CN102225052A - pH-sensitive doxorubicin nano-liposome and preparation method thereof - Google Patents
pH-sensitive doxorubicin nano-liposome and preparation method thereof Download PDFInfo
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- CN102225052A CN102225052A CN201110154329XA CN201110154329A CN102225052A CN 102225052 A CN102225052 A CN 102225052A CN 201110154329X A CN201110154329X A CN 201110154329XA CN 201110154329 A CN201110154329 A CN 201110154329A CN 102225052 A CN102225052 A CN 102225052A
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Abstract
The invention relates to a method for increasing the content of doxorubicin hydrochlorate coated by liposomes. The liposomes according to the invention comprise doxorubicin hydrochlorate, phospholipids, cholesterol, vitamin E, freeze-dried excipients, carboxymethyl chitosan, and so on. The prepared liposomes have high content of coated doxorubicin hydrochlorate, and have pH sensitivity and a long-circulation active targeting drug delivery function.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to responsive doxorubicin nanometer liposome of a kind of pH and preparation method thereof.
Technical background
Doxorubicin (Doxorubicin), be commonly called as amycin again, doxorubicin, be antibiotics antineoplastic agent commonly used clinically, anticancer spectrum is wide, and curative effect is wide, can treat kinds of tumors, but this medicine has serious toxic and side effects to heart, especially serious heart damage, and side reactions such as bone marrow depression have limited its application clinically.For many years, the various countries scientist is seeking the effective ways that reduce its toxicity always, as adjusting dosage regimen, develops the low amycin analog of cardiac toxicity, and the mode of drug combination and change pharmaceutical dosage form alleviates its serious cardiac toxicity.The toxicity of liposome amycin specific ionization medicine reduces 50-70% (Budai M, et al.Liposomes as drug carrier systems:preparation, classification and therapeutic advantages of liposomes.Acta Pharm Hung., 2001,71 (1): 114-8.), but liposome is because it is easily by macrophage phagocytic, content in normal structure is still very high, in order further to reduce the drug toxicity of Evacet, utilize targeting substance or particle that surface of liposome or inside are modified, make liposome overcome the various physiologic barriers that medicine is run in the course of conveying in vivo, medicine is delivered to specific target position, improve the targeting of medicine.PH sensitivity liposome is exactly wherein a kind of, utilize tumor tissues when ischemia, unusual acidify phenomenon can appear in mesenchyma stroma of tumors liquid, pH value is lower than normal structure, utilize this characteristic scientist to adopt distinct methods to carry out finishing, the phospholipid material that has pH sensitivity as the bioabsorbable polymer material that has the pH sensitivity in the surface of liposome grafting or use prepares liposome.
Carboxymethyl chitosan (CMCT) is a kind of soluble derivative that chitosan generates behind carboxymethylation reaction, its stable in properties, and biocompatibility and degradability are good, and toxicity is less.It had both contained weak base cation (NH
3 +) group, contain weak acid anion (COO again
-) group, be a kind of amphipathic electrolyte.Because it has the pH sensitivity, under different pH value conditions, its segmental conformation difference, utilize this characteristic, carboxymethyl chitosan is sugar-modified to surface of liposome, make under different pH value because the drug release that different its active forces of conformation wrap up in liposome reaches the pH sensitivity.In addition, carboxymethyl chitosan has good hydrophilicity, with its as the stereoscopic stable agent to liposome modify (Tong Xinyong etc. not commensurability carboxymethyl chitosan is modified the influence of Paclitaxel liposome to pharmacokinetics in the rat body. Chinese clinical pharmacology and therapeutics, 2006,11 (3): 328-331.), can effectively improve the hydrophilic on liposome particles surface, the hydrophilic chain of CMCT is wrapped in around the liposome and to the albumen in the blood repulsive interaction, can delay opsonic action, reach the cryptomorphic purpose of long circulation in the body.
Summary of the invention
The objective of the invention is pH sensitivity characteristic at deficiency in the application of Doxil and carboxymethyl chitosan uniqueness, the responsive nanometer Mycocet of a kind of pH medicament is provided, is prepared from by doxorubicin hydrochloride, lecithin, cholesterol, vitamin E, carboxymethyl chitosan etc.
The responsive nano-paclitaxel liposome of pH of the present invention, form by the component of following mass fraction ratio:
Wherein, preferably be grouped into by the one-tenth of following ratio of quality and the number of copies:
Described freeze-dried excipient is lactose, sucrose, glycine, sorbose, glucose, mannitol or their mixture.
The preparation of the responsive nanometer Mycocet of pH of the present invention may further comprise the steps:
(1) doxorubicin hydrochloride is dissolved in 0.9% the sodium chloride solution, obtains and the isoosmotic doxorubicin hydrochloride solution of blood plasma;
(2) take by weighing corresponding phospholipids, cholesterol and vitamin E by prescription and put into appropriate containers, add the ultrasonic concussion of dehydrated alcohol then and be dissolved into solution, this solution is changed in the rotary evaporator; Remove organic solvent, film forming at 40 ℃ of water-bath rotary evaporations; Add the buffer solution (pH=4.0) that is dissolved with freeze-dried excipient and wash film, aquation, 0.5h is once ultrasonic at interval, and eluting 2h makes blank liposome;
(3) behind blank liposome multigelation 3-4 time with preparation, ultrasonic or high pressure homogenize makes nano level blank liposome with ultrasonic cell pulverization machine gap, and mistake 0.22 μ m filter membrane obtains the blank nanometer liposome of uniform particle diameter;
(4) regulate the outer aqueous pH values of blank nanometer liposome to 6.8-7.4 with buffer solution (pH=8.0), add the isotonic sodium chlorrde solution that is dissolved with doxorubicin hydrochloride again, by the pH gradient method doxorubicin hydrochloride is written in the blank nanometer liposome, hydration 1h under 37 ℃ of water-baths makes Doxil;
(5) the carboxymethyl chitosan sugar juice is joined in the Doxil hydration 2h under 37 ℃ of water-baths, the responsive nanometer Mycocet of the pH of system.
Described lecithin is selected from Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline or hydrogenated yolk lecithin.
The degree of substitution by carboxymethyl of described carboxymethyl chitosan is 0.6-1.2, and molecular weight is 3000-100000.
Described buffer is selected from the normal saline of phosphate buffered solution or 0.9% sodium chloride.
The described cell pulverization machine intermittently optimization power of ultrasonic blank liposome is 200-300w, off time 5s, ultrasonic time 3s, the working time is 30min; Or to adopt the optimization pressure parameter of high pressure homogenize be 40-90MPa, and cycle-index is 6-15 time.
Adopt method of the present invention, the responsive nanometer Mycocet of pH that can prepare small particle diameter, stable performance, method by multigelation can improve its medicine fat ratio, and the modification of carboxymethyl chitosan can make it possess the pH sensitive property and prolong its body-internal-circulation performance.The present invention adopts dehydrated alcohol as organic solvent, has got rid of the residual of bigger organic solvent chloroform of the toxicity used in the document or methanol, has reduced environmental pollution, has reduced production cost, is more suitable for suitability for industrialized production.
Description of drawings:
Fig. 1 is the liposome transmission electron microscope picture of carboxymethyl chitosan after sugar-modified.
Fig. 2 is the liposome particle size distribution figure of carboxymethyl chitosan after sugar-modified.
The specific embodiment
Below by EXPERIMENTAL EXAMPLE the present invention is specifically described; it is important to point out that present embodiment only is used for that the present invention will be further described; can not be interpreted as limiting the scope of the invention, the person skilled in the art in this field can make some nonessential improvement and adjustment according to the content of the invention described above.
Embodiment 1
Under aseptic condition, take by weighing lecithin 2g, cholesterol 0.5g, vitamin E 0.025g.Above-mentioned material is placed appropriate containers, add the ultrasonic concussion of dehydrated alcohol 100ml to being dissolved into solution fully, above-mentioned solution is transferred in the pyriform bottle, the decompression rotary evaporation is to forming transparent faint yellow thin film in water bath with thermostatic control.In the pyriform bottle, inject PBS (pH=4.0) the buffer solution 100ml eluting that is dissolved with freeze-dried excipient 2g, slowly wash film.Wash film after multigelation is 200-300w with ultrasonic cell pulverization machine at power 3-4 time, off time 5s, ultrasonic time 3s, working time is the 30min Ultrasonic Pulverization, with 0.22 micron membrane filtration degerming, regulate its outer water to pH=6.8 with PBS (pH=8.0) buffer solution, add with the dissolved doxorubicin hydrochloride 0.2g hydration of 0.9% sodium chloride solution 2h, add the aqueous solution that contains the 0.13g carboxymethyl chitosan, obtain the responsive doxorubicin nano-lipid of pH liquid solution behind the hydration 1h.
Embodiment 2
Under aseptic condition, take by weighing lecithin 1.6g, cholesterol 0.4g, vitamin E 0.020g.Above-mentioned material is placed appropriate containers, add the ultrasonic concussion of dehydrated alcohol 100ml to being dissolved into solution fully, above-mentioned solution is transferred in the pyriform bottle, the decompression rotary evaporation is to forming transparent faint yellow thin film in water bath with thermostatic control.Get PBS (pH=4.0) the buffer solution 100ml eluting that adds freeze-dried excipient 1.6g, slowly wash film.Wash film after multigelation 3-4 time, adopt high pressure homogenize, homogenizing is 10 times under the 80MPa, with 0.22 micron membrane filtration degerming, regulate its outer water to pH=7.2 with PBS (pH=8.0) buffer solution, add with the dissolved doxorubicin hydrochloride 0.2g hydration of 0.9% sodium chloride solution 2h, add the aqueous solution that contains the 0.16g carboxymethyl chitosan, hydration 1h obtains the responsive doxorubicin nano-lipid of pH liquid solution.
Claims (7)
1. the responsive doxorubicin nanometer liposome of a pH, it is characterized in that, form by following components in weight percentage: doxorubicin hydrochloride 3.2-16 part, lecithin 16-80 part, cholesterol 4-20 part, vitamin E 0.16-0.8 part, carboxymethyl chitosan 1-5 part, freeze-dried excipient 16-100 part, buffer 800-1000 part; With lecithin, cholesterol and vitamin E, take by weighing corresponding weight respectively in proportion and put into appropriate containers, add the ultrasonic concussion of dehydrated alcohol then and be dissolved into solution, this solution is changed in the rotary evaporator, film forming after dehydrated alcohol is removed in 40 ℃ of water-bath rotary evaporation decompressions, the buffer solution that is dissolved with freeze-dried excipient (pH=4.0) of additional proportion amount is washed film, aquation, 0.5h is once ultrasonic at interval, aquation 2h, make blank liposome, behind blank liposome multigelation 3-4 time, ultrasonic or high pressure homogenize makes nanometer liposome with ultrasonic cell pulverization machine gap, after crossing 0.22 μ m filter membrane, regulating the isotonic sodium chlorrde solution that the adding to the 6.8-7.4 of outer aqueous pH values is dissolved with doxorubicin hydrochloride with buffer solution (pH=8.0) is written into doxorubicin hydrochloride in the blank nanometer liposome by the pH gradient method, hydration 1h under 37 ℃ of water-baths, the carboxymethyl chitosan sugar juice is joined in the doxorubicin hydrochloride nanometer liposome, hydration 2h under 37 ℃ of water-baths, the responsive doxorubicin nanometer liposome of the pH of system.
2. the responsive doxorubicin nanometer liposome of a kind of pH according to claim 1, it is characterized in that, form by following components in weight percentage: doxorubicin hydrochloride 4-12 part, lecithin 20-60 part, cholesterol 4-15 part, vitamin E 0.2-0.6 part, carboxymethyl chitosan 1.25-3.75 part, freeze-dried excipient 20-80 part, buffer 800-1000 part.
3. the responsive nanometer Mycocet of pH according to claim 1 and 2, it is characterized in that: described freeze-dried excipient is lactose, sucrose, glycine, sorbose, glucose, trehalose or their mixture.
4. according to the responsive doxorubicin nanometer liposome of the described a kind of pH of claim 1-2, it is characterized in that described lecithin is selected from Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated soy phosphatidyl choline or hydrogenated yolk lecithin.
5. according to the responsive doxorubicin nanometer liposome of the described pH of claim 1-2, the degree of substitution by carboxymethyl that it is characterized in that described carboxymethyl chitosan is 0.6-1.2, and molecular weight is 3000-100000.
6. according to the method for preparing the responsive nanometer Mycocet of pH described in the claim 1, it is characterized in that described buffer is selected from the sodium chloride normal saline of phosphate buffered solution or 0.9%.
7. according to the method for preparing the responsive nanometer Mycocet of pH described in the claim 1, when it is characterized in that using the cell pulverization machine to pulverize the gained blank liposome, its power is 200-300w, off time 5s, ultrasonic time 3s, the working time is 30min; Or the gained blank liposome carried out high pressure homogenize, and pressure is 40-90MPa, cycle-index is 6-15 time.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130871A (en) * | 2013-02-06 | 2013-06-05 | 广东药学院 | Preparation method and application of prodrug of endopeptidase activated doxorubicin |
| CN108542884A (en) * | 2018-05-04 | 2018-09-18 | 重庆市人民医院 | A kind of sensitive medicament-carried liposomes of pH of SPIO tracers and preparation method thereof |
-
2011
- 2011-06-09 CN CN201110154329XA patent/CN102225052A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130871A (en) * | 2013-02-06 | 2013-06-05 | 广东药学院 | Preparation method and application of prodrug of endopeptidase activated doxorubicin |
| CN103130871B (en) * | 2013-02-06 | 2014-11-12 | 广东药学院 | Preparation method and application of prodrug of endopeptidase activated doxorubicin |
| CN108542884A (en) * | 2018-05-04 | 2018-09-18 | 重庆市人民医院 | A kind of sensitive medicament-carried liposomes of pH of SPIO tracers and preparation method thereof |
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