CN107519132A - A kind of nanometer fat emulsion of Alprostadil - Google Patents
A kind of nanometer fat emulsion of Alprostadil Download PDFInfo
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- CN107519132A CN107519132A CN201710754460.7A CN201710754460A CN107519132A CN 107519132 A CN107519132 A CN 107519132A CN 201710754460 A CN201710754460 A CN 201710754460A CN 107519132 A CN107519132 A CN 107519132A
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- fat emulsion
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- alprostadil
- emulsion
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- 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
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- 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
- A61K47/24—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
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- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Abstract
A kind of nanometer fat emulsion of Alprostadil, the fat emulsion is without using aliphatic acid such as oleic acid as stabilizer, the emulsion has clear and bright shape, the aggegation of drug degradation and emulsion droplet caused by hyperpressure and its high temperature can be reduced, what medicine can be stablized is encapsulated in emulsion droplet, so as to reduce the toxic side effect of medicine, and it is avoided that influence of the application of aliphatic acid to medicine Alprostadil.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of nanometer fat emulsion of Alprostadil.
Background technology
Alprostadil is prostaglandin E1, and Alprostadil has been widely applied in clinic at present, such as treats 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 disease of digestive system such as the cranial vascular disease such as vasopasm, respiratory disease, hepatitis after subarachnoid hemorrhage is prevented,
The renal function diseases such as renal insufficiency, diabetes and erectile dysfunction.
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 continue to occur in the basic conditions to reset hair and should generate prostaglandin B 1 and lose pharmacological activity, thus in the formulation such as
What ensures that its stability becomes important problem.Current lipoalprostadil can when fat emulsion is modulated
It is used as the natural phospholipids such as egg yolk lecithin and the soybean lecithin of emulsifying agent, wherein the dosage of lecithin is about in 10-
Between 20%, but lecithin can have undesirable effect to the stability of prostaglandin, by lecithin in JP Laid-Open 8-18989
Content reduce and improve stability.
Current lipoalprostadil is generally by oil phase plant oil, emulsifying agent phosphatide, cholesterol, assistant for emulsifying agent
Network sand nurse, oleic acid etc. are moored, aqueous phase is prepared.As CN101091890 discloses a kind of mixed emulsifier and with its preparation
Emulsion, the compound emulsifying agent can by two kinds either three kinds or more than three kinds of emulsifying agent be combined, its each composition is in breast
Concentration difference in agent：0%~5% lecithin w/v, 0%~5% poloxamer w/v, 0%~5%Solutol HS15w/
V, 0%~5% vitamin E polyethylene glycol succinic acid ester w/v, 0%~5% DSPE-PEG w/v, wherein PEG molecular weight are
1000~10000.With heat resistanceheat resistant and freeze-thaw stability, average grain diameter is between 50-100nm.
CN101474150 discloses a kind of alprostadil injection emulsion of stabilization, and it is active component that it, which contains Alprostadil,
It is prepared 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, the heat endurance of Alprostadil can be significantly increased, extends the term of validity of alprostadil injection emulsion, while before can substantially reducing
Degraded of the row ground that in lung.
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, uniform particle diameter is made, average grain diameter exists
100nm-280nm lipid microsphere.With the reduction of pH value, the envelop rate of medicine gradually rises, but Zeta potential absolute value
Reduce, be unfavorable for preparation stabilization.PH value range is set to 5.4-6.0, it is ensured that entrapment efficiency maintains more than 90%
Suitable Zeta potential value, increase the stability of emulsion.
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 and carry protogenic interfacial agent.In emulsion composition protogenic boundary is carried using non-
Face activating agent replaces oleic acid, and as coemulsifier, 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.
JP5193870 discloses prostaglandin fat emulsion and its manufacture method and its stabilization method and emulsifying agent,
Contain prostaglandin as active ingredient, and contain PC containing phosphatidyl choline and phosphatidyl glycerol PG phosphatide, in 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.Although make emulsion stability liter due to containing PE in phosphatide
Height, but PGE1 abatement increases.
Current existing lipoalprostadil is needed to be kept in dark place below 5 DEG C mostly, and the term of validity is also only 1 year.
If by the content step-down of lecithin, the function of emulsifying agent also accordingly reduces, thus, allocating fat by the use of phosphatide as emulsifying agent
When emulsion, oleic acid, stearic acid, linoleic acid, leukotrienes, palmitic acid, palmitoleic acid, nutmeg generally can be also further added
The aliphatic acid of acid etc. is as emulsion adjuncts, to further ensure that the stabilization of emulsion.But these fatty acid emulsifier adjuvants
Using can also be impacted to the stability of active constituents of medicine prostaglandin.Therefore inventor makes every effort to overcome above-mentioned technology to lack
Fall into, from reduce lecithin content phosphatide as emulsifying agent to prostaglandin while fat emulsification is carried out, do not allocate work
For the aliphatic acid of emulsion adjuncts, the method for realizing the stability of emulsion.
The content of the invention
The present invention provides a kind of nanometer fat emulsion of Alprostadil, and the fat emulsion is without using the aliphatic acid conduct such as oleic acid
Stabilizer, the emulsion have clear and bright shape, can reduce the aggegation of drug degradation and emulsion droplet caused by hyperpressure and its high temperature,
What medicine can be stablized is encapsulated in emulsion droplet, so as to reduce the toxic side effect of medicine, and is avoided that the application pair of aliphatic acid
The influence of medicine Alprostadil.
The present invention solve technical problem technical scheme be：
The present inventor is by largely testing, and discovery does not use the aliphatic acid stabilizer such as oleic acid, by the dense of grease
Degree, grease and the weight rate and grease of Alprostadil and the mass ratio of phosphatide are concurrently set in a suitable scope, and
Using the pressure such as less than 1500kgf/cm conventional much smaller than high pressure dispersing emulsification machine2Emulsification pressure emulsify, you can before the acquisition
The preparation that row ground that is stable and emulsion stability is good.
The present invention provides a kind of nanometer fat emulsion of Alprostadil, and the nanometer fat emulsion includes Alprostadil, planted
Thing oil, lecithin and water, the wherein content of Alprostadil is 0.001-1.5mg/mL, and the content of vegetable oil is 0.06-2mg/
Ml, the mass ratio of Alprostadil/vegetable oil are 0.0007-10, and the mass ratio of vegetable oil/lecithin is 0.005-1, and oil phase and
Aqueous phase is in 600-1000kgf/cm2Pressure breast it is even.
The nanometer fat emulsion does not include carbon atom 6-22 aliphatic acid, and the aliphatic acid is selected from oleic acid, linoleic acid, hard
Resin acid, leukotrienes, palmitic acid, palmitoleic acid, myristic acid etc..
The average grain diameter of the nanometer fat emulsion is 80-120nm.
The turbidity of the nanometer fat emulsion be less than 0.35, more preferably less than 0.25, less than 0.2, less than 0.18；
The nanometer fat emulsion further comprises glycerine, propane diols, polyvinyl alcohol, PVP, sulfuric acid
It is one or more in chondroitin and chondroitin sulfate salt, hyaluronic acid, hyaluronate and carbohydrate.
The vegetable oil of the present invention is selected from soybean oil, corn oil, peanut oil, palm oil, safflower oil, sesame oil, olive oil, castor
Sesame oil, the one or more in cottonseed oil, preferably soybean oil, or preferred palm oil.
The lecithin is selected from egg yolk lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline
In one or more, preferred egg yolk lecithin.
In addition, the fat emulsion of the present invention also includes being selected from oleic acid, stearic acid, linoleic acid, leukotrienes, palmitic acid, palm
Oleic acid, the one or more in myristic acid, the stabilizer as emulsion.The concentration of above-mentioned emulsion stabilisers is preferably in 0.02-
5mg/mL。
The carbohydrate of the present invention is selected from the monosaccharides such as inositol, glucose, sorbierite, mannitol, trehalose, lactose, sucrose,
The disaccharides such as disaccharides, or maltose, dextrin, cyclodextrin, glucan, the preferably one or more in xylitol, trehalose, institute
State the concentration preferred 20-400mg/mL, more preferably preferably 50-150mg/mL, 80mg/mL of carbohydrate.The addition of carbohydrate of the present invention can
Separated out with effective floating material for suppressing to be likely to occur when reaction.
In addition, the present invention can also further add pH adjusting agent and osmotic pressure regulator regulation pH (to 4-8) and ooze
Pressure thoroughly, can also further add preservative and antioxidant.
The present invention furthermore provides the preparation method of above-mentioned nanometer fat emulsion, and methods described comprises the following steps：
(1) Alprostadil, lecithin are added in vegetable oil, form oil phase；
(2) aqueous phase is prepared；
(3) oil phase is slowly added in aqueous phase, forms colostrum；
(4) colostrum is mended after adding water to full dose, in 600-1000kgf/cm2Pressure under it is homogeneous；
(5) filling rear, high pressure steam sterilization.
0.06-2mg/ml is set in the concentration of emulsion in vegetable oil of the present invention, we send out in substantial amounts of pre-stage test
Existing, if being less than 0.06mg/mL, the stable effect of medicine in vegetable oil can be reduced by being attached to the fatty particle surface of Alprostadil
Fruit, emulsifier and water-soluble degree identical stability are only obtained, and medicine is easier aggegation, separated out, if high
In 2mg/mL, emulsion will produce muddiness, while losing transparent, due to the stability containing an excess amount of oil to medicine
Have undesirable effect.The content of grease is set in 0.1-1mg/mL optimums.
By the weight rate of vegetable oil and medicine (medicine/grease) selection in the range of 0.0007-10, if be less than
0.0007, relative to medicine, vegetable oil is excessive, will result in the excessive useless vegetable oil of injection to patient, if it exceeds 10, phase
For vegetable oil, medicine is more, will destroy the stability of medicine, and medicine is relatively easy to aggegation and precipitation.Vegetable oil is relative
1-8 scope optimums are set in the weight rate of medicine.
On the basis of the above, while by the selection of the quality of vegetable oil/lecithin in 0.005-1, if greater than 1, except meeting
Cause grease to become more, medicament can be allowed to produce muddy, beyond the stability for influenceing medicine, such as in 1500kgf/cm2Following temperature
With under pressure condition be difficult emulsified, if less than 0.005 emulsifying agent be easy to aggegation precipitation.Vegetable oil/lecithin of the present invention
The mass ratio of fat is preferably in 0.01-1.
Nanometer fat emulsion of the present invention, by the concentration of vegetable oil, the mass ratio of vegetable oil/medicine, vegetable oil/lecithin
Weight rate is set in above-mentioned number range, and according to open step, medicine, vegetable oil, lecithin are evenly mixed in into one
Rise and then fully dissolving is changed into oil phase, after adding water, strong stirring allotment turns into colostric fluid, then by colostric fluid by high pressure breast
Change machine is emulsified and can repeatedly emulsified (such as 5-20 times).It is noted that by being set in above-mentioned numerical value
In the range of, such as in 1500kgf/cm2Pressure condition under, optimum pressure is 600-1000kgf/cm2, fatty particle
Average grain diameter be below 200nm, preferably 80-120nm, more preferably 100-110nm, turbidity is preferably smaller than 0.35, more preferably
Less than 0.25, less than 0.2, less than 0.18.
The average grain diameter of the nanometer fat emulsion of the present invention is set in 100-120nm, except that can be relatively easy to filter
Outside sterilization treatment, additionally it is possible to carry out high pressure steam sterilization.High pressure steam sterilization is by the fat emulsion containing medicine of the present invention
It is filled into ampoule or synthesizing polyethylene resin container, in 120-122 DEG C, the time is carried out temperature under 10-15 minutes
High pressure steam sterilization.
Emulsion prepared by the present invention can be as stable emulsion for injection, eyedrops, the nasal spray of micronized or suction
Agent.The nanometer fat emulsion of the present invention, due to excellent in stability, can be preserved, further, since clear and bright property for a long time at normal temperatures
Preferably, with the naked eye can correctly observe whether there is rotten or foreign matter to be mixed into, the change of mixing ratio, sentence beneficial to observation
It is disconnected, also feel at ease to take beneficial to patient.
Simultaneously for this special medicine of Alprostadil, it is both insoluble in water, and there is also the stabilization of thermal degradation or hydrolysis
Sex chromosome mosaicism, applying on the same day on the basis of " nanometer fat emulsion ", we are not only found that to the formulation and technology to the steady of emulsion
It is qualitative favourable, and for this medicine of specific Alprostadil, moreover it is possible to help to reduce the application of the aliphatic acid such as oleic acid, so as to
Improve the stability of Alprostadil medicine.
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, anticipated known to all specialties used in text and scientific words and one skilled in the art
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：Fat emulsion containing Alprostadil
By refined soybean oil 160mg, egg yolk lecithin 2.9g is refined, glycerine 3.4g is put into beaker, under the conditions of 50 DEG C
Blender is uniformly mixed, and 1mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form oil phase；Will be above-mentioned
Oil phase progressively adds 50mL Purified Water, then carries out the first emulsification of 10 minutes in 12000rmp rotating speed.Then essence is supplied again
Water processed, after the capacity of liquid is mixed added to 150mL, using high-pressure homogenizer under nitrogen charging gas shielded, Emulsification pressure setting
For 800kgf/cm2, then circulating emulsion 20 times.After emulsification, pH is adjusted to 5.5 by the pH adjusting agent hydrochloric acid for adding 0.1N, by breast
Change liquid to be put into glass ampule, high pressure steam sterilization is carried out at 121 DEG C 12 minutes, produce the Fat Emulsion containing Alprostadil
Agent.
Embodiment 2：Fat emulsion containing Alprostadil
By refined soybean oil 140mg, egg yolk lecithin 2.3g is refined, glycerine 3.4g is put into beaker, under the conditions of 50 DEG C
Blender is uniformly mixed, and 1mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form oil phase；Will be above-mentioned
Oil phase progressively adds 50mL Purified Water, then carries out the first emulsification of 10 minutes in 12000rmp rotating speed.Then essence is supplied again
Water processed, after the capacity of liquid is mixed added to 150mL, using high-pressure homogenizer under nitrogen charging gas shielded, Emulsification pressure setting
For 750kgf/cm2, then circulating emulsion 20 times.After emulsification, pH is adjusted to 5.5 by the pH adjusting agent hydrochloric acid for adding 0.1N, by breast
Change liquid to be put into glass ampule, high pressure steam sterilization is carried out at 121 DEG C 10 minutes, produce the Fat Emulsion containing Alprostadil
Agent.
Embodiment 3：Fat emulsion containing Alprostadil
By refined soybean oil 310mg, egg yolk lecithin 5.6g is refined, propane diols 6.4g is put into beaker, in 45 DEG C of conditions
Lower blender is uniformly mixed, and 1.8mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form oil phase；Will
Above-mentioned oil phase progressively adds 110mL Purified Water, then carries out the first emulsification of 5 minutes in 11000rmp rotating speed.Then mend again
Sufficient Purified Water, after the capacity of liquid is mixed added to 160mL, using high-pressure homogenizer under nitrogen charging gas shielded, Emulsification pressure
It is set as 600kgf/cm2, then circulating emulsion 20 times, while add 20g mannitol and form emulsion.After emulsification, add
PH is adjusted to 5.5 by 0.1N pH adjusting agent hydrochloric acid, and emulsion is put into glass ampule, and high steam is carried out at 121 DEG C
Sterilizing 10 minutes, produces the fat emulsion containing Alprostadil.
Embodiment 4：Fat emulsion containing Alprostadil
By refined soybean oil 310mg, egg yolk lecithin 5.6g is refined, propane diols 6.4g is put into beaker, in 45 DEG C of conditions
Lower blender is uniformly mixed, and 1.8mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form oil phase；Will
Above-mentioned oil phase progressively adds 110mL Purified Water, then carries out the first emulsification of 5 minutes in 11000rmp rotating speed.Then mend again
Sufficient Purified Water, after the capacity of liquid is mixed added to 160mL, using high-pressure homogenizer under nitrogen charging gas shielded, Emulsification pressure
It is set as 650kgf/cm2, then circulating emulsion 20 times, while add 20g trehaloses and form emulsion.After emulsification, add
PH is adjusted to 5.5 by 0.1N pH adjusting agent hydrochloric acid, and emulsion is put into glass ampule, and high steam is carried out at 121 DEG C
Sterilizing 10 minutes, produces the fat emulsion containing Alprostadil.
Embodiment 5：Fat emulsion containing Alprostadil
By refined soybean oil 120mg, egg yolk lecithin 200mg is refined, propane diols 200mg is put into beaker, in 45 DEG C of bars
Blender is uniformly mixed under part, and 3mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form oil phase；Will
Above-mentioned oil phase progressively adds 50mL Purified Water, then carries out the first emulsification of 5 minutes in 11000rmp rotating speed.Then supply again
Purified Water, after the capacity of liquid is mixed added to 100mL, using high-pressure homogenizer under nitrogen charging gas shielded, Emulsification pressure is set
It is set to 650kgf/cm2, then circulating emulsion 20 times, while add 10g mannitol and form emulsion.After emulsification, 0.1N is added
PH adjusting agent hydrochloric acid pH is adjusted to 5.5, emulsion is put into glass ampule, high pressure steam sterilization is carried out at 121 DEG C
10 minutes, produce the fat emulsion containing Alprostadil.
Embodiment 6：Fat emulsion containing Alprostadil
By refined soybean oil 120mg, egg yolk lecithin 1.8g is refined, propane diols 2.3g is put into beaker, in 45 DEG C of conditions
Lower blender is uniformly mixed, and 5mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form oil phase；Will be upper
The Purified Water that oil phase progressively adds 100mL is stated, then carries out the first emulsification of 5 minutes in 11000rmp rotating speed.Then supply again
Purified Water, after the capacity of liquid is mixed added to 150mL and 10g maltose, using high-pressure homogenizer in nitrogen charging gas shielded
Under, Emulsification pressure is set as 1000kgf/cm2, then circulating emulsion 20 times, form emulsion.After emulsification, add 0.1N's
PH is adjusted to 5.5 by pH adjusting agent hydrochloric acid, and emulsion is put into glass ampule, and high pressure steam sterilization 10 is carried out at 121 DEG C
Minute, produce the fat emulsion containing Alprostadil.
Embodiment 7：Fat emulsion containing Alprostadil
By refined maize oil 160mg, Refined Soybean lecithin 2.9g, glycerine 3.4g is put into beaker, under the conditions of 50 DEG C
Blender is uniformly mixed, and 1mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form oil phase；Will be above-mentioned
Oil phase progressively adds 50mL Purified Water, then carries out the first emulsification of 10 minutes in 12000rmp rotating speed.Then essence is supplied again
Water processed, after the capacity of liquid is mixed added to 150mL, using high-pressure homogenizer under nitrogen charging gas shielded, Emulsification pressure setting
For 800kgf/cm2, then circulating emulsion 20 times.After emulsification, pH is adjusted to 5.5 by the pH adjusting agent hydrochloric acid for adding 0.1N, by breast
Change liquid to be put into glass ampule, high pressure steam sterilization is carried out at 121 DEG C 12 minutes, produce the Fat Emulsion containing Alprostadil
Agent.
Embodiment 8：Fat emulsion containing Alprostadil
By refined maize oil 160mg, Refined Soybean lecithin 2.9g, glycerine 3.4g is put into beaker, under the conditions of 50 DEG C
Blender is uniformly mixed, and 1mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form oil phase；Will be above-mentioned
Oil phase progressively adds 50mL Purified Water, then carries out the first emulsification of 10 minutes in 12000rmp rotating speed.Then essence is supplied again
Water processed, after the capacity of liquid is mixed added to 150mL, using high-pressure homogenizer under nitrogen charging gas shielded, Emulsification pressure setting
For 800kgf/cm2, then circulating emulsion 20 times.After emulsification, pH is adjusted to 5.5 by the pH adjusting agent hydrochloric acid for adding 0.1N, by breast
Change liquid to be put into glass ampule, high pressure steam sterilization is carried out at 121 DEG C 12 minutes, produce the Fat Emulsion containing Alprostadil
Agent.
Comparative example 1：The fat emulsion of Alprostadil containing oleic acid
By refined soybean oil 160mg, egg yolk lecithin 2.9g is refined, glycerine 3.4g and 0.3g oleic acid is put into beaker,
Blender is uniformly mixed under the conditions of 50 DEG C, and 1mg Alprostadil is added under conditions of inflated with nitrogen, and uniform stirring is mixed to form
Oil phase；Above-mentioned oil phase is progressively added to 50mL Purified Water, then carries out the first emulsification of 10 minutes in 12000rmp rotating speed.So
Supply Purified Water again afterwards, after the capacity of liquid is mixed added to 150mL, using high-pressure homogenizer under nitrogen charging gas shielded, breast
Change pressure and be set as 800kgf/cm2, then circulating emulsion 20 times.After emulsification, the pH adjusting agent hydrochloric acid for adding 0.1N adjusts pH
To 5.5, emulsion is put into glass ampule, high pressure steam sterilization is carried out at 121 DEG C 12 minutes, is produced containing forefront
Your fat emulsion.
Comparative example 2：The fat emulsion of Alprostadil containing oleic acid
By refined soybean oil 160mg, egg yolk lecithin 2.9g is refined, glycerine 3.4g and 0.3g linoleic acid is put into beaker
In, blender is uniformly mixed under the conditions of 50 DEG C, and 1mg Alprostadil, uniform stirring mixing are added under conditions of inflated with nitrogen
Form oil phase；Above-mentioned oil phase is progressively added to 50mL Purified Water, then carries out the colostrum of 10 minutes in 12000rmp rotating speed
Change.Then Purified Water is supplied again, after the capacity of liquid is mixed added to 150mL, using high-pressure homogenizer in nitrogen charging gas shielded
Under, Emulsification pressure is set as 800kgf/cm2, then circulating emulsion 20 times.After emulsification, 0.1N pH adjusting agent hydrochloric acid is added
PH is adjusted to 5.5, emulsion is put into glass ampule, high pressure steam sterilization 12 minutes is carried out at 121 DEG C, produce containing
The fat emulsion of Alprostadil.
Experimental example 1
Determine embodiment 1-6, the average grain diameter of emulsion of the sample of comparative example 1,2 after high pressure steam sterilization and muddy
Turbidity.
The measure of average grain diameter：Using the particle diameter and size distribution of LS230 laser diffraction analyzers measure emulsion, its principle
It is that the feature that diffraction occurs for light scattering and light occurs when being irradiated by light using particle, and the scattering strength and diffracted intensity of light
The principle relevant with particle size and optical signature determines particle size.
The measure of turbidity：Using ultraviolet specrophotometer, sample is put into measuring unit according to unit norm, detected
Turbidimetry is carried out under wavelength 620nm, blank control is water.Sample clear is visible, can by naked eyes can determine aggegation,
Sediment etc. rotten and whether there is foreign matter to be mixed into, transparent and translucent scope is below Abs=0.5.
Change before and after the high pressure steam sterilization of table 1
Experimental example 2
Embodiment 1-6, comparative example 1,2 sample are individually positioned under the conditions of 20 DEG C or so of temperature and placed 6 months, respectively
The content of prostaglandin A1 is investigated in the 0th, 3,6 the end of month sampling detection during experiment.
The content assaying method of Alprostadil and prostaglandin A1：C18 chromatographic columns (4.6mm*250mm, 5um)；Flowing
Phase 6.7mmol/L potassium phosphate buffers (pH 6.3)-second eyeball (3.1:1.1)；Past column reaction liquid 1mol/L potassium hydroxide is molten
Liquid；Past column reaction pipe：Polyfluortetraethylene pipe ((O.5mm*10m)；60 DEG C of column temperature；Detection wavelength 278nm；Flow velocity 1ml/min；Enter
Sample amount 20ul.Reference substance：Alprostadil and appropriate prostaglandin A1 are taken respectively, are settled to absolute ethyl alcohol dissolving certain dense
Degree, takes 20ul injecting chromatographs.Test sample：Alprostadil emulsions 1ml, put in 5ml brown measuring bottles, methanol constant volume, shake up, take
20ul injecting chromatographs.
The changes of contents of the prostaglandin A1 of table 2
| Time (moon) | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Comparative example 1 | Comparative example 2 |
| 0 month | 0.42% | 0.43% | 0.45% | 0.35% | 0.42% | 0.43% | 0.62% | 0.61% |
| March | 0.49% | 0.51% | 0.53% | 0.40% | 0.53% | 0.52% | 0.83% | 0.89% |
| June | 0.55% | 0.58% | 0.59% | 0.48% | 0.60% | 0.59% | 1.21% | 1.18% |
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 with the right of application defined in it is identical, also or a kind of equivalent change, will
It is considered as being covered by among the right.
Claims (8)
1. the nanometer fat emulsion of a kind of Alprostadil, it is characterised in that the nanometer fat emulsion includes Alprostadil, plant
Oil, lecithin and water, the wherein content of Alprostadil is 0.001-1.5mg/mL, and the content of vegetable oil is 0.06-2mg/ml,
The mass ratio of Alprostadil/vegetable oil is 0.0007-10, and the mass ratio of vegetable oil/lecithin is 0.005-1, and oil phase and water
Mutually even in 600-1000 kgf/cm2 pressure breast, the nanometer fat emulsion does not include carbon atom 6-22 aliphatic acid.
2. according to claim 1 nanometer of fat emulsion, it is characterised in that the nanometer fat emulsion goes out in high steam
After bacterium, wherein the content of prostaglandin A1 is less than 0.5%.
3. according to claim 1 nanometer of fat emulsion, it is characterised in that the nanometer fat emulsion is under the conditions of 20 DEG C
Place 6 months, the content of prostaglandin A1 is less than 0.6%.
4. according to claim 1 nanometer of fat emulsion, it is characterised in that the aliphatic acid is selected from oleic acid, linoleic acid, hard
One or more in resin acid, leukotrienes, palmitic acid, palmitoleic acid, myristic acid.
5. according to claim 1 nanometer of fat emulsion, it is characterised in that the average grain diameter of the nanometer fat emulsion is
80-120nm。
6. according to claim 1 nanometer of fat emulsion, it is characterised in that the turbidity of the nanometer fat emulsion is less than
0.35, more preferably less than 0.25, less than 0.2, less than 0.18, ultraviolet spectrometry degree instrument measure of the turbidity in the case where being 620nm
Absorbance.
7. according to claim 1 nanometer of fat emulsion, it is characterised in that the nanometer fat emulsion further comprises sweet
It is oil, propane diols, polyvinyl alcohol, PVP, chondroitin sulfate and chondroitin sulfate salt, hyaluronic acid, transparent
It is one or more in matter hydrochlorate and carbohydrate.
8. according to claim 7 nanometer of fat emulsion, it is characterised in that the carbohydrate is selected from inositol, glucose, sorb
One or more in alcohol, mannitol, trehalose, lactose, sucrose, maltose, dextrin, cyclodextrin, glucan, xylitol,
It is preferred that trehalose.
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| CN201710754460.7A CN107519132A (en) | 2017-08-29 | 2017-08-29 | A kind of nanometer fat emulsion of Alprostadil |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113144288A (en) * | 2021-04-26 | 2021-07-23 | 磐升瑞祥(山东)生物工程有限公司 | Composite multi-component collagen micro-emulsion filler and preparation method thereof |
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