CN1872072A - Nano emulsion injection of alprostadil and preparation method - Google Patents
Nano emulsion injection of alprostadil and preparation method Download PDFInfo
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- CN1872072A CN1872072A CN 200610034259 CN200610034259A CN1872072A CN 1872072 A CN1872072 A CN 1872072A CN 200610034259 CN200610034259 CN 200610034259 CN 200610034259 A CN200610034259 A CN 200610034259A CN 1872072 A CN1872072 A CN 1872072A
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Abstract
A nano-emulsion injection of prostaglandin E1 contains the nano-emulsion particles of rostaglandin E1, the oil for injection, hydrophilic emulsifier, lipophilic emulsifier, isotonic agent, and stabilizer. Its preparing process and its quality control method are also disclosed.
Description
Technical field
The present invention relates to a kind of alprostadil injection agent and preparation method thereof, more particularly, the present invention relates to a kind of nano emulsion injection of alprostadil and preparation method thereof.
Background technology
Alprostadil, claim PGE1 (Prostagland E1 again, PGE1), it is the extremely strong biological active substances of a kind of activity, the effect of anticoagulant, thromboxane A2 generation, the formation of tremulous pulse medicated porridge sample lipid speckle and immune complex is arranged, and can expand the pharmacological action of periphery and arteria coronaria blood vessel, be mainly used in and prop up tranquillization pain in April that extremity ulcer that treatment causes by chronic arteria occlusion disease and microcirculation disturbance cause.
The Alprostadil molecular formula is: C
20H
34O
5, structural formula is as follows:
PGE1 metabolism in vivo is very fast, and under pulmonary's oxidase effect, the per pass pulmonary circulation promptly has 60%～90% inactivation.In order to keep drug effect, common medication is heavy dose of intravenously administrable more than 5 hours that continues.Therefore but the side effect that produces blood vessel pain particularly makes the patient be difficult to stand.The PGE1 ejection preparation of clinical practice at present is mainly lyophilized injectable powder, and this type of preparation needs with normal saline or the dissolving of 5% glucose injection before intravenous injection, dilutes and could use.
For example, Chinese patent CN02126054.0 discloses a kind of aseptic freeze-dried prostaglandin injection and preparation method thereof.In this patent for solving existing pharmaceutical properties instability. problem such as pain during injection has proposed the aseptic freeze-dried prostaglandin injection of being made by following component: Alprostadil, alpha-cyclodextrin, HP-or gamma-cyclodextrin, thymosin, dextran.But need dissolving, dilution before this lyophilized injection injection, not only using method is loaded down with trivial details, and the dissolubility of PGE1 in water is very little, performance is extremely unstable, 11 hydroxyl easily its degraded generates PGA1, and 15 hydroxyl can be transformed into 15-ketone group-PGE1 isomers, thus active the reduction, side reaction increases, and has seriously limited its use clinically.
Chinese patent application CN200310102253.1 discloses a kind of injection that contains Alprostadil, and this injection is made by following raw materials according: Alprostadil, dehydrated alcohol, PEG400, dimethyl acetylamide, 2-HP-, cysteine, sterile water for injection.Need not dissolving before this injection injection, it is convenient relatively to use, but its employed solvent is mainly ethanol and Polyethylene Glycol.
Chinese patent application CN200410021253.3 then discloses a kind of Alprostadil freeze-dried emulsion and preparation method thereof, and the composition of the freeze-dried emulsion of this application comprises Alprostadil, oil for injection, stabilizing agent, emulsifying agent, pH regulator agent, freeze drying protectant.This freeze-dried emulsion still needs to dissolve before injection, and it contains freeze drying protectant.In addition, its preparation method is just removed thick emulsion moisture and is obtained freeze-dried emulsion through lyophilization, and the particle diameter of the breast grain in the thick emulsion itself is just bigger, further reunites or agglomeration through taking place after the lyophilizing; Thereby after freeze-dried emulsion was recovered to Emulsion, the breast grain was bigger, and assimilation effect is poor.
Therefore, be necessary to provide a kind of novel alprostadil injection agent, to overcome problems of the prior art.
Summary of the invention
Order of the present invention provides a kind of nano emulsion injection of alprostadil that can be directly used in injection, and this injection is stable emulsion dispersion liquid, and its Alprostadil nano breast granule is a nano-particle, is convenient to absorption of human body.Wherein, the particulate mean diameter of Alprostadil nano breast is between 100-300nm, and 90% particle diameter accumulated value is not more than 500 nanometers; And except that Alprostadil, injection of the present invention also comprises:
(1) one or more oil for injection;
(2) one or more lipophilic emulsifying agent;
(3) one or more injection isotonic agent;
(4) one or more stabilizing agent.
Above-mentioned nano emulsion injection of alprostadil can also comprise one or more hydrophilic emulsifying agent.
Preferably, except that water for injection, in weight percentage, above-mentioned injection comprises each component of following content:
Alprostadil 0.5-500 μ g/ml
Oil for injection 1-30%
Hydrophilic emulsifying agent 1-10%
Lipophilic emulsifying agent 0.1-5%
Isotonic agent glycerol for injection 2-3%
Stabilizing agent 0.1-5%.
More preferably, above-mentioned injection comprises each component of following content:
Alprostadil 0.5-50 μ g/ml
Oil for injection 3-10%
Hydrophilic emulsifying agent 2-5%
Lipophilic emulsifying agent 0.5-3%
Isotonic agent glycerol for injection 2.2-2.5%
Stabilizing agent 0.1-1%.
In injection of the present invention, employed oil for injection is preferably one or more in medium chain triglyceride, vitamin E and injection vegetable oil such as soybean oil, Oleum Cocois, Oleum Ricini, Semen Lini oil, Semen Maydis oil, Radix Oenotherae erythrosepalae oil, Oleum Gossypii semen, olive oil, safflower oil and the Folium Perillae wet goods, more preferably soybean oil and/or vitamin E and/or medium chain triglyceride;
Employed hydrophilic emulsifying agent is preferably one or more in Tweens material (as polysorbate60, Tween 80), poloxamer 188, arabic gum and the Polyethylene Glycol-vitamin e succinate (TPGS), more preferably poloxamer 188 and/or Polyethylene Glycol-vitamin e succinate;
Employed lipophilic emulsifying agent is preferably one or more in spans material (as sorbester p18, sorbester p17), lecithin, soybean phospholipid and the agar, more preferably lecithin and/or soybean phospholipid;
Described isotonic agent is a glycerol;
Employed stabilizing agent is preferably one or more in cholesterol, oleic acid and the enuatrol, more preferably oleic acid.
Can also add components such as antioxidant, pH regulator agent in the nano emulsion injection of alprostadil of the present invention.
On the other hand, the invention provides a kind of method for preparing nano emulsion injection of alprostadil, this method comprises the steps:
(1) utilizes the method for ultra-sonic dispersion or high speed dispersion, make the thick newborn dispersion liquid of Alprostadil;
(2) the thick newborn dispersion liquid to step (1) gained carries out high pressure homogenize emulsifying, forms stable Alprostadil nano breast dispersion liquid;
(3) the Alprostadil nano breast dispersion liquid with step (2) gained carries out the fill sterilization, makes nano emulsion injection of alprostadil.
Wherein, in the process of the thick newborn dispersion liquid of step (1) preparation Alprostadil, can also comprise process for preparing oil phase and the process for preparing water, herein, oil phase forms by Alprostadil is dissolved in the oil for injection; Water is by adding hydrophilic emulsifying agent and lipophilic emulsifying agent dissolving in the injection water, disperse to form.
The high pressure homogenize emulsifying of step (2) can realize by single-stage or multistage high pressure homogenize process, for example can realize by two-stage high pressure homogenize process, wherein, the high pressure homogenize of the first order can carry out under the pressure of 400-1000bar, and partial high pressure homogenize can carry out under the pressure of 10-100bar.First order high pressure homogenize process mainly realizes the nanorize of grain diameter, and second level high pressure homogenize process mainly realizes the homogenization of grain diameter.
In addition, method of the present invention can also comprise the process that the pH value of the thick newborn dispersion liquid of step (1) is regulated, and for example pH value is adjusted to 4.5-6.
Method of the present invention can also comprise following quality control step: on general HPLC instrument, connect peristaltic pump and past column reaction pipe, directly carry out the measurement (for example PGA1 and 15-ketone group-PGE1 isomers) of Alprostadil, Alprostadil product and related substance.
Preparation process of the present invention comprises: get the raw materials ready, steps such as dosing, fill, sterilization, wherein, the dosing process comprises the step of preparation oil phase, preparation water, the thick breast of preparation and preparation nano-emulsion again.
In above-mentioned preparation technology's dosing step, during the preparation water, can add an amount of isotonic agent, can also add an amount of stabilizing agent.
In above-mentioned preparation technology's dosing step, PGE1 can be joined in the oil for injection, make oil phase; With dissolving in the hydrophilic emulsifying agent adding injection water, under at a high speed even matter effect, add injection lipophilic emulsifying agent, make water;
Perhaps, in above-mentioned preparation technology's dosing step, also PGE1 can be joined in the oil for injection, treat its dissolving after, under even matter effect at a high speed, add injection lipophilic emulsifying agent, make oil phase; With dissolving in the hydrophilic emulsifying agent adding injection water, make water.
In above-mentioned preparation technology's dosing step, during the preparation water, preferred 65 ℃ of solution temperature; When preparation is slightly newborn, preferred 60 ℃ of solution temperature; When preparation is slightly newborn, regulate the preferred 5.5-6 of pH value; During the preparation nano-emulsion, the secondary valve pressure of high pressure homogenizer is preferably 40bar, and a step valve pressure is preferably 700bar.
During the injection fill, nano emulsion injection can be filled into the above other any small-volume injection packaging material of saying of ampoule bottle, cillin bottle and pharmaceutics.
Nano emulsion injection of alprostadil of the present invention can increase dissolubility and the stability of PGE1 in water, and make medicine composition PGE1 stable, reduce effective dosage, avoid because heavy dose of long-time instillation penetrated the side reaction of generation, improve medicine distribution in vivo, have the tissue target tropism, improved the curative effect of medicine, obviously be better than conventional medicament.
Nano emulsion injection of alprostadil preparation method of the present invention is practical, realizes commercialization easily.The related substance that the quality control aspect increases another kind of catabolite 15-ketone group-PGE1 isomers detects, and improves the quality standard of PGE1, makes the clinical practice of Alprostadil submicron emulsion agent more reliable.The method of quality control simple and feasible can effectively be checked related substance, the quality of control nano emulsion injection of alprostadil.
In order to understand the present invention better, the present invention is further illustrated below in conjunction with embodiment.
Description of drawings
Fig. 1 and Fig. 2 are respectively the particle size distribution figure of the nano emulsion injection for preparing of the present invention.
Specific embodiment
The inferior nano emulsion injection method of quality control of Alprostadil
Adopt HPLC method and post-column derivatization method to measure content and the related substance inspection of PGE1, on general HPLC instrument, connect peristaltic pump and past column reaction pipe, can directly carry out content and the related substance inspection of PGE1.This analytical method has been simplified existing alprostadil injection content assaying method (national drug standards), need not to use special-purpose past column reaction instrument.
Nano emulsion injection of alprostadil adds the 5-50ml phosphoric acid solution and mixes with 1-10ml oxolane breakdown of emulsion, crosses the C18 pretreatment column, uses the 5-20ml methanol-eluted fractions, collects eluent, and solvent evaporated is with the mobile phase dissolving, standby.
Chromatographic condition: C18 chromatographic column, mobile phase is phosphate buffer (pH6.3,1/500mol/l)-acetonitrile (75: 25), flow velocity 0.8ml/min, detect wavelength 278nm, past column reaction liquid is the 1mol/l potassium hydroxide solution, and the past column reaction pipe is Φ 0.5mm * 10m polyfluortetraethylene pipe, 60 ℃ of column temperatures, past column reaction flow velocity 1.0-5.0ml/min.
The post-column derivatization method is selected peristaltic pump control past column reaction flow velocity for use, after the C18 chromatographic column, mobile phase is mixed with past column reaction liquid with threeway, after carrying out derivative reaction by politef past column reaction pipe, by the HPLC detector, PGE1 and its related substance can be effectively detected, the inspection of PGA1 and 15-ketone group-PGE1 isomers can be carried out simultaneously.
In the system suitability test of HPLC method, the solution that the preparation system employment and suitability test (E ﹠ ST) is investigated can separate Alprostadil the chromatographic condition of HPLC, and can accurately measure the amount of related substance with its catabolite.The chromatographic condition of methodological study proof assay can separate Alprostadil with its catabolite, this law can be used as the related substance inspection method of preproduction.
The investigation of system suitability test: press the chromatographic condition of content assaying method, regulate the ratio of mobile phase and flow velocity etc., get the solution that the system suitability test investigates and inject chromatograph of liquid, write down chromatogram, investigate separating of main composition peak and impurity peaks.The retention time of main composition was at 6-16 minute, the separating effect of its main composition peak and impurity peaks is basic identical, 2 impurity peaks have all been isolated, main composition peak all can thoroughly be separated with adjacent impurity peaks, separating degree R 〉=1.5 meet the requirement under Chinese Pharmacopoeia two appendix liquid chromatography items in 2005.
Blank assay: press the chromatographic condition of content assaying method, get the sky submicronized emulsion and handle sample injection chromatograph of liquid, record chromatogram.The result shows, in the scope of mobile phase mixture of acetonitrile-phosphate buffer ratio at 80/20-70/30, does not disturb the mensuration of related substance inspection.The chromatographic condition that related substance is checked is tested with system suitability: C18 chromatographic column, mobile phase be phosphate buffer (pH6.3,1/500mol/l)-acetonitrile (77: 23), flow velocity 0.8ml/min, detect wavelength 278nm, past column reaction liquid is the 1mol/l potassium hydroxide solution, and the past column reaction pipe is Φ 0.5mm * 10m, 60 ℃ of column temperatures, flow velocity 1.5ml/min, it is an amount of to get the Alprostadil reference substance, and water is made the solution that every 1ml contains 5 μ g approximately, measure 50ul and inject chromatograph of liquid, the record chromatogram.The separating degree of Alprostadil peak and adjacent impurity peaks should (〉=1.5) up to specification.
Press group component and prepare raw material, adjuvant and other components:
Alprostadil 0.5mg
Injection soybean oil 3.0g
Poloxamer 188 1.0g
Injection lecithin 1.0g
Water for injection adds to 100g
Following step is all carried out under the condition of nitrogen protection.0.5mg PGE1 is joined in the 3.0g injection soybean oil, stir,, get solution (1), be oil phase to the PGE1 dissolving.1.0g poloxamer 188 added in the injection waters dissolve, under at a high speed even matter effect, add 1.0g injection lecithin, disperseed 3-6 minute, solution temperature is heated to 70 ℃, be incubated standbyly, get solution (2), be water.Aqueous phase solution (2) is joined in the high speed homogenizer, again oil-phase solution (1) is slowly joined the aqueous phase that is stirring, keeping the dispersion liquid temperature is 55 ℃, disperseed 3 minutes, add water for injection then to total preparation amount, regulate pH value to 5.7, continue to disperse 5 minutes with the 0.1M sodium hydroxide solution, get dispersion liquid (3), be thick emulsion.The preparation nano emulsion injection: thick emulsion (3) is joined in the high pressure homogenizer, and regulating secondary valve pressure is 20bar, and re-adjustment one step valve pressure is 400bar, with thick emulsion homogenize under pressure, circulate continuously 3 times, keeping circulating temperature is 60 ℃, get stable dispersions (4), i.e. nano-emulsion.Under the condition of nitrogen protection, solution (5) is filled in the ampoule bottle, seal.Ampoule bottle after the fill 110 ℃ of flowing steam sterilizations 30 minutes, is promptly got nano emulsion injection of alprostadil of the present invention.
The stability test of present embodiment nano emulsion injection of alprostadil is referring to embodiment 7, and particle size distribution figure sees Fig. 1 and Fig. 2, and its mean diameter is respectively 171nm and 173nm.
Embodiment 2
Press group component and prepare raw material, adjuvant and other components:
Alprostadil 0.5mg
Injection soybean oil 5.0g
Poloxamer 188 3.0g
Injection lecithin 1.0g
Glycerol for injection 2.25g
Oleic acid 0.5g
Water for injection adds to 100g
Following step is all carried out under the condition of nitrogen protection.0.5mg PGE1 is joined in the 5.0g injection soybean oil, stir,, get solution (1), be oil phase to the PGE1 dissolving.With dissolving in the 3.0g poloxamer 188 adding injection waters, under at a high speed even matter effect, add the 2.25g glycerol for injection, add 0.5g oleic acid, add 1.0g injection lecithin, disperseed 3-6 minute, solution temperature is heated to 65 ℃, be incubated standby, solution (2), be water.Aqueous phase solution (2) is joined in the high speed homogenizer, again oil-phase solution (1) is slowly joined the aqueous phase that is stirring, keeping the dispersion liquid temperature is 55 ℃, disperseed 3 minutes, add water for injection then to total preparation amount, regulate pH value to 5.6, continue to disperse 5 minutes with the 0.1M sodium hydroxide solution, get dispersion liquid (3), be thick emulsion.The preparation nano emulsion injection: thick emulsion (3) is joined in the high pressure homogenizer, and regulating secondary valve pressure is 40bar, and re-adjustment one step valve pressure is 600bar, with thick emulsion homogenize under pressure, circulate continuously 5 times, keeping circulating temperature is 60 ℃, get stable dispersions (4), i.e. nano-emulsion.Under the condition of nitrogen protection, solution (5) is filled in the ampoule bottle, seal.Ampoule bottle after the fill 110 ℃ of flowing steam sterilizations 30 minutes, is promptly got nano emulsion injection of alprostadil of the present invention.
The stability test of present embodiment nano emulsion injection of alprostadil is referring to embodiment 7.
Embodiment 3
Press group component and prepare raw material, adjuvant and other components:
Alprostadil 0.5mg
Injection soybean oil 10.0g
Poloxamer 188 2.5g
Injection lecithin 2.0g
Glycerol for injection 2.5g
Oleic acid 1.0g
Water for injection adds to 100g
Other steps promptly obtain nano emulsion injection of alprostadil of the present invention with embodiment 2.The stability test of present embodiment nano emulsion injection of alprostadil is referring to embodiment 7.
Embodiment 4
Press group component and prepare raw material, adjuvant and other components:
Alprostadil 0.5mg
Injection soybean oil 5.0g
TPGS 1.0g
Injection lecithin 0.5g
Water for injection adds to 100g
Following step is all carried out under the condition of nitrogen protection.0.5mg PGE1 is joined in the 5.0g injection soybean oil, stir,, get solution (1), be oil phase to the PGE1 dissolving.Will 1.0g TPGS add in the injection water and dissolve, under at a high speed even matter effect, add 0.5g injection lecithin, disperseed 4 minutes, solution temperature is heated to 60 ℃, be incubated standbyly, get solution (2), be water.Aqueous phase solution (2) is joined in the high speed homogenizer, again oil-phase solution (1) is slowly joined the aqueous phase that is stirring, keeping the dispersion liquid temperature is 55 ℃, disperseed 3 minutes, add water for injection then to total preparation amount, regulate pH value to 5.7, continue to disperse 5 minutes with the 0.1M sodium hydroxide solution, get dispersion liquid (3), be thick emulsion.The preparation nano emulsion injection: thick emulsion (3) is joined in the high pressure homogenizer, and regulating secondary valve pressure is 20bar, and re-adjustment one step valve pressure is 600bar, with thick emulsion homogenize under pressure, circulate continuously 3 times, keeping circulating temperature is 60 ℃, get stable dispersions (4), i.e. nano-emulsion.Under the condition of nitrogen protection, solution (5) is filled in the ampoule bottle, seal.With the ampoule bottle radiosiotope after the fill
60The γShe Xianmiejun of Co radiation promptly gets nano emulsion injection of alprostadil of the present invention.
The stability test of present embodiment nano emulsion injection of alprostadil is referring to embodiment 7.
Embodiment 5
Press group component and prepare raw material, adjuvant and other components:
Alprostadil 0.5mg
Injection soybean oil 5.0g
TPGS 2.0g
Injection lecithin 1.0g
Glycerol for injection 2.25g
Oleic acid 1.0g
Water for injection adds to 100g
Following step is all carried out under the condition of nitrogen protection.0.5mg PGE1 is joined in the 5.0g injection soybean oil, stir,, get solution (1), be oil phase to the PGE1 dissolving.Will 2.0g TPGS add in the injection water and dissolve, under at a high speed even matter effect, add the 2.25g glycerol for injection, add 1.0g oleic acid, add 1.0g injection lecithin, disperseed 5 minutes, solution temperature is heated to 65 ℃, be incubated standbyly, get solution (2), be water.Aqueous phase solution (2) is joined in the high speed homogenizer, again oil-phase solution (1) is slowly joined the aqueous phase that is stirring, keeping the dispersion liquid temperature is 55 ℃, disperseed 3 minutes, add water for injection then to total preparation amount, regulate pH value to 5.6, continue to disperse 5 minutes with the 0.1M sodium hydroxide solution, get dispersion liquid (3), be thick emulsion.The preparation nano emulsion injection: thick emulsion (3) is joined in the high pressure homogenizer, and regulating secondary valve pressure is 40bar, and re-adjustment one step valve pressure is 700bar, with thick emulsion homogenize under pressure, circulate continuously 5 times, keeping circulating temperature is 60 ℃, get stable dispersions (4), i.e. nano-emulsion.Under the condition of nitrogen protection, solution (5) is filled in the ampoule bottle, seal.With the ampoule bottle radiosiotope after the fill
60The γShe Xianmiejun of Co radiation promptly gets nano emulsion injection of alprostadil of the present invention.
The stability test of present embodiment nano emulsion injection of alprostadil is referring to embodiment 7.
Embodiment 6
Press group component and prepare raw material, adjuvant and other components:
Alprostadil 0.5mg
Injection vitamin E 10.0g
TPGS 4.0g
Injection lecithin 2.0g
Glycerol for injection 2.25g
Oleic acid 1.0g
Water for injection adds to 100g
Following step is all carried out under the condition of nitrogen protection.0.5mg PGE1 is joined in the 5.0g injection vitamin E, stir,, get solution (1), be oil phase to the PGE1 dissolving.2.0gTPGS added in the injection water dissolve, under at a high speed even matter effect, add the 2.25g glycerol for injection, add 1.0g oleic acid, add 1.0g injection lecithin, disperseed 5 minutes, solution temperature is heated to 65 ℃, be incubated standbyly, get solution (2), be water.Aqueous phase solution (2) is joined in the high speed homogenizer, again oil-phase solution (1) is slowly joined the aqueous phase that is stirring, keeping the dispersion liquid temperature is 55 ℃, disperseed 3 minutes, add water for injection then to total preparation amount, regulate pH value to 5.7, continue to disperse 5 minutes with the 0.1M sodium hydroxide solution, get dispersion liquid (3), be thick emulsion.The preparation nano emulsion injection: thick emulsion (3) is joined in the high pressure homogenizer, and regulating secondary valve pressure is 40bar, and re-adjustment one step valve pressure is 700bar, with thick emulsion homogenize under pressure, circulate continuously 5 times, keeping circulating temperature is 60 ℃, get stable dispersions (4), i.e. nano-emulsion.Under the condition of nitrogen protection, solution (5) is filled in the ampoule bottle, seal.Ampoule bottle after the fill 110 ℃ of flowing steam sterilizations 30 minutes, is promptly got nano emulsion injection of alprostadil of the present invention.
Embodiment 7
1-6 prescription (seeing Table 1) made 10 days, 40 ℃ Experimental Investigation on Factors of Affecting respectively, and the study on the stability index comprises: medicament contg, related substance PGA1, particle diameter, surface potential, pH value and centrifugal layering situation the results are shown in Table 2.Below, table 1 has provided the composition proportion of each prescription, and table 2 has provided some stability test data of nano emulsion injection of the present invention.
Table 1
| | 1 | 2 | 3 | 4 | 5 | 6 |
| The soybean oil vitamin E | 3％ 0 | 5％ 0 | 10％ 0 | 5％ 0 | 5％ 0 | 10％ 10％ |
| Lecithin TPGS poloxamer 188 | 1％ 0 1％ 0 0 | 1％ 0 3％ 2.25％ 0.5％ | 2％ 0 2.5％ 2.5％ 1％ | 0.5％ 1％ 0 0 0 | 1％ 2％ 0 2.25％ 1.0％ | 2％ 4％ 0 2.25％ 1％ |
Table 2
| Nano- | 0 (my god) | 5 (my god) | 10 (my god) |
| Content (μ g/ml) PGA1 (%) pH value average grain diameter (nm) Zeta potential (mV) centrifugal (4000prm, 15min) nano-emulsion 2 | 4.99 0 5.7 268-32.3 no layerings 0 (my god) | 4.97 0.01 5.7 260-30.9 no layering 5 (my god) | 4.96 0.01 5.7 271-34.2 no layering 10 (my god) |
| Content (μ g/ml) PGA1 (%) pH value average grain diameter (nm) Zeta potential (mV) centrifugal (4000prm, 15min) nano-emulsion 3 | 4.98 0 5.6 171-48.5 no layerings 0 (my god) | 4.98 0 5.7 174-49.3 no layerings 5 (my god) | 4.97 0.01 5.6 170-45.9 no layering 10 (my god) |
| Content (μ g/ml) PGA1 (%) pH value mean diameter (nm) Zeta potential (mV) is centrifugal | 5.03 0 5.7 176-62.1 no layerings | 5.00 0.01 5.7 182-59.7 no layering | 4.98 0.02 5.4 187-55.3 no layering |
| (4000prm, 15min) nano-emulsion 4 | 0 (my god) | 5 (my god) | 10 (my god) |
| Content (μ g/ml) PGA1 (%) pH value average grain diameter (nm) Zeta potential (mV) centrifugal (4000prm, 15min) nano-emulsion 5 | 5.08 0 5.7 178-30.9 no layerings 0 (my god) | 5.04 0.01 5.6 175-26.7 no layering 5 (my god) | 4.96 0.03 5.6 182-28.2 no layering 10 (my god) |
| Content (μ g/ml) PGA1 (%) pH value average grain diameter (nm) Zeta potential (mV) centrifugal (4000prm, 15min) nano-emulsion 6 | 4.96 0 5.5 164-65.7 no layerings 0 (my god) | 4.97 0 5.5 167-64.3 no layerings 5 (my god) | 4.93 0.01 5.5 166-63.8 no layering 10 (my god) |
| Content (μ g/ml) PGA1 (%) pH value mean diameter (nm) Zeta potential (mV) centrifugal (4000prm, 15min) | 5.07 0 5.7 173-60.7 no layerings | 5.07 0 5.7 178-57.3 no layerings | 5.04 0.01 5.7 179-35.6 no layering |
2,5 prescriptions are done 25 ℃ of accelerated test researchs respectively, study in the time of 0,1,2,3,6 month and do quantitative check, the results are shown in Table 3.
Claims (10)
1, a kind of nano emulsion injection of alprostadil is characterized in that, this injection contains Alprostadil nano breast granule, and the particulate mean diameter of described Alprostadil nano breast is between 100-300nm; And except that Alprostadil, described injection also comprises:
(1) one or more oil for injection;
(2) one or more lipophilic emulsifying agent;
(3) one or more injection isotonic agent;
(4) one or more stabilizing agent.
2, injection as claimed in claim 1 is characterized in that, described injection also comprises one or more hydrophilic emulsifying agent.
3, injection as claimed in claim 2 is characterized in that, except that water for injection, in weight percentage, described injection also comprises the component of following content:
Alprostadil 0.5-500 μ g/ml
Oil for injection 1-30%
Hydrophilic emulsifying agent 1-10%
Lipophilic emulsifying agent 0.1-5%
Isotonic agent glycerol for injection 2-3%
Stabilizing agent 0.1-5%.
4, injection as claimed in claim 3 is characterized in that, described injection comprises each component of following content:
Alprostadil 0.5-50 μ g/ml
Oil for injection 3-10%
Hydrophilic emulsifying agent 2-5%
Lipophilic emulsifying agent 0.5-3%
Isotonic agent glycerol for injection 2.2-2.5%
Stabilizing agent 0.1-1%.
5, injection as claimed in claim 2 is characterized in that,
Described oil for injection is selected from one or more in medium chain triglyceride, vitamin E, soybean oil, Oleum Cocois, Oleum Ricini, Semen Lini oil, Semen Maydis oil, Radix Oenotherae erythrosepalae oil, Oleum Gossypii semen, olive oil, safflower oil and the perilla oil, is preferably soybean oil and/or vitamin E;
Described hydrophilic emulsifying agent is selected from one or more in Tweens, poloxamer 188, arabic gum and the Polyethylene Glycol-vitamin e succinate (TPGS), is preferably poloxamer 188 and/or Polyethylene Glycol-vitamin e succinate;
Described lipophilic emulsifying agent is selected from one or more in spans, lecithin, soybean phospholipid and the agar, is preferably lecithin and/or fabaceous lecithin;
Described isotonic agent is a glycerol;
Described stabilizing agent is selected from one or more in cholesterol, oleic acid and the enuatrol, is preferably oleic acid.
6, a kind of method for preparing nano emulsion injection of alprostadil, this method comprises the steps:
(1) utilizes the method for ultra-sonic dispersion or high speed dispersion, make the thick newborn dispersion liquid of Alprostadil;
(2) the thick newborn dispersion liquid to step (1) gained carries out high pressure homogenize emulsifying, forms stable Alprostadil nano breast dispersion liquid;
(3) the Alprostadil nano breast dispersion liquid with step (2) gained carries out the fill sterilization, makes nano emulsion injection of alprostadil.
7, method as claimed in claim 6 is characterized in that, in the process of the thick newborn dispersion liquid of step (1) preparation Alprostadil, also comprises process for preparing oil phase and the process for preparing water, wherein,
Described oil phase forms by Alprostadil is dissolved in the oil for injection;
Described water is by adding hydrophilic emulsifying agent and lipophilic emulsifying agent dissolving in the injection water, disperse to form.
8, method as claimed in claim 6, it is characterized in that described high pressure homogenize emulsifying is by the realization of two-stage high pressure homogenize process, wherein, first order high pressure homogenize is to carry out under the pressure of 400-1000bar, and second level high pressure homogenize is to carry out under the pressure of 10-100bar.
9, method as claimed in claim 6 is characterized in that, described method comprises that also the pH value with described thick newborn dispersion liquid is adjusted to the process of 4.5-6.
As the described method of one of claim 6-9, it is characterized in that 10, described method also comprises following method of quality control:
On general HPLC instrument, connect peristaltic pump and past column reaction pipe, directly carry out the detection of Alprostadil, PGA1 and 15-ketone group-PGE1 isomers.
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