CN101125127A - Artemisinin derivatives freeze-dried preparation and preparation method - Google Patents
Artemisinin derivatives freeze-dried preparation and preparation method Download PDFInfo
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- CN101125127A CN101125127A CNA200710066117XA CN200710066117A CN101125127A CN 101125127 A CN101125127 A CN 101125127A CN A200710066117X A CNA200710066117X A CN A200710066117XA CN 200710066117 A CN200710066117 A CN 200710066117A CN 101125127 A CN101125127 A CN 101125127A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention relates to a frozen dry preparation of drug artemisinin derivatives and the preparation method. The present invention is composed of artemisinin derivatives and water-soluble cyclodextrin derivatives, the weight ratio of the artemisinin derivatives and water-soluble cyclodextrin derivatives is 1: 30 to 70, the smashed artemisinin derivatives are added into the water solution of the water-soluble cyclodextrin derivatives at 50 DEG C to 90 DEG C for agitating and dissolving, then the frozen dry preparation is prepared by the conventional process of the injection and the frozen drying. The low-temperature micro-powder technology of the present invention has the advantages that the technology can ensure the physical and chemical properties of the artemisinin derivatives to be consistent before and after the smashing, the process is relatively simple compared with the prior art, the equipments make use of the existing production equipments of the company, thus saving the investment and shorten the production cycle; the dispensing solvent is the water for injection, without the organic solvents, surfactants and cosolvents, so as to improve the safety; the present invention is easy to be dissolved in water, and has fast dissolution speed and the infinite dilution stability, thus avoiding the secondary pollution caused in the other methods which firstly prepare the artemisinin derivatives into the inclusions by using the organic solvents and then sub-package the inclusions thereof.
Description
Technical field
The present invention relates to field of pharmaceutical technology, artemisinin derivatives lyophilized formulations and preparation method that specifically a kind of injection for intravenous is used.
Background technology
Famous antimalarial artemisinin derivatives, because the uniqueness of chemical constitution, clinical efficacy is good, and toxic and side effects is little, and artemisinin-based drug is the medicine that the clinical recommendation of WHO is used to prevent and treat malaria.Nearest bibliographical information, artemisinin-based drug also has antineoplastic action, but dissolubility is very low in the artemisinin-based drug water, belong to insoluble drug, the preparation injection has used vegetable oil to make solvent, clinical can only intramuscular administration, life-time service easily causes the muscle caking of injection site and downright bad, so a kind of novel formulation that can intravenously administrable of exploitation has clinical realistic meaning.Develop the preparation of intravenously administrable, at first will solve an artemisinin-based drug water solublity difficult problem, the dissolubility of using cyclodextrin derivative to improve medicine is a kind of new method in recent years.
Chinese patent: CN02155140.5 discloses a kind of water solublity clathrate preparation method of insoluble drug, insoluble drug is put in the organic solvent of cyclodextrin derivative, reflux to medicine dissolves fully, flings to organic solvent, promptly obtains the water solublity clathrate.Chinese patent: ZL 02116766.4 has reported organic drug and beta-cyclodextrin derivative complex preparation method, is by solvent switch, concentrating under reduced pressure dry the expanded loose body of coordination compound, aseptic subpackaged again obtaining.Their shortcoming is: the process complexity, easily cause heat time heating time oversize (more than 1 hour) artemisinin-based drug degraded and medicinal liquid pH to descend very fast at least, there is organic solvent residual, the visible foreign matters of wayward preparation and particulate matter, easily microbiological contamination, and not a complete preparation production process, be difficult to reach the GMP production requirement.
Summary of the invention
The objective of the invention is to overcome safety issues such as organic solvent residual that prior art exists, microbial contamination, provide a kind of brand-new medicine form stable, very easily water-soluble, dissolution velocity fast, and stable artemisinin derivatives lyophilized formulations and the preparation method of clinical common infusion fluid compatibility.
The present invention only uses water for injection to prepare artemisinin derivatives water solublity freeze-dried powder, is made up of the artemisinin derivatives and the water soluble cyclodextrin derivant of therapeutic dose.
The present invention is achieved through the following technical solutions:
The artemisinin derivatives lyophilized formulations comprises artemisinin derivatives (object) and water soluble cyclodextrin derivant (main body), forms the hydrotrope of stable supermolecule self assembly effect; The prescription ratio of artemisinin derivatives and water soluble cyclodextrin derivant is 1: 30～70 (weight ratios).
Described artemisinin derivatives comprises arteannuin, dihydroarteannuin, Artemether, arteether.
Described water soluble cyclodextrin derivant comprises one or more in alpha-cyclodextrin derivant, beta-cyclodextrin derivative, gamma-cyclodextrin derivant of various substitution values etc.Wherein said beta-cyclodextrin derivative comprises methyl-beta-schardinger dextrin-, HP-, thioether group-beta-cyclodextrin, one or more couplings in the sulfobutyl ether-beta-cyclodextrin, and all can be used for intravenously administrable.With HP-(HP-β-CD) be the cyclodextrin derivative of representative big, good with safe dose with blood compatibility, do not change characteristics such as drug effect, the water solublity that increases medicine, stability, can be used for preparing intravenous injection.The present invention studies mainly with HP-(HP-β-CD) carry out with artemisinin derivatives.
Preparation method:
Adopt 0 ℃～10 ℃ Lowtemperaturepulverizer, artemisinin derivatives is pulverized.
Artemisinin derivatives after pulverizing joined in 50 ℃～90 ℃ the water soluble cyclodextrin derivant aqueous solution, stir, make dissolving, handle, get product after the lyophilizing again by the injection common process then.(in the clean lyophilizing workshop of obtaining the GMP authentication, carrying out).
Learn by phase saturation solubility method mensuration, HP-concentration is in 0～60% scope, increase along with HP-concentration, the dissolubility of artemisinin derivatives also increases thereupon, and the factor of comprehensive preparation is when making up a prescription, the compound concentration of described water soluble cyclodextrin derivant in aqueous solution is 30%～55%, concentration is too high, is difficult to filter, and is preferable 35%～50%.
Adopt low temperature (0 ℃～10 ℃) micronization crushing technology, avoid conventional crushing technology, cause the artemisinin derivatives degraded because local temperature is too high.Artemisinin derivatives is divided into different particle diameter groups (1.0 μ m～10 μ m, 10 μ m～20 μ m, 20 μ m～40 μ m, 40 μ m～90 μ m, 90 μ m～315 μ m, to be tested more than the 315 μ m, the result shows under the uniform temp, along with the increase of particle diameter, the dissolution velocity of artemisinin derivatives is slack-off.When above, dispensing temperature is 70 ℃～90 ℃ to particle diameter greater than 315 μ m.
Described artemisinin derivatives micropowder diameter of aspirin particle is in 0.5 μ m～20 mu m ranges, and best particle diameter is 1.0 μ m～10 μ m.The increase of temperature is favourable to artemisinin derivatives dissolving when making up a prescription, and optimum dispensing temperature is 50 ℃～60 ℃, can reduce the decomposition, oxidation of medicine etc.
Described water soluble cyclodextrin derivant aqueous solution compound concentration, the bulking value specific concentration of cyclodextrin derivative in solution in the assignment system.
Used dispensing solvent is a water for injection in the preparation method, does not contain organic solvent, has improved the safety of medicine.
Adopt lyophilizing artemisinin derivatives medicine of the present invention, also can use the other administration route except that injecting pathway.
The present invention's advantage compared with prior art is:
1, the advantage of low-temperature fine powder technology can guarantee artemisinin derivatives pulverizing physical and chemical properties unanimity, and technology is simple than prior art, and equipment has all utilized our company's existing equipment, has saved investment, and is with short production cycle;
2, dispensing solvent is a water for injection, does not add organic solvent, surfactant, cosolvent, has improved safety;
3, by the technological process of making up a prescription of injection, aseptic freeze-dried goods are made in aseptic ultrafiltration again, and finished product has loose porous block, thereby very easily or soluble in water, dissolution velocity is fast, has infinite dilution stability; Avoided earlier artemisinin derivatives being made clathrate with organic solvent in the additive method, packing causes secondary pollution again.
The safety testing of Artemether freeze-dried powder: the systemic anaphylaxis test shows that the present invention does not have sensitization to the animal subject Cavia porcellus.External hemolytic test shows that the present invention does not have haemolysis and causes cohesion.The animal blood vessels irritation test shows, does not see vascular endothelial injury under the light microscopic, and no thrombosis forms and other pathological change.Do not see the performance that animal struggles because of pain during administration.Therefore, the present invention has no stimulation to blood vessel and surrounding tissue.
Description of drawings
Fig. 1 is the Artemether freeze-dried powder infrared spectrogram of the inventive method preparation;
Fig. 2 is the Artemether freeze-dried powder ultraviolet spectrogram of the inventive method preparation;
Fig. 3 is the Artemether hydrotrope related substance thin-layer chromatogram of the Artemether freeze-dried powder for preparing of the present invention and control methods preparation; Be labeled as " notes " Artemether hydrotrope among the figure for the control methods preparation, " to " be the Artemether reference substance, " slightly " micro-is the Artemether freeze-dried powder of the present invention's preparation.
The specific embodiment
Embodiment 1:
Prescription:
Artemether (conventional refined powder, particle diameter is greater than more than the 315 μ m) 60g
HP-2350g
Make 1000
Take by weighing the HP-of recipe quantity, getting 1600g earlier is dissolved in the 4000ml water for injection, make 40% concentration, be warmed to 70 ℃～90 ℃, add recipe quantity Artemether (particle diameter is greater than 315 μ m), stir, add the residue HP-again, stir and make dissolving, add water for injection to 5000ml, fill, lyophilizing gets product.
Embodiment 2:
Prescription:
Artemether (micropowder 1.0 μ m～10 μ m) 60g
HP-2200g
Make 1000
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, Artemether is pulverized, obtain the Artemether of 1.0 μ m～10 μ m particle diameters.Other takes by weighing the HP-of recipe quantity, getting 1800g earlier is dissolved in the 4000ml water for injection, make 45% concentration, be warmed to 50 ℃～60 ℃, add the recipe quantity Artemether, stir, add the residue HP-again, stir and make dissolving, add water for injection to 5000ml, fill, lyophilizing gets product.
Embodiment 3:
Prescription:
Artemether (micropowder 1.0 μ m～20 μ m) 80g
Sulfobutyl ether-beta-cyclodextrin 440
Methyl-beta-schardinger dextrin-2000
Make 1000
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, Artemether is pulverized, obtain the Artemether of 1.0 μ m～20 μ m particle diameters.Other takes by weighing the sulfobutyl ether-beta-cyclodextrin and the methyl-beta-schardinger dextrin-of recipe quantity, methyl-beta-schardinger dextrin-of getting 1200g earlier is dissolved in the 4000ml water, make 30% concentration, be warmed to 50 ℃～60 ℃, add the recipe quantity Artemether, stir, add remaining methyl-beta-schardinger dextrin-and sulfobutyl ether-beta-cyclodextrin again, stir and make dissolving, add water for injection to 5000ml, fill, lyophilizing gets product.
Embodiment 4:
Prescription:
Arteannuin (micropowder 1.0 μ m～10 μ m) 60g
HP-2200g
Make 1000
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, arteannuin is pulverized, obtain the arteannuin of 1.0 μ m～10 μ m particle diameters.Other takes by weighing the HP-of recipe quantity, is dissolved in the 4000ml water, makes 55% concentration, is warmed to 50 ℃～60 ℃, adds the recipe quantity arteannuin, stirs, and makes dissolving, adds water for injection to 5000ml, and fill, lyophilizing get product.
Embodiment 5:
Prescription:
Dihydroarteannuin 40g
(micropowder 0.5 μ m～10 μ m)
HP-2000g
Make 1000
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, dihydroarteannuin is pulverized, obtain the dihydroarteannuin of 0.5 μ m～10 μ m particle diameters.Other takes by weighing the HP-of recipe quantity, getting 1600g earlier is dissolved in the 4000ml water, make 40% concentration, be warmed to 50 ℃～60 ℃, add the recipe quantity dihydroarteannuin, stir, add the residue HP-again, stir and make dissolving, add water for injection to 5000ml, fill, lyophilizing gets product.
Embodiment 6:
Prescription:
Dihydroarteannuin 70g
(micropowder 1.0 μ m～10 μ m)
Hydroxypropyl-alpha-cyclodextrin 2200g
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, dihydroarteannuin is pulverized, obtain the dihydroarteannuin of 1.0 μ m～10 μ m particle diameters.Other takes by weighing the hydroxypropyl-alpha-cyclodextrin of recipe quantity, getting 1680g earlier is dissolved in the 4000ml water, make 42% concentration, be warmed to 55 ℃～65 ℃, add the recipe quantity dihydroarteannuin, stir, add residue hydroxypropyl-alpha-cyclodextrin again, stir and make dissolving, add water for injection to 5000ml, fill, lyophilizing gets product.
Claims (9)
1. the lyophilized formulations of a medicine artemisinin derivatives is characterized in that being made up of artemisinin derivatives, water soluble cyclodextrin derivant, and the weight ratio of artemisinin derivatives and water soluble cyclodextrin derivant is 1: 30～70, makes lyophilized formulations.
2. artemisinin derivatives lyophilized formulations according to claim 1 is characterized in that described artemisinin derivatives comprises arteannuin, dihydroarteannuin, Artemether, arteether.
3. artemisinin derivatives lyophilized formulations according to claim 1 is characterized in that water soluble cyclodextrin derivant comprises one or more in the alpha-cyclodextrin derivant, beta-cyclodextrin derivative, gamma-cyclodextrin derivant of various substitution values.
4. artemisinin derivatives lyophilized formulations according to claim 3, wherein said beta-cyclodextrin derivative comprises methyl-beta-schardinger dextrin-, HP-, thioether group-beta-cyclodextrin, one or more couplings in the sulfobutyl ether-beta-cyclodextrin.
5. the preparation method of the described insoluble drug artemisinin derivatives of claim 1 lyophilized formulations is characterized in that artemisinin derivatives is wrapped in formation supermolecule self-assembly system in the water soluble cyclodextrin derivant, carries out according to the following steps:
(1) adopt 0 ℃～10 ℃ Lowtemperaturepulverizer, artemisinin derivatives pulverized:
(2) artemisinin derivatives after will pulverizing joins in 50 ℃～90 ℃ the water soluble cyclodextrin derivant aqueous solution, stirs, and makes dissolving, handles, gets product after the lyophilizing by the injection common process then.
6. insoluble drug artemisinin derivatives lyophilized formulations preparation method according to claim 5 is characterized in that the compound concentration of cyclodextrin derivative in solution is 30%～55% of w/v in the described water soluble cyclodextrin derivant aqueous solution.
7. the preparation method of insoluble drug artemisinin derivatives lyophilized formulations according to claim 5, when it is characterized in that the pulverizing of artemisinin derivatives low-temperature fine powder, diameter of aspirin particle is 0.5 μ m～20 μ m.
8. the preparation method of insoluble drug artemisinin derivatives lyophilized formulations according to claim 5, when it is characterized in that the pulverizing of artemisinin derivatives low-temperature fine powder, the particle diameter of medicine the best is 1.0 μ m～10 μ m.
9. when the preparation method of insoluble drug artemisinin derivatives lyophilized formulations according to claim 5, the particle diameter that it is characterized in that artemisinin derivatives were 1.0 μ m～10 μ m, optimum dispensing temperature was 50 ℃～60 ℃.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101314644B (en) * | 2008-07-22 | 2011-09-21 | 四川大学 | Host-guest complex type supermolecule hollow microsphere, preparation and application thereof |
| CN102652753A (en) * | 2011-03-04 | 2012-09-05 | 湖北武当动物药业有限责任公司 | Veterinary compound diminazene aceturate and artemisinin preparation and preparation technology thereof |
| CN102716491A (en) * | 2012-07-02 | 2012-10-10 | 昆明理工大学 | Clathrate compound of artemisinin series and alkaline cyclodextrin and method for preparing same |
| WO2014082569A1 (en) * | 2012-11-29 | 2014-06-05 | 昆明制药集团股份有限公司 | Use of artemether in preparation of drug for treating leukemia |
| CN103864962A (en) * | 2012-12-14 | 2014-06-18 | 昆明制药集团股份有限公司 | Amino modified cyclodextrin based artemisinin prodrug and its preparation method |
| CN105699584A (en) * | 2016-02-03 | 2016-06-22 | 昆药集团股份有限公司 | Detection method for artemether related matters |
| CN107582529A (en) * | 2016-07-08 | 2018-01-16 | 山东森诺医药科技有限公司 | Artesunate for Injection freeze-dried powder and preparation method thereof |
| CN111505032A (en) * | 2019-01-30 | 2020-08-07 | 昆药集团股份有限公司 | Method for detecting dihydroartemisinin crystal form in dihydroartemisinin tablet |
| CN113350525A (en) * | 2021-06-21 | 2021-09-07 | 哈尔滨氧态健康科技有限公司 | Porous starch-loaded artemisinin hydroxypropyl-beta-cyclodextrin inclusion compound and preparation method and application thereof |
-
2007
- 2007-08-16 CN CN200710066117A patent/CN101125127B/en active Active
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101314644B (en) * | 2008-07-22 | 2011-09-21 | 四川大学 | Host-guest complex type supermolecule hollow microsphere, preparation and application thereof |
| CN102652753A (en) * | 2011-03-04 | 2012-09-05 | 湖北武当动物药业有限责任公司 | Veterinary compound diminazene aceturate and artemisinin preparation and preparation technology thereof |
| CN102652753B (en) * | 2011-03-04 | 2015-08-12 | 湖北武当动物药业有限责任公司 | Animal compound Diminazene Aceturate and Arteannuin preparation and preparation technology thereof |
| CN102716491A (en) * | 2012-07-02 | 2012-10-10 | 昆明理工大学 | Clathrate compound of artemisinin series and alkaline cyclodextrin and method for preparing same |
| CN102716491B (en) * | 2012-07-02 | 2013-12-18 | 昆明理工大学 | Clathrate compound of artemisinin series and alkaline cyclodextrin and method for preparing same |
| JP2016500116A (en) * | 2012-11-29 | 2016-01-07 | 昆明制薬集団股▲ふん▼有限公司Ｋｕｎｍｉｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏｒｐ． | Use of artemether in the preparation of a drug to treat leukemia |
| WO2014082569A1 (en) * | 2012-11-29 | 2014-06-05 | 昆明制药集团股份有限公司 | Use of artemether in preparation of drug for treating leukemia |
| CN103864962B (en) * | 2012-12-14 | 2016-04-06 | 昆药集团股份有限公司 | Based on the Artemisinin prodrug and preparation method thereof of amido modification cyclodextrin |
| CN103864962A (en) * | 2012-12-14 | 2014-06-18 | 昆明制药集团股份有限公司 | Amino modified cyclodextrin based artemisinin prodrug and its preparation method |
| CN105699584A (en) * | 2016-02-03 | 2016-06-22 | 昆药集团股份有限公司 | Detection method for artemether related matters |
| CN105699584B (en) * | 2016-02-03 | 2018-02-09 | 昆药集团股份有限公司 | A kind of detection method of Artemether related substances |
| CN107582529A (en) * | 2016-07-08 | 2018-01-16 | 山东森诺医药科技有限公司 | Artesunate for Injection freeze-dried powder and preparation method thereof |
| CN111505032A (en) * | 2019-01-30 | 2020-08-07 | 昆药集团股份有限公司 | Method for detecting dihydroartemisinin crystal form in dihydroartemisinin tablet |
| CN111505032B (en) * | 2019-01-30 | 2023-11-21 | 昆药集团股份有限公司 | Method for detecting dihydroartemisinin crystal form in dihydroartemisinin tablet |
| CN113350525A (en) * | 2021-06-21 | 2021-09-07 | 哈尔滨氧态健康科技有限公司 | Porous starch-loaded artemisinin hydroxypropyl-beta-cyclodextrin inclusion compound and preparation method and application thereof |
| CN113350525B (en) * | 2021-06-21 | 2022-11-01 | 哈尔滨氧态健康科技有限公司 | Porous starch-loaded artemisinin hydroxypropyl-beta-cyclodextrin inclusion compound and preparation method and application thereof |
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| CN101125127B (en) | 2010-05-19 |
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Address after: 650106 Kunming science and Technology Industrial Development Zone, Yunnan Province Road No. 166 Patentee after: Kun Yao Group Plc Address before: 650106 No. 166, medical Road, hi tech Development Zone, Yunnan, Kunming Patentee before: Kunming Pharmaceutical Industry Group Corp., Ltd. |