CN103110579B - Alprostadil injection - Google Patents
Alprostadil injection Download PDFInfo
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- CN103110579B CN103110579B CN201310054314.5A CN201310054314A CN103110579B CN 103110579 B CN103110579 B CN 103110579B CN 201310054314 A CN201310054314 A CN 201310054314A CN 103110579 B CN103110579 B CN 103110579B
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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 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, has obvious blood vessel dilating, anticoagulant isoreactivity.Listing is its lyophilized injectable powder the earliest, and because metabolism is very fast in vivo, under pulmonary's oxidase effect, per pass pulmonary circulation, 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 is had to 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 (coming from Japanese 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%().Impact for fear of high temperature sterilize on Alprostadil stability reduces the harsh requirement of product to storage and transport simultaneously, and 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 freeze drying protectant lyophilizing to make.Compared with when triumphant, you have many advantages, the 1/6 when limit of its catabolite PGA1 is only also triumphant at storage transporter mask excellent Supreme Being.
Because lipomul is the pharmaceutical carrier of Alprostadil relative ideal, 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 with a certain amount of PLURONICS F87 and soybean phospholipid composition blended emulsifier, prepare lipomul, can tolerate and excessively kill method, can significantly improve the chemical stability of Alprostadil.But poloxamer belongs to Polymer Synthesizing adjuvant, consumption is crossed conference and is 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 on the basis when triumphant, to add the stabilizing agent such as oleic acid and vitamin E, prevents the phospholipid bilayer of drug degradation firm lipoid microsphere.Patent CN102228446 discloses a kind of Alprostadil lipid nanosphere freeze-drying injection and preparation method thereof; be prepared into by emulsifying agent phospholipid, co-emulsifier polyethyleneglycol-12-hydroxy stearin, midchain oil and freeze drying protectant etc. the nanoparticles lyophilized preparation that particle diameter is less than 100nm, impurity PGA1 is less than 5%.
No matter the chemical stability extreme difference of Alprostadil, be 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, although can solve its storage-stable by lyophilizing, drug degradation simultaneously that also can avoid autoclaving to bring, but the fat milk before lyophilizing still adopts conventional fat milk preparation technology (colostrum, high pressure homogenize) preparation.Fat milk preparation process relative complex, need to there is the participation of water, form Water-In-Oil or oil-in-water system, and can produce localized hyperthermia in 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
Alprostadil injection agent, 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 at least comprises with lower one: natural phospholipid, synthetic phospholipid;
Described oil phase at least comprises with lower one: 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 at least comprises with lower one: 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 taking medicine as effective ingredient, the oily solution forming taking oil phase, phospholipid and organic solvent as carrier, matching while using when use, while being administration, with injection after diluted self emulsifying, diluent can be used 5%(W/V) glucose solution, normal saline or water for injection etc.;
Visible, 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, improve 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, the problems such as the emulsion droplet gathering the problem includes: of therefore having avoided problem in fat milk long term storage, local breakdown of emulsion oil spill, have further improved the stability of preparation.
(2) preparation technology of preparation provided by the invention is simple, easier industrialization, owing to not needing the homogenizer of high strength, high pressure, such as high-speed shearing device, so impurity (stainless steel grit etc.) and the extraneous impurity of introducing that product there will not be equipment to come off, gentle preparation condition can be avoided the degraded of Alprostadil in preparation process, the safety that has further improved product simultaneously.
Brief description of the drawings
In order to be illustrated more clearly in the specific embodiment of the present invention, to the accompanying drawing of required use in detailed description of the invention be briefly described below, apparently, accompanying drawing in the following describes is some embodiments of the present invention, for those of ordinary skill in the art, do not paying under the prerequisite of 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.
Detailed description of the invention
For making the object, technical solutions and advantages of the present invention clearer; to technical scheme of the present invention be carried out to clear, complete description below; based on the specific embodiment in the present invention; all other embodiment that those of ordinary skill in the art obtain under the prerequisite of not making creative work, 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 mono-
The non-aqueous injection of Alprostadil that the present embodiment provides, comprising:
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 at least comprises with lower one: natural phospholipid, synthetic phospholipid.
Described oil phase at least comprises with lower one: 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 at least comprises with lower one: ethanol, glycerol, propylene glycol, Polyethylene Glycol.
The medium chain triglyceride (Medium chain triglycerides, MCT) that the present embodiment is mentioned refers to that the fatty acid that contains 6-12 carbon atom is 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 at least comprises with lower one: 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 alprostadil injection agent.
Wherein, in prescription proportioning, can be according to the concentration of each component, determine the quality that each component needs, finally carry out standardize solution with organic solvent.
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 the each component that ensures recipe quantity all can dissolve completely, finally obtain the solution of clear.
The alprostadil injection agent that the present embodiment provides application process clinically:
Be 5%(W/V by described alprostadil injection agent implantation concentration) glucose solution, normal saline or water for injection in, shake up, after self emulsifying, form Injectable Emulsion, 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, can also within the scope of it, change the concentration of the each component in the present embodiment prescription simultaneously.
Compared with existing Alprostadil preparation, the Emulsion that the present embodiment provides has following feature:
(1) the alprostadil injection agent that the present embodiment provides is taking medicine as effective ingredient, the oily solution forming taking oil phase, phospholipid and organic solvent as carrier, matching while using when use, while being administration, with injection after diluted self emulsifying, diluent can be used 5%(W/V) glucose solution, normal saline or water for injection etc.With the storage of 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 forming for multi-phase ingredients, thereby there is the problems such as emulsion droplet gathering, local breakdown of emulsion oil spill in storing, and in this injection storage process, be the homogeneous system of oil phase, therefore avoid these problems, thereby further improved the stability of preparation.
(4) this composition for injection preparation technology is simple, easier industrialization, owing to not needing the homogenizer of high strength, high pressure, such as high-speed shearing device, so impurity (stainless steel grit etc.) and the extraneous impurity of introducing that product there will not be equipment to come off, 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 provide a kind of stable, prepare the non-water injection of simple Alprostadil, avoided existing fat emulsion formulation at the chemical stability of storage process Chinese medicine and the physical stability problem of preparation.
Embodiment bis-to embodiment ten
The prescription of the alprostadil injection agent that following table 1 provides for embodiment bis-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 to form after their mix homogeneously the fluid composition of transparent clarification, can change adding of each component or dissolving order according to actual prescription situation.
The alprostadil injection agent prescription of table 1 embodiment bis-to ten
Above-described embodiment two, in clinical practice, uses 1 ~ 100 times of injection dilution 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 bis-, add 5000 times of purified water (being the membrane filtration of 0.22 μ m in advance with aperture) dilutions, mix, as liquid to be measured, with Ma Erwen laser particle analyzer (Zetasizer 3000HS, Malvem, UK) measure particle diameter and the distribution of the above-mentioned liquid to be measured 25 DEG C time.
Result:
Particle size distribution is shown in Fig. 1, and mean diameter is 146.0nm, and PDI is 0.177.Visible, injection provided by the invention is suitable for intravenous injection.
Embodiment 12
The stability study of alprostadil injection agent
Test method:
High temperature experiment: during respectively by injection in embodiment bis-and commercially available Emulsion-Kai, be to place 10 days in 40 DEG C ± 2 DEG C calorstats in temperature, difference sampling and measuring in the time of 5 days, 10 days.
High light experiment: respectively injection in embodiment tri-is placed in to 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 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:
Stability measurement result is as shown in table 2, as seen from table, the present invention is the catabolite (PGA1) after 5 days and after 10 days under hot conditions, all low by approximately 88% when triumphant than existing, and the catabolite under 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 bis-and when triumphant, the dosage of sample is 5 μ g/kg by tail vein, five groups parallel.Under anesthesia, utilize laser Doppler method to measure foot pad dermal blood flow, use and measure immediately blood flow after sample and change.
Result:
In rat, the result of variations of blood flow is shown in Fig. 2.From this result, 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 good drug effect, and sustainability maintain blood flow, and then illustrate that in preparation body provided by the invention, utilization rate is high.
By the result of the test of embodiment 11 to 13, illustrate further, alprostadil injection agent good stability provided by the invention, in body, utilization rate is high.
Finally it should be noted that: above specific embodiment only, in order to technical scheme of the present invention to be described, is not intended to limit; Although the present invention is had been described in detail with reference to aforementioned specific embodiment, those of ordinary skill in the art is to be understood that: its technical scheme that still can record aforementioned embodiments is modified, or part technical characterictic is wherein equal to replacement; And these amendments or replacement do not make the essence of appropriate technical solution depart from the spirit and scope of the each embodiment of the present invention and specific embodiment technical scheme.
Claims (1)
1. alprostadil injection agent, is characterized in that, is made up of following composition:
100mL dehydrated alcohol, 0.5mg Alprostadil, lecithin 10g, soybean oil 47mg, oleic acid 240mg;
Described alprostadil injection agent adopts following methods to make:
Alprostadil is joined in appropriate dehydrated alcohol, until completely dissolved, then add lecithin, soybean oil, oleic acid and residue recipe quantity dehydrated alcohol, stirring at normal temperature to make to form after their mix homogeneously the fluid composition of transparent clarification.
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| CN201310054314.5A CN103110579B (en) | 2013-02-20 | 2013-02-20 | Alprostadil injection |
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| CN201310054314.5A CN103110579B (en) | 2013-02-20 | 2013-02-20 | Alprostadil injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT518009A1 (en) * | 2015-07-27 | 2017-06-15 | Gebro Holding Gmbh | Concentrate containing alprostadil |
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| CN104706591B (en) * | 2013-12-16 | 2018-09-04 | 天津迈迪瑞康生物医药科技有限公司 | A kind of Alprostadil pharmaceutical composition, preparation method and the usage |
| AT515356B1 (en) * | 2014-01-30 | 2015-11-15 | Gebro Holding Gmbh | Stable alcoholic solution of alprostadil |
| CN105310976B (en) * | 2014-06-04 | 2018-08-21 | 北京蓝丹医药科技有限公司 | A kind of Alprostadil composition of stabilization |
| CN105777601A (en) * | 2014-12-26 | 2016-07-20 | 中国人民解放军第二军医大学 | Alprostadil derivative and pharmaceutical preparation thereof |
| CN107049942A (en) * | 2016-12-30 | 2017-08-18 | 北京普德康利医药科技发展有限公司 | A kind of alprostadil injection |
| CN107184550B (en) * | 2017-06-05 | 2020-11-03 | 辅必成（上海）医药科技有限公司 | Preparation method of alprostadil injection |
| CN107137351B (en) * | 2017-06-05 | 2020-08-04 | 辅必成（上海）医药科技有限公司 | Stable alprostadil emulsion injection |
| CN110269860A (en) * | 2018-03-16 | 2019-09-24 | 蔡海德 | A kind of drug for treating cancer |
| CN108992403A (en) * | 2018-08-31 | 2018-12-14 | 田红卫 | A kind of long-acting slow-release ivermectin injection and preparation method thereof |
| CN114796110A (en) * | 2021-01-28 | 2022-07-29 | 北京德立福瑞医药科技有限公司 | Insoluble drug concentrated solution without ethanol and micelle solution prepared from insoluble drug concentrated solution |
| CN114796111A (en) * | 2021-01-28 | 2022-07-29 | 北京德立福瑞医药科技有限公司 | A concentrated solution containing insoluble drug and emulsion prepared from the same |
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| JP4421699B2 (en) * | 1999-06-30 | 2010-02-24 | 大洋薬品工業株式会社 | Intravenous prostaglandin fat emulsion |
| US20080234376A1 (en) * | 2007-03-21 | 2008-09-25 | Taiwan Liposome Company (A Taiwan Corporation) | Emulsion composition comprising prostaglandin e1 |
| CN101332182B (en) * | 2007-06-29 | 2011-03-16 | 沈阳守正生物技术有限公司 | Preparation method of emulsion containing alprostadil for intravenous transfusion |
| CN101474150B (en) * | 2009-01-19 | 2011-10-19 | 四川思达康药业有限公司 | Stable alprostadil injection emulsion and preparation method thereof |
| CN101912362B (en) * | 2010-09-01 | 2012-08-29 | 北京大学 | Fat emulsion pre-emulsifying concentrated solution for teniposide intravenous injection and preparation method thereof |
| CN102764240B (en) * | 2011-05-03 | 2015-06-03 | 上海现代药物制剂工程研究中心有限公司 | Alprostadil lyophilized microemulsion, and preparation method and application thereof |
| CN102657658B (en) * | 2012-04-24 | 2013-05-29 | 海南碧凯药业有限公司 | Medicine composition for treating myocardial infarction, vascular circulatory disturbance and thrombosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AT518009A1 (en) * | 2015-07-27 | 2017-06-15 | Gebro Holding Gmbh | Concentrate containing alprostadil |
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Effective date of registration: 20210310 Address after: 100094 room 328, 3 / F, building 1, No.13 courtyard, cuihu'nan Ring Road, Haidian District, Beijing Patentee after: Beijing deliyingjie Pharmaceutical Technology Co.,Ltd. Address before: 102101 1456 Kangxi Road, Badaling Economic Development Zone, Yanqing County, Beijing Patentee before: BEIJING DELI FURUI MEDICAL SCIENCE & TECHNOLOGY Co.,Ltd. |