CN103110579A - Alprostadil injection - Google Patents
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- CN103110579A CN103110579A CN2013100543145A CN201310054314A CN103110579A CN 103110579 A CN103110579 A CN 103110579A CN 2013100543145 A CN2013100543145 A CN 2013100543145A CN 201310054314 A CN201310054314 A CN 201310054314A CN 103110579 A CN103110579 A CN 103110579A
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Abstract
The invention belongs to the field of a pharmaceutical preparation, and in particular relates to an alprostadil injection. The injection consists of 0.001-0.05mg/ml of alprostadil, 0.01-100mg/ml of an oil phase, 10-500mg/ml of phospholipid and the balance of an organic solvent. The injection disclosed by the invention is constantly an anhydrous system in storage process, and is used right as long as being ready, so that the injection can prevent oxidization reaction of the phospholipid and degradation reaction of the medicine, and can improve the stability of the alprostadil injection. An alprostadil composition provided by the invention can prepare the alprostadil injection which is excellent in stability, and the preparation process is quite simple.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to the alprostadil injection agent.
Background technology
Alprostadil has another name called prostaglandin E
1(Alprostadil), english abbreviation is PGE
1, it is the extremely strong endogenous biological active substances of a kind of activity, and obvious blood vessel dilating, anticoagulant isoreactivity are arranged.Listing is its lyophilized injectable powder the earliest, and because metabolism is very fast in vivo, under pulmonary's oxidase effect, the per pass pulmonary circulation namely has 60%～90% inactivation, and dosage is large, and the blood vessel pain of generation makes patient's endurable.
1988 at Japan's lipoalprostadil that gone on the market; PGE1 is enclosed in the lipoid microsphere that diameter is 0.2 μ m; lipoid microsphere is desirable pharmaceutical carrier; lesion vessels there is special affinity; PGE1 can be transported to specific diseased region, under the barrier protection of lipoid microsphere, PGE1 obviously reduces at the inactivation rate of pulmonary simultaneously; original lyophilized injectable powder dosage is reduced to 1/10th, has greatly reduced side effect.Domestic Initial Public Offering in 1998 alprostadil injection (come from Japan lipomul), trade name: when triumphant.Adopt traditional fat milk preparation technology when triumphant, as high-temperature sterilizing process, the content of Alprostadil is reduced obviously, and the content of its catabolite PGA1 significantly grows tall.State quality standard WS1-(X-041 when triumphant) in 2002Z-2008, the limit of impurities of PGA1 is decided to be 3.0 μ g/ml, medicine specification 5 μ g/ml when triumphant up to 60%().For fear of the impact of high temperature sterilize on Alprostadil stability, reduce simultaneously product to storing and the harsh requirement of transportation, the Alprostadil dry emulsion is in Initial Public Offering at home in 2010, trade name: excellent Supreme Being you.Your preparation method of excellent Supreme Being is first to utilize traditional fat milk technique to prepare fat milk, then by aseptic filtration, then adds the freeze drying protectant lyophilizing to make.Compare when triumphant, you have many advantages, 1/6 the when limit of its catabolite PGA1 is only also triumphant storing the transporter mask excellent Supreme Being.
Be the pharmaceutical carrier of Alprostadil relative ideal due to lipomul, people this area research worker groundwork in recent years still concentrates on existing fat milk and lyophilizing breast is improved.Chinese patent CN102178650 discloses a kind of stable alprostadil injection Emulsion and preparation method thereof, the method is to form blended emulsifier with a certain amount of PLURONICS F87 and soybean phospholipid, the preparation lipomul, can tolerate and excessively kill method, can significantly improve the chemical stability of Alprostadil.Yet poloxamer belongs to the Polymer Synthesizing adjuvant, and consumption is crossed conference and caused the side effect such as blood pressure lowering and haemolysis.Chinese patent CN101716147 discloses a kind of Alprostadil liposome microsphere preparation that comprises stabilizing agent, is to add the stabilizing agents such as oleic acid and vitamin E on the basis when triumphant, prevents the phospholipid bilayer of drug degradation and firm lipoid microsphere.Patent CN102228446 discloses a kind of Alprostadil lipid nanosphere freeze-drying injection and preparation method thereof; be prepared into particle diameter less than the nanoparticles lyophilized preparation of 100nm by emulsifying agent phospholipid, co-emulsifier polyethyleneglycol-12-hydroxy stearin, midchain oil and freeze drying protectant etc., impurity PGA1 is less than 5%.
No matter the chemical stability extreme difference of Alprostadil is in production process or in storage process, and Alprostadil is all unstable to water and heat, and all easily degraded produces PGA1.In existing many technology, though can solve its storage-stable by lyophilizing, the drug degradation that also can avoid autoclaving to bring simultaneously, the fat milk before lyophilizing still adopts conventional fat milk preparation technology (colostrum, high pressure homogenize) preparation.Fat milk preparation process relative complex, the participation of water need to be arranged, form Water-In-Oil or oil-in-water system, and can produce localized hyperthermia in the high pressure homogenize process, these processes inevitably cause degraded and the phospholipid oxidation of Alprostadil, thereby have affected the stability of medicine.
Summary of the invention
A kind of alprostadil injection agent provided by the invention can obtain the alprostadil injection agent of good stability.
Technical scheme of the present invention is achieved in that
The alprostadil injection agent comprises:
Alprostadil 0.001-0.05mg/mL;
Oil phase 0.01-100mg/mL;
Phosphatidase 11 0-500mg/mL;
All the other are organic solvent;
Described phospholipid comprises at least with lower a kind of: natural phospholipid, synthetic phospholipid;
Described oil phase comprises at least with lower a kind of: soybean oil, Semen Maydis oil, Oleum Ricini, olive oil, Oleum Cocois, Oleum Arachidis hypogaeae semen, fish oil, Oleum Gossypii semen, glyceryl monostearate, glyceryl monooleate, Oleum sesami, safflower oil, C
6-C
8Fatty acid triglycercide, ethyl oleate;
Described organic solvent comprises at least with lower a kind of: ethanol, glycerol, propylene glycol, Polyethylene Glycol.
Further, described natural phospholipid comprise with lower one or more: Ovum Gallus domesticus Flavus lecithin, soybean lecithin.
Further; described synthetic phospholipid comprise with lower one or more: hydrogenated soybean lecithin, DOPC, DMPEA, DPPE, two myristoyl Phosphatidylserine, DSPE, DLPC, two myristoyl lecithin, DPPC, distearoylphosphatidylcholine, distearoylphosphatidylcholine, MPPC, and their polyethylene glycol derivative.
Further, described Polyethylene Glycol is selected from the Polyethylene Glycol that molecular weight ranges is 200-2000.
Further, described oil phase is saturated Trivent OCG, and/or saturated tricaprin.
Further, also comprise following one or more: stabilizing agent, pH value regulator, antioxidant and co-emulsifier.
Further, described stabilizing agent comprise following one or more: cholesterol, polyethylene glycols and derivant thereof, glycerol, xylitol, sorbitol, mannitol, carbamide, sodium salicylate, phosphatidic acid, oleic acid, enuatrol, cholic acid, sodium cholate, hypromellose, sodium carboxymethyl cellulose, starch and derivant thereof, poloxamer, gelatin and derivant thereof, alginic acid and sodium salt thereof, polyvinylpyrrolidone, HP-β-CD.
Further, described pH value regulator comprise following one or more: maleic acid, hydrochloric acid, tartaric acid, sodium hydroxide, acetic acid, acetate, phosphoric acid, phosphate, citric acid, citrate, ethanolamine, triethanolamine, diethanolamine.
Further, described antioxidant comprise following one or more: alpha-tocopherol, α-tocopheryl acid succinate, ascorbyl palmitate, butylated hydroxyarisol, dibutyl phenol or propyl gallate.
Further, described co-emulsifier is alcohol, and/or polyglycerin ester.
Compared with prior art, alprostadil injection agent provided by the invention is take medicine as effective ingredient, the oily solution that forms take oil phase, phospholipid and organic solvent as carrier, during use, matching while using gets final product, get final product with injecting after the diluted self emulsifying when being administration, diluent can be used 5%(W/V) glucose solution, normal saline or water for injection etc.;
As seen, owing to being always anhydrous system in injection storage process of the present invention, so can prevent the oxidation reaction of phospholipid and the degradation reaction of medicine, improved the stability of alprostadil injection agent.
In addition, technical scheme provided by the invention can also reach following technique effect:
(1) because preparation of the present invention is always oily solution in storage process, therefore avoided problem in the fat milk long term storage, the problem includes: problems such as emulsion droplet gathering, local breakdown of emulsion oil spills, further improved the stability of preparation.
(2) preparation technology of preparation provided by the invention is simple, easier industrialization, due to the homogenizer that does not need high strength, high pressure, such as high-speed shearing device, so impurity (stainless steel grit etc.) and the extraneous impurity of introducing that equipment comes off can not appear in product, gentle preparation condition can be avoided the degraded of Alprostadil in preparation process, the safety that has further improved product simultaneously.
Description of drawings
In order to be illustrated more clearly in the specific embodiment of the present invention, the below will do simple the introduction to the accompanying drawing of required use in the specific embodiment, apparently, accompanying drawing in the following describes is some embodiments of the present invention, for those of ordinary skills, under the prerequisite of not paying creative work, can also obtain according to these accompanying drawings other accompanying drawing.
Fig. 1 is the particle size distribution figure of embodiments of the invention 12 alprostadil injection agent;
Fig. 2 is rat serum flow changing curve comparison diagram in the pharmacodynamic study of embodiments of the invention 14 alprostadil injection agent and prior art products.
The specific embodiment
For making the purpose, technical solutions and advantages of the present invention clearer; the below will carry out clear, complete description to technical scheme of the present invention; based on the specific embodiment in the present invention; those of ordinary skills are resulting all other embodiment under the prerequisite of not making creative work, all belong to the scope that the present invention protects.
Further illustrate and explain the present invention by following examples, but any restriction of not carrying out as the present invention.
Embodiment one
The non-aqueous injection of the Alprostadil that the present embodiment provides comprises:
Alprostadil 0.001-0.05mg/mL, oil phase 0.01-100mg/mL, phosphatidase 11 0-500mg/mL, all the other are organic solvent.
In above-mentioned prescription, described phospholipid comprises at least with lower a kind of: natural phospholipid, synthetic phospholipid.
Described oil phase comprises at least with lower a kind of: soybean oil, Semen Maydis oil, Oleum Ricini, olive oil, Oleum Cocois, Oleum Arachidis hypogaeae semen, fish oil, Oleum Gossypii semen, glyceryl monostearate, glyceryl monooleate, Oleum sesami, safflower oil, medium chain triglyceride, ethyl oleate.
Described organic solvent comprises at least with lower a kind of: ethanol, glycerol, propylene glycol, Polyethylene Glycol.
The medium chain triglyceride that the present embodiment is mentioned (Medium chain triglycerides, MCT) refers to contain that the fatty acid of 6-12 carbon atom generated by glycerine esterification.Wherein preferred MCT refers to saturated Trivent OCG, and/or saturated tricaprin.
Described natural phospholipid is Ovum Gallus domesticus Flavus lecithin or soybean lecithin, or they are with the mixture of any ratio composition.described synthetic phospholipid comprises at least with lower a kind of: hydrogenated soybean lecithin (HSPC), DOPC (DOPC), DMPEA (DMPE), DPPE (DPPE), two myristoyl Phosphatidylserine (DMPS), DSPE (DSPE) DLPC (DLPC), two myristoyl lecithin (DMPC), DPPC (DPPC), distearoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), MPPC (MPPC), and their polyethylene glycol derivative.
Described Polyethylene Glycol is selected from the Polyethylene Glycol that molecular weight is 200-2000, and the molecular weight of preferred Polyethylene Glycol is 200-400.
The present embodiment also provides the preparation method of above-mentioned injection, comprises the following steps:
Alprostadil is dissolved in organic solvent or oil phase or both mixed liquors, then adds other component, mix homogeneously obtains the alprostadil injection agent.
Wherein, in the prescription proportioning, can determine the quality that each component needs according to the concentration of each component, come standardize solution with organic solvent at last.
Above-mentioned preparation method is simple, can be completed by stirring at normal temperature.In addition, can change according to actual prescription situation the addition sequence of each component, but need each component of assurance recipe quantity all can dissolve fully, finally obtain the solution of clear.
The alprostadil injection agent application process clinically that the present embodiment provides:
Be 5%(W/V with described alprostadil injection agent implantation concentration) glucose solution, normal saline or water for injection in, shake up, form Injectable Emulsion after self emulsifying, its Average Particle Diameters is at 20nm-5000nm.
By being administered to patient's administration.
This Emulsion is mainly used in blood vessel dilating, anticoagulant etc.
In addition, in the Emulsion that the present embodiment provides, can also further add as required other pharmaceutically acceptable adjuvants, such as stabilizing agent, pH value regulator, antioxidant and co-emulsifier etc.
Stabilizing agent comprises cholesterol, polyethylene glycols and derivant thereof, combinations in glycerol, xylitol, sorbitol, mannitol, carbamide, sodium salicylate, phosphatidic acid, oleic acid, enuatrol, cholic acid, sodium cholate, hypromellose, sodium carboxymethyl cellulose, starch and derivant thereof, poloxamer, gelatin and derivant thereof, alginic acid and sodium salt thereof, polyvinylpyrrolidone, HP-β-CD or several.For example, in injection, the concentration of stabilizing agent can be 0.1-50mg/mL.
Described pH value regulator is in maleic acid, hydrochloric acid, tartaric acid, sodium hydroxide, acetic acid, acetate, phosphoric acid, phosphate, citric acid, citrate, ethanolamine, triethanolamine, diethanolamine or several, regulates pH to 4-8.Antioxidant is in alpha-tocopherol, α-tocopheryl acid succinate, ascorbyl palmitate, butylated hydroxyarisol (BHA), dibutyl phenol (BHT) or propyl gallate or multiple.
Wherein the present embodiment organic solvent used itself also can be used as co-emulsifier, simultaneously can also further add as required other co-emulsifier, comprise in the derivant of various small molecule alcohols and polyglycerin ester or their mixture.According to actual needs simultaneously, can also the concentration of each component in the present embodiment prescription be changed in its scope.
Compare with existing Alprostadil preparation, the Emulsion that the present embodiment provides has following characteristics:
(1) the alprostadil injection agent that provides of the present embodiment is take medicine as effective ingredient, the oily solution that forms take oil phase, phospholipid and organic solvent as carrier, during use, matching while using gets final product, get final product with injecting after the diluted self emulsifying when being administration, diluent can be used 5%(W/V) glucose solution, normal saline or water for injection etc.Namely store with the oiliness system, inject with emulsified state.
(2) owing to being always anhydrous system in this injection storage process, so can prevent the oxidation reaction of phospholipid and the degradation reaction of medicine, improved the stability of alprostadil injection agent.
(3) lipomul is due to the heterogeneous system that forms for multi-phase ingredients, thereby there are the problems such as emulsion droplet gathering, local breakdown of emulsion oil spill in storing, and be the homogeneous system of oil phase in this injection storage process, therefore avoid these problems, thereby further improved the stability of preparation.
(4) this composition for injection preparation technology is simple, easier industrialization, due to the homogenizer that does not need high strength, high pressure, such as high-speed shearing device, so impurity (stainless steel grit etc.) and the extraneous impurity of introducing that equipment comes off can not appear in product, gentle preparation condition can be avoided the degraded of Alprostadil in preparation process, the safety that has further improved product simultaneously.
In a word, the present embodiment provides a kind of stable, non-water injection of the simple Alprostadil of preparation, has avoided existing fat emulsion formulation at the chemical stability of storage process Chinese medicine and the physical stability problem of preparation.
Embodiment two to embodiment ten
The prescription of the alprostadil injection agent that following table 1 provides for embodiment two to ten.
The preparation method of above-mentioned nine embodiment is substantially similar, for example Alprostadil is joined in appropriate dehydrated alcohol or other organic solvents, until completely dissolved, add again lecithin, soybean oil, oleic acid and residue recipe quantity dehydrated alcohol, stirring at normal temperature makes the fluid composition that forms transparent clarification after their mix homogeneously, can change adding of each component or dissolving order according to actual prescription situation.
The alprostadil injection agent prescription of table 1 embodiment two to ten
Above-described embodiment two uses 1 ~ 100 times of injection dilution in clinical practice afterwards, and effect is better,, be more preferably 10 times of dilutions.
In order to illustrate further advantage of the present invention, below also provide concrete test example.
Embodiment 11
The mensuration of alprostadil injection agent particle diameter
Test method:
Get the injection 0.1mL of preparation in embodiment two, add 5000 times of purified water (being the membrane filtration of 0.22 μ m in advance with the aperture) dilutions, mixing, as liquid to be measured, with Ma Erwen laser particle analyzer (Zetasizer 3000HS, Malvem, UK) particle diameter and the distribution of above-mentioned liquid to be measured when measuring 25 ℃.
Result:
Particle size distribution is seen Fig. 1, and mean diameter is 146.0nm, and PDI is 0.177.As seen, injection provided by the invention is suitable for intravenous injection.
Embodiment 12
The stability study of alprostadil injection agent
Test method:
High temperature experiment: be to place 10 days in 40 ℃ ± 2 ℃ calorstats in temperature during respectively with injection in embodiment two and commercially available Emulsion-Kai, distinguished sampling and measuring in the time of 5 days, 10 days.
High light experiment: respectively injection in embodiment three is placed in the lighting box 10 days of illumination 4500lx ± 500lx when triumphant, distinguished sampling and measuring in the time of 5 days, 10 days.
Evaluation index:
Investigate content (with reference to the state quality standard WS1-(X-041) 2002Z-2008 of impurity PGA1 (catabolite of Alprostadil)).
Measuring method:
Use again mass spectroscopy, mass spectrum condition: mass spectrograph assembling electro-spray ionization source, adopt the negative ionization scan mode, under selective response monitoring (MRM) pattern, the ionic reaction of quantitative analysis is respectively m/z335.0 → m/z 317.1(PGA1) and m/z 391.0 → m/z361.2(dexamethasone, interior mark).
Result:
The stability measurement result is as shown in table 2, as seen from table, the present invention under hot conditions after 5 days and 10 days after catabolite (PGA1), all low by approximately 88% when triumphant than existing, and the catabolite under the high light condition after 5 days and after 10 days is during than existing commercially available Emulsion-Kai respectively low 94% and 90%, illustrate compared with prior art, injection provided by the invention has better stability.
The results of stability of table 2 Alprostadil
Embodiment 13
The pharmacodynamic study of alprostadil injection agent
Test method:
Subjects is that Wistar is male rat.Use respectively the alprostadil injection agent of embodiment two and when triumphant, the dosage of sample is 5 μ g/kg by the tail vein, five groups parallel.Utilize laser Doppler method to measure sufficient lift skin blood flow under anesthesia, use and measure immediately blood flow after sample and change.
Result:
In rat, the result of variations of blood flow is seen Fig. 2.By this result as can be known, rat blood flow when the present invention and commercially available Emulsion-Kai increases maximum multiple and is respectively 2.15 times and 1.73 times, illustrate that the present invention has drug effect preferably, and sustainability keep blood flow, and then illustrate that in preparation body provided by the invention, utilization rate is high.
Result of the test by embodiment 11 to 13 illustrates further, and in alprostadil injection agent good stability provided by the invention, body, utilization rate is high.
It should be noted that at last: above specific embodiment only in order to technical scheme of the present invention to be described, is not intended to limit; Although with reference to aforementioned specific embodiment, the present invention is had been described in detail, those of ordinary skill in the art is to be understood that: it still can be modified to the technical scheme that aforementioned embodiments is put down in writing, and perhaps part technical characterictic wherein is equal to replacement; And these modifications or replacement do not make essence disengaging each embodiment of the present invention of appropriate technical solution and the spirit and scope of specific embodiment technical scheme.
Claims (10)
1. alprostadil injection agent is characterized in that, comprising:
Alprostadil 0.001-0.05mg/mL;
Oil phase 0.01-100mg/mL;
Phosphatidase 11 0-500mg/mL;
All the other are organic solvent;
Described phospholipid comprises at least with lower a kind of: natural phospholipid, synthetic phospholipid;
Described oil phase comprises at least with lower a kind of: soybean oil, Semen Maydis oil, Oleum Ricini, olive oil, Oleum Cocois, Oleum Arachidis hypogaeae semen, fish oil, Oleum Gossypii semen, glyceryl monostearate, glyceryl monooleate, Oleum sesami, safflower oil, C
6-C
8Fatty acid triglycercide, ethyl oleate;
Described organic solvent comprises at least with lower a kind of: ethanol, glycerol, propylene glycol, Polyethylene Glycol.
2. alprostadil injection agent as claimed in claim 1, is characterized in that, described natural phospholipid comprise with lower one or more: Ovum Gallus domesticus Flavus lecithin, soybean lecithin.
3. alprostadil injection agent as claimed in claim 1, is characterized in that,
Described synthetic phospholipid comprise with lower one or more: hydrogenated soybean lecithin, DOPC, DMPEA, DPPE, two myristoyl Phosphatidylserine, DSPE, DLPC, two myristoyl lecithin, DPPC, distearoylphosphatidylcholine, distearoylphosphatidylcholine, MPPC, and their polyethylene glycol derivative.
4. alprostadil injection agent as claimed in claim 1, is characterized in that, described Polyethylene Glycol is selected from the Polyethylene Glycol that molecular weight ranges is 200-2000.
5. alprostadil injection agent as claimed in claim 1, is characterized in that, described oil phase is saturated Trivent OCG, and/or saturated tricaprin.
6. alprostadil injection agent as described in claim 1-5 any one, is characterized in that, also comprise following one or more: stabilizing agent, pH value regulator, antioxidant and co-emulsifier.
7. alprostadil injection agent as claimed in claim 6, it is characterized in that, described stabilizing agent comprise following one or more: cholesterol, polyethylene glycols and derivant thereof, glycerol, xylitol, sorbitol, mannitol, carbamide, sodium salicylate, phosphatidic acid, oleic acid, enuatrol, cholic acid, sodium cholate, hypromellose, sodium carboxymethyl cellulose, starch and derivant thereof, poloxamer, gelatin and derivant thereof, alginic acid and sodium salt thereof, polyvinylpyrrolidone, HP-β-CD.
8. alprostadil injection agent as claimed in claim 6, it is characterized in that, described pH value regulator comprise following one or more: maleic acid, hydrochloric acid, tartaric acid, sodium hydroxide, acetic acid, acetate, phosphoric acid, phosphate, citric acid, citrate, ethanolamine, triethanolamine, diethanolamine.
9. alprostadil injection agent as claimed in claim 6, it is characterized in that, described antioxidant comprise following one or more: alpha-tocopherol, α-tocopheryl acid succinate, ascorbyl palmitate, butylated hydroxyarisol, dibutyl phenol or propyl gallate.
10. alprostadil injection agent as claimed in claim 6, is characterized in that, described co-emulsifier is alcohol, and/or polyglycerin ester.
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| WO2015113094A1 (en) * | 2014-01-30 | 2015-08-06 | Gebro Holding Gmbh | Stable alcoholic solution of alprostadil |
| WO2015184981A1 (en) * | 2014-06-04 | 2015-12-10 | 北京蓝丹医药科技有限公司 | Alprostadil composition and injection and lyophilization formulation thereof |
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