), ammonium salt, and organic amine salt, ethylamine salt for example, two-or triethylamine salt, ethyl diisopropyl amine salt, monoethanolamine salt, two-or triethanolamine salt, dicyclohexyl amine salt, dimethylaminoethanol salt, the dibenzyl amine salt, pyridiniujm, N-methylmorpholine salt, dihydro Colophonium amine salt, methyl piperidine salt, ethylenediamine salt or 2-phenethylamine salt etc., and basic amino acid salt, arginine salt for example, lysinate etc.
Radix Et Rhizoma Rhei hydrochlorate of the present invention can be prepared as follows: the aqueous suspension of chrysophanic acid is neutralized to pH value between 7.5-8.5 with NaOH solution, makes dissolving, add acetone and other organic solvent then or by distilling under reduced pressure the Radix Et Rhizoma Rhei hydrochlorate is precipitated out from system in system.Can be by filtering above precipitation and the product drying being obtained corresponding salt.Or chrysophanic acid salt is not separated directly make injection from system.
Radix Et Rhizoma Rhei hydrochlorate of the present invention can also be prepared as follows: in the solution water-soluble and that form with the miscible organic solvent of water, organic solvent can be acetone, dioxane, dimethyl formamide and dimethyl acetylamide with chrysophanic acid.The content of water is in 3-30% (volume ratio) in the mixed solution.
Add the organic base of amount of calculation in above formed solution, organic base can be the tertiary amine organic base, preferred triethylamine, and the volume of adding is added 10-30% than amount of calculation.The temperature of above process should be controlled at 15 ℃--and 20 ℃.
With organic alkali salt of the chrysophanic acid of above formation and salt-forming reagent reaction, form the corresponding salt of chrysophanic acid.The cation of salt-forming reagent can be alkali metal such as Na and K, alkaline-earth metal such as Ca, Mg; The acid group part can be the acid group such as the 2 ethyl hexanoic acid of weak organic acid or mineral acid, carbonic acid etc.The salt-forming reagent that adds should be than stoichiometric excessive 10-15%, and should be dissolved in suitable can with the miscible organic solvent of water in.Can realize by following method as chrysophanic acid sodium precipitation: will be dissolved in the isobutanol of acetone diluted more than the 2 ethyl hexanoic acid sodium of stoichiometric 10-15%, and join then in the formed organic base solution, just product slowly is precipitated out from system.Other salt such as potassium, calcium, magnesium salt also can prepare according to the method described above.
The present invention has following characteristics:
The present invention is transformed into the Radix Et Rhizoma Rhei hydrochlorate that is dissolved in water to water-fast chrysophanic acid, and is made into injectable powder, has overcome the diarrhoea untoward reaction that oral formulations exists in the prior art.
Preliminary test on human body proves, it is compared with the method that patent EP0243968 announces on the unaffected substantially basis of curative effect, has reduced cost of material significantly, if take all factors into consideration from cost of material and dosage two aspects, expense of raw materials required for the present invention is with 1/5 of class methods approximately.
Compare with patent IT1098332 disclosed method, reduced untoward reaction-diarrheal incidence rate.And clinical total effective rate is 80%.Compare with the diacetyl rhein injection basic identical (80-85%).Also basic identical with the curative effect (72-83.3%) of oral diacetyl rhein.
Injectable powder physicochemical property of the present invention is stable, can carry out suitability for industrialized production and long-term between store.And cost of material is low, can alleviate patient's financial burden.
Below in conjunction with embodiment the present invention is described in detail.
Embodiment:
Embodiment 1
15.4 gram chrysophanic acids are put into 170 milliliters of acetone, form suspension, add 20 ml waters then, stir and made abundant dissolving in 15 minutes.9 milliliters of triethylamines are joined in 100 milliliters of acetone, formed solution is joined in the above-mentioned solution, the temperature that keeps course of reaction is at 15 ℃--in 20 ℃ the scope.Obtain settled solution.
The 2 ethyl hexanoic acid sodium isobutanol solution of 70 milliliters of 1M is slowly joined in the above-mentioned solution, approximately finish with interpolation in 90 minutes.And use 100 acetone diluted.Continue to stir after 30 minutes, filtering mixt, and use washing with acetone is under vacuum condition, in 40 ℃ of dryings 12 hours.Obtain 16 gram chrysophanic acid sodium salts.
Analytical data: molecular formula C
15H
7O
6Na, molecular weight 306.20
Theoretical value %:C 58.83%H 2.30%Na7.51%
Test value %:C 58.79%H 2.32Na7.54%
Embodiment 2
100 gram chrysophanic acids are put into 1500 ml waters form suspension A, 16 gram NaOH are added in 300 ml waters, form solution B, B is slowly added among the A, stir the back distilling under reduced pressure, filtration is left standstill in cooling.Use washing with acetone, obtain 85 gram chrysophanic acid sodium.
Embodiment 3
11.36 gram chrysophanic acids are joined in the mixed solution of 14.8ml water and the formation of 220ml acetone, form suspension.In this suspension, add the 6.64ml triethylamine, obtain settled solution A.6.24g three water and sodium acetate are joined in the 5.2ml water, the solution that forms is joined among the A, add 110 milliliters of acetone then.Filtration product, and use washing with acetone, and under 40 ℃ of conditions, vacuum drying 12 hours obtains 10.04g chrysophanic acid sodium.
Embodiment 4
The chrysophanic acid of 2.84g is added in the solution of being made up of 55 milliliters of acetone and 3.7ml water, form suspension, in this suspension, add the 1.66ml triethylamine, form settled solution A.The 1.42g potassium carbonate is dissolved in the 1.5ml water, forms solution B, B is added among the A, add the acetone of 27.5ml then in reaction system, the filtering for crystallizing product is also used washing with acetone, and under 40 ℃ of conditions, vacuum drying 12 hours obtains 2.54g chrysophanic acid potassium.
Embodiment 5
Get 26 gram chrysophanic acid sodium adding waters for injection and make abundant dissolving for 1500 milliliters, with aseptic buchner funnel shop dual-layer sterilization filter paper sucking filtration; Add sodium sulfite 4 grams, it is an amount of to add acetic acid then, makes its pH value between 7.5-8.5.
Add water for injection to 2000 milliliter.Add pin with activated carbon 0.4g (0.2%0), fully stir, spread two-layer sterilization filter paper filtering with aseptic suction funnel, reuse is through the G6 sintered filter funnel fine straining of sterilization.After the filtrate passed examination, be sub-packed in the ampoule, aseptic sealing by fusing has been both after about 26 hours through frozen drying.
Embodiment 6
With chrysophanic acid 26 grams, ascorbic acid 4 grams join uses CO
2In the saturated 1800ml distilled water, slowly being neutralized to whole dissolvings and making pH value with the 0.5MnaOH aqueous solution is 8.5, with sterile-cloth formula funnel shop sterilization filter paper filtering, adds water for injection to 2000 milliliter.Add pin with activated carbon 0.4g (0.2%0), fully stir, spread two-layer sterilization filter paper filtering with aseptic suction funnel, at the G6 sintered filter funnel fine straining of using through sterilization.After the filtrate passed examination, be sub-packed in the ampoule, aseptic sealing by fusing has been both after about 26 hours through frozen drying.
Embodiment 7
Patient's intraarticular injection to 5 routine knee osteoarthritis gives 2 milliliters of 20 milligrams of chrysophanic acid sodium injections, once in a week, carry out clinical evaluation after continuous 5 weeks, treatment rheumatism medicine clinical research guideline is carried out in new drug (Western medicine) the clinical trial guideline that inclusion criteria and clinical evaluation standard are write according to Ministry of Public Health, there are two examples obviously progressive, two examples are progressive, and an example is invalid, and total effective rate is 80%.Do not find the diarrhoea untoward reaction.The diacetyl rhein injection of curative effect and clinical report basic identical (80-85%).Also basic identical with the curative effect (72-83.3%) of oral diacetyl rhein.
Claims (10)
1. the injectable powder of a treatment of arthritis is characterized by with the Radix Et Rhizoma Rhei hydrochlorate as active component.
2. according to the injectable powder of claim 1, the alkali metal salt that described Radix Et Rhizoma Rhei hydrochlorate is a chrysophanic acid, alkali salt or organic base addition salts.
3. according to the injectable powder of claim 1 or 2, wherein the Radix Et Rhizoma Rhei hydrochlorate is a chrysophanic acid sodium.
4. according to the injectable powder of claim 1 or 2, wherein the Radix Et Rhizoma Rhei hydrochlorate is a chrysophanic acid potassium.
5. according to the described injectable powder of claim 1, it can be used for intramuscular injection, intravenous injection, articular cavity local injection.
6. according to the described injectable powder of claim 5, be used for the each 10-50 milligram of muscle or intravenous injection Radix Et Rhizoma Rhei hydrochlorate, every day 1-3 time; Be used for intra-articular injection, weekly, each 20-40 milligram Radix Et Rhizoma Rhei hydrochlorate, continuous 5 weeks.
7. according to the described injectable powder of claim 5, be used for the each 20 milligrams of chrysophanic acid sodium of muscle or intravenous injection, every day secondary; Be used for intra-articular injection, weekly, each 20 milligrams of chrysophanic acid sodium, continuous 5 weeks.
8. method for preparing the injectable powder of claim 1, described injectable powder is by the Radix Et Rhizoma Rhei hydrochlorate, the PH regulator, antioxidant and sterile water for injection are made through lyophilization.
9. a method for preparing the injectable powder of claim 1 wherein directly is adjusted to 6.0-8.5 through the pH value regulator with pH value with chrysophanic acid, makes its whole dissolvings, and the formulation method according to routine makes freeze-dried powder then.
10. the preparation method of the injectable powder of claim 9 wherein is adjusted to 7.5-8.5 with pH value.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410049948 CN1712041A (en) | 2004-06-22 | 2004-06-22 | Chinese medicial powder injection for treating arthritis and preparation thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410049948 CN1712041A (en) | 2004-06-22 | 2004-06-22 | Chinese medicial powder injection for treating arthritis and preparation thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1712041A true CN1712041A (en) | 2005-12-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410049948 Pending CN1712041A (en) | 2004-06-22 | 2004-06-22 | Chinese medicial powder injection for treating arthritis and preparation thereof |
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| Country | Link |
|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007012254A1 (en) * | 2005-07-11 | 2007-02-01 | Jiangsu Lianchuang Pharmaceutical Technology Co., Ltd | Rhein conjugates, preparation method thereof and their uses in producing medicines for treating diabetic nephrosis, intestinal adhesion and osteoarthritis |
| CN101735271A (en) * | 2008-11-05 | 2010-06-16 | 上海慈瑞医药科技有限公司 | Bong-seeking bisphosphonate rhein ester derivates and preparation method thereof |
-
2004
- 2004-06-22 CN CN 200410049948 patent/CN1712041A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007012254A1 (en) * | 2005-07-11 | 2007-02-01 | Jiangsu Lianchuang Pharmaceutical Technology Co., Ltd | Rhein conjugates, preparation method thereof and their uses in producing medicines for treating diabetic nephrosis, intestinal adhesion and osteoarthritis |
| US9181172B2 (en) | 2005-07-11 | 2015-11-10 | Xiaodong Cong | Rhein conjugates, preparation method thereof and their uses in producing medicines for treating diabetic nephrosis, intestinal adhesion and osteoarthritis |
| CN101735271A (en) * | 2008-11-05 | 2010-06-16 | 上海慈瑞医药科技有限公司 | Bong-seeking bisphosphonate rhein ester derivates and preparation method thereof |
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