CN103432072A - In-dissolvable drug food protein stabilizing suspension for injection and preparation method thereof - Google Patents
In-dissolvable drug food protein stabilizing suspension for injection and preparation method thereof Download PDFInfo
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- CN103432072A CN103432072A CN201310418111XA CN201310418111A CN103432072A CN 103432072 A CN103432072 A CN 103432072A CN 201310418111X A CN201310418111X A CN 201310418111XA CN 201310418111 A CN201310418111 A CN 201310418111A CN 103432072 A CN103432072 A CN 103432072A
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Abstract
The invention belongs to the field of drug preparations, and particularly relates to a slightly-soluble drug food protein stabilizing suspension for injection and a preparation method thereof. Compared with some commercially-available slightly-soluble injections, the slightly-soluble drug food protein stabilizing suspension for injection does not contain a conventional surfactant which is toxic to the human body and an organic solvent which easily causes anaphylactic reaction, and therefore, allergy and toxic reaction caused by the surfactant and the solvent are avoided, and the clinical use is convenient. In mouse pharmacodynamic experiment, the slightly-soluble drug food protein stabilizing suspension for injection shows a good curative effect. The slightly-soluble drug food protein stabilizing suspension for injection has the advantages of simple preparation process, good curative effect and the like, and is capable of being stored for a long time.
Description
Technical field: the invention belongs to field of pharmaceutical preparations, particularly a kind of injection insoluble drug food proteins stabilisation nanosuspension and preparation method thereof.
Background technology: the medicament nano technology be improve so far two class drug-elutings and improve its bioavailability the most effectively, drug loading is the highest and be easy to one of nanotechnology of industrialization most.But still there is defect in this technology, as be difficult to maybe can't to realize target administration; After drug administration by injection, drug crystallization falls body cyclic process meeting is dissolved; Optional stabilizing agent is except PVP, HPMC, and EPC, tween, Poloxamer, beyond TPS etc., other selection is very limited.In view of the problem of current existence, the present invention utilizes food proteins (soybean protein, lactalbumin and beta lactoglobulin etc.) to substitute traditional stabilizing agent, prepares the insoluble drug nanocrystal of food proteins stabilisation.
Take paclitaxel as example, and paclitaxel is one of chemotherapeutics commonly used.Paclitaxel (Paclitaxel, trade name Taxol) is a kind of diterpene-kind compound, is separated from the bark of yewtree (Taxus brevifolia) by Wani etc. the earliest and obtains and determine its chemical constitution.Paclitaxel is mainly to make the mitosis of tumor cell stop and make apoptosis of tumor cells by suppressing microtubule depolymerization, finally causes death of neoplastic cells.The tradition paclitaxel, because be insoluble in water, needs the organic solvent polyoxyethylene castor oil as adjuvant, and these adjuvant have obviously increased the relevant toxicity of Drug therapy, have seriously limited curative effect and the safety applications of this medicine.Because paclitaxel content in bark of Ramulus et folium taxi cuspidatae is only 2/10000ths to five, in leaf, stem, containing is only 5/100000ths left and right, the extraction process complexity, not only caused the expensive of paclitaxel, and by the existing few plant resourceses such as Ramulus et folium taxi cuspidatae of considerable damage.Therefore develop good effect, the formulation for paclitaxel that toxic and side effects is low, not only have great economic worth and social value, to preserving the ecological environment, major contribution also arranged.
Summary of the invention: the objective of the invention is the limitation for prior art, provide a kind of using there is fine biocompatibility and the food proteins very strong with the insoluble drug binding ability (as beta lactoglobulin, soybean protein, lactalbumin and monomer separately etc.) the injection insoluble drug food proteins stabilisation nanosuspension as carrier, another object of the present invention is to provide the preparation method of this kind of nanosuspension, the nanoparticle steady quality that just method technique is simple, preparation process is easily controlled, prepare.
The concrete technical scheme of the present invention is: a kind of injection insoluble drug food proteins stabilisation nanosuspension is characterized in that the weight percentage of its component and each component is respectively:
Insoluble drug: 5-90%,
Food proteins: 10-80%, and
Freeze drying protectant: 5-60%, the insoluble drug that wherein best proportion is 40-50%, the food proteins of 40-50% and the freeze drying protectant of 5-10%.
In the present invention, dietary protein origin is in food, and the beta lactoglobulin described in example and lactalbumin derive from milk, soybean protein source bean.
In the present invention, described freeze drying protectant is the protective agent used in the freeze-drying process of this area routine.Freeze drying protectant shields in freeze-drying process, after drying, plays a supportive role, and therefore is called freeze drying protectant, claims again caffolding agent.
In injection insoluble drug food proteins stabilisation nanosuspension of the present invention, also can contain appropriate pH adjusting agent if necessary, to meet the version " requirement of Chinese pharmacopoeia to injection in 2010, this is accomplished than being easier to for a person skilled in the art, mainly comprises a kind of in hydrochloric acid, sodium hydroxide, citrate, phosphate, acetate buffer etc. or its mixture mixed with any ratio.
The present invention also provides the preparation method of above-mentioned insoluble drug food proteins stabilisation nano suspension, and its concrete steps are as follows:
1) crude drug of insoluble drug is added in acetone, after ultrasonic dissolution as organic facies;
2) the food proteins powder is added to the water or buffer solution in, stirring and dissolving is placed on heat denatured 0.5-1h in boiling water;
3) freeze drying protectant is joined in the food proteins solution after the thermal denaturation after dilution, regulate pH to 7-10 after stirring and dissolving as water;
4) under the condition stirred, organic facies being joined to water, Probe Ultrasonic Searching 5-10min after 30s, by the filtering with microporous membrane degerming, be placed in clean container by the solution of gained;
5) solution after filtration sterilization is freezing under-30 ℃～-50 ℃ conditions, through the lyophilization lyophilizing, obtain.
In the present invention, step 1) the slightly solubility solution concentration in described organic facies is every 1 milliliter of acetone containing the insoluble drug of 1～50 milligram, and 10mg is especially good;
Step 3) in the water described in, food proteins and frozen-dried protective agent concentration are respectively to contain the food proteins of 0.1-1 milligram in every 1 ml soln; freeze drying protectant containing the 1-20 milligram; wherein the albumen preferred concentration is 1mg/ml, and the freeze drying protectant preferred concentration is 0.1mg/ml.
Step 2) buffer described in preferably is selected from one or more in citrate, phosphate and acetate buffer.
Step 3) stirring condition and 4) is alr mode commonly used on laboratory or production line, can reach the purpose mixed and get final product, and can adopt manual stirring, magnetic agitation, motor stirrer, high-speed shearing machine to be stirred.In order to make organic facies and water rapid mixing even, preferably rotating speed is not less than the mode of 1200 rev/mins and is stirred.
Step 4) described micro-porous filter is preferably by the filtering with microporous membrane degerming of 0.22 μ m, the preferred cillin bottle of described container.
Step 4) can remove acetone and the water in sample during described freezer dryer lyophilizing, obtain the lyophilized powder that profile is good, profile is loose, preferably can further fill nitrogen, jump a queue, roll lid, then preserve.
Injection insoluble drug food proteins stabilisation nanosuspension of the present invention, add before use the solvents such as water for injection, normal saline, the aqueous solution that contains buffer salt or glucose injection, form the suspension of 100-300nm after redissolution, the suspension of every 1ml can be 1～5mg containing insoluble drug, is preferably 2mg.
The present invention is except specified otherwise, and percentage ratio used is all percentage by weight.
The raw material that the present invention is used or reagent, all commercially available obtaining.
At present, the clinical research of the insoluble drug that we choose is very ripe, so we no longer do concrete experiment, and we will be only do a little research to the particle diameter of the nanosuspension made, release etc.
Adopt Zetasizer particle size distribution instrument, transmission electron microscope etc. to be characterized nanosuspension.
But injection slightly solubility food proteins stabilisation nanosuspension of the present invention has the advantages such as the simple long-term storage of preparation technology.
The accompanying drawing explanation:
The TEM figure that Fig. 1 is the prepared paclitaxel beta lactoglobulin of example 1 nanosuspension.As seen from the figure, beta lactoglobulin coats the paclitaxel nano crystal, and this nanocrystal is bar-shaped, and particle diameter is between 100-300nm.
Fig. 2 is the prepared paclitaxel beta lactoglobulin of example 2 nanosuspension particle size distribution figure, and vertical coordinate is the percentage ratio that accounts for the granule cumulative volume, and abscissa is grain diameter.
Fig. 3 is the stripping curve of prepared paclitaxel beta lactoglobulin nanosuspension in the pH7.4 phosphate buffer in example 3
The stability contrast and experiment that Fig. 4 is experimental example 1 and bovine serum albumin (BSA)
The survival rate figure that Fig. 5 is experimental example 2 pharmacodynamic experiment small mouses
The relative tumor growth rate figure that Fig. 6 is experimental example 2 pharmacodynamic experiment small mouses
The specific embodiment:
Below with example, further illustrate the present invention, but the present invention is not limited.Unreceipted concrete experimental technique in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Example 1
Preparation technology:
Take paclitaxel 10mg, be dissolved in 0.5ml acetone as organic facies; Take the 200mg beta lactoglobulin, be dissolved in 20ml water for injection and be placed in boiling water heating 30min.Measure the 1ml protein solution and be diluted to 10ml with water for injection, add the sodium alginate of 1mg and regulate pH to 7.0-10 as water.Organic facies and water are mixed to 30s under (1200 rev/mins) condition of stirring, be transferred to the ultrasonic 10min of Probe Ultrasonic Searching 400w.Solution, after 0.22 μ m filtering with microporous membrane sterilizing, is sub-packed in clean cillin bottle.Freeze at temperature by cillin bottle under-30 ℃～-50 ℃ conditions, after acetone and moisture are gone out in the freezer dryer lyophilizing, fill nitrogen, jump a queue, roll lid, obtain.
Example 2
Preparation technology 2
Take paclitaxel 10mg, be dissolved in 0.5ml acetone as organic facies; Take the 200mg soybean protein, be dissolved in 20ml water for injection and be placed in boiling water heating 30min.Measure the 1ml protein solution and be diluted to 10ml with water for injection, add the sodium alginate of 1mg and regulate pH to 7.0-10.0 as water.Organic facies and water are mixed to 30s under (1200 rev/mins) condition of stirring, be transferred to the ultrasonic 10min of Probe Ultrasonic Searching 400w.Solution, after 0.22 μ m filtering with microporous membrane sterilizing, is sub-packed in clean cillin bottle.Freeze at temperature by cillin bottle under-30 ℃～-50 ℃ conditions, after acetone and moisture are gone out in the freezer dryer lyophilizing, fill nitrogen, jump a queue, roll lid, obtain.
Example 3
Preparation technology:
Take paclitaxel 10mg, be dissolved in 0.5ml acetone as organic facies; Take the 200mg lactalbumin, be dissolved in 20ml water for injection and be placed in boiling water heating 30min.Measuring the 1ml protein solution is diluted to 10ml with water for injection and adds the sodium alginate of 1mg and regulate pH to 9.0 as water.Organic facies and water are mixed to 30s under (1200 rev/mins) condition of stirring, be transferred to the ultrasonic 10min of Probe Ultrasonic Searching 400w.Solution, after 0.22 μ m filtering with microporous membrane sterilizing, is sub-packed in clean cillin bottle.Freeze at temperature by cillin bottle under-30 ℃～-50 ℃ conditions, after acetone and moisture are gone out in the freezer dryer lyophilizing, fill nitrogen, jump a queue, roll lid, obtain.
Further illustrate beneficial effect of the present invention below by experimental example
The stability contrast experiment of experimental example 1 and bovine serum albumin (BSA)
The preparation of paclitaxel albumin nanometer suspension: take paclitaxel 10mg, be dissolved in 0.5ml acetone as organic facies; Take the 200mg bovine serum albumin, be dissolved in 20ml water for injection.Measuring the 1ml protein solution is diluted to 10ml and regulates pH to 9.0 as water with water for injection.Organic facies and water are mixed to 30s under (1200 rev/mins) condition of stirring, be transferred to the ultrasonic 10min of Probe Ultrasonic Searching 400w.Solution, after 0.22 μ m filtering with microporous membrane sterilizing, is sub-packed in clean cillin bottle.
The preparation of paclitaxel degeneration postalbumin nanosuspension: take paclitaxel 10mg, be dissolved in 0.5ml acetone as organic facies; Take the 200mg lactalbumin, be dissolved in 20ml water for injection and be placed in boiling water heating 30min.Measuring the 1ml protein solution is diluted to 10ml and regulates pH to 9.0 as water with water for injection.Organic facies and water are mixed to 30s under (1200 rev/mins) condition of stirring, be transferred to the ultrasonic 10min of Probe Ultrasonic Searching 400w.Solution, after 0.22 μ m filtering with microporous membrane sterilizing, is sub-packed in clean cillin bottle.
The preparation of paclitaxel beta lactoglobulin nanosuspension: take paclitaxel 10mg, be dissolved in 0.5ml acetone as organic facies; Take the 200mg beta lactoglobulin, be dissolved in 20ml water for injection.Measuring the 1ml protein solution is diluted to 10ml and regulates pH to 9.0 as water with water for injection.Organic facies and water are mixed to 30s under (1200 rev/mins) condition of stirring, be transferred to the ultrasonic 10min of Probe Ultrasonic Searching 400w.Solution, after 0.22 μ m filtering with microporous membrane sterilizing, is sub-packed in clean cillin bottle.
The preparation of paclitaxel beta lactoglobulin nanosuspension: take paclitaxel 10mg, be dissolved in 0.5ml acetone as organic facies; Take the 200mg beta lactoglobulin, be dissolved in 20ml water for injection and be placed in boiling water heating 30min.Measuring the 1ml protein solution is diluted to 10ml and regulates pH to 9.0 as water with water for injection.Organic facies and water are mixed to 30s under (1200 rev/mins) condition of stirring, be transferred to the ultrasonic 10min of Probe Ultrasonic Searching 400w.Solution, after 0.22 μ m filtering with microporous membrane sterilizing, is sub-packed in clean cillin bottle.
Stability contrast experiment: the particle diameter and the PI value that record four kinds of above-mentioned nanosuspensions at the preparation initial stage.Place after 5 days under 4 ℃ and 20 ℃ respectively, again measure particle diameter and the PI value of two kinds of nanosuspensions.Experimental result is shown in Fig. 4.By Fig. 4, we can find out, beta lactoglobulin paclitaxel nano suspension after degeneration be before setting-out or setting-out after its particle diameter and PI value all be better than other preparations, this shows that the stability of the beta lactoglobulin after degeneration obviously is better than other contrast albumen.
Experimental example 2 pharmacodynamic experiments
The preparation of paclitaxel injection: get paclitaxel injection (Haikou Qili Pharmaceutical Co., Ltd) 1ml, inject water 4ml, after jolting evenly, be configured to the paclitaxel of every 1ml suspension containing 1mg.
The preparation of paclitaxel food proteins suspension: get the paclitaxel beta lactoglobulin suspension powder by example 1 preparation, inject water appropriate, after jolting evenly, be configured to the paclitaxel of every 1ml suspension containing 1mg.
Pharmacodynamic experiment: the BALB/c mouse (18-20g) of take is animal model, and the anti-tumor in vivo effect of paclitaxel solution and paclitaxel food proteins nanosuspension is investigated.
1) exponential phase H22 cell is collected in the foundation of lotus H22 transplanted human hepatocellular carcinoma mouse model, and it is 5*10 that the RPMI1640 of take adjusts cell concentration
6individual/ml, in the BALB/c mouse left side, hypogastric region carries out aseptic subcutaneous vaccination, and inoculation quantity is 0.2ml cell suspension, and total cellular score is 1*10
6.
2) laboratory animal grouping and processing treats that gross tumor volume grows up to 100-200mm
3the time, mice is divided into to 3 groups at random, 10 every group, inject respectively paclitaxel injection and paclitaxel food proteins nanosuspension.Take injecting normal saline as matched group.Within every 3 days, be administered once, successive administration 7 times, dosage is 10mg/kg, meanwhile isopyknic normal saline is expelled in the body of mice as negative control.
3) the anti-tumor in vivo activity research is observed the growing state of tumor-bearing mice every day, and before each administration, the body weight of mice and the size of tumor is measured.Adopt slide gauge to determine maximum gauge and the minimum diameter of tumor, then use formula: the path 2 of the volume of tumor=0.5* maximum diameter * calculates gross tumor volumes.After treatment finishes, de-neck is put to death all mouse.
Experimental result is shown in Fig. 5 and Fig. 6.From Fig. 5 we can paclitaxel food proteins nanosuspension group mortality rate to be starkly lower than paclitaxel injection group and matched group; We draw Fig. 6, and after treatment finishes, the relative tumor growth rate of mice of paclitaxel food proteins nanosuspension treatment is minimum, and said preparation demonstrates best therapeutic effect.
Claims (7)
1. an insoluble drug food proteins stabilisation nanosuspension is characterized in that the percentage by weight that its component and each component account for the microsphere total amount is respectively:
Insoluble drug: 5-90%,
Food proteins: 10-80%, and
Freeze drying protectant: 5-60%, the insoluble drug that wherein best proportion is 40-50%, the food of 40-50%
The freeze drying protectant of albumen and 5-10%.
2. insoluble drug food proteins stabilisation nanosuspension as claimed in claim 1, its described food proteins can be beta lactoglobulin, soybean protein, lactalbumin and corresponding monomer thereof, wherein optimum albumen is beta lactoglobulin.
3. insoluble drug food proteins stabilisation nanosuspension as claimed in claim 1, it is characterized in that, described insoluble drug food proteins stabilisation nanosuspension also contains pH adjusting agent, is selected from a kind of in hydrochloric acid, sodium hydroxide, citrate, phosphate, acetate buffer etc. or its mixture mixed with any ratio.
4. the preparation method of an injection insoluble drug food proteins stabilisation nanosuspension as described as claim 1～3 any one, is characterized in that, comprises the following steps:
1) the insoluble drug crude drug is added in acetone, after ultrasonic dissolution as organic facies; In the present invention, active medicine can be selected from hydrophobic drug as paclitaxel, Docetaxel, irinotecan, 5-fluorouracil, carmustine, amycin, phenesterin, piposulfan, tamoxifen, lomustine, gamlogic acid, rubescensine A, podophyllotoxin or their combination, and wherein optimal drug is paclitaxel;
2) the food proteins powder is added to the water or buffer solution in, stirring and dissolving is placed on heat denatured 0.5-1h in boiling water;
3) freeze drying protectant is joined in the food proteins solution after the thermal denaturation after dilution, regulate pH to 7-9 after stirring and dissolving as water;
4) under the condition stirred, organic facies being joined to water, Probe Ultrasonic Searching 5-10min after 30s, by the filtering with microporous membrane degerming, be placed in clean container by the solution of gained;
6) solution after filtration sterilization is freezing under-30 ℃～-50 ℃ conditions, through the lyophilization lyophilizing, obtain.
5. preparation method as claimed in claim 4, is characterized in that step 1) slightly solubility solution concentration in described organic facies is every 1 milliliter of acetone containing the insoluble drug of 1～50 milligram, 10 milligrams are outstanding good; Step 3) in the water described in, food proteins and frozen-dried protective agent concentration are respectively to contain the food proteins of 0.1-1 milligram in every 1 ml soln; freeze drying protectant containing the 1-20 milligram; wherein the albumen preferred concentration is 1mg/ml, and the freeze drying protectant preferred concentration is 0.1mg/ml.
6. preparation method as claimed in claim 4, is characterized in that step 4) described in stirring condition be that rotating speed is not less than 1200 rev/mins.
7. comprise the described injection insoluble drug of claim 1～4 any one food proteins stabilisation nanosuspension.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108309963A (en) * | 2017-09-14 | 2018-07-24 | 中国药科大学 | A kind of stabilization hybridization nanometer suspending agent reversed for multidrug resistance |
| CN112220778A (en) * | 2020-10-16 | 2021-01-15 | 中国药科大学 | Combined delivery system for pulmonary hypertension treatment and preparation method thereof |
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| DE10158035A1 (en) * | 2001-11-27 | 2003-06-12 | Kosmas Kg | Pharmaceutical composition, useful for antineoplastic treatment, comprises a cytostatic agent e.g. trastuzumab, and lactalbumin hydrolyzate |
| CN103251573A (en) * | 2013-05-13 | 2013-08-21 | 李伟 | Protein micro/nano sphere carrying antitumor chemotherapeutic medicine and preparation method of protein micro/nano sphere |
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2013
- 2013-09-11 CN CN201310418111XA patent/CN103432072A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10158035A1 (en) * | 2001-11-27 | 2003-06-12 | Kosmas Kg | Pharmaceutical composition, useful for antineoplastic treatment, comprises a cytostatic agent e.g. trastuzumab, and lactalbumin hydrolyzate |
| CN103251573A (en) * | 2013-05-13 | 2013-08-21 | 李伟 | Protein micro/nano sphere carrying antitumor chemotherapeutic medicine and preparation method of protein micro/nano sphere |
Non-Patent Citations (3)
| Title |
|---|
| WEI HE ET AL: "Food proteins as novel nanosuspension stabilizers for poorly water-soluble drugs", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》, vol. 441, 27 November 2012 (2012-11-27) * |
| WEI HE ET AL: "Food protein-stabilized nanoemulsions as potential", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》, 10 March 2011 (2011-03-10), pages 521 - 533 * |
| WEI HE ET AL: "Formulating food protein-stabilized indomethacin", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》, 13 August 2013 (2013-08-13) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108309963A (en) * | 2017-09-14 | 2018-07-24 | 中国药科大学 | A kind of stabilization hybridization nanometer suspending agent reversed for multidrug resistance |
| CN112220778A (en) * | 2020-10-16 | 2021-01-15 | 中国药科大学 | Combined delivery system for pulmonary hypertension treatment and preparation method thereof |
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Application publication date: 20131211 |