CN107137351A - A kind of Alprostadil emulsions parenteral solution of stabilization - Google Patents
A kind of Alprostadil emulsions parenteral solution of stabilization Download PDFInfo
- Publication number
- CN107137351A CN107137351A CN201710413318.6A CN201710413318A CN107137351A CN 107137351 A CN107137351 A CN 107137351A CN 201710413318 A CN201710413318 A CN 201710413318A CN 107137351 A CN107137351 A CN 107137351A
- Authority
- CN
- China
- Prior art keywords
- alprostadil
- injection
- parenteral solution
- oil
- lecithin
- 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.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Abstract
The present invention relates to a kind of Alprostadil emulsions parenteral solution of stabilization, with homogeneous and stable particle diameter distribution, there is to heat sterilization and in blood plasma the particle size more stablized and distribution, reduce the degraded oxidation of oil for injection, decrease the generation of lysophosphatide, so as to improve the stability and security of medicine, poisonous side effect of medicine is reduced.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of Alprostadil emulsions parenteral solution of stabilization.
Background technology
Alprostadil is prostaglandin E1, and current Alprostadil has been widely applied in clinic, such as treatment arterial occlusion
Property the angiocardiopathy such as disease, coronary heart diseases and angina pectoris, heart failure, peripheral vascular disease, treatment Patients With Acute Cerebral Infarction, cerebral infarction
Extremely, the cranial vascular disease such as vasopasm after subarachnoid hemorrhage is prevented, respiratory disease, the disease of digestive system such as hepatitis,
The renal function diseases such as renal insufficiency, diabetes and erectile dysfunction.
When clinically Alprostadil emulsions parenteral solution enters about 5-6min after kettle, hand site of puncture is moved towards out along blood vessel
Phenomenon rubescent existing l0-15cm, some patientss tell pain and itch, in addition the biology after Alprostadil intravenously administrable in vivo
Stability is poor, and to maintain effective blood drug concentration, the heavy dose of intravenously administrable for a long time of palpus causes to local vascular stimulation mistake
Greatly, the side effect of phlebitis is caused.Alprostadil in vivo through 15 hydroxyls-prostaglandin dehydrogenase in the presence of, be initially formed 15-
Ketone-Alprostadil, then forms end product of metabolism in the presence of a series of enzymes, wherein 15 hydroxyls-prostaglandin dehydrogenase is extensive
It is present in the tissue such as lung, liver, kidney and fat, lungs are main metabolism places, thus Alprostadil is after pulmonary circulation, administration
Amount 60%~90% loses pharmacological activity because being metabolized, therefore strong influence Alprostadil clinical potency.Before solution
The problem of your conventional formulation intravenous formulations of row ground are present, has developed and applied to clinical alprostadil injection emulsion, the system
Agent has the advantage that:(1) targeting and high efficiency injection emulsion are easily gathered in vascular inflammation position, and the medicine of lesion can be made dense
Degree reaches 10~20 times of conventional formulation, so as to reduce whole body toxic side effect;(2) the metabolic inactivation Alprostadil note of medicine is reduced
Interior oil phase and oil-water interfaces that drug molecule is dissolved, be scattered in emulsion by emulsion are penetrated, drug molecule can be avoided to a certain extent
With directly contacting for lung enzyme, and then its metabolic inactivation in lung is reduced.
Alprostadil is except easily by the chemical property of the metabolism of internal 15 hydroxyls-prostaglandin dehydrogenase, in addition Alprostadil
Also unstable, due to containing beta-hydroxy ketone in the chemical constitution of Alprostadil, easily dehydration generates prostaglandin under the conditions of acid, alkali
A1, and continuation generation rearrangement hair should generate prostaglandin B 1 and lose pharmacological activity in the basic conditions.And current injection breast
Liquid mostly use autoclaving, under 121 DEG C of high thermal highs handle after, Alprostadil is easily degraded, degradation rate sometimes more than
30%, and in pressure sterilizing, due to the heated phenomenon for being also easily caused emulsion droplet rupture or merging, and then make Alprostadil
Revealed from emulsion droplet.And existing commercially available alprostadil injection emulsion usually requires to be preserved and transported in the environment of 0~5 DEG C again
Defeated, the term of validity also only has 1 year.
The preparation of current Alprostadil is related to liposome, emulsion for injection, microballoon, micella, gel, nose powder, lyophilized formulations
And the various formulations such as exterior-applied emulsion.
In terms of Lipidosome, generally medicine is wrapped in the bilayer lipid membrane to be formed, is prepared into and is available for before injection
Row parathyrine E1 liposome administration systems, the conventional liposome preparation of the Alprostadil of such as United States Patent (USP) US94/12579 reports,
The long circulation alprostadil administration nano-drug administration system made using polyglycol derivatization phospholipid is added disclosed in CN1739525,
The system can extend the circulation time of liposome in vivo, but encapsulating effect is poor.CN101108188, which also discloses that to use, to be added
Enter the made long circulation alprostadil nano liposomes delivery system of polyglycol derivatization phospholipid, and increase phosphatide consumption and courage
Sterol, improves envelop rate, but and its undeclared steadiness.
Microball preparation, mainly uses high molecular polymer for carrier such as PLA, Vicryl Rapide, poly- second
Glycol and copolymer of poly lactic acid, polyethylene glycol and Vicryl Rapide again with containing prostatitis with phospholipid substance jointly
You, such as CN101088493, but such preparation is difficult to reach corresponding effective blood drug concentration, and the polymer of degradable in vivo
Required technology, cost are all higher.
Micellar preparation, refer to amphiphilic in aqueous concentration exceed critical micelle concentration when (CMC), can be spontaneous
Polymerization forms micella, and micella is different from liposome, without bilayer, and its structure is that hydrophobic part is inside, forms hydrophobic core,
Hydrophilic segment is outwardly formed water-wetted surface.As CN101278913 discloses a kind of used for intravenous injection with high envelop rate and low
Initial release degree prostaglandin E1 micellar preparation, its contain the prostaglandin E1 of therapeutically effective amount, PEG derivatization phospholipids,
Hydrogenated phospholipid and pharmaceutically acceptable assistant agent such as water for injection, CN101439037 also disclose that a kind of Alprostadil lipid
Compound and its injection micelle composition, the Alprostadil lipid complexes and its injection micelle composition are by therapeutic dose
Alprostadil, phosphatide, cholesterol sulfate or/and similar cholesterol derivative, additives and water for injection are constituted.But micella
The drug encapsulation amount of preparation is relatively fewer, is unfavorable for the clinical administration of Alprostadil.
It is the clinical main flow preparation of current Alprostadil that emulsion, which includes emulsion parenteral solution and emulsion lyophilized formulations, is also related
A kind of most preparation of technical research, generally by oil phase plant oil, emulsifying agent phosphatide, cholesterol, assistant for emulsifying agent pool network are husky
Nurse, oleic acid etc., aqueous phase is prepared from.As CN101496787A discloses a kind of prostaglandin E1 lipid microsphere injection of charge
And preparation method thereof, pharmaceutic adjuvant include the oil for injection of 5-20 part weight, the emulsifying agent of 0.2-5 parts of weight, 0-5 parts weigh
Isotonic regulator, appropriate antioxidant, appropriate pH adjusting agent and the appropriate injection of the assistant for emulsifying agent of amount, 0.5-3 parts of weight
, can be with 10-20mL glucose, sodium chloride or the sterile fat emulsion injection controllable without thermal source mass during clinical practice with water
Compatibility is used, and indices meet the requirements after compatibility, no significant difference, and physiological compatibility is good.Can be by more than 85% medicine
Thing is wrapped in oil phase and oil/water interfacial film phase, is free in the medicine in aqueous phase less than 15%, is improved the stabilization of its preparation
Property.Particle size range is 50~500nm, 100~200nm of particle mean size.
CN101664390 discloses a kind of preparation method of Alprostadil liposome microsphere, by Alprostadil, oil for injection, breast
Agent, stabilizer, isotonic agent, and water for injection are made.By the way that medicine and phosphatide are first dissolved into suitable solvent, solvent is removed
After add in oil phase, obtained product packaging rate is significantly improved, and entrapment efficiency is free in water more than 97%
Alprostadil less than 5%, and reduce the generation of catabolite.
CN103655485 discloses a kind of Alprostadil liposome microsphere preparation and preparation method thereof, by Alprostadil and/or its
Salt, oil for injection, emulsifying agent, assistant for emulsifying agent, osmotic pressure regulator, metal chelating agent, antioxidant, pH value regulator and injection
It is made of water, envelop rate is more than 93%, and pressure sterilizing Alprostadil degradation rate is between 6.8%-8.5%, the degraded of high temperature
Rate is 50% or so.
CN101091890 discloses a kind of mixed emulsifier and the emulsion prepared with it, and the compound emulsifying agent can be by
Two kinds or three kinds or more than three kinds of emulsifying agent is combined, concentration difference of its each composition in emulsifying agent:0%~
5% lecithin w/v, 0%~5% poloxamer w/v, 0%~5%Solutol HS15w/v, the poly- second of 0%~5% vitamin E
Glycol succinate w/v, wherein 0%~5% DSPE-PEG w/v, PEG molecular weight are 1000~10000.With heat resistanceheat resistant with
Freeze-thaw stability, average grain diameter is between 50-100nm.
CN101332182 discloses a kind of emulsion containing alprostadil of intravenous transfusion, and it is included:Alprostadil, note
Penetrate with oil 5, emulsifying agent, stabilizer, isotonic agent, antioxidant, appropriate pH adjusting agent, water for injection, oil for injection selected from soybean oil,
One or both of olive oil, fish oil, palm oil, sesame oil, tea oil thing mixed above, described emulsifying agent are selected from yolk ovum
One or both of phosphatide, soybean lecithin, poloxamer thing mixed above;Described stabilizer be selected from oleic acid, enuatrol,
One or both of cholic acid thing mixed above;Described isotonic agent is selected from glycerine.In emulsion made from 60-80 DEG C of temperature section,
Milk particle particle size is uniform, and emulsion stability is high.
CN101474150 discloses a kind of alprostadil injection emulsion of stabilization, and it contains Alprostadil for active component,
It is prepared from plus pharmaceutically acceptable oil for injection, emulsifying agent, glycerol for injection, water for injection through emulsifying technology.It is described
Emulsifying agent in 3g containing PLURONICS F87~30g and injection lecithin 1g~6g, with existing alprostadil injection emulsion phase
Than that can significantly increase the heat endurance of Alprostadil, extend the term of validity of alprostadil injection emulsion, while before can substantially reducing
Degraded of the row ground that in lung.
CN101829054 discloses a kind of Alprostadil submicron emulsion for injection, by Alprostadil, oil for injection, emulsifying agent,
Stabilizer, freeze drying protectant is made.Prepared Alprostadil submicron emulsion for injection uniform particle diameter is stable, and catabolite is down to
10%, extension of validity was to 24 months.Solution ph is 6.0~7.5 before the Submicron Emulsion is lyophilized and after redissolving, Submicron Emulsion it is flat
Equal particle size range is 120~280nm.
CN101843594 discloses a kind of Alprostadil freeze-dried emulsion for injection, and the freeze-dried emulsion uses cyclodextrin thing
Matter and polysaccharose substance are made a kind of higher Alprostadil freeze-dried emulsion for injection of stability, also wrapped as freeze drying protectant
Include oil-based solvent, emulsifying agent, assistant for emulsifying agent, freeze drying protectant, isotonic regulator, pH adjusting agent, by freeze-drying before or redissolve
Afterwards, the level for the PGE1 that dissociates in Alprostadil freeze-dried emulsion for injection is reduced, so as to further reduce the degraded of Alprostadil.
CN102038639 discloses a kind of Alprostadil injection preparation, and injection includes Alprostadil, soybean oil, phosphatide,
Glycerine, oleic acid.Colostrum adjusts pH value 5.4-6.0, and nanometer machine 5 times are crossed in 50MPa, and uniform particle diameter, average grain diameter is made and exists
100nm-280nm lipid microsphere.With the reduction of pH value, the envelop rate of medicine gradually rises, but Zeta potential absolute value
Reduction, is unfavorable for preparation stabilization.PH value range is set to 5.4-6.0, it is ensured that entrapment efficiency is maintained more than 90%
Suitable Zeta potential value, increases the stability of emulsion.
CN102178650 A disclose a kind of alprostadil injection, and its composition is as follows:(a) main ingredient Alprostadil
Its concentration range is the μ g/ml of 5 μ g~15;(b) oil phase is soybean oil, and its concentration range is respectively 10.0~12.0%;(c) emulsify
Soybean lecithin and PLURONICS F87 are selected in agent, and its concentration range is respectively 1.0~1.8% and 0.02%~0.2%;(d) pH is adjusted
Agent citric acid is saved, its concentration range is 5mM to 50mM, and pH scope is 5.0 to 6.0;(e) osmotic pressure regulator glycerine, its is dense
It is respectively 2.0~2.5% to spend scope;Remaining is water for injection.After pressure sterilizing Alprostadil degradation rate 11%-12% it
Between.
CN103599066 discloses a kind of alprostadil injection and preparation method thereof, is prepared by the raw material matched as follows
Form:In per 1000ml parenteral solutions, containing Alprostadil 5mg, 90~110g of soybean oil, 5~20g of phosphatidase 1,2~3g of oleic acid, etc.
Penetration enhancer 22.1-25g, qs pH adjuster, pH are adjusted to 5.0~6.0 and are defined;Deposit December after content, envelop rate 90% with
On, relevant material is below 0.5%.
CN103610640 discloses Long-chain triglycerides in a kind of injection Alprostadil, by 0.01~0.1 parts by weight
Alprostadil, the long chain triglycerides of 10~100 parts by weight, the medium chain triglyceride of 10~100 parts by weight, 1~20 parts by weight
Phosphatide, the oleic acid of 0.01~1 parts by weight, the water for injection group of the glycerine of 5~20 parts by weight and 300~2500 parts by weight
Into.By the way that medium chain triglyceride and long chain triglycerides are effectively combined, Long-chain triglycerides are encapsulated in obtained Alprostadil
Rate is higher, and considerably reduces the blood vessel irritation of alprostadil injection, and its particle diameter is 50~200nm, pH value 5.0~
There is preferable stability, while measuring the catabolite prostatitis of Alprostadil using high performance liquid chromatography in the range of 8.0
The content of parathyrine A1 and prostaglandin B 1 is below 1%.
CN105287376 discloses alprostadil injection, it include Alprostadil, oil for injection, lipophilic emulsifying agent,
Injection isotonic agent and stabilizer, lipophilic emulsifying agent is selected from spans material (such as sorbester p18, sorbester p17), lecithin, big
One or more in Fabaceous Lecithin and agar, wherein the alprostadil injection contains average grain diameter between 100-300nm
And Alprostadil particles of the D90 between 150-350nm, the alprostadil injection is after 2-8 DEG C is placed 12 months
Change of size is less than or equal to 10%.
CN1872072 discloses nano emulsion injection of alprostadil and preparation method thereof, and the injection includes:(1) inject
With oil;(2) hydrophilic emulsifying agent;(3) lipophilic emulsifying agent;(4) isotonic agent;(5) stabilizer.Hydrophilic emulsifying agent is preferably pool
Luo Shamu 188, polyethylene glycol-VE-succinate;Lipophilic emulsifying agent is preferably lecithin, soybean lecithin.
CN102764240 discloses a kind of Alprostadil freeze-dried micro emulsion, and it includes count by weight percentage:Alprostadil
0.001%-0.1%, grease 1.0%-10.0%, emulsifying agent 1.0%-20.0%, assistant for emulsifying agent 1.0%-20.0%, stabilizer
0.3%-1.6%, freeze drying protectant 50.0%-90.0%, and pH adjusting agent 0.005 ‰ -5.0 ‰., thus, the lyophilized PGE1-
After ME preparations are placed three months under the conditions of 4 DEG C and 25 DEG C, its outward appearance, particle diameter, redissolution, pH and content are almost unchanged, wherein
Main reasons is that the lyophilized formulations are solid pharmaceutical preparation, the various instability problems existed in the absence of the liquid preparation of emulsion go out
Bacterium does not also use heat sterilization.CN103301076 also discloses that similar freeze-dried emulsion.
CN103961356 discloses Alprostadil freeze-dried composition of injection and preparation method thereof, and its component is by weight
Counting ratio is:0.001-0.05 parts of Alprostadil;Emulsifying agent:Polyethylene glycol hydroxystearate, polyethylene glycol hydroxystearate
With 1-50 parts of the mixture of phosphatide;1-50 parts of median chain triglyceride oil;Other pharmaceutically acceptable auxiliaries 10-200 parts.The Alprostadil freezes
Solid body preparation show can shady place store 2 years, PGA1 contents be less than 10%;Change of size is small before and after lyophilized, outward appearance after redissolution
Transparent or micro-strip opalescence, can check visible foreign matters, and average grain diameter is free of the emulsion droplet more than 1 μm between 10-100nm.
CN106176600 discloses a kind of Alprostadil freeze-dried microemulsion, and its feedstock composition includes 0.1~10mg/
100mL Alprostadil, 0.5~20g/100mL oil, 0.5~30g/100mL emulsifying agent, 0.5~2g/100mL help breast
Agent, 5~40mg/100mL stabilizer, 5~20g/100mL freeze drying protectant.The emulsifying agent is polyethylene glycol 12
Hydroxy fatty acid, or be the dihydroxy fatty acid ester of polyethylene glycol ten and egg yolk lecithin, soybean lecithin, Pegylation
The compound emulsifying agent of one or more of compositions in lecithin and hydrolecithin.
US2008234376 discloses the emulsion composition of prostaglandin E1, and it includes prostaglandin E1, high-purity phospholipid
And PGE1 the non-of stability can be promoted carry protogenic interfacial agent.In emulsion composition protogenic boundary is carried using non-
Face activating agent replaces oleic acid as coemulsifier, and the non-concentration for carrying protogenic interfacial agent is in the emulsion composition
At least about 1.6% (w/w) of oil base agent, this causes the improved stability of the PGE1 in the emulsion composition.
In addition, the prostaglandin E1 emulsion of American-European countries is mainly used in external curing male erectile dysfunction,
The method that US2002045665 discloses prostaglandin composition and treatment male erectile dysfunction, said composition includes blood vessel
Active prostaglandin, penetration enhancers, the polysaccharide of shear shinning, lipophilic compound, and acid buffer system.
Administration of the Japanese pharmaceutical enterprise to Alprostadil is further developed into emulsion parenteral solution, and such as JP5890599 is disclosed
The fat emulsion of stabilization containing prostaglandin E1, the change containing 5 μ g in 1mL fat emulsion with prostaglandin E1 activity
Compound, 100mg refined soybean oils, the highly purified egg yolk lecithins of 18mg, 2.4mg oleic acid and 22.1mg concentrated glycerins.
JP5193870 discloses prostaglandin fat emulsion and its manufacture method and its stabilization method and emulsifying agent,
Contain prostaglandin as active ingredient, and contain in PC containing phosphatidyl choline and phosphatidyl glycerol PG phosphatide, the phosphatide
PC and the ratio between PG i.e. PC:PG is 85:15~99.7:0.3, because the stability and emulsion stability of active ingredient are excellent, because
This can be substantially free of free higher fatty acids or its salt.Due to although making emulsion stability liter containing PE in phosphatide
Height, but PGE1 abatement increases.
JP2012214430 discloses the fat emulsion containing prostaglandin, and fat emulsion is pH for 4.5-6.0 and wrapped
Prostaglandin-containing, oil component, lecithin, the fat emulsion of water soluble acid or its salt and water, wherein the amount of the lecithin is institute
State the quality of oil component 0.15 times, the water soluble acid has dissociable group and pKa is 4.0-6.0, and water soluble acid is lemon
Lemon acid.Be conducive to improving stability, the stability of emulsion of prostaglandin.
Although the emulsion for injection of current Alprostadil improves the stability of medicine and emulsion to a certain extent,
It is to still suffer from many problems, uses vegetable oil although injecting oil in above-mentioned patented technology and mentioning, also all use soybean oil, and it is big
There is the factor of autoxidation such as light, heat, oxygen, the emulsifying agent employed in metal ion, and system, pH adjusting agent in soya-bean oil
Deng all producing complex effects to the stable of soybean oil, and soybean oil is used as the main component of emulsion for injection, these adverse effects
Also the stability and potential adverse side effect of injection will be directly affected;In addition, current emulsifying agent also all mainly uses ovum
Phosphatide or lecithin and it is other help emulsification compound, but from the point of view of JP5193870, different phosphatide is to medicine and emulsifying agent
There are different influences in stability, lecithin also facile hydrolysis in acid condition, and being likely to result in the rupture of the immobilized artificial membrane of emulsion droplet makes
Oil droplet leakage is obtained, while current research thinks that the Alprostadil in Alprostadil emulsions is largely distributed in the interface of emulsion
Phase, is only distributed in oil phase and aqueous phase on a small quantity, thus, the rupture of emulsion droplet merges, or other additional substances or heated easy
Break the balance of oil-water interfaces, such as distribution consistency degree deviation at present to drop size, is to cause the reduction by one of stability
How factor, reach more preferable stability, how to make in emulsion system each material compatible and medication security is still
The problem of being solved required at present.
The content of the invention
The purpose of the present invention be the defect for overcoming prior art there is provided a kind of Alprostadil emulsions parenteral solution of stabilization,
With homogeneous and stable particle diameter distribution, there is more stable particle size to heat sterilization and in blood plasma and divide
Cloth, reduces the degraded oxidation of oil for injection, the generation of lysophosphatide is decreased, so as to improve the stability and safety of medicine
Property, reduce poisonous side effect of medicine.
The present invention solve the technical problem technical scheme be:
The present invention provides a kind of Alprostadil emulsions parenteral solution, and the parenteral solution includes Alprostadil, glutamic acid, lecithin
Fat, DAG -3- phosphatidic acids, oil for injection and water for injection.
The parenteral solution is nano-emulsion.
The parenteral solution does not include the one or more in oleic acid, antioxidant, EDTA, preferably not comprising oleic acid and antioxygen
Agent, preferably not comprising oleic acid and EDTA, preferably not comprising antioxidant and EDTA.
The parenteral solution also include it is one or more in medium chain triglyceride, glycerine, preferably comprise medium chain triglyceride and
Glycerine.
The weight ratio of its Glutamic Acid and DAG -3- phosphatidic acids is 1:1.
The lecithin is selected from egg yolk lecithin or soybean lecithin, and the oil for injection is selected from soybean oil, sesame oil
Or the one or more in peanut oil, preferred soybean oil.
The parenteral solution is by Alprostadil, glutamic acid, lecithin, DAG -3- phosphatidic acids, injection
It is made of oil, medium chain triglyceride, glycerine and water for injection.
Per in 1000ml parenteral solutions, contain Alprostadil 0.1-10mg, 80~150g of oil for injection, medium chain triglyceride
10-30g, 10~20g of lecithin, 0.1~3g of DAG -3- phosphatidic acids, 0.1~3g of glutamic acid, glycerine
10-30g and water for injection.It is preferred that per in 1000ml parenteral solutions, containing Alprostadil 5mg, oil for injection 100g, medium chain triglyceride
Three ester 20g, lecithin 15g, DAG -3- phosphatidic acids 1g, glutamic acid 1g, glycerine 20g, water for injection add
To 1000ml.
The parenteral solution uses heat sterilization, and preferably 121 DEG C of heat sterilization sterilizes 10-15 minutes, preferably 12 minutes.Heating
After sterilizing, average grain diameter between 105-130nm, preferably 110,111,112,113,114,115,116,117,118nm;Particle diameter
Polydispersity index in 0.1-0.2, preferably 0.11,0.12,0.13,0.14,0.15,0.16.
Described 25 DEG C of decentralizations of parenteral solution are set to 0-6 months, its peroxide value be less than 0.8, preferably smaller than 0.7,0.6,0.5,
0.4,1 month peroxide value is placed at further preferred 25 DEG C it is less than at 0.4, further preferred 25 DEG C and places peroxidating in 2 months
Value is less than 3 months peroxide values of placement at 0.4, further preferred 25 DEG C and is less than placement 6 months at 0.4, further preferred 25 DEG C
Peroxide value is less than 0.4.
The parenteral solution is placed 24 months under 2-8 DEG C of constant-temperature constant-humidity environment, and Alprostadil content is in 95%-99.9%
Between, preferably 95%, 96%.
The present invention furthermore provides a kind of preparation method of Alprostadil emulsions parenteral solution, and methods described includes following step
Suddenly:
(1) lecithin, Alprostadil, medium chain triglyceride, DAG -3- phosphatidic acids are added to
In oil for injection, oil phase is formed;
(2) glycerine, glutamic acid are added in water for injection and forms aqueous phase;
(3) oil phase is slowly added in aqueous phase, forms colostrum;
(4) colostrum is mended after adding to the full amount of water for injection, high pressure homogenization;
(5) filling rear, heat sterilization.
Wherein step (1) is under high-shearing dispersion emulsifying machine, and high speed shear is scattered 1-30 minutes, and preferably 10,15,20,25
Minute, form oil phase;
Step (2) is under high-shearing dispersion emulsifying machine, scattered 1-20 minute of shearing, preferably 10,15,20 minutes, formation water
Phase;
Step (3) is under high-shearing dispersion emulsifying machine, scattered 1-30 minute of shearing, preferably 10,15,20,25 minutes, formation
Colostrum;
Step (4) mesohigh homogeneous 3 times.
Beneficial effects of the present invention:
1st, parenteral solution of the invention is nano-emulsion, and average grain diameter is more stablized, with homogeneous between 100-130 nanometers
And stable particle diameter distribution.
2nd, after 121 DEG C sterilize, still with stable particle size and homogeneous distribution.
3rd, in vitro in blood plasma combined experiments, also still there is stable particle size and homogeneous distribution.
4th, emulsion parenteral solution system of the invention reduces the oxidative degradation of oil for injection, and 6 months mistakes are placed at 25 DEG C
Oxidation number is less than 0.4.
5th, emulsion parenteral solution system of the invention reduces the generation of lysophosphatide, can stablize storage 24 at 2-8 DEG C
Month, and produced afterwards without obvious haemolysis, it is also small to vascular stimulation.
6th, emulsion parenteral solution of the invention has higher envelop rate, and envelop rate and medicament contg are more stable, this
The emulsion parenteral solution system of invention effectively controls the degraded of Alprostadil.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part or according to the condition proposed by manufacturer.
Unless otherwise defined, all specialties used in text known to scientific words and one skilled in the art with anticipating
Justice is identical.In addition, any method similar or impartial to described content and material all can be applied in the inventive method.Wen Zhong
Described preferable implementation only presents a demonstration with material to be used.
Embodiment 1:Emulsion injection formula
By the prescription of table 1,2, weigh each raw material by prescription respectively, by lecithin, Alprostadil, medium chain triglyceride and
Other liposoluble constituents such as oleic acid, phospholipid derivative, poloxamer are added in vegetable oil, then in high cut disperse emulsification
Under machine, high speed shear is scattered 10~20 minutes, forms oil phase.Glycerine, amino acid and other water-soluble substances EDTA are added
In water for injection, under high-shearing dispersion emulsifying machine, shearing is scattered 10 minutes, forms aqueous phase.In the case where high speed shear is scattered, by oil
Mutually it is slowly added in aqueous phase, then proceedes to high speed shear and disperse 20 minutes, form colostrum.Colostrum is mended and added to the full amount of water for injection
Afterwards, high pressure homogenization 3 times, filling, and is sterilized 12 minutes at 121 DEG C.
The different injection formula compatibilities of table 1
The different injection formula compatibilities of table 2
1.1 emulsion particle diameters and uniform particle sizes' degree
The particle diameter and size distribution of emulsion are determined using LS230 laser diffraction analyzers, its principle is by light using particle
Occur the feature that diffraction occurs for light scattering and light during irradiation, and scattering strength and diffracted intensity and the particle size of light and
Optical signature relevant principle determines particle size and size distribution.
Table 3 sterilizes front and rear particle diameter and distribution situation
Wherein polydispersity index is used for weighing the uniform level of emulsion particle diameter distribution, and numerical value is smaller, represents that particle diameter distribution is got over
Homogeneous more to concentrate, the difference in size of particle diameter is just smaller.By above-mentioned testing result, it is found that emulsion grain prepared by prescription 1-16
Footpath is all smaller, and sterilizing forward backward averaging change of size is less, but the uniform particle diameter distribution situation of each prescription has bigger difference,
And the homogeneous distribution situation of particle diameter also becomes big before and after sterilizing, compared with other prescriptions, the emulsion centralized particle diameter of prescription 1,
Particle diameter difference is small, and after heat sterilization, particle diameter distribution is still more concentrated.
1.2 external plasma experiments
0.2ml above-mentioned prescription 1-14 emulsion is mixed with 0.9ml human plasmas in microcentrifugal tube, by sample after mixing
Product are cultivated 6 hours at 37 DEG C, change of size before and after analysis culture.
Table 4 cultivates front and rear change of size situation
Group | Primary particles average grain diameter nm | 1 hour after culture | 2 hours after culture | 4 hours after culture | 6 hours after culture |
Prescription 1 | 118.2 | 129.4 | 140.5 | 151.7 | 162.1 |
Prescription 2 | 135.1 | 170.8 | 197.4 | 230.4 | 275.9 |
Prescription 3 | 132.7 | 168.9 | 201.3 | 220.7 | 287.5 |
Prescription 4 | 152.1 | 181.5 | 210.4 | 258.9 | 301.4 |
Prescription 5 | 123.4 | 143.8 | 197.6 | 246.7 | 304.6 |
Prescription 6 | 146.8 | 189.7 | 267.1 | 331.4 | 378.1 |
Prescription 7 | 158.9 | 205.9 | 258.4 | 314.8 | 365.2 |
Prescription 8 | 130.4 | 178.5 | 240.7 | 303.5 | 355.7 |
Prescription 9 | 127.8 | 168.8 | 224.7 | 298.3 | 351.6 |
Prescription 10 | 128.3 | 170.5 | 218.9 | 287.3 | 347.2 |
Prescription 11 | 132.8 | 185.6 | 238.4 | 310.7 | 375.4 |
Prescription 12 | 139.7 | 196.7 | 248.1 | 328.4 | 401.5 |
Prescription 13 | 150.1 | 208.1 | 274.6 | 347.8 | 411.2 |
Prescription 14 | 153.4 | 211.8 | 296.4 | 368.4 | 421.4 |
1.3 accelerated stabilities are tested
Prescription 1-14 sample is individually positioned under the conditions of 25 DEG C or so of temperature and placed 6 months, during experiment
0th, 1,2,3,6 the end of month sampling detections investigate the indexs such as envelop rate, PGE1 contents, peroxide value and aseptic condition.
Determination method of peroxide value:Take Alprostadil emulsions parenteral solution appropriate, after precise, be placed in 250ml iodine flasks,
It is used as test sample, plus chloroform-glacial acetic acid (2:3, v/v) mixed liquor 30ml, shaking is scattered, adds KI test solution 0.5ml,
Shaking 1 minute, then add water 30ml, is titrated with 0.01mol/L sodium thiosulfate titrating solution, is slowly added into titrating solution and fully shakes
Shake to yellow and almost disappear, plus starch indicator solution 5ml, continue to titrate and shake well to blueness disappear " while blank test is done,
The consumption of sodium thiosulfate titrating solution (0.01mol/L) must not cross 0.1ml in blank test.Peroxide value=10 of test sample
(A-B)/W.In formula:A represents that test sample consumes the volume of sodium thiosulfate titrating solution (0.01mol/L), ml;B represents that blank is tried
Test the volume of consumption sodium thiosulfate titrating solution (0.01mol/L), ml;W represents test sample weight, g.
The measure of envelop rate:Alprostadil reference substance solution 20ul injecting chromatographs are taken respectively, are used as control;Separately take prostatitis
Ground that emulsion parenteral solution 1ml, puts in 5ml brown measuring bottles, with water constant volume, shakes up.Taking above-mentioned solution 1ml to add super filter tube, (film is cut
Stay molecular weight 50KDa), in centrifugal ultrafiltration 45min at 4000*g, 4 DEG C, filtrate 20ul injecting chromatographs are taken, peak area is recorded, and
The amount (W) of free drug is calculated by external standard method;Alprostadil emulsions parenteral solution 1ml separately is taken, is put in 5ml brown measuring bottles, methanol is fixed
Hold, shake up, take 20ul injecting chromatographs, record peak area, and bag is calculated by following equation by total dose (W0) of external standard method calculating
Envelope rate:
EE%=(1-W/W0) * 100%;Wherein EE represents envelop rate.
The accelerated stability experimental result of table 5
The accelerated stability experimental result (Continued) of table 6
Embodiment 2
Prescription:
Preparation method:Each raw material is weighed by prescription respectively, by lecithin, Alprostadil, medium chain triglyceride, the oil of 1,2- bis-
Acyl group-sn- glycerine -3- phosphatidic acids are added in soybean oil, then under high-shearing dispersion emulsifying machine, and high speed shear is scattered 15 points
Clock, forms oil phase.Glycerine, glutamic acid are added in water for injection, under high-shearing dispersion emulsifying machine, shearing is scattered 15 minutes,
Form aqueous phase.In the case where high speed shear is scattered, oil phase is slowly added in aqueous phase, high speed shear is then proceeded to and disperses 20 minutes, shape
Into colostrum.Colostrum is mended after adding to the full amount of water for injection, high pressure homogenization 3 times is filling, and sterilizes and produce at 121 DEG C for 15 minutes.
Embodiment 3
Prescription:
Preparation method:Each raw material is weighed by prescription respectively, by lecithin, Alprostadil, medium chain triglyceride, the oil of 1,2- bis-
Acyl group-sn- glycerine -3- phosphatidic acids are added in soybean oil, then under high-shearing dispersion emulsifying machine, and high speed shear is scattered 20 points
Clock, forms oil phase.Glycerine, glutamic acid are added in water for injection, under high-shearing dispersion emulsifying machine, shearing is scattered 10 minutes,
Form aqueous phase.In the case where high speed shear is scattered, oil phase is slowly added in aqueous phase, high speed shear is then proceeded to and disperses 20 minutes, shape
Into colostrum.Colostrum is mended after adding to the full amount of water for injection, high pressure homogenization 3 times is filling, and sterilizes and produce at 121 DEG C for 10 minutes.
Embodiment 4
Prescription:
Preparation method:Each raw material is weighed by prescription respectively, by lecithin, Alprostadil, medium chain triglyceride, the oil of 1,2- bis-
Acyl group-sn- glycerine -3- phosphatidic acids are added in soybean oil, then under high-shearing dispersion emulsifying machine, and high speed shear is scattered 15 points
Clock, forms oil phase.Glycerine, glutamic acid are added in water for injection, under high-shearing dispersion emulsifying machine, shearing is scattered 15 minutes,
Form aqueous phase.In the case where high speed shear is scattered, oil phase is slowly added in aqueous phase, high speed shear is then proceeded to and disperses 20 minutes, shape
Into colostrum.Colostrum is mended after adding to the full amount of water for injection, high pressure homogenization 3 times is filling, and sterilizes and produce at 121 DEG C for 10 minutes.
Embodiment 5
Prescription:
Preparation method:Each raw material is weighed by prescription respectively, by lecithin, Alprostadil, medium chain triglyceride, the oil of 1,2- bis-
Acyl group-sn- glycerine -3- phosphatidic acids are added in soybean oil, then under high-shearing dispersion emulsifying machine, and high speed shear is scattered 20 points
Clock, forms oil phase.Glycerine, glutamic acid are added in water for injection, under high-shearing dispersion emulsifying machine, shearing is scattered 10 minutes,
Form aqueous phase.In the case where high speed shear is scattered, oil phase is slowly added in aqueous phase, high speed shear is then proceeded to and disperses 20 minutes, shape
Into colostrum.Colostrum is mended after adding to the full amount of water for injection, high pressure homogenization 3 times is filling, and sterilizes and produce at 121 DEG C for 15 minutes.
Embodiment 6
Prescription:
Preparation method:Each raw material is weighed by prescription respectively, by lecithin, Alprostadil, medium chain triglyceride, the oil of 1,2- bis-
Acyl group-sn- glycerine -3- phosphatidic acids are added in soybean oil, then under high-shearing dispersion emulsifying machine, and high speed shear is scattered 15 points
Clock, forms oil phase.Glycerine, glutamic acid are added in water for injection, under high-shearing dispersion emulsifying machine, shearing is scattered 15 minutes,
Form aqueous phase.In the case where high speed shear is scattered, oil phase is slowly added in aqueous phase, high speed shear is then proceeded to and disperses 20 minutes, shape
Into colostrum.Colostrum is mended after adding to the full amount of water for injection, high pressure homogenization 3 times is filling, and sterilizes and produce at 121 DEG C for 10 minutes.
Embodiment 7
Prescription:
Preparation method:Each raw material is weighed by prescription respectively, by lecithin, Alprostadil, medium chain triglyceride, the oil of 1,2- bis-
Acyl group-sn- glycerine -3- phosphatidic acids are added in soybean oil, then under high-shearing dispersion emulsifying machine, and high speed shear is scattered 15 points
Clock, forms oil phase.Glycerine, glutamic acid are added in water for injection, under high-shearing dispersion emulsifying machine, shearing is scattered 15 minutes,
Form aqueous phase.In the case where high speed shear is scattered, oil phase is slowly added in aqueous phase, high speed shear is then proceeded to and disperses 20 minutes, shape
Into colostrum.Colostrum is mended after adding to the full amount of water for injection, high pressure homogenization 3 times is filling, and sterilizes and produce at 121 DEG C for 15 minutes.
Experimental example 1
Long-time stability are investigated
The gained sample of prescription 1 in embodiment 1 is placed under 2-8 DEG C of constant-temperature constant-humidity environment and placed 24 months, and point
Its average grain diameter, content, envelop rate situation of change are not investigated, the results are shown in Table 7.
The long-time stability result of table 7
Detection | 0 month | March | June | December | 18 months | 24 months |
Average grain diameter nm | 118.2 | 121.3 | 124.6 | 126.9 | 127.2 | 128.4 |
Content % | 100.4 | 99.2 | 99.1 | 99.4 | 98.6 | 97.6 |
Envelop rate % | 98.7 | 97.9 | 96.8 | 95.7 | 94.9 | 94.5 |
Result above shows, the storage that emulsion injection agent of the invention can be stable under conditions of 2-8 DEG C 24 months.
The specific safety of experimental example 2 is tested
Vascular stimulation test:Take healthy rabbits 8 to be only individually fixed in rabbit hutch, be randomly divided into 2 groups, every group of 4 rabbit,
The emulsion parenteral solution of left auricular vein instillation sodium chloride injection and prescription 1 of the present invention respectively.Drip velocity 2.8mLmin-1,
Rabbit intravenous infusion amount is 25mLkg-1.Daily respectively to instil 1 time, continuous 3d observes rabbit auricular vein stimulate the reaction.Noted with sodium chloride
Penetrate group to compare, the equal tube wall of the auricular vein of 4 rabbit is complete in prescription 1, blood vessel is without obvious expansion, and tube wall and surrounding are without bright
The lesions such as thrombosis are had no in aobvious inflammatory cell infiltration, tube wall.
Hemolytic is tested:Divide after prescription 1-9 in embodiment 1 is placed 24 months under 2-8 DEG C of constant-temperature constant-humidity environment
Its haemolysis implementations is not investigated, because in storage process, phospholipid composition therein may further be degraded into lysophosphatide, and
There may be haemolysis for other catabolites.2% red blood cell suspension is made into 0.9% sodium chloride injection, 0.9% sodium chloride is molten
Liquid is as blank control group, and distilled water group is positive controls, incubates 0.5 at 37 DEG C, observes result respectively after 1,2,3 hours.
Result of determination:Whole haemolysis:The clear and bright red of solution, residual that ttom of pipe is acellular;Part haemolysis:The clear and bright red or brownish red of solution,
Ttom of pipe has a small amount of red blood cell;Without haemolysis, red blood cell all sinks, upper liquid milky.
The long-time stability result of table 8
It can be seen that, Alprostadil emulsions parenteral solution of the invention obtains preferable drug safety.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not limited to the substantial technological content model of the present invention
Enclose, substantial technological content of the invention is broadly to be defined in the right of application, any technology that other people complete
Entity or method, if identical with defined in the right of application, also or a kind of equivalent change, will
It is considered as being covered by among the right.
Claims (10)
1. a kind of Alprostadil emulsions parenteral solution, it is characterised in that the parenteral solution include Alprostadil, glutamic acid, lecithin,
DAG -3- phosphatidic acids, oil for injection and water for injection.
2. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that the parenteral solution does not include oleic acid, resisted
One or more in oxidant, EDTA, preferably not comprising oleic acid and antioxidant, preferably not comprising oleic acid and EDTA, preferably
Not comprising antioxidant and EDTA.
3. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that the parenteral solution also includes medium chain triglyceride
It is one or more in three esters, glycerine, preferably comprise medium chain triglyceride and glycerine.
4. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that its Glutamic Acid and 1,2- dioleoyl
The weight ratio of base-sn- glycerine -3- phosphatidic acids is 1:1.
5. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that the lecithin is selected from egg yolk lecithin
Or soybean lecithin, one or more of the oil for injection in soybean oil, sesame oil or peanut oil, preferably soybean
Oil.
6. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that the parenteral solution is by Alprostadil, paddy
Propylhomoserin, lecithin, DAG -3- phosphatidic acids, oil for injection, medium chain triglyceride, glycerine and injection
Water is made.
7. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that in every 1000ml parenteral solutions, before containing
Row ground that 0.1-10mg, 80~150g of oil for injection, medium chain triglyceride 10-30g, 10~20g of lecithin, 1,2- dioleoyls
0.1~3g of base-sn- glycerine -3- phosphatidic acids, 0.1~3g of glutamic acid, glycerine 10-30g and water for injection.
8. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that after heat sterilization, average grain diameter exists
Between 105-130nm, preferably 110,111,112,113,114,115,116,117,118nm;The polydispersity index of particle diameter exists
0.1-0.2, preferably 0.11,0.12,0.13,0.14,0.15,0.16;Preferably 121 DEG C of heat sterilization sterilizes 10-15 minutes, preferably
12 minutes.
9. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that described 25 DEG C of decentralizations of parenteral solution set to 0-6
Individual month, its peroxide value, which is less than at 0.8, preferably smaller than 0.7,0.6,0.5,0.4, further preferred 25 DEG C, placed 1 month peroxide
Change value is less than 2 months peroxide values of placement at 0.4, further preferred 25 DEG C and is less than placement 3 at 0.4, further preferred 25 DEG C
Month peroxide value, which is less than at 0.4, further preferred 25 DEG C, places 6 months peroxide values and is less than 0.4.
10. Alprostadil emulsions parenteral solution as claimed in claim 1, it is characterised in that constant temperature of the parenteral solution at 2-8 DEG C
Placed 24 months under constant humidity environment, Alprostadil content is between 95%-99.9%, preferably 95%, 96%.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710413318.6A CN107137351B (en) | 2017-06-05 | 2017-06-05 | Stable alprostadil emulsion injection |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710413318.6A CN107137351B (en) | 2017-06-05 | 2017-06-05 | Stable alprostadil emulsion injection |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107137351A true CN107137351A (en) | 2017-09-08 |
CN107137351B CN107137351B (en) | 2020-08-04 |
Family
ID=59780067
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710413318.6A Active CN107137351B (en) | 2017-06-05 | 2017-06-05 | Stable alprostadil emulsion injection |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107137351B (en) |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0097481A1 (en) * | 1982-06-18 | 1984-01-04 | Taisho Pharmaceutical Co. Ltd | Emulsion containing prostaglandin E1 and method for production thereof |
JPS63145230A (en) * | 1986-12-09 | 1988-06-17 | Green Cross Corp:The | Preventive and remedy for cerebrovascular contraction |
JP2001288080A (en) * | 2000-02-04 | 2001-10-16 | Takeda Chem Ind Ltd | Stable emulsion composition |
WO2007132825A1 (en) * | 2006-05-15 | 2007-11-22 | Takeda Pharmaceutical Company Limited | Pharmaceutical agent |
EP1972334A1 (en) * | 2007-03-21 | 2008-09-24 | Taiwan Liposome Co., Ltd. | Emulsion Composition Comprising Prostaglandin E1 |
JP2011509947A (en) * | 2008-01-16 | 2011-03-31 | シェンヤン・ファーマスーティカル・ユニバーシティ | Drug delivery system and method and use thereof |
CN103110579A (en) * | 2013-02-20 | 2013-05-22 | 北京德立福瑞医药科技有限公司 | Alprostadil injection |
CN103610640A (en) * | 2013-12-06 | 2014-03-05 | 吉林大学 | Alprostadil medium-and-long-chain lipid emulsion for injection and preparation method thereof |
CN105287376A (en) * | 2014-07-14 | 2016-02-03 | 上海信谊药厂有限公司 | Alprostadil injection and preparation method thereof |
CN106667944A (en) * | 2015-11-11 | 2017-05-17 | 北京泰德制药股份有限公司 | Sustained release preparation containing prostaglandin drugs |
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 |
-
2017
- 2017-06-05 CN CN201710413318.6A patent/CN107137351B/en active Active
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0097481A1 (en) * | 1982-06-18 | 1984-01-04 | Taisho Pharmaceutical Co. Ltd | Emulsion containing prostaglandin E1 and method for production thereof |
JPS63145230A (en) * | 1986-12-09 | 1988-06-17 | Green Cross Corp:The | Preventive and remedy for cerebrovascular contraction |
JP2001288080A (en) * | 2000-02-04 | 2001-10-16 | Takeda Chem Ind Ltd | Stable emulsion composition |
WO2007132825A1 (en) * | 2006-05-15 | 2007-11-22 | Takeda Pharmaceutical Company Limited | Pharmaceutical agent |
JPWO2007132825A1 (en) * | 2006-05-15 | 2009-09-24 | 武田薬品工業株式会社 | Medicine |
EP1972334A1 (en) * | 2007-03-21 | 2008-09-24 | Taiwan Liposome Co., Ltd. | Emulsion Composition Comprising Prostaglandin E1 |
JP2011509947A (en) * | 2008-01-16 | 2011-03-31 | シェンヤン・ファーマスーティカル・ユニバーシティ | Drug delivery system and method and use thereof |
CN103110579A (en) * | 2013-02-20 | 2013-05-22 | 北京德立福瑞医药科技有限公司 | Alprostadil injection |
CN103610640A (en) * | 2013-12-06 | 2014-03-05 | 吉林大学 | Alprostadil medium-and-long-chain lipid emulsion for injection and preparation method thereof |
CN105287376A (en) * | 2014-07-14 | 2016-02-03 | 上海信谊药厂有限公司 | Alprostadil injection and preparation method thereof |
CN106667944A (en) * | 2015-11-11 | 2017-05-17 | 北京泰德制药股份有限公司 | Sustained release preparation containing prostaglandin drugs |
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 |
Also Published As
Publication number | Publication date |
---|---|
CN107137351B (en) | 2020-08-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4687661A (en) | Method for producing liposomes | |
US5527537A (en) | Pharmaceutical preparation containing cyclosporine(s) for intravenous administration and a process for its production | |
NL8802657A (en) | MEDICINAL CARRIERS. | |
NO333811B1 (en) | Stealth nanocapsules, processes for their preparation and use as a carrier for active principle / principles | |
CN101396343B (en) | Paclitaxel submicron emulsion using lipid composite as middle carrier | |
HU196700B (en) | Process for producing parenterally administrable, homogenized pharmaceutical compositions in emulsion form, comprising basic hydrophobic active ingredient | |
CN102686217B (en) | Submicro emulsion of paclitaxel using steroid complex as intermediate carrier | |
WO2022160971A1 (en) | Concentrate containing poorly soluble drug, and emulsion prepared therefrom | |
JPH02203A (en) | Drug carrier | |
CN101496787A (en) | Prostaglandin E1 lipid microsphere injection with charge effect and preparation method thereof | |
WO2010127541A1 (en) | A nano-emulsion injection of vinca alkaloids and the preparation method thereof | |
CN104306333B (en) | A kind of Cabazitaxel lipide microsphere injection and preparation method thereof | |
CN101829052B (en) | Self-emulsifying preparation of taxane compound and preparation method thereof | |
CN1857239A (en) | Coenzyme Q10 injection emulsion and its preparing process | |
CN104997759B (en) | A kind of total toadpoison lactone solid lipid nano granule drug delivery system of injection and preparation method thereof | |
CN101524329A (en) | Bicyclo-ethanol submicron emulsion and preparation method thereof | |
CN108883157A (en) | Viscoelastic gel suitable for the Liraglutide being administered once a week or once every two weeks | |
CN101204373A (en) | Paclitaxel lipid microspheres injection and preparation method thereof | |
CN101416963A (en) | Nimodipine freeze-drying sub micellar emulsion for injection and preparation method thereof | |
CN107137351A (en) | A kind of Alprostadil emulsions parenteral solution of stabilization | |
CN101332176A (en) | Medicine composition for injecting cinnarizine lipid microsphere and preparation method thereof | |
US5622714A (en) | Pharmaceutical preparation containing cyclosporine(s) for intravenous administration and process for its production | |
CN101553215B (en) | Stable and ready-to-use oil-in-water propofol microemulsion | |
CN102905693A (en) | Water-soluble pharmaceutical composition comprising at least one therapeutically active substance having hydrophobic properties and at least one compound selected from among sialoglycosphingolipids, glycosphingolipids or a mixture of sialoglycosphingolipids and glycosphingolipids | |
CN105381469A (en) | Medicine preparation for treating brain diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |