CN100594940C - Supermolecule water soluble freeze drying matter of indissoluble medicament and method of preparing the same - Google Patents
Supermolecule water soluble freeze drying matter of indissoluble medicament and method of preparing the same Download PDFInfo
- Publication number
- CN100594940C CN100594940C CN200710066098A CN200710066098A CN100594940C CN 100594940 C CN100594940 C CN 100594940C CN 200710066098 A CN200710066098 A CN 200710066098A CN 200710066098 A CN200710066098 A CN 200710066098A CN 100594940 C CN100594940 C CN 100594940C
- Authority
- CN
- China
- Prior art keywords
- water soluble
- insoluble drug
- cyclodextrin
- rubescensine
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention relates to a super molecule water soluble freeze-drying substance of difficult soluble drug and making method through dispensing difficult soluble drug and water soluble cyclodextrin derivative with weight ratio at 1:1-80 to form stable super molecule self-assembled water soluble substance, which is characterized by the following: the invention overcomes secure problems of organic solvent remaining in current technology and microbial contamination; the technology is simpler than current technology with short production circle and security, low production cost and supporting quality to be for industrialization. The invention has merits of stable composition and is easy to dissolve in water at fast dissolving speed and of stable injection compatibility with common clinic fluidinfusion, which guarantees drug having consistent physicochemical property before and after disintegrating because of characteristic of low-temperature micronizing technology and improves security ofagent because of not adding organic solvent, surface active agent and latent solvent.
Description
Technical field
The present invention relates to field of pharmaceutical technology, specifically a kind of supermolecule water soluble freeze drying thing and preparation method of insoluble drug.
Background technology
Along with the development of high flux screening and combinatorial chemistry, usually most of activated chemical compound all belongs to insoluble chemical compound, and wherein the drug candidate 40% or more is owing to slightly solubility does not cause biopharmaceutics character good and fail in the drug development development process.Though, to make traditional methods such as salt, solubilising, particle diameter minimizing, polymorphic or solvate and be widely used for increasing stripping so that improve oral absorption and bioavailability, all there is limitation these methods in itself.For neutral compound and some weak acid, weak base, it is unrealistic to make salt.Simple particle diameter minimizing method commonly used exists that limit that particle diameter reduces and follow-up preparation difficult treatment, hydrophobicity increase, problems such as making the reduction of powder wettability may reassociate.
Improve the dissolubility of insoluble drug or dissolution rate and become one of the most difficult challenge that current medicament scholar faces.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.Chinese patent: CN 1 883497A discloses the ginsenoside Rh2 through hydroxypropyl-beta-cyclodextrin inclusion and preparation and preparation method, the ginsenoside Rh2 is dissolved in the organic solvent (in the mixed solvent of chloroform, methanol, water or in the mixed solvent of dichloromethane, methanol, water or methanol, also can for sough in the dimethyl Asia, tween and mix reagent).Chinese patent: CN1895220A discloses 20 (R)-ginseng sapoglycoside Rg 3 medicinal soluble intermediate and preparation methoies, 20 (R)-ginsenoside Rg3s are dissolved in make ginsenoside's solution in the mixed organic solvents, join in the aqueous solution that contains HP-.Chinese patent: ZL01119929.6 has reported panaxoside Rg 3 hydroxypropyl-beta-cyclodextrin inclusions and preparation and preparation method, join in the aqueous solution that contains HP-by the panaxoside Rg 3 that will be dissolved in organic solvent, after the stirring, drying forms clathrate soluble in water.Their shortcoming is: the process complexity, if make injection, and the then visible foreign matters of wayward preparation and particulate matter, easily microbiological contamination, the untoward reaction that organic solvent residual causes has reduced patient's compliance and commercialization.And not a complete preparation production process, be difficult to reach GMP production requirement or investment in practice greatly.
Chinese patent: CN 1739537A discloses cyclodextrin clathrate of breviscapine and preparation thereof, the cyclodextrin compound concentration is 5%-20%, acid adjustment alkali repeatedly, can cause the medicinal liquid fluid properties to change in the actual production, lyophilizing eutectic point fluctuation very big (5 ℃ to-25 ℃) appears, breviscapine, easily decomposes under acidity or alkali condition as the slightly solubility weak acidic drug.The preparation of the breviscapine clathrate freeze-dried powder of Chinese Pharmaceutical Journal the 42nd volume the 6th phase report March in 2007 and a literary composition of safety preliminary observation, the HP-that drops into breviscapine to 20% makes the breviscapine supersaturation, filter unnecessary undissolved material, this method exists bigger to the waste of medicine, reclaims also difficulty.
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 that a kind of brand-new safe, low-cost, quality is easy to ensure, the supermolecule water soluble freeze drying thing and the preparation method of the insoluble drug of suitability for industrialized.That the water soluble drug of gained is formed is stable, very easily water-soluble, dissolution velocity fast, injection and clinical common infusion fluid compatibility are stablized.
Novelty of the present invention is to organically combine drug micronization technology and water soluble cyclodextrin derivant supermolecule technological merit, be the integrated innovation achievement of integrated physics medicament, supermolecule technology, freeze drying technology and suitability for industrialized production technology, only use water for injection to prepare insoluble drug water solublity lyophilized products.
The present invention is achieved through the following technical solutions: insoluble drug water solublity lyophilized products of the present invention is made up of the insoluble drug and the water soluble cyclodextrin derivant of therapeutic dose, by weight 1: 1～80 preparations.
Described insoluble drug water solublity lyophilized products, its formulation characteristics comprise insoluble drug (object) and water soluble cyclodextrin derivant (main body), form the hydrotrope of stable supermolecule self assembly effect; Used dispensing solvent is a water for injection in the preparation method, does not contain organic solvent, has improved the safety of medicine.The water solublity lyophilized products that adopts the present invention to make can be used for preparing preparation.
Described insoluble drug, artemisinin derivatives (comprising arteannuin, Artemether, arteether), breviscapine, rabdosia rubescens diterpene compounds (comprising rubescensine A, rubescensine B or derivatives thereof, rubescensine C, rubescensine D or derivatives thereof, rubescensine E or derivatives thereof or rubescensine H), coenzyme Q10, vitamin A, spironolactone (spironolactone have been comprised, SP, spironolactone), panoxadiol, panaxatriol.
Described water soluble cyclodextrin derivant comprises one or more in alpha-cyclodextrin derivant, beta-cyclodextrin derivative, gamma-cyclodextrin derivant of various substitution values etc.Described beta-cyclodextrin derivative comprises methyl-beta-schardinger dextrin-, HP-, thioether group-beta-cyclodextrin, one or more couplings such as 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.
Preparation method:
Adopt low temperature (0 ℃～10 ℃) micropowder pulverizer, insoluble drug is pulverized, obtain micropowder, join in 25 ℃～90 ℃ the water soluble cyclodextrin derivant aqueous solution, the ratio of insoluble drug and water soluble cyclodextrin derivant is 1: 1～80 (weight ratios), stirs, and makes dissolving, packing, lyophilizing.
In order to accelerate to dissolve and make drug degradation minimum, the optimum temperature of making up a prescription is 50 ℃～70 ℃; Behind the insoluble drug micronization, insoluble drug micropowder and water soluble cyclodextrin derivant form the supermolecule self-assembly system by the nonbonding active force, and insoluble drug micronization particle diameter is in 0.5 μ m～40 mu m ranges, and best particle diameter is 0.5 μ m～20 μ m.
Learn by phase solubility method mensuration, HP-concentration is in 0～60% scope, increase along with HP-concentration, the dissolubility of medicine also increases thereupon, the factor of comprehensive preparation, described water soluble cyclodextrin derivant aqueous solution compound concentration is 20%～60%, preferred 35%～55%.
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.
Method of the present invention has the following advantages:
1, the low-temperature fine powder technical characterstic can guarantee medicine 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, do not add organic solvent, surfactant, cosolvent, thus the safety that has improved preparation.
The specific embodiment
Embodiment 1:
Prescription:
Artemether (micropowder 0.5 μ m～10 μ m) 12g
HP-460g
Water for injection 1000ml
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, Artemether is pulverized, obtain the Artemether of 0.5 μ m～10 μ m particle diameters.Other takes by weighing the HP-of recipe quantity, is dissolved in the 1000ml water, makes 46% concentration, is warmed to 50 ℃～60 ℃, adds the recipe quantity Artemether, stirs, and makes dissolving, fill, and lyophilizing gets product.
Embodiment 2:
Prescription:
Artemether (micropowder 1.0 μ m～20 μ m) 12g
Sulfobutyl ether-beta-cyclodextrin 460g
Water for injection 1000ml
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 of recipe quantity, is dissolved in the 1000ml water, makes 46% concentration, is warmed to 60 ℃～65 ℃, adds the recipe quantity Artemether, stirs, and makes dissolving, fill, and lyophilizing gets product.
Embodiment 3:
Prescription:
Arteannuin (micropowder 0.5 μ m～10 μ m) 12g
HP-350g
Water for injection 1000ml
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, arteannuin is pulverized, obtain the arteannuin of 0.5 μ m～10 μ m particle diameters.Other takes by weighing the HP-of recipe quantity, is dissolved in the 1000ml water, makes 35% concentration, is warmed to 55 ℃～65 ℃, adds the recipe quantity arteannuin, stirs, and makes dissolving, fill, and lyophilizing gets product.
Embodiment 4:
Prescription:
Spironolactone (micropowder 0.5 μ m～5 μ m) 8g
Hydroxypropyl-alpha-cyclodextrin 380g
Water for injection 1000ml
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, spironolactone is pulverized, obtain the spironolactone of 0.5 μ m～5 μ m particle diameters.Other takes by weighing the hydroxypropyl-alpha-cyclodextrin of recipe quantity, is dissolved in the 690ml water, makes 55% concentration, is warmed to 25 ℃～30 ℃, adds the recipe quantity spironolactone, stirs, and makes dissolving, adds water for injection to 1000ml, fill, and lyophilizing gets product.
Embodiment 5:
Prescription:
Breviscapine (micropowder 20 μ m～40 μ m) 10g
Thioether group-beta-cyclodextrin 400g
Water for injection 1000ml
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, breviscapine is pulverized, obtain the breviscapine of 20 μ m～40 μ m particle diameters.Other takes by weighing the thioether group-beta-cyclodextrin of recipe quantity, is dissolved in the 1000ml water, makes 40% concentration, is warmed to 85 ℃～90 ℃, adds the recipe quantity breviscapine, stirs, and makes dissolving, fill, and lyophilizing gets product.
Embodiment 6:
Prescription:
Coenzyme Q10 (micropowder 0.5 μ m～10 μ m) 5g
Sulfobutyl ether-beta-cyclodextrin 6g
Water for injection 1000ml
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, coenzyme Q10 is pulverized, obtain the coenzyme Q10 of 0.5 μ m～10 μ m particle diameters.Other takes by weighing the sulfobutyl ether-beta-cyclodextrin of recipe quantity, is dissolved in the 15ml water, makes 40% concentration, is warmed to 60 ℃～65 ℃, adds the recipe quantity coenzyme Q10, stirs, and makes dissolving, adds water for injection to 1000ml, fill, and lyophilizing gets product.
Embodiment 7:
Prescription:
Rubescensine A (micropowder 10 μ m～20 μ m) 100g
Sulfobutyl ether-beta-cyclodextrin 420g
Water for injection 1000ml
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, rubescensine A is pulverized, obtain the rubescensine A of 10 μ m～20 μ m particle diameters.Other takes by weighing the sulfobutyl ether-beta-cyclodextrin of recipe quantity, is dissolved in the 1000ml water, makes 42% concentration, is warmed to 65 ℃～75 ℃, adds the recipe quantity rubescensine A, stirs, and makes dissolving, fill, and lyophilizing gets product.
Embodiment 8:
Prescription:
Ginsenoside Rb1 (the 5g of micropowder 1.0 μ m～10m)
Sulfobutyl ether-beta-cyclodextrin 220g
Water for injection 1000ml
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, the ginsenoside Rb1 is pulverized, obtain the ginsenoside Rb1 of 1.0 μ m～10 μ m particle diameters.Other takes by weighing the sulfobutyl ether-beta-cyclodextrin of recipe quantity, is dissolved in the 550ml water, makes 40% concentration, is warmed to 65 ℃～70 ℃, adds the recipe quantity ginsenoside Rb1, stirs, and makes dissolving, adds water for injection to 1000ml, fill, and lyophilizing gets product.
Embodiment 9:
Prescription:
Ginsenoside Rg1 (micropowder 1.0 μ m～10 μ 6gm)
Methyl-beta-schardinger dextrin-400g
Sulfobutyl ether-beta-cyclodextrin 80g
Water for injection 1000ml
Adopt pulverize at low temperature (0 ℃～10 ℃) machine, the ginsenoside Rg1 is pulverized, obtain the ginsenoside Rg1 of 1.0 μ m～10 μ m particle diameters.Other takes by weighing the methyl-beta-schardinger dextrin-and the sulfobutyl ether-beta-cyclodextrin of recipe quantity, is dissolved in the 1000ml water, makes 48% concentration, is warmed to 65 ℃～70 ℃, adds the recipe quantity ginsenoside Rg1, stirs, and makes dissolving, fill, and lyophilizing gets product.
Claims (3)
1, a kind of preparation method of supermolecule water soluble freeze drying thing of insoluble drug, it is characterized in that preparing by weight 1: 1～80 by insoluble drug and water soluble cyclodextrin derivant, adopt 0 ℃～10 ℃ micropowder pulverizers of low temperature to pulverize the acquisition micropowder insoluble drug, micropowder insoluble drug particle diameter is in 0.5 μ m～40 mu m ranges, in the water soluble cyclodextrin derivant aqueous solution with 25 ℃～90 ℃ of micropowder insoluble drug addings, stirring makes dissolving, packing, lyophilizing forms the hydrotrope of stable supermolecule self assembly effect; Wherein the compound concentration of cyclodextrin derivative in solution is 35%～55% of w/v in the aqueous solution, water soluble cyclodextrin derivant is methyl-beta-schardinger dextrin-, HP-, thioether group-beta-cyclodextrin, one or more couplings in the sulfobutyl ether-beta-cyclodextrin.
2, the preparation method of insoluble drug supermolecule water soluble freeze drying thing according to claim 1 is characterized in that described insoluble drug is arteannuin, Artemether, arteether, breviscapine, rubescensine A, rubescensine B, rubescensine C, rubescensine D, rubescensine E, rubescensine H, coenzyme Q10, vitamin A, spironolactone, panoxadiol, panaxatriol.
3, the preparation method of insoluble drug supermolecule water soluble freeze drying thing according to claim 1 is characterized in that micropowder insoluble drug particle diameter is 0.5 μ m～20 μ m.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710066098A CN100594940C (en) | 2007-08-08 | 2007-08-08 | Supermolecule water soluble freeze drying matter of indissoluble medicament and method of preparing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710066098A CN100594940C (en) | 2007-08-08 | 2007-08-08 | Supermolecule water soluble freeze drying matter of indissoluble medicament and method of preparing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101130088A CN101130088A (en) | 2008-02-27 |
| CN100594940C true CN100594940C (en) | 2010-03-24 |
Family
ID=39127594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710066098A Active CN100594940C (en) | 2007-08-08 | 2007-08-08 | Supermolecule water soluble freeze drying matter of indissoluble medicament and method of preparing the same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100594940C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103845322A (en) * | 2012-11-29 | 2014-06-11 | 昆明制药集团股份有限公司 | Use of artemether in preparation of drug for treating leukemia |
| CN105816422B (en) * | 2015-01-05 | 2020-08-14 | 天士力医药集团股份有限公司 | Silibinin injection and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424112A (en) * | 2002-12-17 | 2003-06-18 | 上海医药工业研究院 | Water soluble dressing for insoluble medicines and preparation thereof |
| CN1853726A (en) * | 2005-04-18 | 2006-11-01 | 汕头大学医学院 | Polymer system for improving insoluble medicine water solubility and preparation thereof |
| CN1857253A (en) * | 2006-03-28 | 2006-11-08 | 陈俊辉 | Anticancer injection of rabdosia diterpene compound or its derivative and its preparing method |
-
2007
- 2007-08-08 CN CN200710066098A patent/CN100594940C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424112A (en) * | 2002-12-17 | 2003-06-18 | 上海医药工业研究院 | Water soluble dressing for insoluble medicines and preparation thereof |
| CN1853726A (en) * | 2005-04-18 | 2006-11-01 | 汕头大学医学院 | Polymer system for improving insoluble medicine water solubility and preparation thereof |
| CN1857253A (en) * | 2006-03-28 | 2006-11-08 | 陈俊辉 | Anticancer injection of rabdosia diterpene compound or its derivative and its preparing method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101130088A (en) | 2008-02-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100467494C (en) | Organic medicine and betacyclodextrin derivative and preparation process thereof | |
| CN101125127B (en) | Artemisinin derivatives freeze-dried preparation and preparation method | |
| CN102811718A (en) | Pharmaceutical composition for improving solubility of prasugrel and its preparation method | |
| CN101053556B (en) | Water soluble coenzyme Q10 hydroxyl-beta-cyclodextrin inclusion compound and its preparation method | |
| CN105997875B (en) | A kind of water-in-oil type nanoemulsion and preparation method thereof significantly improving insoluble drug bioavilability | |
| CN102370622A (en) | Medicament carrying nano particles and preparation method and application thereof | |
| CN100508969C (en) | Nano particles of taxane cyclodextrin inclusion compound and preparation method thereof | |
| Suo et al. | Lentinan as a natural stabilizer with bioactivities for preparation of drug–drug nanosuspensions | |
| CN104414983B (en) | A kind of injection fosaprepitant dimeglumine sterile lyophilized powder and its preparation process | |
| CN105999279A (en) | Medicine composition comprising butylphthalide and cosolvent | |
| Tian et al. | Fabrication of nanosuspensions to improve the oral bioavailability of total flavones from Hippophae rhamnoides L. and their comparison with an inclusion complex | |
| CN100594940C (en) | Supermolecule water soluble freeze drying matter of indissoluble medicament and method of preparing the same | |
| CN102961368A (en) | Curcumin nanosuspension and preparation method thereof | |
| AU2003205930A1 (en) | Pharmaceutical composition | |
| EP1469886A2 (en) | Pharmaceutical composition | |
| CN101984958A (en) | Nanoscale albendazole micropowder and preparation method thereof | |
| CN101317832B (en) | Oral administration nano-drug administration system of resveratrol | |
| CN105902518A (en) | Preparation method of novel water-soluble nanoparticles | |
| JP6592091B2 (en) | Silibinin injection and preparation method thereof | |
| CN105534947A (en) | Preparation method of celecoxib nanosuspension capsules | |
| CN115969833A (en) | Amiodarone medicinal composition, injection, preparation method thereof and injector containing amiodarone medicinal composition and injection | |
| CN104095816B (en) | Lutein ester nano-particle and preparation method thereof | |
| CN102293753A (en) | Coenzyme Q10 nanosuspension freeze-dried composition and preparation method and application thereof | |
| CN101011385A (en) | Pharmaceutical composition of coumarin derivative and its preparation and application | |
| CN107184566A (en) | Pharmaceutical composition containing lutein and preparation method thereof and preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: KPC CO., LTD. Free format text: FORMER NAME: KUNMING PHARMACEUTICAL INDUSTRY GROUP CORP., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 650106 No. 166, medical Road, hi tech Development Zone, Yunnan, Kunming 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. |