CN101926760A - Dexamethasone injecta coated with 2-hydroxypropyl-beta-cyclodextrin - Google Patents
Dexamethasone injecta coated with 2-hydroxypropyl-beta-cyclodextrin Download PDFInfo
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Abstract
The invention relates to a dexamethasone injecta coated with 2-hydroxypropyl-beta-cyclodextrin. The molar ratio of a dexamethasone to the 2-hydroxypropyl-beta-cyclodextrin is 1:1-20, the substitution degree of the utilized 2-hydroxypropyl-beta-cyclodextrin is preferably 4-7, and the molar ratio of the dexamethasone to the 2-hydroxypropyl-beta-cyclodextrin is preferably 1:2-5.
Description
The present invention relates to the 17-hydroxy-11-dehydrocorticosterone injection, particularly a kind of cyclodextrin inclusion compound dexamethasone injection.
Background technology
Dexamethasone is a kind of potent glucocorticoid, have pharmacological actions such as stronger antiinflammatory, antiendotoxin, inhibition immunity, shock and enhancing stress, dexamethasone and different ester thereof or salt are widely used in each section and treat multiple disease, as autoimmune disease, allergy, inflammation, asthma and department of dermatologry, ophthalmic diseases, be used for intravenous injection when treatment when being used for dexamethasone, adopt dexamethasone sodium phosphate is the injection dosage form of active component more.Because powerful antiinflammatory action, the Antishock function of dexamethasone, dexamethasone sodium phosphate injection has become the requisite first aid medicine that gives emergency treatment to a dying patient.Because dexamethasone sodium phosphate is a kind of prodrug, after injection, need to be dissociated into the onset of dexamethasone ability by phosphate in vivo, and in emergency treatment, the onset speed of first aid medicine has often determined patient's final and decisive juncture, therefore seek a kind of onset faster dexamethasone preparation become us and wish the technical problem that solves always.
In addition, prior art China produces in the dexamethasone sodium phosphate injection contains 30% propylene glycol, in fact abroad, as far back as last century the '30s begin just to set about deep research has been carried out in the propylene glycol safety, accumulated great mass of data, security related and the clinical research document delivered at present have more than 160 piece.The seventies in last century, G.Martin writes articles at the department of pediatrics magazine and points out, the propylene glycol tool genotoxic potential problem in the liquid dosage form.K.Arulananthan in 1978 have reported the maincenter toxicity of propylene glycol.After this in the period of 1985～1988, Demey and partner thereof report that the nitroglycerin preparation that intravenous drip contains propylene glycol can cause that height oozes untoward reaction, haemolysis, lactic acidosis and nervus centralis dysfunction.The topical application of having reported Fligner contains the propylene glycol silver sulfadiazin in the burn patient, because the Transdermal absorption of propylene glycol, the propylene glycol peak concentration is up to 1059 μ g/ml in the blood, and except that being oozed by height the untoward reaction that causes, breathing still can appear in the patient, heart beating stops.After this Keiner report, when 5 patients accept to contain the treatment of propylene glycol intravenous pharmacy, propylene glycol concentration is respectively 6～711 μ g/ml and 11～599 μ g/ml in 35 parts of serum samples and the 8 parts of CSF sample, because the metabolism of propylene glycol, lactic acidosis has appearred in the patient.This shows, as adjuvant and solvent, propylene glycol has potential danger, can produce hyperosmosis, lactic acidosis, central nervous system's inhibition, haemolysis, local phlebitis and breathing, cardiac toxicity reaction, its safety especially uses the safety of emergency treatment troubling.
Beta-schardinger dextrin-can form clathrate with many medicines, thereby increase the water solublity of medicine, but can not be used for injection because it has nephrotoxicity, and the hydroxy alkylene beta-schardinger dextrin-that the beta-schardinger dextrin-chemical modification is obtained, hydroxypropyl particularly, its enclose ability is stronger, can significantly improve dissolubility, the stability of a lot of medicines, and because its good hydrophilic property, it is compatible to be easy to biotic environment, and less because of surface activity, be difficult for haemolysis, also less during injection to the zest of tissue.The injection that multiple employing HP-has been arranged at present.Chinese patent application CN200410071922.8 discloses a kind of hydroxypropyl-beta-cyclodextrin inclusion and preparation and preparation method of Borneolum Syntheticum, though also be enclose to the effective ingredient that is insoluble in water, but Borneolum Syntheticum and dexamethasone isocortex hormone physics, chemical property, chemical molecular structure all have a great difference, are used for the technology and the prescription of enclose Borneolum Syntheticum and are not suitable for dexamethasone isocortex hormone.
World patent WO2004/069280 has mentioned the supernatant liquid antibiotic/17-hydroxy-11-dehydrocorticosterone liquid that can local be used for ear and eyes and has dripped agent, the inventive point of this patent application is, by dexamethasone that obtains in the dehydrated alcohol and hydroxypropyl beta cyclodextrin enclose crystal, process is to be dissolved in an amount of dehydrated alcohol under dexamethasone and hydroxypropyl beta cyclodextrin 40-45 ℃, concentrate and separate out the enclose crystal, last pulp, cold filtration obtains dexamethasone and hydroxypropyl beta cyclodextrin clathrate.Yet, inclusion complex in solution is concentrated into last needs and stays certain volume mother solution among disclosed this clathrate preparation technology of application, because hydroxypropyl beta cyclodextrin is soluble in ethanol, its dissolubility in ethanol is also more than 50g/100ml, in addition because the saturated alcoholic solution viscosity of hydroxypropyl beta cyclodextrin is higher, therefore the clathrate that obtains is a slurry, viscosity is very big, almost be difficult to filter, even and filter, because the high-dissolvability of hydroxypropyl beta cyclodextrin in ethanol, also have quite a few clathrate and not the HP-of enclose be left in the mother solution.Simultaneously because this clathrate preparation process is used pure solvent dehydrated alcohol, ethanol itself can be by enclose (chem.pharm in hydroxypropyl beta cyclodextrin when preparation clathrate thing, Bull, 720-750,1988), so in order to improve inclusion rate, can only further improve the consumption of hydroxypropyl beta cyclodextrin, and the clathrate ethanol solvent that obtains is residual higher.Because in HP-, conventional method is difficult to handle ethanol by enclose, make this clathrate be difficult to be applied in the preparation to the residual injection of having relatively high expectations of solvent.
Chinese patent application CN200610130124.7 discloses 17-hydroxy-11-dehydrocorticosterone enclose aqueous solution and application thereof always, disclose with dexamethasone, fluorometholone is the 17-hydroxy-11-dehydrocorticosterone enclose aqueous solution of active component, in the technical scheme of this application, most preferably the 2-HP-as the enclose adjuvant, yet show according to the disclosed content of European Pharmacopoeia, the substitution value scope of HP-is 2.8-10.5, yet equal substitution value of unexposed used HP-in the above-mentioned application, and HP-and its enclose ability and nephrotoxicity, hemolytic is all closely related.Substitution value is crossed the low or too high enclose effect in when injection that all can influence, and the HP-of therefore preferred a kind of suitable substitution value is used for preparing the problem that enclose medicaments injection prior art kind exists.
Summary of the invention:
Our surprised discovery in experiment, substitution value scope by preferred 2-hydroxy-beta-cyclodextrin, the dexamethasone inject that is provided is except having advantages of higher stability, injection safety, can rapider onset after injection, thus more help treatment.
The invention provides a kind of dexamethasone injection of 2-HP-enclose, the mol ratio of described dexamethasone and 2-HP-is 1: 1～20, it is characterized in that used 2-HP-substitution value is preferably 4～7 and is preferably 4～6 especially.
The mol ratio of described dexamethasone and 2-HP-is preferably 1: 2～and 5.
Described injection, dexamethasone content is 0.05%～1%, is preferably 0.1%～0.5%, is preferably 0.1%, 0.2%, 0.5% especially.
Can also add the PH regulator in the described injection; As: hydrochloric acid solution, sodium hydroxide solution, sodium bicarbonate solution, Sha Shi phosphate buffer, Palitzsch, lucky Fei Shi buffer, borate buffer or the like, preferably phosphoric acid/phosphate buffer.The pH value of described injection is preferably 5～7
Described injection can also add additives common in the injection, and the adding of described additives can be added according to " pharmaceutics " (Cui Fude, 2003 November the 5th edition) chapter 3 second joint disclosed additives kind of invading the exterior 3-4 and concentration range.The preferred disodium edetate 0.01%-0.1% that adds as chelating agen, as one or more 0.05%-0.2% in sodium sulfite, sodium sulfite, alpha-tocopherol, sodium pyrosulfite and the sodium thiosulfate of antioxidant, as 0.4%-0.9% sodium chloride, 4%～5% glucose, 1%～2.5% glycerol of osmotic pressure regulator, more than various additives can add one or more.
The preparation method of dexamethasone inject provided by the invention is as follows: 2-hydroxy-beta-cyclodextrin, dexamethasone are added in the moisture or water-free polar organic solvent, make it molten clear, add or do not add dilution water, steam organic solvent, obtain the aqueous solution of dexamethasone clathrate, other additives are dissolved in the proper amount of water for injection, mixed and be diluted to the concentration that needs promptly with the clathrate aqueous solution, filter, sterilization, encapsulate.
Optional six carbon of described polar organic solvent are with in interior alcohol, ketone, ether, organic amine or its their analog one or more; Preferred alcohol, acetone, oxolane, in one or more; Most preferred ethanol and acetone.The moisture requirement of this organic solvent is not high, can dissolve cyclodextrin derivative and 17-hydroxy-11-dehydrocorticosterone is as the criterion with process for preparation.Such as the ethanol water that can select 80%-96% for use, general medicinal alcohol (94%-96%) all can use; Be no more than 10% acetone such as moisture, can use.The dilution water that process for preparation adds can steam except that disposable adding before and after the organic solvent, also can gradation add; The method that adds such as dilution water is divided into concentrating to steam and adds once before removing, and concentrates to steam in the process of removing to add twice again; Perhaps divide three addings in the concentrated process of removing of steaming.The process for preparation temperature requirement is not strict, under 0-50 ℃ can, under the general room temperature 20-25 ℃ best.
The preferred water for injection of dilution water.If use aqueous organic solvent, under the situation that the enough whole process for preparation of its water content uses, can add dilution water, perhaps only add a spot of dilution water.
The weight ratio of dexamethasone and water is 1: 2 to 1: 500 during preparation dexamethasone enclose solution, and the weight ratio of dexamethasone and organic solvent is 1: 3 to 1: 200.The weight ratio of dexamethasone and water is preferably 1: 5 to 1: 100; The weight ratio of dexamethasone and organic solvent is preferably 1: 5 to 1: 50.
We find unexpectedly, compare with existing dexamethasone sodium phosphate injection, dexamethasone clathrate injection provided by the invention, prepared injection can be kept higher DEX blood drug level the long period when intravenous injection, thereby can in the curative effect of better bringing into play dexamethasone, reduce the concentration of DEX in the injection, thereby overcome the side effect of 17-hydroxy-11-dehydrocorticosterone.Simultaneously blood drug level detect the dexamethasone clathrate injection that shows gained in technical scheme provided by the invention can quick acting, it injects blood drug level in back one hour apparently higher than dexamethasone sodium phosphate (in the dexamethasone) injection of same concentration.And with compare without the enclose injection of preferred substitution value scope, the injection of gained of the present invention measured blood drug level on each sampling time point also significantly improves, may be substitution value scope according to one's analysis by preferred 2-HP-, make by the dexamethasone of the enclose speed of dissociating more stable, the speed of dissociating is faster, has produced fast, continued the technique effect of onset.During especially for the rescue critical patient, can often can produce the decisive role of saving life by medicine quicker, that continue onset, therefore dexamethasone clathrate injection provided by the invention has compared with prior art produced having produced also obvious improvement aspect the effect of rescuing for the critical patient, particularly preferred
In addition, because the preferred substitution value of 2-hydroxypropyl-cyclodextrin, the physicochemical properties of the feasible dexamethasone clathrate that makes are more consistent, therefore with dexamethasone injection of the prior art and not preferably the clathrate of 2-HP-substitution value compare, the stability of dexamethasone enclose injection provided by the invention is also better.
The specific embodiment:
The employed 2-HP-of embodiment of the invention 1-7 is commercially available, and substitution value is 4.1-5.9
Embodiment 1
Under the room temperature 20g 2-HP-is dissolved in (the substitution value scope is 4.1～5.9) 150ml acetone, add the 5g dexamethasone, stir molten clear, restir 30 minutes, micro-pore-film filtration (220nm), the water for injection of adding 200ml, stirred 5 minutes, concentrating under reduced pressure steams and removes solvent, obtains dexamethasone/2-hydroxypropyl-clathrate aqueous solution.
Other gets water for injection and adds 1g EDTA-2Na, phosphate buffered solution is transferred pH to 7.5, reuse sodium chloride transfers to etc. and to ooze, micro-pore-film filtration (220nm), join in aforementioned dexamethasone/3-hydroxypropyl beta cyclodextrin clathrate aqueous solution to 1000ml, filter, sterilize, encapsulate, gained injection concentration is 5mg/ml.
Embodiment 2
Under 40 ± 2 ℃ 4g 2-hydroxy propyl-Beta cyclodextrin (the substitution value scope is 4.1～5.9) is dissolved in the 80ml acetone, adds the 1g dexamethasone, stir molten clear, restir 30 minutes, micro-pore-film filtration (220nm), the water for injection of adding 6mL stirred 5 minutes, concentrating under reduced pressure, concentration process adds water for injection at twice, and each 6ml eliminates solvent, obtain dexamethasone/2-hydroxypropyl-enclose aqueous solution, standby.
Other gets water for injection and adds 1g EDTA-2Na; phosphate buffered solution is transferred pH to 6.5; reuse sodium chloride transfers to etc. and to ooze; micro-pore-film filtration (220nm); join in aforementioned dexamethasone/2-hydroxypropyl-clathrate aqueous solution to 1000ml; filter, sterilize, encapsulate, process for preparation carries out under nitrogen protection, and gained injection concentration is 1mg/ml.
Embodiment 3
Under the room temperature 28g hydroxy propyl-Beta cyclodextrin (the substitution value scope is 4.1～5.9) is dissolved in the 80ml dehydrated alcohol, add the 2g dexamethasone, stirs molten clearly, restir 30 minutes, micro-pore-film filtration (220nm), stirred 5 minutes, concentrating under reduced pressure, concentration process divide three times and add water for injection, each 15ml, steam and remove ethanol, obtain dexamethasone/HP-enclose aqueous solution, standby.
Other gets water for injection and adds 1g EDTA-2Na; phosphate buffered solution is transferred pH to 7; reuse sodium chloride transfers to etc. and to ooze; micro-pore-film filtration (220nm); join in aforementioned dexamethasone/3-hydroxypropyl beta cyclodextrin clathrate aqueous solution to 1000ml; filter, sterilize, encapsulate, process for preparation carries out under nitrogen protection, and gained injection concentration is 2mg/ml.
Embodiment 4
Under the room temperature 20g 2-HP-is dissolved in (the substitution value scope is 4.1～5.9) 80ml acetone, add the 5g dexamethasone, stir molten clear, restir 30 minutes, micro-pore-film filtration (220nm), the water for injection of adding 25ml, stirred 5 minutes, concentrating under reduced pressure steams and removes solvent, obtains dexamethasone/2-hydroxypropyl-beta-cyclodextrin inclusion aqueous solution.
Other gets water for injection and adds 1g EDTA-2Na; the 1g alpha-tocopherol; phosphate buffered solution is transferred pH to 7.5; reuse sodium chloride transfers to etc. and to ooze; micro-pore-film filtration (220nm) joins in aforementioned dexamethasone/3-hydroxypropyl beta cyclodextrin clathrate aqueous solution to 1000ml, filters, sterilization, encapsulation; process for preparation carries out under nitrogen protection, and gained injection concentration is 5mg/ml.
Embodiment 5
Under 40 ± 2 ℃ 40g 2-hydroxy propyl-Beta cyclodextrin (the substitution value scope is 4.1～5.9) is dissolved in the 100ml acetone, adds the 0.5g dexamethasone, stir molten clear, restir 30 minutes, micro-pore-film filtration (220nm), the water for injection of adding 25mL stirred 5 minutes, concentrating under reduced pressure, concentration process adds water for injection at twice, and each 15ml eliminates solvent, obtain dexamethasone/2-hydroxypropyl-enclose aqueous solution, standby.
Other gets water for injection and adds 1g EDTA-2Na; the 1g alpha-tocopherol; phosphate buffered solution is transferred pH to 6.5; reuse sodium chloride transfers to etc. and to ooze; micro-pore-film filtration (220nm) joins in aforementioned dexamethasone/2-hydroxypropyl-clathrate aqueous solution to 1000ml, filters, sterilization, encapsulation; process for preparation carries out under nitrogen protection, and gained injection concentration is 0.5mg/ml.
Embodiment 6
Under the room temperature 28g HP-(the substitution value scope is 4.1～5.9) is dissolved in the 100ml dehydrated alcohol, add the 2g dexamethasone, stirs molten clearly, restir 30 minutes, micro-pore-film filtration (220nm), stirred 5 minutes, concentrating under reduced pressure, concentration process divide three times and add water for injection, each 15ml, steam and remove ethanol, obtain dexamethasone/HP-enclose aqueous solution, standby.
Other gets water for injection and adds 1gEDTA-2Na; the 1g alpha-tocopherol; phosphate buffered solution is transferred pH to 7; reuse sodium chloride transfers to etc. and to ooze; micro-pore-film filtration (220nm) joins in aforementioned dexamethasone/3-hydroxypropyl beta cyclodextrin clathrate aqueous solution to 1000ml, filters, sterilization, encapsulation; process for preparation carries out under nitrogen protection, and gained injection concentration is 2mg/ml.
Embodiment 7
Under 40 ± 2 ℃ 2g 2-hydroxy propyl-Beta cyclodextrin (the substitution value scope is 4.1～5.9) is dissolved in the 20ml acetone, adds the 0.5g dexamethasone, stir molten clear, restir 30 minutes, micro-pore-film filtration (220nm), the water for injection of adding 3mL stirred 5 minutes, concentrating under reduced pressure, concentration process adds water for injection at twice, and each 15ml eliminates solvent, obtain dexamethasone/2-hydroxypropyl-enclose aqueous solution, standby.
Other gets water for injection and adds 1g EDTA-2Na; the 1g alpha-tocopherol; phosphate buffered solution is transferred pH to 6.5; reuse sodium chloride transfers to etc. and to ooze; micro-pore-film filtration (220nm) joins in aforementioned dexamethasone/2-hydroxypropyl-clathrate aqueous solution to 1000ml, filters, sterilization, encapsulation; process for preparation carries out under nitrogen protection, and gained injection concentration is 0.5mg/ml.
The used 2-HP-of embodiment 7-1 present embodiment is commercially available, and the substitution value scope is 2.8-10.5, and other technologies are identical with embodiment 7 with prescription
Embodiment 8 stable contrast experiments
The dexamethasone clathrate aqueous solution (2) that will make preparation among dexamethasone clathrate aqueous solution (1-1) and the Chinese patent application CN200610130124.7 embodiment 2 by dexamethasone clathrate aqueous solution (1), the embodiment 7-1 scheme that the embodiment of the invention 7 schemes make carries out stable contrast experiment.
The preparation of laboratory sample:
(1) and (2) respectively with water for injection dilution the becoming injection that dexamethasone sodium phosphate concentration is 1mg/ml, and are transferred to wait with sodium chloride and ooze, adopt the glass ampule encapsulation of 1ml specification, be respectively injection (1) and injection (2)
Stability experiment:
The injection that injection (1) and (2) make is got 15 respectively, and lucifuge is packaged in constant temperature placement under the hot conditions (60 ± 2 ℃), in, 0,5, indexs such as the content of sampling and detection medicine, clarity are taken a sample 5 at every turn during 10d.(
n＝5)
Stability test shows, adopt the stable content of the injection (1) of cyclodextrin inclusion compound and injection (1-1) will be higher than the dexamethasone sodium phosphate injection (2) of routine, having adopted substitution value is the injection (1-1) that the stable content of injection (1) of the 2-HP-of 4.1-5.9 also will be higher than substitution value 2.8-10.5.Illustrate that preferred substitution value scope can be so that the clathrate injection that makes stability be better.
Embodiment 9 pharmacokinetic parameters are measured
The dexamethasone clathrate injection of experiment medicine: embodiment of the invention 1-7 and embodiment 7-1 preparation is divided into experimental group 1～7 and experimental group 7-1.
Get commercially available dexamethasone sodium phosphate is mixed with 2mg/ml (in dexamethasone) with water for injection injection (3) (earlier water for injection is transferred to pH=7.5 with phosphate buffer, the injection that is mixed with transfers to etc. with sodium chloride and oozes)
Experimental facilities: Agilent 1100LC; The TGL-16G high speed centrifuge; Sartorious1712 type analysis balance
Chromatographic condition: methanol-0.02MKH
2PO
4(phosphoric acid is transferred pH to 4.0)-55:45; Dikma Diamosil-C18 (4.6 * 150mm, 5 μ m) chromatographic column; Detect wavelength 240nm, 30 ℃ of column temperatures, flow velocity 1mL/min.
Laboratory animal and administration: Cavia porcellus, male and female are not limit, and body weight 250～300g is divided into experimental group 1～7 and experimental group 7-1 and matched group 1 at random, every group 10, give embodiment 1～7 and embodiment 7-1 and homemade dexamethasone sodium phosphate injection (3) intravenous injection respectively.
Experimental technique: overnight fasting before the administration, every other experiment medicine of laboratory animal intravenous injection respective sets, dosage experimental group 1,4 injection 0.4ml (dexamethasone meter 2mg), other each experimental group injection 1ml, matched group injection 1ml (dexamethasone meter 2mg), experimental group and matched group are all in injection back 0.25h, 0.5h, 1h, 2h, 3h gets blood to the laboratory animal auricular vein, and 0.5ml takes a sample at every turn.The blood sample centrifugalize obtains blood plasma, adds doubling dose methanol, and mixing is centrifugal, gets supernatant and measures.In the different group animal blood slurrys dexamethasone (DEX) and dexamethasone sodium phosphate (DSP) concentration see the following form (
N=10)
Data from table as can be seen, be in dosage under the situation of 2mg (in dexamethasone), it is suitable to adopt the embodiment of the invention to make experimental group DEX blood drug level and matched group of laboratory animal when 0.5h of dexamethasone clathrate injection, and in 0.25～3h in other sample points its DEX blood drug level all be significantly higher than matched group (P＜0.05) with the time.When dosage is 2mg, the AUC of experimental group 0.25～3h animal subject DEX in the time after injection of employing embodiment of the invention gained injection is apparently higher than matched group, blood drug level data from all experimental grouies, the experimental group that adopts embodiment of the invention gained injection after injection in 0.25～3h inner blood DEX concentration discharge comparatively rapidly, can keep higher blood drug level of long period.In addition, be the experimental group of 2mg in dosage, the DEX blood drug level in the 0.25-1h of injection back is also apparently higher than matched group.Compare with experimental group 7 in addition, the employing substitution value is that the AUC of 0.25～1h animal DEX was lower after the experimental group 7-1 of the 2-HP-of 2.8-10.5 injected, and the clathrate injection that has demonstrated preferably the 2-HP-preparation of substitution value has remarkable result aspect the rapid release of effective ingredient.
Claims (10)
1. the dexamethasone injection of a 2-HP-enclose, the mol ratio of described dexamethasone and 2-HP-is 1: 1～20, it is characterized in that, used 2-HP-substitution value is preferably 4～7.
2. injection as claimed in claim 1, it is characterized in that the mol ratio of described dexamethasone and 2-HP-is preferably 1: 2～5.
3. as arbitrary described injection in the claim 1 to 2, it is characterized in that described dexamethasone content is 0.05%～1%.
4. as arbitrary described injection in the claim 1 to 3, it is characterized in that also can adding the pH regulator agent in the described injection, the pH of described injection preferably is adjusted to 5-7.
5. as arbitrary described injection in the claim 1 to 4, it is characterized in that to add in the described injection disodium edetate 0.01%-0.1% of chelating agen, as one or more 0.05%-0.2% in sodium sulfite, sodium sulfite, alpha-tocopherol, sodium pyrosulfite and the sodium thiosulfate of antioxidant, as in the 0.4%-0.9% sodium chloride of osmotic pressure regulator, 4%～5% glucose, 1%～2.5% glycerol one or more.
6. as arbitrary described injection in the claim 1 to 5, the compound method that it is characterized in that described injection is as follows: 2-hydroxy-beta-cyclodextrin, dexamethasone are added in the moisture or water-free polar organic solvent, make it molten clear, add or do not add dilution water, steam organic solvent, obtain the aqueous solution of dexamethasone clathrate, other additives are dissolved in the proper amount of water for injection, mixed and be diluted to the concentration that needs promptly with the clathrate aqueous solution, filter, sterilization, encapsulate.
7. injection as claimed in claim 6, the polar organic solvent preferred alcohol that adds when it is characterized in that described injection, one or more in acetone, the oxolane.
8. injection as claimed in claim 7, the polar organic solvent preferred alcohol that adds when it is characterized in that described injection, one or more in the acetone.
9. as arbitrary described injection in the claim 6 to 8, the weight ratio of dexamethasone and water when it is characterized in that preparing dexamethasone enclose solution: 1: 2 to 1: 500, the weight ratio of dexamethasone and organic solvent: 1: 3 to 1: 200.
10. injection as claimed in claim 9, the weight ratio of dexamethasone and water is preferred 1: 5 to 1: 100 when it is characterized in that preparing dexamethasone enclose solution, preferred 1: 5 to 1: 50 of the weight ratio of dexamethasone and organic solvent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102743396A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Cortical hormone alkali metal phosphate composition |
| CN102743398A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Dexamethasone sodium phosphate composition |
| US12090162B2 (en) | 2019-07-01 | 2024-09-17 | Oculis Operations Sárl | Treatment of diabetic retinopathy |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199855A (en) * | 2006-12-13 | 2008-06-18 | 天津药业研究院有限公司 | Skinniness hormone packing matter water solution and application thereof |
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2009
- 2009-06-24 CN CN2009100694083A patent/CN101926760A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199855A (en) * | 2006-12-13 | 2008-06-18 | 天津药业研究院有限公司 | Skinniness hormone packing matter water solution and application thereof |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102743396A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Cortical hormone alkali metal phosphate composition |
| CN102743398A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Dexamethasone sodium phosphate composition |
| CN102743396B (en) * | 2011-04-22 | 2015-04-08 | 天津金耀集团有限公司 | Cortical hormone alkali metal phosphate composition |
| CN102743398B (en) * | 2011-04-22 | 2015-07-15 | 天津金耀集团有限公司 | Dexamethasone sodium phosphate composition |
| US12090162B2 (en) | 2019-07-01 | 2024-09-17 | Oculis Operations Sárl | Treatment of diabetic retinopathy |
| US12090160B2 (en) | 2019-07-01 | 2024-09-17 | Oculis Operations Sárl | Stabilized dexamethasone compositions |
| US12090161B2 (en) | 2019-07-01 | 2024-09-17 | Oculis Operations Sàrl | Treatment of ocular inflammation |
| US12097209B2 (en) | 2019-07-01 | 2024-09-24 | Oculis Operations Sàrl | Diabetic retinopathy treatment with stabilized dexamethasone |
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Application publication date: 20101229 |