CN102000025A - Novel painless diluent, dilution compatibility method and application of alprostadil fat emulsion preparation - Google Patents
Novel painless diluent, dilution compatibility method and application of alprostadil fat emulsion preparation Download PDFInfo
- Publication number
- CN102000025A CN102000025A CN 201010527600 CN201010527600A CN102000025A CN 102000025 A CN102000025 A CN 102000025A CN 201010527600 CN201010527600 CN 201010527600 CN 201010527600 A CN201010527600 A CN 201010527600A CN 102000025 A CN102000025 A CN 102000025A
- Authority
- CN
- China
- Prior art keywords
- fat milk
- blank
- alprostadil
- fat
- fat emulsion
- 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
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a painless alprostadil fat emulsion composition and a preparation method thereof. The fat emulsion composition is prepared from alprostadil fat emulsion and blank fat emulsion according to the minimum ratio of 1:5. By taking active adsorption, physical isolation and protection of the stability of the preparation as strategies, a novel preparation diluting method is established, injection stimulation and injection pain caused by the alprostadil fat emulsion preparation can be removed or obviously reduced, and the treatment tolerance of a patient is improved.
Description
One, technical field
The invention belongs to medical drugs series, relate to a kind of diluent, diluted formulations and use of medicine novel formulation, particularly relate to diluent, dilution medicine compatibility method and the application of painless novel prostadil fatty emulsion formulation.
Two, background technology
Alprostadil (PGE1, PGE1), it is a member in the prostaglandin family, it is current internationally recognized wide spectrum endogenous substance of new generation, extensively be present in the body, be the oxidation product of polyunsaturated fatty acid (two high γ-oleum lini fat acids), have significant blood vessel dilating, blood flow increasing and anticoagulant, prevent effects such as thrombosis that cardiovascular disease is had obvious curative effects.Its pharmacological action comprises: blood vessel dilating, improve the end and circulate slightly; Anticoagulant; Suppress the synthetic thromboxane A2 (TXA2) of platelet, prevent thrombosis; The protection platelet cell prolongs its life-span; Suppressing atherosclerotic plaque forms; The protection ischemic myocardial dwindles infarct size.
The chemical property instability of PGE1, metabolism is very fast in vivo, and under pulmonary's oxidase effect, the per pass pulmonary circulation promptly has 60%～90% inactivation.Conventional Alprostadil preparation is an injectable powder, and specification mostly is 1ml:0.1mg, in use, in order to keep drug effect, adopt heavy dose of method that continues intravenously administrable more than 5 hours usually, but the huge pain of side effect, particularly blood vessel that therefore produces makes the patient be difficult to stand.
The famous physician's Yutaka Mizushima of Japan has been taught according to the drug delivery system theoretical invention prostadil fatty breast (being referred to as Alprostadil liposome microsphere again) targeting preparation, be that Alprostadil is dissolved in the soybean oil, in the high pressure homogenizer it is enclosed diameter only in 0.2 micron the fat milk (lipoid microsphere).The advantage of fat milk dosage form: (1) targeting: fat milk is easy to be gathered in diseased region with its distinctive characteristic; (2) persistence: under the barrier protection effect of fat milk, Alprostadil obviously reduces in the deactivation of pulmonary; (3) high efficiency: only need the dosage of conventional dosage forms 1/10th, curative effect is better; (4) low side effect: under the barrier protection of fat milk, reduced the stimulation and the inflammatory reaction of blood vessel; (5) easy to use: directly intravenous injection, can be in out-patient treatment.
But fat emulsion formulation can not being wrapped in the fat milk prostaglandin 100%, inevitably still there is the small-amount free prostaglandin to have the outer aqueous phase of emulsion droplet, therefore require in clinical use, to dilute to reduce the concentration of free prostate gland element with sugar, saline, nonetheless also can cause the injection pain of injection site incidence rate in clinical injection administration process up to (70-90%), vascular stimulation and inflammation, patient's body and spirit caused had a strong impact on [2,3,4], thus limited it and further applied clinical.
The prostadil fatty breast is an O/W type Emulsion, is that emulsifying agent is rolled into emulsion droplet with soybean oil with phospholipid, is scattered in aqueous phase, and prostaglandin is a fat-soluble compound, thus the dissolving and be dispersed in the oil phase.The stability of fat milk is subjected to the concentration affects of emulsifying agent in the solution (phospholipid), and when emulsifier content in the solution was lower than minimum emulsifying concentration, the stability of emulsion can be destroyed, and emulsion droplet can polymerization, breakdown of emulsion.So sugar and saline dilution fat milk have certain harm to stability of formulation, and nonideal diluent, more are not ideal dilution process.
The present invention is according to our research to prostadil fatty emulsion injection injection pain mechanism, according to our understanding to the fat emulsion formulation theory, replace common sugar by blank fat milk, saline dilutes the prostadil fatty emulsion formulation, can adsorb free prostaglandin in the medicinal liquid by blank fat milk, diluted medicinal liquid, fully reduced the concentration of free prostate gland element, vascular stimulation, inflammation and the pain of having avoided prostaglandin to cause have reached painless or painless substantially ideal effect.Guarantee the stability of prostadil fatty breast again, prevented breakdown of emulsion danger and side effect that table sugar, saline dilution cause.Broken through the local concentration of simple dilution prostatitis pixel, to alleviate the conventional method of vascular stimulation.Adopt the bonded generations that guarantee to have removed substantially fully injection pain of multiple technologies such as fat milk absorption, dilution and physical isolation.
Three, summary of the invention
The object of the present invention is to provide a kind of vascular stimulation that the prostadil fatty breast causes that reduces, reduce the novel diluent and the medicine compatibility method of injection pain.Adopt the free prostate gland element of blank fat milk absorption Alprostadil preparation aqueous phase, free prostaglandin in the dilution prostadil fatty emulsion formulation, physical barrier free prostate gland element contacts with blood vessel, reduce vascular stimulation, reduce injection pain, improve patient's toleration, very important clinical meaning is arranged.
Painless prostadil fatty dairy compositions provided by the invention is to be prepared from blank fat milk dilution prostadil fatty breast.Wherein said prostadil fatty breast belongs to prior art, be with any prostadil fatty emulsion formulation of Alprostadil as active constituents of medicine, as be selected from Alprostadil liposome microsphere preparation, other non-common prostaglandin formulations, perhaps common prostaglandin lyophilized formulations, preferred Alprostadil liposome microsphere preparation.
Fat emulsion composition of the present invention, according to 1: 5 or 5 above=prostadil fatty breasts: the volume ratio of blank fat milk mixed the prostadil fatty breast and obtains with blank fat milk, another kind of proportionate relationship is, the usage ratio of the consumption of its empty fat milk and prostadil fatty breast is: the prostadil fatty Ruzhong of per 1 milligram of Alprostadil adds the blank fat milk of 0.1-20ml, the preferred blank fat milk that adds 0.5-5ml more preferably adds the blank fat milk of 0.8-1.2ml.
Fat emulsion composition of the present invention, the grease separation that its empty fat milk uses is from: the fatty glyceride of refined soybean oil, refined maize oil, refining Oleum Helianthi, refining Oleum Arachidis hypogaeae semen, refining Oleum sesami, refining rapeseed oil, refining olive oil, refining Oleum Hippophae, refine fish oil or other any crude vegetal, artificial or half artificial preparation or any or several mixture in other oils and fats; The lecithin that uses is selected from: any of Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, synthetic lecithin; The oil content of blank fat milk is: 5%-35%; The fat milk particle diameter is from 80nm to 500nm.Any one of the oil content that preferred blank fat milk is 10%-30%; The particle size distribution of blank fat milk from 100nm to 300nm between.
The preferred prostadil fatty breast of the present invention prescription is as follows
Blank fat milk prescription is as follows
The most preferred prostadil fatty breast of the present invention prescription is as follows:
Blank fat milk prescription is as follows:
The present invention also provides a kind of assembly packaging, is formed by prostadil fatty breast of the present invention and blank fat milk assembly packaging, and two kinds of medicaments are loaded in respectively in the container, discrete placement, and assembly packaging is together.
Fat emulsion composition of the present invention, its preparation method are that prostadil fatty breast and blank fat milk mixed according to the rules can be used.If the prostadil fatty breast is preserved under the same conditions with blank fat milk, so earlier the prostadil fatty breast was placed 5-10 minute in room temperature, then according to the mixed that designs.Alprostadil is added blank fat milk or blank fat milk is added the difference that the prostadil fatty breast does not have essence, convenient for well according to operation.
Fat emulsion composition of the present invention adopts the injection injection during use, reduced pain during injection, has also reduced the pain after the injection.
Following data declaration beneficial effect of the present invention by experiment:
(1), aqueous phase free prostate gland cellulose content detection method
Prostadil fatty emulsion formulation aqueous phase prostaglandin Determination on content is measured respectively after can adopting centrifuging that water, oil phase and emulsifying agent layer are separated.Bibliographical information has the people to adopt the profit partition coefficient to calculate oil phase Chinese medicine concentration, but we think that oil phase and aqueous phase drug distribution are write out a prescription and multiple factor affecting such as process conditions, but is not profit partition coefficient simple analog.Therefore, utilize in this experiment and centrifugal the emulsifying agent layer effectively separated with water, adopt HPLC to measure fat milk aqueous phase content of prostaglandin then:
A, chromatographic condition and system suitability test
A-1. chromatographic condition and system suitability test:
Chromatographic column: octadecylsilane chemically bonded silica is a filler.Mobile phase: (get potassium dihydrogen phosphate 9.07g with 0.0067mol/L phosphate buffer (PH is 6.3), add water and make dissolving, make 1000ml, other gets AMSP 9.46g, adds water and makes dissolving, make 1000ml, the latter is added among the former, is 6.3 until PH, gets this liquid 100ml and adds water to 1000ml, shake up, promptly)-acetonitrile (3: 1) is a mobile phase; Flow velocity: be per minute 1ml; Answering liquid behind the post is the 1mol/L potassium hydroxide solution, and the past column reaction pipe is polyfluortetraethylene pipe (Φ 0.5mm * 10m); 60 ℃ of column temperatures; Detect wavelength 278nm.The separating degree of Alprostadil and internal standard substance should meet the requirements.
A-2. the preparation of inner mark solution: get the about 25mg of betanaphthol, the accurate title, decide, and puts in the 50ml measuring bottle, adds anhydrous alcohol solution and be diluted to scale, measures 5ml, puts in the 50ml measuring bottle, adds mobile phase and be diluted to scale, shakes up, as solution (1).Get solution (1) 5ml, put in the 50ml measuring bottle, add mobile phase and be diluted to scale, as inner mark solution.
A-3. precision takes by weighing the about 5mg of Alprostadil reference substance (in phosphorus pentoxide desiccator, drying at room temperature 4 hours), puts in the 50ml measuring bottle, add dehydrated alcohol 10ml dissolving, and be diluted to scale, shake up, precision is measured 5ml, puts in the 25ml measuring bottle, adds mobile phase and is diluted to scale, shake up, precision is measured 5ml and solution (1) 5ml, to the 50ml measuring bottle, adds mobile phase and is diluted to scale, shake up, in contrast product solution.(prepare in back two hours and use)
A-4. the preparation of need testing solution:
A-4.1. get the 5ml syringe, earlier with chromatograph washed with methanol 18# puncture needle, reuse water flushing puncture needle (guaranteeing that no methanol is residual in the pin).
A-4.2. [implant is an octadecylsilane chemically bonded silica, and particle diameter is 70 μ m, Φ 10mm * 9mm polypropylene tube (SEP-PAK C18 post to inhale the washed with methanol pretreatment column with syringe, Waters), imitate to improve post, extract water again and wash this pre-column, residual to there not being methanol; It is standby to the 10ml tool plug small test tube to collect the water of 10ml by this pre-column.
A-4.3. in the black out environmental operations: the straight shape scale with band " blowing " word is carved pipe, precision is measured this product 0.5ml, to 20ml tool plug test tube, (blow out most advanced and sophisticated emulsion at last), add oxolane 2.5ml, jog, mixing, add phosphoric acid solution (1 → 1000) 15ml, cover stopper, spin upside down for several times, jog, mixing.
A-4.4. extract this liquid with thread a needle pin and 5ml needle tubing of 18#, remove puncture needle, by the above-mentioned pretreatment column of handling well, speed is wanted slow (dripping drop by drop) with the solution in the needle tubing, and solution discards, and repeats aforesaid operations, to solution all by little pre-column.With above-mentioned good excessively 10ml water, divide three times towards liquid 20ml tool plug test tube, flushing liquor is the same all by little pre-column (it is slow that speed is wanted).
A-4.5. reuse methanol 7ml eluting pretreatment column, eluent all moves in the 50ml round-bottomed flask, in 50 ℃ of distilling under reduced pressure 10 minutes, solvent evaporated, residue shakes up, promptly with inner mark solution 1.0ml dissolving.(prepare in back two hours and use)
A-5. algoscopy: precision measures above-mentioned reference substance solution and each 20 μ l of need testing solution inject chromatograph of liquid, and the record chromatogram is pressed internal standard method with calculated by peak area.
A-6. calculate:
Correction factor (f)=(a in mark/c in mark)/(a right/c to)
----the concentration of mark----internal standard substance in the reference substance in the target peak area c in the reference substance of mark in a
------right--the concentration that----contrasts in the reference substance of the peak area c that contrasts in the reference substance that a is right
Content=f * (a sample/(the interior sample of sample/c in a))
----------the concentration of internal standard substance in the sample of sample in the target peak area c in the sample of sample in a
(2), fat milk method for analyzing stability
After the prostadil fatty breast diluted with different diluent, the stability of medicinal liquid can be estimated by the particle diameter that detects fat milk.It is an amount of to get prostadil fatty breast sample, deionized water, injection sucrose solution, injection saline, the dilution of injection fat milk with experimental amount, mixed liquor after the dilution is placed the period in difference, laser light scattering particle diameter instrument PSS NICOMP 380 (Santa Barbara are adopted in sampling, Calif, USA) the grain warp and the particle size distribution of determination experiment mixed liquor.
(3), the animal evaluation methodology of injection pain
A, instrument
Electromyogram monitor (AB-621G, Nihon Kohden Corp.), constant temperature blender with magnetic force (Shanghai intelligence light instrument and meter company limited), 100,000/electronic analytical balance (BP211D Germany Sai Duolisi), coaxial needle electrode of electromyogram and reference electrode (indifferent electrode) digital display thermostat water bath (Jintan City's Fuhua Instr Ltd.).
B, reagent
Triumphant real Alprostadil liposome microsphere injection (commercially available), embodiment sample (Alprostadil liposome microsphere injection, self-control), blank fat milk (self-control), normal saline (commercially available).
C, animal
The SD rat, body constitution amount 200～250g, male, provide by The Fourth Military Medical University's Experimental Animal Center.
D. experimental technique
At first male SD rat is divided into 6 groups, every group 6, etherization, be fixed in the Mus platform to face upward appearance, remove right rear leg field of operation and electrode and insert the position hair, expose femoral artery, with the polyethylene catheter intubate in the rat right femoral artery, the while A/C, electromyogram places right rear leg with coaxial needle electrode and reference electrode, and is connected to the electromyogram monitor.
Alprostadil liposome microsphere is respectively with 10ml distilled water, G/W, triumph saline and fat milk dilution.These samples are injected the femoral artery of rat by conduit, be close to the degree of the electromyography evaluation blood vessel pain at position by the tremulous pulse of administration sample.The electromyography method is estimated blood vessel pain according to list of references method [33].Begin the electromyography record before the administration.To performing the operation back 1 hour, the electromyography waveform stabilization dilutes the embodiment sample by the difference of intubate difference administration Alprostadil liposome microsphere, writes down electromyogram after the administration respectively, and area under the peak in the calculating electromyogram.
After the administration 1 hour, calculate in the electromyography waveform area under the peak.Measure the value of respectively organizing every rat and compare with reference to sample with " Alprostadil liposome microsphere distilled water diluting liquid ", to determine its " electromyogram area ratio ", with (%) expression, the index of expression blood vessel pain.When this index less than 100% the time, it shows that the inventive method compatibility compares the blood vessel pain relief with matched group.And index (electromyogram area ratio) is more little, and blood vessel pain relief effect is good more.
(4), the evaluation of the clinical therapeutic efficacy of different diluent dilution Alprostadil liposome microspheres
A, administrated method
After case is selected, choose the research medicament categories of using according to the test group, 2ml every day (Alprostadil 10 μ g)+10ml normal saline or quiet notes of blank fat milk, or directly into the pipkin intravenous drip, 1 time/day, successive administration 20 days.Back application in the 1st day is being followed up a case by regular visits in medication for the first time 0 week; Use in last 1 day was followed up a case by regular visits in last medication at 20 days.The patient does not accept intravenously administrable more than 4 days or 4 days, be considered as coming off.
B, observation item and index
Patient's B-1 basic condition
Reply patient's ordinary circumstance (sex, age, body weight, height etc.) before on-test, current diagnosis and history of past illness (record and relevant important current diagnosis of research and history of past illness, and history of medications), hepatic and renal functions etc. are understood record.
The B-2 clinical observation
Before the administration and the subjective symptoms (pain, painless travel distance and can tolerate the maximum travel distance etc. of pain) that should in the regular hour section, observe patient after the administration, finish the back patient is carried out overall merit (degree of improvement, always degree of safety and efficiency evaluation etc.) comprehensively and efficiency evaluation.Observe relevant with underlying diseases or the irrelevant sign of patient during the research in detail and change, and by observation table requirement accurate recording.
The auxiliary examination of B-3 laboratory
Inspection patient's blood pressure, pulse, 12 lead electrocardiogram, fasting glucose (FBG), routine blood test (leukocyte, hemoglobin, platelet), glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), blood urea nitrogen (BUN), creatinine (Cr), routine urinalysis (greasy urine cell, erythrocyte, albumen), coagulation function [prothrombin time (PT), activated partial thromboplastin time (APTT)], Fibrinogen, platelet aggregation rate etc. before the administration.There is the experimenter of fertility need do urine pregnancy test.
Should monitor patient's blood pressure, pulse, clinical symptoms and sign after the administration every day.
Inspections such as patient's blood pressure, pulse, 12 lead electrocardiogram, fasting glucose (FBG), routine blood test (leukocyte, hemoglobin, platelet), glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), blood urea nitrogen (BUN), creatinine (Cr), routine urinalysis (greasy urine cell, erythrocyte, albumen), coagulation function (PT, APTT), Fibrinogen, platelet aggregation rate are checked in administration after 20 days.
C, effectiveness and safety evaluatio index and standard
C-1 effectiveness and safety evaluatio index
Efficiency evaluation
Leading indicator: painless travel distance (having gone to pain) and maximum travel distance (go to and to walk).
Less important index: (1) pain scores (specifically list: no pain=1 minute by five point-scores; Idol has pain=2 minute; Frequent pain, but can tolerate, usefulness analgesic=3 minute by chance; Frequent pain, warp analgesic commonly used=4 minutes; Constant pain, influence sleep, general analgesic is invalid=and 5 minutes); (2) ABI; (3) vessel diameter of lower limb vascular ultrasonic examination: Jian Cha popliteal tremulous pulse and dorsal artery of foot, blood flow rate (peak systolic flow velocity, diastasis flow velocity), vascular resistance index.
Safety evaluatio
(1) routine blood test, routine urinalysis, coagulation function, Fibrinogen, platelet aggregation rate;
(2) blood urea nitrogen, creatinine, glutamate pyruvate transaminase, glutamic oxaloacetic transaminase, GOT;
(3) 12 lead electrocardiogram;
(4) adverse events;
Effectiveness and safety evaluatio index and standard
Produce effects: meet following any one condition: travel distance increases more than 100%; Numbness, pain and paraesthesia are improved more than 2 grades; Vascular Ultrasonography Doppler shows vessel diameter, blood flow rate; ABI increases more than 10%;
Effectively: meet following any one condition: travel distance increases 50%-99%; Numbness, pain and paraesthesia are improved 1 grade; Vascular Ultrasonography Doppler shows vessel diameter, blood flow rate; ABI one of increases below 10%;
Invalid: the following index does not all have improvement or worsens: travel distance increases less than 50%; Numbness, pain and paraesthesia; Vascular Ultrasonography Doppler shows vessel diameter, blood flow rate; ABI.
Four, description of drawings
Fig. 1, different diluent are to the influence of prostadil fatty breast particle diameter
The commercially available fat milk of Fig. 2, blank fat milk, different content of vegetable oil is as the influence of diluent to prostadil fatty breast particle diameter
Fig. 3, long-chain, commercially available 20% fat milk of middle long-chain are as the influence of diluent to prostadil fatty breast particle diameter
The concentration of Fig. 4, the free Alprostadil of different diluent dilution back aqueous phase
The concentration of Fig. 5, the free Alprostadil of different content fat milk dilution back aqueous phase
The concentration of Fig. 6, long-chain, the free Alprostadil of middle long chain fat emulsion dilution back aqueous phase
Vascular stimulation behind Fig. 7, the different diluent dilution Alprostadil liposome microsphere relatively
Vascular stimulation behind Fig. 8, the different content fat milk diluent dilution Alprostadil liposome microsphere relatively
Vascular stimulation behind Fig. 9, long-chain, the middle long chain fat emulsion diluent dilution Alprostadil liposome microsphere relatively
Five, the specific embodiment
Further specify the present invention by the following examples, but not as limitation of the present invention.
First, different diluent are for the investigation of the influence of prostadil fatty breast stability.
Embodiment 1: normal saline, injectable dextrose monohydrate water and blank fat milk are investigated as diluent
Get normal saline, injectable dextrose monohydrate water and each 10ml of 10% long chain fat emulsion respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml.The container that fills admixing medical solutions is positioned in 25 ℃ of water-baths, sampling in required time, the particle diameter of mensuration mixed liquor.As shown in Figure 1, no matter dilute the prostadil fatty breast with the sort of diluent, the particle diameter that mixes back solution all still meets the quality standard requirement.But in longer standing time, the particle diameter of mixed liquor presents the trend of increase as diluent for G/W and normal saline, and blank fat milk does not have to change although place the particle diameter of 24 hours mixed liquors when being diluent substantially.Illustrate that the prostadil fatty breast adopts blank fat milk dilution rationally stable more.
Embodiment 2: blank fat milk, 10%, 20% and 30% commercially available fat milk are as the investigation of diluent
Get homemade blank fat milk and 10%, 20% and 30% each 10ml of commercially available long chain fat emulsion respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml.The container that fills admixing medical solutions is positioned in 25 ℃ of water-baths, sampling in required time, the particle diameter of mensuration mixed liquor.As shown in Figure 2, the particle diameter of the blank fat milk of this experiment oneself preparation and the particle diameter of Alprostadil liposome microsphere are basic identical, so after mixing, the particle diameter of mixed liquor is consistent with the particle diameter of initial Alprostadil liposome microsphere, and the particle diameter of commercially available fat milk is all bigger, and dilution accounts for the great majority of determining with diluent, so mixed particle diameter is just close with commercially available fat milk.But no matter the sort of fat milk is as diluent, and it is all fine to mix rear stability, does not find breakdown of emulsion, oil spill, does not find that also the fat milk particle diameter increases, the accumulative phenomenon of breast grain.
The blank fat milk of long-chain is investigated as diluent in the embodiment 3:20% long-chain and 20%
Get each 10ml of long chain fat emulsion in commercially available 20% long chain fat emulsion and 20% respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml.The container that fills admixing medical solutions is positioned in 25 ℃ of water-baths, sampling in required time, the particle diameter of mensuration mixed liquor.As shown in Figure 3, the variation of the oil-phase component of fat milk and the different differences that as the diluent of Alprostadil liposome microsphere, do not have essence for them.Dilution back particle diameter does not have significant change substantially.
Second portion, blank fat milk adsorb the The effects of water middle reaches from prostaglandin
Embodiment 4: normal saline, injectable dextrose monohydrate water and blank fat milk are to the absorption of free prostate gland element
Get distilled water, normal saline, injectable dextrose monohydrate water and each 10ml of blank fat milk respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml.The container that fills admixing medical solutions was positioned in 25 ℃ of water-baths 30 minutes.
Get the mix preparation of method for preparing, detect the prostaglandin of aqueous phase according to " aqueous phase free prostate gland cellulose content detection method ".As Fig. 4, blank fat milk has adsorbed a large amount of free Alprostadils, thus can detected free Alprostadil total amount, only be 1/10 of other diluent.And the normal saline of clinical present use and G/W diluent do not have adsorption basically to free Alprostadil, basic identical with the result of distilled water matched group, just reduced the drug level of unit volume by solubilising, make patient can stand reluctantly, do not change the total amount of the free Alprostadil of aqueous phase.
Embodiment 5: the blank fat milk of different content of vegetable oil is to the plain adsorbing case expedition of free prostate gland
Get 10%, 20% and 30% each 10ml of long chain fat emulsion respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml.The container that fills admixing medical solutions was positioned in 25 ℃ of water-baths 30 minutes.
Get the mix preparation of method for preparing, adopt supercentrifugation to analyze the content of the free prostate gland element of aqueous phase, " aqueous phase free prostate gland cellulose content detection method " seen in concrete operations.See Fig. 5, the fat milk of various content can both the free Alprostadil of active adsorption aqueous phase, and the effect of absorption is directly proportional with the content of oil, and the absorbability of 10%, 20%, 30% fat milk is risen progressively successively.The increase of this adsorption effect is relevant with total specific surface area of fat emulsion formulation, because along with the increase of the content of vegetable oil in the fat milk, though the particle diameter of emulsion droplet also has a little to increase, not to be into the change of multiple big for change of size on the whole.Become big influence and do not remember if ignore particle diameter, the increase of oil mass must increase the quantity of emulsion droplet in the unit volume so, also with regard to the corresponding specific surface area that increases the fat milk in the unit volume, so the amount of the free Alprostadil of absorption also increases thereupon.
Embodiment 6: the blank fat milk of variety classes vegetable oil is investigated the adsorption of free prostate gland element
Get each 10ml of long chain fat emulsion in 20% long chain fat emulsion and 20% respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml.The container that fills admixing medical solutions was positioned in 25 ℃ of water-baths 30 minutes.
Get the mix preparation of method for preparing, adopt supercentrifugation to analyze the content of the free prostate gland element of aqueous phase, " aqueous phase free prostate gland cellulose content detection method " seen in concrete operations.Fig. 6 shows that the Alprostadil absorbability of long chain fat emulsion and middle long chain fat emulsion is basic identical, can both effectively remove the free Alprostadil of aqueous phase.This discussion with the embodiment 5 of front is corresponding, and owing to being to finish by the outer surface of fat milk to free Alprostadil absorption, plant oil properties certain and the fat milk internal package is irrelevant substantially.
Third part, fat milk alleviate the investigation of injection pain and vascular stimulation as diluent
Embodiment 7: the comparison that normal saline, injectable dextrose monohydrate water and blank fat milk alleviate injection pain
Get distilled water for injection, normal saline, injectable dextrose monohydrate water and each 10ml of 10% long chain fat emulsion respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml.These samples are operated according to " the animal evaluation methodology of injection pain " in " 4.3, important analytical method ".Testing sample is injected the femoral artery of rat by conduit, be close to the degree of the electromyography evaluation blood vessel pain at position by the tremulous pulse of administration sample.Write down electromyogram after the administration respectively, and area under the peak in the calculating electromyogram.Each is organized, and area value compares with reference to sample with " Alprostadil liposome microsphere distilled water diluting liquid " under the peak in the electromyogram that every rat measures, the index of " electromyogram area than " expression blood vessel pain of acquisition.Fig. 7 shows that normal saline and G/W dilution Alprostadil liposome microsphere can not effectively reduce injection pain, and blank fat milk side can significantly reduce injection pain.
Embodiment 8: the blank fat milk of different content alleviates the case expedition of injection pain
Get 10%, 20% and 30% each 10ml of long chain fat emulsion respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml, these samples are operated according to " the animal evaluation methodology of injection pain " in " 4.3, important analytical method ".Testing sample is injected the femoral artery of rat by conduit, be close to the degree of the electromyography evaluation blood vessel pain at position by the tremulous pulse of administration sample.Write down electromyogram after the administration respectively, and area under the peak in the calculating electromyogram.Each is organized, and area value compares with reference to sample with " Alprostadil liposome microsphere distilled water diluting liquid " under the peak in the electromyogram that every rat measures, the index of " electromyogram area than " expression blood vessel pain of acquisition.As shown in Figure 8, the fat milk of various concentration can both effectively reduce injection pain as diluent, and the effect that reduces pain from the meansigma methods fat milk that relatively oil content is high is stronger, and this trend with the free Alprostadil content of aqueous phase is corresponding.The free Alprostadil content of aqueous phase is low, and is just low to the zest of blood vessel, pain also just a little less than.
Embodiment 9: the investigation that the blank fat milk of variety classes vegetable oil alleviates injection pain
Get each 10ml of long chain fat emulsion in 20% long chain fat emulsion and 20% respectively with prostadil fatty breast (the 5 μ g/ml) mix homogeneously of 2ml, these samples are operated according to " the animal evaluation methodology of injection pain " in " 4.3, important analytical method ".Testing sample is injected the femoral artery of rat by conduit, be close to the degree of the electromyography evaluation blood vessel pain at position by the tremulous pulse of administration sample.Write down electromyogram after the administration respectively, and area under the peak in the calculating electromyogram.Each is organized, and area value compares with reference to sample with " Alprostadil liposome microsphere distilled water diluting liquid " under the peak in the electromyogram that every rat measures, the index of " electromyogram area than " expression blood vessel pain of acquisition.Two kinds of different fat milks can both effectively reduce injection pain (as shown in Figure 9) as diluent.
Fat milk is as the investigation of the therapeutic effect of prostadil fatty breast diluent
Main efficacy analysis
After normal saline (A group) and fat milk (B group) are treated patient candidate as prostadil fatty breast dilution, the painless travel distance of A group and B group is significantly improved, 603.25 ± 1130.16 and 707.40 ± 1209.18 meters have been increased respectively, the improvement rate has reached 177.71 ± 336.77% and 193.09 ± 672.98%, front and back comparing difference highly significant, but compare no significant difference between two groups, see Table 1 and 2.But normal saline is the A group 90% of diluent the injection pain sense is arranged, and 20% observes vasculitis, vein blood vessel hyperemia, rubescent.And fat milk to be the B group of diluent only have 23% pain is arranged, the record that does not have vasculitis to take place.The proof fat milk has remarkable advantages as the diluent of Alprostadil liposome microsphere, can significantly improve patient's toleration.
Table 1 baseline is to the variation of the painless travel distance in treatment back
A: matched group B: test group
Table 2 baseline is to comparative result between the set of variations of the painless travel distance in treatment back
Maximum travel distance
After the treatment, the maximum travel distance of A group and B group has increased by 832.31 ± 1267.59 and 935.54 ± 1517.63 meters respectively, the improvement rate has reached 112.77 ± 195.25% and 153.63 ± 557.12%, front and back comparing difference highly significant, but compare no significant difference between two groups, see Table 5.10 and 5.11.
Table 5.10 baseline is to the variation of the maximum travel distance in treatment back
A: matched group B: test group
Table 5.11 baseline is to comparative result between the set of variations of the maximum travel distance in treatment back
Prostadil fatty breast prescription is as follows:
Blank fat milk prescription is as follows:
Its preparation method is that prostadil fatty breast and blank fat milk can be used according to 1: 5 volume ratio mixing.If the prostadil fatty breast is preserved under the same conditions with blank fat milk, so earlier the prostadil fatty breast was placed 5-10 minute in room temperature, then according to the mixed that designs.Alprostadil is added blank fat milk or blank fat milk is added the difference that the prostadil fatty breast does not have essence, convenient for well according to operation.
Embodiment 11,
Assembly packaging,
Prostadil fatty breast 1ml and blank fat milk 10ml assembly packaging form, and two kinds of medicaments are loaded in respectively in the container, discrete placement, and assembly packaging is together.
Embodiment 12,
Assembly packaging,
Prostadil fatty breast 2ml and blank fat milk 10ml assembly packaging form, and two kinds of medicaments are loaded in respectively in the container, discrete placement, and assembly packaging is together.
Claims (10)
1. a painless prostadil fatty dairy compositions is characterized in that, said composition is to be prepared from blank fat milk dilution prostadil fatty breast.
2. fat emulsion composition as claimed in claim 1 is characterized in that wherein the prostadil fatty breast is selected from Alprostadil liposome microsphere, perhaps other non-common prostaglandin formulations, perhaps common prostaglandin lyophilized formulations.
3. fat emulsion composition as claimed in claim 1 is characterized in that, the consumption of its empty fat milk is the blank fat milk that the prostadil fatty Ruzhong of per 1 milligram of Alprostadil adds 0.1-20ml.
4. fat emulsion composition as claimed in claim 1 is characterized in that, the consumption of its empty fat milk is the blank fat milk that the fat milk of per 1 milligram of Alprostadil adds 0.5-5ml.
5. fat emulsion composition as claimed in claim 1 is characterized in that, the consumption of its empty fat milk is the blank fat milk that the fat milk of per 1 milligram of Alprostadil adds 0.8-1.2ml.
6. fat emulsion composition as claimed in claim 1, it is characterized in that the grease separation that its empty fat milk uses is from: the fatty glyceride of refined soybean oil, refined maize oil, refining Oleum Helianthi, refining Oleum Arachidis hypogaeae semen, refining Oleum sesami, refining rapeseed oil, refining olive oil, refining Oleum Hippophae, refine fish oil or other any crude vegetal, artificial or half artificial preparation or any or several mixture in other oils and fats; The lecithin that uses is selected from: any of Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, synthetic lecithin; The oil content of blank fat milk is: 5%-35%; The fat milk particle diameter is from 80nm to 500nm.
7. fat emulsion composition as claimed in claim 1 is characterized in that, blank fat milk is any one of oil content of 10%-30%; The particle size distribution of blank fat milk from 100nm to 300nm between.
8. fat emulsion composition as claimed in claim 1 is characterized in that, prostadil fatty breast prescription 1000mL
Blank fat milk prescription 1000mL
9. fat emulsion composition as claimed in claim 1 is characterized in that, prostadil fatty breast prescription 1000mL
Blank fat milk prescription 1000mL
10. an assembly packaging is characterized in that, is formed by described prostadil fatty breast of claim 9 and blank fat milk assembly packaging, and two kinds of medicaments are loaded in respectively in the container, discrete placement, and assembly packaging is together.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105276005A CN102000025B (en) | 2010-10-26 | 2010-10-26 | Novel painless diluent, dilution compatibility method and application of alprostadil fat emulsion preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105276005A CN102000025B (en) | 2010-10-26 | 2010-10-26 | Novel painless diluent, dilution compatibility method and application of alprostadil fat emulsion preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102000025A true CN102000025A (en) | 2011-04-06 |
| CN102000025B CN102000025B (en) | 2011-11-23 |
Family
ID=43807895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010105276005A Active CN102000025B (en) | 2010-10-26 | 2010-10-26 | Novel painless diluent, dilution compatibility method and application of alprostadil fat emulsion preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102000025B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526065A (en) * | 2011-12-26 | 2012-07-04 | 西安力邦制药有限公司 | Compound injection preparation for treating cardiovascular and cerebrovascular diseases and preparation method thereof |
| WO2020108193A1 (en) * | 2018-11-27 | 2020-06-04 | 西安力邦肇新生物科技有限公司 | Lyophilized preparation for prostaglandin e1 methyl ester injection, preparation thereof and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1903206A (en) * | 2005-07-29 | 2007-01-31 | 上海万特医药科技有限公司 | Alprostadil freeze-dried emulsion and its prepn. method |
-
2010
- 2010-10-26 CN CN2010105276005A patent/CN102000025B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1903206A (en) * | 2005-07-29 | 2007-01-31 | 上海万特医药科技有限公司 | Alprostadil freeze-dried emulsion and its prepn. method |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526065A (en) * | 2011-12-26 | 2012-07-04 | 西安力邦制药有限公司 | Compound injection preparation for treating cardiovascular and cerebrovascular diseases and preparation method thereof |
| CN102526065B (en) * | 2011-12-26 | 2014-08-13 | 西安力邦制药有限公司 | Compound injection preparation for treating cardiovascular and cerebrovascular diseases and preparation method thereof |
| WO2020108193A1 (en) * | 2018-11-27 | 2020-06-04 | 西安力邦肇新生物科技有限公司 | Lyophilized preparation for prostaglandin e1 methyl ester injection, preparation thereof and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102000025B (en) | 2011-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mittendorfer et al. | What does the measurement of whole-body fatty acid rate of appearance in plasma by using a fatty acid tracer really mean? | |
| Bhattacharya et al. | GHB (γ-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier | |
| Gil et al. | Effect of intravenous lipid emulsion in patients with acute glyphosate intoxication | |
| JP2013537192A (en) | Method for reducing adverse drug events using omega-3 fatty acid as a parenteral therapeutic drug vehicle | |
| Li et al. | Pharmacokinetic profiles of hydroxysafflor yellow A following intravenous administration of its pure preparations in healthy Chinese volunteers | |
| CN102000025B (en) | Novel painless diluent, dilution compatibility method and application of alprostadil fat emulsion preparation | |
| CN101700229B (en) | Prostaglandin E1 long-circulation fat microsphere preparation for intravenous injection and preparation method thereof | |
| CN102621246B (en) | Method for simultaneous determination of contents of six active ingredients in Danhong injection using HPLC-DAD | |
| Coskun et al. | The effect of K ATP channel blocker glibenclamide on CGRP-induced headache and hemodynamic in healthy volunteers | |
| Brodersen et al. | Bilirubin-displacing effect of ampicillin, indomethacin, chlorpromazine, gentamicin, and parabens in vitro and in newborn infants | |
| De Vries et al. | Real time monitoring of propofol blood concentration in ponies anaesthetized with propofol and ketamine | |
| Sjöstrand et al. | Distribution of bupivacaine in the rabbit under normal and acidotic conditions | |
| CN105944108A (en) | Liposome pH-sensitivity modifier containing menthone 1,2-glycerol ketal and paclitaxel-curcumin compound liposome preparation | |
| Jaben et al. | Lipid emulsion solution: a novel cause of hemolysis in serum and plasma blood samples | |
| CN103610640B (en) | Alprostadil medium-and-long-chain lipid emulsion for injection and preparation method thereof | |
| Xiong et al. | Characterization, biodistribution and targeting evaluation of breviscapine lipid emulsions following intravenous injection in mice | |
| Sun et al. | Chuanzhitongluo capsule ameliorates microcirculatory dysfunction in rats: efficacy evaluation and metabolic profiles | |
| CN109580834A (en) | Detection method in relation to substance in a kind of pharmaceutical preparation containing C14H25N4NaO11P2 | |
| Cho et al. | Spontaneous whole blood platelet aggregation in insulin-dependent diabetes mellitus: An evaluation in an epidemiologic study | |
| CN107693484A (en) | A kind of rifampin gel and preparation method thereof | |
| MacLeod et al. | Practical concepts of drug absorption, distribution and loss | |
| Athanikar et al. | Chlorpheniramine. II. Effect of the first-pass metabolism on the oral bioavailability in dogs | |
| Sayed et al. | Stability study and clinical evaluation of lipid injectable emulsion in parenteral nutrition admixtures used for preterm neonates | |
| CN103263411A (en) | Ginkgolide composition and application thereof | |
| Télessy et al. | Kinetic stability of all-in-one parenteral nutrition admixtures in the presence of high dose Ca 2+ additive under clinical application circumstances |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |