CN101439037A - Alprostadil lipid complexes and micelle composition thereof for injection - Google Patents
Alprostadil lipid complexes and micelle composition thereof for injection Download PDFInfo
- Publication number
- CN101439037A CN101439037A CNA200710158465XA CN200710158465A CN101439037A CN 101439037 A CN101439037 A CN 101439037A CN A200710158465X A CNA200710158465X A CN A200710158465XA CN 200710158465 A CN200710158465 A CN 200710158465A CN 101439037 A CN101439037 A CN 101439037A
- Authority
- CN
- China
- Prior art keywords
- injection
- alprostadil
- cholesterol
- lipid complexes
- micelle composition
- 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.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the pharmaceutical preparation field and relates to an alprostadil lipid compound, a micellar compound used in the injection of the alprostadil lipid compound and a preparation method of the alprostadil lipid compound. The alprostadil lipid compound and the micellar compound used in the injection of the alprostadil lipid compound are composed of alprostadil with a therapeutic dose, phospholipid, cholesterol sulfate or/and similar cholesterol derivative, additive and injection water. The alprostadil lipid compound and the micellar compound used in the injection of the alprostadil lipid compound have the advantages of small side effect, low blood vessel simulation, high drug-loading rate, narrow particle size distribution, capability of filtering and degerming, good pharmaceutical stability, etc.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of Alprostadil lipid complexes and injection micelle composition thereof.More particularly, the present invention relates to a kind of entrapment efficiency that improves, reduce zest, but Entkeimung and can stablize the Alprostadil lipid complexes of storage and its injection micelle composition of injection micelle composition and preparation method thereof.
Background technology
Alprostadil (PGE
1), have another name called prostaglandin E
1It is the extremely strong endogenous biological active substances of a kind of activity, pharmacological actions such as tangible expansion periphery and arteria coronaria blood vessel, anticoagulant, the formation of inhibition tremulous pulse medicated porridge sample lipid speckle are arranged, be used for the treatment of myocardial infarction, thrombophlebitis, atherosclerosis obliterans, the limbs chronic ulcer due to chronic arteria occlusion disease such as thromboangiitis obliterans, the atherosis disease of chronic arterial, extremity tranquillization pain due to the blood capillary circulatory disturbance also can be used for the thromboembolism preventing treatment of blood vessel transplantation postoperative.Alprostadil is a white, needle-shaped crystals, and is easily molten in ethanol, slightly soluble in the water.At present domestic existing how tame pharmaceutical manufacturer production injection Alprostadil, but Alprostadil is very unstable in water, easily degrades, and the quite a few untoward reaction of Alprostadil in addition makes its pharmacologically active be difficult to normal performance.
Cholesterol is a kind of neutral lipid, also belong to parents' molecule, but lipophile is better than hydrophilic, and there is certain similarity in the structure of its structure and cholic acid, shown in chemical formula,
The cholic acid cholesterol
Can form a hydrophilic radical after the cholesterol molecule derived and become amphiphatic molecule, its amphoterisation method is with the salify of deriving of the hydroxyl in the molecule, can be made into sulfate, phosphate and sulfonate etc. usually.The cholesterol salt that forms after this process is derived has nontoxic, non-irritating characteristics, exist certain similarity with cholate on the structure, in water the cholesterol molecule of some drug molecules and amphoterisation by lipotropy part hydrophobic force and may be also polarity affinity by hydrophilic parts, and form polymolecular complex according to certain molecule mole ratio.This complex has following characteristics:
1. formed this complex evenly and stably is scattered in the aqueous medium with colloidal form, can concentrate arbitrarily within the specific limits, is suitable as the carrier of high dose medicament.
2. because the cholesterol molecule and the drug molecule of amphoterisation combine with certain mole ratio, covered the structure of drug molecule, drug molecule contacts with the direct of tissue when having avoided drug administration by injection, can solve the zest problem of medicine.
3. the particle diameter of this complex generally below 100nm, accepted by the patient easily for slightly opalescent clear and bright solution by outward appearance, and because the complex particle diameter is little, but filtration sterilization has guaranteed the safety of administrated by injection.
4. under proper condition, the cholesterol molecule of amphoterisation can disperse in aqueous medium automatically with medicine, need not special handling, and preparation process is simple, and preparation is with low cost.
5. has good physical and chemical stability.
The preparation technology of Alprostadil lipid complexes that this law provides and injection micelle composition thereof is simple, and preparation is with low cost, and stability is stronger, and medicine is difficult for dissociating out from composite system, is expected to solve the zest of medicine in the injection site.Cholesterol sulfate and analog thereof also can produce the commissure effect with hydrophilic head and two hydrophobic afterbodys of phospholipid, increase the drug loading of Alprostadil.
Summary of the invention
An object of the present invention is to provide a kind of novel form of Alprostadil, promptly a kind of Alprostadil lipid complexes and injection micelle composition thereof, said preparation make Alprostadil have higher chemical stability, are difficult for degraded; Reduced the local irritation of Alprostadil, improved patient's compliance, added long circulation adjuvant and also can avoid reticuloendothelial system phagocytic in the body, prolong drug effective time.
Another purpose of the present invention provides a kind of method for preparing Alprostadil lipid complexes of the present invention and its injection micelle composition of injection micelle composition thereof.
For achieving the above object, the invention provides a kind of Alprostadil lipid complexes and injection micelle composition thereof, form by Alprostadil, phospholipid, cholesterol sulfate or similar cholesterol derivative, additives, long circulation adjuvant and the water for injection of treatment effective dose.
In technique scheme, Alprostadil lipid complexes provided by the invention and injection micelle composition thereof contain following composition:
Alprostadil 0.000001～5wt%
Cholesterol sulfate or similar cholesterol derivative 0.0001～20wt%
Long circulation adjuvant 0～15wt%
Additives 0～15wt%
The water for injection surplus.
Described phospholipid comprises the phospholipid of natural origin and the phospholipid in synthetic source, the phospholipid of the phospholipid of described natural origin for extracting by physical refining processes from plant or animal is as soybean lecithin, Ovum Gallus domesticus Flavus lecithin, cephalin, phosphatidylinositols, sphingomyelin, serinephosphatide etc.; The phospholipid in described synthetic source is by phospholipid semi-synthetic or that synthetic method makes, as hydrogenated phospholipid, polyene phosphatidylcholine, DMPC, DPPC, DMPG, DPPG, DPPE, DSPE, DPPA, DSPA and structural modification thing thereof such as PEGization derivant DSPE-PEG2000 etc.Preferably, this phospholipid is soybean lecithin.
Described cholesterol sulfate is or/and similar cholesterol derivative comprises above-mentioned cholesterol derivative and the combination in any thereof that cholesterol sodium sulfate, cholesterol potassium sulfate, cholesterol sodium phosphate, cholesterol potassium phosphate, cholesterol sodium sulfonate, cholesterol potassium sulfonate and alternate manner are modified.Preferably this cholesterol sulfate is a cholesterol sodium sulfate.
Described long circulation adjuvant is 1000～10000 stearate for the PEG molecular weight for the PEG molecular weight; the PEG molecular weight is 1000～10000 vitamin e succinate; PEG stearate and molecular weight are the mixture of 200～10000 PEG; the Myrj class; the Brij class; PEG-distearyl acyl group PHOSPHATIDYL ETHANOLAMINE; PEG-dipalmitoyl phosphatidyl choline; PEG-two palmityl PHOSPHATIDYL ETHANOLAMINE; ganglioside; polyacrylamide; chitosan; Polyethylene Glycol gathers cetyl itrile group propionic ester; molecular weight is 200～10000 PEG; PVP or PVA and combination in any thereof.Preferably ganglioside, PEG-distearyl acyl group PHOSPHATIDYL ETHANOLAMINE, PEG-dipalmitoyl phosphatidyl choline and combination in any thereof.
Alprostadil lipid complexes provided by the invention and injection micelle composition thereof further comprise the additives of 0～15wt%, preferably include the additives of 0～5wt%.Described additives can play increases preparation stability, regulate effects such as osmotic pressure, antioxidation, is selected from osmotic pressure regulator, as glycerol, propylene glycol, mannitol etc.; The interfacial film stabilizing agent is as oleic acid, enuatrol etc.; The complexing of metal ion agent is pressed Sequestrene AA, calcium salt etc. as EDTA, second two; Antiseptic is as benzalkonium bromide, Benzalkonii Chloridum, parabens, sorbic acid etc.; Antioxidant is as vitamin C, vitamin E etc.; Molecular weight is 200～10000 PEG, PVP or PVA and combination in any thereof.Preferably, these additives are glycerol, mannitol, enuatrol, EDTA, vitamin C, vitamin E, PEG and combination in any thereof.
Alprostadil lipid complexes provided by the invention and injection micelle composition thereof have the following advantages:
1, compare with the injection of Alprostadil, preparation of the present invention is wrapped in the lipid complex Alprostadil, and the minimizing medicine contacts with water, but and Entkeimung, reduce the Alprostadil inactivation that high temperature sterilize causes, make it stability increase and zest and reduce.
2, compare with Emulsion, the liposome of Alprostadil, preparation of the present invention is modified the lipid complex surface by long circulation adjuvant, and what help avoid the interior liver spleen reticuloendothelial system of body engulfs prolong drug circulation time in vivo.
3, preparation of the present invention can dilute or disperses with normal saline or glucose injection, be used for intravenous administration, lipid complex granularity little (particle mean size is less than 100nm) in the optimal technical scheme, narrow distribution, but Entkeimung, and the entrapment efficiency height helps to improve injection safety.
The present invention also provides the preparation method of a kind of Alprostadil lipid complexes of the present invention and injection micelle composition thereof, and this method may further comprise the steps:
(1) with Alprostadil, phospholipid, cholesterol sulfate or the similar cholesterol derivative of recipe quantity or, long circulation adjuvant, additives be scattered in the organic solvent, to constitute organic facies;
(2) will grow the circulation adjuvant, additives are dissolved in the water for injection, to constitute water;
(3) under 0～60 ℃ temperature, stirring or/and under the shear conditions described organic facies and water are mixed, adopt method such as reduction vaporization to remove organic solvent again, thereby make Alprostadil lipid complexes and injection micelle composition thereof.
(4) with gained Alprostadil lipid complexes and injection micelle composition thereof filter membrane Entkeimung, packing with 0.22 μ m.
Can further carry out the lyophilizing processing or place 4 ℃ of lower seals preservations Alprostadil lipid complexes and the injection micelle composition thereof that makes.Wherein, resulting Alprostadil lipid complexes and injection micelle composition thereof are carried out the technology that lyophilizing handles be can be: the freeze drying protectant of 1～40wt% (weight ratio) is dissolved in the aqueous dispersion of Alprostadil lipid complexes of the present invention and injection micelle composition thereof; this freeze drying protectant is selected from trehalose; mannitol; sucrose; glucose; sodium chloride; lactose; sorbitol; dextran; glycerol or glycine and combination in any thereof; be sub-packed in the cillin bottle then; and place freezer dryer-45 ℃ pre-freeze 3h; be warming up to-50 ℃ with 5 ℃/h then; keep 10h; be warming up to 0 ℃ with 5 ℃/h again; keep 8h; be warming up at last 10 ℃ the insulation 10 hours after outlet, jump a queue the sealing get final product.
Description of drawings
Fig. 1 is the particle size distribution figure of Alprostadil lipid complexes and injection micelle composition thereof.
Fig. 2 is NaCl injection negative control group blood vessel irritation test section result
Fig. 3 is commercially available injection Alprostadil group blood vessel irritation test section result
Fig. 4 is Alprostadil lipid complexes and injection micelle composition group blood vessel irritation test section result thereof
The specific embodiment
Get Alprostadil 10mg, Ovum Gallus domesticus Flavus lecithin 2.0g, cholesterol sodium sulfate 400mg, vitamin E 10mg is dissolved in 30 ℃ the methanol as organic facies; PEG400 0.5g is dissolved in the 90ml water for injection, be heated to 30 ℃ as water, under 30 ℃ of stirrings, organic facies is injected water, continue to stir 5min, the decompression rotation boils off methanol again, must be with blue opalescent Alprostadil lipid complexes and injection micelle composition thereof, add the injection water mend to cumulative volume be 100ml, with the microporous filter membrane Entkeimung of 0.22 μ m.
To add the trehalose of 5% (w/v) in the Alprostadil lipid complexes of gained and the injection micelle composition aqueous dispersion thereof, lyophilization under the sterile working, packing are promptly.
Preparation after the lyophilizing is diluted with normal saline, and surveying its mean diameter is 72.8 ± 19.8nm (seeing accompanying drawing 1).
Get Alprostadil 20mg, soybean lecithin 3.0g, cholesterol sodium sulfate 500mg is dissolved in 35 ℃ the dehydrated alcohol as organic facies; PEG200 1.0g is dissolved in the 90ml water for injection, be heated to 35 ℃ as water, under 35 ℃ of stirrings, organic facies is injected water, continue to stir 10min, decompression rotation boils off ethanol again, must be with blue opalescent Alprostadil lipid complexes and injection micelle composition thereof, add the injection water mend to cumulative volume be 100ml, with the microporous filter membrane Entkeimung of 0.22 μ m, packing promptly.
Embodiment 3
Get Alprostadil 500mg, soybean lecithin 10g, cholesterol sodium sulfonate 5g is dissolved in 35 ℃ the oxolane as organic facies; Poloxamer 188 5g are dissolved in the 950ml water for injection, be heated to 35 ℃ as water, under 35 ℃ of stirrings, organic facies is injected water, continue to stir 10min, the decompression rotation boils off oxolane again, must be with blue opalescent Alprostadil lipid complexes and injection micelle composition thereof, add the injection water mend to cumulative volume be 1000ml, with the microporous filter membrane Entkeimung of 0.22 μ m.
To add the trehalose of 5% (w/v) in the Alprostadil lipid complexes of gained and the injection micelle composition aqueous dispersion thereof, lyophilization under the sterile working, packing are promptly.
Embodiment 4
Table 1 has been enumerated the specification (in Alprostadil) of prescription and the lyophilized injection and the injection of several Alprostadil lipid complexes and injection micelle composition micelle composition thereof, but used prescription composition, each ratio of adjuvant and preparation specification are not limited to the listed concentration of following table.Preparation method and technology are with embodiment 1-3.
Table 1 Alprostadil lipid complexes and injection micelle composition prescription thereof
| Preparation specification (in Alprostadil) | Phospholipid | Cholesterol sulfate is or/and similar cholesterol derivative | Long circulation adjuvant | Freeze drying protectant | Additives | Water for injection |
| 20 μ g/ prop up | Soybean phospholipid (1%) | Cholesterol sodium sulfate (0.4%) | — | Trehalose (5%) | — | Mend to capacity (removing with lyophilization at last) |
| 40μg/ | Egg yolk phosphorus | Cholesterol sulphuric acid | PEG | Lactose/ | Support one's family | Mend to foot |
| {。##.##1}, | Fat (2%) | Potassium (0.6%) | 4000 vitamin e succinate (0.1%) | Mannitol (6%) | Plain C (0. 01%) | Amount (removing with lyophilization at last) |
| 100 μ g/ prop up | Sphingomyelin/soybean phospholipid (3%) | Cholesterol sodium sulfonate (2%) | PEG-10 000 vitamin E succinate (0.05 %) | Sucrose/mannitol (6%) | Enuatrol (0. 2%) | Mend to capacity (removing with lyophilization at last) |
| 200 μ g/ prop up | Hydrogenated phospholipid (2.5%) | Cholesterol potassium sulfonate (1.5%) | — | Sucrose (5%) | — | Mend to capacity (removing with lyophilization at last) |
| 500 μ g/ prop up | Polyene phosphatidylcholine (2%) | Cholesterol sodium phosphate (1.5%) | |
Trehalose/dextran (15 | Vitamin E (0. 01%) | Mend to capacity and (remove with lyophilization at last |
| ) | ％) | Go) | ||||
| 10μ g/ml | DMPC/DP PC/ soybean phospholipid (0.8%) | Cholesterol potassium phosphate (0.2%) | |
— | — | Mend to capacity |
| 20μ g/ml | DMPG/DP PG (1.2％) | Cholesterol sodium sulfate/cholesterol potassium sulfonate (0.4%) | PEG100 00— DPPP (0.2％ ) | — | — | Mend to capacity |
| 50μ g/ml | DPPE/DS PE/ hydrogenated phospholipid (2%) | Cholesterol potassium sulfate (0.7%) | Chitosan (0.5%) | — | — | Mend to capacity |
| 100μ g/ml | DPPA/DS PA/ lecithin (2.2%) | Cholesterol sodium sulfonate (1%) | Polyethylene Glycol gathers cetyl itrile group propionic ester (0.2%) | — | — | Mend to capacity |
| 200μ g/ml | DSPE-PE G2000/ egg yolk lecithin (2.5%) | Cholesterol potassium sulfonate (1%) | Ganglioside (0.6%) | — | — | Mend to capacity |
Embodiment 5
According to the new drug guideline, adopt the preparation of embodiment 1 to carry out following several security inspections.
(1) irritation test
Get 6 of healthy rabbits and be individually fixed in the rabbit hutch, be divided into 2 groups at random, every group of 3 rabbit, left and right sides auricular vein instil respectively normal saline and injection Alprostadil, Alprostadil lipid complexes injection micelle composition suspension.Be that left ear is given normal saline, auris dextra is given injection Alprostadil or Alprostadil lipid complexes injection micelle composition suspension (the sodium chloride injection dilution with 0.9%).The injection Alprostadil is identical with Alprostadil lipid complexes injection micelle composition dosage, only is 10 μ g/, and overall solution volume is 12ml//time.Left side ear auricular vein instillation normal saline, dropped amount and drip velocity are with inspection product group.Respectively instil every day 1 time, for three days on end, observe the reaction of rabbit ear edge venous stimulation.Behind last administration 24h,, take off two ears and carry out tissue slice inspection (slice position is apart from inserting needle position 2.6cm),, be designated as "-" according to lesion degree with the rabbit sacrificed by exsanguination, "+", " ++ ", " +++", " ++ ++ ".The section pathological examination is the result show:
1) an auricular vein tube wall of respectively drawing materials of left ear negative control (sodium chloride injection) is complete, and blood vessel does not have obvious expansion.Clear, the no swelling of endotheliocyte, necrosis, the obvious inflammatory cell infiltration of tube wall and Guan Zhouwu is not seen pathological changes such as thrombosis in the tube wall.See accompanying drawing 2.
2) auris dextra positive control (injection Alprostadil) group respectively draw materials a blood vessel obviously expansion be " ++ ", endotheliocytic swelling, necrosis are " ++ ", see that thrombosis is " ++ ", the hemorrhage and inflammatory cell infiltration of tube wall and Guan Zhoujian is " +++".See accompanying drawing 3.
3) an auricular vein tube wall of respectively drawing materials of auris dextra Alprostadil lipid complexes and injection micelle composition group thereof is complete, and blood vessel does not have obvious expansion.Do not see pathological changes such as thrombosis in the tube chamber.Alprostadil lipid complexes and the morphology of injection micelle composition group thereof are significantly better than commercially available injection Alprostadil group, no obvious irritation.See accompanying drawing 4.
Result of the test shows that Alprostadil lipid complexes and injection micelle composition thereof are not seen the obvious stimulation effect to tame rabbit ear vein blood vessel.
(2) hemolytic test
Get tame Sanguis Leporis seu oryctolagi 10mL, place the centrifuge tube that scribbles heparin, the centrifugal 5min of 4000rpm, discard upper plasma, with hemocyte repeatedly with normal saline 10mL flushing, the centrifugal supernatant of removing in each flushing back, till supernatant does not take on a red color, draw a certain amount of erythrocyte then, the red blood cell suspension of dilution preparation by volume 2%, 4 ℃ of refrigerator and cooled are hidden standby.Recording mode:
"---" coagulation: haemolysis not, but it is agglomerating red blood cell condensation to occur, can separate again after rocking.
"-" be haemolysis not: erythrocyte all sinks, and the upper strata is faint yellow muddy slightly solution.
"+" part haemolysis: solution is faint yellow or light red, and the test tube bottom has a small amount of erythrocyte residual.
" ++ " haemolysis: solution takes on a red color, and the no erythrocyte in test tube bottom is residual.
Table 2 hemolytic result of the test
The result shows that made Alprostadil lipid complexes injection micelle composition solution does not cause erythrocytic hemolytic reaction, meets intravenous standard.
(3) sensitivity test
The result shows that made Alprostadil lipid complexes injection micelle composition solution does not cause the Cavia porcellus anaphylaxis, meets intravenous standard.
Claims (10)
1, a kind of Alprostadil lipid complexes and injection micelle composition thereof, by the Alprostadil, phospholipid, cholesterol sulfate of treatment effective dose or/and similar cholesterol derivative, additives and water for injection form.
2, Alprostadil lipid complexes according to claim 1 and injection micelle composition thereof, contain following composition:
Alprostadil 0.000001～5wt%
Phosphatidase 10 .0001～20wt%
Cholesterol sulfate is or/and similar cholesterol derivative 0.0001～20wt%
Long circulation adjuvant 0～15wt%
Additives 0～15wt%
The water for injection surplus.
3, according to each described Alprostadil lipid complexes of claim 1～2 and injection micelle composition thereof, wherein said phospholipid is selected from the phospholipid and the combination in any thereof in all natural origins and synthetic source.
4, Alprostadil lipid complexes according to claim 3 and injection micelle composition thereof, the phospholipid of the phospholipid of wherein said natural origin for extracting by various processing methods from plant or animal is as soybean phospholipid, egg yolk lecithin, cephalin, phosphatidylinositols, sphingomyelin, serinephosphatide; The phospholipid in described synthetic source is by phospholipid semi-synthetic or that synthetic method makes, as hydrogenated phospholipid, polyene phosphatidylcholine, DMPC, DPPC, DMPG, DPPG, DPPE, DSPE, DPPA, DSPA and structural modification thing thereof such as PEGization derivant DSPE-PEG2000.
5, according to each described Alprostadil lipid complexes of claim 1～2 and injection micelle composition thereof, wherein said cholesterol sulfate is or/and similar cholesterol derivative comprises above-mentioned cholesterol derivative and the combination in any thereof that cholesterol sodium sulfate, cholesterol potassium sulfate, cholesterol sodium phosphate, cholesterol potassium phosphate, cholesterol sodium sulfonate, cholesterol potassium sulfonate and alternate manner are modified.
6; according to each described Alprostadil lipid complexes of claim 1～2 and injection micelle composition thereof, wherein said long circulation adjuvant is 1000～10000 stearate for the PEG molecular weight; the PEG molecular weight is 1000～10000 vitamin e succinate; PEG stearate and molecular weight are the mixture of 200～10000 PEG; the Myrj class; the Brij class; PEG-distearyl acyl group PHOSPHATIDYL ETHANOLAMINE; PEG-dipalmitoyl phosphatidyl choline; PEG-two palmityl PHOSPHATIDYL ETHANOLAMINE; ganglioside; polyacrylamide; chitosan; Polyethylene Glycol gathers cetyl itrile group propionic ester; molecular weight is 200～10000 PEG; PVP or PVA and combination in any thereof.
7, according to each described Alprostadil lipid complexes of claim 1～2 and injection micelle composition thereof, it is 200～10000 PEG, PVP or PVA and combination in any thereof that wherein said additives are selected from osmotic pressure regulator, interfacial film stabilizing agent, complexing of metal ion agent, antiseptic, antioxidant, molecular weight.
8, a kind of method for preparing each described Alprostadil lipid complexes in the claim 1～7 and injection micelle composition thereof, this method may further comprise the steps:
(1) with Alprostadil, phospholipid, cholesterol sulfate or the similar cholesterol derivative of recipe quantity or, long circulation adjuvant, additives be scattered in the organic solvent, to constitute organic facies;
(2) will grow the circulation adjuvant, additives are dissolved in the water for injection, to constitute water;
(3) under 0～60 ℃ temperature, stirring or/and under the shear conditions described organic facies and water are mixed, adopt method such as reduction vaporization to remove organic solvent again, thereby make Alprostadil lipid complexes and injection micelle composition thereof.
(4) with gained Alprostadil lipid complexes and injection micelle composition thereof filter membrane Entkeimung, packing with 0.22 μ m.
9, method according to claim 8, wherein said organic solvent is selected from dichloromethane, chloroform, acetone, methanol, ethanol, ether, oxolane or isopropyl alcohol and combination in any thereof; Further add freeze drying protectant to make lyophilized formulations to described Alprostadil lipid complexes that makes and injection micelle composition thereof.
10, according to Claim 8 or 9 described methods, wherein said freeze drying protectant is selected from trehalose, mannitol, sucrose, glucose, sodium chloride, lactose, sorbitol, dextran, glycine and combination in any thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710158465XA CN101439037A (en) | 2007-11-22 | 2007-11-22 | Alprostadil lipid complexes and micelle composition thereof for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710158465XA CN101439037A (en) | 2007-11-22 | 2007-11-22 | Alprostadil lipid complexes and micelle composition thereof for injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101439037A true CN101439037A (en) | 2009-05-27 |
Family
ID=40723737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200710158465XA Pending CN101439037A (en) | 2007-11-22 | 2007-11-22 | Alprostadil lipid complexes and micelle composition thereof for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101439037A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103315999A (en) * | 2013-07-05 | 2013-09-25 | 四川省惠达药业有限公司 | Compound amino acid composition and preparation method thereof |
| CN104138383A (en) * | 2013-05-08 | 2014-11-12 | 亚宝药业集团股份有限公司 | Pharmaceutical composition for cardiovascular disease treatment and preparation method thereof |
| CN109828046A (en) * | 2019-02-25 | 2019-05-31 | 浙江长典医药有限公司 | A kind of detection method of alprostadil injection |
| CN109820820A (en) * | 2019-02-25 | 2019-05-31 | 浙江长典医药有限公司 | A kind of alprostadil injection and preparation method thereof |
-
2007
- 2007-11-22 CN CNA200710158465XA patent/CN101439037A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104138383A (en) * | 2013-05-08 | 2014-11-12 | 亚宝药业集团股份有限公司 | Pharmaceutical composition for cardiovascular disease treatment and preparation method thereof |
| CN103315999A (en) * | 2013-07-05 | 2013-09-25 | 四川省惠达药业有限公司 | Compound amino acid composition and preparation method thereof |
| CN103315999B (en) * | 2013-07-05 | 2015-04-01 | 四川省惠达药业有限公司 | Compound amino acid composition and preparation method thereof |
| CN109828046A (en) * | 2019-02-25 | 2019-05-31 | 浙江长典医药有限公司 | A kind of detection method of alprostadil injection |
| CN109820820A (en) * | 2019-02-25 | 2019-05-31 | 浙江长典医药有限公司 | A kind of alprostadil injection and preparation method thereof |
| CN109820820B (en) * | 2019-02-25 | 2021-12-21 | 浙江长典药物技术开发有限公司 | Alprostadil injection and preparation method thereof |
| CN109828046B (en) * | 2019-02-25 | 2022-04-22 | 浙江长典药物技术开发有限公司 | Detection method of alprostadil injection |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2734236C2 (en) | Bendamustine and cyclopolysaccharide compositions | |
| CN103040748B (en) | Pemetrexed disodium liposome injection | |
| JPH0262829A (en) | Preventive and remedy for trauma caused by ischemia | |
| CN101439033A (en) | Polyenic taxusol lipid complexes and micelle composition thereof for injection | |
| CN101439032A (en) | Paclitaxel lipid complexes and micelle composition thereof for injection | |
| CN102579341A (en) | Docetaxel solid lipid nanoparticle and preparation method thereof | |
| CN103432013A (en) | Preparation method of anthocyanin lipidosome | |
| CN103655487B (en) | Injection alprostadil freeze-dried emulsion | |
| CN101439037A (en) | Alprostadil lipid complexes and micelle composition thereof for injection | |
| CN102526065B (en) | Compound injection preparation for treating cardiovascular and cerebrovascular diseases and preparation method thereof | |
| CN101439034A (en) | Tanshinone IIA lipid complexes and micelle composition thereof for injection | |
| CN103622909A (en) | Cardiolipin-containing new liposome preparation, and its application in antitumor drugs | |
| CN102626390B (en) | Gastrodin multiphase liposome injection | |
| CN105287406A (en) | Propofol liposome freeze-drying preparation and preparation method thereof | |
| CN102805729A (en) | Vinflunine liposome preparation and preparation method of vinflunine liposome preparation | |
| CN109562068A (en) | Micro- rouge body composition containing faintly acid agent | |
| CN102058531B (en) | Preparation method of fat emulsion of cerebral protection therapeutic drug | |
| CN102552149B (en) | Calcium heparin liposome preparation for injection | |
| CN102579347B (en) | Thymalfasin liposome preparation for injecting | |
| CN102512379A (en) | Novel Echinocandin antifungal pharmaceutical composition and preparation method thereof | |
| CN101797264B (en) | Amphotericin B lipid complex for injection and preparation method thereof | |
| CN101849915A (en) | Vinorelbine stealth liposome freeze-dried powder injection and preparation method thereof | |
| CN102048740B (en) | Liposome injection prepared from ceftriaxone sodium tazobactam sodium medicinal composition | |
| CN104546718B (en) | A kind of long circulating Rabeprazole liposome composition and its preparation method and application | |
| CN105497871A (en) | Liposome lyophilized composition of carfilzomib drug and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090527 |